WO2012006963A1 - Polymer reinforcing agent in controlled release preparation - Google Patents

Polymer reinforcing agent in controlled release preparation Download PDF

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Publication number
WO2012006963A1
WO2012006963A1 PCT/CN2011/077190 CN2011077190W WO2012006963A1 WO 2012006963 A1 WO2012006963 A1 WO 2012006963A1 CN 2011077190 W CN2011077190 W CN 2011077190W WO 2012006963 A1 WO2012006963 A1 WO 2012006963A1
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WO
WIPO (PCT)
Prior art keywords
polymer
controlled release
cellulose
ethylene
hydrochloride
Prior art date
Application number
PCT/CN2011/077190
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French (fr)
Chinese (zh)
Inventor
钟术光
Original Assignee
Zhong Shuguang
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from CN201010227702.5A external-priority patent/CN102018658B/en
Priority claimed from CN 201010227666 external-priority patent/CN102018962B/en
Priority claimed from CN 201010228319 external-priority patent/CN101987083B/en
Application filed by Zhong Shuguang filed Critical Zhong Shuguang
Publication of WO2012006963A1 publication Critical patent/WO2012006963A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes

Definitions

  • the present invention relates to the use of a polymeric enhancer in the manufacture or storage of a controlled release formulation, particularly a zero release sustained release formulation. It also relates to a controlled release formulation, in particular a zero release release controlled release formulation, and a process for its preparation.
  • a controlled release preparation having improved performance particularly a zero-order release controlled release preparation comprising a core material containing a biologically active substance and a plurality of air-filled materials overlying the core material a microporous drug release controlled release film comprising a polymer enhancer, wherein the contact angle of the polymer with the polymer enhancer is less than 90°, and the above-mentioned release micropores are sublimated and sublimable Obtained by substances and/or degradation of substances that can be degraded into harmless gases.
  • Some water insoluble polymers control drug release by coating in controlled release formulations, particularly zero release sustained release formulations. Due to the water insolubility of the polymer, micropores of the coating film are often required to improve the permeability of the controlled release coating to facilitate moisture penetration and drug release, especially the low solubility of the drug and the total surface area of the formulation. When it is small.
  • the prior art proposes a method for preparing a controlled release preparation for controlling release of a drug by forming a micropore by volatilizing a volatile component in the film or a component which degrades into a harmless gas in the film. .
  • a method for preparing a controlled release preparation for controlling release of a drug by forming a micropore by volatilizing a volatile component in the film or a component which degrades into a harmless gas in the film.
  • EP 0425023 (or US Pat. No. 4,256, 1989, US Pat. No. 5,126, 146) discloses a device for the release of a drug by osmotic pressure controlled release containing a microporous fibrous film coating having an average pore diameter of 10 angstroms to 100 micrometers, which is 5 to the volume of the film coating. 95%.
  • the inventors have mentioned a method of forming micropores in a film by generating a gas in a film during a film curing process. The method of producing gas is to volatilize a volatile component in a film or to produce a gas by a chemical reaction.
  • micropore size 5-30.
  • the average pore size of the pores is 0. 1-30.
  • the osmotic pump is filled with a gas. Micron, accounting for 5-15% of the film coat volume.
  • the inventors have referred to a method of forming micropores in a film coat using particles of sublimable or degradable constituents such as menthol, naphthalene, camphor, phenol, ammonium acetate, ammonium carbonate, and the like.
  • the stability of the preparation has a big problem: after the controlled release preparation prepared by the technology is stored for a period of time, the release property or the rate of drug release often decreases greatly, and the drug content in the preparation does not substantially change or The magnitude of the change is relatively small.
  • the products after storage for a certain period of time were observed with a microscope, and it was found that the size of the micropores in the film was smaller or even completely closed than the initial stage.
  • the degree of micropore shrinkage is related to the storage time. The time is long and the aperture is reduced.
  • the degree of micropore shrinkage is also related to the original pore size. The original pore size is large, the pore size is reduced by Yu Xiao, the original pore size is small, and the pore size is reduced. Yu Da.
  • the release property or release rate of the controlled release preparation prepared by the technique is often significantly lower than that of a membrane-controlled release preparation using a water-soluble material of the same size as the porogen, and theoretically adopted.
  • Membrane controlled release preparations with controlled diameters of hollow pores (without porogens) of the same size should be faster or at least not lower than membrane controlled release preparations containing porogens of the same size.
  • the porogen needs to be dissolved into micropores to control the release of the drug, and the porogen needs to dissolve for a certain period of time.
  • the mechanical strength of the preparation prepared by the above method is often unsatisfactory.
  • the glass transition temperature (Tg) of the polymer coating film is high, the controlled release coating film may be broken by an external force due to insufficient mechanical strength.
  • dose-dumping of the controlled release formulation may be caused, which may affect the safety of administration.
  • the coating process is carried out at a lower polymer glass transition temperature (Tg), such as the commonly used ethyl cellulose (EC) (Aquacoat® and Surelease®) and acrylic resins. (Eudragit) and so on. Therefore, in the reality, there is still a need for further technical improvements in the preparation of controlled release formulations of the above controlled release formulations, particularly zero-order release.
  • Tg polymer glass transition temperature
  • One of the primary objects of the present invention is to provide a use of a polymeric enhancer in a controlled release formulation as described above, particularly a zero release release controlled release formulation.
  • One of the main objects of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a preparation method thereof, which have relatively high storage stability in terms of release.
  • a primary object of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a process for the preparation thereof, which formulation has a relatively high production reproducibility in terms of release.
  • a primary object of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a process for the preparation thereof, which have a relatively large improvement in the performance in terms of release.
  • Another main object of the present invention is to provide a controlled release preparation, especially a zero-order release controlled release preparation, and a preparation method thereof, wherein the controlled release film of the preparation has relatively good mechanical properties and has a low dose release The possibility and higher medication safety.
  • the present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly
  • the drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film.
  • the polymer enhancer is used to delay the reduction of the pore diameter of the air-filled drug-releasing micropores during the production process and/or storage process, wherein the above polymer enhancer is as described above.
  • the contact angle of the polymer in the polymer controlled release coating film is less than 90°.
  • the present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly
  • the drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film.
  • the polymer enhancer is used to improve the stability of the release rate of the above controlled release preparation during storage, and the polymerization of the above polymer enhancer and the above polymer controlled release coating film
  • the contact angle of the object is below 90°.
  • the present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly
  • the drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film.
  • the polymer enhancer is used to improve the reproducibility of the release rate of the above controlled release preparation in the production process, and the above polymer enhancer is in the above-mentioned polymer controlled release coating film.
  • the contact angle of the polymer is below 90°.
  • the present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly
  • the drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film.
  • the polymer enhancer is used to improve the above controlled release.
  • the release property of the book preparation such as increasing the release rate, is such that the contact angle of the above polymer reinforcing agent with the polymer in the above polymer controlled release coating film is less than 90°.
  • the present invention provides a controlled release preparation having improved performance, in particular a zero-order release controlled release preparation comprising: 1) a core material containing at least one biologically active substance; 2) overlying the core a controlled release coating comprising a plurality of air-filled drug delivery microwells, wherein the controlled release film comprises a pharmaceutically acceptable polymer which is insoluble or hardly soluble in water and a digestive juice and is pharmaceutically acceptable
  • the polymer reinforcing agent having a contact angle of less than 90° with the above polymer reinforcing agent, wherein the release micropores are sublimed and pharmaceutically acceptable sublimable in the polymer controlled release coating film. Substance and/or degradation of a pharmaceutically acceptable material which is degradable into a harmless gas in the above polymer controlled release coating film.
  • the invention provides a method for preparing a controlled release preparation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, in particular a zero-order release controlled release preparation, the preparation method
  • the following basic steps are included: 1) preparing a core material containing at least one biologically active substance; 2) using particles of a substance containing pharmaceutically acceptable sublimable material particles and/or degradable into a harmless gas and a solution or aqueous dispersion of a pharmaceutically acceptable polymer-enhancing agent in a polymer-insoluble or hardly soluble in water and a digestive solution, said core coated polymer controlled release coating film, wherein a sublimable substance and/or a substance degradable into a harmless gas and a solution or aqueous dispersion in which the above polymer reinforcing agent is insoluble or hardly soluble in the above polymer, and the contact angle of the above polymer with the above polymer reinforcing agent is low At 90°; 3) sublimating the pharmaceutically
  • controlled release coating film means a material containing a sufficient amount of hydrophobic (polymeric) material coated on the outer surface of the core of the controlled release preparation and having sufficient mechanical strength to maintain the controlled release preparation.
  • the non-ruptured coating film in the aqueous solution release process, the coating film can delay the release of the drug or the therapeutic active agent contained in the controlled release preparation when it is placed in an aqueous solution.
  • polymeric enhancer as used in the present invention means a polymer phase (continuous phase) which is distributed in a polymer film in a separate form (dispersion phase) and which can improve or enhance the polymer film including mechanical (mechanical).
  • the term "contact angle" means that the polymer in a fluid state is at the liquid (polymer)-solid (polymer enhancer)-gas (air) tristate junction when it is on the solid surface of the polymer enhancer.
  • the angle formed especially when the polymer in the above fluid state is further solidified and cooled to room temperature at 25 ° C, at the equilibrium of the solid (polymer)-solid (polymer enhancer) - gas (air) tristate junction The angle formed.
  • the term "many" as used in the present invention means that the number of drug-releasing micropores which are coated on the polymer (controlled release) film of the preparation is not only one, but also plural, generally not less than 20, usually not low. In 50, especially not less than 100, more particularly not less than 1000, especially not less than 5,000.
  • active ingredient means any substance as it Detectable biological effects when administered to a living body include any physiological, diagnostic, prophylactic or pharmacological effects. This term is intended to include, but is not limited to, any pharmaceutically, therapeutic, prophylactic, nutritional material.
  • a as used in the present invention means at least one, and may be one type or two or more types.
  • pharmaceutically acceptable as used in the present invention means that it can be mixed with each other in the preparation without adverse effects on each other without lowering the stability and/or efficacy of the preparation and is suitable for topical or systemic administration.
  • the present invention employs a pharmaceutically acceptable sublimable substance and/or a substance which can be degraded into a harmless gas as a porogenic substance in a polymer film (controlled release film) (hereinafter pharmaceutically acceptable sublimation) Substance and / or degradable into harmless gas Description
  • a substance called a porogen which is formed by sublimation of a component having an ascending property in a polymer film (controlled release film) or a component degradable in a film which degrades into a harmless gas. Micropores to release controlled release of the drug.
  • the important factors affecting the properties of the above-mentioned porogens in polymer coatings (controlled release coatings) and controlled release preparations are their melting point and their sublimable or degradable temperature, solubility in the coating solution and their average granules. path.
  • the melting point of the above porogen at 1 standard atmosphere (101. 325 ka) and its sublimation (sublimation point) or degradation at 1 standard atmosphere (101. 325 ka) is usually higher than 40 ° C, preferably not Below 60 ° C, more preferably not lower than 80 ° C, optimally not lower than 100 ° C; and the melting point of the above-mentioned porogen at 1 standard atmospheric pressure (101.
  • the temperature of degradation should be higher than the minimum film forming temperature of the mixed coating liquid of the above polymer or the glass transition temperature of the above polymer film, usually higher (including) 10 ° C, preferably higher (including ) 20 ° C, better than (including) 30 ° C, optimally higher (including) 40 ° C.
  • the solubility of the above-mentioned porogen in the coating liquid should be not higher than 30 mg/ml, preferably not higher than 10 mg/ml, more preferably Lmg/ ⁇ Not more than lmg / ml, preferably not higher than 0.
  • the above pore-forming substance should have an average particle diameter of 30 to 1200 ⁇ , preferably 50 to 900 ⁇ m, more preferably 100 to 600 ⁇ m, and most preferably 150 to 400 ⁇ m. Since the average particle size of the porogen is the main factor affecting or determining the size of the released pores in the polymer coating (control release coating), the average size of the released micropores in the coating should be approximately 30 to 1200 ⁇ m. Preferably, it is located at 50 to 900 ⁇ m, more preferably between 100 and 600 ⁇ m, and most preferably between 150 and 400 ⁇ m.
  • micropore additional pressure 2./r, where ⁇ ⁇ denotes micropore additional pressure, polymer-air surface tension, r denotes micropore radius
  • ⁇ ⁇ micropore additional pressure
  • the production or storage process is gradually reduced by itself, so that the drug release of the membrane controlled release preparation becomes less stable and the production reproducibility is poor. It has been confirmed by repeated experiments that the stability is related to the pore size of the controlled release membrane, the pore size is large, the stability is good, the pore size is small, the stability is poor, and the stability is increased (or decreased). The magnitude is greater than the increase (or decrease) in the pore size of the micropore. Therefore, the present invention employs relatively large drug delivery micropores to control release of the drug to improve the stability of drug release of the formulation. However, excessive drug release micropores are also prone to problems such as poor production reproducibility.
  • the amount of porogenic material in the coating fluid is determined by the skilled artisan skilled in the art in light of the nature of the drug and the desired rate of drug delivery.
  • the amount of the porogen is usually determined by the particle size, the type and amount of the polymer, the nature of the drug, the desired rate of release, etc., and is usually 5% to 95% by weight or volume ratio, preferably It is from 25% to 90%, more preferably from 40% to 80%, based on the total dry weight of the polymer film (controlled release film) component or the volume of the polymer film (controlled release film).
  • the amount of porogen is the main factor affecting or determining the porosity of the polymer film (controlled release film). Therefore, the porosity of the polymer film (controlled release film) should be basically 5% ⁇ 95%. It is preferably between 25% and 90%, more preferably between 40% and 80%.
  • porosity refers to the proportion of the space left by the porogen in the polymer coating film (controlled release film) to the volume of the original polymer film (controlled release film). .
  • Preferred examples of the sublimable component as the porogen or the component which can be degraded into a harmless gas include, but not limited to, benzoic acid (mpl 21. 5 to 123. 5 ° C, 100 ° C begins to sublimate (latm )), benzoate and benzoate compounds
  • benzoic acid ethyl ester ethyl ester, phenyl benzoate, benzoic acid propyl ester, benzyl benzoate, methyl benzoate, benzoate such as sodium salt
  • vanillin mp 81 ⁇ 83 ° C
  • ethyl vanillin mp76 ⁇ 81 °C, pure mp77 ⁇ 78°C
  • natural or synthetic camphor natural camphor mpl76 ⁇ 18rC, synthetic camphor 1 ⁇ 174 ⁇ 179°0, right-handed camphor (mp about 179. 8°C, 204 °C begins to sublimate
  • di-tert-butylhydroxytoluene (2,6 di-tert-butyl-p-cresol) ( ⁇ 69 ⁇ 7 ⁇
  • salicylic acid mpl58°C, 76°C begins to sublimate
  • aspirin salicylamine
  • Caffeine compounds eg caffeine 1 hydrate (ie 238°, 178° sublimation), caffeine anhydrate, caffeine citrate, caffeine benzoate such as sodium salt
  • alanine, leucine isoleucine, valine, phenylalanine, urea, urethane
  • ammonium halides such as ammonium chloride, ammonium hydrogencarbonate, ammonium carbonate, ammonium acetate, and mixtures thereof.
  • the coating polymer suitable for the present invention may be a pharmaceutically acceptable block polymer or copolymer which is insoluble or hardly soluble in water and digestive juices.
  • Suitable polymers may be selected from, but not limited to, cellulose esters, acrylic polymers, polyvinyl acetates, polyvinyl chlorides, and combinations thereof that are insoluble or nearly insoluble in water and digestive juices.
  • suitable polymers of preferred examples include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cel lulose acetate propionate ⁇ nitrocellulose, triamyl) Acid cellulose, cellulose dodecanoate, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, polyvinyl acetate, methacrylate polymer, vinyl chloride-vinyl alcohol Terpolymer of vinyl acetate, polycarbonate, polymethyl methacrylate, ethyl acrylate, a methyl acrylate polymer, vinyl chloride-ethylene acetate copolymer, polyvinyl chloride, polyethylene, polyisobutylene , poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride).
  • Another useful example is an aqueous dispersion coating containing 50 to 100% polyvinyl chloride and 0 to 50% polyvinyl acetate copolymer.
  • the proportion of the coating polymer in the dry coat is determined by the type of polymer selected, the type and amount of the porogen, the nature of the drug, the selected dosage form and the desired mode of release, etc., usually 40. % to 95% by weight, preferably 50% to 90% by weight, more preferably 55% to 85°/.
  • the weight ratio which is based on the total dry weight of the polymer film (controlled release film) component.
  • plasticizers are often added to the coating formulation to lower the glass transition temperature (Tg) of the polymer to a suitable range, and to improve the film forming ability of the coating material and enhance the flexibility of the film. Sex and strength, improve the adhesion of the film to the substrate.
  • the glass transition temperature (Tg) of the polymer is used at a lower value, such as 25-80 ° C, during the general coating process.
  • the glass transition temperature (T g ) of the plasticized plastic is usually required to be not higher than 90 ° C, not lower than 15 ° C, preferably 25 to 80 ° C, more preferably 35 to 70 °.
  • the glass transition temperature (7;) of the polymer film should also be lower than the sublimable substance and/or the substance degradable into a harmless gas at 1 standard atmosphere (101
  • the temperature at which 325 ka) begins to sublimate or degrade is usually 10 ° C lower, preferably 20 ° C lower, more preferably 20 ° C lower, and most preferably 40 ° C lower.
  • a lower glass transition temperature (Tg) is adopted, so that a lower temperature can be used in the coating process, which is advantageous for the smooth progress of the coating process, and particularly for reducing the porosity of the pore-forming material during processing.
  • Sublimation or degradation which is beneficial to improve the release performance, process stability and production reproducibility of the preparation.
  • the glass transition temperature of the polymer film should not be too high, which will increase the process difficulty and cost.
  • the plasticizer is usually a liquid substance having a high boiling point, a low volatility and being miscible with a polymer (Mr is about 150 to 800, preferably 300 to 500), or a solid substance having a low melting point.
  • Mr is about 150 to 800, preferably 300 to 500
  • a solid substance having a low melting point examples of useful plasticizers are physiologically compatible from C 6 to C 4 . (preferably C 6 to C 3 ., particularly preferably ( ⁇ . ⁇ (: 16 ) aliphatic or aromatic mono- to tricarboxylic acid and ⁇ ( 8 (preferably C 2 to C 6 , particularly preferably C 2 to C 5 ) fat a lipophilic ester formed by a steroid.
  • plasticizers examples include dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, citric acid. Triethyl ester, acetyl triethyl citrate, triacetin, tributyl succinate, sorbitan ester, sucrose ester. Examples of other useful plasticizers such as glycerin, propylene glycol, polyethylene glycol Castor oil.
  • the amount of the plasticizer depends on the properties of the desired film, such as the glass transition temperature, mechanical properties, etc., the type of plasticizer, the type and amount of the film-forming agent (ie, the water-insoluble film-forming polymer), and usually The amount is 5 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 10 to 30% by weight, based on the dry weight of the polymer film (controlled release film) component. total weight.
  • T g glass transition temperature
  • the conversion temperature is lower, the ability or tendency of the polymer molecules to freely “flow” or “slip” is relatively strong, and the release micropores are easier to produce and/or store (in the present invention the term “storage process” generally refers to the preparation of the preparation from production. From the end to the time when the user (patient) is used, the process is reduced or even completely closed; in addition, there is still room for improvement in the functional properties of the above polymer film such as tensile properties. In order to improve these properties of the prepared formulations, the present invention requires the addition of a specific polymer reinforcing agent to the coating liquid.
  • a contact angle with the above polymer is added to the coating liquid or coating ((a polymer enhancer lower than 90°, preferably the above contact angle ( ⁇ is lower than or equal to 60°, more Preferably, the content is lower than or equal to 30°, and most preferably lower than or equal to 10°.
  • the term “polymer enhancer” as used herein refers to a distribution in a separate form (dispersed phase) to a polymer film (controlled release coating). a polymer phase (continuous phase) in the film) and a pharmaceutically acceptable additive that improves the mechanical properties of the polymer film including mechanical (mechanical) strength and stiffness.
  • Polymer contact angle means the angle formed when the polymer in a fluid state is at the liquid (polymer)-solid (polymer enhancer)-gas (air) tristate junction when it is located on the solid surface of the polymer enhancer. More preferably, after the above fluid state polymer is further cured, in particular, after solidification and cooling to room temperature of 25 ° C, in a solid (polymer)-solid (polymer enhancer) - gas (air) tristate The angle formed when the junction is balanced.
  • the present invention usually Refers to the static (state) contact angle ( ⁇ , a static (state) contact angle that can be used in the present invention (the ⁇ , the measurement method is as follows: heating makes the temperature greater than the rheological temperature of the polymer to make the polymer in a fluid state, Add the polymer solution and let it rest on the surface of the polymer enhancer (usually clean and smooth horizontal plane). After the shape is stabilized (more preferably further solidified and cooled to room temperature 25 ° C), the contact measured by the appropriate method The angle, for example, is measured directly by a microscope or directly measured from a television image or photograph.
  • the contact angle (usually considered as the quantitative indicator that the solid is wet by the liquid
  • the contact angle ( ) Yu Xiao the degree to which the solid is wet by the liquid is large
  • the compatibility between the two is good
  • two Affinity between the two two Affinity between the two.
  • the contact angle of the polymer with the polymer enhancer is lower than 90 °, more than 60 °, especially lower than or equal to 30 °, especially less than or equal to 10
  • the polymer has good compatibility with the polymer reinforcing agent, and there is a strong affinity between the two, which can cause "surface wetting" or even “spreading". At this time, it is enhanced by polymer and polymer.
  • the agents have a strong interaction with each other, and the polymer reinforcing agent is dispersed in the polymer in the form of particles (molecular aggregates) or in the form of "islands", and the ability of the polymer molecules to "flow” or “slip” freely Attenuated by polymer enhancers, the range of free “flow” or “slip” of polymer molecules is limited by the polymer enhancer to a relatively small range, and the polymer macroscopically exhibits "viscosity" rise, "flowability” Decline.
  • the polymer reinforcing agent can attenuate or delay the production and/or storage process (such as sublimation and/or degradation of the above-mentioned sublimable substance located in the above polymer film and/or a substance degradable into a harmless gas, etc.)
  • the tendency of the formed micropores to shrink or close by themselves has a stable release pore size. Therefore, the above polymer enhancer can improve (or improve) the storage stability and production reproducibility of the preparation, Release performance, etc., but also can increase the mechanical strength of the film, reduce the possibility of dose dumping of the preparation, and improve the safety of medication.
  • the above contact angles indirectly reflect the compatibility or affinity between the polymer and the polymer reinforcing agent.
  • the compatibility or affinity between the polymer and the polymer enhancer can also be evaluated or predicted using the "similar compatibility" principle, such as polar or non-polar similarity.
  • the solubility parameter between the polymer and the polymer enhancer can be evaluated using a solubility parameter that characterizes the cohesive force between the molecules of the polymer. 5 ⁇ , ⁇
  • the difference between the solubility parameter of the polymer and the organic solvent is less than 1.5.
  • the person can be mixed in any proportion, and the two have good compatibility.
  • two- or three-dimensional solubility parameters can be used to determine system compatibility (see: Shaw MT, J Appl Polym) Sci, 1974, 18: 449).
  • the present invention recommends the following simple methods to prove or predict the compatibility between the polymer and the polymer: 1), the common solvent method, the two polymers are separately dissolved in the same solvent, and then mixed, according to The solution is mixed to judge the compatibility of the polymer. 2), microscopic method, phase contrast microscopy, especially electron microscopy, can directly observe the degree of compatibility. 3), solution viscosity method, the viscosity of the solution can reveal the compatibility degree of the polymer blend solution, in different polymers At the concentration of the specification, the viscosity is plotted against the percent composition of the polymer.
  • the present invention is especially recommend this method, a polymer alloy system, three kinds of change of Tg occurs, assuming the binary alloy system of two T g of the polymer T gl and Tg 2 respectively (T gl ⁇ Tg 2 (1), fully compatible system: only one Tg appears, T gl ⁇ Tg ⁇ Tg 2 ; (2), completely incompatible system: two Tg appear, Tg Tg 2 ; (3), partially compatible system: two Tg/, Tg, T gl ⁇ T gl ' ⁇ Tg 2 ' ⁇ Tg 2 appear.
  • Polymeric enhancers useful in the present invention include, but are not limited to, pharmaceutically acceptable filler reinforcing agents, microfiber reinforcing agents, and mixtures thereof.
  • the filler reinforcing agent useful in the present invention may be pharmaceutically acceptable rigid inorganic particles and rigid organic particles.
  • Rigid inorganic particles useful in the present invention include, but are not limited to, carbonates, sulfates, metal oxides, metal powders, carbon compounds, silicon-containing compounds (such as silicon oxides, silicates), and mixtures thereof, or Ultrafine particles.
  • the rigid inorganic particles usable in the present invention include, but are not limited to, attapulgite, soap clay, calcium carbonate, calcium sulfate, barium sulfate, carbon black, silica, alumina, zinc oxide, titanium dioxide, white clay, Mica, talc, calcium phosphate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium trisilicate.
  • the rigid inorganic particles used in the present invention preferably have used a surface active material (such as a higher fatty acid, a higher fatty acid salt, a higher fatty acid ester) or a polymeric dispersant (such as a polyolefin, a polyester, a polyacrylate or a polyether).
  • Adsorption coating treatment or treatment with a coupling agent such as a silicone germanium coupling agent, a titanate coupling agent, a zirconium aluminate coupling agent, an aluminate coupling agent, or grafting or block polymerization on the surface of the particles.
  • a coupling agent such as a silicone germanium coupling agent, a titanate coupling agent, a zirconium aluminate coupling agent, an aluminate coupling agent, or grafting or block polymerization on the surface of the particles.
  • the surface modification can be carried out by encapsulation polymerization or by other suitable means.
  • Preferred examples of rigid organic particles useful in the present invention include, but are not limited to, polymethyl methacrylate (PMMA), polystyrene (PS), methyl methacrylate/styrene copolymer (MMA/ST), and styrene. / Acrylonitrile copolymer (SAN).
  • the above-mentioned rigid particles have an average particle diameter (diameter) of usually not more than 1 m, preferably not more than 400 nm, more preferably not more than 100, more preferably not more than 20 nm, and most preferably not more than 5 nm.
  • Nano-sized particles (not more than 100 can increase strength, toughness, impact resistance, and release pore size stability to a greater extent, and are therefore preferred.
  • Microfiber reinforcing agents useful in the present invention include inorganic microfibers, organic microfibers, and metal microfibers.
  • Inorganic microfibers Chemical microfibers made of mineral materials, such as glass microfibers, quartz glass microfibers, boron microfibers, ceramic microfibers, and metal microfibers.
  • useful organic microfibers such as synthetic microfibers such as aramid microfibers, aramid microfibers, polyester microfibers, nylon microfibers, vinylon microfibers, polypropylene microfibers, polyimide microfibers, etc.; Fibers such as cotton microfibers, sisal microfibers, wood microfibers, and the like.
  • the metal microfibers are metal microfibers such as silver, copper, and nickel.
  • microfiber refers to a particulate material that can be generally described as fibers due to their aspect ratio, and preferred microfibers for use herein have an aspect ratio of from about 10:1 to about 500:1. More preferably, it is about 25: 1-300: 1.
  • the above fibers generally have an average diameter of not more than 1 ⁇ m, preferably not more than 400, more preferably not more than 100 nm, still more preferably not more than 20 nm, most preferably not more than 5 nm.
  • the average length of the above fibers is usually not more than ⁇ ⁇ ⁇ , preferably not more than ⁇ ⁇ ⁇ , more preferably not more than 1 ⁇ m, and most preferably not more than 100 nm.
  • polymeric toughening agent means having reduced film brittleness and improved film resistance.
  • a pharmaceutically acceptable component of impact properties the same as below, thereby forming a "hard shell-soft core structure".
  • shell may completely or partially coat "nuclear”;
  • shell may contain one or more "nuclear”;
  • shell may also contain smaller "nuclear”
  • the "core” in the shell may also contain a "shell” component or a smaller “core-shell structure”; it may also be a more complex hard/soft/hard layer; soft/ Instruction manual
  • Hard/soft/hard four-layer modal particles Hard/soft/hard four-layer modal particles.
  • the above-mentioned “core-shell structure” particles have a better reinforcing and toughening effect at the same time, and are superior to a simple polymer reinforcing agent or a polymer toughening agent, which is preferable.
  • the “shell” usually accounts for 0.5 to 50%, preferably 1 30%, more preferably 2 to 10%, of the entire structure volume.
  • the above “nuclear-shell structure” particles also have the "fluidity” and “ductility” of increasing the film polymer at temperatures above its glass transition temperature (7;), reducing the “melt” internal tension. At the same time, it can maintain high “melt” strength, accelerate “melting”, promote “plasticization”, and improve “processability”, which is beneficial to the coating and healing of polymer film (controlled release film). The time required for their processing is shortened, and the volatilization or degradation of the above porogen in the above process is reduced, thereby having a stronger effect of stabilizing the release pore size. Therefore, the above "core-shell structure” particles are most preferred in the present invention.
  • Polymeric toughening agents suitable as "nuclear” in the “core-shell structure” include natural and synthetic elastomeric polymers such as natural rubber, synthetic rubber and thermoplastic elastomers. They are usually derived from various monomers such as olefins (such as ethylene, propylene, 1 butene, 4 methyl-1-pentene in C2-C8 olefins), alkenyl aromatic monomers (such as C2-C8 olefins).
  • olefins such as ethylene, propylene, 1 butene, 4 methyl-1-pentene in C2-C8 olefins
  • alkenyl aromatic monomers such as C2-C8 olefins
  • Styrene and ⁇ -methylstyrene in aromatic monomers conjugated dienes (such as butadiene, isoprene and chloroprene in C4-C8 conjugated dienes) and vinyl Carboxylic acids and derivatives thereof (such as vinyl acetate, acrylic acid, methacrylic acid, ethyl acrylate, methyl methacrylate, acrylonitrile). They may be homopolymers or copolymers.
  • polymer rubber-based materials such as those derived from acrylic acid, methyl methacrylate-butadiene-styrene (MBS) type impact resistance improvers; silicon-containing rubber polymers And copolymers such as silicones, silicones, etc.; synthetic rubbers such as butadiene rubber, styrene-butadiene rubber (SBR), and isoprene, etc.; containing flexible chains to reduce vitrification Temperature-changing polymers, such as polyesters; polyolefins; vinyl aromatic hydrocarbon-diene block copolymers; polyurethanes; rubbery polyethers, polymers such as ethylene glycol and propylene glycol type, and the like; Blends, grafts, and copolymers.
  • MFS methyl methacrylate-butadiene-styrene
  • SBR styrene-butadiene rubber
  • isoprene etc.
  • Temperature-changing polymers such as polyesters; polyolefins;
  • the component of the "core” which is suitable for the "core-shell structure” of the present invention may comprise a polyolefin polymer which is a general structure of C n H 2n , including polyethylene, polypropylene and polyisobutylene, preferably The homopolymers are polyethylene, ULDPE (ultra low density polyethylene), LLDPE (linear low density polyethylene), HDPE (high density polyethylene) and MDPE (medium density polyethylene) and isotactic polypropylene.
  • ULDPE ultra low density polyethylene
  • LLDPE linear low density polyethylene
  • HDPE high density polyethylene
  • MDPE medium density polyethylene
  • the general structure of polyolefin resins and methods for their preparation are well known in the art and are described, for example, in U.S. Patent Nos. 2,933,480, 3,309,621, 3,211,709, 3,646,168, 3,790,519, 3,884,993, 3,894,999, 4,059,654, 4,166,055, and 48
  • the polymer toughening agent which is suitable for the "core” in the "core-shell structure" of the present invention may also include copolymers of various polyolefins such as ethylene and ⁇ -olefins of propylene and 4-methyl-1- a copolymer of pentene.
  • a suitable example is a copolymer of ethylene and a C3-C10 monoolefin and a non-conjugated diene (referred to herein as an EPDM copolymer).
  • the "core” component of the "core-shell structure”, i.e., the polymeric toughening agent, may also include conjugated diene homopolymers and random copolymers. Examples thereof include polybutadiene, butadiene-styrene copolymer, butadiene-acrylate copolymer, isoprene-isobutylene copolymer, chloroprene polymer, butadiene acrylonitrile polymer, Polyisoprene.
  • An example of a "core-shell structure" particle suitable as a mechanical property improver (polymeric enhancer) includes bismuth (double-block), (AB) mR (double-block), and ABA' (tri-block).
  • Block copolymer Blocks A and A' are typically alkenyl aromatic units, and block B is typically a conjugated diene unit.
  • block copolymer of formula (AB) m-R the integer m is at least 2, and R is a polyfunctional coupling agent for the block of structure AB.
  • SBR polystyrene-polybutadiene
  • polystyrene-poly(ethylene-propylene) polystyrene-polyisoprene
  • poly( ⁇ -methylstyrene)-polybutylene Diene polystyrene-polybutadiene-polystyrene
  • polystyrene-poly(ethylene-propylene)-polystyrene polystyrene-polyisoprene-polystyrene and poly( ⁇ - ⁇ Styrene) - polybutadiene-poly( ⁇ -methylstyrene) and its selective hydrogenation products and the like.
  • copolymers can also be used.
  • Such copolymers are commercially available from a variety of sources, such as the product named S OLPRENE from Phi llips Petroleum, the product named KRAT0N from Shell Chemical Co., the product under the name VECTOR from Dexco, and the product named SEPT0N from Kuraray. .
  • a "core-shell structure" particle suitable as a mechanical property improving agent is a star block copolymer comprising a vinyl aromatic monomer and a conjugated diene monomer.
  • Copolymers of this type generally comprise from about 60% to about 95% by weight of the polymeric vinyl aromatic monomer and from about 40% to about 5% by weight of the polymeric conjugated diene monomer.
  • the copolymer has at least Description
  • core-shell structure particles suitable as mechanical property improvers include but are limited to polyethylene-vinyl acetate (EVA), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymers. (E-VA-C0), ethylene_C1 ⁇ C8 (preferably C1 ⁇ C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-CI ⁇ C8 (preferably CI ⁇ C4) methacrylic acid copolymerization And polyacrylonitrile-butadiene-styrene (ABS).
  • EVA polyethylene-vinyl acetate
  • E-VA-C0 ethylene_C1 ⁇ C8 (preferably C1 ⁇ C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer
  • ABS polyacrylonitrile-butadiene-styrene
  • the above-mentioned "core-shell structure" particles used in the present invention are present in a polymer film (control release film) as a mechanical property improving agent (polymer reinforcing agent) in a certain shape and size.
  • the particles constituting the "core-shell structure” are typically spherical. However, they may have any suitable shape, and particles of various shapes may be prepared by methods known in the art of polymer particle technology. Examples of other suitable particle shapes include, but are not limited to, ellipsoidal particles having a major aspect ratio greater than 1:1, raspberry shaped particles, multi-lobed particles, dumbbell shaped particles, agglomerated particles, double-lobed particles, and hollow spherical particles, and the like. .
  • its average particle diameter is not more than l w m.
  • the average particle diameter is not more than 400 nm, more preferably not more than 100 nm, still more preferably not more than 20 minutes, and most preferably not more than 5 nm.
  • smaller particles contribute to improved impact strength.
  • the melting point (or crystal melting temperature, Crystall ine Melt Temperature) or/and Vicat Softening Point of a "core-shell structure" particle suitable for the mechanical property improving agent (polymer reinforcing agent) of the present invention is generally not low.
  • the glass transition temperature (Tg) of the polymer in the controlled release film is preferably 5 ° C (inclusive), more preferably 10 ° C (inclusive), and most preferably 20 °C (inclusive); and its (center) glass transition temperature (Glass Transition Temperature) is usually required to be lower than the glass transition temperature (Tg) of the polymer in the controlled release coating film, usually not higher than the temperature of 15 ° C, Preferably, the temperature is not higher than 0 ° C; in addition, the above "core-shell structure" particles should also have good mechanical properties, such as high tensile strength, high elongation at break or tensile strength at break. .
  • ⁇ -shell structure particles suitable as mechanical property improvers are preferably as follows: Melting point (or crystal melting temperature, Crystall ine Melt Temperature) (DSC, via ASTM D3418 ISO 3146) or / and dimension Vicat Softening Point (via ASTM D1525 ISO 306) is preferably 60 to 2000 ° C, more preferably 80 to 1000 ° C, particularly preferably 100 to 500 ° C; Vicat Softening Point, via ASTM D1525 ISO 306) is preferably 45 to 150 ° C, more preferably 45 to 100 ° C, particularly preferably 50 to 80 ° C; elongation at break
  • Tensi le Elongation @ Break is preferably 200 to 5000% (via ASTM D638 / ISO 527-2); Tensile Strength (Tensi le Strength ⁇ Break) is preferably 1 to 50 MPa (via ASTM D638/IS0 527-2) ;
  • (Center) Glass Transition Temperature is preferably -10 to -200 ° C (via ASTM D5418 loss modulus peak at 1 hz ); Melt Flow Rate (190 ° C / 2.16 kg) It is preferably 0.5 to 150 g/10 min (via ASTM D1238 ISO 1133), more preferably 1 to 100 g/10 min, and particularly preferably 2 to 50 g/10 min.
  • the polymer reinforcing agent is usually used in an amount of from 0.5 to 50% by weight, preferably 1 ° /. ⁇ 30% (by weight), more preferably 2% ⁇ 20%
  • a film-coated polymer in combination with a polymer reinforcing agent is that the film-forming polymer is selected from a polymer containing a polar group that is insoluble or hardly soluble in water and a digestive solution, such as a cellulose ester polymer, An acrylic polymer, polyvinyl acetate, and the polymer enhancer is selected from fine or ultrafine particles of polar rigid inorganic particles (particle diameter is preferably not more than 100 nm)
  • a polar polymeric dispersant such as polyacrylate
  • the surface is subjected to surface-modified fine or ultrafine particles (the particle diameter is preferably not more than 100 nm (diameter)).
  • polar group-containing cellulose ester polymer are cellulose acetate, cellulose propionate, cellulose acetate butyrate, cel lulose acetate propionate. nitrocellulose, trivaleric acid Cellulose, cellulose succinate.
  • Applicable examples of the above-mentioned polar group-containing acrylic polymer, polyvinyl acetate include, but are not limited to, polyvinyl acetate, methacrylic acid polymer, vinyl chloride-vinyl alcohol- Terpolymer of vinyl acetate, polymethyl methacrylate, ethyl acrylate, a methyl acrylate polymer, polyvinyl acetate, ethyl acrylate-ethyl acrylate-trimethylaminoethyl chloride Methyl acrylate polymer (poly Instruction manual
  • a preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from a cellulose ester polymer containing a non-polar group that is insoluble or hardly soluble in water and a digestive juice (such as B).
  • Cellulose, cellulose dodecanoate, cellulose tripalmitate, cellulose dipalmitate), and polymer enhancer is selected from surfactants (such as higher fatty acids, higher fatty acid salts, higher fatty acid esters)
  • surfactants such as higher fatty acids, higher fatty acid salts, higher fatty acid esters
  • Adsorption-encapsulation treatment of surface-modified polar rigid inorganic particles such as carbonates, sulfates, metal oxides, silicon oxides, silicates, and mixtures thereof, fine or ultrafine particles (particle size is preferably not greater than 100 nm (diameter)), particularly preferably nano-sized calcium carbonate particles having a surface coated with stearic acid (particle diameter is preferably not more than 100 nm (diameter)).
  • an example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of cellulose ester polymers which are insoluble or hardly soluble in water and digestive juice, and the polymer reinforcing agent particles are selected from the group consisting of Methyl methacrylate-styrene copolymer (MMA-ST), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer containing both polar and non-polar groups (ABS), methyl methacrylate-butadiene-styrene terpolymer (MBS), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1 ⁇ C8 (preferably C1 to C4) methacrylic acid-carbonyl (carbon monooxide) trimer, ethylene-(C1 to C8) (preferably C1 to
  • coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of acrylic acid polymers which are insoluble or hardly soluble in water and digestive juice, and polymer reinforcing agent particles are selected.
  • PMMA Self-polymethyl methacrylate
  • MMA-ST methyl methacrylate-styrene copolymer
  • MBS methyl methacrylate-butadiene-styrene terpolymer
  • E-VA-C0 ethylene-ethylene acetate -carbonyl (carbon monooxide) terpolymer
  • E-VA-C0 ethylene-C1 ⁇ C8 (preferably C1 ⁇ C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer
  • ethylene-C1 ⁇ C8 preferably C1 to C4
  • mercaptoacrylic acid copolymer acrylic resin type impact modifier or a mixture thereof
  • particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm
  • Applicable examples of the above polymers include, but are not limited to, methacrylic acid polymers, polymethyl methacrylate, ethyl acrylate-m-methyl acrylate polymer, acrylic acid which are insoluble or hardly soluble in water and digestive juices.
  • an example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of polyvinyl acetate which is insoluble or hardly soluble in water and digestive juice, and the polymer reinforcing agent particles are selected from the group consisting of Methyl acrylate-styrene copolymer (MMA-ST), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer (ABS), methyl methacrylate-butyl Alkene-styrene terpolymer (MBS), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1 ⁇ C8 (preferably C1 ⁇ C4) methacrylic acid-carbonyl (Carbon monooxide) terpolymer, ethylene-C1 to C8 (preferably C1 to C4) mercap
  • polyvinyl acetate a terpolymer of vinyl chloride-vinyl alcohol-vinyl acetate, a vinyl chloride-vinyl acetate copolymer, and mixtures thereof.
  • MMA-ST methyl methacrylate-styrene copolymer
  • SAN styrene-acrylonitrile copolymer
  • ABS styrene-butadiene-acrylonitrile terpolymer
  • MVS methyl methacrylate-butadiene-styrene terpolymer
  • E-VA-C0 ethylene- Ethylene acetate-carbonyl (carbon monooxide) terpolymer
  • E-VA-C0 ethylene-C1 ⁇ C8 (preferably C1 ⁇ C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer
  • ethylene-C1 ⁇ C8 preferably C1 to C4 methacrylic acid copolymer or a mixture thereof
  • particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm (diameter)).
  • Elvaloy® series products eg Elvaloy AC 1 , 2, 3 series, Elvaloy HP series.
  • Acrylic anti-impact modifiers are available in listed products such as the PARALOID BP series of nanoscale products manufactured by Rohm and Haas.
  • a film-forming general additive material may be added to the coating liquid of the invention.
  • the amount and application of the film-forming general additive material in the drug coating layer is well known to those skilled in the art.
  • Common additives include, but are not limited to, anti-adherents (separators), stabilizers, pigments, defoamers, antioxidants, penetration enhancers, gloss agents, perfumes or flavoring agents. They are used as processing aids and should ensure safe and reproducible preparation methods as well as long-term storage stability or additional beneficial properties imparted to the pharmaceutical dosage form. They are added to the formulated polymer prior to processing and can affect the permeability of the coating, which can also be used as an additional conditioning parameter.
  • the separating agent is typically a beneficial hydrophobic material and is typically added to the spray suspension. They prevent the accumulation of nuclei during film formation. Preference is given to using talc, magnesium stearate or calcium stearate, finely divided silicic acid, kaolin or a nonionic emulsifier having an HLB value of from 3 to 8. 5 ⁇ 100% ( ⁇ )
  • the polymer is usually used in the coating layer of the present invention.
  • the separating agent is added as a final coating in concentrated form. The coating is carried out by spraying in the form of a powder or a suspension having a solid content of 5 to 30%. 1 ⁇ 2% ⁇ The amount of the dosage of the pharmaceutical dosage form is 0. 1 ⁇ 2%.
  • the stabilizer is preferably an emulsifier or a surfactant, and has an interfacial active substance to stabilize the aqueous dispersion.
  • suitable stabilizers are diethanolamine, monoethanolamine, triethanolamine, fatty acids, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), nonoxynol, octoxynol, oil Acid, poloxamer, polyoxyethylene 50 stearate, polyoxyl fatty acid, polyoxyl hydrocarbon ether, polysorbate (Tween), dehydration Sorbic acid ester (Span), fatty acid salts, povidone, sodium lauryl sulfate, sodium decyl stearyl sulphate, sucrose stearate, polysorbate and mixtures thereof.
  • the stabilizer is contained in an amount of from 1 to 15% by weight, preferably from 5 to 10% by weight, based on the wet weight of the component of the aqueous dispersion coating liquid.
  • Alumina or an iron oxide pigment is generally dispersedly added. Titanium dioxide is used as a white pigment.
  • the pigment is added in the coating layer of the present invention in an amount of from 20 to 60% by weight based on the polymer mixture. However, due to the high pigment binding capacity, the addition amount can be as high as 100% by weight.
  • the antifoaming agent is generally dimethicone.
  • the final coating is used directly in concentrated form.
  • the coating is carried out in the form of a powder or by spraying with an aqueous suspension having a solid content of 5 to 30%. 1 ⁇ 2% ⁇
  • the amount of the dosage of the pharmaceutical dosage form is 0.1 to 2%.
  • Coated cores (carriers) useful in the present invention include, but are not limited to, regular or irregular forms of tablets, granules, (micro) pellets, crystals, drug-loaded resins.
  • the size of the granules, (micro) pellets or crystals is usually 0. 01 ⁇ 2. 5mm, the size of the sheet is usually 2. 5 ⁇ 30mm. They usually contain up to 95% (by weight, unless otherwise stated) bioactive substances (active substances) and up to 99.9% of other pharmaceutical additives.
  • the biologically active substance (active substance) used in the present invention has no other limitation except for those which are degraded, volatilized, and inactivated due to thermal effects during the preparation process, but there is no other limitation, if a certain method (such as a ring) is applied.
  • Dextrin inclusion, microencapsulation technology can prevent degradation, volatilization, and inactivation of biologically active substances during preparation, and these biologically active substances can also be used in the present invention.
  • the active ingredient used in the present invention may be any of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description
  • Central stimulant idebenone, benzotrizepine, piracetam, pyrithione, vinpocetine, dimethylformin, aniracetam, meclofenoxate, caffeine, modafinil, Pentylenetetrazol.
  • An analgesic chlorpheniramine, buprenorphine, dihydroetorphine, florofinine, bicuculline, codeine, rotundine, morphine, ergotamine, meptazin, methadone, nai Fructus, pethidine, pirimidin, oxycodone, hydromorphol, tramadol, sumatriptan, tetrahydropalmatine, dextropropoxyphene, dextromethorphan, levonorol, left mala amine.
  • Antipyretic analgesics aspirin, acetaminophen, phenacetin, hydroxybzon, thiramite, magnesium salicylate, imidazole salicylate, isopropylantipyrine.
  • Anti-inflammatory analgesics aminclofen, acemetacin, azaprozin, ampoxicam, augusin, olsalazine, benolyl ester, pirfen, ibuprofen, bucillamine , aceclofenac, butyl hydroxy acid, diflunisal, fenbufen, flurbiprofen, flufenamic acid, citrictin, cyclohexanoic acid, mefenamic acid, meclofenamic acid , gold thioglucose, auranofine, leflunomide, chlorpheniric acid, loxoprofen, aristolochic acid, meloxicam, mesalazine, nabumetone, naproxen, niflut Acid, etodolac, zaltoprofen, guaiac blue hydrocarbon, etofenamate, escitoxicam, ketoprofen,
  • An anti-gout drug glucosamine, benzbromarone, allopurinol, colchicine, probenecid, etimabazole.
  • An anti-shock paralysis drug trihexyphenidate, biperiden, dorepeptide, entacapone, adamantamine, carbidopa, quetiapine, rasagiline, memantine, selegiline, Tokapeng, bromocriptine, levodopa, mobilis, moxifensin, palitide, donepezil.
  • Antipsychotics alipidide, anibirdolol, azaiperone, apixipide, amisulpride, oxaporone, oxaflurazine, oxybuterazine, chlorpromazine, fluoride Perphenazine, haloperidol, droperidol, flupentixol, flupriline, risperidone, linacazole, thiopril, thioridazine, clozapine, clopidogrel, chlorine Piperazine, cloprofen, loxapine, mazapamine, nemiride, piperazine, pimozide, pramipexole, rimopride, sulpiride, penfluridol, zooti Ping, epoprazol, olanzapine.
  • An anti-anxiety drug alprazolam, estazolam, buspirone, flazodazole, lorazepam, clomiprazole, metaxalone, beta chlorophenidate, etidazolam, Fludisazine.
  • Antidepressant drugs amitriptyline, amoxapine, bupropion, opipadol, desipramine, dexmedeline, fluvoxamine, fluoxetine, carbipipamine, chlorine Mipamamine, Maprotiline, Mianserin, Paroxetine, Methylphenidate, Protriptyline, Trimemamine, Sertraline, St. John's Wort Extract, Veloxacin, Venlafa Xin, Sibutramine, Citalopram, Icaroline.
  • An antiepileptic drug oxcarbazepine, bequesamine, phenytoin, valproic acid and its sodium, magnesium salt, methyl ethyl ketone, carbamazepine, casinitide, lamotrigine, riluzole, primidone , Topiramate, esadiazepine, ethecoxibine, etoposide, ethosuxamine, zonisamide, tiagabin, mefentoin.
  • a sedative, hypnotic, anticonvulsant and others oxazuron, barbital, phenobarbital, glutamine, quetiapine, niazophenone, gastrodin, bromoisoval, relying on Mimidate, acetyl gastrodin, zaleplon, zopiclone, zolpidem, betahistine, vincamine, flunarizine, flumethenone, fluentil, cyclomandelate, pentoxifylline , meglumine dihydroergotamine, rizatriptan, mesalamine, naratriptan, nicotinol, nigralin, kallikrein, niacin, iripusone, eletriptan , epoprostenol, isoprozol, papaverine, zolmitriptan, levetiracetam.
  • Autonomic nervous system drugs arololol, aplolol, atenolol, esmolol, benzaltropium, bisoprolol, scopolamine, metoprolol tartrate, carteolol, carvedil Lo, Labetalol, Metoprolol, Mopelol, Moseselli, Nadolol, Anisodamine, Celilol, Cedarol, Thiololol, Tamsulosin, Sotalol, yohimbine, anisodine, carvedilol, tamsulosin, tropicamide, bromopropylamine.
  • a circulatory system drug is a circulatory system drug
  • One calcium antagonist anipamil, benidipine, benidipine, bepridil, valparaprin, faripamil, cinnarizine, lacidipine, manidipine, thiophane, dimension Lapami, right Vera Paimi.
  • a drug for the treatment of chronic heart failure Bradyxin, Digoxin, Dinomamine, Poisonin, Dobutamine, Instruction manual
  • An antiarrhythmic drug aprilin, amiodarone, pyridoxine, propiamine, flecainide, quinidine, modicani, orexizine, procainamide, propa Ketone, ivabradine, itraconi, tocic bromide, mexiletine, stenicai.
  • a drug for preventing and treating angina pectoris oxyxitox, isosorbide mononitrate, ligustrazine, diltiazem, tetrabutyl nitrite, hysopidine, cyclophosphamide, levopraz, musk ketone, dipyridamole, pentaerythritol Nitrate, nitroglycerin, imoramin, etanoterone, cyclic adenosine.
  • Peripheral vasodilator apovinamine, vincamine, pinacidil, vinpocet, vinorelbine, dagapamil, buflomedil, fasudil, golopamil, hydralazine , kalazine, minoxidil, nicorandil, naproxil, tripidil, diterpenoid, urapidil, bromo-vincoamine, nicotinic acid inositol, enalappine, isopropanol, Isosaramine, poppy peony, valvadil, left emolim, zoelepine.
  • a blood pressure lowering drug alfuzosin, alapril, analipide, amlodipine, betaxetidine, benazepril, octapeptide, bunazosin, diazepam, dilapid Lee, Delilorol, Butyzolamine, Doxazosin, Irbesartan, Felodipine, Fosinopril, Tetrandrine, Methyldopa, Daidzein, Tartrate Tartrate, Card Topily, candesartan, quinapril, clonidine, lisinopril, ramipril, limonidine, lishepine, spiropril, lofexidine, mecaramine, Nilvadipine, nicardipine, nimodipine, nitrendipine, nisoldipine, pagilin, perindopril, trandolapril, terazosin, temocap
  • Regulating blood lipids and anti-atherosclerosis drugs atorvastatin, acixil, phenylpropanolamine, benzepressin, bezafibrate, pikacin, benzyl chloride, darvastatin, Elastase, dopamine, dopamine, fenofibrate, fluvastatin, ciprofibrate, gemfibrozil, colestipol, cholestyramine, kevastatin, clebate, lysibine , clofibrate, clofibrate, lovastatin, mevastatin, nicaratin, niketabate, pravastatin, probucol, cerivastatin, simvastatin, linoleic acid , Yiduoester, dextrothyroxine, hyodeoxycholic acid.
  • a respiratory system drug aminophylline, ambroxol, oxycin, oxicillin, benproperine, bitoterol, benzonatate, pyrbuterol, sodium zoate, dimethoate Ester, putotropine, erdosteine, fenoterol, forcodine, hexolin, clenbuterol, chlorobutano, mabuterol, montelukast, picotazide Lin, terbutaline, guaifenesin, guaiacol sulfonate, zaloterol, levopropoxyphene, isomirier, acetylcysteine, ketotifen, terbutaline, Trolotrol, epradolone, terpineol.
  • a digestive system drug is a digestive system drug
  • An antacid and a peptic ulcer drug omeprazole, balsalazide, ornoprost, enprostin, famotidine, galac aluminum, bismuth potassium citrate, lansoprazole, Rabeprazole, sucralfate, aluminum-magnesium plus, barium aluminate, magnesium aluminum carbonate, rosaprost, roxatidine, misoprostol, nizatidine, pirenzepine, Pronoto, Pantoprazole, Traxapat, Sophorone, Tirenoxapine, Vitamin U, Isoladine, Ekabit.
  • Gastrointestinal antispasmodic Adifenin.
  • a helper digestive drug oxcarbin, trypsin amylase, citric acid, carnitine, pepsin, cisapride, trypsin, trypsin, pancreatic lipase.
  • An antiemetic, emetic, and gastrointestinal drug ondansetron, domperidone, granisetron, metoclopramide, clopirol, tolztron, itopride, bergenin, sulpiride , quercetin, lystron, lintobili, mojistan, mosapride.
  • Auxiliary medication for hepatobiliary diseases olamimet, chenodeoxycholic acid, non-bupropanol, anthranil, inositol, inosine, biphenyl diester, leucovorin, tiopronin, lipoic acid, marlow Terephthalate, glucurolactone, oleanolic acid, hydroxymethyl coumarin, hydroxymethanolamine, dehydrocholic acid, sodium dehydrocholate, deoxycholic acid, lactulose, silybin, silymarin, Sianiol, adenosylmethionine, ursodeoxycholic acid, sodium protoporphyrin.
  • a urinary system drug amiloride, azosemide, triamterene, bethiazine, polibizine, bumetanide, Instruction manual
  • Pyrrhotanib furosemide, cyclopentazine, clonsophan, spirronone, metyrapone, spironolactone, mefsit, lysine, indapamide, epitazine, yi Soxazole, etanic acid, sodium citrate, etazozoline, thiazide, acetazolamide, isopropyl iodide, isopamine, desmopressin, diclofenac, Purrexone, metyrapone.
  • a drug that affects the blood and hematopoietic system sarpogrelate, bis-coumarin, ethyl acetophenone, warfarin, benzoquinone, acenocoumarol, ferrous sulfate, ferrous gluconate, ar Calcium folate, folic acid, iron dextran, mecobalamin, ferrous fumarate, iron glucoheptone, sodium ferulate, nucleotides, anethole, valerate, squalyl alcohol, chloramine, aca Dixin, anagrelide, aprostin, ozagrel, beraprost, picogreline, dalgregre, dazooxaphene, furoic acid, limatoprost, clopidogrel, rolagrel, imidazole , motodipine, narfagre, pamidrex, alprostadil, trox rutin, ticlopidine, tribe
  • Primary antihistamines avastin, alimazine, astemizole, oxapramine, oxomamycin, diphenhydramine, benzoguanamine, propionylazine, bupizine, tea benzene Hamming, promethazine tea, azelastine, diflupromide, dolastatin, doxylamine, embramin, febrinamide, fexofenadine, dimethylformidine , loratadine, clemastine, cloperastine, chlorpheniramine maleate, mepyrazine, meclozine, mequitazine, niprazine, cyproheptadine, stastatin, Ebastine, estramustine, epilin, bromophenamine, zafirlukast, levocabastine.
  • An allergic reaction medium release agent and others azastatin, amlexanox, lodosamide, tranilast, cromolyn, cetirizine, zapastast, pkromi, pu Hydrazine, his zastel.
  • An adrenocortical hormone and adrenocorticotropic hormone difluxate, dexamethasone, methylprednisolone, prednisone, cortisone, triamcinolone.
  • Sex hormones and gonadotropins bicalutamide, estrone, estriol, medroxyprogesterone acetate, danazol, prazzab, flutamide, diethylstilbestrol, hexaerythritol, diethylstilbestrol, nail Progesterone, medroxyprogesterone, raloxifene, nilutamide, gestrinone, toremifene, stanozolol, norgestrel.
  • Islet hormones and other drugs that affect blood sugar acarbose, pioglitazone, metformin, voglibose, glibenclamide, glibenclamide, glipizide, glibenclamide, glibenclamide, lattice Derivazolone, glimepiride, gliclazide, tolbutamide, miglitol, troglitazone, repaglinide, tolazamide.
  • a thyroid hormone drug and an antithyroid drug oltipreline, botinidrine, nitrexine, liothyronine, dibromotyrosine, thyropropionate, thyroidine, thyroglobulin, montetine Relin, miprazole, diiodotyrosine, telazocine, levothyroxine, levothyroxine sodium, aminothiazole, propylthiouracil, iodothiouracil, methylthiouracil, methimazole, Carbazole, thiazoline.
  • a penicillin amoxicillin, ampicillin, bamcillin, oxacillin, flucloxacillin, hetacillin, cyclohexillin, sulfacillin, carbocillin, cloxacillin, lenazocillin, nafcillin , pirazicillin, pimecillin, penicillin ⁇ , sultamicillin, diclocillin, and acesulfame.
  • Cephalosporins chlorocarbon cephalosporin, cephalexin, cefprozil, cefpodoxime, ceftibuten, cefaclor, cefaclor, cefradine, cefradine, ceftriaxone, cefadroxil, cefacitdine, cephalosporin Telun, cefdinir.
  • Beta-lactamase inhibitors clavulanic acid, sulbactam, bromobactam.
  • Aminoglycosides Paromomycin, kanamycin, gentamicin, neomycin.
  • One tetracyclines and others dimecycline, doxycycline, indomethacin, metacycline, minocycline, oxytetracycline, tetracycline, chloramphenicol.
  • Macrolides azithromycin, oleandomycin, dirithromycin, erythromycin, erythromycin ethylsuccinate, guitarmycin, josamycin, clarithromycin, roxithromycin, rosacea , spiramycin, melamycin, medimycin, erythromycin, erythromycin, acetylspiramycin.
  • antibacterial agents levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, polymyxin £, clindamycin, lincomycin, fosfomycin, micammycin, mold , yellow saponin, berberine, gentian, houttuyfonate sodium.
  • Antituberculosis drugs pyrazinamide, salicylic acid, sodium salicylate, propionamide, cycloserine, rifabutin, rifapentine, rifampicin, ethambutol, isoniazid .
  • An antifungal drug flucytosine, fluconazole, griseofulvin, miconazole, itraconazole, ketoconazole, nystatin.
  • An antiviral drug acyclovir, famciclovir, valaciclovir, lamivudine, ribavirin, morpholinium, zidovudine, deoxyfluorouridine, didanosine, zhaxi coast.
  • Antineoplastic agents busulfan, cyclophosphamide, lomustine, semustine, thioguanine, guanidine, idarubicin, aminoglutethimide, tamoxifen, anastrozole, procarbazine Quinoa, cantharidin, capecitabine, letrozole, melphalan.
  • Drugs that affect the body's immune function acetalivir, propacetam, azathioprine, imidazolyl, tacrolimus.
  • a protein DNase, alginate, superoxide dismutase and lipase, peptide, oligopeptide.
  • Vitamins and nutrients vitamins A, B, C, D, E, K, etc. and their derivatives, amino acids;
  • a diet pill Amiris, amfepramone, amphetamine, amphetamine, oltipamine, fenfluramine, phenyltol, benzethetamine, propylhexidine, p-chloro Phentermine, non-Nyles, fenbufen, fluramine, fenmetrazine, fenpres, phentermine, furfurex.
  • One other drug finasteride, alendronate, alosetron, orlistat, eric acid, epalrestat, tolterodine, torista, herbal extracts.
  • More preferred examples of the medicament for use in the present invention include, but are not limited to, LEC0Z0TAN (SRA-333), amoxicillin, amoxicillin-clavulanate potassium compound, asdamamo, aspirin-phosphoric acid ligustrazine compound, aspirin-dipyridamole Mo Fufang, piperazine ferulate, acyclovir, paracetamol-pseudoephedrine-d-butenoic acid dextrobromide compound, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, Aceclofenac, isosorbide mononitrate-aspirin compound, isosorbide mononitrate, diazepam, metformin-roglitazone combination, famciclovir, felodipine, fenofibrate, pseudoephedrine hydrochloride pseudoephedrine Compound, fluvastatin sodium, acyclovir
  • the controlled release preparation in particular the osmotic pump type controlled release preparation, can simultaneously push out various components of the herbal extract, and there is no problem that the release of the active ingredients is not synchronized due to the different nature of the ingredients, Therefore, the controlled release preparations, particularly the osmotic pump type controlled release preparations, to which the present invention relates are particularly suitable for use in controlled release Chinese herbal extracts.
  • the actives useful in the present invention include the pharmaceutically acceptable salt forms, free acid forms, free base forms, hydrates, various crystal forms, and optical isomers of the following active ingredients.
  • the core material may also contain other pharmaceutical auxiliaries such as slow release materials, porogens, fillers, binders, disintegrants, disintegrators, lubricants (including glidants, anti-adhesion).
  • An agent an osmotic pressure active substance (ie, an osmotic pressure promoter), a permeation-promoting polymer (a penetration enhancer), and the like.
  • it may also contain solubilizers, suspending agents, sweeteners, aromas, pigments, absorbents and surfactants (such as wetting, dispersing, solubilizing, emulsifying, etc.).
  • Pharmaceutical auxiliaries and their use are selected by those skilled in the art based on actual conditions such as the nature of the drug, the desired rate of drug release, and the like. The basic steps in the preparation method of the controlled release preparation are described in detail below.
  • the preparation method of the core material used in the present invention is not particularly limited in the present invention.
  • the core preparation method may employ a direct extrusion method, a dry, wet or sintered particle extrusion method, extrusion and subsequent rounding, wet or dry granulation or direct pelleting (for example on a disk).
  • a method of bonding a powder (powder layer) to a sphere (particle) of an inactive material or a particle containing an active material, or a method of forming a tablet in a certain manner such as pressing, or a mixture of the above methods may be employed.
  • Coating step a solution or aqueous dispersion of a polymer which is insoluble or hardly soluble in water and a digestive liquid containing a substance which can be sublimed and/or which can be degraded into a harmless gas and a polymer reinforcing agent.
  • the sublimable substance and/or the substance which can be degraded into a harmless gas is insoluble or hardly soluble in the solution or aqueous dispersion of the polymer, and the polymer and the polymer reinforcing agent
  • the contact angle is below 90°.
  • the step of coating the coating film of the core material containing at least one biologically active substance usually includes the following steps (process).
  • other polymer coating film controlled release film
  • general additives such as polymer plasticizer may be added, and even bioactive substances may be added, and the mixed coating liquid may be uniformly mixed.
  • the above-mentioned sublimable substance and/or a substance which can be degraded into a harmless gas is insoluble or hardly soluble in a solution or an aqueous dispersion of the above polymer, and the contact angle of the above polymer with the polymer reinforcing agent is low. At 90°.
  • the solvent or dispersing agent of the above polymer is a pharmaceutically acceptable organic solvent and water or a mixture thereof.
  • the organic solvent can be used as the organic solvent a solvent for the above polymer; when the above sublimable substance and/or a substance degradable to a harmless gas is insoluble or hardly soluble in water, water is preferably used as a dispersing agent for the polymer, that is, a polymer is selected. Aqueous dispersion.
  • Organic solvents which may be used in the present invention include, but are not limited to, ethanol, propylene glycol, tetrahydrofuran, n-butanol, 2-butanol, methyl ethyl ketone, propyl acetate, isopropyl acetate, ethyl formate, pentamidine, n-propanol, 2-propene Alcohol, dichloromethane, acetone, diethyl ether, methyl ethyl ether, ethyl acetate, methyl acetate, and mixtures thereof.
  • the content of the above polymer in the organic solution is usually from 0.5 to 12%, preferably from 1 to 8%, more preferably from 2 to 5%.
  • the content of the above polymer in the aqueous dispersion suspension is usually from 5 to 30%, preferably from 8 to 20%, more preferably from 10 to 15»/. .
  • preparing a coating layer of the above-prepared core material by a coating method such as melting, casting, painting or spraying by using the mixed coating liquid obtained above. It is preferably carried out by spraying.
  • the film formation process is carried out by energy input independent of the coating method. This can be done by convection (heat), radiation (infrared or microwave) or conduction. Thereby, the organic solvent or water used as a solvent or a suspending agent for coating is evaporated, and if necessary, vacuum accelerated evaporation may be applied. This process requires high drying efficiency, so the present invention often employs high efficiency coating equipment (e.g., fluidized bed, high efficiency coating pan).
  • high efficiency coating equipment e.g., fluidized bed, high efficiency coating pan.
  • the surface temperature of the core should be higher than the minimum film forming temperature (MFT) of the polymer.
  • MFT minimum film forming temperature
  • the minimum film forming temperature refers to the lowest temperature at which the polymer forms a continuous film. Below the minimum film forming temperature, the polymer particles cannot be deformed. Fusion film), usually higher than the minimum film forming temperature of 10 ⁇ 20 ° C, but the surface temperature of the core material should not be so high that some substances in the coating material are completely softened or melted to cause adhesion of the film, and should not Some of the components in the core material are completely softened or melted or degraded.
  • the surface temperature of the core material should not be so high that the sublimable material of the coating material and/or the substance degradable into a harmless gas can be sublimated and degraded. Therefore, the surface temperature of the core material is preferably lower than the melting point of the sublimable substance and/or the substance degradable to a harmless gas or its sublimable or degradable temperature is at least 10 ° C, more preferably 20 ° C , optimally 30 ° C.
  • the surface temperature of the core material can not be too low in the present invention, because the surface temperature of the core material is too low, the coating film is brittle and cracks may occur, which affects the release characteristics of the preparation; meanwhile, the surface temperature of the core material cannot be too high, because the surface temperature of the core material is too high. Excessive softening of the polymer leads to adhesion of the film, and also causes sublimation and degradation of the sublimable substance and Z or a substance degradable into a harmless gas, which is prematurely lost from the film.
  • the core material When coating, the core material is usually preheated (the temperature is relatively low when the polymer organic solution is used, and the temperature is relatively high when the polymer aqueous dispersion is used) to 20 to 70 ° C, preferably 30 to 60 ° C. More preferably 30 ⁇ 50 ° C, first coating at a lower spray rate, after the surface of the core material has been coated with a thin film, and then increasing the spray rate to the end of the coating, this operation can avoid solvents especially It is the dispersant (water) that penetrates into the core material, causing changes in the properties of the core material during storage.
  • the dispersant water
  • the most suitable or suitable process parameters are determined by those skilled in the art based on the coating material and core properties and experimental results.
  • the fluidized bed coating is used for pouring, and the process conditions such as coating temperature, fluidizing air volume, atomization pressure and liquid spraying rate can be optimized according to actual conditions.
  • nitrogen can be used to replace the air in a confined environment such as a closed enclosure.
  • the porogenic substance in the coating film needs to be volatilized to obtain a film having a porosity which is satisfactory in controlling the release rate.
  • the porogen is volatilized, usually at a temperature lower than the glass transition temperature of the film and under normal pressure, reduced pressure or vacuum, preferably at a temperature below 5 ° C below the glass transition temperature of the film, most Preferably, it is carried out at a temperature below 10 ° C below the glass transition temperature of the film. Too high a temperature may cause the formed micropores to shrink or even heal completely, and the most severe cause adhesion of the coating.
  • the present invention is intended to improve the stability of drug release of the formulation, preferably during the step 2) (coating) and/or after the step 2) (coating), and before the step 3) (without the porogen)
  • the above-mentioned coating film is healed to eliminate a large number of tiny pores in the coating film during the coating process and form a dense coating film to ensure relatively stable drug release.
  • the solvent or dispersant of the polymer in the film is substantially volatilized, leaving many tiny pores in the film, and the polymer particles in the film are often not completely fused. It is believed that under the action of the micropore additional pressure ( ⁇ ⁇ ) generated by the interfacial tension between the polymer and the air, these tiny micropores are automatically and gradually reduced, and fusion occurs during storage to make the membrane permeability. Constant changes occur, making the drug release behavior of the formulation unstable.
  • ⁇ ⁇ micropore additional pressure
  • ⁇ polymer - air surface tension ( ⁇ ⁇ )
  • r micropore radius
  • the time required is usually related to the pore size of the membrane, the interfacial tension between the polymer and the air, and the like.
  • Polymer - When the surface tension of the air is constant, the smaller the micropore diameter of the membrane, the larger the additional pressure of the micropores, the shorter the time required for fusion, the larger the pore diameter of the membrane, the smaller the additional pressure of the micropores, and the longer the time required for fusion. Because of this, the present invention employs relatively large pores to control release of the drug and eliminates numerous tiny pores resulting from evaporation of the solvent or dispersant during the coating process.
  • the invention is characterized in that it has sublimation in a film having an ascending component or a degradation in a film which is degradable into a harmless gas.
  • the microporous controlled release drug release is formed, and these relatively large micropores still produce a certain micropore additional pressure (AP) during the healing process, so that the micropore is reduced to some extent (for example, when the micropore is less than 30 nm) , especially when it is less than lwm).
  • AP micropore additional pressure
  • the healing process is reduced, the stability of the permeability of the film is improved (related to the release performance), and the production reproducibility is improved.
  • the stability and production reproducibility of the mechanical properties of the film, in the present invention, the film healing process is optimally before the formation of relatively large pores for controlled release of the drug (ie, the wave-forming hole Material before) is completed.
  • the healing process is completed before the porogen is removed. Compared with the porogen and the healing process, the healing process has many incomparable advantages after the porogen is removed.
  • the healing process is performed simultaneously with the wagging substance and the healing process is performed after the porogen is removed or the end of the healing process is not achieved, or although the healing reaches the end point, the drug release is very slow or even non-released.
  • the micropores that have been formed, including controlled release of the drug are constantly shrinking or even completely closed, and the permeability or release properties, mechanical properties, etc. of the film are difficult to stabilize and reproduce. .
  • the healing process can be completed before the porogen is removed, so that the sublimable and/or degraded porogen can be kept in the film at all times, so as to avoid the release of micropores produced by the porogen. It shrinks during the healing process, and the film can be completely healed. It can completely eliminate many tiny micropores produced by solvent evaporation during the coating process and form a dense film to stabilize, reproduce and improve the clothes. Membrane permeability or release properties, mechanical properties, etc.
  • the curing treatment includes the following process: after the solvent or dispersant (water) in the above film is substantially evaporated, the core of the coated polymer film is placed in a closed environment. At a temperature of the glass transition temperature of the above film, which is long enough to reach the end point, the polymer particles in the coating film of the above formulation are completely or substantially completely fused, and the micropores formed during the coating process are eliminated or substantially eliminated.
  • the fully dense or substantially intact dense film, the permeation performance or the release property of the above controlled release film reaches a stable state or a substantially constant state.
  • the above-mentioned coating preparation is healed at a temperature higher than the glass transition point of the above film until the preparation is at a temperature of, for example, about 40 ⁇ 2 ° C and not less than 50% and not higher than the above.
  • Sublimated material particles and/or substances that can be degraded into harmless gases (hygroscopic) are placed under accelerated storage conditions at a relative humidity of 3 months and/or 6 months or longer, such as 9 months or 12
  • the dissolution characteristics of the month are basically unaffected.
  • the in vitro dissolution of the biologically active substance immediately after the healing treatment is at a temperature of about 40 ⁇ 2 ° C and not less than 50% and not higher than the above-mentioned sublimable substance particles and / or degradable into harmless
  • the healing treated coating formulation has stable dissolution characteristics.
  • stable means that the dissolution in vitro is within acceptable limits compared to the dissolution characteristics of a cured coating formulation, which is acceptable to regulatory agencies such as the China Food and Drug Administration. The US Food and Drug Administration et al.
  • the above dissolution test preferably employs all of the components contained in the above-mentioned controlled release polymer coating film (but does not include the above-mentioned water-soluble porogen substances (i.e., the above-mentioned sublimable substance particles and/or substances which can be degraded into harmless gases).
  • Particles here is the release medium (dissolution medium) which is required to dissolve the pores and which is saturated with all of the above components.
  • the net dissolution amount of all the components in the controlled release polymer coating film is 0 in the above dissolution test (excluding the above water-soluble porogen Dissolution), thereby facilitating the judgment that the dissolved drug is eluted from the micropores of the original controlled release polymer coating film rather than being dissolved in the micropores produced by the dissolution of the components therein, since it is more advantageous to judge the above controlled release
  • the polymeric film has healed completely or has reached the end state or has healed substantially completely or has been substantially to the end state.
  • the time required for the healing treatment is usually several tens of hours or longer.
  • the temperature selected for the healing treatment should be higher than the glass transition temperature of the coating film, preferably higher than the glass transition temperature of the coating film by 10 ° C or higher, more preferably higher than the glass transition temperature of the coating film by 20 to 30 ° C, and healed.
  • the selected temperature is treated and should be such that the ingredients in the coating material are not completely softened or melted or the film adhesion does not occur. It is preferable to use a certain humidity during the healing treatment, and the glass transition temperature of the controlled release coating film is significantly lowered by the action of moisture or moisture, thereby facilitating the accelerated healing treatment.
  • the selected humidity is usually not lower than 50% relative humidity, preferably not lower than 60% relative humidity, and more preferably not lower than 70% relative humidity.
  • the selected humidity is usually not too low, because the humidity is too low. The healing process takes a long time.
  • the selected humidity is usually generally not higher than the above-mentioned sublimable substance particles and Z or the (hygroscopic) critical relative humidity of the substance degradable into a harmless gas, because it is higher than the above. Description
  • the above-mentioned sublimable substance particles and/or substances degradable into harmless gases may significantly absorb moisture, particularly water solubility.
  • Sublimable material particles and/or substances which can be degraded into harmless gases, and the above-mentioned sublimable substance particles and/or substances which can be degraded into harmless gases will exhibit partial or total dissolution-crystallization after significant moisture absorption, thereby It may precipitate from the film, and the phenomenon of "pan-cream" may appear, which may cause the release micropores to shrink during the healing process and affect the stability of drug release.
  • the above-mentioned sublimable substance and/or the refractory substance which can be degraded into a harmless gas in the above polymer film are not reduced in net solid content.
  • the micropores are prevented from being smaller than expected, or the above sublimable substances and/or degradable into harmless gases are caused.
  • the net solid content of the pore material is not reduced, thereby further preventing the inter-batch variability of the microporous with the same batch of porogen, improving the production reproducibility, stability and release rate of the preparation, usually healing treatment
  • the equilibrium partial pressure of the sublimable porogen which is greater than or equal to the conditions, such as temperature, and/or the equilibrium partial pressure of all degradation products of the refractory porogen at greater than or equal to the conditions such as temperature. Performing at or below a temperature below the lowest degradation temperature of the degradable porogen, such as under pressure, during which the above-described sublimable and/or degradable in the polymer film is The net solids of the porogenic material of the harmless gas will not decrease.
  • the equilibrium partial pressure of a porogen means that the porogen in the gas phase (or all of its degradation products) and the porogen in the solid phase are in equilibrium at a certain temperature in a closed environment.
  • the partial pressure at which the solid or net reduction of the pore material is zero.
  • it is common practice to blow (charge) a sublimable porogen in a closed environment eg, a closed enclosure.
  • a sublimable or degradable porogen that is in excess ie, usually has a portion of the balance of solids present, raised at a temperature for a period of time to allow degradation of the porogen or degradable porogen in the gas phase It is in equilibrium with the sublimable porogen or the degradable porogen in the solid phase.
  • the healing treatment can be carried out by heat treatment such as an oven and a fluidized bed.
  • the fluidized bed heat treatment has the characteristics of high efficiency and time saving, and the coating and heat treatment operations can be completed in the same equipment, and the industrial applicability is high.
  • the temperature of the system is raised, and the material is continuously fluidized and dried in the same fluidized bed apparatus, which promotes the healing of the membrane in a short time.
  • the fluidized bed method compared with the oven mode, the fluidized bed method has higher requirements on the mechanical properties of the film, and the degree of film healing is relatively low after heat treatment. Therefore, the present invention preferably employs an oven heat treatment method.
  • the preparation prepared by any of the above methods may be coated with a thin layer of water-soluble coating material to improve the surface integrity of the preparation or prevent the preparation from sticking to each other during storage or to prevent or delay the release of micropores during storage.
  • Suitable coating materials include, but are not limited to, disaccharides such as sucrose, polysaccharides such as maltodextrin and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose, however, any coating It should be sufficiently thin and water soluble so as not to interfere with the release properties of the formulation. After the thin layer is coated, the water-soluble coating material partially seals the release pores and leaves the release micropores (occupying the original part of the air), so that the formed release micropores are (size) stable. effect.
  • the pharmaceutical dosage form prepared by any of the above methods can be used substantially directly, such as directly orally.
  • the granules, pellets or granules prepared as described above may also be filled into a gelatin capsule, a pouch (small sachet) or a suitable multi-meter container by means of a metering device. If possible, it is obtained by pressing after mixing with other auxiliaries.
  • the preparation is decomposed after taking it, and most of the coated small units are released. It is also conceivable to embed the aggregates in polyethylene glycol or lipids to prepare a test or vaginal dosage form.
  • the coated tablets are packaged in semi-spherical containers or multi-dose containers and taken directly before administration.
  • Diltiazem hydrochloride, lactose, hydroxypropylcellulose and povidone are uniformly mixed and granulated with ethanol; the wet granulated material is forced through an 18-mesh sieve and dried for 24 hours; after the granules, magnesium stearate is added.
  • the sheet was pressed with a standard concave circular die of 12 mm, using a pressing force of 1200 to 2000 kg and a pressing time of 2 s. The hardness is 6 ⁇ 10kg.
  • the core of the film is coated according to the following prescriptions and techniques:
  • Salicylic acid (61 ⁇ 80 ⁇ ⁇ ) 37. 05
  • the cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50 ⁇ 60 ° C; outlet temperature, 40 ⁇ 42 ° C; core temperature 40 ° C; core weight gain 16%.
  • a water-soluble film coat is applied before the above-mentioned controlled release film.
  • the coating material for the water-soluble film coating was 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52 ° /.
  • the water-soluble film coat has a weight gain of about 1%.
  • the healing treatment is carried out in a closed oven.
  • the tank is filled with a sufficient amount of salicylic acid (that is, there is always a surplus of solids).
  • hot air containing a saturated amount of salicylic acid gas at a temperature of 65 ° C was charged.
  • the healing temperature was 50 ° C and the healing time was 56 hours.
  • the salicylic acid in the film was removed at a temperature of 20 ° C and an approximate vacuum.
  • Example 2 The surface of the coating liquid was removed by the stearic acid-coated calcium carbonate, and the others were unchanged. The same procedure as in Example 1 was carried out.
  • Example 2 and Comparative Example 2
  • Adding 5% solution of acetic acid to ethyl acetate monoacetate (95:5) as an oil phase using 3 mg/ml aqueous solution of sodium sulfonate as the aqueous phase; using a high-speed emulsion homogenizer, stirring
  • the water phase is slowly added dropwise to the oil phase at a speed of not less than 3000 rpm to form a W/0 type emulsion, and the dropwise addition is continued until a 0/W type colostrum is formed.
  • the colostrum was passed through a high pressure homogenizer for 6 times.
  • the organic solvent was removed from the obtained emulsion using a rotary evaporator at 40 ° C under reduced pressure.
  • the controlled release film is coated with a moisture barrier protective coating.
  • the coating for the moisture barrier protective coating is a suspension containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. . Coating conditions Parameters: Spraying time is about 20 seconds, blasting time is about 30 40 seconds, blasting temperature is 50 55 °C, core temperature is 30 40 °C, moisture barrier coating weight gain is about 1%
  • Ethyl vanillin 60 80 mesh
  • polyacrylate-coated nano-alumina dispersion slurry (average diameter 10 nm, contact angle ⁇ with coated polymer) were added to the cellulose acetate aqueous dispersion prepared above. 70 ° ) and as a plasticizer diacetin, wherein cellulose acetate: ethyl vanillin: nano alumina (by dry weight): diacetin is 1: 2 : 0. 06 : 1 (Weight ratio), a coating liquid was prepared by diluting with water to a suspension containing 3% cellulose acetate. The core-coated release film was coated with the prepared coating liquid. Controlled release film coating weight gain of 18%
  • Coating with a timed automatic film coater the coating conditions are: spraying time of about 20 seconds, blasting time of about 30 40 seconds, blast temperature 50 70 ° C, core temperature 45 50 ° C
  • the healing treatment is carried out in a closed oven.
  • the oven contains a sufficient amount (ie, there is always a residual solids) of ethyl vanillin.
  • the healing air was filled with hot air at a temperature of 70 ° C containing a saturated amount of ethyl vanillin gas.
  • the healing temperature was 65 °C and the healing time was 64 hours.
  • the ethyl vanillin in the coating film was removed at a temperature of 35 ° C and an approximate vacuum.
  • Comparative Example 2 was prepared according to the method of Example 2 Example 3 and Comparative Example 3
  • diltiazem hydrochloride, sodium dihydrogen citrate and povidone are uniformly mixed and granulated with an anhydrous ethanol solution; the wet granulated material is forced through an 18-mesh sieve and dried for 24 hours; after the granules, stearin is added.
  • the magnesium acetate was mixed and pressed with a standard concave circular die of 12 mm, using a pressing force of 1200 to 2000 kg and a pressing time of 2 s. The hardness is 6 ⁇ 10kg.
  • the core of the film is coated according to the following prescriptions and techniques:
  • Methyl methacrylate-styrene copolymer 2. 52. 52
  • Methyl methacrylate / styrene copolymer (MMA / ST), wherein the methyl methacrylate content is about 52%, the styrene is about 48%, and the contact angle with the coated polymer is 12 °.
  • the cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50 ⁇ 60 ° C; outlet temperature, 35 ⁇ 37 ° C; core temperature 36 ⁇ 38 ° C; core weight gain 12. 6%.
  • the healing process is carried out in a closed supply tank.
  • the oven has a sufficient amount of benzoic acid (ie, there is always a residual solids).
  • hot air containing a saturated amount of benzoic acid gas at a temperature of 50 ° C was charged.
  • the healing temperature was 45 ° C and the healing time was 48 hours.
  • the benzoic acid in the film was removed at a temperature of 20 ° C and an approximate vacuum.
  • Example 4 The methyl methacrylate/styrene copolymer (Li A/ST) in the coating liquid formulation was removed, and the others were unchanged.
  • a sample of Comparative Example 3 was prepared according to the method of Example 3.
  • the core of the film is coated according to the following prescriptions and techniques:
  • PARALOID BPM-500 is a nano-sized acrylic hard shell-soft core structured impact modifier produced by Rohm and Haas.
  • the contact angle with the coated polymer 9 is determined as ⁇ .
  • the cores were coated on a Hicoater/Fruend coater. 6% ⁇ The coating temperature parameters: inlet temperature, 50 ⁇ 60 ° C; outlet temperature, 30 ⁇ 35 ° C; core temperature 31 ⁇ 36 ° C; core weight gain 12.6%.
  • the healing treatment is carried out in a closed oven.
  • the oven contains a sufficient amount (i.e., there is always a residual solids) of tert-butyl p-hydroxyanisole.
  • hot air containing a saturated amount of tert-butyl-p-hydroxyanisole gas at a temperature of 50 °C was charged.
  • the healing temperature was 45 °C and the healing time was 60 hours.
  • the tert-butyl p-hydroxyanisole in the film was removed at a temperature of 10 ° C and an approximate vacuum.
  • the core of the film is coated according to the following prescriptions and techniques:
  • ⁇ methyl methacrylate-butadiene-styrene terpolymer (MBS), wherein the polybutadiene content is about 70%, the styrene content is about 20%, the methyl methacrylate content is about 10%, and the coating
  • the contact angle ⁇ of the polymer was determined to be 47°.
  • the cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50 ⁇ 60 ° C; outlet temperature, 40 ⁇ 42 ° C; core temperature 40 ° C; core weight gain 16%.
  • a water-soluble film coat is applied before the above-mentioned controlled release film.
  • the coating for water-soluble film coating was an aqueous solution containing 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. Coating conditions parameter inlet temperature, 55 ° C; outlet temperature, 30 ° C. The water-soluble film coat has a weight gain of about 1%.
  • Dit-butylhydroxytoluene in the film was removed at a temperature of 15 ° C and an approximate vacuum.
  • Example 6 The methyl methacrylate-butadiene-styrene (MBS) in the coating liquid formulation was removed, and the others were unchanged.
  • a sample of Comparative Example 5 was prepared in the same manner as in Example 5.
  • simvastatin, carbopol, sodium citrate, lactose and polyvinylpyrrolidone ground through a 200 mesh sieve, and use a 10% (by weight) aqueous solution of ethanol (containing the desired hydrazine). Granulation is carried out. The wet material was sieved through a 18 mesh screen and dried overnight. The whole pellet was lubricated by adding magnesium stearate. The uniform mixture was pressed with a 1/4 inch standard concave circular tool. The pressing force was 1000 lbs. . The tablet after pressing has a thickness of 3.89 mm and a hardness of 8-10 kg.
  • a water-soluble film coat was applied to the core piece by a timed automatic film coater.
  • the coating material for the water-soluble film coating was an aqueous solution containing 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc.
  • the water-soluble film coat has a weight gain of about 2%.
  • MMS Methyl methacrylate-butadiene-styrene
  • ⁇ methyl methacrylate-butadiene-styrene (MBS), wherein the content of butadiene is about 70%, the content of styrene is about 15%, the content of methyl methacrylate is about 15%, and the contact with the coated polymer
  • the angle of ⁇ was determined to be 16°.
  • a 120 mm thick coating was applied to the tablets using a Freand type HCT micro high performance coater (8 inch disc).
  • the urea in the film was removed at a temperature of 30 ° C and an approximate vacuum.
  • Example 7 The sample of Comparative Example 6 was prepared by the method of Example 6 by removing the polymethyl methacrylate (PMMA) from the coating liquid formulation and leaving the others unchanged.
  • PMMA polymethyl methacrylate
  • Example 7 The polyacrylate-coated nano-alumina dispersion slurry of Example 2 was replaced with an equal-weight (dry weight) methyl methacrylate/styrene copolymer latex (average particle size of about 15 nm, wherein, methacrylic acid The ester content was about 60%, the styrene content was about 40%, and the contact angle with the coating polymer was determined to be 39°.)
  • Example 7 was prepared in the same manner.
  • Example 8
  • Example 8 Replace only the polyacrylate-coated nano-alumina dispersion in Example 2 with an equal-weight (dry weight) Elvaloy® HP 662 latex (ethylene/butyl acrylate/carbonyl (carbon monooxide) terpolymer, average The particle size was about 60 nm, and the contact angle with the coated polymer was measured to be 30°.)
  • Example 8 was prepared in the same manner.
  • Example 9
  • Example 3 The methyl methacrylate/styrene copolymer in Example 3 was replaced by an equal weight (dry weight) methyl methacrylate-butadiene-styrene terpolymer latex (average particle size about ⁇ , wherein, The butadiene content was about 70%, the styrene content was about 15%, the methyl methacrylate content was about 15%, and the contact angle with the coating polymer was determined to be 12°.)
  • Example 10 was prepared in the same manner.
  • Example 11 Example 11
  • Example 12 The PARAL0ID BPM-500 in Example 4 was changed to an equal weight (dry weight) methyl methacrylate latex (average particle diameter of about 4 nm, and the contact angle with the coating polymer was measured to be 4°).
  • Example 11 Example 12
  • Example 12 The PARALOID BPM-500 in Example 4 was replaced with an equal weight (dry weight) methyl methacrylate/styrene copolymer latex (average particle size of about 55 nm, wherein methyl methacrylate content was about 70%, benzene The ethylene content was about 30%, and the contact angle with the coating polymer was measured to be 2 ⁇ .)
  • Example 12 was prepared in the same manner.
  • Example 13
  • Example 14 Replace the methyl methacrylate-butadiene-styrene (MBS) in Example 6 with an equal weight (dry weight) of DuPontTM Elvaloy® HP4051 latex (average particle size of approximately 150 nm, contact with the coated polymer) The angle of enthalpy was determined to be 14 °).
  • Example 13 was prepared in the same manner.
  • Example 14
  • Example 14 was prepared in the same manner. Test Example 1 In vitro release performance (release) test
  • Diltiazem Hydrochloride Release Test Method Determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotation speed is 100r/min, the temperature is (37 ⁇ 1) °C, and the transmitter is 1000 mL each of artificial gastric juice (pH 1.2 hydrochloric acid) and artificial intestinal juice (pH 7.5 phosphate buffer). The samples of the examples and the control samples were directly placed in a dissolution cup, and 5 mL was sampled at regular intervals, and the same volume of the eluted carrier was added. The amount of diltiazem hydrochloride into the dissolution medium was determined by HPLC, and the release of each tablet at different dissolution times was calculated.
  • Glipizide release test method Take the sample at 37 ° C according to the release method (Chinese Pharmacopoeia 2005 edition Appendix XD first method), with Tris buffer (0. 004M Tris, pH 8.7) 1000ml Solvent, rotating at 100 rpm, operate according to law. Sampling 5 mL at regular intervals and replenishing the same volume of dissolved transmitter. The amount of glipizide into the dissolution medium was determined by HPLC. The release of each elution time of glipizide was calculated.
  • the simvastatin release test method is as follows: after each sampling at 37 ° C, with a USP 2 type device at 50 rpm, under laboratory conditions, the value of 7.4, containing sodium decyl sulfate 0. The drug release test was carried out in 1000% of a 4% citrate buffer solution. Sampling 5 mL at regular intervals and replenishing the same volume of dissolved transmitter. The amount of simvastatin entering the dissolution medium was determined by HPLC. The release rate of each dissolution time of simvastatin was calculated. The test results are shown in Table 1-6.
  • Example 4 hours (°/.) 8 hours (%) 12 hours (%)
  • Example 3 32.2 ⁇ 7.7 59.8 ⁇ 7.6 85.4 ⁇ 7.8
  • Example 10 33.6 ⁇ 8.2 64.2 ⁇ 7.9 89.5 ⁇ 8.6
  • Comparative Example 3 18.8 ⁇ 21.8 35.6 ⁇ 22.6 53.2 ⁇ 23.7
  • Example 4 33.7 ⁇ 7.2 58.3 ⁇ 7.5 92.5 ⁇ 8.7
  • Example 11 35.3 ⁇ 7.9 67.8 ⁇ 8.6 95.4 ⁇ 9.3 Comparative Example 4 17.2 ⁇ 31.6 32.4 ⁇ 31 ⁇ 4 57 ⁇ 2 ⁇ 32 ⁇ 8
  • Example 6 Preparation drug release stability test Description
  • Test method for the amount of drug eluted into the dissolution medium See Test Example 1; Test Method for Drug Amount in Preparation: The drug was completely extracted into the preparation and then determined by HPLC. The test results are shown in Table 7-12.
  • Example 1 Test results of the drug release amount of Example 1 and its Comparative Example 1 for 8 hours Test article 0 (%) December (%) ⁇ 24 (%) ⁇ 36 (%) ⁇ Example 1 65. 3/ 100 97. 5 95. 1 91. 3 Comparative Example 1 40. 5/100 76. 5 52. 6 28. 2 Table 8 Example 2 and its control 2 sample 4 hours of drug release: test results test article 0 month (%) acceleration of 3 months (%) ⁇ June acceleration (° /.) Example 3 ⁇ 4 2 57. 6/100 92. 7 87. 9 61. 7/100 Example 7 95.3 91.7 Example 8 64. 5/100 96. 7 93. 2 Comparative Example 2 42. 3/100 85. 3 64.
  • Example 3 and its control 3 sample 8 hours of drug release test results Test article 0 (%) December (%) ⁇ 24 months (%) ⁇ 36 months (%) ⁇
  • Example 4 and its Comparative Example 4 sample 4 hours of drug Release amount: test result test article 0 month (%) December (%) 24 months (%) 58 36 months (%) 55
  • Example 5 94 3 91. 6
  • Example 12 52. 2/100 92. 3 89. 2 82. 5 Comparative Example 4 30. 8/100 76. 0 51. 6 21. 8 Table 11
  • Example 5 and its Comparative Example 5 Sample 6 Hours of drug release: test results test product 0 months (%) December (%) * 24 months (%) 36 months (%) ⁇ Example 5 72. 6/100 97. 1 93. 4 89. 0 Control Example 5 45. 7/100 84. 2 61. 7 39. 6
  • Table 12 Example 6 and its Comparative Example 6 Samples of drug release for 4 hours: Test results Test article 0 (%) Accelerated 3 months (%) Acceleration 6 Month (%) ⁇ - Example 6 60. 7/100 96. 92. 2 Specification Example 13 59. 6/100 97. 7 93. 8 Example 14 57. 4/100 93. 7 84. 8 Comparative Example 6 35. 8/100 65 ⁇ 37 ⁇ Note, ⁇ , indicates original with 0 month The percentage of the
  • test results of the examples and their comparative examples show that the release stability of the pharmaceutical preparations of the examples is superior to that of the comparative examples.
  • Test Example 3 Preparation of controlled release film mechanical properties test
  • Test Example 1 in vitro release (release degree) test test 1-6 and its comparative examples 1-6 test half of the wet residue (ie, the controlled release film directly taken out from the eluate) and another Half of the dry residue obtained by vacuum drying at a temperature below 0 ° C, the maximum tensile force at which the tensile force is broken at a temperature of 25 ° C and the percentage of the elongation length at the time of being pulled off and the original length are determined ( That is, elongation at break).
  • the test results are shown in Table 13.
  • Example 1-6 and Comparative Examples 1-6 Preparation Controlled Release Film Mechanical Properties Test Results Port Breakage Maximum Tensile Elongation at Break (%) Wet Dry and Wet Dry Example 1 9 4 250 180 Comparative Example 1 2 1 120 80 Example 2 25 18 340 240 Example 7 31 23 450 320 Example 8 37 28 870 450 Comparative Example 2 12 7 210 130 Example 3 11 5 330 170 Example 9 15 8 520 330 Example 10 13 6 410 220 Example 3 4 1 220 60 Example 4 13 7 440 370 Example 11 15 9 470 380 Example 12 10 5 380 220 Comparative Example 4 3 1 120 90 Example 5 15 7 390 290 Comparative Example 5 2 1 110 70 Example 6 24 17 350 250 Example 13 26 19 390 280 Example 14 21 14 310 230 Comparative Example 6 9 5 180 120 Example The test results of the comparative examples show that the mechanical properties of the controlled release film of the example formulation are superior to those of the comparative example. This shows that the formulation of the embodiment has better anti-drug release properties and higher drug safety. Test Example 4
  • Example 12 114. 6 108. 7 103. 7

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Abstract

Disclosed is a use of a polymer reinforcing agent in production or storage of a controlled-release preparation and especially a controlled-release preparation of zero-order release. A performance-improved, controlled-release preparation and especially controlled-release preparation of zero-order release are further disclosed. The controlled-release preparation comprises a core containing a biologically active substance, and a controlled-release polymer coat externally applied to the core containing both numerous air-filled agent-releasing micro-pores and a polymer reinforcing agent, wherein the contact angle between the polymer and the polymer reinforcing agent is less than 90°, and the agent-releasing micro-pores are obtained by sublimating a sublimable substance and/or degrading a substance that is capable of being degraded into a harmless gas. The controlled-release coat of the controlled-release preparation has good mechanical performance, and has high storage stability with respect to drug releasing.

Description

说 明 书 在控释制剂中的聚合物增强剂 技术领域  Description Polymer enhancer in controlled release formulations
本发明涉及一种聚合物增强剂在控释制剂特别是零级释放的控释制剂的生产或贮藏中的 用途。 它也涉及一种控释制剂特别是零级释放的控释制剂及其制备方法。 更具体地说， 它涉 及一种性能改善的控释制剂特别是零级释放的控释制剂， 该控释制剂包含含有生物活性物质 的芯料及外覆于上述芯料的含有众多充有空气的释药微孔的及含有聚合物增强剂的聚合物控 释衣膜， 其中， 上述聚合物与上述聚合物增强剂的接触角低于 90° ， 上述上述释药微孔是经 升华可升华的物质和 /或降解可降解成无害气体的物质而获得的。 背景技术  The present invention relates to the use of a polymeric enhancer in the manufacture or storage of a controlled release formulation, particularly a zero release sustained release formulation. It also relates to a controlled release formulation, in particular a zero release release controlled release formulation, and a process for its preparation. More particularly, it relates to a controlled release preparation having improved performance, particularly a zero-order release controlled release preparation comprising a core material containing a biologically active substance and a plurality of air-filled materials overlying the core material a microporous drug release controlled release film comprising a polymer enhancer, wherein the contact angle of the polymer with the polymer enhancer is less than 90°, and the above-mentioned release micropores are sublimated and sublimable Obtained by substances and/or degradation of substances that can be degraded into harmless gases. Background technique
一些水不溶性聚合物在控释制剂，特别是零级释放的控释制剂中通过包衣控制药物释放。 由于聚合物的水不溶性， 常常需要衣膜的微孔来改善控释衣膜的通透性 （permeabil ity) 以 利于水分的渗透及药物的释放， 特别是药物的溶解性偏低及制剂总表面积较小时。  Some water insoluble polymers control drug release by coating in controlled release formulations, particularly zero release sustained release formulations. Due to the water insolubility of the polymer, micropores of the coating film are often required to improve the permeability of the controlled release coating to facilitate moisture penetration and drug release, especially the low solubility of the drug and the total surface area of the formulation. When it is small.
例如， 已有技术提出一些控释制剂制备方法， 其通过挥发在薄膜中的具有挥发性的成分 或降解在薄膜中的可降解成无害气体的成分来形成微孔的方法来控释药物释放。 例如：  For example, the prior art proposes a method for preparing a controlled release preparation for controlling release of a drug by forming a micropore by volatilizing a volatile component in the film or a component which degrades into a harmless gas in the film. . E.g:
EP0425023 (或 US42561989、 US5126146 ) 揭示了一种含有微孔的纤维质薄膜衣的通过渗透压 控释释放药物的装置， 此微孔的平均孔径为 10埃一 100微米， 占薄膜衣体积的 5— 95%。在此专 利技术实施方案中， 发明人提及了一种通过在薄膜愈合 （固化， curing) 处理过程中在薄膜 中产生气体使薄膜形成微孔的方法。 所述产气的方法是挥发在薄膜中的具有挥发性的成分或 通过化学反应生产气体。 EP 0425023 (or US Pat. No. 4,256, 1989, US Pat. No. 5,126, 146) discloses a device for the release of a drug by osmotic pressure controlled release containing a microporous fibrous film coating having an average pore diameter of 10 angstroms to 100 micrometers, which is 5 to the volume of the film coating. 95%. In this patented technical embodiment, the inventors have mentioned a method of forming micropores in a film by generating a gas in a film during a film curing process. The method of producing gas is to volatilize a volatile component in a film or to produce a gas by a chemical reaction.
此外， US5798119揭示了一种含有微孔的薄膜衣及一释药开口的在非水环境中控释释放有 效成分的渗透泵装置， 此微孔被气体充满， 其平均孔径为 0. 1— 30微米， 占薄膜衣体积的 5— 95%。 在此专利技术实施方案中， 发明人提及了利用薄荷脑、 萘、 樟脑、 苯酚、 乙酸铵、 碳酸 铵等可升华的或可降解的成分颗粒在薄膜衣中形成微孔的方法。  5-30. The average pore size of the pores is 0. 1-30. The osmotic pump is filled with a gas. Micron, accounting for 5-15% of the film coat volume. In this patented embodiment, the inventors have referred to a method of forming micropores in a film coat using particles of sublimable or degradable constituents such as menthol, naphthalene, camphor, phenol, ammonium acetate, ammonium carbonate, and the like.
上述提及的二专利技术没有对利用挥发在薄膜中的具有挥发（或升华）性的成分（物质) 或降解在薄膜中的可降解成无害气体的成分（物质）来形成微孔的方法作进一步的说明，同时 至今没有此类其他相关技术。 本发明人对此方法作进一歩深入的研究， 结果发现， 制成的控 释制剂制具有一些较严重的问题， 特别中聚合物增塑后其玻璃化温度 （Tg)较低时。 The above-mentioned two patented techniques do not have a method for forming micropores by using a volatile (or sublimating) component (substance) volatilized in a film or a component (substance) which degrades into a harmless gas which is degraded in a film. For further explanation, there are no such other related technologies. The present inventors conducted intensive studies on this method, and as a result, found that the prepared controlled release preparation has some serious problems, particularly when the glass transition temperature (T g ) of the polymer after plasticization is low.
例如， 制剂的稳定性有较大的问题： 此技术制备的控释制剂存放一段时间后， 其释药性 能或释药的速率常常较大幅度的下降， 而制剂中的药物含量基本没有变化或者变化幅度相对 小得多。 用显微镜对这些贮藏一定时间后的产品进行观测， 结果发现其薄膜中的微孔的大小 较起始阶段縮少甚至完全闭合了。 微孔縮少的程度与贮藏时间有关， 时间俞长， 孔径縮小俞 大； 微孔缩少的程度还与原始孔径大小有关， 原孔径俞大， 孔径缩小俞小， 原孔径俞小， 孔 径缩小俞大。  For example, the stability of the preparation has a big problem: after the controlled release preparation prepared by the technology is stored for a period of time, the release property or the rate of drug release often decreases greatly, and the drug content in the preparation does not substantially change or The magnitude of the change is relatively small. The products after storage for a certain period of time were observed with a microscope, and it was found that the size of the micropores in the film was smaller or even completely closed than the initial stage. The degree of micropore shrinkage is related to the storage time. The time is long and the aperture is reduced. The degree of micropore shrinkage is also related to the original pore size. The original pore size is large, the pore size is reduced by Yu Xiao, the original pore size is small, and the pore size is reduced. Yu Da.
再如， 较差的生产重现性： 有时有些批次药物释放相对较快， 但大都非常缓慢甚至不释 放； 即使用同一批次 （颗粒大小一致） 的可升华的物质颗粒来制备控释制剂制， 结果制成的 控释制剂制的药物释放速率在不同批次间差异非常大， 在实际生产非常难控制。 用显微镜对 上述不同批次的产品进行观测， 结果发现其薄膜中的微孔的大小较原挥发性的成分颗粒大小 大幅缩少甚至完全闭合； 在不同批次间平均孔径差异非常大， 尽管原挥发性的成分颗粒平均 大小一致。  For example, poor production reproducibility: Sometimes some batches of drugs are released relatively quickly, but most are very slow or even not released; that is, the same batch (consistent particle size) of sublimable material particles is used to prepare controlled release preparations. The resulting drug release rate of the controlled release formulation is very different between batches and is very difficult to control in actual production. Microscopic observation of the above different batches of products revealed that the size of the micropores in the film was significantly smaller or even completely closed than the original volatile component particles; the average pore size difference between different batches was very large, despite the original Volatile constituent particles have the same average size.
又如， 此技术制备的控释制剂的释药性能或释药的速率常常明显偏低于采用颗径同等大 小的水溶性较好的物质作致孔剂的膜控释制剂， 而理论上采用颗径同等大小的中空 （无致孔 剂存在） 的微孔来控释药物的膜控释制剂应快于或至少不低于含有颗径同等大小的致孔剂的 膜控释制剂， 因为致孔剂需要溶解成微孔才能控释药物， 而致孔剂需要溶解需要一定的时间， 说 明 书 For example, the release property or release rate of the controlled release preparation prepared by the technique is often significantly lower than that of a membrane-controlled release preparation using a water-soluble material of the same size as the porogen, and theoretically adopted. Membrane controlled release preparations with controlled diameters of hollow pores (without porogens) of the same size should be faster or at least not lower than membrane controlled release preparations containing porogens of the same size. The porogen needs to be dissolved into micropores to control the release of the drug, and the porogen needs to dissolve for a certain period of time. Instruction manual
使药物释放时会出现一定的时滞性。 There is a certain time lag when the drug is released.
此外， 按上述方法制得的制剂的机械强度常常不令人满意， 特别是聚合物衣膜的玻璃化 温度 （Tg)较高时， 因机械强度不够， 控释衣膜受外力作用可能破裂， 因而， 可能引起控释 制剂的剂量倾释 （dose- dumping), 影响用药安全。  In addition, the mechanical strength of the preparation prepared by the above method is often unsatisfactory. In particular, when the glass transition temperature (Tg) of the polymer coating film is high, the controlled release coating film may be broken by an external force due to insufficient mechanical strength. Thus, dose-dumping of the controlled release formulation may be caused, which may affect the safety of administration.
然而， 现实中大多数情况下， 包衣工艺是在较低的聚合物的玻璃化温度（Tg)下进行的， 如常用的乙基纤维素（EC) (Aquacoat®和 Surelease®) 及丙烯酸树脂 (Eudragit ) 等。 因此， 现实中还需要对上述控释制剂特别是零级释放的控释制剂制备方法作进一步的技术改进。 发明目的  However, in most cases, the coating process is carried out at a lower polymer glass transition temperature (Tg), such as the commonly used ethyl cellulose (EC) (Aquacoat® and Surelease®) and acrylic resins. (Eudragit) and so on. Therefore, in the reality, there is still a need for further technical improvements in the preparation of controlled release formulations of the above controlled release formulations, particularly zero-order release. Purpose of the invention
本发明主要目的之一就是提供一种聚合物增强剂在上述的控释制剂特别是零级释放的控 释制剂中的用途。  One of the primary objects of the present invention is to provide a use of a polymeric enhancer in a controlled release formulation as described above, particularly a zero release release controlled release formulation.
本发明主要目的之一就是提供一种上述的控释制剂特别是零级释放的控释制剂及其制备 方法， 该制剂在释药方面具有相对较高贮藏稳定性。  One of the main objects of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a preparation method thereof, which have relatively high storage stability in terms of release.
本发明主要目的就是提供一种上述的控释制剂特别是零级释放的控释制剂及其制备方 法， 该制剂在释药方面具有相对较高生产重现性。  SUMMARY OF THE INVENTION A primary object of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a process for the preparation thereof, which formulation has a relatively high production reproducibility in terms of release.
本发明主要目的就是提供一种上述的控释制剂特别是零级释放的控释制剂及其制备方 法， 该制剂在释药方面的性能获得相对较大的改善。  SUMMARY OF THE INVENTION A primary object of the present invention is to provide a controlled release preparation of the above-mentioned controlled release preparation, particularly a zero-order release, and a process for the preparation thereof, which have a relatively large improvement in the performance in terms of release.
本发明另一个主要目的就是提供一种上述的控释制剂特别是零级释放的控释制剂及其制 备方法， 该制剂的控释膜具有相对较好的机械性能， 具有较低的剂量倾释的可能性及较高的 用药安全性。  Another main object of the present invention is to provide a controlled release preparation, especially a zero-order release controlled release preparation, and a preparation method thereof, wherein the controlled release film of the preparation has relatively good mechanical properties and has a low dose release The possibility and higher medication safety.
其它目的详见下列说明书。 发明内容  For other purposes, please refer to the following instructions. Summary of the invention
本发明提供一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包 覆的控释制剂特别是零级释放的控释制剂中的用途， 特别是上述释药微孔是经升华掉位于上 述聚合物控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于上述聚合物控释衣膜 中的药学上可接受的可降解成无害气体的物质而得的， 该聚合物增强剂被用作延缓上述充有 空气的释药微孔的孔径在生产过程和 /或贮藏过程中的减少，其中， 上述聚合物增强剂与上述 聚合物控释衣膜中的聚合物的接触角低于 90° 。  The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to delay the reduction of the pore diameter of the air-filled drug-releasing micropores during the production process and/or storage process, wherein the above polymer enhancer is as described above. The contact angle of the polymer in the polymer controlled release coating film is less than 90°.
本发明提供一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包 覆的控释制剂特别是零级释放的控释制剂中的用途， 特别是上述释药微孔是经升华掉位于上 述聚合物控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于上述聚合物控释衣膜 中的药学上可接受的可降解成无害气体的物质而得的， 该聚合物增强剂被用作提高上述控释 制剂的释药速率在贮藏过程中的稳定性， 上述聚合物增强剂与上述聚合物控释衣膜中的聚合 物的接触角低于 90° 。  The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to improve the stability of the release rate of the above controlled release preparation during storage, and the polymerization of the above polymer enhancer and the above polymer controlled release coating film The contact angle of the object is below 90°.
本发明提供一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包 覆的控释制剂特别是零级释放的控释制剂中的用途， 特别是上述释药微孔是经升华掉位于上 述聚合物控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于上述聚合物控释衣膜 中的药学上可接受的可降解成无害气体的物质而得的， 该聚合物增强剂被用作提高上述控释 制剂的释药速率在生产过程中的重现性， 上述聚合物增强剂与上述聚合物控释衣膜中的聚合 物的接触角低于 90° 。  The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to improve the reproducibility of the release rate of the above controlled release preparation in the production process, and the above polymer enhancer is in the above-mentioned polymer controlled release coating film. The contact angle of the polymer is below 90°.
本发明提供一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包 覆的控释制剂特别是零级释放的控释制剂中的用途， 特别是上述释药微孔是经升华掉位于上 述聚合物控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于上述聚合物控释衣膜 中的药学上可接受的可降解成无害气体的物质而得的， 该聚合物增强剂被用作改善上述控释 说 明 书 制剂释药性能， 如提高释药速度， 上述聚合物增强剂与上述聚合物控释衣膜中的聚合物的接 触角低于 90° 。 The present invention provides a use of a polymeric enhancer in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly a zero-order release controlled release formulation, particularly The drug release microwell is a pharmaceutically acceptable sublimable material that is sublimed in the polymer controlled release coating film and/or degrades the pharmaceutically acceptable degradable material in the above polymer controlled release coating film. The polymer enhancer is used to improve the above controlled release. The release property of the book preparation, such as increasing the release rate, is such that the contact angle of the above polymer reinforcing agent with the polymer in the above polymer controlled release coating film is less than 90°.
本发明提供了一种性能改善的控释制剂特别是零级释放的控释制剂， 该控释制剂包含： 1 )、 含有至少一种生物活性物质的芯料； 2)、 外覆于上述芯料的含有众多充有空气的释药微 孔的控释衣膜， 其中， 该控释衣膜包含有药学上可接受的不溶于或几乎不溶于水及消化液的 聚合物及药学上可接受的聚合物增强剂，上述聚合物与上述聚合物增强剂的接触角低于 90° ， 上述释药微孔是经升华掉位于上述聚合物控释衣膜中的药学上可接受的可升华的物质和 /或 降解掉位于上述聚合物控释衣膜中的药学上可接受的可降解成无害气体的物质而获得的。  The present invention provides a controlled release preparation having improved performance, in particular a zero-order release controlled release preparation comprising: 1) a core material containing at least one biologically active substance; 2) overlying the core a controlled release coating comprising a plurality of air-filled drug delivery microwells, wherein the controlled release film comprises a pharmaceutically acceptable polymer which is insoluble or hardly soluble in water and a digestive juice and is pharmaceutically acceptable The polymer reinforcing agent having a contact angle of less than 90° with the above polymer reinforcing agent, wherein the release micropores are sublimed and pharmaceutically acceptable sublimable in the polymer controlled release coating film. Substance and/or degradation of a pharmaceutically acceptable material which is degradable into a harmless gas in the above polymer controlled release coating film.
本发明提供了一种性能改善的外被含有众多充有空气的释药微孔的聚合物控释衣膜包覆 的控释制剂特别是零级释放的控释制剂的制备方法，该制备方法包含下列几个基本步骤： 1 )、 制备含有至少一种生物活性物质的芯料； 2)、 用含有药学上可接受的可升华的物质颗粒和 / 或可降解成无害气体的物质颗粒及药学上可接受的聚合物增强剂的药学上可接受的不溶于或 几乎不溶于水及消化液的聚合物的溶液或水分散液对上述芯料包覆聚合物控释衣膜， 其中， 上述可升华的物质和 /或可降解成无害气体的物质及上述聚合物增强剂不溶于或几乎不溶于 上述聚合物的溶液或水分散液， 上述聚合物与上述聚合物增强剂的接触角低于 90° ； 3)、 升 华掉位于上述聚合物控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于上述聚合 物控释衣膜中的药学上可接受的可降解成无害气体的物质。 本发明使用的术语 "控释衣膜"是指包覆于控释制剂的核芯外表面上的含有足够量的疏 水性 （聚合物）材料的并具有足够机械强度维持控释制剂在置于水溶液释药过程中的不破裂 的包衣膜， 该包衣膜能延缓释放上述控释制剂被置于水溶液时其所含的药物或洽疗活性剂。  The invention provides a method for preparing a controlled release preparation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, in particular a zero-order release controlled release preparation, the preparation method The following basic steps are included: 1) preparing a core material containing at least one biologically active substance; 2) using particles of a substance containing pharmaceutically acceptable sublimable material particles and/or degradable into a harmless gas and a solution or aqueous dispersion of a pharmaceutically acceptable polymer-enhancing agent in a polymer-insoluble or hardly soluble in water and a digestive solution, said core coated polymer controlled release coating film, wherein a sublimable substance and/or a substance degradable into a harmless gas and a solution or aqueous dispersion in which the above polymer reinforcing agent is insoluble or hardly soluble in the above polymer, and the contact angle of the above polymer with the above polymer reinforcing agent is low At 90°; 3) sublimating the pharmaceutically acceptable sublimable material in the above polymer controlled release coating film and/or degrading the pharmaceutically acceptable substance in the above polymer controlled release coating film Accepted substances that degrade into harmless gases. The term "controlled release coating film" as used herein means a material containing a sufficient amount of hydrophobic (polymeric) material coated on the outer surface of the core of the controlled release preparation and having sufficient mechanical strength to maintain the controlled release preparation. The non-ruptured coating film in the aqueous solution release process, the coating film can delay the release of the drug or the therapeutic active agent contained in the controlled release preparation when it is placed in an aqueous solution.
本发明使用的术语 "聚合物增强剂"是指以独立的形态 (分散相)分布于聚合物衣膜中的 聚合物相 (连续相）并能改善或增强聚合物衣膜包括机械 （力学） 强度和刚度在内的机械性能 的药学上可接受的添加剂。  The term "polymeric enhancer" as used in the present invention means a polymer phase (continuous phase) which is distributed in a polymer film in a separate form (dispersion phase) and which can improve or enhance the polymer film including mechanical (mechanical). A pharmaceutically acceptable additive for mechanical properties including strength and stiffness.
本发明使用的术语 "接触角"是指处于流体态的聚合物位于聚合物增强剂固体表面时在 液 （聚合物） -固 （聚合物增强剂） -气 （空气） 三态交接处平衡时所形成的角度； 尤其是指 上述流体态的聚合物进一步固化并冷却至室温 25°C后， 在固 （聚合物） -固 （聚合物增强剂） -气 （空气） 三态交接处平衡时所形成的角度。  As used herein, the term "contact angle" means that the polymer in a fluid state is at the liquid (polymer)-solid (polymer enhancer)-gas (air) tristate junction when it is on the solid surface of the polymer enhancer. The angle formed; especially when the polymer in the above fluid state is further solidified and cooled to room temperature at 25 ° C, at the equilibrium of the solid (polymer)-solid (polymer enhancer) - gas (air) tristate junction The angle formed.
本发明使用的术语 "众多"是指外覆于制剂的聚合物 （控释） 衣膜上的释药微孔的数量 不只是一个， 有多个， 一般地不低于 20个， 通常不低于 50个， 尤其是不低于 100个， 更尤 其是不低于 1000个,特别是不低于 5000个。  The term "many" as used in the present invention means that the number of drug-releasing micropores which are coated on the polymer (controlled release) film of the preparation is not only one, but also plural, generally not less than 20, usually not low. In 50, especially not less than 100, more particularly not less than 1000, especially not less than 5,000.
本发明使用的术语 "活性成分"、 "生物活性成分"、 "药用活性组分"、 "活性物"、 "活性 剂"及 "生物活性物质"、 "药物"等是指任何物质当其施予活体时具有可检测的生物效应包 括任何生理学的、 诊断的、 预防性的或药理学效应。 此术语旨在包括但不限于任何药学的、 治疗学的、 预防性的、 营养学的物质。  The terms "active ingredient", "biologically active ingredient", "pharmaceutically active ingredient", "active substance", "active agent" and "biologically active substance", "drug" and the like as used herein mean any substance as it Detectable biological effects when administered to a living body include any physiological, diagnostic, prophylactic or pharmacological effects. This term is intended to include, but is not limited to, any pharmaceutically, therapeutic, prophylactic, nutritional material.
本发明使用的术语 "包含"及 "含有"是指包括但不限于或除了此物还可以包含其他成 分等类似的含义。  The terms "comprising" and "containing", as used in the present invention, are meant to include, but not limited to, or in addition to the meaning of other components and the like.
本发明使用的术语 "一种"是指至少为一种， 可以为只有一种， 也可以为二种或多种。 本发明使用的术语 "药学上可接受的"是指在制剂中能彼此混合且相互无有害作用而不 会降低制剂稳定性和 /或效力且适用于局部或全身给药的意思。 具体实施方式  The term "a" as used in the present invention means at least one, and may be one type or two or more types. The term "pharmaceutically acceptable" as used in the present invention means that it can be mixed with each other in the preparation without adverse effects on each other without lowering the stability and/or efficacy of the preparation and is suitable for topical or systemic administration. detailed description
下面详细介绍上述控释制剂的聚合物衣膜 （控释衣膜） 中的主要成分。  The main components in the polymer coating film (controlled release coating film) of the above controlled release preparation are described in detail below.
本发明采用药学上可接受的可升华的物质和 /或可降解成无害气体的的物质作为聚合物 衣膜（控释衣膜）中的致孔物质（以下把药学上可接受的可升华的物质和 /或可降解成无害气 说 明 书 The present invention employs a pharmaceutically acceptable sublimable substance and/or a substance which can be degraded into a harmless gas as a porogenic substance in a polymer film (controlled release film) (hereinafter pharmaceutically acceptable sublimation) Substance and / or degradable into harmless gas Description
体的的物质称作致孔物质）， 通过升华在聚合物衣膜（控释衣膜）中的具有升化性的成分或降 解在薄膜中的可降解成无害气体的成分来形成释药微孔来控释药物释放。 a substance called a porogen), which is formed by sublimation of a component having an ascending property in a polymer film (controlled release film) or a component degradable in a film which degrades into a harmless gas. Micropores to release controlled release of the drug.
上述致孔物质影响聚合物衣膜 （控释衣膜） 及控释制剂的性能的重要因素重要是其熔点 及其可升华的或可降解的温度、 在包衣液中的溶解度及其平均粒径。 上述致孔物质在 1标准 大气压 （101. 325ka) 下的熔点及其在 1标准大气压 （101. 325ka) 下的开始升华 （升华点） 或降解的温度通常高于 40°C， 较佳地不低于 60°C ,更佳地不低于 80°C，最佳地不低于 100°C； 且上述致孔物质在 1标准大气压（101. 325ka)下的熔点及其开始升华（升华点）或降解的温 度应高于上述聚合物的混合包衣液的最低成膜温度或上述聚合物衣膜的玻璃化转变温度， 通 常高出 （含） 10°C , 较佳地高出 （含） 20°C，更佳高出 （含） 30°C，最佳地高出 （含） 40°C。 上述致孔物质在包衣液中的溶解度 （温度 25°C，较佳地为包衣工艺进行时的温度） 应不高于 30mg/ml , 较佳地不高于 10mg/ml， 更佳地不高于 lmg/ml， 最佳地不高于 0. lmg/ml。 上述致 孔物质的平均粒径应为 30〜1200 μ ηι， 较佳地为 50〜900 μ πι， 更佳地为 100〜600 μ πι， 最佳 地为 150〜400 μ ιη。 由于致孔物质的平均粒径是影响或决定聚合物衣膜 （控释衣膜） 中释药 微孔大小的主要因素，故衣膜中释药微孔平均大小应基本位于 30〜1200 μ m，较佳地位于 50〜 900 μ m， 更佳地位于 100〜600 μ m， 最佳地位于 150〜400 μ m。  The important factors affecting the properties of the above-mentioned porogens in polymer coatings (controlled release coatings) and controlled release preparations are their melting point and their sublimable or degradable temperature, solubility in the coating solution and their average granules. path. The melting point of the above porogen at 1 standard atmosphere (101. 325 ka) and its sublimation (sublimation point) or degradation at 1 standard atmosphere (101. 325 ka) is usually higher than 40 ° C, preferably not Below 60 ° C, more preferably not lower than 80 ° C, optimally not lower than 100 ° C; and the melting point of the above-mentioned porogen at 1 standard atmospheric pressure (101. 325 ka) and its sublimation (sublimation point) Or the temperature of degradation should be higher than the minimum film forming temperature of the mixed coating liquid of the above polymer or the glass transition temperature of the above polymer film, usually higher (including) 10 ° C, preferably higher (including ) 20 ° C, better than (including) 30 ° C, optimally higher (including) 40 ° C. The solubility of the above-mentioned porogen in the coating liquid (temperature 25 ° C, preferably the temperature at which the coating process is carried out) should be not higher than 30 mg/ml, preferably not higher than 10 mg/ml, more preferably Lmg/毫升。 Not more than lmg / ml, preferably not higher than 0. lmg / ml. The above pore-forming substance should have an average particle diameter of 30 to 1200 μηη, preferably 50 to 900 μm, more preferably 100 to 600 μm, and most preferably 150 to 400 μm. Since the average particle size of the porogen is the main factor affecting or determining the size of the released pores in the polymer coating (control release coating), the average size of the released micropores in the coating should be approximately 30 to 1200 μm. Preferably, it is located at 50 to 900 μm, more preferably between 100 and 600 μm, and most preferably between 150 and 400 μm.
过低的熔点、 过低可升华的或可降解的温度不利于包衣及释药微孔的形成， 还会使可升 华的物质和 /或可降解成无害气体的物质在包衣过程中可能大量升华及降解，过早从衣膜中损 失， 从而影响制剂的释药性能及生产重现性。 过小的释药微孔可能在生产引起生产重现性及 贮藏稳定性较差等的问题，更重要的是，过小的释药微孔将产生较大的微孔附加压（Δ Ρ) (因 A P=2。/r，其中， Δ Ρ表示微孔附加压， 。聚合物一空气表面张力， r表示微孔半径）， 而较 大的微孔附加压（Δ Ρ)将使微孔在生产或贮藏过程自行缓缓缩小， 从而使膜控释制剂的药物 释放变得不够稳定， 生产重现性较差。 经反复实验证实， 其稳定性与控释膜微孔孔径大小相 关， 微孔孔径俞大， 其稳定性俞好， 微孔孔径俞小， 其稳定性俞差， 其稳定性增加（或减少) 的幅度较微孔孔径增加 （或减少） 的幅度更大。 故， 本发明采用相对较大的释药微孔来控释 药物释放， 以提高提高制剂的药物释放的稳定性。 但过大的释药微孔也易在生产引起生产重 现性较差等的问题。  Too low a melting point, too low sublimable or degradable temperature is detrimental to the formation of coating and release micropores, and also allows sublimable substances and/or substances that can be degraded into harmless gases during the coating process. It may be a large amount of sublimation and degradation, which is lost prematurely from the film, thereby affecting the release performance and reproducibility of the preparation. Too small release micropores may cause problems such as production reproducibility and poor storage stability. More importantly, too small release micropores will produce larger micropore additional pressure (Δ Ρ). (Because AP=2./r, where Δ Ρ denotes micropore additional pressure, polymer-air surface tension, r denotes micropore radius), and larger micropore additional pressure (Δ Ρ) will make micropores The production or storage process is gradually reduced by itself, so that the drug release of the membrane controlled release preparation becomes less stable and the production reproducibility is poor. It has been confirmed by repeated experiments that the stability is related to the pore size of the controlled release membrane, the pore size is large, the stability is good, the pore size is small, the stability is poor, and the stability is increased (or decreased). The magnitude is greater than the increase (or decrease) in the pore size of the micropore. Therefore, the present invention employs relatively large drug delivery micropores to control release of the drug to improve the stability of drug release of the formulation. However, excessive drug release micropores are also prone to problems such as poor production reproducibility.
致孔物质在包衣液中的用量由此技术领域中技能熟练的技术人员依据药物的性质及所期 望的释药速率决定。 致孔物质的用量通常依其粒径、 聚合物的种类及其用量、 药物的性质、 所希望的释药速率等决定， 通常为 5%〜95% (重量比或体积比）， 较佳地为 25%〜90%， 更佳地为 40%〜80%， 这是基于聚合物衣膜 （控释衣膜） 组分的干的总重量或聚合物衣膜 （控释衣膜） 体积。  The amount of porogenic material in the coating fluid is determined by the skilled artisan skilled in the art in light of the nature of the drug and the desired rate of drug delivery. The amount of the porogen is usually determined by the particle size, the type and amount of the polymer, the nature of the drug, the desired rate of release, etc., and is usually 5% to 95% by weight or volume ratio, preferably It is from 25% to 90%, more preferably from 40% to 80%, based on the total dry weight of the polymer film (controlled release film) component or the volume of the polymer film (controlled release film).
致孔物质的用量是影响或决定聚合物衣膜 （控释衣膜） 的孔隙率的主要因素， 因此， 聚 合物衣膜（控释衣膜）的孔隙率应基本位于 5%〜95%，较佳地位于 25%〜90%，更佳地位于 40%〜 80%。 此处所用的术语 "孔隙率"是指挥去聚合物衣膜（控释衣膜）中的致孔物质后所留下的 空间占整个原聚合物衣膜 （控释衣膜） 的体积的比例。  The amount of porogen is the main factor affecting or determining the porosity of the polymer film (controlled release film). Therefore, the porosity of the polymer film (controlled release film) should be basically 5%~95%. It is preferably between 25% and 90%, more preferably between 40% and 80%. The term "porosity" as used herein refers to the proportion of the space left by the porogen in the polymer coating film (controlled release film) to the volume of the original polymer film (controlled release film). .
适合本发明的作为致孔物质的可升华的组分或可降解成无害气体的组分优选实例包括但 不限于苯甲酸（mpl21. 5〜123. 5°C， 100°C开始升华（latm))、 苯甲酸酯及苯甲酸盐类化合物 Preferred examples of the sublimable component as the porogen or the component which can be degraded into a harmless gas, which is suitable for the present invention, include, but not limited to, benzoic acid (mpl 21. 5 to 123. 5 ° C, 100 ° C begins to sublimate (latm )), benzoate and benzoate compounds
(如苯甲酸乙脂、 苯甲酸苯酯、 苯甲酸丙脂、 苯甲酸苄酯、 苯甲酸甲酯、 苯甲酸盐如钠盐） 、 香草醛（mp81〜83°C )、 乙基香草醛（mp76〜81 °C， 纯品 mp77〜78°C )、天然或合成樟脑（天 然樟脑 mpl76〜18rC， 合成樟脑1^174〜179°0 、 右旋樟脑 （mp约 179. 8°C， 204°C开始升华(eg benzoic acid ethyl ester, phenyl benzoate, benzoic acid propyl ester, benzyl benzoate, methyl benzoate, benzoate such as sodium salt), vanillin (mp 81 ~ 83 ° C), ethyl vanillin (mp76~81 °C, pure mp77~78°C), natural or synthetic camphor (natural camphor mpl76~18rC, synthetic camphor 1^174~179°0, right-handed camphor (mp about 179. 8°C, 204 °C begins to sublimate
( latm) )、左旋樟脑 (mp约 178. 6°C， 204°C开始升华（ latm) )、外消旋薄荷脑 (醇) (mp42~ 44°C )、左旋薄荷醇（mp41〜45°C )、天然或合成冰片（mp205- 210°C )、右旋龙脑（mp约 208°C )、 左旋龙脑 （mp约 204°C )、 右旋异龙脑 （mp约 214°C )、 左旋异龙脑 （mp约 214°C )、 外消旋异龙 脑（mp约 212°C )、二硫代草酰胺（二硫代二酰胺） （mp约 4ΓΟ、 6—甲基一 2—硫脲嘧啶（甲 基硫氧嘧啶）（即约330°0， 326〜331 °C分解）、萸磺酸盐如钠盐、叔丁基对羟基茴香醚（mp57〜 说 明 书 (latm)), left-handed brain (mp about 178.6 ° C, 204 ° C began to sublimate (latm)), racemic menthol (alcohol) (mp42 ~ 44 ° C), L-menthol (mp41 ~ 45 ° C), natural or synthetic borneol (mp205-210 ° C), right-handed borneol (mp about 208 ° C), left-handed borneol (mp about 204 ° C), right-handed borneol (mp about 214 ° C) , L-isobornanol (mp about 214 ° C), racemic isoborne brain (mp about 212 ° C), dithiooxamide (dithiodiamide) (mp about 4 ΓΟ, 6-methyl one 2 - thiouracil (methylthiouracil) (ie about 330 ° 0, 326 ~ 331 ° C decomposition), sulfonium sulfonate such as sodium salt, tert-butyl p-hydroxyanisole (mp57~ Instruction manual
65 °C )、二特丁基羟基甲苯（2， 6 二特丁基对甲酚） （πιρ69〜7ΓΟ、水杨酸（mpl58°C， 76°C 开始升华）、阿司匹林、乙水杨胺、咖啡因类化合物（如咖啡因 1水合物 (即 238° ， 178° 升华）、 咖啡因无水物、 柠檬酸咖啡因、 咖啡因苯甲酸盐如钠盐）、 丙氨酸、 亮氨酸、 异亮氨酸、 缬氨 酸、 苯丙氨酸、 尿素、 乌拉坦、 卤化铵如氯化铵、 碳酸氢铵、 碳酸铵、 醋酸铵及其混合物。  65 °C), di-tert-butylhydroxytoluene (2,6 di-tert-butyl-p-cresol) (πιρ69~7ΓΟ, salicylic acid (mpl58°C, 76°C begins to sublimate), aspirin, salicylamine, Caffeine compounds (eg caffeine 1 hydrate (ie 238°, 178° sublimation), caffeine anhydrate, caffeine citrate, caffeine benzoate such as sodium salt), alanine, leucine , isoleucine, valine, phenylalanine, urea, urethane, ammonium halides such as ammonium chloride, ammonium hydrogencarbonate, ammonium carbonate, ammonium acetate, and mixtures thereof.
适合本发明的包衣聚合物可以为药学上可接受的不溶于或几乎不溶于水及消化液的的嵌 段聚合物或共聚物。 合适的聚合物可选自但不限于不溶于或几乎不溶于水及消化液的纤维素 酯类、 丙烯酸 (酯)类聚合物、 聚醋酸乙烯酯类、 聚氯乙烯类及其组合物。 优选的示例的合适 的聚合物实例包括但不限于乙基纤维素、 醋酸纤维素、 丙酸纤维素、 醋酸丁酸纤维素、 醋酸 丙酸纤维素 （cel lulose acetate propionate^ 硝酸纤维素、 三戊酸纤维素、 三十二酸纤维 素、 三棕榈酸纤维素、 二琥珀酸纤维素、 二棕榈酸纤维素、 聚乙烯乙酸酯、 甲基丙烯酸 (酯） 聚合物、 氯乙烯一乙烯醇一醋酸乙烯酯的三元共聚物、 聚碳酸酯、 聚甲基丙烯酸甲酯、 丙烯 酸乙酯一间丙烯酸甲酯聚合物、 氯乙烯-乙烯乙酸酯共聚物、 聚氯乙烯、 聚乙烯、 聚异丁烯、 poly ( ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride)。  The coating polymer suitable for the present invention may be a pharmaceutically acceptable block polymer or copolymer which is insoluble or hardly soluble in water and digestive juices. Suitable polymers may be selected from, but not limited to, cellulose esters, acrylic polymers, polyvinyl acetates, polyvinyl chlorides, and combinations thereof that are insoluble or nearly insoluble in water and digestive juices. Examples of suitable polymers of preferred examples include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cel lulose acetate propionate^ nitrocellulose, triamyl) Acid cellulose, cellulose dodecanoate, cellulose tripalmitate, cellulose disuccinate, cellulose dipalmitate, polyvinyl acetate, methacrylate polymer, vinyl chloride-vinyl alcohol Terpolymer of vinyl acetate, polycarbonate, polymethyl methacrylate, ethyl acrylate, a methyl acrylate polymer, vinyl chloride-ethylene acetate copolymer, polyvinyl chloride, polyethylene, polyisobutylene , poly (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride).
可采用上述聚合物商业上可供应的胶乳、 伪胶乳及乳状液进行包衣， 如乙基纤维素 (EC) 有： Aquacoat®和 Surelease®,丙烯酸树脂有： Eudragit® RS30D、 Eudragit® RE30D及 Eudragit® RL30D, 醋酸纤维索（CA)有： CA398— 10。  It can be coated with commercially available latexes, pseudo-latexes and emulsions of the above polymers, such as ethyl cellulose (EC): Aquacoat® and Surelease®, acrylics are: Eudragit® RS30D, Eudragit® RE30D and Eudragit ® RL30D, Cellulose Acetate (CA): CA398-10.
一个可采用的实例为 US4557925所提供的含 80〜95%的聚氯乙烯、 0. 5〜19%的聚乙烯乙酸酯 及 0. 5〜10%聚乙烯醇的三元共聚物的水分散体包衣液。  An example of a water dispersion of a ternary copolymer containing 80 to 95% of polyvinyl chloride, 0.5 to 19% of polyvinyl acetate, and 0.5 to 10% of polyvinyl alcohol, which is provided by US Pat. Body coating solution.
另一个可用的实例为含 50〜100%聚氯乙烯及 0〜50%聚乙烯乙酸酯共聚物的水分散体包衣 液。  Another useful example is an aqueous dispersion coating containing 50 to 100% polyvinyl chloride and 0 to 50% polyvinyl acetate copolymer.
包衣聚合物在干衣中的比例依所选择的聚合物的种类、 致孔物质的种类及其用量、 药物 的性质、所选择的剂型及其所希望的释药模式等决定， 通常为 40%〜95%重量比， 较佳地 50%〜 90%重量比， 更佳地 55%〜85°/。重量比， 这是基于聚合物衣膜 （控释衣膜） 组分的干的总重量。  The proportion of the coating polymer in the dry coat is determined by the type of polymer selected, the type and amount of the porogen, the nature of the drug, the selected dosage form and the desired mode of release, etc., usually 40. % to 95% by weight, preferably 50% to 90% by weight, more preferably 55% to 85°/. The weight ratio, which is based on the total dry weight of the polymer film (controlled release film) component.
为改进衣膜的质量， 常在包衣处方中添加增塑剂以降低聚合物的玻璃化转变温度 （Tg) 至合适的范围内， 并提高包衣材料的成膜能力， 增强衣膜的柔韧性和强度， 改善衣膜对底物 的粘附状态。 通常在一般的包衣过程中， 聚合物的玻璃化转变温度 （Tg)采用较低的值， 如 25-80°C。 在本发明中， 增塑后聚合物的玻璃化转变温度 （Tg) 通常要求不高于 90°C， 不低 于 15°C，优选为 25〜80°C， 更优选为 35〜70°C， 更优选为 45〜65°C ; 聚合物衣膜的玻璃化转 变温度 （7；) 还应低于该可升华的物质和 /或可降解成无害气体的物质在 1 标准大气压 ( 101. 325ka)下开始升华或降解的温度， 通常低出 10°C， 较佳地低出 20 °C,更佳低出 20 °C, 最佳地低出 40°C。 在本发明采用较低的玻璃化转变温度 （Tg)， 从而可以在包衣过程中采用 较低的温度， 这样有利于包衣工艺的顺利进行， 特别是有利于减少致孔物质在加工中的升华 或降解， 因而有利于提高制剂的释药性能、 工艺稳定性及生产重现性。 聚合物衣膜的玻璃化 转变温度 不应太高， 因较高将增加工艺难度及成本。 In order to improve the quality of the film, plasticizers are often added to the coating formulation to lower the glass transition temperature (Tg) of the polymer to a suitable range, and to improve the film forming ability of the coating material and enhance the flexibility of the film. Sex and strength, improve the adhesion of the film to the substrate. Generally, the glass transition temperature (Tg) of the polymer is used at a lower value, such as 25-80 ° C, during the general coating process. In the present invention, the glass transition temperature (T g ) of the plasticized plastic is usually required to be not higher than 90 ° C, not lower than 15 ° C, preferably 25 to 80 ° C, more preferably 35 to 70 °. C, more preferably 45 to 65 ° C; the glass transition temperature (7;) of the polymer film should also be lower than the sublimable substance and/or the substance degradable into a harmless gas at 1 standard atmosphere (101 The temperature at which 325 ka) begins to sublimate or degrade is usually 10 ° C lower, preferably 20 ° C lower, more preferably 20 ° C lower, and most preferably 40 ° C lower. In the present invention, a lower glass transition temperature (Tg) is adopted, so that a lower temperature can be used in the coating process, which is advantageous for the smooth progress of the coating process, and particularly for reducing the porosity of the pore-forming material during processing. Sublimation or degradation, which is beneficial to improve the release performance, process stability and production reproducibility of the preparation. The glass transition temperature of the polymer film should not be too high, which will increase the process difficulty and cost.
增塑剂通常为高沸点、 低挥发性并能与聚合物混溶的小分子 (Mr约为 150〜800， 较佳地 为 300〜500)的液体物质或低熔点的固体物质。 可用增塑剂的实例如生理学相容的由 C6〜 C4。 (优选 C6〜C3。、 特别优选 (^。〜(：16)脂肪族或芳香族一至三元羧酸与 〜( 8 (优选 C2〜C6、 特别 优选 C2〜C5)脂肪族醇形成的亲脂性的酯。 这种增塑剂的实例如邻苯二甲酸二丁酯、 邻苯二甲 酸二乙酯、 癸二酸二丁酯、 癸二酸二乙酯、 枸橼酸三乙基酯、 乙酰柠檬酸三乙酯、 甘油三乙 酸酯、 三丁基葵二酸酯、 脱水山梨醇酯、 蔗糖酯。 其他可用增塑剂的实例如甘油、 丙二醇、 聚乙二醇、 蓖麻油。 The plasticizer is usually a liquid substance having a high boiling point, a low volatility and being miscible with a polymer (Mr is about 150 to 800, preferably 300 to 500), or a solid substance having a low melting point. Examples of useful plasticizers are physiologically compatible from C 6 to C 4 . (preferably C 6 to C 3 ., particularly preferably (^.~(: 16 ) aliphatic or aromatic mono- to tricarboxylic acid and ~( 8 (preferably C 2 to C 6 , particularly preferably C 2 to C 5 ) fat a lipophilic ester formed by a steroid. Examples of such plasticizers are dibutyl phthalate, diethyl phthalate, dibutyl sebacate, diethyl sebacate, citric acid. Triethyl ester, acetyl triethyl citrate, triacetin, tributyl succinate, sorbitan ester, sucrose ester. Examples of other useful plasticizers such as glycerin, propylene glycol, polyethylene glycol Castor oil.
增塑剂的用量依据所期望衣膜的性质， 如玻璃化转变温度、机械性能等， 增塑剂的种类， 成膜剂 （即水不溶性成膜聚合物） 的种类、 用量等而定， 通常用量为 5〜50% (重量比）， 优选 10〜40% (重量比）， 特别优选 10〜30% (重量比）， 这是基于聚合物衣膜 （控释衣膜） 组分的 干的总重量。 说 明 书 需要特别指出的是， 聚合物衣膜采用较低的玻璃化转变温度 （Tg) 通常会降低制得的制 剂释药贮藏稳定性、 释药生产重现性， 因聚合物衣膜的玻璃化转变温度较低， 聚合物分子自 由 "流动"或 "滑动"的能力或趋势较强， 释药微孔较易生产和 /或贮藏 (在本发明术语"贮 藏过程"通常是指制剂从生产结束时起至被使用者（患者)使用时的过程)过程中缩少甚至完 全闭合； 此外， 上述聚合物衣膜的机能性能如抗拉性能仍有改善的空间。 为了提高制得的制 剂的这些性能， 本发明在包衣液需要加入特定聚合物增强剂。 具体地说， 在包衣液或包衣中 加入与上述的聚合物的接触角 （ ( 低于 90° 的聚合物增强剂， 较佳地上述的接触角 ( Θ 低于或等于 60° ， 更佳地低于或等于 30° ， 最佳地低于或等于 10° 。 此处所述的 "聚合物 增强剂"是指以独立的形态 (分散相)分布于聚合物衣膜 （控释衣膜） 中的聚合物相 (连续相） 并能改善聚合物衣膜包括机械（力学）强度和刚度在内的机械性能的药学上可接受的添加剂。 此处所述的 "聚合物增强剂与聚合物接触角"是指处于流体态的聚合物位于聚合物增强剂固 体表面时在液（聚合物） -固 （聚合物增强剂） -气（空气）三态交接处平衡时所形成的角度； 更佳地，是指上述流体态的聚合物进一步固化后，特别是固化并冷却至室温 25°C后，在固（聚 合物） -固 （聚合物增强剂） -气 （空气）三态交接处平衡时所形成的角度。 在本发明， 通常 是指静止（态）接触角 （ θ、。一种可用于本发明的静止（态）接触角 ( θ、测定方法实例如 下： 加热使温度大于聚合物的流变温度 使聚合物处于流体态， 滴加聚合物液并使之静止 位于聚合物增强剂的表面 （通常为清洁光滑水平平面） 待其形态稳定后 （更佳地进一步固化 并冷却至室温 25°C后）用适当方法测得的接触角， 例如， 用显微镜直接测定或者从电视图象 或照片上直接测定的接触角。 The amount of the plasticizer depends on the properties of the desired film, such as the glass transition temperature, mechanical properties, etc., the type of plasticizer, the type and amount of the film-forming agent (ie, the water-insoluble film-forming polymer), and usually The amount is 5 to 50% by weight, preferably 10 to 40% by weight, particularly preferably 10 to 30% by weight, based on the dry weight of the polymer film (controlled release film) component. total weight. It should be noted in the specification that the lower glass transition temperature (T g ) of the polymer film generally reduces the storage stability of the prepared drug release, the reproducibility of drug release production, and the glass of the polymer film. The conversion temperature is lower, the ability or tendency of the polymer molecules to freely "flow" or "slip" is relatively strong, and the release micropores are easier to produce and/or store (in the present invention the term "storage process" generally refers to the preparation of the preparation from production. From the end to the time when the user (patient) is used, the process is reduced or even completely closed; in addition, there is still room for improvement in the functional properties of the above polymer film such as tensile properties. In order to improve these properties of the prepared formulations, the present invention requires the addition of a specific polymer reinforcing agent to the coating liquid. Specifically, a contact angle with the above polymer is added to the coating liquid or coating ((a polymer enhancer lower than 90°, preferably the above contact angle (Θ is lower than or equal to 60°, more Preferably, the content is lower than or equal to 30°, and most preferably lower than or equal to 10°. The term “polymer enhancer” as used herein refers to a distribution in a separate form (dispersed phase) to a polymer film (controlled release coating). a polymer phase (continuous phase) in the film) and a pharmaceutically acceptable additive that improves the mechanical properties of the polymer film including mechanical (mechanical) strength and stiffness. "Polymer contact angle" means the angle formed when the polymer in a fluid state is at the liquid (polymer)-solid (polymer enhancer)-gas (air) tristate junction when it is located on the solid surface of the polymer enhancer. More preferably, after the above fluid state polymer is further cured, in particular, after solidification and cooling to room temperature of 25 ° C, in a solid (polymer)-solid (polymer enhancer) - gas (air) tristate The angle formed when the junction is balanced. In the present invention, usually Refers to the static (state) contact angle (θ, a static (state) contact angle that can be used in the present invention (the θ, the measurement method is as follows: heating makes the temperature greater than the rheological temperature of the polymer to make the polymer in a fluid state, Add the polymer solution and let it rest on the surface of the polymer enhancer (usually clean and smooth horizontal plane). After the shape is stabilized (more preferably further solidified and cooled to room temperature 25 ° C), the contact measured by the appropriate method The angle, for example, is measured directly by a microscope or directly measured from a television image or photograph.
希望不完全受此原理的限制， 接触角 （ 通常认为是固体被液体湿润的量化指针， 接 触角 （ )俞小， 固体被液体湿润的程度俞大， 二者间的相容性俞好， 二者间的亲合力俞强。 当聚合物与聚合物增强剂的接触角低于 90° ， 更甚地低于或等于 60° , 尤其是低于或等于 30° ， 特别是低于或等于 10° 时， 聚合物与聚合物增强剂间相容性较好， 二者间有较强的亲 合力， 能发生 "表面润湿"甚至"展铺"。此时， 因聚合物与聚合物增强剂相互间作用力较强， 且聚合物增强剂以颗粒物 （分子聚合体） 或者形象地说以 "岛屿" 的形式分散于聚合物中， 聚合物分子自由 "流动"或 "滑动"的能力则被聚合物增强剂减弱， 聚合物分子的自由 "流 动"或 "滑动" 的范围被聚合物增强剂限制在相对较小的范围内， 聚合物宏观上表现出 "粘 度"上升， "流动性"下降。 因而， 上述聚合物增强剂可以减弱或延缓在生产和 /或贮藏过程 中 （如升华和 /或降解掉位于上述聚合物衣膜中的上述可升华的物质和 /或可降解成无害气体 的物质等）已形成的释药微孔自行缩小或闭合等的变化趋势， 具有稳定释药微孔大小的作用。 因此， 上述聚合物增强剂可以提高 （或改善）制剂贮藏稳定性及生产重现性、 释药性能等， 而且还可以增加衣膜的机械强度， 降低制剂的剂量倾释的可能性， 提高用药安全性。  I hope that it is not completely limited by this principle, the contact angle (usually considered as the quantitative indicator that the solid is wet by the liquid, the contact angle ( ) Yu Xiao, the degree to which the solid is wet by the liquid is large, the compatibility between the two is good, two Affinity between the two. When the contact angle of the polymer with the polymer enhancer is lower than 90 °, more than 60 °, especially lower than or equal to 30 °, especially less than or equal to 10 At ° °, the polymer has good compatibility with the polymer reinforcing agent, and there is a strong affinity between the two, which can cause "surface wetting" or even "spreading". At this time, it is enhanced by polymer and polymer. The agents have a strong interaction with each other, and the polymer reinforcing agent is dispersed in the polymer in the form of particles (molecular aggregates) or in the form of "islands", and the ability of the polymer molecules to "flow" or "slip" freely Attenuated by polymer enhancers, the range of free "flow" or "slip" of polymer molecules is limited by the polymer enhancer to a relatively small range, and the polymer macroscopically exhibits "viscosity" rise, "flowability" Decline. Thus, The polymer reinforcing agent can attenuate or delay the production and/or storage process (such as sublimation and/or degradation of the above-mentioned sublimable substance located in the above polymer film and/or a substance degradable into a harmless gas, etc.) The tendency of the formed micropores to shrink or close by themselves has a stable release pore size. Therefore, the above polymer enhancer can improve (or improve) the storage stability and production reproducibility of the preparation, Release performance, etc., but also can increase the mechanical strength of the film, reduce the possibility of dose dumping of the preparation, and improve the safety of medication.
上述的接触角间接地反应了聚合物与聚合物增强剂间的相容性或亲合力。 聚合物与聚合 物增强剂间的相容性或亲合力也可应用 "相似相容"原则来评价或预测， 如极性或非极性的 相似性。  The above contact angles indirectly reflect the compatibility or affinity between the polymer and the polymer reinforcing agent. The compatibility or affinity between the polymer and the polymer enhancer can also be evaluated or predicted using the "similar compatibility" principle, such as polar or non-polar similarity.
当聚合物增强剂为聚合物时， 可以用能表征聚合物分子间内聚力的大小的溶解度参数用 来评价聚合物与聚合物增强剂间的相容性。 通常情况下， 尤其对于非极性无定形聚合物共混 物， 当两聚合物的溶度参数之差小于 0. 5或聚合物与有机溶剂的溶度参数之差小于 1. 5时， 二 者便能以任意比例混容， 二者具有很好的相容性。 对于含有结晶聚合物的共混体系或者聚合 物分子具有很强的极性及能形成氢键时， 可以采用二维或三维溶解度参数来判断体系的相容 性（参见： Shaw M. T. , J Appl Polym Sci, 1974, 18： 449)。  When the polymer enhancer is a polymer, the solubility parameter between the polymer and the polymer enhancer can be evaluated using a solubility parameter that characterizes the cohesive force between the molecules of the polymer. 5之间,二。 The difference between the solubility parameter of the polymer and the organic solvent is less than 1.5. The person can be mixed in any proportion, and the two have good compatibility. For blends containing crystalline polymers or polymer molecules with strong polarity and ability to form hydrogen bonds, two- or three-dimensional solubility parameters can be used to determine system compatibility (see: Shaw MT, J Appl Polym) Sci, 1974, 18: 449).
本发明推荐应用下列较简便的方法来证明或预测聚合物与聚合物间的相容性： 1 )、 共同 溶剂法， 把两种高分子分别溶解到同一种溶剂中， 然后相混合， 根据两溶液混合情况来判断 高分子相容性大小。 2)、 显微镜法， 用相差显微镜法特别是电子显微镜法可直接观察其混相 容程度。 3)、 溶液粘度法， 溶液的粘度可以揭示共混聚合物溶液的相容程度， 在不同聚合物 说 明 书 浓度下， 以粘度对聚合物的百分组成作图， 如其关系成线性， 表明聚合物间达到分子水平的 完全相容； 如其关系成非线性， 则是部分相容； 当是完全不相容共混体系， 则其关系呈 s型曲 线。 4)、 热方法及动态力学分析方法（测玻璃化温度 Tg)， 本发明特别推荐此方法， 聚合物合 金体系会出现三种 Tg变化趋势， 假设二元合金体系中两种聚合物的 Tg分别为 Tgl和 Tg2 (Tgl< Tg2 （1)、 完全相容体系： 只出现一个 Tg, Tgl<Tg<Tg2; (2)、 完全不相容体系：出现二个 Tg ， 分别为 Tg Tg2; (3)、 部分相容体系： 出现二个 Tg/、 Tg ， Tgl<Tgl' <Tg2' <Tg2 。 The present invention recommends the following simple methods to prove or predict the compatibility between the polymer and the polymer: 1), the common solvent method, the two polymers are separately dissolved in the same solvent, and then mixed, according to The solution is mixed to judge the compatibility of the polymer. 2), microscopic method, phase contrast microscopy, especially electron microscopy, can directly observe the degree of compatibility. 3), solution viscosity method, the viscosity of the solution can reveal the compatibility degree of the polymer blend solution, in different polymers At the concentration of the specification, the viscosity is plotted against the percent composition of the polymer. If the relationship is linear, it indicates that the polymer is fully compatible at the molecular level; if the relationship is nonlinear, it is partially compatible; For the volume blending system, the relationship is s-shaped. 4), and dynamic mechanical thermal analysis method (measured glass transition temperature Tg), the present invention is especially recommend this method, a polymer alloy system, three kinds of change of Tg occurs, assuming the binary alloy system of two T g of the polymer T gl and Tg 2 respectively (T gl < Tg 2 (1), fully compatible system: only one Tg appears, T gl <Tg<Tg 2 ; (2), completely incompatible system: two Tg appear, Tg Tg 2 ; (3), partially compatible system: two Tg/, Tg, T gl <T gl '<Tg 2 '<Tg 2 appear.
更多或更为详细的聚合物与衣膜聚合物间的相容性的评价或预测方法可参考相关文献， 如， 聚合物合金相容性的预测和表征， 叶佳佳等， 工程塑料应用, 2007年， 第 35卷， 第 12 期， 第 81〜83页； 改善聚合物共混材料界面相容性的研究进展， 董萌等， 涂料涂装与电镀, 2006年 10月， 第 4卷第 5期， 第 24〜29页； 高分子合金膜的聚合物间相容性预测及表征， 谷晓昱等， 高分子材料科学与工程， 2004年 1月， 第 20卷第 1期， 第 5〜8页； 聚合物共混： II .聚合物的相容性， 姜胶东， 高分子通报, 1993年 9月， 第 3期， 第 178〜184页； 聚合物 共混的相容性及其理论计算， 吕飞杰等， 热带农业科学， 1985年 02期， 第 15〜19页。  More or more detailed methods for evaluating or predicting the compatibility between polymers and coating polymers can be found in related literature, eg, prediction and characterization of polymer alloy compatibility, Ye Jiajia et al., Engineering Plastics Applications, 2007 Year, Vol. 35, No. 12, pp. 81-83; Research Progress in Improving the Interfacial Compatibility of Polymer Blends, Dong Meng et al., Coatings and Plating, October 2006, Volume 4, Section 5 Period, pp. 24-29; Prediction and Characterization of Polymer Interlinkage Compatibility of Polymer Alloy Membranes, Gu Xiaotong, et al., Polymer Materials Science and Engineering, January 2004, Vol. 20, No. 1, pp. 5-8 Polymer blending: II. Compatibility of polymers, Ginger Jiaodong, Polymer Bulletin, September 1993, No. 3, pp. 178-184; Compatibility of polymer blends and their theoretical calculations, Lu Feijie et al., Tropical Agricultural Sciences, 1985, 02, pp. 15-19.
可用于本发明的聚合物增强剂包括但不限于药学可接受的填料增强剂、 微纤维增强剂及 其混合物。  Polymeric enhancers useful in the present invention include, but are not limited to, pharmaceutically acceptable filler reinforcing agents, microfiber reinforcing agents, and mixtures thereof.
可用于本发明的填料增强剂可以为药学可接受的刚性无机粒子及刚性有机粒子。 可用于 本发明的刚性无机粒子包括但不限于碳酸盐类、 硫酸盐类、 金属氧化物、 金属粉、 碳素化合 物、 含硅化合物 （如硅氧化物、 硅酸盐） 及其混合物的细或超细颗粒。 可用于本发明的刚性 无机粒子优选的实例包括但不限于绿坡缕石、 皂粘土、 碳酸钙、 硫酸钙、 硫酸钡、 炭黑、 二 氧化硅、 氧化铝、 氧化锌、 二氧化钛、 白陶土、 云母、 滑石、 磷酸钙、 碳酸镁、 氧化镁、 硅 酸镁、 三硅酸镁。 用于本发明的刚性无机粒子较佳地已用表面活性物质 （如高级脂肪酸、 高 级脂肪酸盐、 高级脂肪酸酯） 或高分子分散剂 （如聚烯烃、 聚酯、 聚丙烯酸酯或聚醚） 吸附 包裹处理或用有机硅垸偶联剂、 钛酸酯偶联剂、 锆铝酸酯偶联剂、 铝酸酯偶联剂等偶联剂处 理或在粒子表面上接枝或嵌段聚合或胶囊化聚合或用其他合适方式进行了表面改性。 可用于 本发明的刚性有机粒子优选的实例包括但不限于聚甲基丙烯酸甲酯 (PMMA)、 聚苯乙烯 (PS)、 甲基丙烯酸甲酯 /苯乙烯共聚物 (MMA/ST)及苯乙烯 /丙烯腈共聚物 (SAN)。  The filler reinforcing agent useful in the present invention may be pharmaceutically acceptable rigid inorganic particles and rigid organic particles. Rigid inorganic particles useful in the present invention include, but are not limited to, carbonates, sulfates, metal oxides, metal powders, carbon compounds, silicon-containing compounds (such as silicon oxides, silicates), and mixtures thereof, or Ultrafine particles. Preferable examples of the rigid inorganic particles usable in the present invention include, but are not limited to, attapulgite, soap clay, calcium carbonate, calcium sulfate, barium sulfate, carbon black, silica, alumina, zinc oxide, titanium dioxide, white clay, Mica, talc, calcium phosphate, magnesium carbonate, magnesium oxide, magnesium silicate, magnesium trisilicate. The rigid inorganic particles used in the present invention preferably have used a surface active material (such as a higher fatty acid, a higher fatty acid salt, a higher fatty acid ester) or a polymeric dispersant (such as a polyolefin, a polyester, a polyacrylate or a polyether). Adsorption coating treatment or treatment with a coupling agent such as a silicone germanium coupling agent, a titanate coupling agent, a zirconium aluminate coupling agent, an aluminate coupling agent, or grafting or block polymerization on the surface of the particles. Alternatively, the surface modification can be carried out by encapsulation polymerization or by other suitable means. Preferred examples of rigid organic particles useful in the present invention include, but are not limited to, polymethyl methacrylate (PMMA), polystyrene (PS), methyl methacrylate/styrene copolymer (MMA/ST), and styrene. / Acrylonitrile copolymer (SAN).
上述刚性粒子的平均粒径 （直径）通常不大于 l m， 较佳地不大于 400nm， 更佳地不大 于 100 更更佳地不大于 20nm， 最佳地不大于 5nm。 纳米级的粒子（不大于 100 可以更 大程度地同时提高强度、 韧性、 抗冲击能力及释药微孔尺寸稳定性， 因而为优选。  The above-mentioned rigid particles have an average particle diameter (diameter) of usually not more than 1 m, preferably not more than 400 nm, more preferably not more than 100, more preferably not more than 20 nm, and most preferably not more than 5 nm. Nano-sized particles (not more than 100 can increase strength, toughness, impact resistance, and release pore size stability to a greater extent, and are therefore preferred.
可用于本发明的微纤维增强剂包括无机微纤维、 有机微纤维和金属微纤维。 无机微纤维 是以矿物质为原料制成的化学微纤维， 可用的实例如玻璃微纤维、 石英玻璃微纤维、 硼微纤 维、 陶瓷微纤维和金属微纤维等。 可用的有机微纤维实例如合成微纤维如芳纶微纤维、 奥纶 微纤维、 聚酯微纤维、 尼龙微纤维、 维尼微纶纤维、 聚丙烯微纤维、 聚酰亚胺微纤维等； 天 然微纤维如棉微纤维、 剑麻微纤维、 木微纤维等。 金属微纤维的实例如银、 铜、 镍等金属微 纤维。  Microfiber reinforcing agents useful in the present invention include inorganic microfibers, organic microfibers, and metal microfibers. Inorganic microfibers Chemical microfibers made of mineral materials, such as glass microfibers, quartz glass microfibers, boron microfibers, ceramic microfibers, and metal microfibers. Examples of useful organic microfibers such as synthetic microfibers such as aramid microfibers, aramid microfibers, polyester microfibers, nylon microfibers, vinylon microfibers, polypropylene microfibers, polyimide microfibers, etc.; Fibers such as cotton microfibers, sisal microfibers, wood microfibers, and the like. Examples of the metal microfibers are metal microfibers such as silver, copper, and nickel.
本文此处所使用的术语 "微纤维"是指由于它们的长宽比可通常描述为纤维的颗粒材料， 用于本文的优选的微纤维的长宽比为约 10 : 1-约 500 : 1， 更优选约 25 : 1-300 : 1。 上述纤维的 平均直径通常不大于 1 μ m,较佳地不大于 400 更佳地不大于 100nm，更更佳地不大于 20nm 最佳地不大于 5nm。 上述纤维的平均长度通常不大于 ΙΟΟ μ πι, 较佳地不大于 ΙΟ μ πι, 更佳地 不大于 1 μ m, 最佳地不大于 100nm。  The term "microfiber" as used herein, refers to a particulate material that can be generally described as fibers due to their aspect ratio, and preferred microfibers for use herein have an aspect ratio of from about 10:1 to about 500:1. More preferably, it is about 25: 1-300: 1. The above fibers generally have an average diameter of not more than 1 μm, preferably not more than 400, more preferably not more than 100 nm, still more preferably not more than 20 nm, most preferably not more than 5 nm. The average length of the above fibers is usually not more than ΙΟΟ μ πι, preferably not more than ΙΟ μ πι, more preferably not more than 1 μ m, and most preferably not more than 100 nm.
用于本发明的聚合物增强的刚性粒子特别是刚性聚合物还可以外覆于聚合物增韧剂 （此 处述的 "聚合物增韧剂"是指具有降低衣膜脆性和提高衣膜抗冲击性能的药学可接受的成分， 下同）， 从而形成 "硬壳一软核结构"。 上述的 "核一壳结构"中， "壳"可以完全或部分包覆 "核 "； "壳"内可以含有一个或多个 "核 "； "壳"中还可以含有更小的 "核 "； 壳"内的 "核" 中也可以包含 "壳" 的组分或更小的 "核一壳结构"； 还可以是更复杂的硬 /软 /硬三层； 软 / 说 明 书 The polymer-reinforced rigid particles used in the present invention, particularly rigid polymers, may also be coated with a polymeric toughening agent (herein referred to as "polymeric toughening agent" means having reduced film brittleness and improved film resistance. A pharmaceutically acceptable component of impact properties, the same as below, thereby forming a "hard shell-soft core structure". In the above "nuclear-shell structure", "shell" may completely or partially coat "nuclear";"shell" may contain one or more "nuclear";"shell" may also contain smaller "nuclear" The "core" in the shell may also contain a "shell" component or a smaller "core-shell structure"; it may also be a more complex hard/soft/hard layer; soft/ Instruction manual
硬 /软 /硬四层等模态的粒子。上述的 "核一壳结构"粒子同时具有较好的增强及增韧的作用， 作用优于单纯的聚合物增强剂或聚合物增韧剂， 故为优选。 上述的 "核一壳结构"中， "壳" 通常占整个结构体积的 0. 5— 50%, 较佳地 1 30%, 更佳地 2— 10%。 Hard/soft/hard four-layer modal particles. The above-mentioned "core-shell structure" particles have a better reinforcing and toughening effect at the same time, and are superior to a simple polymer reinforcing agent or a polymer toughening agent, which is preferable. In the above "core-shell structure", the "shell" usually accounts for 0.5 to 50%, preferably 1 30%, more preferably 2 to 10%, of the entire structure volume.
据信，上述"核一壳结构"粒子还具有增加衣膜聚合物在温度高于其玻璃化转变温度（7；) 时的 "流动性"及 "延展性"， 减少 "熔体" 内部张力且同时还能维持较高的 "熔体"强度， 加快 "熔融"， 促进 "塑化"， 改善 "加工性"， 这些有利于聚合物衣膜 （控释衣膜） 的包衣及 愈合， 缩短它们加工所需的时间， 减少上述致孔剂在上述加工过程中的挥发或降解， 因而具 有更强的稳定释药微孔大小的作用。 因此， 上述 "核一壳结构"粒子在本发明最优选。  It is believed that the above "nuclear-shell structure" particles also have the "fluidity" and "ductility" of increasing the film polymer at temperatures above its glass transition temperature (7;), reducing the "melt" internal tension. At the same time, it can maintain high "melt" strength, accelerate "melting", promote "plasticization", and improve "processability", which is beneficial to the coating and healing of polymer film (controlled release film). The time required for their processing is shortened, and the volatilization or degradation of the above porogen in the above process is reduced, thereby having a stronger effect of stabilizing the release pore size. Therefore, the above "core-shell structure" particles are most preferred in the present invention.
适宜作为 "核一壳结构"中 "核" 的成分即聚合物增韧剂包括天然和合成弹性聚合物， 如天然橡胶、合成橡胶和热塑性弹性体。它们通常衍生自各种单体， 如烯烃 (如 C2-C8烯烃中 的乙烯、 丙烯、 1 丁烯、 4 甲基一 1一戊烯）、链烯基芳族单体 (如 C2-C8烯基芳族单体中的 苯乙烯和 α -甲基苯乙烯）、 共轭二烯（如 C4-C8共轭二烯中的丁二烯、 异戊二烯和氯丁二烯） 和乙烯基羧酸及其衍生物（如乙酸乙烯酯、 丙烯酸、 垸基丙烯酸、 丙烯酸乙酯、 甲基丙烯酸甲 酯、 丙烯腈）。 它们可以是均聚物， 也可以是共聚物。  Polymeric toughening agents suitable as "nuclear" in the "core-shell structure" include natural and synthetic elastomeric polymers such as natural rubber, synthetic rubber and thermoplastic elastomers. They are usually derived from various monomers such as olefins (such as ethylene, propylene, 1 butene, 4 methyl-1-pentene in C2-C8 olefins), alkenyl aromatic monomers (such as C2-C8 olefins). Styrene and α-methylstyrene in aromatic monomers, conjugated dienes (such as butadiene, isoprene and chloroprene in C4-C8 conjugated dienes) and vinyl Carboxylic acids and derivatives thereof (such as vinyl acetate, acrylic acid, methacrylic acid, ethyl acrylate, methyl methacrylate, acrylonitrile). They may be homopolymers or copolymers.
更具体地说， 包括不限于所有聚合物橡胶基材料， 如从丙烯酸、 甲基丙烯酸甲酯-丁二烯 -苯乙烯 (MBS)型耐冲击性改进剂衍生的那些； 含硅的橡胶聚合物和共聚物， 如硅氧烷， 硅酮 等等； 合成橡胶， 如丁二烯橡胶， 苯乙烯一丁二烯橡胶 （SBR), 和异戊二烯， 等等； 含有柔 性链以降低玻璃化转变温度的聚合物， 如聚酯； 聚烯烃类； 乙烯基芳族烃一二烯烃嵌段共聚 物； 聚氨酯类； 橡胶状聚醚， 如乙二醇和丙二醇型的聚合物， 等等； 以及它们的共混物， 接 枝物， 和共聚物。  More specifically, it includes, without limitation, all polymer rubber-based materials such as those derived from acrylic acid, methyl methacrylate-butadiene-styrene (MBS) type impact resistance improvers; silicon-containing rubber polymers And copolymers such as silicones, silicones, etc.; synthetic rubbers such as butadiene rubber, styrene-butadiene rubber (SBR), and isoprene, etc.; containing flexible chains to reduce vitrification Temperature-changing polymers, such as polyesters; polyolefins; vinyl aromatic hydrocarbon-diene block copolymers; polyurethanes; rubbery polyethers, polymers such as ethylene glycol and propylene glycol type, and the like; Blends, grafts, and copolymers.
适宜本发明的 "核一壳结构" 中 "核" 的成分即聚合物增韧剂可以包括聚烯烃聚合物， 其为 CnH2n的一般结构， 包括聚乙烯、 聚丙烯和聚异丁烯， 优选的均聚物为聚乙烯、 ULDPE (超 低密度聚乙烯）、 LLDPE (线性低密度聚乙烯）、 HDPE (高密度聚乙烯)和 MDPE (中密度聚乙烯）以 及全同立构聚丙烯。 该一般结构的聚烯烃树脂及其制备方法在本领域中是众所周知的， 并见 述于例如美国专利号 2933480、 3093621、 3211709、 3646168、 3790519、 3884993、 3894999、 4059654、 4166055和 484334中。 The component of the "core" which is suitable for the "core-shell structure" of the present invention, that is, the polymer toughening agent may comprise a polyolefin polymer which is a general structure of C n H 2n , including polyethylene, polypropylene and polyisobutylene, preferably The homopolymers are polyethylene, ULDPE (ultra low density polyethylene), LLDPE (linear low density polyethylene), HDPE (high density polyethylene) and MDPE (medium density polyethylene) and isotactic polypropylene. The general structure of polyolefin resins and methods for their preparation are well known in the art and are described, for example, in U.S. Patent Nos. 2,933,480, 3,309,621, 3,211,709, 3,646,168, 3,790,519, 3,884,993, 3,894,999, 4,059,654, 4,166,055, and 484,334.
适宜本发明的 "核一壳结构" 中 "核" 的成分即聚合物增韧剂也可以包括各种聚烯烃的 共聚物， 如乙烯与 α -烯烃类的丙烯和 4-甲基 -1-戊烯的共聚物。 一个合适的例子如乙烯与 C3-C10单烯烃和非共轭二烯的共聚物（此处称之为 EPDM共聚物）。  The polymer toughening agent which is suitable for the "core" in the "core-shell structure" of the present invention may also include copolymers of various polyolefins such as ethylene and α-olefins of propylene and 4-methyl-1- a copolymer of pentene. A suitable example is a copolymer of ethylene and a C3-C10 monoolefin and a non-conjugated diene (referred to herein as an EPDM copolymer).
适宜的 "核一壳结构"中 "核"的成分即聚合物增韧剂还可以包括共轭二烯均聚物和无 规共聚物。 其例子包括聚丁二烯、 丁二烯-苯乙烯共聚物、 丁二烯 -丙烯酸酯共聚物、 异戊二 烯-异丁烯共聚物、 氯丁二烯聚合物、 丁二烯丙烯腈聚合物、 聚异戊二烯。  The "core" component of the "core-shell structure", i.e., the polymeric toughening agent, may also include conjugated diene homopolymers and random copolymers. Examples thereof include polybutadiene, butadiene-styrene copolymer, butadiene-acrylate copolymer, isoprene-isobutylene copolymer, chloroprene polymer, butadiene acrylonitrile polymer, Polyisoprene.
一个适宜作为机械性能改善剂 （聚合物增强剂） 的 "核一壳结构"粒子例子包括 ΑΒ (双 -嵌段）、 (AB) m-R (双-嵌段)和 ABA' (三-嵌段)嵌段共聚物。 嵌段 A和 A'， 通常为链烯基芳族 单元， 嵌段 B通常为共轭二烯单元。 对式 (AB) m-R的嵌段共聚物而言， 整数 m为至少 2， R为 用于结构 AB的嵌段的多官能偶合剂。特别适宜的例子如聚苯乙烯-聚丁二烯 (SBR)，聚苯乙烯- 聚（乙烯-丙烯）、聚苯乙烯-聚异戊二烯、聚（α -甲基苯乙烯） -聚丁二烯、聚苯乙烯-聚丁二烯 -聚苯乙烯，聚苯乙烯-聚（乙烯-丙烯) -聚苯乙烯、 聚苯乙烯-聚异戊二烯-聚苯乙烯及聚（α - 甲基苯乙烯) -聚丁二烯-聚（α -甲基苯乙烯）以及其选择性氢化产物等。 也可使用前述嵌段共 聚物的混合物。 这类共聚物可购自多种渠道， 如包括 Phi llips Petroleum的名为 S OLPRENE 的商品、 Shell Chemical Co. , 的名为 KRAT0N的商品、 Dexco名为 VECTOR的商品及 Kuraray 的名为 SEPT0N的商品。  An example of a "core-shell structure" particle suitable as a mechanical property improver (polymeric enhancer) includes bismuth (double-block), (AB) mR (double-block), and ABA' (tri-block). Block copolymer. Blocks A and A' are typically alkenyl aromatic units, and block B is typically a conjugated diene unit. For the block copolymer of formula (AB) m-R, the integer m is at least 2, and R is a polyfunctional coupling agent for the block of structure AB. Particularly suitable examples are polystyrene-polybutadiene (SBR), polystyrene-poly(ethylene-propylene), polystyrene-polyisoprene, poly(α-methylstyrene)-polybutylene Diene, polystyrene-polybutadiene-polystyrene, polystyrene-poly(ethylene-propylene)-polystyrene, polystyrene-polyisoprene-polystyrene and poly(α-甲Styrene) - polybutadiene-poly(α-methylstyrene) and its selective hydrogenation products and the like. Mixtures of the foregoing block copolymers can also be used. Such copolymers are commercially available from a variety of sources, such as the product named S OLPRENE from Phi llips Petroleum, the product named KRAT0N from Shell Chemical Co., the product under the name VECTOR from Dexco, and the product named SEPT0N from Kuraray. .
另一个适宜作为机械性能改善剂 （聚合物增强剂） 的 "核一壳结构"粒子例子如包含乙 烯基芳族单体和共轭二烯单体的星形嵌段共聚物。 该类型的共聚物一般包含约 60%至 95% (重 量）的聚合乙烯基芳族单体和约 40%至 5% (重量）的聚合共轭二烯单体。 所述共聚物具有至少 说 明 书 Another example of a "core-shell structure" particle suitable as a mechanical property improving agent (polymer reinforcing agent) is a star block copolymer comprising a vinyl aromatic monomer and a conjugated diene monomer. Copolymers of this type generally comprise from about 60% to about 95% by weight of the polymeric vinyl aromatic monomer and from about 40% to about 5% by weight of the polymeric conjugated diene monomer. The copolymer has at least Description
3个形成星形构型的聚合物链。 各链的末端为其上连接有弹性聚合物链段的基本上为非弹性 的链段。 有时将这些嵌段共聚物称为 "支化的"聚合物 (如美国专利号 4097550中所述）， 并 且其用量类似于其它共轭二烯基作为机械性能改善剂。  Three polymer chains forming a star configuration. The ends of each chain are substantially inelastic segments to which are attached elastic polymer segments. These block copolymers are sometimes referred to as "branched" polymers (as described in U.S. Patent No. 4,097,550) and are used in amounts similar to other conjugated dienyl groups as mechanical property improvers.
适宜作为机械性能改善剂 （聚合物增强剂） 的 "核一壳结构"粒子例子还包括但局限于 聚乙烯-乙酸乙烯（EVA)、 乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物 （E-VA-C0) 、 乙烯 _C1〜 C8 (优选 C 1〜C4)烷基丙烯酸 -羰基 (碳单氧化物)三聚物、乙烯 -CI〜C8 (优选 CI〜C4)垸基丙烯 酸共聚物和聚丙烯腈-丁二烯一苯乙烯 (ABS)。  Examples of "core-shell structure" particles suitable as mechanical property improvers (polymeric enhancers) include but are limited to polyethylene-vinyl acetate (EVA), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymers. (E-VA-C0), ethylene_C1~C8 (preferably C1~C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-CI~C8 (preferably CI~C4) methacrylic acid copolymerization And polyacrylonitrile-butadiene-styrene (ABS).
本发明所用的上述 "核一壳结构"粒子以一定的形状及大小的粒子存于聚合物衣膜 （控 释衣膜） 中作为机械性能改善剂 （聚合物增强剂）。 关于其形状， 构成所述 "核一壳结构"的 粒子典型地为球形。 但它们可有任何适合的形状， 各种形状的粒子可通过聚合物粒子技术领 域已知的方法制备。 其他适合的粒子形状的例子包括但不限于：长径比大于 1 : 1 的椭圆体粒 子、 莓形粒子、 多瓣形粒子、 哑铃形粒于、 凝聚粒子、 双瓣形粒子和空心球粒子等。 关于其 大小， 通常其平均粒径 （直径） 不大于 l w m。 较佳地， 其平均粒径不大于 400nm， 更佳地不 大于 100nm， 更更佳地不大于 20歷， 最佳地不大于 5nm。 一般地， 较小的粒子有利于改善抗 冲强度。  The above-mentioned "core-shell structure" particles used in the present invention are present in a polymer film (control release film) as a mechanical property improving agent (polymer reinforcing agent) in a certain shape and size. Regarding its shape, the particles constituting the "core-shell structure" are typically spherical. However, they may have any suitable shape, and particles of various shapes may be prepared by methods known in the art of polymer particle technology. Examples of other suitable particle shapes include, but are not limited to, ellipsoidal particles having a major aspect ratio greater than 1:1, raspberry shaped particles, multi-lobed particles, dumbbell shaped particles, agglomerated particles, double-lobed particles, and hollow spherical particles, and the like. . Regarding its size, usually its average particle diameter (diameter) is not more than l w m. Preferably, the average particle diameter is not more than 400 nm, more preferably not more than 100 nm, still more preferably not more than 20 minutes, and most preferably not more than 5 nm. Generally, smaller particles contribute to improved impact strength.
适宜本发明的机械性能改善剂 （聚合物增强剂） 的 "核一壳结构"粒子的熔点 （或晶体 熔化温度， Crystall ine Melt Temperature ) 或 /和维氏软化点（Vicat Softening Point)通 常不低于上述控释衣膜中的聚合物的玻璃化转变温度 （Tg)， 较佳地高出其 5°C (含） ， 更佳 地高出 10°C (含） ， 最佳地高出 20°C (含） ； 而其（中心） 玻璃化温度 （Glass Transition Temperature )通常要求低于上述控释衣膜中的聚合物的玻璃化转变温度 （Tg)， 通常不高于 温度 15°C，最佳地不高于温度 0°C ;此外，上述"核一壳结构"粒子还应具有较好的机械性能， 如较高的抗拉能力， 有较高断裂伸长率或断裂拉伸强度。  The melting point (or crystal melting temperature, Crystall ine Melt Temperature) or/and Vicat Softening Point of a "core-shell structure" particle suitable for the mechanical property improving agent (polymer reinforcing agent) of the present invention is generally not low. The glass transition temperature (Tg) of the polymer in the controlled release film is preferably 5 ° C (inclusive), more preferably 10 ° C (inclusive), and most preferably 20 °C (inclusive); and its (center) glass transition temperature (Glass Transition Temperature) is usually required to be lower than the glass transition temperature (Tg) of the polymer in the controlled release coating film, usually not higher than the temperature of 15 ° C, Preferably, the temperature is not higher than 0 ° C; in addition, the above "core-shell structure" particles should also have good mechanical properties, such as high tensile strength, high elongation at break or tensile strength at break. .
适宜作为机械性能改善剂 （聚合物增强剂） 的 "核一壳结构"粒子其他参数优选如下： 熔点 （或晶体熔化温度， Crystall ine Melt Temperature ) (DSC, via ASTM D3418 ISO 3146) 或 /和维氏软化点（Vicat Softening Point, via ASTM D1525 ISO 306)优选为 60〜2000°C， 更优选为 80〜1000°C，特别优选为 100〜500°C ;维氏软化点（Vicat Softening Point , via ASTM D1525 ISO 306)优选为 45〜150°C , 更优选为 45〜100°C，特别优选为 50〜80°C； 断裂伸长率 Other parameters of the "core-shell structure" particles suitable as mechanical property improvers (polymeric enhancers) are preferably as follows: Melting point (or crystal melting temperature, Crystall ine Melt Temperature) (DSC, via ASTM D3418 ISO 3146) or / and dimension Vicat Softening Point (via ASTM D1525 ISO 306) is preferably 60 to 2000 ° C, more preferably 80 to 1000 ° C, particularly preferably 100 to 500 ° C; Vicat Softening Point, via ASTM D1525 ISO 306) is preferably 45 to 150 ° C, more preferably 45 to 100 ° C, particularly preferably 50 to 80 ° C; elongation at break
(Tensi le Elongation @ Break)优选为 200〜5000% (via ASTM D638 /ISO 527-2 ) ； 断裂 拉伸强度 (Tensi le Strength § Break )优选为 l〜50MPa (via ASTM D638/IS0 527-2 ) ；(Tensi le Elongation @ Break) is preferably 200 to 5000% (via ASTM D638 / ISO 527-2); Tensile Strength (Tensi le Strength § Break) is preferably 1 to 50 MPa (via ASTM D638/IS0 527-2) ;
(中心)玻璃化温度 (Glass Transition Temperature)优选为 - 10〜- 200°C (via ASTM D5418 loss modulus peak at 1 hz ) ； 熔体流动速率（Melt Flow Rate) (190°C/2. 16kg)优选为 0. 5〜 150g/10min( via ASTM D1238 ISO 1133)，更优选为 l〜100g/10min，特别优选为 2〜50g/10min。 (Center) Glass Transition Temperature is preferably -10 to -200 ° C (via ASTM D5418 loss modulus peak at 1 hz ); Melt Flow Rate (190 ° C / 2.16 kg) It is preferably 0.5 to 150 g/10 min (via ASTM D1238 ISO 1133), more preferably 1 to 100 g/10 min, and particularly preferably 2 to 50 g/10 min.
聚合物增强剂通常用量 0. 5〜50% (重量比）， 较佳地 1°/。〜30% (重量比）， 更佳地 2%〜20% The polymer reinforcing agent is usually used in an amount of from 0.5 to 50% by weight, preferably 1 ° /. ~30% (by weight), more preferably 2%~20%
(重量比）， 这是基于聚合物衣膜 （控释衣膜） 组分的干的总重量。 (by weight), which is based on the total dry weight of the polymer film (controlled release film) component.
一个衣膜聚合物与聚合物增强剂联合应用的实例为， 衣膜聚合物选自含极性基团的不溶 于或几乎不溶于水及消化液的聚合物， 如纤维素酯类聚合物、 丙烯酸 (酯)类聚合物、 聚醋酸 乙烯酯类，而聚合物增强剂选自极性的刚性无机粒子的细或超细颗粒（粒径优选不大于 lOOnm An example of a film-coated polymer in combination with a polymer reinforcing agent is that the film-forming polymer is selected from a polymer containing a polar group that is insoluble or hardly soluble in water and a digestive solution, such as a cellulose ester polymer, An acrylic polymer, polyvinyl acetate, and the polymer enhancer is selected from fine or ultrafine particles of polar rigid inorganic particles (particle diameter is preferably not more than 100 nm)
(直径））， 如碳酸盐、 硫酸盐、 金属氧化物、 硅氧化物、 硅酸盐及其混合物， 更佳地为其已 用极性高分子分散剂（如聚丙烯酸酯）吸附包裹处理方式进行了表面改性的细或超细颗粒（粒 径优选不大于 lOOnm (直径）） 。 上述含极性基团的纤维素酯类聚合物的实例如醋酸纤维素、 丙酸纤维素、 醋酸丁酸纤维素、 醋酸丙酸纤维素 （cel lulose acetate propionate). 硝酸纤 维素、 三戊酸纤维素、 二琥珀酸纤维素。 上述上述含极性基团的丙烯酸 (酯)类聚合物、 聚醋 酸乙烯酯类的可应用实例包括但不限于聚乙烯乙酸酯、 甲基丙烯酸 (酯)聚合物、氯乙烯 -乙烯 醇-醋酸乙烯酯的三元共聚物、聚甲基丙烯酸甲酯、丙烯酸乙酯一间丙烯酸甲酯聚合物、聚乙 烯乙酸酯、 丙烯酸乙酯-丙烯酸乙酯-氯化三甲基氨基乙基间丙烯酸甲酯聚合物 （poly 说 明 书 (diameter)), such as carbonates, sulfates, metal oxides, silicon oxides, silicates, and mixtures thereof, more preferably coated with a polar polymeric dispersant (such as polyacrylate) The surface is subjected to surface-modified fine or ultrafine particles (the particle diameter is preferably not more than 100 nm (diameter)). Examples of the above polar group-containing cellulose ester polymer are cellulose acetate, cellulose propionate, cellulose acetate butyrate, cel lulose acetate propionate. nitrocellulose, trivaleric acid Cellulose, cellulose succinate. Applicable examples of the above-mentioned polar group-containing acrylic polymer, polyvinyl acetate include, but are not limited to, polyvinyl acetate, methacrylic acid polymer, vinyl chloride-vinyl alcohol- Terpolymer of vinyl acetate, polymethyl methacrylate, ethyl acrylate, a methyl acrylate polymer, polyvinyl acetate, ethyl acrylate-ethyl acrylate-trimethylaminoethyl chloride Methyl acrylate polymer (poly Instruction manual
( ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride))。  (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride)).
一个优选衣膜聚合物与聚合物增强剂联合应用的实例为， 衣膜聚合物选自含非极性基团 的不溶于或几乎不溶于水及消化液的纤维素酯类聚合物 （如乙基纤维素、 三十二酸纤维素、 三棕榈酸纤维素、 二棕榈酸纤维素）， 而聚合物增强剂选自用表面活性物质（如高级脂肪酸、 高级脂肪酸盐、 高级脂肪酸酯） 吸附包裹处理方式进行了表面改性的极性刚性无机粒子， 如 碳酸盐、 硫酸盐、 金属氧化物、 硅氧化物、 硅酸盐及其混合物的细或超细颗粒 （粒径优选不 大于 lOOnm (直径）），特别优选表面被硬脂酸包覆的纳米级碳酸钙粒子（粒径优选不大于 lOOnm (直径）） 。  An example of a preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from a cellulose ester polymer containing a non-polar group that is insoluble or hardly soluble in water and a digestive juice (such as B). Cellulose, cellulose dodecanoate, cellulose tripalmitate, cellulose dipalmitate), and polymer enhancer is selected from surfactants (such as higher fatty acids, higher fatty acid salts, higher fatty acid esters) Adsorption-encapsulation treatment of surface-modified polar rigid inorganic particles, such as carbonates, sulfates, metal oxides, silicon oxides, silicates, and mixtures thereof, fine or ultrafine particles (particle size is preferably not greater than 100 nm (diameter)), particularly preferably nano-sized calcium carbonate particles having a surface coated with stearic acid (particle diameter is preferably not more than 100 nm (diameter)).
另一个优选衣膜聚合物与聚合物增强剂联合应用的实例为， 衣膜聚合物选自不溶于或几 乎不溶于水及消化液的纤维素酯类聚合物， 而聚合物增强剂粒子选自同时含有极性及非极性 基团的甲基丙烯酸甲酯-苯乙烯共聚物 (MMA-ST)、 苯乙烯-丙烯腈共聚物 (SAN)、 苯乙烯 -丁二 烯-丙烯腈三聚物 (ABS)、 甲基丙烯酸甲酯-丁二烯-苯乙烯三聚物 (MBS)、乙烯-乙烯醋酸 -羰基 (碳单氧化物）三聚物（E-VA-C0)、 乙烯 -C1〜C8 (优选 C1〜C4)垸基丙烯酸 -羰基 (碳单氧化物） 三聚物、 乙烯 - (C1〜C8) (优选 C1〜C4)垸基丙烯酸共聚物或它们的混合物 （粒径优选不大于 400nm (直径）， 更优选不大于 lOOnm (直径）），其中甲基丙烯酸甲酯-苯乙烯共聚物 (MMA-ST)、 甲基丙烯酸甲酯-丁二烯-苯乙烯三聚物 (MBS)为更优选。上述纤维素酯类聚合物的可应用实例 包括但不限于乙基纤维素、 醋酸纤维素、 丙酸纤维素、 醋酸丁酸纤维素、 醋酸丙酸纤维素 An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of cellulose ester polymers which are insoluble or hardly soluble in water and digestive juice, and the polymer reinforcing agent particles are selected from the group consisting of Methyl methacrylate-styrene copolymer (MMA-ST), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer containing both polar and non-polar groups (ABS), methyl methacrylate-butadiene-styrene terpolymer (MBS), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~ C8 (preferably C1 to C4) methacrylic acid-carbonyl (carbon monooxide) trimer, ethylene-(C1 to C8) (preferably C1 to C4) methacrylic acid copolymer or a mixture thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm (diameter), wherein methyl methacrylate-styrene copolymer (MMA-ST), methyl methacrylate-butadiene-styrene terpolymer (MBS) More preferred. Useful examples of the above cellulose ester-based polymer include, but are not limited to, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate
( cellulose acetate propionate ), 硝酸纤维素、 三戊酸纤维素、 二琥珀酸纤维素及它们的 混合物。 (cellulose acetate propionate ), nitrocellulose, cellulose trivalerate, cellulose succinate, and mixtures thereof.
另一个优选衣膜聚合物与聚合物增强剂联合应用的实例为， 衣膜聚合物选自不溶于或几 乎不溶于水及消化液的丙烯酸 (酯)类聚合物， 而聚合物增强剂粒子选自聚甲基丙烯酸甲酯 (PMMA)、 甲基丙烯酸甲酯-苯乙烯共聚物 (MMA-ST)、 甲基丙烯酸甲酯-丁二烯-苯乙烯三聚物 (MBS)、 乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物 （E-VA-C0) 、 乙烯 -C1〜C8 (优选 C1〜C4) 烷基丙烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C8 (优选 C1〜C4)垸基丙烯酸共聚物、 丙烯 酸树脂类抗冲击改性剂或它们的混合物（粒径优选不大于 400nm (直径）， 更优选不大于 lOOnm An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of acrylic acid polymers which are insoluble or hardly soluble in water and digestive juice, and polymer reinforcing agent particles are selected. Self-polymethyl methacrylate (PMMA), methyl methacrylate-styrene copolymer (MMA-ST), methyl methacrylate-butadiene-styrene terpolymer (MBS), ethylene-ethylene acetate -carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~C8 (preferably C1~C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C8 (preferably C1 to C4) mercaptoacrylic acid copolymer, acrylic resin type impact modifier or a mixture thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm
(直径））。上述聚合物的可应用实例包括但不限于不溶于或几乎不溶于水及消化液的甲基丙 烯酸 (酯)聚合物、 聚甲基丙烯酸甲酯、 丙烯酸乙酯-间丙烯酸甲酯聚合物、 丙烯酸乙酯 -丙烯 酸乙酯一氯化三甲基氨基乙基间丙烯酸甲酯聚合物 （poly (diameter)). Applicable examples of the above polymers include, but are not limited to, methacrylic acid polymers, polymethyl methacrylate, ethyl acrylate-m-methyl acrylate polymer, acrylic acid which are insoluble or hardly soluble in water and digestive juices. Ethyl ester-ethyl acrylate monomethyl trimethylaminoethyl methyl acrylate polymer (poly
( ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride))及它们 的混合物。  (ethylacrylate, methylmetacrylate, trimethylamonioethylmetacrylatchloride)) and mixtures thereof.
另一个优选衣膜聚合物与聚合物增强剂联合应用的实例为， 衣膜聚合物选自不溶于或几 乎不溶于水及消化液的聚醋酸乙烯酯类，而聚合物增强剂粒子选自甲基丙烯酸甲酯-苯乙烯共 聚物 (MMA-ST)、苯乙烯-丙烯腈共聚物 (SAN)、苯乙烯-丁二烯-丙烯腈三聚物 (ABS)、 甲基丙烯 酸甲酯-丁二烯-苯乙烯三聚物 (MBS)、 乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物（E-VA-C0) 、 乙烯 -C1〜C8 (优选 C1〜C4)垸基丙烯酸 -羰基 (碳单氧化物)三聚物、乙烯 -C1〜C8 (优选 C1〜C4) 垸基丙烯酸共聚物及它们的混合物（粒径优选不大于 400nm (直径）， 更优选不大于 lOOnm (直 径））。上述聚合物的可应用实例包括但不限于聚乙烯乙酸酯、氯乙烯一乙烯醇一醋酸乙烯酯 的三元共聚物、 氯乙烯一醋酸乙烯酯共聚物及它们的混合物。  An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of polyvinyl acetate which is insoluble or hardly soluble in water and digestive juice, and the polymer reinforcing agent particles are selected from the group consisting of Methyl acrylate-styrene copolymer (MMA-ST), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer (ABS), methyl methacrylate-butyl Alkene-styrene terpolymer (MBS), ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~C8 (preferably C1~C4) methacrylic acid-carbonyl (Carbon monooxide) terpolymer, ethylene-C1 to C8 (preferably C1 to C4) mercaptoacrylic acid copolymer and mixtures thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm (diameter)) . Useful examples of the above polymers include, but are not limited to, polyvinyl acetate, a terpolymer of vinyl chloride-vinyl alcohol-vinyl acetate, a vinyl chloride-vinyl acetate copolymer, and mixtures thereof.
另一个优选衣膜聚合物与聚合物增强剂联合应用的实例为， 衣膜聚合物选自聚氯乙烯， 而聚合物增强剂粒子选自甲基丙烯酸甲酯-苯乙烯共聚物 (MMA-ST)、 苯乙烯-丙烯腈共聚物 (SAN)、 苯乙烯-丁二烯-丙烯腈三聚物 (ABS)、 甲基丙烯酸甲酯-丁二烯-苯乙烯三聚物 (MBS)、 乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物 （E-VA-C0) 、 乙烯 -C1〜C8 (优选 C1〜C4)烷基丙烯 酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C8 (优选 C1〜C4)垸基丙烯酸共聚物或它们的混合物 (粒径优选不大于 400nm (直径）， 更优选不大于 lOOnm (直径）） 。  An example of another preferred coating film polymer in combination with a polymer reinforcing agent is that the coating film polymer is selected from the group consisting of polyvinyl chloride and the polymer reinforcing agent particles are selected from the group consisting of methyl methacrylate-styrene copolymer (MMA-ST). ), styrene-acrylonitrile copolymer (SAN), styrene-butadiene-acrylonitrile terpolymer (ABS), methyl methacrylate-butadiene-styrene terpolymer (MBS), ethylene- Ethylene acetate-carbonyl (carbon monooxide) terpolymer (E-VA-C0), ethylene-C1~C8 (preferably C1~C4) alkyl acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 ~C8 (preferably C1 to C4) methacrylic acid copolymer or a mixture thereof (particle diameter is preferably not more than 400 nm (diameter), more preferably not more than 100 nm (diameter)).
上述乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物 （E-VA-C0) 、 乙烯 -C1〜C8 (优选 C1〜C4) 说 明 书 The above ethylene-ethylene acetate-carbonyl (carbon monooxide) trimer (E-VA-C0), ethylene-C1 to C8 (preferably C1 to C4) Instruction manual
烷基丙烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C8 (优选 C1〜C4)垸基丙烯酸共聚物的可有 上市的商品如 DuPont公司的 Elvaloy®系列产品 （如 Elvaloy AC 1、 2、 3系列， Elvaloy HP系 列） 。 丙烯酸树脂类抗冲击改性剂可有上市的商品如 Rohm and Haas公司生产的纳米级产品 PARALOID BP系列产品。 Alkylacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C8 (preferably C1~C4) mercaptoacrylic acid copolymers available on the market, such as DuPont's Elvaloy® series products (eg Elvaloy AC 1) , 2, 3 series, Elvaloy HP series). Acrylic anti-impact modifiers are available in listed products such as the PARALOID BP series of nanoscale products manufactured by Rohm and Haas.
在发明涉及的包衣液中可以添加衣膜通用添加剂材料。 衣膜通用添加剂材料在药物包衣 层中的加入量和应用是专业人员熟悉的。通用的添加剂包括但不限于抗粘着剂（分离剂）、稳 定剂、 颜料、 消泡剂、 抗氧化剂、 促渗透剂、 光泽剂、 香料或调味剂。 它们用作加工助剂， 并应该保证安全和可重现的制备方法以及长时间贮存稳定性或赋予药物剂型附加的有利特 性。 它们在加工前加入配制的聚合物中， 能影响衣层的渗透性， 这同样可以用作附加的调节 参数。  A film-forming general additive material may be added to the coating liquid of the invention. The amount and application of the film-forming general additive material in the drug coating layer is well known to those skilled in the art. Common additives include, but are not limited to, anti-adherents (separators), stabilizers, pigments, defoamers, antioxidants, penetration enhancers, gloss agents, perfumes or flavoring agents. They are used as processing aids and should ensure safe and reproducible preparation methods as well as long-term storage stability or additional beneficial properties imparted to the pharmaceutical dosage form. They are added to the formulated polymer prior to processing and can affect the permeability of the coating, which can also be used as an additional conditioning parameter.
一些常用的添加剂的介绍如下。  Some commonly used additives are described below.
•抗粘着剂 （分离剂）  •Anti-adhesive (separator)
分离剂通常为有益的疏水材料， 一般加入喷射悬浮液中。 它们阻止成膜期间核的聚集。 优选使用滑石， 硬脂酸镁或硬脂酸钙， 研细的硅酸， 高岭土或 HLB值为 3〜8的非离子型乳化 剂。 在本发明的衣层中的通常用量为聚合物的 0. 5〜100% (重量比）。 在特别有利的实施方案 中， 分离剂以浓缩形式作为最终涂层加入。 涂覆以粉末形式或由 5〜30%固含量的悬浮液通过 喷涂而进行。 需要量比加工入聚合物层中时的量少， 占药物剂型重量的 0. 1〜2%。  The separating agent is typically a beneficial hydrophobic material and is typically added to the spray suspension. They prevent the accumulation of nuclei during film formation. Preference is given to using talc, magnesium stearate or calcium stearate, finely divided silicic acid, kaolin or a nonionic emulsifier having an HLB value of from 3 to 8. 5〜100% (重量百分比) The polymer is usually used in the coating layer of the present invention. In a particularly advantageous embodiment, the separating agent is added as a final coating in concentrated form. The coating is carried out by spraying in the form of a powder or a suspension having a solid content of 5 to 30%. 1〜2%。 The amount of the dosage of the pharmaceutical dosage form is 0. 1~2%.
•稳定剂  •stabilizer
稳定剂优选为乳化剂或表面活性剂， 有界面活性物质， 对水分散体起稳定作用。 合适的 稳定剂实例如有二乙醇胺、 单乙醇胺、 三乙醇胺、 脂肪酸类、 羟丙基甲基纤维素 （HPMC) 、 羟丙基纤维素 （HPC) 、 壬苯醇醚、 辛苯昔醇、 油酸、 泊洛沙姆、 聚氧乙烯 50硬脂酸酯、 聚 乙二醇脂肪酸类 (Polyoxyl fatty acid)、 聚乙二醇垸基醚 (Polyoxyl hydrocarbon ether), 聚山梨醇酯 （Tween) 、 脱水山梨糖醇酯 （Span) 、 脂肪酸盐类、 聚维酮、 月桂基硫酸钠、 十 六垸基硬脂基硫酸钠、 蔗糖硬脂酸脂、 多乙氧基醚及其混合物。 稳定剂的含量为 1〜15% (重 量比）， 优选 5〜10% (重量比）， 这是基于水分散体包衣液组分的湿重量。  The stabilizer is preferably an emulsifier or a surfactant, and has an interfacial active substance to stabilize the aqueous dispersion. Examples of suitable stabilizers are diethanolamine, monoethanolamine, triethanolamine, fatty acids, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), nonoxynol, octoxynol, oil Acid, poloxamer, polyoxyethylene 50 stearate, polyoxyl fatty acid, polyoxyl hydrocarbon ether, polysorbate (Tween), dehydration Sorbic acid ester (Span), fatty acid salts, povidone, sodium lauryl sulfate, sodium decyl stearyl sulphate, sucrose stearate, polysorbate and mixtures thereof. The stabilizer is contained in an amount of from 1 to 15% by weight, preferably from 5 to 10% by weight, based on the wet weight of the component of the aqueous dispersion coating liquid.
•颜料  • Pigments
很少以可溶性颜料形式加入。 一般将氧化铝或氧化铁颜料分散加入。 二氧化钛用作白色 颜料。 在本发明的衣层中颜料的加入量为聚合物混合物的 20〜60% (重量比）。 然而由于颜料 结合能力高， 加入量也可以高至 100% (重量比）。  Rarely added as a soluble pigment. Alumina or an iron oxide pigment is generally dispersedly added. Titanium dioxide is used as a white pigment. The pigment is added in the coating layer of the present invention in an amount of from 20 to 60% by weight based on the polymer mixture. However, due to the high pigment binding capacity, the addition amount can be as high as 100% by weight.
•消泡剂  • Defoamer
消泡剂一般地为二甲基硅油。  The antifoaming agent is generally dimethicone.
特别有利的实施方案中， 直接以浓缩形式用作最终涂层。 涂覆以粉末形态或以 5〜30%固 含量的含水悬浮液喷涂而进行。 需要量低于加工入聚合物层中时的用量， 占药物剂型重量的 0. 1〜2%。  In a particularly advantageous embodiment, the final coating is used directly in concentrated form. The coating is carried out in the form of a powder or by spraying with an aqueous suspension having a solid content of 5 to 30%. 1〜2%。 The amount of the dosage of the pharmaceutical dosage form is 0.1 to 2%.
衣膜中所有使用的物质原则上必须是药学上可接受的、无毒的，在药物中对病人无危险。 下面对本发明所用的芯料作说明。  All substances used in the film must in principle be pharmaceutically acceptable, non-toxic and not dangerous to the patient in the drug. The core material used in the present invention will be described below.
可用于本发明的被包衣的芯料 （载体）包括但不限于规则或不规则形式片、 颗粒、 （微） 丸、晶体、载药树脂。颗粒、（微）丸或晶体的尺寸通常为 0. 01〜2. 5mm,片的尺寸通常在 2. 5〜 30mm。 它们通常含有最高达 95% (重量比， 以下无特别说明同此）的生物活性物质 (活性物质) 以及最高达 99. 9%的其它制药助剂。  Coated cores (carriers) useful in the present invention include, but are not limited to, regular or irregular forms of tablets, granules, (micro) pellets, crystals, drug-loaded resins. The size of the granules, (micro) pellets or crystals is usually 0. 01~2. 5mm, the size of the sheet is usually 2. 5~ 30mm. They usually contain up to 95% (by weight, unless otherwise stated) bioactive substances (active substances) and up to 99.9% of other pharmaceutical additives.
用于本发明的生物活性物质 (活性物质）除了那些在制备过程中因热效应发生降解、挥发、 失活而造成药效损失的外， 就没有其他的限制， 但如果应用一定的方法 （如环糊精包合、 微 囊化技术） 能防止生物活性物质在制备过程中发生降解、 挥发、 失活， 这些生物活性物质也 可以用于本发明。  The biologically active substance (active substance) used in the present invention has no other limitation except for those which are degraded, volatilized, and inactivated due to thermal effects during the preparation process, but there is no other limitation, if a certain method (such as a ring) is applied. Dextrin inclusion, microencapsulation technology) can prevent degradation, volatilization, and inactivation of biologically active substances during preparation, and these biologically active substances can also be used in the present invention.
作为本发明所用的活性成分， 可以是上述的任何药学上的或营养学上的具有治疗作用的 说 明 书 As the active ingredient used in the present invention, it may be any of the above-mentioned pharmaceutically or nutritionally therapeutic effects. Description
或预防作用的物质。 本发明可用的活性成分实例列举如下： Or a substance that prevents it. Examples of active ingredients useful in the present invention are listed below:
中枢神经***药物：  Central nervous system drugs:
中枢兴奋药： 艾地苯醌、 苯甲曲秦、 吡拉西坦、 吡硫醇、 长春西丁、 二甲弗林、 茴拉 西坦、 甲氯芬酯、 咖啡因、 ***、 戊四氮。  Central stimulant: idebenone, benzotrizepine, piracetam, pyrithione, vinpocetine, dimethylformin, aniracetam, meclofenoxate, caffeine, modafinil, Pentylenetetrazol.
一镇痛药： 布桂嗪、 丁丙诺啡、 二氢埃托啡、 夫洛非宁、 荷包牡丹碱、 可待因、 罗通定、 ***、 麦角胺、 美普他酚、 ***、 奈福泮、 哌替啶、 匹米诺定、 羟考酮、 氢***醇、 曲马 多、 舒马普坦、 四氢帕马丁、 右丙氧芬、 右美沙芬、 左啡诺、 左吗拉胺。  An analgesic: chlorpheniramine, buprenorphine, dihydroetorphine, florofinine, bicuculline, codeine, rotundine, morphine, ergotamine, meptazin, methadone, nai Fructus, pethidine, pirimidin, oxycodone, hydromorphol, tramadol, sumatriptan, tetrahydropalmatine, dextropropoxyphene, dextromethorphan, levonorol, left mala amine.
解热镇痛药： 阿司匹林、 对乙酰氨基酚、 非那西丁、 羟布宗、 噻拉米特、 水杨酸镁、 水杨酸咪唑、 异丙安替比林。  Antipyretic analgesics: aspirin, acetaminophen, phenacetin, hydroxybzon, thiramite, magnesium salicylate, imidazole salicylate, isopropylantipyrine.
抗炎镇痛药： 阿明洛芬、 阿西美辛、 阿扎丙宗、 安吡昔康、 奧古蛋白、 奥沙拉秦、 贝 诺酯、 吡洛芬、 布洛芬、 布西拉明、 醋氯芬酸、 丁苯羟酸、 二氟尼柳、 芬布芬、 氟比洛芬、 氟芬那酸、 胍西替柳、 环氯茚酸、 甲芬那酸、 甲氯芬那酸、 金硫葡糖、 金诺芬、 来氟米特、 氯芬那酸、 洛索洛芬、 马兜铃酸、 美洛昔康、 美沙拉秦、 萘丁美酮、 萘普生、 尼氟酸、 依托 度酸、 扎托洛芬、 愈创蓝油烃、 依托芬那酯、 伊索昔康、 酮洛芬、 替诺昔康。  Anti-inflammatory analgesics: aminclofen, acemetacin, azaprozin, ampoxicam, augusin, olsalazine, benolyl ester, pirfen, ibuprofen, bucillamine , aceclofenac, butyl hydroxy acid, diflunisal, fenbufen, flurbiprofen, flufenamic acid, citrictin, cyclohexanoic acid, mefenamic acid, meclofenamic acid , gold thioglucose, auranofine, leflunomide, chlorpheniric acid, loxoprofen, aristolochic acid, meloxicam, mesalazine, nabumetone, naproxen, niflut Acid, etodolac, zaltoprofen, guaiac blue hydrocarbon, etofenamate, escitoxicam, ketoprofen, tenoxicam.
一抗痛风药： 氨基葡萄糖、 苯溴马隆、 别嘌醇、 秋水仙碱、 丙磺舒、 伊替马唑。  An anti-gout drug: glucosamine, benzbromarone, allopurinol, colchicine, probenecid, etimabazole.
一抗震颤麻痹药： 苯海索、 比哌立登、 多瑞肽、 恩他卡朋、 金刚垸胺、 卡比多巴、 喹高 利特、 雷沙吉兰、 美金刚、 司来吉兰、 托卡朋、 溴隐亭、 左旋多巴、 莫非吉兰、 莫西芬辛、 帕立太特、 多奈哌齐。  An anti-shock paralysis drug: trihexyphenidate, biperiden, dorepeptide, entacapone, adamantamine, carbidopa, quetiapine, rasagiline, memantine, selegiline, Tokapeng, bromocriptine, levodopa, mobilis, moxifensin, palitide, donepezil.
抗精神病药： 阿立必利、 阿尼哌醇、 阿扎哌隆、 安哌齐特、 氨磺必利、 奥卡哌酮、 奧 沙氟嗪、 奥昔哌汀、 丙氯拉嗪、 氟奋乃静、 氟哌啶醇、 氟哌利多、 氟哌噻吨、 氟司必林、 利 培酮、 林卡唑、 硫必利、 硫利达嗪、 氯氮平、 氯哌帕生、 氯哌噻吨、 氯普噻吨、 洛沙平、 莫 沙帕明、 奈莫必利、 哌泊噻嗪、 匹莫齐特、 普拉克索、 瑞莫必利、 舒必利、 五氟利多、 佐替 平、 溴哌利多、 奥氮平。  Antipsychotics: alipidide, anibirdolol, azaiperone, apixipide, amisulpride, oxaporone, oxaflurazine, oxybuterazine, chlorpromazine, fluoride Perphenazine, haloperidol, droperidol, flupentixol, flupriline, risperidone, linacazole, thiopril, thioridazine, clozapine, clopidogrel, chlorine Piperazine, cloprofen, loxapine, mazapamine, nemiride, piperazine, pimozide, pramipexole, rimopride, sulpiride, penfluridol, zooti Ping, epoprazol, olanzapine.
一抗焦虑药： 阿普***、 艾司***、 丁螺环酮、 氟他***、 劳拉西泮、 氯美扎酮、 美他 沙酮、 珠氯噻醇、 依替***、 氟***。  An anti-anxiety drug: alprazolam, estazolam, buspirone, flazodazole, lorazepam, clomiprazole, metaxalone, beta chlorophenidate, etidazolam, Fludisazine.
抗抑郁症药： 阿米替林、 阿莫沙平、 安非他酮、 奥匹哌醇、 地昔帕明、 地美替林、 氟 伏沙明、 氟西汀、 卡匹帕明、 氯米帕明、 马普替林、 米安色林、 帕罗西汀、 哌甲酯、 普罗替 林、 曲米帕明、 舍曲林、 圣 ·约翰草提取物片、 维洛沙秦、 文拉法辛、 ***、 西酞普兰、 异卡波肼。  Antidepressant drugs: amitriptyline, amoxapine, bupropion, opipadol, desipramine, dexmedeline, fluvoxamine, fluoxetine, carbipipamine, chlorine Mipamamine, Maprotiline, Mianserin, Paroxetine, Methylphenidate, Protriptyline, Trimemamine, Sertraline, St. John's Wort Extract, Veloxacin, Venlafa Xin, Sibutramine, Citalopram, Icaroline.
一抗癫痫药： 奥卡西平、 贝克拉胺、 苯妥英、 丙戊酸及其钠、 镁盐、 甲乙双酮、 卡马西 平、 卡西尼特、 拉莫三嗪、 利鲁唑、 扑米酮、 托吡酯、 依沙双酮、 依他西平、 乙苯妥英、 乙 琥胺、 唑尼沙胺、 噻加宾、 美芬妥英。  An antiepileptic drug: oxcarbazepine, bequesamine, phenytoin, valproic acid and its sodium, magnesium salt, methyl ethyl ketone, carbamazepine, casinitide, lamotrigine, riluzole, primidone , Topiramate, esadiazepine, ethecoxibine, etoposide, ethosuxamine, zonisamide, tiagabin, mefentoin.
一镇静药、 催眠药、 抗惊厥药及其他： 奧沙***、 巴比妥、 ***、 格鲁米特、 喹硫 平、 尼唑苯酮、 天麻素、 溴米索伐、 依托咪酯、 乙酰天麻素、 扎来普隆、 佐匹克隆、 唑吡坦、 倍他司汀、 长春胺、 氟桂利嗪、 氟美烯酮、 氟替尔、 环扁桃酯、 己酮可可碱、 甲磺双氢麦角 胺、 利扎曲普坦、 美西麦角、 那拉曲坦、 尼可占替诺、 尼麦角林、 血管舒缓素、 烟酸、 伊普 吲哚、 依来曲普坦、 依前列醇、 异丙佐罗、 罂粟碱、 佐米曲普坦、 左乙拉西坦。  A sedative, hypnotic, anticonvulsant and others: oxazuron, barbital, phenobarbital, glutamine, quetiapine, niazophenone, gastrodin, bromoisoval, relying on Mimidate, acetyl gastrodin, zaleplon, zopiclone, zolpidem, betahistine, vincamine, flunarizine, flumethenone, fluentil, cyclomandelate, pentoxifylline , meglumine dihydroergotamine, rizatriptan, mesalamine, naratriptan, nicotinol, nigralin, kallikrein, niacin, iripusone, eletriptan , epoprostenol, isoprozol, papaverine, zolmitriptan, levetiracetam.
植物神经***药物： 阿罗洛尔、 阿普洛尔、 阿替洛尔、 艾司洛尔、 苯扎托品、 比索洛 尔、 东莨菪碱、 酒石酸美托洛尔、 卡替洛尔、 卡维地洛、 拉贝洛尔、 美托洛尔、 莫普洛尔、 莫西赛利、 纳多洛尔、 山莨菪碱、 塞利洛尔、 塞他洛尔、 噻吗洛尔、 坦洛新、 索他洛尔、 育 亨宾、 樟柳碱、 卡维地洛、 坦洛新、 托吡卡胺、 溴丙胺太林。  Autonomic nervous system drugs: arololol, aplolol, atenolol, esmolol, benzaltropium, bisoprolol, scopolamine, metoprolol tartrate, carteolol, carvedil Lo, Labetalol, Metoprolol, Mopelol, Moseselli, Nadolol, Anisodamine, Celilol, Cedarol, Thiololol, Tamsulosin, Sotalol, yohimbine, anisodine, carvedilol, tamsulosin, tropicamide, bromopropylamine.
一循环***药物：  A circulatory system drug:
一钙拮抗药： 阿尼帕米、 巴尼地平、 贝尼地平、 苄普地尔、 地伐帕米、 法利帕米、 桂利 嗪、 拉西地平、 马尼地平、 噻帕米、 维拉帕米、 右维拉帕米。  One calcium antagonist: anipamil, benidipine, benidipine, bepridil, valparaprin, faripamil, cinnarizine, lacidipine, manidipine, thiophane, dimension Lapami, right Vera Paimi.
一治疗慢性心功能不全的药物： 布拉地新、地高辛、地诺帕明、毒毛花苷^多巴酚丁胺、 说 明 书 A drug for the treatment of chronic heart failure: Bradyxin, Digoxin, Dinomamine, Poisonin, Dobutamine, Instruction manual
多卡巴胺、 黄夹苷、 米力农、 依诺昔酮、 左西孟旦、 阿利非君。 Docarbaamine, paclitaxel, milrinone, enoxacin, levosimendan, alfifron.
一抗心律失常药： 阿普林定、 胺碘酮、 吡西卡尼、 丙吡胺、 氟卡尼、 奎尼丁、 莫地卡尼、 莫雷西嗪、 普鲁卡因胺、 普罗帕酮、 伊伐布雷定、 伊曲卡尼、 托西溴苄铵、 美西律、 司替卡 尼。  An antiarrhythmic drug: aprilin, amiodarone, pyridoxine, propiamine, flecainide, quinidine, modicani, orexizine, procainamide, propa Ketone, ivabradine, itraconi, tocic bromide, mexiletine, stenicai.
一防治心绞痛药： 奥昔非君、 单硝酸异山梨酯、 川芎嗪、 地尔硫卓、 丁四硝酯、 海索苯 定、 环磷腺苷、 利多氟嗪、 麝香酮、 双嘧达莫、 戊四硝酯、 ***、 伊莫拉明、 依他苯酮、 环磷腺苷。  A drug for preventing and treating angina pectoris: oxyxitox, isosorbide mononitrate, ligustrazine, diltiazem, tetrabutyl nitrite, hysopidine, cyclophosphamide, levopraz, musk ketone, dipyridamole, pentaerythritol Nitrate, nitroglycerin, imoramin, etanoterone, cyclic adenosine.
一周围血管扩张药： 阿扑长春胺、 长春胺、 吡那地尔、 长春考酯、 长春培醇、 达加帕米、 丁咯地尔、 法舒地尔、 戈洛帕米、 肼屈嗪、 卡屈嗪、 米诺地尔、 尼可地尔、 萘呋胺、 曲匹地 尔、 双肼屈嗪、 乌拉地尔、 溴长春胺、 烟酸肌醇、 依那地平、 异丙地、 异丙沙明、 罂粟林、 甾伐地尔、 左依莫帕米、 佐勒汀。  Peripheral vasodilator: apovinamine, vincamine, pinacidil, vinpocet, vinorelbine, dagapamil, buflomedil, fasudil, golopamil, hydralazine , kalazine, minoxidil, nicorandil, naproxil, tripidil, diterpenoid, urapidil, bromo-vincoamine, nicotinic acid inositol, enalappine, isopropanol, Isosaramine, poppy peony, valvadil, left emolim, zoelepine.
一降血压药： 阿夫唑嗪、 阿拉普利、 阿那立肽、 氨氯地平、 倍他尼定、 贝那普利、 八厘 麻毒素、 布那唑嗪、 地巴唑、 地拉普利、 地来洛尔、 丁吡考胺、 多沙唑嗪、 厄贝沙坦、 非洛 地平、 福辛普利、 粉防己碱、 甲基多巴、 黄豆苷元、 酒石酸喷托铵、 卡托普利、 坎地沙坦、 喹那普利、 可乐定、 赖诺普利、 雷米普利拉、 利美尼定、 利舍平、 螺普利、 洛非西定、 美卡 拉明、 尼伐地平、 尼卡地平、 尼莫地平、 尼群地平、 尼索地平、 帕吉林、 培哚普利、 群多普 利、 特拉唑嗪、 替莫普利、 托洛尼定、 西拉普利、 硝苯地平、 缬沙坦、 伊拉地平、 依利沙坦、 依那吉仑、 依那普利、 依那普利拉、 依普罗沙坦、 吲哚拉明、 左洛非西定、 佐芬普利、 佐芬 普利拉、 替米沙坦。  A blood pressure lowering drug: alfuzosin, alapril, analipide, amlodipine, betaxetidine, benazepril, octapeptide, bunazosin, diazepam, dilapid Lee, Delilorol, Butyzolamine, Doxazosin, Irbesartan, Felodipine, Fosinopril, Tetrandrine, Methyldopa, Daidzein, Tartrate Tartrate, Card Topily, candesartan, quinapril, clonidine, lisinopril, ramipril, limonidine, lishepine, spiropril, lofexidine, mecaramine, Nilvadipine, nicardipine, nimodipine, nitrendipine, nisoldipine, pagilin, perindopril, trandolapril, terazosin, temocapril, tolonedine, sira Puli, nifedipine, valsartan, isradipine, elishartan, enalapril, enalapril, enalapril, eprosartan, valeramine, zolofexine , Zofenopril, Zofenpril, Telmisartan.
调节血脂药及抗动脉粥样硬化药： 阿托伐他汀、 阿昔莫司、 苯丙醇胺、 苯赖加压素、 苯扎贝特、 吡卡酯、 苄氯贝特、 达伐他汀、 弹性酶、 多巴胺、 多培沙明、 非诺贝特、 氟伐他 汀、 环丙贝特、 吉非贝齐、 考来替泊、 考来烯胺、 克伐他汀、 克利贝特、 来西贝特、 氯贝丁 酯、 氯贝酸铝、 洛伐他汀、 美伐他汀、 尼卡那汀、 尼可贝特、 普伐他汀、 普罗布考、 西立伐 他汀、 辛伐他汀、 亚油酸、 益多酯、 右甲状腺素钠、 猪去氧胆酸。  Regulating blood lipids and anti-atherosclerosis drugs: atorvastatin, acixil, phenylpropanolamine, benzepressin, bezafibrate, pikacin, benzyl chloride, darvastatin, Elastase, dopamine, dopamine, fenofibrate, fluvastatin, ciprofibrate, gemfibrozil, colestipol, cholestyramine, kevastatin, clebate, lysibine , clofibrate, clofibrate, lovastatin, mevastatin, nicaratin, niketabate, pravastatin, probucol, cerivastatin, simvastatin, linoleic acid , Yiduoester, dextrothyroxine, hyodeoxycholic acid.
一呼吸***药物： 氨茶碱、 氨溴索、 奥西那林、 奧昔拉定、 苯丙哌林、 比托特罗、 苯佐 那酯、 吡布特罗、 地布酸钠、 地美索酯、 地普托品、 厄多司坦、 非诺特罗、 福尔可定、 海索 那林、 克仑特罗、 氯丁替诺、 马布特罗、 孟鲁司特、 匹考哌林、 特布他林、 愈创甘油醚、 愈 创木酚磺酸钾、 扎莫特罗、 左丙氧芬、 异米尼尔、 乙酰半胱氨酸、 酮替芬、 特布他林、 妥洛 特罗、 依普拉酮、 萜品醇。  A respiratory system drug: aminophylline, ambroxol, oxycin, oxicillin, benproperine, bitoterol, benzonatate, pyrbuterol, sodium zoate, dimethoate Ester, putotropine, erdosteine, fenoterol, forcodine, hexolin, clenbuterol, chlorobutano, mabuterol, montelukast, picotazide Lin, terbutaline, guaifenesin, guaiacol sulfonate, zaloterol, levopropoxyphene, isomirier, acetylcysteine, ketotifen, terbutaline, Trolotrol, epradolone, terpineol.
一消化***药物：  A digestive system drug:
一抗酸药及治疗消化性溃疡病药： 奥美拉唑、 巴柳氮、 奥诺前列素、 恩前列素、 法莫替 丁、 甘羟铝、 枸橼酸铋钾、 兰索拉唑、 雷贝拉唑、 硫糖铝、 铝镁加、 铝酸铋、 铝碳酸镁、 罗 沙前列醇、 罗沙替丁、 米索前列醇、 尼扎替丁、 哌仑西平、 普劳诺托、 泮托拉唑、 曲昔派特、 索法酮、 替仑西平、 维生素 u、 伊索拉定、 依卡倍特。  An antacid and a peptic ulcer drug: omeprazole, balsalazide, ornoprost, enprostin, famotidine, galac aluminum, bismuth potassium citrate, lansoprazole, Rabeprazole, sucralfate, aluminum-magnesium plus, barium aluminate, magnesium aluminum carbonate, rosaprost, roxatidine, misoprostol, nizatidine, pirenzepine, Pronoto, Pantoprazole, Traxapat, Sophorone, Tirenoxapine, Vitamin U, Isoladine, Ekabit.
胃肠解痉药： 阿地芬宁。  Gastrointestinal antispasmodic: Adifenin.
一助消化药： 奥西肽、 促胰酶素淀粉酶、 枸橼酸、 卡尼汀、 胃蛋白酶、 西沙必利、 胰蛋 白酶、 胰酶、 胰脂肪酶。  A helper digestive drug: oxcarbin, trypsin amylase, citric acid, carnitine, pepsin, cisapride, trypsin, trypsin, pancreatic lipase.
一止吐药、 催吐药及肠胃推动药： 昂丹司琼、 多潘立酮、 格拉司琼、 甲氧氯普胺、 氯波 必利、 托垸司琼、 伊托必利、 岩白菜素、 左舒必利、 四羟黄酮、 来立司琼、 林托必利、 莫吉 司坦、 莫沙必利。  An antiemetic, emetic, and gastrointestinal drug: ondansetron, domperidone, granisetron, metoclopramide, clopirol, tolztron, itopride, bergenin, sulpiride , quercetin, lystron, lintobili, mojistan, mosapride.
肝胆疾病辅助用药： 奥拉米特、 鹅去氧胆酸、 非布丙醇、 茴三硫、 肌醇、 肌苷、 联苯 双酯、 亮菌甲素、 硫普罗宁、 硫辛酸、 马洛替酯、 葡醛内酯、 齐墩果酸、 羟甲香豆素、 羟甲 烟胺、 去氢胆酸、 去氢胆酸钠、 去氧胆酸、 乳果糖、 水飞蓟宾、 水飞蓟素、 西阿尼醇、 腺苷 蛋氨酸、 熊去氧胆酸、 原卟啉钠。  Auxiliary medication for hepatobiliary diseases: olamimet, chenodeoxycholic acid, non-bupropanol, anthranil, inositol, inosine, biphenyl diester, leucovorin, tiopronin, lipoic acid, marlow Terephthalate, glucurolactone, oleanolic acid, hydroxymethyl coumarin, hydroxymethanolamine, dehydrocholic acid, sodium dehydrocholate, deoxycholic acid, lactulose, silybin, silymarin, Sianiol, adenosylmethionine, ursodeoxycholic acid, sodium protoporphyrin.
一泌尿***药物： 阿米洛利、 阿佐塞米、 氨苯蝶啶、 贝美噻嗪、 泊利噻嗪、 布美他尼、 说 明 书 A urinary system drug: amiloride, azosemide, triamterene, bethiazine, polibizine, bumetanide, Instruction manual
吡咯他尼、 呋塞米、 环戊噻嗪、 氯索隆、 螺利酮、 美替拉酮、 螺内酯、 美夫西特、 赖氨加压 素、 吲达帕胺、 依匹噻嗪、 依索唑胺、 依他尼酸、 依他尼酸钠、 依托唑啉、 乙噻嗪、 乙酰唑 胺、 异丙碘铵、 异波帕胺、 去氨加压素、 双氯非那胺、 替普瑞酮、 美替拉酮。 Pyrrhotanib, furosemide, cyclopentazine, clonsophan, spirronone, metyrapone, spironolactone, mefsit, lysine, indapamide, epitazine, yi Soxazole, etanic acid, sodium citrate, etazozoline, thiazide, acetazolamide, isopropyl iodide, isopamine, desmopressin, diclofenac, Purrexone, metyrapone.
一影响血液及造血***的药物： 沙格雷酯、 乙双香豆素、 乙双豆乙酯、 华法林、 苯茚二 酮、 醋硝香豆素、 硫酸亚铁、 葡萄糖酸亚铁、 亚叶酸钙、 叶酸、 右旋糖酐铁、 甲钴胺、 富马 酸亚铁、 葡庚糖酐铁、 阿魏酸钠、 核苷酸、 茴香脑、 茜草双酯、 鲨肝醇、 小檗胺、 阿卡地新、 阿那格雷、 阿前列素、 奥扎格雷、 贝前列素、 吡吗格雷、 达美格雷、 达唑氧苯、 呋格雷酸、 利马前列素、 氯吡格雷、 罗拉格雷、 咪唑格雷、 莫地帕泛、 那法格雷、 帕米格雷、 前列地尔、 曲克芦丁、 噻氯匹定、 三苯格雷、 沙替格雷、 舒那格雷、 西洛他唑、 西前列烯、 烟格雷酯、 氧格雷酯、 伊他格雷、 羟苯磺酯钙。  A drug that affects the blood and hematopoietic system: sarpogrelate, bis-coumarin, ethyl acetophenone, warfarin, benzoquinone, acenocoumarol, ferrous sulfate, ferrous gluconate, ar Calcium folate, folic acid, iron dextran, mecobalamin, ferrous fumarate, iron glucoheptone, sodium ferulate, nucleotides, anethole, valerate, squalyl alcohol, chloramine, aca Dixin, anagrelide, aprostin, ozagrel, beraprost, picogreline, dalgregre, dazooxaphene, furoic acid, limatoprost, clopidogrel, rolagrel, imidazole , motodipine, narfagre, pamidrex, alprostadil, trox rutin, ticlopidine, tribexyrene, sartrimrel, sultagreride, cilostazol, cisprost, tobacco Greg ester, oxydresyl ester, iptagrel, calcium hydroxybenzene sulfonate.
一抗***反应药物：  Primary anti-allergic drugs:
一抗组胺药： 阿伐斯汀、 阿利马嗪、 阿司咪唑、 奥沙米特、 奥索马嗪、 苯海拉明、 苯茚 胺、 丙酰马嗪、 布克力嗪、 茶苯海明、 茶氯酸异丙嗪、 氮卓斯汀、 丁夫罗林、 多拉斯汀、 多 西拉敏、 恩布拉敏、 非尼拉敏、 非索非那定、 二甲茚定、 氯雷他定、 氯马斯汀、 氯哌斯汀、 马来酸氯苯那敏、 美海屈林、 美克洛嗪、 美喹他嗪、 尼普拉嗪、 赛庚啶、 司他斯汀、 依巴斯 汀、 依美斯汀、 依匹斯汀、 右溴苯那敏、 扎鲁司特、 左卡巴斯汀。  Primary antihistamines: avastin, alimazine, astemizole, oxapramine, oxomamycin, diphenhydramine, benzoguanamine, propionylazine, bupizine, tea benzene Hamming, promethazine tea, azelastine, diflupromide, dolastatin, doxylamine, embramin, febrinamide, fexofenadine, dimethylformidine , loratadine, clemastine, cloperastine, chlorpheniramine maleate, mepyrazine, meclozine, mequitazine, niprazine, cyproheptadine, stastatin, Ebastine, estramustine, epilin, bromophenamine, zafirlukast, levocabastine.
一过敏反应介质阻释剂及其他： 阿扎他定、氨来咕诺、 洛度沙胺、 曲尼司特、 色甘酸钠、 西替利嗪、 扎普司特、 普克罗米、 普昔罗米、 他扎司特。  An allergic reaction medium release agent and others: azastatin, amlexanox, lodosamide, tranilast, cromolyn, cetirizine, zapastast, pkromi, pu Hydrazine, his zastel.
一肾上腺皮质激素及促肾上腺皮质激素： 地夫可特、 ***、 甲泼尼龙、 甲***、 可的松、 曲安西龙。  An adrenocortical hormone and adrenocorticotropic hormone: difluxate, dexamethasone, methylprednisolone, prednisone, cortisone, triamcinolone.
性激素及促性激素： 比卡鲁胺、 雌酮、 雌三醇、 醋酸甲羟孕酮、 达那唑、 夫拉扎勃、 氟他胺、 己二烯雌酚、 己垸雌酚、 己烯雌酚、 甲地孕酮、 甲羟孕酮、 雷洛昔芬、 尼鲁米特、 孕三烯酮、 托瑞米芬、 司坦唑醇、 炔诺孕酮。  Sex hormones and gonadotropins: bicalutamide, estrone, estriol, medroxyprogesterone acetate, danazol, prazzab, flutamide, diethylstilbestrol, hexaerythritol, diethylstilbestrol, nail Progesterone, medroxyprogesterone, raloxifene, nilutamide, gestrinone, toremifene, stanozolol, norgestrel.
胰岛激素及其它影响血糖的药物： 阿卡波糖、 吡格列酮、 二甲双胍、 伏格列波糖、 格 列本脲、 格列吡脲、 格列吡嗪、 格列丙唑、 格列波脲、 格列喹酮、 格列美脲、 格列齐特、 甲 苯磺丁脲、 米格列醇、 曲格列酮、 瑞格列奈、 妥拉磺脲。  Islet hormones and other drugs that affect blood sugar: acarbose, pioglitazone, metformin, voglibose, glibenclamide, glibenclamide, glipizide, glibenclamide, glibenclamide, lattice Derivazolone, glimepiride, gliclazide, tolbutamide, miglitol, troglitazone, repaglinide, tolazamide.
一甲状腺激素类药物及抗甲状腺药物： 奥替瑞林、 泊替瑞林、 氮替瑞林、 碘塞罗宁、 二 溴酪氨酸、 甲状丙酸、 甲状米登、 甲状球蛋白、 孟替瑞林、 咪匹马唑、 双碘酪氨酸、 替拉曲 考、 左甲状腺素、 左甲状腺素钠、 氨噻唑、 丙硫氧嘧啶、 碘硫氧嘧啶、 甲硫氧嘧啶、 甲巯咪 唑、 卡比马唑、 硫苯唑林。  A thyroid hormone drug and an antithyroid drug: oltipreline, botinidrine, nitrexine, liothyronine, dibromotyrosine, thyropropionate, thyroidine, thyroglobulin, montetine Relin, miprazole, diiodotyrosine, telazocine, levothyroxine, levothyroxine sodium, aminothiazole, propylthiouracil, iodothiouracil, methylthiouracil, methimazole, Carbazole, thiazoline.
抗微生物药物 /抗生素：  Antimicrobial / Antibiotics:
一青霉素类： 阿莫西林、 氨苄西林、 巴氨西林、 苯唑西林、 氟氯西林、 海他西林、 环己 西林、 磺苄西林、 卡茚西林、 氯唑西林、 仑氨西林、 萘夫西林、 匹氨西林、 匹美西林、 青霉 素¥、 舒他西林、 双氯西林、 酞氨西林。  A penicillin: amoxicillin, ampicillin, bamcillin, oxacillin, flucloxacillin, hetacillin, cyclohexillin, sulfacillin, carbocillin, cloxacillin, lenazocillin, nafcillin , pirazicillin, pimecillin, penicillin ¥, sultamicillin, diclocillin, and acesulfame.
头孢菌素类： 氯碳头孢、 头孢氨苄、 头孢丙烯、 头孢泊肟、 头孢布烯、 头孢克洛、 头 孢克肟、 头孢拉定、 头孢拉宗、 头孢来星、 头孢羟氨苄、 头孢沙定、 头孢特仑、 头孢地尼。  Cephalosporins: chlorocarbon cephalosporin, cephalexin, cefprozil, cefpodoxime, ceftibuten, cefaclor, cefaclor, cefradine, cefradine, ceftriaxone, cefadroxil, cefacitdine, cephalosporin Telun, cefdinir.
β -内酰胺酶抑制剂： 克拉维酸、 舒巴坦、 溴巴坦。  Beta-lactamase inhibitors: clavulanic acid, sulbactam, bromobactam.
氨基糖苷类： 巴龙霉素、 卡那霉素、 庆大霉素、 新霉素。  Aminoglycosides: Paromomycin, kanamycin, gentamicin, neomycin.
一四环素类及其他： 地美环素、 多西环素、 胍甲环素、 美他环素、 米诺环素、 土霉素、 四环素、 氯霉素。  One tetracyclines and others: dimecycline, doxycycline, indomethacin, metacycline, minocycline, oxytetracycline, tetracycline, chloramphenicol.
大环内酯类： 阿奇霉素、 醋竹桃霉素、 地红霉素、 红霉素、 琥乙红霉素、 吉他霉素、 交沙霉素、 克拉霉素、 罗红霉素、 罗他霉素、 螺旋霉素、 麦白霉素、 麦迪霉素、 司丙红霉素、 依托红霉素、 乙酰螺旋霉素。  Macrolides: azithromycin, oleandomycin, dirithromycin, erythromycin, erythromycin ethylsuccinate, guitarmycin, josamycin, clarithromycin, roxithromycin, rosacea , spiramycin, melamycin, medimycin, erythromycin, erythromycin, acetylspiramycin.
其他抗细菌感染药： 左氧氟沙星、 氧氟沙星、 环丙沙星、 诺氟沙星、 多粘菌素£、 克林 霉素、 林可霉素、 磷霉素、 米卡霉素、 制霉素、 黄藤素、 小檗碱、 雪胆素、 鱼腥草素钠。 说 明 书 Other antibacterial agents: levofloxacin, ofloxacin, ciprofloxacin, norfloxacin, polymyxin £, clindamycin, lincomycin, fosfomycin, micammycin, mold , yellow saponin, berberine, gentian, houttuyfonate sodium. Instruction manual
抗结核病药： 吡嗪酰胺、 对氨水杨酸、 对氨水杨酸钠、 丙硫异烟胺、 环丝氨酸、 利福 布汀、 利福喷汀、 利福平、 乙胺丁醇、 异烟肼。  Antituberculosis drugs: pyrazinamide, salicylic acid, sodium salicylate, propionamide, cycloserine, rifabutin, rifapentine, rifampicin, ethambutol, isoniazid .
一抗真菌药： 氟胞嘧啶、 氟康唑、 灰黄霉素、 咪康唑、 伊曲康唑、 酮康唑、 制霉菌素。 一抗病毒药： 阿昔洛韦、 泛昔洛韦、 伐昔洛韦、 拉米夫定、 利巴韦林、 吗啉胍、 齐多夫 定、 去氧氟尿苷、 去羟肌苷、 扎西他滨。  An antifungal drug: flucytosine, fluconazole, griseofulvin, miconazole, itraconazole, ketoconazole, nystatin. An antiviral drug: acyclovir, famciclovir, valaciclovir, lamivudine, ribavirin, morpholinium, zidovudine, deoxyfluorouridine, didanosine, zhaxi coast.
抗肿瘤药物： 白消安、 环磷酰胺、 洛莫司汀、 司莫司汀、 硫鸟嘌呤、 巯嘌呤、 伊达比 星、 氨鲁米特、 他莫昔芬、 阿那曲唑、 丙卡巴肼、 斑蝥素、 卡培他滨、 来曲唑、 美法仑。  Antineoplastic agents: busulfan, cyclophosphamide, lomustine, semustine, thioguanine, guanidine, idarubicin, aminoglutethimide, tamoxifen, anastrozole, procarbazine Quinoa, cantharidin, capecitabine, letrozole, melphalan.
影响机体免疫功能的药物： 阿克他利、 丙帕锗、 硫唑嘌呤、 咪唑立宾、 他克莫司。 一蛋白质： DNA酶、 藻酸酶、 超氧化物歧化酶及脂肪酶、 多肽、 寡肽。  Drugs that affect the body's immune function: acetalivir, propacetam, azathioprine, imidazolyl, tacrolimus. A protein: DNase, alginate, superoxide dismutase and lipase, peptide, oligopeptide.
一核苷酸。  One nucleotide.
维生素及营养类药： 维生素 A、 B、 C、 D、 E、 K等及其衍生物、 氨基酸；  Vitamins and nutrients: vitamins A, B, C, D, E, K, etc. and their derivatives, amino acids;
一减肥药： 阿米雷司、 安非拉酮、 安非雷司、 安非氯醛、 奥替他明、 苯氟雷司、 苯托雷 司、 苄非他明、 丙己君、 对氯苯丁胺、 非尼雷司、 芬布酯芬、 氟拉明、 芬美曲秦、 芬普雷司、 芬特明、 呋芬雷司。  A diet pill: Amiris, amfepramone, amphetamine, amphetamine, oltipamine, fenfluramine, phenyltol, benzethetamine, propylhexidine, p-chloro Phentermine, non-Nyles, fenbufen, fluramine, fenmetrazine, fenpres, phentermine, furfurex.
一其他药物： 非那雄胺、 阿仑膦酸钠、 阿洛司琼、 奥利司他、 依立雄胺、 依帕司他、 托 特罗定、 托瑞司他、 中草药提取物。  One other drug: finasteride, alendronate, alosetron, orlistat, eric acid, epalrestat, tolterodine, torista, herbal extracts.
更优选用于本发明的药物实例包括但不限于 LEC0Z0TAN ( SRA-333 ) , 阿莫西林、 阿莫西 林一克拉维酸钾复方、 阿司达莫、 阿司匹林一磷酸川芎嗪复方、 阿司匹林一双嘧达莫复方、 阿魏酸哌嗪、 阿昔洛韦、 扑热息痛一盐酸伪麻黄碱一顺丁烯二酸右旋溴苯吡胺复方、别嘌醇、 丙硫氧嘧啶、 丙戊酸镁、 布洛芬、 醋氯芬酸、 单硝酸异山梨酯一阿司匹林复方、 单硝酸异山 梨酯、 ***、 二甲双胍一罗格列酮复方、 泛昔洛韦、 非洛地平、 非诺贝特、 盐酸非索那定 盐酸伪麻黄碱复方、 氟伐他汀钠、 阿昔莫司及复方、 非洛地平一酒石酸美托洛尔复方、 洛 伐他汀一烟酸复方、维生素 B6复方、西替利嗪一盐酸伪麻黄碱复方、盐酸非索非那定一盐酸 伪麻黄碱复方、 愈创甘油醚一伪麻黄碱一右美沙芬复方、 富马酸喹硫平、 富马酸美托洛尔、 富马酸依美斯汀、 格列吡嗪一盐酸二甲双胍复方、 格列喹酮、 格列美脲一二甲双胍复方、 格 列齐特、 枸橼酸钾、 枸櫞酸他莫昔芬、 枸橼酸他莫昔芬、 琥珀酸去甲文拉法辛、 环丙沙星、 茴拉西坦、 己酮可可碱、 甲硝唑、 酒石酸托特罗定、 酒石酸唑吡坦、 克拉霉素、 苦参素、 雷 诺嗪、 利巴韦林、 磷酸苯丙哌林、 磷酸川芎嗪、 硫普罗宁、 硫酸***、 硫酸沙丁胺醇、 氯雷 他定一扑热息痛一伪麻黄碱复方、 氯雷他定一伪麻黄碱复方、 罗格列酮、 罗红霉素、 洛伐他 汀、 马来酸曲美布汀、 马来酸依那普利一非洛地平复方、 美沙拉嗪、 美托法宗、 咪唑斯汀、 萘哌地尔、 萘普生钠、 尼可他汀、 尼美舒利、 尼群地平、 尼索地平、 帕潘立酮、 帕普拉唑、 氢溴酸达非那新、 氢溴酸加兰他敏、 石杉碱甲、 双环醇、 司他夫定、 天麻素、 酮洛芬、 头孢 克洛、 头孢克肟、 维生素 C***控释片、 维生素 E烟酸酯、 伪麻黄碱一萘普生钠复方、 乌拉 地尔、 烟酸、 烟酸一辛伐他汀复方、 盐酸安非他酮、 盐酸氨溴索、 盐酸奥昔布宁、 盐酸倍他 司汀、 盐酸二甲双胍、 盐酸伐昔洛韦、 盐酸环丙沙星、 盐酸拉贝洛尔、 盐酸尼卡地平、 盐酸 帕罗西汀、 盐酸哌唑嗪、 盐酸普罗帕酮、 盐酸***、 盐酸氢***酮、 ***马多、 盐酸 曲美他嗪、 盐酸坦洛新、 盐酸坦索罗辛、、 盐酸左旋沙丁胺醇、 盐酸左氧氟沙星、 氧氟沙星、 依托度酸、 吲达帕胺、 愈创甘油醚、 愈创甘油醚一盐酸伪麻黄碱复方、 左羟丙哌嗪、 苯扎贝 特、 吡贝地尔、 茶碱、 长春胺、 甲磺酸二氢麦角碱、 甲磺酸多沙唑嗪、 酒石酸美托洛尔、 酒 石酸双氢可待因、 卡比多巴一左旋多巴复方、 硫酸***、 硫酸庆大霉、 硫酸亚铁、 氯化钾、 吗多明、 萘呋胺、 尼莫地平、 双氯芬酸钠、 维拉帕米、 维铁、 硝苯地平、 盐酸地尔硫卓、 盐 酸***、 格列吡嗪、 盐酸地尔硫、 吲哚美辛、 阿西美辛、 茶碱一沙丁胺醇复方、 地塞米 松、 对乙酰氨基酚、 格列齐特、 琥珀酸亚铁、 卡马西平、 磷酸可待因、 洛芬待因、 马洛替酯、 萘普生、 碳酸锂、 头孢氨苄、 盐酸阿夫唑嗪、 盐酸丁咯地尔、 盐酸噻氯匹啶、 异丁司特、 右 美沙芬、 正清风痛宁、 5-单硝异山梨醇酯、 丙戊酸钠、 多巴丝肼、 硫酸庆大霉素一二氧化锆 说 明 书 More preferred examples of the medicament for use in the present invention include, but are not limited to, LEC0Z0TAN (SRA-333), amoxicillin, amoxicillin-clavulanate potassium compound, asdamamo, aspirin-phosphoric acid ligustrazine compound, aspirin-dipyridamole Mo Fufang, piperazine ferulate, acyclovir, paracetamol-pseudoephedrine-d-butenoic acid dextrobromide compound, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, Aceclofenac, isosorbide mononitrate-aspirin compound, isosorbide mononitrate, diazepam, metformin-roglitazone combination, famciclovir, felodipine, fenofibrate, pseudoephedrine hydrochloride pseudoephedrine Compound, fluvastatin sodium, acyclovir and compound, felodipine-metoprolol tartrate compound, lovastatin-nicotinic acid compound, vitamin B6 compound, cetirizine-pseudoephedrine compound, fesofine hydrochloride That is a compound of pseudoephedrine hydrochloride, guaifenesin-pseudoephedrine-dextromethorphan, quetiapine fumarate, metoprolol fumarate, ezetimidate fumarate, grid Pyrazine-Metformin Hydrochloride, Glipizide, Glimepiride-Metformin Compound, Gliclazide, Potassium Citrate, Tamoxifen Citrate, Tamoxifen Citrate, Succinic Acid Venlafaxine, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, tolterodine tartrate, zolpidem tartrate, clarithromycin, oxymatrine, ranolazine, ribavirin , benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, loratadine-paracetamol-pseudoephedrine compound, loratadine-pseudoephedrine compound, rosiglitazone, roxithromycin, lo Rutastatin, trimebutine maleate, enalapril maleate-felodipine, mesalazine, metotropine, mizolastine, naftopidil, naproxen sodium, niketatin , nimesulide, nitrendipine, nisoldipine, paliperidone, paprazole, dafenazone hydrobromide, galantamine hydrobromide, huperzine A, bicyclol, statin Fuding, gastrodin, ketoprofen, cefaclor, cefac , vitamin C vaginal controlled release tablets, vitamin E nicotinate, pseudoephedrine, naproxen sodium compound, urapidil, niacin, niacin-simvastatin compound, bupropion hydrochloride, ambroxol hydrochloride, hydrochloric acid Xibutin, betahistine hydrochloride, metformin hydrochloride, valacyclovir hydrochloride, ciprofloxacin hydrochloride, labetalol hydrochloride, nicardipine hydrochloride, paroxetine hydrochloride, prazosin hydrochloride, propafenone hydrochloride, Propranolol hydrochloride, hydromorphone hydrochloride, tramadol hydrochloride, trimetazidine hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, l-salbutamol hydrochloride, levofloxacin hydrochloride, ofloxacin, etodolac, Indapamide, guaifenesin, guaifenesin-pseudoephedrine hydrochloride, levodropropizine, bezafibrate, pyridyl, theophylline, vincamine, dihydroergotamine mesylate, A Doxazosin sulfonate, metoprolol tartrate, dihydrocodeine tartrate, carbidopa-levodopa compound, morphine sulfate, gentamic sulfate, ferrous sulfate, potassium chloride, domoti, Furanamine, nimodipine, diclofenac sodium, verapamil, retinoic iron, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetacin , theophylline-salbutamol compound, dexamethasone, acetaminophen, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, loffeine, marlotidate, naproxen, carbonic acid Lithium, cephalexin, alfuzosin hydrochloride, buflomedil hydrochloride, ticlopidine hydrochloride, ibudilast, dextromethorphan, Zhengqingfengtongning, 5-mononitrate, sodium valproate , dopas, gentamicin sulfate, zirconia Description
复方、 马来酸氯苯那敏、 巴尼地平、 布那唑嗪、 戈洛帕米、 盐酸哌甲酯、 盐酸羟考酮、 中草 药提取物。 Compound, chlorpheniramine maleate, bainidipine, bunazosin, golopamil, methylphenidate hydrochloride, oxycodone hydrochloride, herbal extracts.
由于， 本发明涉及的控释制剂特别是渗透泵型控释制剂能同步地把中草药提取物中的各 种成分推出制剂， 不存在因成分性质不一样而出现的活性成分释放不同步的问题， 因此， 本 发明涉及的控释制剂特别是渗透泵型控释制剂特别适用于需要控释中草药提取物。  Since the controlled release preparation, in particular the osmotic pump type controlled release preparation, can simultaneously push out various components of the herbal extract, and there is no problem that the release of the active ingredients is not synchronized due to the different nature of the ingredients, Therefore, the controlled release preparations, particularly the osmotic pump type controlled release preparations, to which the present invention relates are particularly suitable for use in controlled release Chinese herbal extracts.
用于本发明活性物包括以下活性成分其药学上可选用的盐形式、 游离酸形式、 游离碱形 式、 水合物、 各种晶型及光学异构体。  The actives useful in the present invention include the pharmaceutically acceptable salt forms, free acid forms, free base forms, hydrates, various crystal forms, and optical isomers of the following active ingredients.
芯料除了生物活性物质还可以含有其它制药助剂， 如缓控释材料、 致孔剂、 填充剂、 粘 合剂、 崩解剂、促崩解剂、 润滑剂 (包括助流剂、 抗粘着剂）、 渗透压活性物质（即渗透压促进 剂）、 促渗透聚合物（助渗剂）等基本成分。 此外， 还可以包含增溶剂、 助悬剂、 甜味剂、 芳 香剂、 色素、 吸收剂及表面活性剂 (如起润湿、 分散、 增溶、 乳化等作用）。 制药助剂及其用 量由此领域技术熟练的技术人员根据实际情况如药物的性质、 所希望的释药速率等选择。 下面就控释制剂的制备方法中的各个基本步骤作详细说明。  In addition to bioactive substances, the core material may also contain other pharmaceutical auxiliaries such as slow release materials, porogens, fillers, binders, disintegrants, disintegrators, lubricants (including glidants, anti-adhesion). An agent, an osmotic pressure active substance (ie, an osmotic pressure promoter), a permeation-promoting polymer (a penetration enhancer), and the like. In addition, it may also contain solubilizers, suspending agents, sweeteners, aromas, pigments, absorbents and surfactants (such as wetting, dispersing, solubilizing, emulsifying, etc.). Pharmaceutical auxiliaries and their use are selected by those skilled in the art based on actual conditions such as the nature of the drug, the desired rate of drug release, and the like. The basic steps in the preparation method of the controlled release preparation are described in detail below.
1 )、 制备含有至少一种生物活性物质的芯料  1) preparing a core material containing at least one biologically active substance
用于本发明的芯料的制备方法在本明无特别的限制。 通常， 芯料制备方法可采用直接挤 压方法， 干、湿或烧结颗粒的挤压方法， 挤出和随后倒圆法， 湿或干态造粒或直接造丸 (例如 在圆盘上)法，或者采用将粉末 (粉末层)粘结到无活性物质的球 (粒子)或含活性物质的颗粒上 的方法， 或者采用以一定方式如压制制成片剂的方法， 或者混合使用上述方法。  The preparation method of the core material used in the present invention is not particularly limited in the present invention. In general, the core preparation method may employ a direct extrusion method, a dry, wet or sintered particle extrusion method, extrusion and subsequent rounding, wet or dry granulation or direct pelleting (for example on a disk). Alternatively, a method of bonding a powder (powder layer) to a sphere (particle) of an inactive material or a particle containing an active material, or a method of forming a tablet in a certain manner such as pressing, or a mixture of the above methods may be employed.
2)、包衣步骤： 用含有可升华的物质和 /或可降解成无害气体的物质颗粒及聚合物增强剂 的不溶于或几乎不溶于水及消化液的聚合物的溶液或水分散液对上述芯料包覆衣膜， 该可升 华的物质和 /或可降解成无害气体的物质不溶于或几乎不溶于该聚合物的溶液或水分散液，该 聚合物与聚合物增强剂的接触角低于 90° 。  2) Coating step: a solution or aqueous dispersion of a polymer which is insoluble or hardly soluble in water and a digestive liquid containing a substance which can be sublimed and/or which can be degraded into a harmless gas and a polymer reinforcing agent. For the above-mentioned core coating film, the sublimable substance and/or the substance which can be degraded into a harmless gas is insoluble or hardly soluble in the solution or aqueous dispersion of the polymer, and the polymer and the polymer reinforcing agent The contact angle is below 90°.
在本发明， 对含有至少一种生物活性物质的芯料包覆衣膜的歩骤更详细地， 通常还包含 下列步骤 （过程）。  In the present invention, the step of coating the coating film of the core material containing at least one biologically active substance, in more detail, usually includes the following steps (process).
a)、将可升华的物质和 /或可降解成无害气体的物质颗粒及聚合物增强剂分散并混悬或溶 解于不溶于或几乎不溶于水及消化液的聚合物的溶液或 （水） 分散体混悬液中， 必要时， 还 可加入其他聚合物衣膜 （控释衣膜）通用添加剂如聚合物增塑剂， 甚至还可以加入生物活性 物质， 混合均匀得混合包衣液。需特别指出的是， 上述可升华的物质和 /或可降解成无害气体 的物质不溶于或几乎不溶于上述聚合物的溶液或水分散液， 上述聚合物与聚合物增强剂的接 触角低于 90° 。上述聚合物的溶剂或分散剂为药学上可接受的有机溶剂及水或它们的混合物。 当上述可升华的物质和 /或可降解成无害气体的物质不溶于或几乎不溶于某种药学上可接受 的有机溶剂， 且此有机溶剂能溶解上述聚合物时，可选用此有机溶剂作为上述聚合物的溶剂; 当上述可升华的物质和 /或可降解成无害气体的物质不溶于或几乎不溶于水时，较佳地选用水 作为该聚合物的分散剂， 即选用聚合物的水分散体。 可用本发明的有机溶剂包括但不限于乙 醇、 丙二醇、 四氢呋喃、 正丁醇、 2-丁醇、 甲乙酮、 乙酸丙酯、 乙酸异丙酯、 甲酸乙酯、 戊 垸、 正丙醇、 2-丙醇、 二氯甲烷、 丙酮、 ***、 甲***、 乙酸乙酯、 乙酸甲酯及它们的混合 物。 上述聚合物在有机溶液中的含量通常为 0. 5〜12%， 较佳地 1〜8%， 更佳地 2〜5%。 上述聚 合物在水分散体混悬液中的含量通常为 5〜30%， 较佳地 8〜20%， 更佳地 10〜15»/。。  a) dispersing and suspending or dissolving a sublimable substance and/or a substance particle which can be degraded into a harmless gas and a polymer enhancer or a solution of a polymer which is insoluble or hardly soluble in water and a digestive solution or (water) In the dispersion suspension, if necessary, other polymer coating film (controlled release film) general additives such as polymer plasticizer may be added, and even bioactive substances may be added, and the mixed coating liquid may be uniformly mixed. It should be particularly noted that the above-mentioned sublimable substance and/or a substance which can be degraded into a harmless gas is insoluble or hardly soluble in a solution or an aqueous dispersion of the above polymer, and the contact angle of the above polymer with the polymer reinforcing agent is low. At 90°. The solvent or dispersing agent of the above polymer is a pharmaceutically acceptable organic solvent and water or a mixture thereof. When the above-mentioned sublimable substance and/or substance degradable into a harmless gas is insoluble or hardly soluble in a pharmaceutically acceptable organic solvent, and the organic solvent can dissolve the above polymer, the organic solvent can be used as the organic solvent a solvent for the above polymer; when the above sublimable substance and/or a substance degradable to a harmless gas is insoluble or hardly soluble in water, water is preferably used as a dispersing agent for the polymer, that is, a polymer is selected. Aqueous dispersion. Organic solvents which may be used in the present invention include, but are not limited to, ethanol, propylene glycol, tetrahydrofuran, n-butanol, 2-butanol, methyl ethyl ketone, propyl acetate, isopropyl acetate, ethyl formate, pentamidine, n-propanol, 2-propene Alcohol, dichloromethane, acetone, diethyl ether, methyl ethyl ether, ethyl acetate, methyl acetate, and mixtures thereof. The content of the above polymer in the organic solution is usually from 0.5 to 12%, preferably from 1 to 8%, more preferably from 2 to 5%. The content of the above polymer in the aqueous dispersion suspension is usually from 5 to 30%, preferably from 8 to 20%, more preferably from 10 to 15»/. .
b)、 利用上述所得的混合包衣液通过熔融、 浇铸、 涂刷或喷涂等涂层方法对上述制得的 芯料制备衣层。 较佳地采用喷涂方式进行。 成膜过程不依赖于涂层方法而通过能量输入来进 行。 这可以通过对流(热）、 辐射 (红外或微波)或传导来完成。 由此将为涂覆而作为溶剂或悬 浮剂使用的有机溶剂或水蒸发掉， 必要的话也可能应用真空加速蒸发。 此过程需要较高干燥 效率， 因此本发明常采用高效率包衣设备 (如流化床、 高效包衣锅）。  b), preparing a coating layer of the above-prepared core material by a coating method such as melting, casting, painting or spraying by using the mixed coating liquid obtained above. It is preferably carried out by spraying. The film formation process is carried out by energy input independent of the coating method. This can be done by convection (heat), radiation (infrared or microwave) or conduction. Thereby, the organic solvent or water used as a solvent or a suspending agent for coating is evaporated, and if necessary, vacuum accelerated evaporation may be applied. This process requires high drying efficiency, so the present invention often employs high efficiency coating equipment (e.g., fluidized bed, high efficiency coating pan).
芯料包衣前， 还可根据实际对芯料包隔离层衣， 这有助于： ①避免药物随溶剂或分散剂 说 明 书 Before the core material is coated, it can also be separated according to the actual core package, which helps: 1 Avoid the drug with solvent or dispersant Description
(水） 而迁移至衣膜； ②改善芯料脆碎度， 避免包衣过程中的破碎现象； ③提高芯料的表面 平整性， 减小孔隙率， 保证衣膜连续性； ④改善芯料表面疏水性， 以利于水性包衣液的铺展; ⑤避免水敏感性药物在包衣过程中水解。根据实际情况， 可选择水溶性聚合物 (如羟丙基甲基 纤维素溶液和羟丙基纤溶液)进行隔离层包衣。然而， 此任一包衣都应充分薄， 以免妨制剂的 释药性能。  (water) and migrate to the film; 2 improve the brittleness of the core material, avoid the breakage during the coating process; 3 improve the surface flatness of the core material, reduce the porosity, ensure the continuity of the film; 4 improve the core material The surface is hydrophobic to facilitate the spreading of the aqueous coating solution; 5 to avoid hydrolysis of the water sensitive drug during the coating process. Depending on the actual situation, a water-soluble polymer such as hydroxypropylmethylcellulose solution and hydroxypropylcellulose solution may be selected for the barrier coating. However, any of these coatings should be sufficiently thin to avoid the release properties of the formulation.
包衣时芯料表面温度应高于聚合物的最低成膜温度 (MFT) (最低成膜温度是指聚合物形成 连续性衣膜的最低温度， 在最低成膜温度以下， 聚合物粒子不能变形融合而成膜） ， 通常高 出最低成膜温度 10〜20°C， 但芯料表面温度不应高到使包衣物料的一些物质完全软化或熔化 从而使衣膜发生粘连， 且也不应高到芯料中的一些成分被完全软化或熔化或者降解， 芯料表 面温度尤其是不应高到使包衣物料的可升华的物质和 /或可降解成无害气体的物质大量升华 及降解， 因此， 芯料表面温度较佳地低于可升华的物质和 /或可降解成无害气体的物质的熔点 或其可升华的或可降解的温度至少 10°C， 更佳地 20°C， 最佳地 30°C。 芯料表面温度在本发明 不能过低， 因芯料表面温度过低使衣膜易脆可能出现裂缝， 影响制剂释药特性； 同时， 芯料 表面温度不能过高， 因芯料表面温度过高则过分软化聚合物， 导致衣膜粘连， 而且还会使可 升华的物质和 Z或可降解成无害气体的物质大量升华及降解， 过早从衣膜中损失。  When coating, the surface temperature of the core should be higher than the minimum film forming temperature (MFT) of the polymer. (The minimum film forming temperature refers to the lowest temperature at which the polymer forms a continuous film. Below the minimum film forming temperature, the polymer particles cannot be deformed. Fusion film), usually higher than the minimum film forming temperature of 10~20 ° C, but the surface temperature of the core material should not be so high that some substances in the coating material are completely softened or melted to cause adhesion of the film, and should not Some of the components in the core material are completely softened or melted or degraded. The surface temperature of the core material should not be so high that the sublimable material of the coating material and/or the substance degradable into a harmless gas can be sublimated and degraded. Therefore, the surface temperature of the core material is preferably lower than the melting point of the sublimable substance and/or the substance degradable to a harmless gas or its sublimable or degradable temperature is at least 10 ° C, more preferably 20 ° C , optimally 30 ° C. The surface temperature of the core material can not be too low in the present invention, because the surface temperature of the core material is too low, the coating film is brittle and cracks may occur, which affects the release characteristics of the preparation; meanwhile, the surface temperature of the core material cannot be too high, because the surface temperature of the core material is too high. Excessive softening of the polymer leads to adhesion of the film, and also causes sublimation and degradation of the sublimable substance and Z or a substance degradable into a harmless gas, which is prematurely lost from the film.
包衣时， 芯料通常预热 （采用聚合物有机溶液时此温度相对较低， 采用聚合物水分散体 时此温度相对较高） 至 20〜70°C， 较佳地 30〜60°C， 更佳地 30〜50°C， 先以较低喷液速率包 衣， 至芯料表面已包覆一薄层衣膜后， 再提高喷液速率至包衣结束， 此操作可避免溶剂尤其 是分散剂 （水）渗入芯料内部， 造成储存过程芯料性质发生变化。  When coating, the core material is usually preheated (the temperature is relatively low when the polymer organic solution is used, and the temperature is relatively high when the polymer aqueous dispersion is used) to 20 to 70 ° C, preferably 30 to 60 ° C. More preferably 30~50 ° C, first coating at a lower spray rate, after the surface of the core material has been coated with a thin film, and then increasing the spray rate to the end of the coating, this operation can avoid solvents especially It is the dispersant (water) that penetrates into the core material, causing changes in the properties of the core material during storage.
最合适或较合适的工艺参数由此领域技术熟练的技术人员根据包衣材料和芯料性质及实 验结果等确定。 以流化床包衣为倒， 包衣温度、 流化风量、 雾化压力和喷液速率等工艺条件 均可根据实际情况优化定量控制。  The most suitable or suitable process parameters are determined by those skilled in the art based on the coating material and core properties and experimental results. The fluidized bed coating is used for pouring, and the process conditions such as coating temperature, fluidizing air volume, atomization pressure and liquid spraying rate can be optimized according to actual conditions.
为了保护不稳定的活性成分在愈合处理中免于降解， 可以使用氮气置换密闭的环境 （如 密闭的箱体） 中的空气。  To protect the unstable active ingredient from degradation during the healing process, nitrogen can be used to replace the air in a confined environment such as a closed enclosure.
3 )、 挥去致孔物质  3), wave the porogen
在本发明中， 制剂衣膜中的致孔物质需要挥去以获得一定孔隙率的释药速率控制满意的 衣膜。  In the present invention, the porogenic substance in the coating film needs to be volatilized to obtain a film having a porosity which is satisfactory in controlling the release rate.
使致孔物质挥去， 通常在低于衣膜玻璃化转变温度及常压、 减压或真空下进行， 较佳地 在低于衣膜玻璃化转变温度 5°C以下的温度下进行， 最佳地在低于衣膜玻璃化转变温度 10°C 以下的温度下进行。 过高的温度可能使已形成的释药微孔缩小甚至完全愈合， 最严重者导致 衣膜粘连。  The porogen is volatilized, usually at a temperature lower than the glass transition temperature of the film and under normal pressure, reduced pressure or vacuum, preferably at a temperature below 5 ° C below the glass transition temperature of the film, most Preferably, it is carried out at a temperature below 10 ° C below the glass transition temperature of the film. Too high a temperature may cause the formed micropores to shrink or even heal completely, and the most severe cause adhesion of the coating.
4)、 愈合 （固化） 处理  4), healing (curing) treatment
本发明为了提高制剂的药物释放的稳定性， 较佳地在步骤 2 ) (包衣）过程中和 /或步骤 2) (包衣）结束后， 及步骤 3) (挥去致孔物质）前，愈合处理上述衣膜以消除衣膜中在包衣过程 中产生众多极小的微孔并形成致密的衣膜， 以确保药物释放的相对稳定。  The present invention is intended to improve the stability of drug release of the formulation, preferably during the step 2) (coating) and/or after the step 2) (coating), and before the step 3) (without the porogen) The above-mentioned coating film is healed to eliminate a large number of tiny pores in the coating film during the coating process and form a dense coating film to ensure relatively stable drug release.
包衣结束后， 在衣膜中聚合物的溶剂或分散剂基本已挥发， 在衣膜中留有许多极小的微 孔， 衣膜中聚合物粒子往往未完全融合。 据信， 在聚合物一空气间的界面张力产生的微孔附 加压（Δ Ρ)作用下， 这些极小的微孔自动缓缓缩小， 存放过程中发生融合现象， 使衣膜的通 透性发生不断的改变， 从而使制剂的药物释放行为变得不稳定。 依微孔附加压（A P)的公式 ( Δ Ρ=2 σ /Γ, 其中， Δ Ρ表示微孔附加压， σ聚合物-空气表面张力， r表示微孔半径） 可得 推得， 融合所需时间通常与膜微孔径大小、聚合物一空气间的界面张力大小等相关。聚合物- 空气表面张力一定时， 膜微孔径越小， 微孔附加压越大， 融合所需时间越短， 膜微孔径越大， 微孔附加压越小， 融合所需时间越长。 正因为此， 本发明采用相对较大的微孔来控释药物释 放， 并消除包衣过程中因溶剂或分散剂挥发而产生的众多极小的微孔。 After the coating is finished, the solvent or dispersant of the polymer in the film is substantially volatilized, leaving many tiny pores in the film, and the polymer particles in the film are often not completely fused. It is believed that under the action of the micropore additional pressure (Δ Ρ) generated by the interfacial tension between the polymer and the air, these tiny micropores are automatically and gradually reduced, and fusion occurs during storage to make the membrane permeability. Constant changes occur, making the drug release behavior of the formulation unstable. According to the formula of microporous additional pressure (AP) ( Δ Ρ = 2 σ / Γ , where Δ Ρ represents micropore additional pressure, σ polymer - air surface tension, r represents micropore radius) can be derived, fusion The time required is usually related to the pore size of the membrane, the interfacial tension between the polymer and the air, and the like. Polymer - When the surface tension of the air is constant, the smaller the micropore diameter of the membrane, the larger the additional pressure of the micropores, the shorter the time required for fusion, the larger the pore diameter of the membrane, the smaller the additional pressure of the micropores, and the longer the time required for fusion. Because of this, the present invention employs relatively large pores to control release of the drug and eliminates numerous tiny pores resulting from evaporation of the solvent or dispersant during the coating process.
本发明通过升华在薄膜中的具有升化性的成分或降解在薄膜中的可降解成无害气体的成 说 明 书 The invention is characterized in that it has sublimation in a film having an ascending component or a degradation in a film which is degradable into a harmless gas. Description
分来形成微孔控释药物释放， 而这些相对较大的微孔在愈合处理过程仍然会产生一定的微孔 附加压 （A P)， 使微孔一定程度上縮小 （如微孔小于 30 n m时， 特别是小于 l w m时）。 为了防 止或延缓这些已产生的用来控释药物释放的相对较大的微孔在愈合处理缩小， 提高衣膜的通 透性能的稳定性 （与释药性能相关） 及生产重现性， 提高衣膜机械性能等方面的稳定性及生 产重现性， 在本发明中， 衣膜愈合处理过程最佳地在用来控释药物释放的相对较大的微孔形 成前 （即挥去致孔物质前） 完成。 The microporous controlled release drug release is formed, and these relatively large micropores still produce a certain micropore additional pressure (AP) during the healing process, so that the micropore is reduced to some extent (for example, when the micropore is less than 30 nm) , especially when it is less than lwm). In order to prevent or delay the relatively large micropores that have been produced for controlled release drug release, the healing process is reduced, the stability of the permeability of the film is improved (related to the release performance), and the production reproducibility is improved. The stability and production reproducibility of the mechanical properties of the film, in the present invention, the film healing process is optimally before the formation of relatively large pores for controlled release of the drug (ie, the wave-forming hole Material before) is completed.
愈合处理过程在挥去致孔物质前完成较挥去致孔物质与愈合处理同时进行及愈合处理在 较挥去致孔物质之后完成有许多无法比拟的优势。 愈合处理与挥去致孔物质同时进行及愈合 处理在较挥去致孔物质之后进行或完成无法达到预期的愈合处理终点， 或者虽然愈合到达终 点， 但药物释放非常缓慢甚至基本不释药， 因在愈合处理过程中， 已形成的包括用来控释药 物释放的微孔也在不断地縮小甚至直至完全闭合， 并使衣膜的通透性能或释药特性、 机械性 能等难以稳定及重现。愈合处理过程在挥去致孔物质前完成即可以使可升华和 /或降解的致孔 物质始终净固体量不变地位于衣膜中， 避免由致孔物质产生的释药微孔在衣膜愈合过程中缩 小， 又可以使衣膜完全愈合， 可以完全消除衣膜中在包衣过程中由溶剂挥发产生的众多极小 的微孔并形成致密的衣膜， 从而稳定、重现并提高衣膜的通透性能或释药性能、机械性能等。  The healing process is completed before the porogen is removed. Compared with the porogen and the healing process, the healing process has many incomparable advantages after the porogen is removed. The healing process is performed simultaneously with the wagging substance and the healing process is performed after the porogen is removed or the end of the healing process is not achieved, or although the healing reaches the end point, the drug release is very slow or even non-released. During the healing process, the micropores that have been formed, including controlled release of the drug, are constantly shrinking or even completely closed, and the permeability or release properties, mechanical properties, etc. of the film are difficult to stabilize and reproduce. . The healing process can be completed before the porogen is removed, so that the sublimable and/or degraded porogen can be kept in the film at all times, so as to avoid the release of micropores produced by the porogen. It shrinks during the healing process, and the film can be completely healed. It can completely eliminate many tiny micropores produced by solvent evaporation during the coating process and form a dense film to stabilize, reproduce and improve the clothes. Membrane permeability or release properties, mechanical properties, etc.
在本发明中，愈合处理（curing treating)包括下列过程：上述衣膜中溶剂或分散剂（水） 基本蒸发后， 在封闭环境中， 将上述已包覆聚合物衣膜的芯料置于高于上述衣膜的玻璃化转 变温度的温度下足够长时间直至终点，使上述制剂衣膜中的聚合物粒子融合完全或基本完全, 消除或基本消除包衣过程中形成的极小微孔并形成完整致密或基本完整致密的衣膜， 上述控 释衣膜的渗透性能或者说释药性能达到稳定的状态或者说基本不变的状态。 更具体地说， 就 是在高于上述衣膜的玻璃化点的温度下愈合处理上述包衣制剂直至制剂在例如约 40 ± 2°C的 温度及不低于 50%且不高于上述的可升华的物质颗粒和 /或可降解成无害气体的物质的（吸湿） 临界相对湿度的相对湿度下的加速贮存条件下放置 3个月和 /或 6个月或更长如 9个月或 12 个月其溶出特性基本上不受影响为止。 或者换言之， 将刚愈合处理后的生物活性物质的体外 溶出与在约 40± 2°C的温度及不低于 50%且不高于上述的可升华的物质颗粒和 /或可降解成无 害气体的物质的 （吸湿）临界相对湿度的相对湿度下的加速贮存条件下被放置 3个月和 /或 6 个月或更长如 9个月或 12个月的生物活性物质的体外溶出相比，愈合处理的包衣制剂具有稳 定的溶出特性。 此外术语 "稳定的"的意思是与刚固化结束的、 固化包衣制剂的溶出特性比 较， 其体外溶出处于可接受的限度内， 可接受的限度由管理机构， 如中国药品食品管理监督 局、 美国食品和药品管理局等确定。 基本不受加速贮存条件影响的稳定的溶出特性。 上述溶 出试验较佳地采用含有上述的控释聚合物衣膜中的所有成分 （但不包括上述水溶性的致孔物 质（即上述可升华的物质颗粒和 /或可降解成无害气体的物质颗粒）， 这里是因需要其溶出致 孔）的且上述所有成分均饱和的释放介质（溶出介质）。采用上述控释聚合物衣膜中的所有成 分的饱和溶液可以使在上述溶出试验中， 上述控释聚合物衣膜中的所有成分的净溶出量为 0 (不包括上述水溶性的致孔物质的溶出），从而有利于判断溶出的药物是从原控释聚合物衣膜 微孔中溶出的而不是因其中的成分溶出而产生的微孔中溶出的， 因从更有利于判断上述控释 聚合物衣膜已愈合完全或已至终点状态或者愈合基本完全或已基本至终点状态。  In the present invention, the curing treatment includes the following process: after the solvent or dispersant (water) in the above film is substantially evaporated, the core of the coated polymer film is placed in a closed environment. At a temperature of the glass transition temperature of the above film, which is long enough to reach the end point, the polymer particles in the coating film of the above formulation are completely or substantially completely fused, and the micropores formed during the coating process are eliminated or substantially eliminated. The fully dense or substantially intact dense film, the permeation performance or the release property of the above controlled release film reaches a stable state or a substantially constant state. More specifically, the above-mentioned coating preparation is healed at a temperature higher than the glass transition point of the above film until the preparation is at a temperature of, for example, about 40 ± 2 ° C and not less than 50% and not higher than the above. Sublimated material particles and/or substances that can be degraded into harmless gases (hygroscopic) are placed under accelerated storage conditions at a relative humidity of 3 months and/or 6 months or longer, such as 9 months or 12 The dissolution characteristics of the month are basically unaffected. Or in other words, the in vitro dissolution of the biologically active substance immediately after the healing treatment is at a temperature of about 40 ± 2 ° C and not less than 50% and not higher than the above-mentioned sublimable substance particles and / or degradable into harmless The in vitro dissolution of biologically active substances placed under accelerated storage conditions of gaseous (sublimation) critical relative humidity at relative humidity for 3 months and/or 6 months or longer, such as 9 months or 12 months. The healing treated coating formulation has stable dissolution characteristics. In addition, the term "stable" means that the dissolution in vitro is within acceptable limits compared to the dissolution characteristics of a cured coating formulation, which is acceptable to regulatory agencies such as the China Food and Drug Administration. The US Food and Drug Administration et al. Stable dissolution characteristics that are substantially unaffected by accelerated storage conditions. The above dissolution test preferably employs all of the components contained in the above-mentioned controlled release polymer coating film (but does not include the above-mentioned water-soluble porogen substances (i.e., the above-mentioned sublimable substance particles and/or substances which can be degraded into harmless gases). Particles), here is the release medium (dissolution medium) which is required to dissolve the pores and which is saturated with all of the above components. Using the saturated solution of all the components in the controlled release polymer coating film, the net dissolution amount of all the components in the controlled release polymer coating film is 0 in the above dissolution test (excluding the above water-soluble porogen Dissolution), thereby facilitating the judgment that the dissolved drug is eluted from the micropores of the original controlled release polymer coating film rather than being dissolved in the micropores produced by the dissolution of the components therein, since it is more advantageous to judge the above controlled release The polymeric film has healed completely or has reached the end state or has healed substantially completely or has been substantially to the end state.
在本发明， 愈合处理所需的时间通常为数十小时甚至更长。 愈合处理所选择的温度应高 于衣膜玻璃化转变温度， 较佳地高于衣膜玻璃化转变温度 10°C以上， 更佳地高于衣膜玻璃化 转变温度 20〜30°C , 愈合处理所选择的温度且应以不使包衣物料中的成分完全软化或熔化或 不发生衣膜粘连为度。 愈合处理时较佳地使用一定的湿度， 因控释衣膜在水分或湿气的作用 下， 其玻璃化转变温度会显著下降， 从而有利于加速愈合处理。 所选择的湿度通常不低于相 对湿度 50%， 较佳地不低于相对湿度 60%， 更佳地不低于相对湿度 70%， 所选择的湿度通常不 要太低， 因湿度太低会使愈合处理的时间较长。 但所选择的湿度通常通常不应高于上述的可 升华的物质颗粒和 Z或可降解成无害气体的物质的（吸湿）临界相对湿度， 因高于上述的可升 说 明 书 In the present invention, the time required for the healing treatment is usually several tens of hours or longer. The temperature selected for the healing treatment should be higher than the glass transition temperature of the coating film, preferably higher than the glass transition temperature of the coating film by 10 ° C or higher, more preferably higher than the glass transition temperature of the coating film by 20 to 30 ° C, and healed. The selected temperature is treated and should be such that the ingredients in the coating material are not completely softened or melted or the film adhesion does not occur. It is preferable to use a certain humidity during the healing treatment, and the glass transition temperature of the controlled release coating film is significantly lowered by the action of moisture or moisture, thereby facilitating the accelerated healing treatment. The selected humidity is usually not lower than 50% relative humidity, preferably not lower than 60% relative humidity, and more preferably not lower than 70% relative humidity. The selected humidity is usually not too low, because the humidity is too low. The healing process takes a long time. However, the selected humidity is usually generally not higher than the above-mentioned sublimable substance particles and Z or the (hygroscopic) critical relative humidity of the substance degradable into a harmless gas, because it is higher than the above. Description
华的物质颗粒和 /或可降解成无害气体的物质的（吸湿）临界相对湿度后， 上述的可升华的物 质颗粒和 /或可降解成无害气体的物质会显著吸湿， 特别是水溶性的可升华的物质颗粒和 /或 可降解成无害气体的物质，显著吸湿后上述可升华的物质颗粒和 /或可降解成无害气体的物质 将出现局部或全部的溶解 -结晶现象， 从而可能从衣膜中析出， 出现 "泛霜"现象， 进而可能 使释药微孔在愈合过程中缩小， 影响释药稳定性。 After the material particles and/or the (hygroscopic) critical relative humidity of the substance degradable into a harmless gas, the above-mentioned sublimable substance particles and/or substances degradable into harmless gases may significantly absorb moisture, particularly water solubility. Sublimable material particles and/or substances which can be degraded into harmless gases, and the above-mentioned sublimable substance particles and/or substances which can be degraded into harmless gases will exhibit partial or total dissolution-crystallization after significant moisture absorption, thereby It may precipitate from the film, and the phenomenon of "pan-cream" may appear, which may cause the release micropores to shrink during the healing process and affect the stability of drug release.
在上述愈合处理过程中及上述的加速贮存条件下放置过程中， 要求位于上述聚合物衣膜 中的上述可升华的物质和 /或可降解成无害气体的致孔物质的净固体量不减少。为了防止可升 华或可降解性致孔物质在衣膜未完全融合前挥去或损失， 防止微孔比预期的小， 或者说使上 述可升华的物质和 /或可降解成无害气体的致孔物质的净固体量不减少，从而进一步地防止微 孔用同一批次的致孔剂也能出现的批间差异性，提高制剂的生产重现性、稳定性及释药速率， 通常愈合处理过程在大于或等于所处条件如温度下的可升华性致孔物质的平衡分压和 /或在 大于或等于所处条件如温度下的可降解性致孔物质的所有降解产物的平衡分压下或者在低于 所处条件如压力下的可降解性致孔物质的最低降解温度的温度下进行， 在该过程中， 位于上 述聚合物衣膜中的上述可升华的和 /或可降解成无害气体的致孔物质的净固体量不会减少。致 孔物质 （或其降解产物） 的平衡分压是指封闭环境中一定温度下， 气相中的致孔物质 （或其 所有降解产物）及其固相中的致孔物质处于平衡状态时即致孔物质的固体净增或净减量为零 时的分压。 为了获得大于或等于可升华性或可降解性致孔物质的平衡分压， 通常的做法是在 密闭的环境 （如密闭的箱体） 中吹 （充） 入大于或等于可升华性致孔物质的平衡分压的可升 华性致孔物质气体和 /或入大于或等于可降解性致孔物质的降解产物的平衡分压的所有降解 产物气体， 或者在密闭的环境 （或箱体） 中放入过量 （即通常总有一部分余量固体存在） 的 可升华性或可降解性致孔物质， 升高温度一定时间使气相中的可升华性致孔物质或可降解性 致孔物质的降解产物与固相中的可升华性致孔物质或可降解性致孔物质处于平衡状态。  During the above-described healing process and during the above-described accelerated storage conditions, it is required that the above-mentioned sublimable substance and/or the refractory substance which can be degraded into a harmless gas in the above polymer film are not reduced in net solid content. . In order to prevent the sublimable or degradable porogens from being undone or lost before the film is completely fused, the micropores are prevented from being smaller than expected, or the above sublimable substances and/or degradable into harmless gases are caused. The net solid content of the pore material is not reduced, thereby further preventing the inter-batch variability of the microporous with the same batch of porogen, improving the production reproducibility, stability and release rate of the preparation, usually healing treatment The equilibrium partial pressure of the sublimable porogen which is greater than or equal to the conditions, such as temperature, and/or the equilibrium partial pressure of all degradation products of the refractory porogen at greater than or equal to the conditions such as temperature. Performing at or below a temperature below the lowest degradation temperature of the degradable porogen, such as under pressure, during which the above-described sublimable and/or degradable in the polymer film is The net solids of the porogenic material of the harmless gas will not decrease. The equilibrium partial pressure of a porogen (or its degradation product) means that the porogen in the gas phase (or all of its degradation products) and the porogen in the solid phase are in equilibrium at a certain temperature in a closed environment. The partial pressure at which the solid or net reduction of the pore material is zero. In order to obtain a balanced partial pressure greater than or equal to the sublimable or degradable porogen, it is common practice to blow (charge) a sublimable porogen in a closed environment (eg, a closed enclosure). A balanced partial pressure sublimable porogen gas and/or all degradation products of a equilibrium partial pressure greater than or equal to the degradation product of the degradable porogen, or placed in a closed environment (or tank) A sublimable or degradable porogen that is in excess (ie, usually has a portion of the balance of solids present), raised at a temperature for a period of time to allow degradation of the porogen or degradable porogen in the gas phase It is in equilibrium with the sublimable porogen or the degradable porogen in the solid phase.
愈合处理可以以烘箱和流化床等热处理方式进行。 流化床热处理具有高效、 省时等特点， 可在同一设备中完成包衣和热处理操作， 产业化适用性较高。 包衣结束后升高***温度， 物 料在同一流化床设备中继续流化干燥， 短时间内可促进膜愈合平衡。 但与烘箱方式相比， 流 化床方式对丧膜机械性能的要求较高， 且热处理后膜愈合程度相对较低。 故本发明较佳地采 用烘箱热处理方式。  The healing treatment can be carried out by heat treatment such as an oven and a fluidized bed. The fluidized bed heat treatment has the characteristics of high efficiency and time saving, and the coating and heat treatment operations can be completed in the same equipment, and the industrial applicability is high. After the coating is finished, the temperature of the system is raised, and the material is continuously fluidized and dried in the same fluidized bed apparatus, which promotes the healing of the membrane in a short time. However, compared with the oven mode, the fluidized bed method has higher requirements on the mechanical properties of the film, and the degree of film healing is relatively low after heat treatment. Therefore, the present invention preferably employs an oven heat treatment method.
最合适或较合适的工艺参数， 如愈合温度、 湿度、 时间由此领域技术熟练的技术人员根 据实验结果等确定。  The most suitable or suitable process parameters, such as healing temperature, humidity, time, are determined by those skilled in the art based on experimental results and the like.
用上述任一方法制备的制剂都可以包上一薄层水溶性包衣材料以改善制剂的表面整体性 或防止在贮存过程中制剂相互粘结或防止或延缓在贮存过程中释药微孔发生变化。 合适的包 衣材料包括但不限于二糖如蔗糖、 多糖如麦芽糖糊精和果胶、 和纤维素衍生物如羟丙基甲基 纤维素和羟丙基纤维素， 然而， 任一包衣都应充分薄并且是水溶性的， 以免妨碍制剂的释药 性能。 包上此薄层后， 可水溶性包衣材料会部分封闭挥去致孔物质而留下的释药微孔 （占有 原部分空气）， 故对已形成的释药微孔有 （尺寸） 稳定作用。  The preparation prepared by any of the above methods may be coated with a thin layer of water-soluble coating material to improve the surface integrity of the preparation or prevent the preparation from sticking to each other during storage or to prevent or delay the release of micropores during storage. Variety. Suitable coating materials include, but are not limited to, disaccharides such as sucrose, polysaccharides such as maltodextrin and pectin, and cellulose derivatives such as hydroxypropylmethylcellulose and hydroxypropylcellulose, however, any coating It should be sufficiently thin and water soluble so as not to interfere with the release properties of the formulation. After the thin layer is coated, the water-soluble coating material partially seals the release pores and leaves the release micropores (occupying the original part of the air), so that the formed release micropores are (size) stable. effect.
用上述任一方法制备的药物剂型基本上可直接使用， 如直接口服。 用上述制备的颗粒、 丸或颗粒也可用计量设备装入如明胶胶囊、 袋 (小药囊)或合适的多计量容器中。 可能的话在 与其它助剂混合后通过压制得到， 制剂在服用后分解， 大部分包覆的小单元释放出来。 同样 可以考虑将聚集物包埋入聚乙二醇或脂质中以制备检剂或***用药物剂型。 包覆的片剂用半 球形容器或多剂量容器包装， 病人服用前直接取出。  The pharmaceutical dosage form prepared by any of the above methods can be used substantially directly, such as directly orally. The granules, pellets or granules prepared as described above may also be filled into a gelatin capsule, a pouch (small sachet) or a suitable multi-meter container by means of a metering device. If possible, it is obtained by pressing after mixing with other auxiliaries. The preparation is decomposed after taking it, and most of the coated small units are released. It is also conceivable to embed the aggregates in polyethylene glycol or lipids to prepare a test or vaginal dosage form. The coated tablets are packaged in semi-spherical containers or multi-dose containers and taken directly before administration.
由此已详细地描述了本发明， 对本领域技术人员而言在本发明的范围内显然还可有各种 改变， 本发明并不受说明书所述的限制。 实施例  The present invention has been described in detail, and it is obvious to those skilled in the art that various modifications may be made without departing from the scope of the invention. Example
以下非选择性实施例进一步描述了本发明范围内的优选实施例。 在本发明的范围内这些 说 明 书 实施例还可有许多变化。 实施例 1及对照例 1 The following non-selective examples further describe preferred embodiments within the scope of the invention. Within the scope of the invention There are many variations to the description of the embodiment. Example 1 and Comparative Example 1
1、 制备实施例 1样品  1. Preparation Example 1 Sample
1 )、 按下列处方及工艺制备片芯:  1), prepare the core according to the following prescriptions and processes:
组分 mg/片  Component mg/tablet
盐酸地尔硫卓 90  Diltiazem hydrochloride 90
乳糖 255  Lactose 255
羟丙纤维素（Klucel HXF) 250  Hydroxypropylcellulose (Klucel HXF) 250
聚维酮（K29/32) 25  Povidone (K29/32) 25
硬脂酸镁 10  Magnesium stearate 10
总计 630  Total 630
将盐酸地尔硫卓、 乳糖、 羟丙纤维素和聚维酮混合均匀， 用乙醇进行造粒; 将湿的粒状 物料强制穿过一个 18目的筛子并干燥 24小时； 整粒后， 加入硬脂酸镁混匀， 用一个 12mm的 标准的凹形圆形冲模压制片，所用的压制力为 1200〜2000kg，压制时间 2s。硬度为 6〜10kg。  Diltiazem hydrochloride, lactose, hydroxypropylcellulose and povidone are uniformly mixed and granulated with ethanol; the wet granulated material is forced through an 18-mesh sieve and dried for 24 hours; after the granules, magnesium stearate is added. Uniformly, the sheet was pressed with a standard concave circular die of 12 mm, using a pressing force of 1200 to 2000 kg and a pressing time of 2 s. The hardness is 6~10kg.
2)、 对片芯按下列处方及工艺包衣：  2), the core of the film is coated according to the following prescriptions and techniques:
包衣液处方：  Coating liquid prescription:
组分 含量 (g)  Component content (g)
Aquacoat (乙基纤维素水分散体） 96. 0  Aquacoat (ethyl cellulose dispersion) 96. 0
癸二酸二丁酯 4. 8  Dibutyl sebacate 4. 8
水杨酸（61〜80 μ ιη) 37. 05  Salicylic acid (61~80 μ ιη) 37. 05
表面被硬脂酸包覆的碳酸钙（WINN0FIL® 3. 45  Calcium carbonate coated with stearic acid (WINN0FIL® 3. 45
FX) ^ (平均料径约 20nm)  FX) ^ (average diameter about 20nm)
去离子水 321. 9  Deionized water 321. 9
总计 463. 2  Total 463. 2
※， 表面被硬脂酸包覆的碳酸钙 （WIN IL® FX), Solvay公司生产， 与包衣聚合物的 接触角 Θ测定为 2Γ 。  * The calcium carbonate (WIN IL® FX) coated with stearic acid on the surface, produced by Solvay, has a contact angle of 2 Γ with the coated polymer.
将片芯在 Hicoater/Fruend包衣机上包衣。 包衣条件参数： 入口温度， 50〜60°C ; 出口 温度， 40〜42°C ; 片芯温度 40°C ; 片芯增重 16%。  The cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 40~42 ° C; core temperature 40 ° C; core weight gain 16%.
在包上述控释衣膜前包一水溶性薄膜衣。包水溶性薄膜衣用的包衣料为含 4. 5%羟丙基甲 基纤维素（Pharmacoat , 603/ShinEtsu)、 0. 52°/。的 PEG 400及 1. 5%微粉化的滑石的水溶液。 包衣条件参数入口温度， 55°C ; 出口温度， 30°C。 水溶性薄膜衣包衣增重约为 1%。  A water-soluble film coat is applied before the above-mentioned controlled release film. The coating material for the water-soluble film coating was 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52 ° /. An aqueous solution of PEG 400 and 1.5% micronized talc. Coating conditions parameter inlet temperature, 55 ° C; outlet temperature, 30 ° C. The water-soluble film coat has a weight gain of about 1%.
3)、 愈合控释衣膜  3), healing controlled release film
愈合处理在密闭烘箱中进行。 供箱内置足量（即总有剰余固体量）的水杨酸。 愈合处理前 充入含饱和量的水杨酸气体的温度 65°C的热空气。 愈合温度为 50°C， 愈合时间为 56小时。  The healing treatment is carried out in a closed oven. The tank is filled with a sufficient amount of salicylic acid (that is, there is always a surplus of solids). Before the healing treatment, hot air containing a saturated amount of salicylic acid gas at a temperature of 65 ° C was charged. The healing temperature was 50 ° C and the healing time was 56 hours.
4)、 挥去致孔剂  4), whistling agent
在温度 20 °C及近似真空的条件下抽去衣膜中的水杨酸。  The salicylic acid in the film was removed at a temperature of 20 ° C and an approximate vacuum.
2、 制备对照例 1样品  2. Preparation of Comparative Example 1 Sample
把包衣液处方中的表面被硬脂酸包覆的碳酸钙去掉， 其他不变， 依实施例 1方法制备对 照例 1。 实施例 2及对照例 2  The surface of the coating liquid was removed by the stearic acid-coated calcium carbonate, and the others were unchanged. The same procedure as in Example 1 was carried out. Example 2 and Comparative Example 2
1、 制备实施例 2样品  1. Preparation Example 2 Sample
1 )、 制备片芯： 说 明 书 组分 mg/片 1), preparation of the core: Specification component mg/piece
格列吡嗪 20  Glipizide 20
聚氧化乙烯 （PE0- 100K) 380  Polyethylene oxide (PE0- 100K) 380
氯化钠 100  Sodium chloride 100
硬脂酸镁 2  Magnesium stearate 2
总计 502  Total 502
将格列吡嗪、 聚氧化乙烯和氯化钠混匀， 再与硬脂酸镁混合后模压制成 502mg的片芯， 用一个 12 的标准的凹形圆形冲模压制片，所用的压制力为 1200 1800kg，压制时间 l 2s 6 8kg Mixing glipizide, polyethylene oxide and sodium chloride, mixing with magnesium stearate, molding into 502 mg core, pressing a 12 standard concave circular die, using the pressed The force is 1200 1800kg, pressing time l 2s 6 8kg
2)、 制备包衣液：  2), preparation of coating liquid:
将醋酸纤维素加入乙酸乙醋一乙醇 (95 : 5)中制得 5%的溶液作为油相， 以 3mg/ml的十二 垸基硫酸钠水溶液为水相； 用高速乳匀机， 在搅拌速度不小于 3000转 /分钟的条件下把水相 缓缓滴加入油相中形成 W/0型乳剂， 继续滴加直至形成 0/W型的初乳。 将初乳通过高压匀质 机， 反复 6次。 使用旋转蒸发仪在 40°C， 减压条件下将有机溶剂从所得乳剂中除去。  Adding 5% solution of acetic acid to ethyl acetate monoacetate (95:5) as an oil phase, using 3 mg/ml aqueous solution of sodium sulfonate as the aqueous phase; using a high-speed emulsion homogenizer, stirring The water phase is slowly added dropwise to the oil phase at a speed of not less than 3000 rpm to form a W/0 type emulsion, and the dropwise addition is continued until a 0/W type colostrum is formed. The colostrum was passed through a high pressure homogenizer for 6 times. The organic solvent was removed from the obtained emulsion using a rotary evaporator at 40 ° C under reduced pressure.
3)、 包衣：  3), coating:
控释衣膜包衣前包隔湿保护涂层。 隔湿保护涂层用的包衣料为含 4. 5%羟丙基甲基纤维素 (Pharmacoat , 603/ShinEtsu) , 0. 52%的 PEG 400及 1. 5%微粉化的滑石的混悬液。 包衣条件 参数： 喷洒时间约 20秒， 鼓风时间约 30 40秒， 鼓风温度 50 55°C， 片芯温度 30 40°C 隔湿保护涂层包衣增重约为 1%  The controlled release film is coated with a moisture barrier protective coating. The coating for the moisture barrier protective coating is a suspension containing 4.5% hydroxypropyl methylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. . Coating conditions Parameters: Spraying time is about 20 seconds, blasting time is about 30 40 seconds, blasting temperature is 50 55 °C, core temperature is 30 40 °C, moisture barrier coating weight gain is about 1%
在上述制得的醋酸纤维素加水分散体中加入乙基香草醛 (60 80目）、聚丙烯酸酯包覆的 纳米氧化铝分散浆（平均料径 10nm， 与包衣聚合物的接触角 Θ测定为 70° )及作增塑剂用的 二乙酸甘油酯， 其中醋酸纤维素：乙基香草醛：纳米氧化铝 （以干重计） ：二乙酸甘油酯为 1 : 2 : 0. 06 : 1 (重量比）， 用水稀释至含 3%的醋酸纤维素混悬液制得包衣液。 用制得的包衣液对 片芯包控释衣膜。 控释衣膜包衣增重为 18%  Ethyl vanillin (60 80 mesh) and polyacrylate-coated nano-alumina dispersion slurry (average diameter 10 nm, contact angle Θ with coated polymer) were added to the cellulose acetate aqueous dispersion prepared above. 70 ° ) and as a plasticizer diacetin, wherein cellulose acetate: ethyl vanillin: nano alumina (by dry weight): diacetin is 1: 2 : 0. 06 : 1 (Weight ratio), a coating liquid was prepared by diluting with water to a suspension containing 3% cellulose acetate. The core-coated release film was coated with the prepared coating liquid. Controlled release film coating weight gain of 18%
用定时自动薄膜包衣机包衣， 包衣条件参数为： 喷洒时间约 20秒， 鼓风时间约 30 40 秒， 鼓风温度 50 70°C， 片芯温度 45 50°C  Coating with a timed automatic film coater, the coating conditions are: spraying time of about 20 seconds, blasting time of about 30 40 seconds, blast temperature 50 70 ° C, core temperature 45 50 ° C
4)、 愈合控释衣膜  4), healing controlled release film
愈合处理在密闭烘箱中进行。 烘箱内置足量（即总有剰余固体量）的乙基香草醛。 愈合处 理前充入含饱和量的乙基香草醛气体的温度 70°C的热空气。 愈合温度为 65 °C， 愈合时间为 64小时。  The healing treatment is carried out in a closed oven. The oven contains a sufficient amount (ie, there is always a residual solids) of ethyl vanillin. The healing air was filled with hot air at a temperature of 70 ° C containing a saturated amount of ethyl vanillin gas. The healing temperature was 65 °C and the healing time was 64 hours.
5)、 挥去致孔剂  5), whistling agent
在温度 35°C及近似真空的条件下抽去衣膜中的乙基香草醛。  The ethyl vanillin in the coating film was removed at a temperature of 35 ° C and an approximate vacuum.
2、 制备对照例 2样品  2. Preparation of Comparative Example 2 Sample
把包衣液处方中的纳米氧化铝去掉， 其他不变， 依实施例 2方法制备对照例 2 实施例 3及对照例 3  The nano-alumina in the coating liquid prescription was removed, and the others were unchanged. Comparative Example 2 was prepared according to the method of Example 2 Example 3 and Comparative Example 3
1、 制备实施例 3样品  1. Preparation Example 3 Sample
1 )、 按下列处方及工艺制备片芯：  1), prepare the core according to the following prescriptions and processes:
组分 mg/片  Component mg/tablet
盐酸地尔硫卓 300  Diltiazem hydrochloride 300
柠檬酸二氢钠 218  Sodium dihydrogen citrate 218
聚维酮 (K25) 42. 4  Povidone (K25) 42. 4
硬脂酸镁 12. 6  Magnesium stearate 12. 6
总计 573 说 明 书 将盐酸地尔硫卓、 柠檬酸二氢钠和聚维酮混合均匀， 用无水乙醇溶液进行造粒； 将湿的 粒状物料强制穿过一个 18目的筛子并干燥 24小时；整粒后，加入硬脂酸镁混匀，用一个 12mm 的标准的凹形圆形冲模压制片，所用的压制力为 1200〜2000kg，压制时间 2s。硬度为 6〜10kg。 Total 573 In the instructions, diltiazem hydrochloride, sodium dihydrogen citrate and povidone are uniformly mixed and granulated with an anhydrous ethanol solution; the wet granulated material is forced through an 18-mesh sieve and dried for 24 hours; after the granules, stearin is added. The magnesium acetate was mixed and pressed with a standard concave circular die of 12 mm, using a pressing force of 1200 to 2000 kg and a pressing time of 2 s. The hardness is 6~10kg.
2)、 对片芯按下列处方及工艺包衣：  2), the core of the film is coated according to the following prescriptions and techniques:
包衣液处方 （1000片用量）：  Coating liquid prescription (1000 tablets):
组分 含量 (g) 干重 g  Component Content (g) Dry weight g
Kol l icoat SR 30 D (聚乙烯乙酸酯 77. 8 21  Kol l icoat SR 30 D (polyvinyl acetate 77. 8 21
水分散体）  Aqueous dispersion
苯甲酸（38〜58 μ πι) 49 49  Benzoic acid (38~58 μ πι) 49 49
甲基丙烯酸甲酯-苯乙烯共聚物 2. 52 2. 52  Methyl methacrylate-styrene copolymer 2. 52 2. 52
(MMA/ST) (平均料径 15nm)  (MMA/ST) (average material diameter 15nm)
去离子水 323. 93  Deionized water 323. 93
总计 453. 25 72. 52  Total 453. 25 72. 52
※， 甲基丙烯酸甲酯 /苯乙烯共聚物 (MMA/ST) , 其中甲基丙烯酸甲酯含量约 52%, 苯乙烯 约 48%， 与包衣聚合物的接触角 Θ测定为 12° 。  *, Methyl methacrylate / styrene copolymer (MMA / ST), wherein the methyl methacrylate content is about 52%, the styrene is about 48%, and the contact angle with the coated polymer is 12 °.
将片芯在 Hicoater/Fruend包衣机上包衣。 包衣条件参数： 入口温度， 50〜60°C ; 出口 温度， 35〜37°C ; 片芯温度 36〜38°C ; 片芯增重 12. 6%。  The cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 35~37 ° C; core temperature 36~38 ° C; core weight gain 12. 6%.
3)、 愈合控释衣膜  3), healing controlled release film
愈合处理在密闭供箱中进行。 烘箱内置足量（即总有剰余固体量）的苯甲酸。 愈合处理前 充入含饱和量的苯甲酸气体的温度 50°C的热空气。 愈合温度为 45°C， 愈合时间为 48小时。  The healing process is carried out in a closed supply tank. The oven has a sufficient amount of benzoic acid (ie, there is always a residual solids). Before the healing treatment, hot air containing a saturated amount of benzoic acid gas at a temperature of 50 ° C was charged. The healing temperature was 45 ° C and the healing time was 48 hours.
4)、 挥去致孔剂  4), whistling agent
在温度 20°C及近似真空的条件下抽去衣膜中的苯甲酸。  The benzoic acid in the film was removed at a temperature of 20 ° C and an approximate vacuum.
2、 制备对照例 3样品  2. Preparation of Comparative Example 3 Sample
把包衣液处方中的甲基丙烯酸甲酯 /苯乙烯共聚物 (丽 A/ST)去掉， 其他不变， 依实施例 3 方法制备对照例 3样品。 实施例 4及对照例 4  The methyl methacrylate/styrene copolymer (Li A/ST) in the coating liquid formulation was removed, and the others were unchanged. A sample of Comparative Example 3 was prepared according to the method of Example 3. Example 4 and Comparative Example 4
1、 制备实施例 4样品  1. Preparation Example 4 Sample
1 )、 按实施例 3的处方及工艺制备片芯  1), preparing the core according to the prescription and process of Example 3.
2)、 对片芯按下列处方及工艺包衣：  2), the core of the film is coated according to the following prescriptions and techniques:
包衣液处方 （1000片用量）：  Coating liquid prescription (1000 tablets):
组分 含量 (g) 干重  Component content (g) dry weight
EUDRAGIT® RS 30 D 54. 6 16. 38  EUDRAGIT® RS 30 D 54. 6 16. 38
EUDRAGIT® RL 30 D 15. 4 4. 62  EUDRAGIT® RL 30 D 15. 4 4. 62
叔丁基对羟基茴香醚（96〜150 μ m) 49 49  Tert-butyl-p-hydroxyanisole (96~150 μm) 49 49
PARALOID BPM- 500 2. 1 2. 1  PARALOID BPM- 500 2. 1 2. 1
柠檬酸三乙脂 3. 15 3. 15  Triethyl citrate 3. 15 3. 15
去离子水 346. 05  Deionized water 346. 05
总计 470. 3 75. 25  Total 470. 3 75. 25
※， PARALOID BPM-500 为 Rohm and Haas 公司生产的纳米级丙烯酸树脂类硬壳一软核 结构型抗冲击改性剂， 与包衣聚合物的接触角 9测定为 Γ 。  *, PARALOID BPM-500 is a nano-sized acrylic hard shell-soft core structured impact modifier produced by Rohm and Haas. The contact angle with the coated polymer 9 is determined as Γ.
将片芯在 Hicoater/Fruend包衣机上包衣。 包衣条件参数： 入口温度， 50〜60°C ; 出口 温度， 30〜35°C ; 片芯温度 31〜36°C ; 片芯增重 12. 6%。 说 明 书 The cores were coated on a Hicoater/Fruend coater. 6%。 The coating temperature parameters: inlet temperature, 50~60 ° C; outlet temperature, 30~35 ° C; core temperature 31~36 ° C; core weight gain 12.6%. Instruction manual
3)、 愈合控释衣膜  3), healing controlled release film
愈合处理在密闭烘箱中进行。烘箱内置足量（即总有剰余固体量）的叔丁基对羟基茴香醚。 愈合处理前充入含饱和量的叔丁基对羟基茴香醚气体的温度 50 °C的热空气。 愈合温度为 45 °C , 愈合时间为 60小时。  The healing treatment is carried out in a closed oven. The oven contains a sufficient amount (i.e., there is always a residual solids) of tert-butyl p-hydroxyanisole. Before the healing treatment, hot air containing a saturated amount of tert-butyl-p-hydroxyanisole gas at a temperature of 50 °C was charged. The healing temperature was 45 °C and the healing time was 60 hours.
4)、 挥去致孔剂  4), whistling agent
在温度 10°C及近似真空的条件下抽去衣膜中的叔丁基对羟基茴香醚。  The tert-butyl p-hydroxyanisole in the film was removed at a temperature of 10 ° C and an approximate vacuum.
2、 制备对照例样品 4。  2. Prepare a comparative sample 4.
把包衣液处方中的 PARALOID BPM-500去掉， 其他不变， 依实施例 4方法制备对照例 4样 实施例 5及对照例 5  The PARALOID BPM-500 in the coating liquid prescription was removed, and the others were unchanged. A comparative example was prepared according to the method of Example 4 Example 5 and Comparative Example 5
1、 制备实施例 5样品  1. Preparation Example 5 Sample
1 )、 按实施例 1的处方及工艺制备片芯  1), preparing the core according to the prescription and process of Example 1.
2)、 对片芯按下列处方及工艺包衣：  2), the core of the film is coated according to the following prescriptions and techniques:
包衣液处方：  Coating liquid prescription:
组分 含量 (g)  Component content (g)
Aquacoat (乙基纤维素水分散体） 96  Aquacoat (ethyl cellulose dispersion) 96
癸二酸二丁酯 4. 32  Dibutyl sebacate 4. 32
二特丁基羟基甲苯（96〜 150 μ m) 36  Di-tert-butylhydroxytoluene (96~ 150 μ m) 36
甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物 2. 88  Methyl methacrylate-butadiene-styrene terpolymer 2. 88
(MBS)胶乳※ （颗径： 200- 300nm) (以干  (MBS) latex ※ (size: 200-300nm) (to dry
重计）  Recalculation)
去离子水 适量  Deionized water
总计 450  Total 450
※， 甲基丙烯酸甲酯-丁二烯-苯乙烯三聚物 (MBS) , 其中聚丁二烯含量约 70%， 苯乙烯含 量约 20%， 甲基异丁烯酸含量约 10%, 与包衣聚合物的接触角 Θ测定为 47° 。  ※, methyl methacrylate-butadiene-styrene terpolymer (MBS), wherein the polybutadiene content is about 70%, the styrene content is about 20%, the methyl methacrylate content is about 10%, and the coating The contact angle 聚合物 of the polymer was determined to be 47°.
将片芯在 Hicoater/Fruend包衣机上包衣。 包衣条件参数： 入口温度， 50〜60°C ; 出口 温度， 40〜42°C ; 片芯温度 40°C ; 片芯增重 16%。  The cores were coated on a Hicoater/Fruend coater. Coating conditions parameters: inlet temperature, 50~60 ° C; outlet temperature, 40~42 ° C; core temperature 40 ° C; core weight gain 16%.
在包上述控释衣膜前包一水溶性薄膜衣。包水溶性薄膜衣用的包衣料为含 4. 5%羟丙基甲 基纤维素（Pharmacoat , 603/ShinEtsu) , 0. 52%的 PEG 400及 1. 5%微粉化的滑石的水溶液。 包衣条件参数入口温度， 55°C ; 出口温度， 30°C。 水溶性薄膜衣包衣增重约为 1%。  A water-soluble film coat is applied before the above-mentioned controlled release film. The coating for water-soluble film coating was an aqueous solution containing 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. Coating conditions parameter inlet temperature, 55 ° C; outlet temperature, 30 ° C. The water-soluble film coat has a weight gain of about 1%.
3)、 挥去致孔剂  3), volatizing porogen
在温度 15 °C及近似真空的条件下抽去衣膜中的二特丁基羟基甲苯。  Dit-butylhydroxytoluene in the film was removed at a temperature of 15 ° C and an approximate vacuum.
2、 制备对照例样品 4。  2. Prepare a comparative sample 4.
把包衣液处方中的甲基丙烯酸甲酯-丁二烯-苯乙烯 (MBS)去掉，其他不变，依实施例 5方 法制备对照例 5样品。 实施例 6及对照例 6  The methyl methacrylate-butadiene-styrene (MBS) in the coating liquid formulation was removed, and the others were unchanged. A sample of Comparative Example 5 was prepared in the same manner as in Example 5. Example 6 and Comparative Example 6
1、 制备实施例 6样品  1. Preparation Example 6 Sample
1 )、 制备片芯：  1), preparation of the core:
组分 mg/片  Component mg/tablet
辛伐他汀 40  Simvastatin 40
卡波普（CARB0P0L) 974P 26. 7  CARBOP (CARB0P0L) 974P 26. 7
柠檬酸钠 （二水） 26. 7 说 明 书 Sodium citrate (dihydrate) 26. 7 Instruction manual
α -乳糖 26. 6  --lactose 26. 6
聚乙烯吡咯烷酮 （Κ29-32 ) 6. 0  Polyvinylpyrrolidone (Κ29-32) 6. 0
叔丁基对甲氧酚 （ΒΗΑ) 0. 08  Tert-butyl-p-methoxyphenol (ΒΗΑ) 0. 08
硬脂酸镁 0. 6  Magnesium stearate 0. 6
总计 126. 68  Total 126. 68
将辛伐他汀、卡波普、磨碎并过 200目筛的柠檬酸钠、乳糖和聚乙烯吡咯垸酮混合均匀， 并用含水 10% (按重量计）的乙醇溶液 (含所需的 ΒΗΑ)进行造粒。 将湿物料过 18目筛并干燥整 夜， 整粒， 加入硬脂酸镁润滑混匀， 用一个 1/4英寸的标准的凹形圆形工具压制均匀的混合 物， 所用的压制力为 1000磅。 压制后片剂的厚度为 3. 89mm， 硬度为 8-10kg。  Mix simvastatin, carbopol, sodium citrate, lactose and polyvinylpyrrolidone ground through a 200 mesh sieve, and use a 10% (by weight) aqueous solution of ethanol (containing the desired hydrazine). Granulation is carried out. The wet material was sieved through a 18 mesh screen and dried overnight. The whole pellet was lubricated by adding magnesium stearate. The uniform mixture was pressed with a 1/4 inch standard concave circular tool. The pressing force was 1000 lbs. . The tablet after pressing has a thickness of 3.89 mm and a hardness of 8-10 kg.
2)、 对片芯包水溶性薄膜衣  2), the core pack water-soluble film coat
用定时自动薄膜包衣机包衣对上述片芯包一水溶性薄膜衣。 包水溶性薄膜衣用的包衣料 为含 4. 5%羟丙基甲基纤维素（Pharmacoat , 603/ShinEtsu) 、 0. 52%的 PEG 400及 1. 5%微粉化 的滑石的水溶液。 水溶性薄膜衣包衣增重约为 2%。  A water-soluble film coat was applied to the core piece by a timed automatic film coater. The coating material for the water-soluble film coating was an aqueous solution containing 4.5% hydroxypropylmethylcellulose (Pharmacoat, 603/ShinEtsu), 0.52% PEG 400 and 1.5% micronized talc. The water-soluble film coat has a weight gain of about 2%.
3)、 对包水溶性薄膜衣片芯按下列处方及工艺包控释衣：  3), for the water-soluble film coated core of the package according to the following prescription and process control release:
控释包衣液处方  Controlled release coating solution
组分 含量 ω  Component content ω
醋酸纤维素丁酸酯 CAB381-20 80  Cellulose acetate butyrate CAB381-20 80
三 、  three ,
乙基柠檬酸酯 3≤里  Ethyl citrate 3 ≤
甲基丙烯酸甲酯-丁二烯-苯乙烯 (MBS) ^ 9. 6  Methyl methacrylate-butadiene-styrene (MBS) ^ 9. 6
尿素（96〜150 μ πι) 120  Urea (96~150 μ πι) 120
氯仿 4000ml  Chloroform 4000ml
※， 甲基丙烯酸甲酯-丁二烯-苯乙烯 (MBS) , 其中丁二烯含量约 70%, 苯乙烯含量约 15%, 甲基异丁烯酸含量约 15%， 与包衣聚合物的接触角 Θ测定为 16° 。  ※, methyl methacrylate-butadiene-styrene (MBS), wherein the content of butadiene is about 70%, the content of styrene is about 15%, the content of methyl methacrylate is about 15%, and the contact with the coated polymer The angle of Θ was determined to be 16°.
采用一个 Freand型 HCT微型高性能涂覆机（(8英寸盘）， 给片剂涂上一个厚度为 200微 米的涂层。  A 120 mm thick coating was applied to the tablets using a Freand type HCT micro high performance coater (8 inch disc).
注： ※， 依需要调整至衣膜 （干） 的玻璃化温度 （7；) 为 50°C所需的量。  Note: ※, adjust the amount required for the glass transition temperature (7;) of the film (dry) to 50 °C as needed.
4)、 挥去致孔剂  4), whistling agent
在温度 30 °C及近似真空的条件下抽去衣膜中的尿素。  The urea in the film was removed at a temperature of 30 ° C and an approximate vacuum.
2、 制备对照例 6样品  2. Preparation of Comparative Example 6 Sample
把包衣液处方中的聚甲基丙烯酸甲酯 (PMMA)去掉， 其他不变， 依实施例 6方法制备对照 例 6样品。 实施例 7  The sample of Comparative Example 6 was prepared by the method of Example 6 by removing the polymethyl methacrylate (PMMA) from the coating liquid formulation and leaving the others unchanged. Example 7
把实施例 2中的聚丙烯酸酯包覆的纳米氧化铝分散浆换成等重 （干重） 的甲基丙烯酸甲 酯 /苯乙烯共聚物胶乳（平均粒径约 15nm， 其中， 甲基丙烯酸甲酯含量约 60°/。， 苯乙烯含量约 40%, 与包衣聚合物的接触角 Θ测定为 39° ) 同法制备实施例 7。 实施例 8  The polyacrylate-coated nano-alumina dispersion slurry of Example 2 was replaced with an equal-weight (dry weight) methyl methacrylate/styrene copolymer latex (average particle size of about 15 nm, wherein, methacrylic acid The ester content was about 60%, the styrene content was about 40%, and the contact angle with the coating polymer was determined to be 39°.) Example 7 was prepared in the same manner. Example 8
仅把实施例 2中的聚丙烯酸酯包覆的纳米氧化铝分散浆换成等重（干重）的 Elvaloy® HP 662胶乳 （乙烯 /丁垸基丙烯酸 /羰基 (碳单氧化物)三聚物， 平均粒径约 60nm， 与包衣聚合物 的接触角 Θ测定为 30° ) 同法制备实施例 8。 实施例 9  Replace only the polyacrylate-coated nano-alumina dispersion in Example 2 with an equal-weight (dry weight) Elvaloy® HP 662 latex (ethylene/butyl acrylate/carbonyl (carbon monooxide) terpolymer, average The particle size was about 60 nm, and the contact angle with the coated polymer was measured to be 30°.) Example 8 was prepared in the same manner. Example 9
把实施例 3中的甲基丙烯酸甲酯 /苯乙烯共聚物换成等重 （干重） 的 Elvaloy® AC 2618 说 明 书 Replace the methyl methacrylate/styrene copolymer of Example 3 with an equal weight (dry weight) of Elvaloy® AC 2618 Instruction manual
胶乳（乙烯 /乙基丙烯酸共聚物）， 平均粒径约 200nm， 与包衣聚合物的接触角 Θ测定为 5° ) 同法制备实施例 9。 实施例 10 The latex (ethylene/ethyl acrylate copolymer) having an average particle diameter of about 200 nm and a contact angle with the coating polymer was measured to be 5 °). Example 10
把实施例 3中的甲基丙烯酸甲酯 /苯乙烯共聚物换成等重 （干重） 的甲基丙烯酸甲酯-丁 二烯 -苯乙烯三聚物胶乳（平均粒径约 ΙΟΟηιη, 其中， 丁二烯含量约 70%， 苯乙烯含量约 15%， 甲基异丁烯酸含量约 15%， 与包衣聚合物的接触角 Θ测定为 12° ) 同法制备实施例 10。 实施例 11  The methyl methacrylate/styrene copolymer in Example 3 was replaced by an equal weight (dry weight) methyl methacrylate-butadiene-styrene terpolymer latex (average particle size about ΙΟΟηιη, wherein, The butadiene content was about 70%, the styrene content was about 15%, the methyl methacrylate content was about 15%, and the contact angle with the coating polymer was determined to be 12°.) Example 10 was prepared in the same manner. Example 11
把实施例 4中的 PARAL0ID BPM-500换成等重（干重） 的甲基丙烯酸甲酯胶乳（平均粒径 约 4nm， 与包衣聚合物的接触角 Θ测定为 4° ) 同法制备实施例 11。 实施例 12  The PARAL0ID BPM-500 in Example 4 was changed to an equal weight (dry weight) methyl methacrylate latex (average particle diameter of about 4 nm, and the contact angle with the coating polymer was measured to be 4°). Example 11. Example 12
把实施例 4中的 PARALOID BPM-500换成等重 （干重） 的甲基丙烯酸甲酯 /苯乙烯共聚物 胶乳 （平均粒径约 55nm, 其中， 甲基丙烯酸甲酯含量约 70%， 苯乙烯含量约 30%， 与包衣聚 合物的接触角 Θ测定为 2Γ ) 同法制备实施例 12。 实施例 13  The PARALOID BPM-500 in Example 4 was replaced with an equal weight (dry weight) methyl methacrylate/styrene copolymer latex (average particle size of about 55 nm, wherein methyl methacrylate content was about 70%, benzene The ethylene content was about 30%, and the contact angle with the coating polymer was measured to be 2 Γ.) Example 12 was prepared in the same manner. Example 13
把实施例 6 中的甲基丙烯酸甲酯-丁二烯-苯乙烯（MBS)换成等重 （干重） 的 DuPont™ Elvaloy® HP4051胶乳 （平均粒径约 150nm， 与包衣聚合物的接触角 Θ测定为 14° ) 同法制 备实施例 13。 实施例 14  Replace the methyl methacrylate-butadiene-styrene (MBS) in Example 6 with an equal weight (dry weight) of DuPontTM Elvaloy® HP4051 latex (average particle size of approximately 150 nm, contact with the coated polymer) The angle of enthalpy was determined to be 14 °). Example 13 was prepared in the same manner. Example 14
把实施例 6 中的甲基丙烯酸甲酯-丁二烯-苯乙烯 (MBS)换成等重 （干重） 的 DuPont™ Elvaloy® HP441胶乳 （平均粒径约 150nm, 与包衣聚合物的接触角 Θ测定为 28° ) 同法制备 实施例 14。 检测例 1 体外释药性能（释放度）试验  The methyl methacrylate-butadiene-styrene (MBS) in Example 6 was replaced with an equal weight (dry weight) DuPontTM Elvaloy® HP441 latex (average particle size of about 150 nm, contact with the coated polymer). The angle of enthalpy was determined to be 28°.) Example 14 was prepared in the same manner. Test Example 1 In vitro release performance (release) test
取样方法： 在每一批次样品取 12片制剂， 以其平均值计每批释药速率， 共取 9批次样 品（每批次生产工艺相同， 且所有批次所用原辅料均源于同一批次产品）， 即 n=9。  Sampling method: Take 12 preparations in each batch of samples, and take 9 batches of samples according to the average release rate of each batch (the production process is the same for each batch, and the raw materials used in all batches are all from the same Batch product), ie n=9.
盐酸地尔硫释放度测试方法： 采用中国药典 2005年版桨法测定。 转速为 100r/min， 温 度为（37 ± 1) °C ,递质用人工胃液 (pHl. 2盐酸液)及人工肠液 (pH7. 5磷酸盐缓冲液)各 1000mL。 将实施例及对照用样品分别直接投入溶出杯中， 每隔一定时间取样 5mL， 并补充同体积溶出 递质。用 HPLC法测定盐酸地尔硫进入溶出介质中的量，计算出每片在不同溶出时间的释放度。  Diltiazem Hydrochloride Release Test Method: Determined by the Chinese Pharmacopoeia 2005 version of the paddle method. The rotation speed is 100r/min, the temperature is (37 ± 1) °C, and the transmitter is 1000 mL each of artificial gastric juice (pH 1.2 hydrochloric acid) and artificial intestinal juice (pH 7.5 phosphate buffer). The samples of the examples and the control samples were directly placed in a dissolution cup, and 5 mL was sampled at regular intervals, and the same volume of the eluted carrier was added. The amount of diltiazem hydrochloride into the dissolution medium was determined by HPLC, and the release of each tablet at different dissolution times was calculated.
格列吡嗪释放度测试方法： 取样品，在 37°C下照释放度测定法（中国药典 2005年版附录 XD第一法）， 以 Tris缓冲液（0. 004M Tris , pH8. 7) 1000ml为溶剂， 转速为每分钟 100转， 依法操作。 每隔一定时间取样 5mL， 并补充同体积溶出递质。 用 HPLC法测定格列吡嗪进入溶 出介质中的量。 计算格列吡嗪各溶出时间的释放度。  Glipizide release test method: Take the sample at 37 ° C according to the release method (Chinese Pharmacopoeia 2005 edition Appendix XD first method), with Tris buffer (0. 004M Tris, pH 8.7) 1000ml Solvent, rotating at 100 rpm, operate according to law. Sampling 5 mL at regular intervals and replenishing the same volume of dissolved transmitter. The amount of glipizide into the dissolution medium was determined by HPLC. The release of each elution time of glipizide was calculated.
辛伐他汀释放度测试方法： 每次取样后在 37°C下， 用 USP 2型装置按每分钟 50转在实 验室条件下进行向 值为 7. 4、 含十二垸基硫酸钠 0. 4%的磯酸盐缓冲溶液 1000ml中释放药 物的试验。 每隔一定时间取样 5mL， 并补充同体积溶出递质。 用 HPLC法测定辛伐他汀进入溶 出介质中的量。 计算出辛伐他汀各溶出时间的释放度。 测试结果见表 1-6。  The simvastatin release test method is as follows: after each sampling at 37 ° C, with a USP 2 type device at 50 rpm, under laboratory conditions, the value of 7.4, containing sodium decyl sulfate 0. The drug release test was carried out in 1000% of a 4% citrate buffer solution. Sampling 5 mL at regular intervals and replenishing the same volume of dissolved transmitter. The amount of simvastatin entering the dissolution medium was determined by HPLC. The release rate of each dissolution time of simvastatin was calculated. The test results are shown in Table 1-6.
表 1 实施例 1及其对照例 1样品药物释放速率测试结果 （X ±5r(%) ( n=9) Table 1 Sample drug release rate test results of Example 1 and its Comparative Example 1 (X ± 5 r (%) ( n = 9)
4小时 «) 8小时 （％) 16小时 （％) 说 明 书 实施例 1 35.4±8.2 63.7±8.6 91.8±8.8 对照例 1 19.6士 32.6 37.5士 33.9 72.8士 34.4 表 2 实施例 2及其对照例 2样品药物释放速率测试结果 （ ± (%)) (n=9) 4 hours «) 8 hours (%) 16 hours (%) Specification Example 1 35.4±8.2 63.7±8.6 91.8±8.8 Comparative Example 1 19.6士32.6 37.5士33.9 72.8士34.4 Table 2 Example 2 and its Comparative Example 2 Sample drug release rate test results (± (%)) (n= 9)
测试品 2小时 （％) 4小时 （％) 6小时 （％) 实施例 2 33.7±5.7 62.7±5.9 85.5±6.2 实施例 7 38.7±6.8 75.3±7.7 91.3±9.8 对照例 2 20.4士 12.7 41.3±13.2 60.2±13.5 表 3 实施例 3及其对照例 3样品药物释放速率测试结果 ± τ{%» (η=9) Test article 2 hours (%) 4 hours (%) 6 hours (%) Example 2 33.7 ± 5.7 62.7 ± 5.9 85.5 ± 6.2 Example 7 38.7 ± 6.8 75.3 ± 7.7 91.3 ± 9.8 Comparative Example 2 20.4 ± 12.7 41.3 ± 13.2 60.2±13.5 Table 3 Sample drug release rate test results of Example 3 and its Comparative Example 3 ± τ {%» (η=9)
测试品 4小时 （°/。） 8小时 （％) 12小时 （％) 实施例 3 32.2±7.7 59.8±7.6 85.4±7.8 实施例 10 33.6±8.2 64.2±7.9 89.5±8.6 对照例 3 18.8±21.8 35.6±22.6 53.2±23.7 表 4 实施例 4及其对照例 4样品药物释放速率测试结果 ( :±.S;.(¾¾)) (n=9) Test article 4 hours (°/.) 8 hours (%) 12 hours (%) Example 3 32.2 ± 7.7 59.8 ± 7.6 85.4 ± 7.8 Example 10 33.6 ± 8.2 64.2 ± 7.9 89.5 ± 8.6 Comparative Example 3 18.8 ± 21.8 35.6 ±22.6 53.2±23.7 Table 4 Sample drug release rate test results of Example 4 and its Comparative Example 4 ( :±.S ; .(3⁄43⁄4)) (n=9)
测试品 2小时 （％) 4小时 （％) 8小时 （°/。） 实施例 4 33.7±7.2 58.3±7.5 92.5±8.7 实施例 11 35.3±7.9 67.8±8.6 95.4±9.3 对照例 4 17.2士 31.6 32.4±31·4 57· 2±32·8 表 5 实施例 5及其对照例 5样品药物释放速率测试结果 （S.± (¾)) (n=9)  Test article 2 hours (%) 4 hours (%) 8 hours (° /.) Example 4 33.7 ± 7.2 58.3 ± 7.5 92.5 ± 8.7 Example 11 35.3 ± 7.9 67.8 ± 8.6 95.4 ± 9.3 Comparative Example 4 17.2 ± 31.6 32.4 ±31·4 57· 2±32·8 Table 5 Sample drug release rate test results of Example 5 and its Comparative Example 5 (S.± (3⁄4)) (n=9)
测试品 3小时 （％) 6小时 （％) 9小时 （％) 实施例 5 38.7±5.3 72.3±5.8 94.5±6.2 对照例 5 23.7 ±30.7 42.7 ±30.9 70.6 ±32.3 表 6 实施例 6及其对照例 6样品药物释放速率测试结果 (l±Sr(%}) (n=9) Test article 3 hours (%) 6 hours (%) 9 hours (%) Example 5 38.7 ± 5.3 72.3 ± 5.8 94.5 ± 6.2 Comparative Example 5 23.7 ± 30.7 42.7 ± 30.9 70.6 ± 32.3 Table 6 Example 6 and its comparative example 6 sample drug release rate test results (l ± S r (%}) (n = 9)
测试品 2小时 （％) 4小时 （％) 6小时 ( ) 实施例 6 30.6±5.0 57.3±5.1 84.5±6· 4 实施例 13 32.8±5.0 61.7±6.7 90.2±8· 3 对照例 6 18.5士 15.6 32.7±16.6 52.9±17· 4 实施例 1-6及对照例 1-6的试验结果显示， 实施例药物制剂释药性能及生产重现性较对 照例好 （释药速率相对较大， 相对偏差 5相对较少） 检测例 2 制剂药物释放稳定性测试 说 明 书 Test article 2 hours (%) 4 hours (%) 6 hours ( ) Example 6 30.6 ± 5.0 57.3 ± 5.1 84.5 ± 6 · 4 Example 13 32.8 ± 5.0 61.7 ± 6.7 90.2 ± 8 · 3 Comparative Example 6 18.5 ± 15.6 32.7±16.6 52.9±17·4 The test results of Examples 1-6 and Comparative Examples 1-6 show that the release performance and production reproducibility of the pharmaceutical preparations of the examples are better than the control examples (relative release rate is relatively large, relative deviation) 5 relatively few) Test Example 2 Preparation drug release stability test Description
测定样品： 实施例 1-6及对照例 1-6第 1批 中的的样品。  Measurement samples: Samples of Examples 1-6 and Comparative Examples 1-6 Batch 1.
检测方法： 样品在温度 25°C， 相对湿度 60%的同一环境下放置（其中， 实施例 2、 6与对 照例 2、 6置入温度 42 °C， 相对湿度 80%的加速环境下）， 定期取样并测定制剂未进行药物释 放测试时的药物含量及药物释放度（测定 12片， 以平均值计）， 其中， 药物释放度 (%) =溶出 进入溶出介质中的药物量 /制剂中的药物量 X 100%。 溶出进入溶出介质中的药物量的测试方 法： 参见检测例 1 ; 制剂中的药物量测试方法： 药物完全提取制剂中后以 HPLC法测定。 测试 结果见表 7-12。  Detection method: The sample was placed in the same environment at a temperature of 25 ° C and a relative humidity of 60% (wherein Examples 2, 6 and Comparative Example 2, 6 were placed at an accelerating temperature of 42 ° C and a relative humidity of 80%), Sampling and measuring the drug content and drug release rate of the preparation without drug release test (12 tablets, on average), wherein drug release rate (%) = amount of drug dissolved in the dissolution medium / preparation The amount of drug X is 100%. Test method for the amount of drug eluted into the dissolution medium: See Test Example 1; Test Method for Drug Amount in Preparation: The drug was completely extracted into the preparation and then determined by HPLC. The test results are shown in Table 7-12.
表 7 实施例 1与其对照例 1样品 8小时的药物释放量测试结果 测试品 0月 （％) 12月 （％) ^ 24月 （％) ^ 36月 （％) ^ 实施例 1 65. 3/100 97. 5 95. 1 91. 3 对照例 1 40. 5/100 76. 5 52. 6 28. 2 表 8 实施例 2与其对照例 2样品 4小时的药物释放量:测试结果 测试品 0月 （％) 加速 3月 （％) ^ 加速 6月 （°/。） ¾ 实施例 2 57. 6/100 92. 7 87. 9 实施例 7 61. 7/100 95. 3 91. 7 实施例 8 64. 5/100 96. 7 93. 2 对照例 2 42. 3/100 85. 3 64. 5 表 9 实施例 3与其对照例 3样品 8小时的药物释放量测试结果 测试品 0月 （％) 12月 （％) ^ 24月 （％) ^ 36月 （％) ^ 实施例 3 58. 6/100 96. 2 90. 4 82. 1 实施例 9 58. 6/100 97. 3 93. 6 88. 6 实施例 10 59. 2/100 96. 9 90. 1 83. 4 对照例 3 33. 7/100 86. 6 50. 1 30. 6 表 10 实施例 4与其对照例 4样品 4小时的药物释放量 ：测试结果 测试品 0月 （％) 12月 （％) 24月 （％) 58 36月 （％) 55 实施例 4 56. 6/100 95. 9 92. 0 88. 9 实施例 11 58. 7/100 97. 5 94. 3 91. 6 实施例 12 52. 2/100 92. 3 89. 2 82. 5 对照例 4 30. 8/100 76. 0 51. 6 21. 8 表 11 实施例 5与其对照例 5样品 6小时的药物释放量 ：测试结果 测试品 0月 （％) 12月 （％) * 24月 （％) 36月 （％) ^ 实施例 5 72. 6/100 97. 1 93. 4 89. 0 对照例 5 45. 7/100 84. 2 61. 7 39. 6 表 12 实施例 6与其对照例 6样品 4小时的药物释放量 ：测试结果 测试品 0月 （％) 加速 3月 （％) 加速 6月 （％) 《- 实施例 6 60. 7/100 96. 92. 2 说 明 书 实施例 13 59. 6/100 97. 7 93. 8 实施例 14 57. 4/100 93. 7 84. 8 对照例 6 35. 8/100 65^ 37^ 注， ※， 表示与 0月原始量相比的百分比例 《)。 Table 7 Test results of the drug release amount of Example 1 and its Comparative Example 1 for 8 hours Test article 0 (%) December (%) ^ 24 (%) ^ 36 (%) ^ Example 1 65. 3/ 100 97. 5 95. 1 91. 3 Comparative Example 1 40. 5/100 76. 5 52. 6 28. 2 Table 8 Example 2 and its control 2 sample 4 hours of drug release: test results test article 0 month (%) acceleration of 3 months (%) ^ June acceleration (° /.) Example ¾ 2 57. 6/100 92. 7 87. 9 61. 7/100 Example 7 95.3 91.7 Example 8 64. 5/100 96. 7 93. 2 Comparative Example 2 42. 3/100 85. 3 64. 5 Table 9 Example 3 and its control 3 sample 8 hours of drug release test results Test article 0 (%) December (%) ^ 24 months (%) ^ 36 months (%) ^ Example 3 58. 6/100 96. 2 90. 4 82. 1 Example 9 58. 6/100 97. 3 93. 6 88 6 Example 5 59. 2/100 96. 9 90. 1 83. 4 Comparative Example 3 33. 7/100 86. 6 50. 1 30. 6 Table 10 Example 4 and its Comparative Example 4 sample 4 hours of drug Release amount: test result test article 0 month (%) December (%) 24 months (%) 58 36 months (%) 55 Example 4 56. 6/100 95. 9 92. 0 88. 9 Example 11 58 . 7/100 97. 5 94 3 91. 6 Example 12 52. 2/100 92. 3 89. 2 82. 5 Comparative Example 4 30. 8/100 76. 0 51. 6 21. 8 Table 11 Example 5 and its Comparative Example 5 Sample 6 Hours of drug release: test results test product 0 months (%) December (%) * 24 months (%) 36 months (%) ^ Example 5 72. 6/100 97. 1 93. 4 89. 0 Control Example 5 45. 7/100 84. 2 61. 7 39. 6 Table 12 Example 6 and its Comparative Example 6 Samples of drug release for 4 hours: Test results Test article 0 (%) Accelerated 3 months (%) Acceleration 6 Month (%) <<- Example 6 60. 7/100 96. 92. 2 Specification Example 13 59. 6/100 97. 7 93. 8 Example 14 57. 4/100 93. 7 84. 8 Comparative Example 6 35. 8/100 65^ 37^ Note, ※, indicates original with 0 month The percentage of the amount compared to the example ").
实施例及其对照例的测试结果显示， 实施例药物制剂释药稳定性较对对照例优。 检测例 3 制剂控释衣膜机械性能测试  The test results of the examples and their comparative examples show that the release stability of the pharmaceutical preparations of the examples is superior to that of the comparative examples. Test Example 3 Preparation of controlled release film mechanical properties test
取检测例 1体外释药 （释放度）测试试验中实施例 1-6及其对照例 1-6的测试后的一半 的湿残留物（即从溶出液直接取出的控释衣膜)及另一半在温度低于 0°C时真空干燥得的干残 留物，测定其在温度 25°C时受拉力作用发生断裂时的最大拉力及其被拉断时伸长长度与原有 长度的百分比（即断裂伸长率）。 测试结果见表 13。  Test Example 1 in vitro release (release degree) test test 1-6 and its comparative examples 1-6 test half of the wet residue (ie, the controlled release film directly taken out from the eluate) and another Half of the dry residue obtained by vacuum drying at a temperature below 0 ° C, the maximum tensile force at which the tensile force is broken at a temperature of 25 ° C and the percentage of the elongation length at the time of being pulled off and the original length are determined ( That is, elongation at break). The test results are shown in Table 13.
实施例 1-6及其对照例 1-6制剂控释衣膜机械性能测试结果 口 断裂最大拉力 断裂伸长率 (%) 湿 干 湿 干 实施例 1 9 4 250 180 对照例 1 2 1 120 80 实施例 2 25 18 340 240 实施例 7 31 23 450 320 实施例 8 37 28 870 450 对照例 2 12 7 210 130 实施例 3 11 5 330 170 实施例 9 15 8 520 330 实施例 10 13 6 410 220 对照例 3 4 1 220 60 实施例 4 13 7 440 370 实施例 11 15 9 470 380 实施例 12 10 5 380 220 对照例 4 3 1 120 90 实施例 5 15 7 390 290 对照例 5 2 1 110 70 实施例 6 24 17 350 250 实施例 13 26 19 390 280 实施例 14 21 14 310 230 对照例 6 9 5 180 120 实施例其对照例测试结果显示: 实施例制剂控释衣膜的机械性能较对照例优。 这寓示实 施例制剂具有更好的抗药物倾释的性能， 更高的用药安全性。 检测例 4 聚合物衣膜释药微孔平均孔径测试  Examples 1-6 and Comparative Examples 1-6 Preparation Controlled Release Film Mechanical Properties Test Results Port Breakage Maximum Tensile Elongation at Break (%) Wet Dry and Wet Dry Example 1 9 4 250 180 Comparative Example 1 2 1 120 80 Example 2 25 18 340 240 Example 7 31 23 450 320 Example 8 37 28 870 450 Comparative Example 2 12 7 210 130 Example 3 11 5 330 170 Example 9 15 8 520 330 Example 10 13 6 410 220 Example 3 4 1 220 60 Example 4 13 7 440 370 Example 11 15 9 470 380 Example 12 10 5 380 220 Comparative Example 4 3 1 120 90 Example 5 15 7 390 290 Comparative Example 5 2 1 110 70 Example 6 24 17 350 250 Example 13 26 19 390 280 Example 14 21 14 310 230 Comparative Example 6 9 5 180 120 Example The test results of the comparative examples show that the mechanical properties of the controlled release film of the example formulation are superior to those of the comparative example. This shows that the formulation of the embodiment has better anti-drug release properties and higher drug safety. Test Example 4 Polymer film release micropore average pore size test
方法：在第一批次制剂样品取 0月样品（刚制备好的样品)及其在温度 25°C，相对湿度 60% 的同一环境下放置 24个和 36个月的样品， 分离剥取聚合物衣膜，用 IM4000型画面概念分析 器（Analytical Imaging Concepts, IM4000)根据显微画面测定衣膜的释药微孔（算术）平均（定 向）孔径， 结果见表 14。  Method: Take the 0 month sample (just prepared sample) in the first batch of the preparation sample and place the sample for 24 and 36 months under the same environment at a temperature of 25 ° C and a relative humidity of 60%, and separate the stripping polymerization. For the coating film, the micropore (arithmetic) average (orientation) pore diameter of the coating film was measured according to the microscopic image using an IM4000 type Image Concept Analyzer (IM4000). The results are shown in Table 14.
表 14 聚合物衣膜释药微孔平均孔径测试结果 （ μ m) 说 明 书 Table 14 Mesoporous average pore diameter test results of polymer coating film release ( μ m) Instruction manual
0月 24月 36月 October 24 months 36 months
实施例 1 74. 6 72. 2 70. 3  Example 1 74. 6 72. 2 70. 3
对照例 1 57. 1 40. 9 31. 0  Comparative Example 1 57. 1 40. 9 31. 0
实施例 2 223. 6 217. 8 212. 4  Example 2 223. 6 217. 8 212. 4
实施例 8 233. 5 231. 5 228. 6  Example 8 233. 5 231. 5 228. 6
对照例 2 180. 4 150. 4 130. 5  Comparative Example 2 180. 4 150. 4 130. 5
实施例 3 52. 7 50. 1 48. 2  Example 3 52. 7 50. 1 48. 2
实施例 9 55. 6 54. 7 52. 8  Example 9 55. 6 54. 7 52. 8
对照例 3 36. 8 24. 6 18. 9  Comparative Example 3 36. 8 24. 6 18. 9
实施例 4 116. 8 112. 2 109. 4  Example 4 116. 8 112. 2 109. 4
实施例 12 114. 6 108. 7 103. 7  Example 12 114. 6 108. 7 103. 7
对照例 4 78. 3 55. 6 36. 8  Comparative Example 4 78. 3 55. 6 36. 8
实施例 5 103. 7 100. 8 96. 8  Example 5 103. 7 100. 8 96. 8
对照例 5 80. 5 64. 2 47. 2  Comparative Example 5 80. 5 64. 2 47. 2
实施例 6 125. 8 123. 8 120. 9  Example 6 125. 8 123. 8 120. 9
实施例 14 122. 6 119. 6 115. 7  Example 14 122. 6 119. 6 115. 7
对照例 6 94. 6 74. 2 55. 8  Comparative Example 6 94. 6 74. 2 55. 8
结果显示， 在聚合物衣膜中添加有效的聚合物增强剂有利于延缓释药微孔在生产过程及 贮藏过程中縮少。  The results show that the addition of an effective polymer enhancer to the polymer film is advantageous in delaying the shrinkage of the drug release micropores during the production process and during storage.

Claims

权 利 要 求 书 Claim
1.一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包覆的控释 制剂特别是零级释放的控释制剂中用作延缓所述释药微孔的孔径在生产过程和 /或贮藏过程 中减少的用途， 其中， 所述聚合物增强剂与所述聚合物的接触角低于 90。  A polymeric enhancer for use in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled release micropores, particularly in a zero-order release controlled release formulation, for delaying said release The reduced pore size of the micropores during production and/or storage, wherein the polymer enhancer has a contact angle with the polymer of less than 90.
2.一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包覆的控释 制剂特别是零级释放的控释制剂中用于提高所述控释制剂的释药速率在贮藏过程中的稳定性 的用途， 其中， 所述聚合物增强剂与所述聚合物的接触角低于 90。  2. A polymer enhancer for use in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled drug delivery micropores, particularly in a zero-order release controlled release formulation for enhancing said controlled release The use of the release rate of the formulation for stability during storage wherein the polymer enhancer has a contact angle with the polymer of less than 90.
3.一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包覆的控释 制剂特别是零级释放的控释制剂中用于提高所述控释制剂的释药速率在生产过程中的重现性 的用途， 其中， 所述聚合物增强剂与所述聚合物的接触角低于 90。  3. A polymeric enhancer for use in a controlled release formulation coated with a polymer controlled release coating containing a plurality of air-filled release micropores, particularly in a zero-order release controlled release formulation for enhancing said controlled release The use of a release rate of a formulation for reproducibility in a production process wherein the contact angle of the polymer enhancer with the polymer is less than 90.
4.一种聚合物增强剂在外被含有众多充有空气的释药微孔的聚合物控释衣膜包覆的控释 制剂特别是零级释放的控释制剂中用于改善所述控释制剂的释药性能， 如提高释药速度的用 途， 其中， 所述聚合物增强剂与所述聚合物的接触角低于 90。  4. A polymeric enhancer for use in a controlled release formulation coated with a polymer controlled release coating comprising a plurality of air-filled release micropores, particularly in a zero-order release controlled release formulation for improving said controlled release The release properties of the formulation, such as the use for increasing the rate of drug release, wherein the contact angle of the polymer enhancer to the polymer is less than 90.
5. 根据前述权利要求中任意一项的用途， 其中所述的接触角低于或等于 60° 。  The use according to any of the preceding claims, wherein the contact angle is lower than or equal to 60°.
6. 根据前述权利要求中任意一项的用途， 其中所述的接触角低于或等于 30° 。  6. Use according to any of the preceding claims, wherein the contact angle is lower than or equal to 30°.
7. 根据前述权利要求中任意一项的用途， 其中所述的接触角低于或等于 10° 。  The use according to any of the preceding claims, wherein the contact angle is lower than or equal to 10°.
8.根据前述权利要求中任意一项的用途，其中所述的释药微孔是经升华掉位于所述聚合 物控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于所述聚合物控释衣膜中的药 学上可接受的可降解成无害气体的物质而获得的。  The use according to any one of the preceding claims, wherein the release micropores are sublimed and pharmaceutically acceptable sublimable substances located in the polymer controlled release coating film and/or degraded Obtained from a pharmaceutically acceptable substance that degrades into a harmless gas in the polymer controlled release coating film.
9. 根据前述权利要求中任意一项的用途， 其中所述的聚合物增强剂具有 "硬壳一软核" 结构。  The use according to any of the preceding claims, wherein the polymer reinforcing agent has a "hard shell-soft core" structure.
10. 根据权利要求 9的用途， 其中所述的聚合物增强剂的熔点 （或晶体熔化温度） 或 /和 维氏软化点（Vicat Softening Point)不低于所述控释衣膜中的聚合物的玻璃化转变温度 10. The use according to claim 9, wherein the polymer enhancer has a melting point (or crystal melting temperature) or/and a Vicat Softening Point of not less than the polymer in the controlled release film. Glass transition temperature
(Tg)， 且其中心玻璃化温度不高于 0°C。 (Tg), and its central glass transition temperature is not higher than 0 °C.
11. 根据权利要求 9的用途， 其中所述的聚合物增强剂的熔点 （或晶体熔化温度） 或 /和 维氏软化点（Vicat Softening Point) 高出 10°C (含） 于所述控释衣膜中的聚合物的玻璃化 转变温度 （/¾)， 且其中心玻璃化温度为 -10〜- 200°C。  11. The use according to claim 9, wherein said polymer enhancer has a melting point (or crystal melting temperature) or/and a Vicat Softening Point higher than 10 ° C (inclusive) of said controlled release The glass transition temperature (/3⁄4) of the polymer in the film and its central glass transition temperature is -10 to -200 °C.
12. 根据权利要求 9的用途， 所述的聚合物增强剂的断裂伸长率为 200〜5000%。  12. The use according to claim 9, wherein the polymer reinforcing agent has an elongation at break of 200 to 5000%.
13. 根据权利要求 1至 4中任意一项的用途， 其中所述的聚合物选自乙基纤维素、 三十二 酸纤维素、 三棕榈酸纤维素、 二棕榈酸纤维素或它们的混合物， 所述的聚合物增强剂选自用 表面活性物质吸附包裹处理方式进行了表面改性的极性刚性无机粒子。  The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof The polymer reinforcing agent is selected from the group consisting of polar rigid inorganic particles surface-modified by a surface active material adsorption coating treatment.
14. 根据权利要求 1至 4中任意一项的用途， 其中所述的聚合物选自乙基纤维素、 三十 二酸纤维素、 三棕榈酸纤维素、 二棕榈酸纤维素或它们的混合物， 所述的聚合物增强剂选自 表面被硬脂酸包覆的碳酸钙粒子。  The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof The polymer enhancer is selected from calcium carbonate particles whose surface is coated with stearic acid.
15. 根据权利要求 1至 4中任意一项的用途， 其中所述的聚合物选自乙基纤维素、 醋酸 纤维素、 丙酸纤维素、醋酸丁酸纤维素、醋酸丙酸纤维素（cel lulose acetate propionate) 硝酸纤维素、 三戊酸纤维素、 二琥珀酸纤维素或它们的混合物， 所述的聚合物增强剂选自甲 基丙烯酸甲酯-苯乙烯共聚物、 苯乙烯-丙烯腈共聚物、 苯乙烯 -丁二烯-丙烯腈三聚物、 甲基 丙烯酸甲酯 -丁二烯-苯乙烯三聚物、 乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C4 烷基丙烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C4烷基丙烯酸共聚物或它们的混合物。  The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cel) Lulose acetate propionate) nitrocellulose, cellulose trivalerate, cellulose succinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymerization , styrene-butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 ~C4 Alkylacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 to C4 alkyl acrylate copolymer or a mixture thereof.
16. 根据权利要求 1至 4中任意一项的用途， 其中所述的聚合物选自乙基纤维素、 醋酸 纤维素、 丙酸纤维素、醋酸丁酸纤维素、醋酸丙酸纤维素（cel lulose acetate propionate)、 硝酸纤维素、 三戊酸纤维素、 二琥珀酸纤维素或它们的混合物， 所述的聚合物增强剂选自甲 基丙烯酸甲酯-苯乙烯共聚物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物或它们的混合物。  The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate (cel) Lulose acetate propionate), nitrocellulose, cellulose trivalerate, cellulose succinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, methyl methacrylate a butadiene-styrene trimer or a mixture thereof.
17. 根据权利要求 1至 4中任意一项的用途， 其中所述的聚合物选自不溶于或几乎不溶 权 利 要 求 书 The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of insoluble or almost insoluble Claim
于水及消化液的甲基丙烯酸 (酯)聚合物、 聚甲基丙烯酸甲酯、 丙烯酸乙酯一间丙烯酸甲酯聚 合 物 、 poly ( ethylacrylate methylmetacrylate trimethylamonioethylmetacrylatchloride ) 或它们的混合物， 所述的聚合物增强剂选自聚 甲基丙烯酸甲酯、 甲基丙烯酸甲酯-苯乙烯共聚物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物、 乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1 C4垸基丙烯酸 -羰基 (碳单氧化物)三聚 物、 乙烯 -C1 C4垸基丙烯酸共聚物、 丙烯酸树脂类抗冲击改性剂或它们的混合物。 a methacrylic acid polymer of water and digestive juice, polymethyl methacrylate, ethyl acrylate methylmeracrylate trimethylamonioethylmetacrylate chloride, or a mixture thereof, said polymer reinforced The agent is selected from the group consisting of polymethyl methacrylate, methyl methacrylate-styrene copolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) III Polymer, ethylene-C1 C4 mercaptoacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 C4 mercaptoacrylic acid copolymer, acrylic resin impact modifier or a mixture thereof.
18. 根据权利要求 1至 4中任意一项的用途， 其中所述的聚合物选自不溶于或几乎不溶 于水及消化液的聚乙烯乙酸酯、氯乙烯一乙烯醇一醋酸乙烯酯的三元共聚物、氯乙烯-乙烯乙 酸酯共聚物或它们的混合物，所述的聚合物增强剂选自甲基丙烯酸甲酯-苯乙烯共聚物、苯乙 烯-丙烯腈共聚物、 苯乙烯 -丁二烯-丙烯腈三聚物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物、 乙烯-乙烯醋酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1 C4垸基丙烯酸 -羰基 (碳单氧化物)三聚 物、 乙烯 -C1 C4烷基丙烯酸共聚物或它们的混合物。  The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of polyvinyl acetate, vinyl chloride-vinyl alcohol-vinyl acetate, which is insoluble or hardly soluble in water and digestive juice. a terpolymer, a vinyl chloride-ethylene acetate copolymer or a mixture thereof, the polymer enhancer being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, styrene- Butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 C4 methacrylic acid- a carbonyl (carbon monooxide) terpolymer, an ethylene-C1 C4 alkyl acrylate copolymer or a mixture thereof.
19. 根据权利要求 1至 4中任意一项的用途， 其中所述的聚合物选自聚氯乙烯， 所述的 聚合物增强剂选自甲基丙烯酸甲酯-苯乙烯共聚物、 苯乙烯-丙烯腈共聚物、 苯乙烯 -丁二烯- 丙烯腈三聚物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物、 乙烯-乙烯醋酸 -羰基 (碳单氧化物） 三聚物、 乙烯 -C1 C4垸基丙烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1 C4烷基丙烯酸共聚 物及它们的混合物。  The use according to any one of claims 1 to 4, wherein the polymer is selected from the group consisting of polyvinyl chloride, and the polymer reinforcing agent is selected from the group consisting of methyl methacrylate-styrene copolymer, styrene- Acrylonitrile copolymer, styrene-butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, Ethylene-C1 C4 mercapto acrylate-carbonyl (carbon monooxide) terpolymer, ethylene-C1 C4 alkyl acrylate copolymer, and mixtures thereof.
20. 根据前述权利要求中任意一项的用途， 其中所述的聚合物增强剂的平均粒径（直径) 不大于 400nm  The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 400 nm
21. 根据前述权利要求中任意一项的用途， 其中所述的聚合物增强剂的平均粒径（直径) 不大于 100nm  The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 100 nm
22. 根据前述权利要求中任意一项的用途， 其中所述的聚合物增强剂的平均粒径（直径) 不大于 20nm  The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 20 nm
23. 根据前述权利要求中任意一项的用途， 其中所述的聚合物增强剂的平均粒径（直径) 不大于 5  The use according to any one of the preceding claims, wherein the polymer reinforcing agent has an average particle diameter (diameter) of not more than 5
24. 根据前述权利要求中任意一项的用途， 其中所述的聚合物控释衣膜的玻璃化转变温 度 （¾) 为 25 80°C  The use according to any one of the preceding claims wherein the polymer controlled release film has a glass transition temperature (3⁄4) of 25 80 ° C
25. 根据前述权利要求中任意一项的用途， 其中所述的聚合物增强剂的用量为 1% 30°/ (重量比）， 这是基于聚合物控释衣膜组分的干的总重量。  The use according to any of the preceding claims, wherein the polymer reinforcing agent is used in an amount of 1% 30°/(by weight) based on the total dry weight of the polymer controlled release coating component. .
26. 一种性能改善的控释制剂特别是零级释放的控释制剂的制备方法， 该制备方法包括: 26. A method for preparing a controlled release formulation having improved properties, in particular a controlled release formulation of zero order release, the method comprising:
1 )、 制备含有至少一种生物活性物质的芯料； 1) preparing a core material containing at least one biologically active substance;
2)、用含有药学上可接受的可升华的物质颗粒和 /或可降解成无害气体的物质颗粒及药学 上可接受的聚合物增强剂的药学上可接受的不溶于或几乎不溶于水及消化液的聚合物的溶液 或水分散液对上述芯料包覆聚合物控释衣膜，其中， 上述可升华的物质和 /或可降解成无害气 体的物质及上述聚合物增强剂不溶于或几乎不溶于上述聚合物的溶液或水分散液， 上述聚合 物与上述聚合物增强剂的接触角低于 90°  2) pharmaceutically acceptable insoluble or nearly insoluble in water with particles of pharmaceutically acceptable sublimable material and/or particles which are degradable into a harmless gas and a pharmaceutically acceptable polymer enhancer And a polymer solution or aqueous dispersion of the digestive juice coated with the polymer controlled release coating film, wherein the sublimable substance and/or the substance degradable into a harmless gas and the polymer enhancer are insoluble a solution or an aqueous dispersion of the above polymer which is or is insoluble in the above polymer, the contact angle of the above polymer with the above polymer reinforcing agent is less than 90°
3)、升华掉位于上述聚合物控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于 上述聚合物控释衣膜中的药学上可接受的可降解成无害气体的物质。  3) sublimating the pharmaceutically acceptable sublimable material in the above polymer controlled release coating film and/or degrading the pharmaceutically acceptable degradable gas into the controlled release film of the above polymer Substance.
27. 根据权利要求 26的制备方法， 其中所述的接触角低于或等于 60°  27. The preparation method according to claim 26, wherein said contact angle is lower than or equal to 60
28. 根据权利要求 26的制备方法， 其中所述的接触角低于或等于 30°  28. The preparation method according to claim 26, wherein said contact angle is lower than or equal to 30
29. 根据权利要求 26的制备方法， 其中所述的接触角低于或等于 10°  29. The preparation method according to claim 26, wherein said contact angle is lower than or equal to 10
30. 根据权利要求 26至 29中任意一项的制备方法， 其中所述的聚合物增强剂具有 "硬壳 软核"结构。  The production method according to any one of claims 26 to 29, wherein said polymer reinforcing agent has a "hard shell soft core" structure.
31. 根据权利要求 30的制备方法， 其中所述的聚合物增强剂的熔点 （或晶体熔化温度） 或 /和维氏软化点（Vicat Softening Point)不低于所述控释衣膜中的聚合物的玻璃化转变温 权 利 要 求 书 The preparation method according to claim 30, wherein said polymer reinforcing agent has a melting point (or crystal melting temperature) or/and a Vicat Softening Point of not lower than that in said controlled release coating film. Vitrification temperature Claim
度 （¾)， 且其中心玻璃化温度不高于 o°c。 Degree (3⁄4), and its central glass transition temperature is not higher than o °c.
32. 根据权利要求 30的制备方法， 其中所述的聚合物增强剂的熔点 （或晶体熔化温度） 或 /和维氏软化点（Vicat Softening Point) 高出 10°C (含） 于所述控释衣膜中的聚合物的玻 璃化转变温度 （¾)， 且其中心玻璃化温度为 -10〜- 200°C。  32. The production method according to claim 30, wherein said polymer enhancer has a melting point (or crystal melting temperature) or/and a Vicat Softening Point higher than 10 ° C (inclusive) of said control The glass transition temperature (3⁄4) of the polymer in the release film, and its central glass transition temperature is -10 to -200 °C.
33. 根据权利要求 30的制备方法， 所述的聚合物增强剂的断裂伸长率为 200〜5000%。 The preparation method according to claim 30, wherein the polymer reinforcing agent has an elongation at break of 200 to 5000%.
34. 根据权利要求 26的制备方法， 其中所述的聚合物选自乙基纤维素、三十二酸纤维素、 三棕榈酸纤维素、 二棕榈酸纤维素或它们的混合物， 所述的聚合物增强剂选自用表面活性物 质吸附包裹处理方式进行了表面改性的极性刚性无机粒子。 The production method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof, said polymerization The material enhancer is selected from the group consisting of polar rigid inorganic particles surface-modified by a surface active material adsorption coating treatment.
35.根据权利要求 26的制备方法，其中所述的聚合物选自乙基纤维素、三十二酸纤维素、 三棕榈酸纤维素、 二棕榈酸纤维素或它们的混合物， 所述的聚合物增强剂选自表面被硬脂酸 包覆的碳酸钙粒子。  The production method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose tridodate, cellulose tripalmitate, cellulose dipalmitate or a mixture thereof, said polymerization The enhancer is selected from calcium carbonate particles whose surface is coated with stearic acid.
36. 根据权利要求 26的制备方法， 其中所述的聚合物选自乙基纤维素、醋酸纤维素、 丙 酸纤维素、 醋酸丁酸纤维素、 醋酸丙酸纤维素 （cellulose acetate propionate ) 硝酸纤维 素、 三戊酸纤维素、 二琥珀酸纤维素或它们的混合物， 所述的聚合物增强剂选自甲基丙烯酸 甲酯-苯乙烯共聚物、 苯乙烯-丙烯腈共聚物、 苯乙烯 -丁二烯-丙烯腈三聚物、 甲基丙烯酸甲 酯 -丁二烯-苯乙烯三聚物、 乙烯-乙烯醋酸 -羰基 (碳单氧化物）三聚物、 乙烯 -C1〜C4烷基丙 烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C4垸基丙烯酸共聚物或它们的混合物。  The preparation method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, and nitrocellulose. a cellulose, cellulose triacetate, cellulose succinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, styrene-butyl Diene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C4 alkyl acrylate- a carbonyl (carbon monooxide) terpolymer, an ethylene-C1 to C4 methacrylic acid copolymer or a mixture thereof.
37. 根据权利要求 26的制备方法， 其中所述的聚合物选自乙基纤维素、醋酸纤维素、 丙 酸纤维素、 醋酸丁酸纤维素、 醋酸丙酸纤维素 （cellulose acetate propionate ), 硝酸纤维 素、 三戊酸纤维素、 二琥珀酸纤维素或它们的混合物， 所述的聚合物增强剂选自甲基丙烯酸 甲酯-苯乙烯共聚物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物或它们的混合物。  37. The production method according to claim 26, wherein said polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate propionate, nitric acid. Cellulose, cellulose trivalerate, cellulose disuccinate or a mixture thereof, the polymer reinforcing agent being selected from the group consisting of methyl methacrylate-styrene copolymer, methyl methacrylate-butadiene-benzene Ethylene terpolymer or a mixture thereof.
38.根据权利要求 26的制备方法， 其中所述的聚合物选自不溶于或几乎不溶于水及消化 液的甲基丙烯酸 (酯)聚合物、 聚甲基丙烯酸甲酯、 丙烯酸乙酯一间丙烯酸甲酯聚合物、 poly The production method according to claim 26, wherein said polymer is selected from the group consisting of methacrylic acid polymers, polymethyl methacrylate and ethyl acrylate which are insoluble or hardly soluble in water and digestive juice. Methyl acrylate polymer, poly
( ethylacrylate , methylmetacrylate , trimethylamonioethylmetacrylatchloride ) 或它 们的混合物， 所述的聚合物增强剂选自聚甲基丙烯酸甲酯、 甲基丙烯酸甲酯-苯乙烯共聚物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物、 乙烯-乙烯醋酸 -羰基（碳单氧化物）三聚物、 乙烯(ethylacrylate , methylmetacrylate , trimethylamonioethylmetacrylatchloride ) or a mixture thereof, the polymer enhancer selected from the group consisting of polymethyl methacrylate, methyl methacrylate-styrene copolymer, methyl methacrylate-butadiene-benzene Ethylene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene
-C1〜C4垸基丙烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C4垸基丙烯酸共聚物、 丙烯酸树 脂类抗冲击改性剂或它们的混合物。 -C1 to C4 mercaptoacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 to C4 mercaptoacrylic acid copolymer, acrylic resin impact modifier or a mixture thereof.
39.根据权利要求 26的制备方法， 其中所述的聚合物选自不溶于或几乎不溶于水及消化 液的聚乙烯乙酸酯、氯乙烯一乙烯醇一醋酸乙烯酯的三元共聚物、氯乙烯 -乙烯乙酸酯共聚物 或它们的混合物， 所述的聚合物增强剂选自甲基丙烯酸甲酯-苯乙烯共聚物、 苯乙烯-丙烯腈 共聚物、苯乙烯 -丁二烯-丙烯腈三聚物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物、 乙烯 -乙烯 醋酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C4垸基丙烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C4烷基丙烯酸共聚物或它们的混合物。  The production method according to claim 26, wherein said polymer is selected from the group consisting of polyvinyl acetate, vinyl chloride-vinyl alcohol-vinyl acetate terpolymer which is insoluble or hardly soluble in water and digestive juice, a vinyl chloride-ethylene acetate copolymer or a mixture thereof, the polymer enhancer being selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, styrene-butadiene-propylene Nitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C4 methacrylic acid-carbonyl (carbon single Oxide) terpolymer, ethylene-C1 to C4 alkyl acrylate copolymer or a mixture thereof.
40. 根据权利要求 26的制备方法， 其中所述的聚合物选自聚氯乙烯， 所述的聚合物增强 剂选自甲基丙烯酸甲酯-苯乙烯共聚物、 苯乙烯-丙烯腈共聚物、 苯乙烯-丁二烯 -丙烯腈三聚 物、 甲基丙烯酸甲酯 -丁二烯-苯乙烯三聚物、 乙烯-乙烯醋酸 -羰基 (碳单氧化物）三聚物、 乙 烯 -C1〜C4烷基丙烯酸 -羰基 (碳单氧化物)三聚物、 乙烯 -C1〜C4垸基丙烯酸共聚物及它们的 混合物。  40. The production method according to claim 26, wherein said polymer is selected from the group consisting of polyvinyl chloride, said polymer reinforcing agent is selected from the group consisting of methyl methacrylate-styrene copolymer, styrene-acrylonitrile copolymer, Styrene-butadiene-acrylonitrile terpolymer, methyl methacrylate-butadiene-styrene terpolymer, ethylene-ethylene acetate-carbonyl (carbon monooxide) terpolymer, ethylene-C1~C4 Alkylacrylic acid-carbonyl (carbon monooxide) terpolymer, ethylene-C1 to C4 mercaptoacrylic acid copolymer, and mixtures thereof.
41. 根据权利要求 26至 40中任意一项的制备方法 ， 其中所述的聚合物增强剂的平均粒 径 （直径） 不大于 400nm。  The production method according to any one of claims 26 to 40, wherein said polymer enhancer has an average particle diameter (diameter) of not more than 400 nm.
42. 根据权利要求 26至 40中任意一项的制备方法， 其中所述的聚合物增强剂的平均粒 径 （直径） 不大于 100nm。  The production method according to any one of claims 26 to 40, wherein said polymer reinforcing agent has an average particle diameter (diameter) of not more than 100 nm.
43. 根据权利要求 26至 40中任意一项的制备方法， 其中所述的聚合物增强剂的平均粒 权 利 要 求 书 43. The production method according to any one of claims 26 to 40, wherein the average particle of the polymer enhancer Claim
径 （直径） 不大于 20nm。 The diameter (diameter) is not more than 20 nm.
44. 根据权利要求 26至 40中任意一项的制备方法， 其中所述的聚合物增强剂的平均粒 径 （直径） 不大于 5nm。  The production method according to any one of claims 26 to 40, wherein said polymer reinforcing agent has an average particle diameter (diameter) of not more than 5 nm.
45.根据权利要求 26至 44中任意一项的制备方法，其中所述的释药微孔平均大小为 50〜 900 μ πι。  The preparation method according to any one of claims 26 to 44, wherein said release micropores have an average size of 50 to 900 μm.
46.根据权利要求 26至 44中任意一项的制备方法，其中所述的释药微孔平均大小为 100〜 600 μ πι。  The preparation method according to any one of claims 26 to 44, wherein said release micropores have an average size of from 100 to 600 μm.
47. 根据权利要求 26至 46中任意一项的制备方法， 其中所述的聚合物控释衣膜的玻璃 化转变温度 （Tg ) 为 25〜80°C。  The production method according to any one of claims 26 to 46, wherein the polymer controlled release film has a glass transition temperature (Tg) of 25 to 80 °C.
48. 根据权利要求 26至 47中任意一项的制备方法， 其中所述的聚合物控释衣膜的孔隙 率为 5%〜95%。  The production method according to any one of claims 26 to 47, wherein said polymer controlled release film has a porosity of from 5% to 95%.
49. 根据权利要求 26至 48中任意一项的制备方法， 其中所述的聚合物增强剂的用量为 1%〜30% (重量比）， 这是基于聚合物控释衣膜组分的干的总重量。  The production method according to any one of claims 26 to 48, wherein the polymer reinforcing agent is used in an amount of from 1% to 30% by weight based on the dry weight of the polymer controlled release coating film component. The total weight.
50. 根据权利要求 26至 49中任意一项的制备方法， 其中所述的芯料为规则或不规则形 式的片、 颗粒、 丸、 晶体或载药树脂。  The production method according to any one of claims 26 to 49, wherein the core material is a sheet, a pellet, a pellet, a crystal or a drug-loading resin in a regular or irregular form.
51. 根据权利要求 26至 50中任意一项的制备方法， 其中所述的生物活性物质选自中枢兴 奋药、 镇痛药、 解热镇痛药、 抗炎镇痛药、 抗痛风药、 抗震颤麻痹药、 抗精神病药、 抗焦虑 药、 抗抑郁症药、 抗癫痫药、 镇静药、 催眠药、 抗惊厥药、 植物神经***药物、 钙拮抗药、 治疗慢性心功能不全的药物、 抗心律失常药、 防治心绞痛药、 周围血管扩张药、 降血压药、 调节血脂药及抗动脉粥样硬化药、 呼吸***药物、 抗酸药及治疗消化性溃疡病药、 胃肠解痉 药、 助消化药、 止吐药、 催吐药及肠胃推动药、 肝胆疾病辅助用药、 泌尿***药物、 影响血 液及造血***的药物、 抗组胺药、 过敏反应介质阻释剂、 肾上腺皮质激素及促肾上腺皮质激 素、 性激素及促性激素、 胰岛激素及其它影响血糖的药物、 甲状腺激素类药物及抗甲状腺药 物、 青霉素类、 头孢菌素类、 β -内酰胺酶抑制剂、 氨基糖苷类、 四环素类、 大环内酯类、 抗 结核病药、 抗真菌药、 抗病毒药、 抗肿瘤药物、 影响机体免疫功能的药物、 维生素及营养类 药、 减肥药及它们的混合物。  The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of a central stimulant, an analgesic, an antipyretic analgesic, an anti-inflammatory analgesic, an anti-gout, and an antibiotic Tremor palsy, antipsychotics, anxiolytics, antidepressants, antiepileptics, sedatives, hypnotics, anticonvulsants, autonomic nervous drugs, calcium antagonists, drugs for chronic heart failure, anti-heart rhythm Disorders, prevention and treatment of angina pectoris, peripheral vasodilators, blood pressure lowering drugs, blood lipid regulating and anti-atherosclerotic drugs, respiratory medicines, antacids and peptic ulcer drugs, gastrointestinal antispasmodics, digestion Medicine, antiemetics, emetics and gastrointestinal drugs, hepatobiliary diseases, urinary system drugs, drugs that affect blood and hematopoietic system, antihistamines, allergic mediators, adrenocortical hormones and adrenocorticotropic hormones , sex hormones and gonadotropins, islet hormones and other drugs that affect blood sugar, thyroid hormones and antithyroid drugs, Penicillins, cephalosporins, β-lactamase inhibitors, aminoglycosides, tetracyclines, macrolides, antituberculosis drugs, antifungals, antivirals, antitumor drugs, affecting immune function Drugs, vitamins and nutrients, diet pills and mixtures thereof.
52. 根据权利要求 26至 50中任意一项的制备方法， 其中所述的生物活性物质选自中草药 提取物。  The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of herbal extracts.
53. 根据权利要求 26至 50中任意一项的制备方法， 其中所述的生物活性物质选自 LECOZOTAN ( SRA-333 ) , 阿莫西林、 阿司达莫、阿魏酸哌嗪、 阿昔洛韦、别嘌醇、丙硫氧嘧啶、 丙戊酸镁、 布洛芬、 醋氯芬酸、 单硝酸异山梨酯、 ***、 泛昔洛韦、 非洛地平、 非诺贝特、 氟伐他汀钠、 阿昔莫司、 维生素 B6、 富马酸喹硫平、 富马酸美托洛尔、 富马酸依美斯汀、 格 列喹酮、 格列齐特、 枸橼酸钾、 拘橼酸他莫昔芬、 拘橼酸他莫昔芬、 琥珀酸去甲文拉法辛、 环丙沙星、 茴拉西坦、 己酮可可碱、 甲硝唑、 酒石酸托特罗定、 酒石酸唑吡坦、 克拉霉素、 苦参素、 雷诺嗪、 利巴韦林、 磷酸苯丙哌林、 磷酸川芎嗪、 硫普罗宁、 硫酸***、 硫酸沙丁 胺醇、 罗格列酮、 罗红霉素、 洛伐他汀、 马来酸曲美布汀、 美沙拉嗪、 美托法宗、 咪唑斯汀、 萘哌地尔、 萘普生钠、 尼可他汀、 尼美舒利、 尼群地平、 尼索地平、 帕潘立酮、 帕普拉唑、 氢溴酸达非那新、 氢溴酸加兰他敏、 石杉碱甲、 双环醇、 司他夫定、 天麻素、 酮洛芬、 头孢 克洛、头孢克肟、维生素 C (***控释片）、维生素 E烟酸酯、乌拉地尔、烟酸、盐酸安非他酮、 盐酸氨溴索、 盐酸奧昔布宁、 盐酸倍他司汀、 盐酸二甲双胍、 盐酸伐昔洛韦、 盐酸环丙沙星、 盐酸拉贝洛尔、 盐酸尼卡地平、 盐酸帕罗西汀、 盐酸哌唑嗪、 盐酸普罗帕酮、 盐酸***、 盐酸氢***酮、 ***马多、 ***美他嗪、 盐酸坦洛新、 盐酸坦索罗辛、 盐酸左旋沙丁胺 醇、 盐酸左氧氟沙星、 氧氟沙星、 依托度酸、 吲达帕胺、 愈创甘油醚、 左羟丙哌嗪、 苯扎贝 特、 吡贝地尔、 茶碱、 长春胺、 甲磺酸二氢麦角碱、 甲磺酸多沙唑嗪、 酒石酸美托洛尔、 酒 石酸双氢可待因、 硫酸***、硫酸庆大霉、 硫酸亚铁、 氯化钾、 吗多明、 萘呋胺、 尼莫地平、 权 利 要 求 书 The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of LECOZOTAN (SRA-333), amoxicillin, asdamamo, piperazine ferulate, acyclovir. Wei, allopurinol, propylthiouracil, magnesium valproate, ibuprofen, aceclofenac, isosorbide mononitrate, diazepam, famciclovir, felodipine, fenofibrate, fluvastatin sodium , acipimox, vitamin B6, quetiapine fumarate, metoprolol fumarate, ezetimidate fumarate, gliclazone, gliclazide, potassium citrate, citrate Tamoxifen, tamoxifen, venlafaxine succinate, ciprofloxacin, aniracetam, pentoxifylline, metronidazole, tolterodine tartrate, zolazole tartrate Tantan, clarithromycin, oxymatrine, ranolazine, ribavirin, benproperine phosphate, ligustrazine phosphate, tiopronin, morphine sulfate, salbutamol sulfate, rosiglitazone, roxithromycin, lovra Statins, trimebutine maleate, mesalazine, metoprolazine, mizolastine, naftopide , naproxen sodium, niketatin, nimesulide, nitrendipine, nisoldipine, paliperidone, paprazole, dafenazone hydrobromide, galantamine hydrobromide, stone Alkaloids, bicyclol, stavudine, gastrodin, ketoprofen, cefaclor, cefixime, vitamin C (vaginal controlled release tablets), vitamin E nicotinate, urapidil, niacin, hydrochloric acid Bupropion, ambroxol hydrochloride, oxybutynin hydrochloride, betahistine hydrochloride, metformin hydrochloride, valacyclovir hydrochloride, ciprofloxacin hydrochloride, labetalol hydrochloride, nicardipine hydrochloride, hydrochloric acid Roxioxine, prazosin hydrochloride, propafenone hydrochloride, propranolol hydrochloride, hydromorphone hydrochloride, tramadol hydrochloride, trimetazidine hydrochloride, tamsulosin hydrochloride, tamsulosin hydrochloride, L-salbutamol hydrochloride, hydrochloric acid Levofloxacin, ofloxacin, etodolac, indapamide, guaifenesin, levodropropizine, bezafibrate, piracetil, theophylline, vincamine, dihydroergotamine mesylate , doxazosin mesylate, metoprolol tartrate Dihydrocodeine tartrate, morphine sulfate, Qing Trappe sulfate, ferrous sulfate, potassium chloride, molsidomine, naftidrofuryl, nimodipine, Claim
双氯芬酸钠、 维拉帕米、 维铁、 硝苯地平、 盐酸地尔硫卓、 盐酸***、 格列吡嗪、 盐酸 地尔硫、 吲哚美辛、 阿西美辛、 ***、 对乙酰氨基酚、 格列齐特、 琥珀酸亚铁、 卡马西 平、 磷酸可待因、 洛芬待因、 马洛替酯、 萘普生、 碳酸锂、 头孢氨苄、 盐酸阿夫唑嗪、 盐酸 丁咯地尔、 盐酸噻氯匹啶、 异丁司特、 右美沙芬、 青藤碱、 5-单硝异山梨醇酯、 丙戊酸钠、 多巴丝肼、 马来酸氯苯那敏、 巴尼地平、 布那唑嗪、 戈洛帕米、 盐酸哌甲酯、 盐酸羟考酮。 Diclofenac sodium, verapamil, ferrotitanium, nifedipine, diltiazem hydrochloride, propranolol hydrochloride, glipizide, diltiazem hydrochloride, indomethacin, acemetame, dexamethasone, p-acetyl Aminophenol, gliclazide, ferrous succinate, carbamazepine, codeine phosphate, pirfenine, malotilate, naproxen, lithium carbonate, cephalexin, alfuzosin hydrochloride, butyl chloride Lodil, ticlopidine hydrochloride, ibudilast, dextromethorphan, sinomenine, 5-mononitrate, sodium valproate, dopasine, chlorpheniramine maleate, Banidipine, bunazosin, golopamil, methylphenidate hydrochloride, oxycodone hydrochloride.
54. 根据权利要求 26至 50中任意一项的制备方法， 其中所述的生物活性物质选自阿莫西 林一克拉维酸钾复方、 阿司匹林一磷酸川芎嗪复方、 阿司匹林一双嘧达莫复方、 扑热息痛一 盐酸伪麻黄碱一顺丁烯二酸右旋溴苯吡胺复方、 单硝酸异山梨酯一阿司匹林复方、 二甲双胍 一罗格列酮复方、 盐酸非索那定一盐酸伪麻黄碱复方、 非洛地平一酒石酸美托洛尔复方、 洛 伐他汀一烟酸复方、 西替利嗪一盐酸伪麻黄碱复方、 盐酸非索非那定一盐酸伪麻黄碱复方、 愈创甘油醚一伪麻黄碱一右美沙芬复方、 格列吡嗪一盐酸二甲双胍复方、 格列美脲一二甲双 胍复方、 氯雷他定一扑热息痛一伪麻黄碱复方、 氯雷他定一伪麻黄碱复方、 马来酸依那普利 一非洛地平复方、 伪麻黄碱一萘普生钠复方、 烟酸一辛伐他汀复方、 愈创甘油醚一盐酸伪麻 黄碱复方、卡比多巴一左旋多巴复方、茶碱一沙丁胺醇复方、硫酸庆大霉素一二氧化锆复方。  The preparation method according to any one of claims 26 to 50, wherein the biologically active substance is selected from the group consisting of amoxicillin-clavulanate potassium compound, aspirin monophosphate complex, ligustrazine compound, aspirin-dipyridamole compound, paracetamol Pseudoephedrine hydrochloride, dextrobromide compound of maleic acid, isosorbide mononitrate-aspirin compound, metformin-roglitazone combination, fesopidine hydrochloride-pseudoephedrine hydrochloride, felodipine-tartaric acid Torolol compound, lovastatin-nicotinic acid compound, cetirizine-pseudoephedrine compound, fexofenadine hydrochloride pseudoephedrine hydrochloride compound, guaifenesin-pseudoephedrine-dextromethorphan compound, glipizide Metformin hydrochloride compound, glimepiride-metformin compound, loratadine-paracetamol-pseudoephedrine compound, loratadine-pseudoephedrine compound, enalapril maleate-felodipine compound, pseudoephedrine-naproxen sodium compound , niacin-simvastatin combination, guaifenesin-pseudoephedrine hydrochloride, Kabi Dopa-levofopa compound, theophylline-salbutamol compound, gentamicin sulfate-zirconia compound.
55.根据权利要求 26至 54中任意一项的制备方法，其中所述的可升华的物质和 /或可降 解成无害气体的物质在 1标准大气压（101. 325ka)下的熔点及其开始升华（升华点）或降解 的温度高出 （含） 10°C于所述的聚合物的混合包衣液的最低成膜温度或所述聚合物控释衣膜 的玻璃化转变温度。  The production method according to any one of claims 26 to 54, wherein the sublimable substance and/or the substance degradable to a harmless gas has a melting point at 1 standard atmospheric pressure (101. 325 ka) and the start thereof The sublimation (sublimation point) or degradation temperature is higher than (including) the minimum film formation temperature of the mixed coating solution of the polymer at 10 ° C or the glass transition temperature of the polymer controlled release coating film.
56.根据权利要求 26至 55中任意一项的制备方法，其中所述的可升华的物质和 /或可降 解成无害气体的物质在 1标准大气压（101. 325ka)下的熔点及其开始升华（升华点）或降解 的温度高出 （含） 20°C于所述的聚合物的混合包衣液的最低成膜温度或所述聚合物控释衣膜 的玻璃化转变温度。  The production method according to any one of claims 26 to 55, wherein the sublimable substance and/or the substance degradable to a harmless gas has a melting point at 1 standard atmospheric pressure (101. 325 ka) and the start thereof The sublimation (sublimation point) or degradation temperature is higher than (including) the minimum film formation temperature of the mixed coating liquid of the polymer at 20 ° C or the glass transition temperature of the polymer controlled release film.
57.根据权利要求 26至 56中任意一项的制备方法，其中所述的可升华的物质和 /或可降 解成无害气体的物质选自苯甲酸、 苯甲酸酯及苯甲酸盐类化合物、 香草醛、 乙基香草醛、 天 然或合成樟脑、 右旋樟脑、 左旋樟脑、 外消旋薄荷脑（醇） 、 左旋薄荷醇、 天然或合成冰片、 右旋龙脑、 左旋龙脑、 右旋异龙脑、 左旋异龙脑、 外消旋异龙脑、 二硫代草酰胺 （二硫代二 酰胺） 、 6—甲基一 2—硫脲嘧啶 （甲基硫氧嘧啶） 、 萸磺酸盐、 叔丁基对羟基茴香醚、 二特 丁基羟基甲苯 （2， 6—二特丁基对甲酚） 、 水杨酸、 阿司匹林、 乙水杨胺、 咖啡因类化合物、 丙氨酸、 亮氨酸、 异亮氨酸、 缬氨酸、 苯丙氨酸、 尿素、 乌拉坦、 卤化铵、 碳酸氢铵、 碳酸 铵、 醋酸铵或它们混合物。  The production method according to any one of claims 26 to 56, wherein the sublimable substance and/or the substance degradable to a harmless gas is selected from the group consisting of benzoic acid, benzoate and benzoate compounds. , vanillin, ethyl vanillin, natural or synthetic camphor, right-handed camphor, left-handed camphor, racemic menthol (alcohol), levo-menthol, natural or synthetic borneol, right-handed borneol, left-handed borneol, right-handed Iso-borne brain, L-isobornolone, racemic isoborneol, dithiooxamide (dithiodiamide), 6-methyl-2-thiouracil (methylthiouracil), sulfonic acid Salt, tert-butyl-p-hydroxyanisole, di-tert-butylhydroxytoluene (2,6-di-tert-butyl-p-cresol), salicylic acid, aspirin, salicylamine, caffeine, alanine, Leucine, isoleucine, valine, phenylalanine, urea, urethane, ammonium halide, ammonium hydrogencarbonate, ammonium carbonate, ammonium acetate or a mixture thereof.
58.根据权利要求 26至 57中任意一项的制备方法，其中在升华和 /或降解掉所述的可升华 性的物质和 /或可降解成无害气体的物质形成释药微孔前，将所述已包覆聚合物控释衣膜的芯 料置于高于所述聚合物控释衣膜的玻璃化转变温度的温度下愈合处理， 直至该包衣芯料具有 稳定的溶出特性，愈合处理终点通过比较刚结束愈合处理的包衣芯料与在 40 ± 2 °C的温度及不 低于 50%且不高于上述的可升华的物质颗粒和 /或可降解成无害气体的物质的 （吸湿） 临界相 对湿度的相对湿度下的加速贮存条件中放置 3个月和 /或 6个月的包衣芯料的溶出特性而确定， 在上述愈合处理过程中及上述加速贮存条件中放置过程中， 位于上述聚合物衣膜中的上述可 升华的物质及可降解成无害气体的物质的净固体量不减少。  The production method according to any one of claims 26 to 57, wherein before the release micropores are formed by sublimation and/or degradation of the sublimable substance and/or a substance degradable into a harmless gas, The core material of the coated polymer controlled release coating film is subjected to a healing treatment at a temperature higher than a glass transition temperature of the polymer controlled release coating film until the coating core material has stable dissolution characteristics. The end point of the healing treatment is obtained by comparing the coating core material which has just finished the healing treatment with the temperature at 40 ± 2 ° C and not less than 50% and not higher than the above-mentioned sublimable substance particles and/or degradable into a harmless gas. Determination of the dissolution characteristics of the coated core material in an accelerated storage condition at a relative humidity of the relative relative humidity at a relative humidity of 3 months and/or 6 months, during the above healing process and in the above accelerated storage conditions. During the placement process, the above-mentioned sublimable substance located in the above polymer film and the net solidity of the substance degradable into a harmless gas are not reduced.
59.根据权利要求 58的制备方法，其中所述的愈合处理在大于或等于所述的愈合处理进 行时条件如温度下的所述可升华的物质的平衡分压和 /或在大于或等于所述的愈合处理进行 时条件如温度下的所述可降解成无害气体的物质的所有降解产物的平衡分压下或者在低于所 述的愈合处理进行时条件如压力下的所述可降解的物质的最低降解温度的温度下进行。  59. The production method according to claim 58, wherein said healing treatment has a equilibrium partial pressure of said sublimable substance at a temperature greater than or equal to said healing treatment, such as temperature, and/or at greater than or equal to Said healing treatment is carried out under conditions such as equilibrium at a partial pressure of all degradation products of said substance degradable to a harmless gas at a temperature or at a lower than said healing treatment, conditions such as pressure The lowest degradation temperature of the substance is carried out at a temperature.
60.根据权利要求 26至 59中任意一项的制备方法，其中升华所述的可升华性的物质和 / 或降解掉所述的可降解成无害气体的物质是在减压或真空下及在低于衣膜玻璃化转变温度 权 利 要 求 书 The production method according to any one of claims 26 to 59, wherein sublimating said sublimable substance and/or degrading said substance degradable into a harmless gas is under reduced pressure or under vacuum Below the film glass transition temperature Claim
5°C以下的温度下进行的。  It is carried out at a temperature below 5 °C.
61 . 根据权利要求 26至 60中任意一项的制备方法， 所述的聚合物控释衣膜外进一歩包覆 水溶性衣膜。  The preparation method according to any one of claims 26 to 60, wherein said polymer controlled release coating film is coated with a water-soluble coating film.
62. 一种性能改善的控释制剂特别是零级释放的控释制剂， 该控释制剂包含：  62. A controlled release formulation having improved properties, in particular a zero release release controlled release formulation, the controlled release formulation comprising:
1 )、 含有至少一种生物活性物质的芯料；  1) a core material containing at least one biologically active substance;
2 )、 外覆于上述芯料的含有众多充有空气的释药微孔的控释衣膜， 其中， 该控释衣膜包 含药学上可接受的不溶于或几乎不溶于水及消化液的聚合物及药学上可接受的聚合物增强 剂， 上述聚合物与上述聚合物增强剂的接触角低于 90° ， 上述释药微孔是经升华掉位于上述 控释衣膜中的药学上可接受的可升华的物质和 /或降解掉位于上述控释衣膜中的药学上可接 受的可降解成无害气体的物质而获得的。  2) a controlled release coating film comprising a plurality of air-filled drug delivery micropores covering the core material, wherein the controlled release coating film comprises pharmaceutically acceptable insoluble or hardly soluble in water and digestive juice. a polymer and a pharmaceutically acceptable polymer enhancer, wherein the contact angle of the polymer with the polymer enhancer is less than 90°, and the release micropores are pharmaceutically acceptable by sublimation in the controlled release coating film The acceptable sublimable material and/or the degradation of the pharmaceutically acceptable material which is degradable into a harmless gas in the above controlled release coating film.
63. 根据权利要求 62的控释制剂， 其中所述的接触角低于或等于 60° 。  63. The controlled release formulation according to claim 62, wherein said contact angle is less than or equal to 60°.
64. 根据权利要求 62或 63的控释制剂， 其中所述的接触角低于或等于 30° 。  64. A controlled release formulation according to claim 62 or 63 wherein said contact angle is less than or equal to 30°.
65.根据权利要求 62至 64中任意一项的控释制剂，其中所述的接触角低于或等于 10° 。  A controlled release preparation according to any one of claims 62 to 64, wherein said contact angle is lower than or equal to 10°.
PCT/CN2011/077190 2010-07-16 2011-07-15 Polymer reinforcing agent in controlled release preparation WO2012006963A1 (en)

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CN201010227702.5A CN102018658B (en) 2010-07-16 2010-07-16 Controlled release preparation and preparation method thereof
CN201010227666.2 2010-07-16
CN201010228319.1 2010-07-16
CN 201010227666 CN102018962B (en) 2010-07-16 2010-07-16 Polymer intensifier in controlled release preparation
CN201010227702.5 2010-07-16
CN 201010228319 CN101987083B (en) 2010-07-16 2010-07-16 Preparation method for controlled release preparation, especial for zero-order release controlled release preparation

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