WO2019019962A1 - 渗透泵控释制剂 - Google Patents

渗透泵控释制剂 Download PDF

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Publication number
WO2019019962A1
WO2019019962A1 PCT/CN2018/096611 CN2018096611W WO2019019962A1 WO 2019019962 A1 WO2019019962 A1 WO 2019019962A1 CN 2018096611 W CN2018096611 W CN 2018096611W WO 2019019962 A1 WO2019019962 A1 WO 2019019962A1
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Prior art keywords
osmotic pump
controlled release
pump controlled
core
drug
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PCT/CN2018/096611
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English (en)
French (fr)
Inventor
刘荣
李伟
张志宏
王诺
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广州玻思韬控释药业有限公司
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Publication of WO2019019962A1 publication Critical patent/WO2019019962A1/zh

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • A61J3/06—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms into the form of pills, lozenges or dragees
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B30—PRESSES
    • B30B—PRESSES IN GENERAL
    • B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/02—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space
    • B30B11/04—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses using a ram exerting pressure on the material in a moulding space co-operating with a fixed mould
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B30—PRESSES
    • B30B—PRESSES IN GENERAL
    • B30B11/00—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses
    • B30B11/34—Presses specially adapted for forming shaped articles from material in particulate or plastic state, e.g. briquetting presses, tabletting presses for coating articles, e.g. tablets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B30—PRESSES
    • B30B—PRESSES IN GENERAL
    • B30B15/00—Details of, or accessories for, presses; Auxiliary measures in connection with pressing
    • B30B15/06—Platens or press rams
    • B30B15/065—Press rams
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • 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

Definitions

  • the present disclosure generally relates to the field of pharmaceutical formulations. More specifically, the present disclosure relates to controlled release formulations.
  • the osmotic pump controlled release preparation is a typical representative of the controlled release preparation, and is a release system with the osmotic pressure difference inside and outside the coating film as the release power.
  • the present disclosure relates to an osmotic pump controlled release tablet comprising a core and a coating film, the coating film being coated on an outer surface of the core, wherein the tablet has at least one drug delivery channel
  • the drug delivery channel communicates the core of the tablet to the outer surface of the tablet, and the bottom end of the drug delivery channel has a convex portion.
  • the present disclosure relates to a tablet press for preparing an osmotic pump controlled release tablet, the inner surface of the punch of the tablet press having protrusions for forming the release of the tablet
  • the drug channel, the end surface of the protrusion has a recess.
  • the present disclosure is directed to a method of making an osmotic pump controlled release tablet comprising:
  • the present disclosure is directed to a method of improving release of a drug in an individual comprising administering to an individual in need of the method an osmotic pump controlled release tablet, wherein the osmotic pump controlled release tablet comprises a core and a coating film, The coating film is coated on an outer surface of the core, wherein the tablet has at least one drug delivery channel, the drug delivery channel communicating the core to the outer surface of the tablet, the release The bottom end of the drug channel has a raised portion.
  • Figure 1 is a schematic illustration of the structure and release channel structure of an osmotic pump controlled release formulation in accordance with one embodiment of the present disclosure.
  • Figure 2 is a schematic illustration of a longitudinal section of an osmotic pump controlled release tablet in accordance with an embodiment of the present disclosure, in which only the structure of the drug delivery channel is shown.
  • Figure 3 is a schematic illustration of a longitudinal section of an osmotic pump controlled release tablet of another embodiment of the present disclosure, wherein only the structure of the drug delivery channel is shown.
  • Figure 4 is a schematic illustration of a longitudinal section of an osmotic pump controlled release tablet in yet another embodiment of the present disclosure, wherein only the structure of the drug delivery channel is shown.
  • Figure 5 is a controlled release tablet of paliperidone osmotic pump in the present disclosure Release the curve comparison chart.
  • Figure 6 is a controlled release tablet of oxybutynin hydrochloride osmotic pump in the present disclosure XL release curve comparison chart.
  • Figure 7 is a glipizide osmotic pump controlled release tablet of the present disclosure XL release curve comparison chart.
  • Figure 8 is a controlled release tablet of nifedipine osmotic pump in the present disclosure XL release curve comparison chart.
  • Figure 9 is a controlled release tablet of doxazosin mesylate osmotic pump in the present disclosure XL release curve comparison chart.
  • Figure 10 is a comparison of release behavior of glipizide osmotic pump tablets prepared by different methods.
  • Figure 11 is a graph showing the release of six parallel samples of a glipizide osmotic pump controlled release tablet of Example 5 of the present disclosure.
  • Figure 12 is a graph showing six parallel sample release profiles of a glipizide osmotic pump controlled release tablet of Comparative Example 1 of the present disclosure.
  • Figure 13 is a graph showing the release of six parallel samples of a glipizide osmotic pump controlled release tablet prepared in Comparative Example 2 of the present disclosure.
  • Figure 14 is a graph comparing the release behavior of nifedipine osmotic pump tablets prepared by different methods of the present disclosure.
  • Figure 15 is a graph showing the release of six parallel samples of a nifedipine osmotic pump controlled release tablet prepared in Example 7 of the present disclosure.
  • Figure 16 is a graph showing the release of six parallel samples of a controlled release tablet of nifedipine osmotic pump in Example 9 of the present disclosure.
  • Figure 17 is a graph showing the release of six parallel samples of a nifedipine osmotic pump controlled release tablet prepared in Comparative Example 3 of the present disclosure.
  • Figure 18 is a graph showing the release of six parallel samples of a nifedipine osmotic pump controlled release tablet prepared in Comparative Example 4 of the present disclosure.
  • Figure 19 is a graph showing the release of six parallel samples of a nifedipine osmotic pump controlled release tablet prepared in Comparative Example 5 of the present disclosure.
  • references to “an embodiment”, “an embodiment”, “in another embodiment” or “in certain embodiments” throughout the specification are meant to include in the at least one embodiment Relevant specific reference elements, structures or features.
  • the appearances of the phrase “in one embodiment” or “in an embodiment” or “in another embodiment” or “in some embodiments” are not necessarily all referring to the same embodiment.
  • the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
  • maximum lateral length of the boss refers to the largest radial dimension of the boss in the drug delivery channel.
  • maximum lateral length of the cross-section of the drug delivery channel refers to the maximum radial dimension of the channels formed in the core during compression of the core.
  • depth of the drug delivery channel refers to the distance from the opening to the bottom of the channel formed in the core during compression of the core.
  • pharmaceutically acceptable salts includes “acceptable acid addition salts” and “acceptable base addition salts.”
  • the term "acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free base, which are biologically or otherwise suitable and which are inorganic in nature.
  • an acid or an organic acid such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid Alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzenecarboxylic acid, 4-acetamidobenzenecarboxylic acid, camphoric acid, camphor-10-sulfonic acid, citric acid, caproic acid, octanoic acid, carbonic acid, cinnamic acid , citric acid, cyclohexanesulfamic acid, dodecyl sulfate, ethane-1,2-d
  • the term "acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acid, which are biologically or otherwise suitable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. In certain embodiments, the inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, salts of cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, Caffeine, procaine, seabamin, choline, betaine, benzylamine, phenylethylenediamine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, Anthraquinone, piperazine, piperidine, N-ethylpiperidine, polyamine resin, and the like.
  • the like such
  • the term "pharmaceutically active ingredient” refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • the term "pharmaceutically acceptable excipient” refers to an excipient that can be used in the pharmaceutical field, is not harmful to the product or to the mammal, or has a reasonable or acceptable benefit/risk ratio.
  • Pharmaceutically acceptable excipients include, but are not limited to: a) fillers/diluents such as starch, compressible starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, inorganic salts, sugar alcohols, etc.; b) moisturizing Agents/adhesives such as water, ethanol, starch syrup, dextrin, powdered sugar and syrup, cement, polyethylene glycol 4000, cellulose derivatives, methylcellulose, hydroxypropylcellulose, hydroxypropyl Methylcellulose, sodium carboxymethylcellulose, ethylcellulose, etc.; c) disintegrants, such as dry starch, sodium hydroxymethyl starch, low-substituted hydroxypropylcellulose, cross-linked polyvin
  • coating weight gain refers to the ratio of the weight of the coating film to the weight of the core before coating.
  • drug-containing layer refers to a core layer containing a pharmaceutically active ingredient in an osmotic pump sheet.
  • water enters the drug-containing layer under the action of osmotic pressure difference to form a pharmaceutically active ingredient solution or suspension, which can be released from the drug release channel.
  • blocking layer refers to a core layer that does not contain a pharmaceutically active ingredient in an osmotic pump sheet.
  • the release of the pharmaceutically active ingredient can be adjusted by adjusting the composition of the retardation layer and the ratio to the other core layers.
  • the term "pushing layer” refers to a swellable core layer containing an osmotically active substance in an osmotic pump sheet. In an aqueous environment, the push layer swells and promotes release of the pharmaceutically active ingredient solution or suspension from the drug delivery layer from the drug delivery channel.
  • in situ porogenic technique refers to the technique of simultaneously forming a drug delivery channel prior to tablet coating, followed by application of a semi-permeable membrane to form an osmotic pump tablet.
  • the present disclosure relates to an osmotic pump controlled release tablet comprising a core and a coating film, the coating film being coated on an outer surface of the core, wherein the tablet has at least one drug delivery channel
  • the drug delivery channel communicates the core of the tablet to the outer surface of the tablet, and the bottom end of the drug delivery channel has a convex portion.
  • the base area of the raised portion is no greater than the cross-section of the drug delivery channel.
  • the raised portion has a height of between about 0.5 and 3.0 mm.
  • the raised portion has a height of between about 0.6 and 2.0 mm.
  • the raised portion has a height of between about 0.7 and 1.5 mm.
  • the raised portion has a maximum transverse length of between about 0.5 and 2.9 mm.
  • the raised portion has a maximum transverse length of between about 0.7 and 2.5 mm.
  • the raised portion has a maximum transverse length of between about 1.0 and 2.0 mm.
  • the raised portion can take a variety of forms as long as it is capable of preventing the coating fluid from forming a continuous coating film at the bottom end of the drug delivery channel during the coating process.
  • the drug delivery channel has a raised portion at the bottom end. Due to the presence of the raised portion, the coating liquid is prevented from forming a continuous coating film in the drug delivery channel, allowing the osmotic pump controlled release formulation to have a predictable and stable release behavior.
  • illustrative examples of raised portions that can be used with the present disclosure include, but are not limited to, spherical, cylindrical, conical, prismatic, pyramidal, and other regular or irregularly shaped projections.
  • illustrative examples of pyramidal protrusions that can be used with the present disclosure include, but are not limited to, a triangular pyramid, a quadrangular pyramid, and a pentagonal pyramid.
  • the drug delivery channel has a plurality of raised portions at the bottom end.
  • the plurality of raised portions at the bottom end of the drug delivery channel are in one or more rows.
  • the plurality of raised portions at the bottom end of the drug delivery channel are continuously or discontinuously distributed.
  • the plurality of raised portions at the bottom end of the drug delivery channel are regularly or irregularly distributed.
  • the plurality of raised portions at the bottom end of the drug delivery channel are of the same height.
  • the plurality of raised portions at the bottom end of the drug delivery channel are of different heights.
  • illustrative examples of protrusions that can be used with the present disclosure include, but are not limited to, sawtooth and nail plate-like protrusions.
  • the method of preparation is applicable to a variety of formulation coating devices, such as fluidized bed and coating machines, and to a greater extent due to the presence of raised portions in the osmotic pump controlled release tablet release channel. Wide process parameter conditions greatly increase the productivity and practicality of the method.
  • the height of the raised portion is no less than about 50% of the maximum transverse length of the cross-section of the drug delivery channel.
  • the height of the raised portion does not exceed the outer surface of the coating film.
  • illustrative examples of drug delivery channel cross-sections that can be used with the present disclosure include, but are not limited to, circles, squares, rectangles, triangles, and other shapes.
  • the cross-sectional length of the drug delivery channel has a maximum transverse length of from about 0.5 mm to about 3.0 mm.
  • the cross-sectional length of the drug delivery channel has a maximum transverse length of from about 1.00 to about 3.00 mm.
  • the maximum transverse length of the cross-section of the drug delivery channel is between about 1.40 and 2.50 mm.
  • the maximum transverse length of the cross-section of the drug delivery channel is between about 1.70 and 2.20 mm.
  • the maximum transverse length of the cross-section of the drug delivery channel is about 1.95 mm.
  • the depth of the drug delivery channel is greater than or equal to 1 mm and the depth of the drug delivery channel is limited to not penetrating the formulation.
  • the release channel has a depth of between about 1.00 and about 3.00 mm.
  • the release channel has a depth of between about 2.05 and 2.95 mm.
  • the depth of the drug delivery channel is between about 2.25 and 2.75 mm.
  • the depth of the drug delivery channel is about 2.50 mm.
  • the core comprises a drug-containing layer.
  • the core further includes a boost layer, and optionally a retardation layer.
  • the core is a single layer or multiple layers.
  • the core is a three-layer structure comprising a retardation layer, a drug-containing layer, and a boost layer.
  • the core is a two-layer structure comprising a drug-containing layer and a boost layer.
  • the drug-containing layer comprises a pharmaceutically active ingredient, a penetration enhancing polymer, and optionally other pharmaceutically acceptable excipients.
  • the drug-containing layer further comprises an antioxidant.
  • antioxidants that can be used in the present disclosure include, but are not limited to, t-butylhydroxyanisole (BHA) and dibutylhydroxytoluene (BHT).
  • the drug-containing layer further comprises a penetration enhancer.
  • the boost layer comprises a penetration enhancing polymer, a penetration enhancing agent, and optionally other pharmaceutically acceptable excipients.
  • the boost layer further comprises a colorant.
  • the retardation layer comprises a permeation-promoting polymer, a penetration enhancing agent, and optionally other pharmaceutically acceptable excipients.
  • the permeation-promoting polymers that can be used in the present application include, but are not limited to, polyoxyethylene, polyvinylpyrrolidone, polyacrylic acid, hypromellose, polyhydroxyalkyl methacrylates, and mixtures thereof.
  • the permeation enhancing polymer that can be used in the present application is a mixture of polyoxyethylene and hypromellose.
  • illustrative examples of penetration promoting agents that can be used in the present disclosure include, but are not limited to, sodium chloride, magnesium chloride, magnesium sulfate, sodium sulfate, potassium sulfate, tartaric acid, lactose, mannitol, urea, and mixtures thereof. .
  • the tablet further comprises a lubricant.
  • illustrative examples of lubricants that can be used in the present disclosure include, but are not limited to, magnesium stearate, stearic acid, glyceryl behenate, and mixtures thereof.
  • the coating film comprises a semipermeable membrane material.
  • the coating film further comprises a porogen, a plasticizer, an anti-adherent, and/or other pharmaceutically acceptable excipients.
  • illustrative examples of semipermeable membrane materials that can be used in the present disclosure include, but are not limited to, cellulose acetate, aqueous cellulose acetate dispersion, ethyl cellulose, polyvinyl chloride, polycarbonate, ethylene. Alcohol-vinyl acetate, ethylene-propylene polymers, and mixtures thereof.
  • porogens that can be used in the present disclosure include, but are not limited to, glycerol, sorbitol, polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 1000, poly Ethylene glycol 1500, polyethylene glycol 4000, hypromellose, polyvinyl alcohol, and mixtures thereof.
  • plasticizers that can be used in the present disclosure include, but are not limited to, phthalates, glycerides, succinates, benzoates, phosphates, adipates. , tartaric acid esters and mixtures thereof.
  • anti-tack agents that can be used in the present disclosure include, but are not limited to, talc, micronized silica gel, glyceryl monostearate, magnesium stearate, titanium dioxide, and mixtures thereof.
  • illustrative examples of pharmaceutically active ingredients include, but are not limited to, antihypertensives, hypolipidemic agents, oral antidiabetic agents, non-steroidal anti-inflammatory drugs, beta receptor antagonists. Calcium channel blockers, serotonin reuptake inhibitors, antipsychotics and antibacterials.
  • antihypertensive agents include, but are not limited to, sympathetic drugs, such as reserpine, dextropine, mesopine, mecamylamine, and panbital; blood vessels Dilatation drugs, such as hydralazine, diterpenoid, torazine, facedazine, minoxidil, pinacidil, and sodium nitroprusside; drugs that affect the renin-angiotensin-aldosterone system, such as ina Kelun, remiclofen, aliskiren, tetoprolide, captopril, enalapril maleate and losartan; and calcium channel blockers such as nifedipine, nicardipine hydrochloride, Nitrendipine, felodipine, elaradiide, amlodipine besylate, cilnidipine, lacidipine, clevidipine,
  • sympathetic drugs such as reserpine, dextropine, mes
  • hypolipidemic agents that can be used in the present disclosure include, but are not limited to, niacin, acesulfame, inositol niacin, clofibrate, lovastatin, pravastatin, Statins, atorvastatin, probucol, cholestyramine, colestipol, dextroenamide, fenofibrate, pantethine, linoleic acid and omega-3 fatty acids.
  • oral anti-diabetic agents that can be used in the present disclosure include, but are not limited to, insulin and analogs thereof, such as common insulin, insulin aspart, insulin lispro, and insulin glargine; insulin secretion promotion Agents such as sulfabutamide, tolbutamide, glipizide, glimepiride and repaglinide; insulin sensitizers such as metformin hydrochloride; alpha-glucosidase inhibitors such as voglibine Sugar and miglitol; dipeptidyl peptidase-4-inhibitors, such as sitagliptin phosphate.
  • insulin and analogs thereof such as common insulin, insulin aspart, insulin lispro, and insulin glargine
  • insulin secretion promotion Agents such as sulfabutamide, tolbutamide, glipizide, glimepiride and repaglinide
  • insulin sensitizers such as metformin hydrochloride
  • non-steroidal anti-inflammatory drugs that can be used in the present disclosure include, but are not limited to, indomethacin, diclofenac sodium, ibuprofen, naproxen, pyrrooxicam, meloxi Kang, celecoxib and ericoxib.
  • beta receptor antagonists that can be used in the present disclosure include, but are not limited to, propranolol, guanolol, timolol, metoprolol, atenolol , Betatalol, Bisoprol, Labetal, Cavillol and Almar.
  • illustrative examples of calcium channel blockers that can be used in the present disclosure include, but are not limited to, nifedipine, nicardipine hydrochloride, nitrendipine, felodipine, erradipine, benzenesulfonate Amlodipine, cilnidipine, lacidipine, clevidipine, diltiazem, verapamil hydrochloride and bepridil.
  • illustrative examples of serotonin reuptake inhibitors that can be used in the present disclosure include, but are not limited to, fluoxetine, sertraline, paroxetine, citalopram, and fluvoxamine.
  • antipsychotics include, but are not limited to, chlorpromazine hydrochloride, perphenazine, fluphenazine, chlorpromazine, piperidol and sulpiride.
  • synthetic antibacterial agents such as sulfamethoxazole, trimethoprim, norfloxacin, ciprofloxacin, levofloxacin, and Linezolid
  • antibiotic drugs such as penicillin, cephalosporin C, clavulanic acid and sulbactam.
  • illustrative examples of pharmaceutically active ingredients include, but are not limited to, prazosin hydrochloride, phenylpropanolamine hydrochloride, doxazosin mesylate, verapamil hydrochloride, hydrochloric acid Oxybutynin, isradipine, paliperidone, chlorpheniramine maleate, glipizide, nifedipine, pseudoephedrine hydrochloride, pseudoephedrine sulfate, aluminum sulfate, carbamazepine, leuprolide acetate, Sufentanil citrate and methylphenidate hydrochloride.
  • the pharmaceutically active ingredient is selected from the group consisting of doxazosin mesylate, paliperidone, nifedipine, oxybutynin hydrochloride, and glipizide.
  • the formulation techniques disclosed in the present disclosure are obviously applicable to other active pharmaceutical ingredients, which are adjusted and optimized by conventional methods in the art to achieve the same or similar osmotic pump formulation as in the embodiments of the present disclosure.
  • the effect is that the drug is released in a stable manner.
  • the osmotic pump controlled release tablet has a diameter of between about 5 and 15 mm.
  • the osmotic pump controlled release tablet has a diameter of about 8 mm.
  • the osmotic pump controlled release tablet has a diameter of about 9 mm.
  • the osmotic pump controlled release tablet has a diameter of about 10 mm.
  • the osmotic pump controlled release tablet has a diameter of about 11 mm.
  • the osmotic pump controlled release tablet has a diameter of about 12 mm.
  • the osmotic pump controlled release tablet has a hardness of from about 15 to about 30 Kg.
  • the osmotic pump controlled release tablet has a hardness of about 15-20 Kg.
  • the osmotic pump controlled release tablet has a hardness of about 18-23 Kg.
  • the osmotic pump controlled release tablet has a hardness of from about 20 to about 25 Kg.
  • the osmotic pump controlled release tablet has a hardness of about 23-28 Kg.
  • the osmotic pump controlled release tablets prepared by the in situ porogenic method provided by the present disclosure can ensure a stable drug release behavior while simplifying the production process and improving production efficiency.
  • the present disclosure relates to a tablet press for preparing an osmotic pump controlled release tablet, the inner surface of the punch of the tablet press having protrusions for forming a release of the tablet In the tunnel, the end surface of the protrusion has a recess.
  • the inner surface of the punch of the tablet press has cylindrical or prismatic projections.
  • the inner surface of the upper punch of the tablet press has cylindrical or prismatic projections.
  • illustrative examples of prismatic shapes that can be used in the present disclosure include, but are not limited to, a triangular prism shape, a quadrangular prism shape, and a pentagonal prism shape.
  • illustrative examples of cans that can be used in the present disclosure include, but are not limited to, spherical, cylindrical, conical, prismatic, pyramidal, and other shaped depressions.
  • the height of the cylindrical or prismatic projections is adjustable.
  • the present disclosure is directed to a method of making an osmotic pump controlled release tablet comprising:
  • the coating gains from about 1% to about 30%.
  • the coating gains from about 3 to 10%.
  • the coating gains from about 8-15%.
  • the coating gains from about 10% to about 17%.
  • the coating gains from about 13-20%.
  • the coating gains from about 18-25%.
  • the coating gains from about 23% to about 30%.
  • the remaining components except the lubricant are separately mixed in each layer of the core, and finally a lubricant is added to each layer and uniformly mixed.
  • the core is coated with a coating fluid.
  • the formulation of the coating fluid comprises the steps of:
  • organic solvents that can be used in the present disclosure include, but are not limited to, methanol, ethanol, isopropanol, dichloromethane, acetone, aqueous solutions of the above organic solvents, and mixtures thereof.
  • the osmotic pump controlled release formulations of the present disclosure can be single or multiple chambers.
  • the osmotic pump controlled release formulation of the present disclosure is a two compartment.
  • the osmotic pump controlled release formulation of the present disclosure is a three compartment.
  • one skilled in the art can select a suitable osmotic pump controlled release formulation structure type in accordance with well-known teachings.
  • the factors affecting the drug release rate of osmotic pump controlled release preparations mainly include four factors: film thickness, membrane permeability coefficient, osmotic pressure difference inside and outside the coating film and drug solubility.
  • the release pore size also has a certain effect on drug release.
  • the thickness of the film directly affects the rate of penetration of water into the core, which in turn affects the dissolution of the drug in the film, and the swelling of the polymer material; the thickness of the film must be able to withstand the high osmotic pressure generated by the penetration enhancer in the film to ensure that the film does not deform or crack. In turn, it ensures the safety and stability of drug release.
  • the coating material, the coating composition of the coating liquid, and the preparation process of the coating film directly affect the permeability coefficient of the coating film, and the water permeability of the coating film can be increased by adding a water-soluble plasticizer or a porogen to the prescription of the coating film. . It is common knowledge in the art to select an appropriate prescription composition based on the nature of the drug molecule.
  • the formulation techniques disclosed in the present disclosure are obviously applicable to other active pharmaceutical ingredients, which are adjusted and optimized by conventional methods in the art to achieve the same or similar osmotic pump formulation as in the embodiments of the present disclosure.
  • the effect is that the drug is released in a stable manner.
  • suitable in vitro or in vivo assays are performed to determine the effectiveness of the osmotic pump controlled release formulations of the present disclosure and whether the administration is suitable for treating a disease or medical condition in a subject. Examples of such assays are described below in connection with specific diseases or medical treatments in non-limiting embodiments.
  • an effective amount of the osmotic pump controlled release formulation of the present disclosure sufficient to achieve a prophylactic or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day.
  • the dosage is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the dosage may range from about 0.01 to 1000 mg/kg of host body weight per day, every two days or every three days, more typically from 0.1 to 500 mg/kg of host body weight.
  • An exemplary treatment regimen is once every two days or once a week or once a month.
  • the formulation is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly or yearly.
  • the dosage and frequency will vary depending on the half-life of the formulation in the subject. It can also be different depending on whether it is a preventive treatment or a therapeutic treatment.
  • relatively low doses are administered chronically at relatively low frequency intervals.
  • the osmotic pump preparation release behavior is extremely unstable.
  • the inventors of the present disclosure believe that it may be that the fluid-bed relative movement state of the fluidized bed and the coating machine is different, the spray in the fluidized bed moves in the same direction as the solid core, and the spray in the coating machine is sprayed vertically. On the solid core, the latter increases the contact area of the spray with the solid core and the impact of the spray, so that the coating liquid penetrates into the release channel to form a continuous or irregular coating film.
  • the material movement principle in the fluidized bed is that the compressed air is blown from the lower part of the material, and the material is completely fluidized by the wind, which has considerable quality and density. Materials such as tablets are difficult to achieve in large-scale production.
  • the inventors of the present disclosure have discovered a new in-situ perforation preparation method for osmotic pump controlled release preparation through a large number of exploratory experiments, which forms a special release channel during the process of pressing the core of the preparation, and the release channel is connected.
  • the inside of the core is to the outer surface of the tablet, and the inside of the core has a convex portion at the bottom end of the drug release channel, and the convex portion prevents the coating liquid from forming a continuous coating film in the drug release channel during the coating process. It can improve the production efficiency while ensuring normal and stable release behavior of the product.
  • the present disclosure is directed to a method of improving release of a drug in an individual comprising administering to an individual in need of the method an osmotic pump controlled release tablet, wherein the osmotic pump controlled release tablet comprises a core and a coating film, The coating film is coated on an outer surface of the core, wherein the tablet has at least one drug delivery channel, the drug delivery channel communicating the core to the outer surface of the tablet, the release The bottom end of the drug channel has a raised portion.
  • osmotic pump controlled release tablets are administered twice daily.
  • osmotic pump controlled release tablets are administered once a day.
  • osmotic pump controlled release tablets are administered once every 2 days.
  • Example 1 Preparation of paliperidone osmotic pump controlled release tablets
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the retardation layer, the drug-containing layer and the boosting layer, the materials other than stearic acid are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then Add stearic acid and mix well to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8 mm, and the surface of the punch has a protrusion, which is a regular square prism with a height of 2 mm and a side length of 2 mm, and the end face of the regular square prism has 0.7.
  • the conical depression with a depth of mm and a diameter of 1 mm is controlled to have a hardness of 23-28 kg.
  • the prepared core has a regular quadrangular prismatic drug delivery channel with a bottom side of 2 mm and a depth of 2 mm, and the drug-containing layer has a conical convex shape with a height of 0.7 mm and a bottom surface diameter of 1 mm at the bottom end of the drug delivery channel.
  • Preparation of the coating liquid Polyethylene glycol 4000 is dissolved in water to obtain an aqueous solution of polyethylene glycol 4000. The cellulose acetate and the phthalic acid ester are dissolved in acetone, and then an aqueous solution of polyethylene glycol 4000 is added, and the mixture is stirred uniformly to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 8-15%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a paliperidone osmotic pump controlled release tablet having a specification of 6 mg.
  • the resulting tablets did not form a continuous coating at the conical projections.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than glyceryl behenate are weighed out, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added to the hawthorn. The glyceride is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets. The punch adopts a shallow concave circular punch with a diameter of 8mm.
  • the punch surface has a positive triangular prism with a height of 3mm and a base length of 1.82mm, and the end face of the positive triangular prism has a depth of 1.05mm and the length of the bottom side is
  • the 1.6mm positive triangular pyramidal depression controls the hardness of the tablet to 20-25kg.
  • the prepared core has a positive triangular prismatic drug release channel having a base side length of 1.82 mm and a depth of 3 mm, and the drug-containing layer has a height of 1.05 mm at the bottom end of the drug release channel and a bottom side length of 1.6 mm.
  • Positive triangular pyramidal projections are positive triangular pyramidal projections.
  • Preparation of the coating liquid The polyethylene glycol 400 is dissolved in water to obtain an aqueous solution of polyethylene glycol 400.
  • the ethyl cellulose and the glyceride were dissolved in ethanol, and then a polyethylene glycol 400 aqueous solution was added thereto, and the mixture was stirred to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 3-10%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a paliperidone osmotic pump controlled release tablet having a specification of 6 mg.
  • the resulting tablet did not form a continuous coating at the regular triangular pyramidal projections.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8mm.
  • the punch surface has a cylinder with a height of 2.5mm and a bottom diameter of 2.5mm, and the end face of the cylinder has a depth of 1mm and the length of the bottom side is 2mm.
  • the positive quadrangular pyramid depression controls the hardness of the tablet to 20-25kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 2.5 mm and a depth of 2.5 mm, and the drug-containing layer has a regular square pyramidal protrusion with a height of 1 mm and a bottom side length of 2 mm at the bottom end of the drug delivery channel.
  • Preparation of coating liquid Polyethylene glycol 4000 is dissolved in water to obtain a polyethylene glycol 4000 aqueous solution. The cellulose acetate and the phthalic acid ester were dissolved in acetone, and then an aqueous solution of polyethylene glycol 4000 was added and stirred to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 23-30%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain an oxybutynin osmotic pump controlled release tablet having a specification of 15 mg.
  • the resulting tablet did not form a continuous coating at the regular quadrangular pyramidal projections.
  • the preparation process is as follows:
  • the punch surface has a cylinder with a height of 2.3 mm and a bottom diameter of 1.9 mm, and the end face of the cylinder has a depth of 0.9 mm and the length of the bottom side is 1.2mm positive triangular pyramidal depression, control the hardness of the tablet is 18-23kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 1.9 mm and a depth of 2.3 mm, and the drug-containing layer has a positive triangular pyramid with a height of 0.9 mm and a bottom side length of 1.2 mm at the bottom end of the drug delivery channel. Shaped raised portion.
  • Preparation of coating liquid Polyethylene glycol 4000 is dissolved in water to obtain a polyethylene glycol 4000 aqueous solution.
  • the polyvinyl chloride and the phthalic acid ester were dissolved in acetone, and then an aqueous solution of polyethylene glycol 4000 was added thereto, and the mixture was uniformly stirred to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 10-17%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain an oxybutynin osmotic pump controlled release tablet having a specification of 15 mg.
  • the resulting tablet did not form a continuous coating at the regular triangular pyramidal projections.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8mm.
  • the punch surface has a cylinder with a height of 2.7mm and a bottom diameter of 3mm, and the end face of the cylinder has a depth of 1.2mm and a bottom diameter of 2mm. Conical depression, control the hardness of the tablet is 15-20kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 3 mm and a depth of 2.7 mm, and the drug-containing layer has a conical convex portion having a height of 1.2 mm and a bottom surface diameter of 2 mm at the bottom end of the drug delivery channel. .
  • Preparation of coating liquid Polyethylene glycol 4000 is dissolved in water to obtain a polyethylene glycol 4000 aqueous solution. The cellulose acetate was dissolved in acetone, and then a polyethylene glycol 4000 aqueous solution was added thereto, and the mixture was stirred uniformly. The talc powder was added under stirring, and the mixture was stirred and uniformly dispersed to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 18-25%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a glipizide osmotic pump controlled release tablet having a specification of 10 mg.
  • the resulting tablets did not form a continuous coating at the conical projections.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8mm.
  • the punch surface has a cylinder with a height of 2.85mm and a bottom diameter of 2.12mm, and the end face of the cylinder has a depth of 0.95mm and a diameter of the bottom surface of 1.6.
  • the conical depression of mm controls the hardness of the tablet to be 18-23kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 2.12 mm and a depth of 2.85 mm, and the drug-containing layer has a conical convex shape with a height of 0.95 mm and a bottom surface diameter of 1.6 mm at the bottom end of the drug delivery channel.
  • Preparation of coating liquid Polyethylene glycol 4000 is dissolved in water to obtain a polyethylene glycol 4000 aqueous solution. The cellulose acetate was dissolved in acetone, and then a polyethylene glycol 4000 aqueous solution was added thereto, and the mixture was stirred uniformly. The talc powder was added under stirring, and the mixture was stirred and uniformly dispersed to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 13-20%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a glipizide osmotic pump controlled release tablet having a specification of 10 mg.
  • the resulting tablets did not form a continuous coating at the conical projections.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8mm.
  • the punch surface has a cylinder with a height of 2.25mm and a bottom diameter of 2.5mm, and the end face of the cylinder has a depth of 0.85mm and a diameter of the bottom surface of 1.62.
  • the conical depression of mm controls the hardness of the tablet to 23-28kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 2.5 mm and a depth of 2.25 mm, and the drug-containing layer has a conical convex shape having a height of 0.85 mm and a bottom surface diameter of 1.62 mm at the bottom end of the drug delivery channel.
  • Preparation of coating liquid Polyethylene glycol 600 is dissolved in water to obtain a polyethylene glycol 600 aqueous solution. The cellulose acetate and the benzoic acid ester were dissolved in ethanol, and then an aqueous solution of polyethylene glycol 600 was added thereto, and the mixture was stirred to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 10-17%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled release tablet of nifedipine osmotic pump with a specification of 90 mg.
  • the resulting tablets did not form a continuous coating at the conical projections.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8mm.
  • the punch surface has a cylinder with a height of 2.6mm and a bottom diameter of 2.25mm, and the end face of the cylinder has a depth of 1.1mm and a diameter of the bottom surface of 2mm.
  • the conical depression controls the hardness of the tablet to 20-25kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 2.25 mm and a depth of 2.6 mm, and the drug-containing layer has a conical protrusion having a height of 1.1 mm and a bottom surface diameter of 2 mm at the bottom end of the drug delivery channel. unit.
  • Preparation of coating liquid Polyethylene glycol 4000 is dissolved in water to obtain a polyethylene glycol 4000 aqueous solution. The cellulose acetate and the phthalic acid ester were dissolved in acetone, and then a polyethylene glycol 4000 aqueous solution was added thereto, followed by stirring to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 18-25%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled release tablet of nifedipine osmotic pump with a specification of 90 mg.
  • the resulting tablets did not form a continuous coating at the conical projections.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8 mm.
  • the punch surface has a cylinder with a height of 2.5 mm and a diameter of 1.56 mm, and the end face of the cylinder has a depth of 1.3 mm and a diameter of the bottom surface of 1 mm.
  • the conical depression controls the hardness of the tablet to 20-25kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 1.56 mm and a depth of 2.5 mm, and the drug-containing layer has a conical protrusion having a height of 1.3 mm and a bottom surface diameter of 1 mm at the bottom end of the drug delivery channel. unit.
  • Preparation of coating liquid Polyethylene glycol 600 is dissolved in water to obtain a polyethylene glycol 600 aqueous solution. The cellulose acetate and the benzoic acid ester were dissolved in ethanol, and then an aqueous solution of polyethylene glycol 600 was added thereto, and the mixture was stirred to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 10-17%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled release tablet of nifedipine osmotic pump with a specification of 90 mg.
  • the resulting tablets did not form a continuous coating at the conical projections.
  • Example 10 Preparation of doxazosin mesylate osmotic pump controlled release tablets
  • the preparation process is as follows:
  • the punch surface has a quadrangular prism with a height of 2.9 mm, a bottom surface length of 2.7 mm and a bottom surface width of 2 mm, and the end face of the quadrangular prism has a depth of 1.5 mm.
  • the quadrangular pyramid recess with a bottom surface length of 2 mm and a bottom surface width of 1 mm controls the hardness of the tablet to be 23-28 kg.
  • the prepared core has a quadrangular prismatic drug delivery channel with a bottom surface length of 2.7 mm, a bottom surface width of 2 mm and a depth of 2.9 mm, and the drug-containing layer has a height of 1.5 mm and a bottom surface at the bottom end of the drug delivery channel. It is a quadrangular pyramid-shaped convex portion of 2 mm and a bottom surface width of 1 mm.
  • Preparation of coating liquid Polyethylene glycol 4000 is dissolved in water to obtain a polyethylene glycol 4000 aqueous solution. The cellulose acetate was dissolved in acetone, and then a polyethylene glycol 4000 aqueous solution was added thereto, and the mixture was stirred uniformly. The talc powder was added under stirring, and the mixture was stirred and uniformly dispersed to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 13-20%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled-release tablet of doxazosin mesylate osmotic pump having a specification of 8 mg.
  • the resulting tablet did not form a continuous coating at the quadrangular pyramidal projections.
  • Example 11 Preparation of doxazosin mesylate osmotic pump controlled release tablets
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The different layers of the mixture were placed in separate hoppers of a multi-layer laminator and pressed into tablets.
  • the punch adopts a shallow concave circular punch with a diameter of 8 mm.
  • the punch surface has a cylinder with a height of 2.1 mm and a bottom diameter of 2.15 mm, and the end face of the cylinder has a depth of 1.2 mm and a bottom length of 1.9.
  • the mm-shaped conical depression with a width of 1.5 mm on the bottom surface controls the hardness of the tablet to be 23-28 kg.
  • the prepared core has a cylindrical drug delivery channel having a diameter of 2.15 mm and a depth of 2.1 mm, and the drug-containing layer has a height of 1.2 mm at the bottom end of the drug delivery channel, a bottom surface length of 1.9 mm, and a bottom surface width of 1.5mm quadrangular pyramidal projection.
  • Preparation of coating liquid Polyethylene glycol 4000 is dissolved in water to obtain a polyethylene glycol 4000 aqueous solution. The cellulose acetate was dissolved in acetone, and then a polyethylene glycol 4000 aqueous solution was added thereto, and the mixture was stirred uniformly. The talc powder was added under stirring, and the mixture was stirred and uniformly dispersed to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 18-25%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled release tablet of doxazosin mesylate osmotic pump having a specification of 8 mg.
  • the resulting tablet did not form a continuous coating at the quadrangular pyramidal projections.
  • the preparation process is as follows:
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 5-15%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a glipizide osmotic pump controlled release tablet having a specification of 10 mg.
  • the preparation process is as follows:
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 5-15%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a glipizide osmotic pump controlled release tablet having a specification of 10 mg.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The mixture of different layers was placed in different hoppers of the multi-layer laminator and pressed into tablets. The punch was made of a shallow concave circular punch with a diameter of 8 mm. The surface of the punch was provided with a height of 2.25 mm and a diameter of the bottom surface. For a 2.5 mm cylinder, the control tablet hardness is 23-28 kg. The resulting core has a cylindrical drug delivery channel having a diameter of 2.5 mm and a depth of 2.25 mm, and the drug-containing layer has no projections at the bottom end of the drug delivery channel.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 5-15%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled release tablet of nifedipine osmotic pump with a specification of 90 mg.
  • the preparation process is as follows:
  • Preparation of core According to the prescription of the drug-containing layer and the boosting layer, the materials other than magnesium stearate are weighed, passed through a 30 mesh sieve, placed in a V-mixer, premixed, and then added with hard fat. The magnesium acid is uniformly mixed to obtain a mixture of each layer. The mixture of different layers was placed in different hoppers of the multi-layer laminator and pressed into tablets. The punch was made of a shallow concave circular punch with a diameter of 8 mm. The surface of the punch was provided with a height of 2.25 mm and a diameter of the bottom surface. For a 2.50 mm cone, the control tablet hardness is 23-28 kg. The resulting core has an inverted conical release orifice having a bottom diameter of 2.50 mm and a depth of 2.25 mm.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the control coating weight gain is about 5-15%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled release tablet of nifedipine osmotic pump with a specification of 90 mg.
  • the preparation process is as follows:
  • Preparation of coating liquid Polyethylene glycol 600 is dissolved in water to obtain a polyethylene glycol 600 aqueous solution. The cellulose acetate and the benzoic acid ester were dissolved in ethanol, and then an aqueous solution of polyethylene glycol 600 was added thereto, and the mixture was stirred to obtain a coating liquid.
  • Coating The core is placed in the coating machine, the speed of the coating machine is adjusted to 5-15 rpm, the spraying speed is 150-500 ml/min, the inlet air temperature is 25-50 ° C, and the atomizing pressure is 0.1-0.4 MPa. The sheet temperature is between 15 and 30 ° C, and the controlled coating weight gain is about 10-17%. After coating, it was kept warm at 40 ° C for about 2 h.
  • the above preparation method can obtain a controlled release tablet of nifedipine osmotic pump with a specification of 90 mg.
  • the resulting tablets did not form a continuous coating at the conical projections.
  • the release test was performed using a Tianda Tianyue Dissolver and Agilent HPLC.
  • the release test was performed using a Tianda Tianyue Dissolver and Agilent HPLC.
  • the rotation speed was 50 rpm
  • the water bath temperature was (37.0 ⁇ 0.5) ° C
  • the dissolution medium was 900 mL of pH 6.8 phosphate buffer containing 0.5% sodium dodecyl sulfate (SLS).
  • SLS sodium dodecyl sulfate
  • the sample to be tested was put into the dissolution cup, and 5 mL was sampled at 2h, 4h, 8h, 12h, 16h, 20h, 24h, respectively, filtered with a 0.45 ⁇ m microporous membrane, and 5mL of the dissolution medium at the same temperature was added, and the filtrate was taken for HPLC determination.
  • the cumulative release of oxybutynin at different dissolution times was calculated separately, as shown in Table 2, and the cumulative release profile was plotted as shown in FIG.
  • glipizide osmotic pump controlled release tablets as a control (trade name: XL, specification: 10mg);
  • the release test was performed using a Tianda Tianyue Dissolver and Agilent HPLC.
  • the sample to be tested was put into a dissolution cup, and 5 mL was sampled at 2h, 4h, 6h, 8h, 12h, 16h, 20h, 24h, respectively, and filtered with a 0.45 ⁇ m microporous membrane, and 5 mL of the dissolution medium at the same temperature was added, and the filtrate was taken. Determined by HPLC. The cumulative release of glipizide at different dissolution times was calculated separately, as shown in Table 3, and the cumulative release profile was plotted as shown in FIG.
  • nifedipine osmotic pump controlled release tablets as a control (trade name: XL, specification: 90mg);
  • the release test was performed using a Tianda Tianyue Dissolver and Agilent HPLC.
  • Example 9 The 90 mg-sized nifedipine osmotic pump controlled release tablets prepared in Example 9 were prepared; 6 parallel samples were set for each sample.
  • the release test was performed using a Tianda Tianyue Dissolver and Agilent HPLC.
  • the sample to be tested was put into the dissolution cup, and 5 mL was sampled at 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, respectively, and filtered through a 0.45 ⁇ m microporous membrane, and 5 mL of the dissolution medium at the same temperature was added, and the filtrate was taken for HPLC determination. .
  • the cumulative release of doxazosin at different dissolution times was calculated separately, as shown in Table 6, and the cumulative release profile was plotted as shown in FIG.
  • Example 5 Comparative Examples 1 and 2 were prepared as 10 mg-sized glipizide osmotic pump controlled release tablets; 6 parallel samples were set for each sample.
  • the cumulative release of glipizide at different dissolution times was calculated separately, as shown in Table 7, and the cumulative release profile was plotted as shown in FIG.
  • Table 7 and Figure 10 compared with the glipizide osmotic pump tablets prepared in Comparative Examples 1 and 2, the RSD of the cumulative release in vitro of the glipizide osmotic pump tablets prepared in Example 5 was compared. Small, drug release behavior is more stable.
  • the cumulative release curves were plotted for the six parallel samples of Example 5, Comparative Examples 1 and 2, as shown in Figures 11-13. The results further show that the glipizide osmotic pump tablets prepared in Example 5 have small fluctuations in cumulative release between samples and more stable release behavior. Compared with the glipizide osmotic pump tablets prepared in Examples 1 and 2, the samples were sampled. The cumulative release is highly volatile and the release behavior is very unstable.
  • Example 10 Comparative Examples 3 and 4 prepared 10 mg-size nifedipine osmotic pump controlled release tablets; 6 parallel samples were set for each sample.
  • Example 7 The cumulative release curves were plotted for the six parallel samples of Example 7, Comparative Examples 3 and 4, as shown in Figures 15 and 17-18. The results further show that the nifedipine osmotic pump controlled release tablets prepared in Example 7 have small fluctuations in cumulative release between samples and more stable release behavior. Compared with the controlled release tablets of nifedipine osmotic pump prepared in Examples 3 and 4, The cumulative release between samples fluctuated greatly and the release behavior was very unstable.
  • the 90 mg-sized nifedipine osmotic pump controlled release tablets prepared in Comparative Example 5 were compared; six parallel samples were set for each sample.
  • Example 9 The cumulative release curves were plotted for the six parallel samples of Example 9 and Comparative Example 5, as shown in FIGS. 16 and 19. The results further show that the nifedipine osmotic pump controlled release tablets prepared in Example 9 have small fluctuations in cumulative release between samples and more stable release behavior. The nifedipine osmotic pump controlled release tablets prepared in Example 5 were sampled. The cumulative release is highly volatile and the release behavior is very unstable.
  • the osmotic pump controlled release preparation of the present disclosure has a stable release behavior, and the osmotic pump controlled release preparation of the present disclosure forms a special release channel during the tablet core pressing process, hindering the coating liquid during the coating process.
  • the continuous coating film is formed at the bottom of the drug release channel, so that the preparation method can be applied to various preparation coating equipments, and a wider range of process parameter conditions, increasing production efficiency and practicality of the method, and ensuring stable products. Drug release behavior.

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Abstract

渗透泵控释片剂，包括片芯和包衣膜，包衣膜包覆在片芯的外表面上，片剂具有至少一个释药孔道，释药孔道连通片芯至片剂外表面，释药孔道的底端处具有凸起部。用于制备渗透泵控释片剂的压片机，压片机的冲头内表面带有突起物，突起物用于形成所述片剂的释药孔道，突起物的端面具有凹陷部。

Description

渗透泵控释制剂
相关申请的引用
本公开要求2017年7月25日向中华人民共和国国家知识产权局提交的申请号为201710609061.1、发明名称为“一种利用原位制孔技术制备的渗透泵控释制剂”的中国专利申请的全部权益，以及2017年7月25日向中华人民共和国国家知识产权局提交的申请号为201720902800.1、实用新型名称为“一种利用原位制孔技术制备的渗透泵控释制剂”的中国专利申请的全部权益，并将两件申请以援引的方式全部并入本公开中。
领域
本公开大体上涉及药物制剂领域。更具体地，本公开涉及控释制剂。
背景
渗透泵控释制剂作为缓控释制剂的典型代表，是以包衣膜内外的渗透压差作为释药动力的一种释药***。
概述
一方面，本公开涉及渗透泵控释片剂，其包括片芯和包衣膜，所述包衣膜包覆在所述片芯的外表面上，其中所述片剂具有至少一个释药孔道，所述释药孔道连通所述片芯至所述片剂外表面，所述释药孔道的底端处具有凸起部。
另一方面，本公开涉及用于制备渗透泵控释片剂的压片机，所述压片机的冲头内表面带有突起物，所述形突起物用于形成所述片剂的释药孔道，所述突起的端面具有凹陷部。
再一方面，本公开涉及制备渗透泵控释片剂的方法，其包括：
(1)压制片芯，并在压制的过程中形成通道，从而得到具有至少一个释药孔道的片芯；以及
(2)对所述片芯进行包衣，从而得到所述渗透泵控释片剂。
又一方面，本公开涉及改善药物在个体内释放的方法，其包括对需要所述方法的个体给予渗透泵控释片剂，其中所述渗透泵控释片剂包括片芯和包衣膜，所述包衣膜包覆在所述片芯的外表面上，其中所述片剂具有至少一个释药孔道，所述释药孔道连通所述片芯至所述片剂外表面，所述释药孔道的底端处具有凸起部。
附图简要说明
图1为本公开的一实施方案中渗透泵控释制剂结构和释药孔道结构的示意图。
图2为本公开的一实施方案中渗透泵控释片的纵切面的示意图，其中仅示出了释药孔道的结构。
图3为本公开的另一实施方案中渗透泵控释片的纵切面的示意图，其中仅示出了释药孔道的结构。
图4为本公开的又一实施方案中渗透泵控释片的纵切面的示意图，其中仅示出了释药孔道的结构。
图5为本公开中帕利哌酮渗透泵控释片和
Figure PCTCN2018096611-appb-000001
释放曲线对比图。
图6为本公开中盐酸奥昔布宁渗透泵控释片和
Figure PCTCN2018096611-appb-000002
XL释放曲线对比图。
图7为本公开中格列吡嗪渗透泵控释片和
Figure PCTCN2018096611-appb-000003
XL释放曲线对比图。
图8为本公开中硝苯地平渗透泵控释片和
Figure PCTCN2018096611-appb-000004
XL释放曲线对比图。
图9为本公开中甲磺酸多沙唑嗪渗透泵控释片和
Figure PCTCN2018096611-appb-000005
XL释放曲线对比图。
图10为不同方法制备的格列吡嗪渗透泵片释放行为对比图。
图11为本公开的实施例5中格列吡嗪渗透泵控释片6个平行样品释放曲线。
图12为本公开的对比实施例1中格列吡嗪渗透泵控释片6个平行 样品释放曲线。
图13为本公开的对比实施例2制备的格列吡嗪渗透泵控释片6个平行样品释放曲线。
图14为本公开的不同方法制备的硝苯地平渗透泵片释放行为对比图。
图15为本公开的实施例7制备的硝苯地平渗透泵控释片6个平行样品释放曲线。
图16为本公开的实施例9中硝苯地平渗透泵控释片6个平行样品释放曲线。
图17为本公开的对比实施例3制备的硝苯地平渗透泵控释片6个平行样品释放曲线。
图18为本公开的对比实施例4制备的硝苯地平渗透泵控释片6个平行样品释放曲线。
图19为本公开的对比实施例5制备的硝苯地平渗透泵控释片6个平行样品释放曲线。
详述
在以下的说明中，包括某些具体的细节以对各个公开的实施方案提供全面的理解。然而，相关领域的技术人员会认识到，不采用一个或多个这些具体的细节，而采用其他方法、部件、材料等的情况下仍实现实施方案。
除非本公开中另有要求，在整个说明书和所附的权利要求书中，词语“包括”、“包含”、“含有”和“具有”应解释为开放式的、含括式的意义，即“包括但不限于”。
在整个说明书中提到的“一实施方案”、“实施方案”、“在另一实施方案中”或“在某些实施方案中”意指在至少一实施方案中包括与该实施方案所述的相关的具体参考要素、结构或特征。因此，在整个说明书中不同位置出现的短语“在一实施方案中”或“在实施方案中”或“在另一实施方案中”或“在某些实施方案中”不必全部指同一实施方案。此外，具体要素、结构或特征可以任何适当的方式在一个或多个实施方 案中结合。
定义
在本公开中，术语“凸起部的最大横向长度”系指释药孔道中的凸起部所具有的最大径向尺寸。
在本公开中，术语“释药孔道横截面的最大横向长度”系指在压制片芯的过程中，在片芯中形成的孔道所具有的最大径向尺寸。
在本公开中，术语“释药孔道的深度”系指在压制片芯的过程中，在片芯中形成的孔道的开口至底部的距离。
在本公开中，术语“药物可接受的盐”包括“可以接受的酸加合盐”和“可以接受的碱加合盐”。
在本公开中，术语“可以接受的酸加合盐”系指保持游离碱的生物学有效性和性质的那些盐，所述酸加合盐是在生物学或其它方面合适的并且是使用无机酸或有机酸来形成的，所述无机酸例如但不限于盐酸、氢溴酸、硫酸、硝酸、磷酸等，所述有机酸例如但不限于乙酸、2,2-二氯乙酸、己二酸、褐藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯羧酸、4-乙酰胺基苯羧酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙烷磺酸、2-羟基乙烷磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、乙醇酸、马尿酸、异丁酸、乳酸、乳糖醛酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲烷磺酸、黏酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、丁二酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一碳烯酸等。
在本公开中，术语“可以接受的碱加合盐”系指保持游离酸的生物学有效性和性质的那些盐，所述碱加合盐是在生物学或其它方面合适的。向游离酸中加入无机碱或有机碱来制备这些盐。由无机碱衍生的盐包括但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。 在某些实施方案中，无机盐为铵、钠、钾、钙及镁盐。由有机碱衍生的盐包括但不限于伯、仲和叔胺的盐、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂的盐，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、苄胺、苯乙二胺、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、三乙醇胺、氨基丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。在某些实施方案中，有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
在本公开中，术语“药物活性成分”系指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
在本公开中，术语“药物可接受的辅料”系指制药领域可使用，对产品或者对哺乳动物无害，或具有合理的或可接受的利益/风险比的辅料。药物可接受的辅料包括但不限于：a)填充剂/稀释剂，例如淀粉、可压性淀粉、糖粉、糊精、乳糖、微晶纤维素、无机盐、糖醇类等；b)湿润剂/粘合剂，例如水、乙醇、淀粉浆、糊精、糖粉与糖浆、胶浆、聚乙二醇4000、纤维素衍生物、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟甲基纤维素钠、乙基纤维素等；c)崩解剂，例如干淀粉、羟甲基淀粉钠、低取代基羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、泡腾崩解剂等；d)表面活性剂，例如***胶、西黄蓍胶、明胶、单硬脂酸丙二酯、单硬脂酸甘油酯、二硬脂酸乙二酯、单油酸二甘油酯、十二烷基硫酸钠、司盘20、司盘40、司盘60、司盘65、司盘80、司盘83、司盘85、油酸钾、油酸钠、油酸三乙醇胺、卵磷脂、蔗糖酯、泊洛沙姆188、阿特拉斯G-263、吐温20、吐温21、吐温40、吐温60、吐温61、吐温65、吐温80、吐温81、吐温85、卖泽45、卖泽49、卖泽51、卖泽52、聚氧乙烯400单月桂酸酯、聚氧乙烯400单硬脂酸酯、聚氧乙烯400单油酸酯、苄泽35、苄泽30、聚西托醇、聚氧乙烯氢化蓖麻油、聚氧乙烯烷基酚、聚氧乙烯壬烷基酚醚等；e)润滑剂，例如硬脂酸镁、硬脂酸、山嵛酸甘油酯、微粉硅胶、滑石粉、氢化植物油、聚乙二醇、月桂醇硫酸镁等；f)着 色剂，例如苋菜红、胭脂红、新红、氧化铁红、柠檬黄、日落黄、靛蓝、亮蓝、甜菜红、紫胶红、越桔红、辣椒红、红米红等；g)矫味剂，例如甜味剂、芳香剂、胶浆剂、泡腾剂等；h)抗氧剂或防腐剂，例如叔丁基羟基茴香醚、二丁基羟基甲苯等；i)促渗透聚合物，例如聚氧乙烯、聚乙烯吡咯烷酮、聚丙烯酸、羟丙甲纤维素、聚羟基甲基丙烯酸烷烃酯类等；以及j)促渗透剂，例如氯化钠、氯化镁、硫酸镁、硫酸钠、硫酸钾、酒石酸、乳糖、甘露醇、尿素等。
在本公开中，术语“包衣增重”系指包衣膜的重量与包衣前片芯的重量之比。
在本公开中，术语“含药层”系指渗透泵片中含有药物活性成分的片芯层。在含水环境下，水分在渗透压差的作用下进入含药层，形成药物活性成分溶液或混悬液，使之可从释药孔道中释放。
在本公开中，术语“阻滞层”系指渗透泵片中不含有药物活性成分的片芯层。通过调节阻滞层的组成，及与其他片芯层的比例，可调节药物活性成分的释放。
在本公开中，术语“推动层”系指渗透泵片中的含有促渗活性物质的、可溶胀的片芯层。在含水环境中，推动层吸水膨胀，推动含药层中的药物活性成分溶液或混悬液从释药孔道中释放。
在本公开中，术语“原位致孔技术”系指在片剂包衣前，压片的同时形成释药孔道，再涂覆半渗透膜形成渗透泵片剂的技术。
具体实施方式
一方面，本公开涉及渗透泵控释片剂，其包括片芯和包衣膜，所述包衣膜包覆在所述片芯的外表面上，其中所述片剂具有至少一个释药孔道，所述释药孔道连通所述片芯至所述片剂外表面，所述释药孔道的底端处具有凸起部。
在某些实施方案中，凸起部的底面积不大于释药孔道的横截面。
在某些实施方案中，凸起部具有约0.5-3.0mm的高度。
在某些实施方案中，凸起部具有约0.6-2.0mm的高度。
在某些实施方案中，凸起部具有约0.7-1.5mm的高度。
在某些实施方案中，凸起部具有约0.5-2.9mm的最大横向长度。
在某些实施方案中，凸起部具有约0.7-2.5mm的最大横向长度。
在某些实施方案中，凸起部具有约1.0-2.0mm的最大横向长度。
在某些实施方案中，凸起部可以有多种形式，只要其能够在包衣过程中阻止包衣液在释药孔道底端形成连续的包衣膜均在本公开的保护之列。
在某些实施方案中，释药孔道的底端处具有一个凸起部。由于该凸起部的存在，阻碍了包衣液在释药孔道中形成连续的包衣膜，使渗透泵控释制剂具有可预期的、稳定的释药行为。
在某些实施方案中，能够用于本公开的凸起部的示例性实例包括但不限于球缺形、圆柱形、圆锥形、棱柱形、棱锥形和其他规则或不规则形状的凸起。
在某些实施方案中，能够用于本公开的棱锥形凸起部的示例性实例包括但不限于三棱锥、四棱锥和五棱锥。
在某些实施方案中，释药孔道的底端处具有多个凸起部。
在某些实施方案中，释药孔道的底端处的多个凸起部为一排或多排的。
在某些实施方案中，释药孔道的底端处的多个凸起部为连续或不连续分布的。
在某些实施方案中，释药孔道的底端处的多个凸起部为规律或不规律分布的。
在某些实施方案中，释药孔道的底端处的多个凸起部为高度相同的。
在某些实施方案中，释药孔道的底端处的多个凸起部为高度不同的。
在某些实施方案中，能够用于本公开的凸起部的示例性实例包括但不限于锯齿样和钉板样凸起部。
在某些实施方案中，由于渗透泵控释片剂释药孔道中凸起部的存在，使该制备方法可适用于多种制剂包衣设备，如流化床和包衣机，及范围更宽的工艺参数条件，大大增加了生产效率和方法的实用性。
在某些实施方案中，凸起部的高度不小于释药孔道横截面的最大横向长度的约50％。
在某些实施方案中，凸起部的高度最高不超过包衣膜外表面。
在某些实施方案中，能够用于本公开的释药孔道横截面的示例性实例包括但不限于圆形、正方形、长方形、三角形和其他形状。
在某些实施方案中，释药孔道横截面的最大横向长度约为0.5-3.0mm。
在某些实施方案中，释药孔道横截面的最大横向长度约为1.00-3.00mm。
在某些实施方案中，释药孔道横截面的最大横向长度约为1.40-2.50mm。
在某些实施方案中，释药孔道横截面的最大横向长度约为1.70-2.20mm。
在某些实施方案中，释药孔道横截面的最大横向长度约为1.95mm。
在某些实施方案中，释药孔道的深度大于等于1mm，并且释药孔道的深度以不穿透制剂为限。
在某些实施方案中，释药孔道的深度约为1.00-3.00mm。
在某些实施方案中，释药孔道的深度约为2.05-2.95mm。
在某些实施方案中，释药孔道的深度约为2.25-2.75mm。
在某些实施方案中，释药孔道的深度约为2.50mm。
在某些实施方案中，片芯包括含药层。
在某些实施方案中，片芯还包括助推层，以及任选地阻滞层。
在某些实施方案中，片芯为单层或多层。
在某些实施方案中，片芯为包括阻滞层、含药层和助推层的三层结构。
在某些实施方案中，片芯为包括含药层和助推层的两层结构。
在某些实施方案中，含药层包含药物活性成分、促渗透聚合物以及任选地其它药物可接受的辅料。
在某些实施方案中，含药层还包含抗氧化剂。
在某些实施方案中，能够用于本公开的抗氧化剂的示例性实例包括但不限于叔丁基羟基茴香醚(BHA)和二丁基羟基甲苯(BHT)。
在某些实施方案中，含药层还包含促渗透剂。
在某些实施方案中，助推层包含促渗透聚合物、促渗透剂以及任选地其它药物可接受的辅料。
在某些实施方案中，助推层还包含着色剂。
在某些实施方案中，能够用于本公开的着色剂的示例性实例包括但不限于氧化铁红、氧化铁黄、氧化铁黑、氧化铁棕、氧化铁紫和其他药物可接受的着色剂及其混合物。
在某些实施方案中，阻滞层包含促渗透聚合物、促渗透剂以及任选地其它药物可接受的辅料。
在某些实施方案中，能够用于本申请的促渗透聚合物包括但不限于聚氧乙烯、聚乙烯吡咯烷酮、聚丙烯酸、羟丙甲纤维素、聚羟基甲基丙烯酸烷烃酯类及其混合物。
在某些实施方案中，能够用于本公开的聚氧乙烯的示例性实例包括但不限于PEO-N80和PEO-WSR301。
在某些实施方案中，能够用于本申请的促渗透聚合物为聚氧乙烯和羟丙甲纤维素的混合物。
在某些实施方案中，能够用于本公开的促渗透剂的示例性实例包括但不限于氯化钠、氯化镁、硫酸镁、硫酸钠、硫酸钾、酒石酸、乳糖、甘露醇、尿素及其混合物。
在某些实施方案中，片剂还包含润滑剂。
在某些实施方案中，能够用于本公开的润滑剂的示例性实例包括但不限于硬脂酸镁、硬脂酸、山嵛酸甘油酯及其混合物。
在某些实施方案中，包衣膜包含半透膜材料。
在某些实施方案中，包衣膜还包含致孔剂、增塑剂、抗粘剂和/或其它药物可接受的辅料。
在某些实施方案中，能够用于本公开的半透膜材料的示例性实例包括但不限于醋酸纤维素、醋酸纤维素水分散体、乙基纤维素、聚氯乙烯、聚碳酸酯、乙烯醇-乙烯基乙酸酯、乙烯-丙烯聚合物及其混合 物。
在某些实施方案中，能够用于本公开的致孔剂的示例性实例包括但不限于丙三醇、山梨醇、聚乙二醇400、聚乙二醇600、聚乙二醇1000、聚乙二醇1500、聚乙二醇4000、羟丙甲纤维素、聚乙烯醇及其混合物。
在某些实施方案中，能够用于本公开的增塑剂的示例性实例包括但不限于邻苯二甲酸酯、甘油酯、琥珀酸酯、苯甲酸酯、磷酸酯、己二酸酯、酒石酸酯及其混合物。
在某些实施方案中，能够用于本公开的抗粘剂的示例性实例包括但不限于滑石粉、微粉硅胶、单硬脂酸甘油酯、硬脂酸镁、二氧化钛及其混合物。
在某些实施方案中，能够用于本公开的药物活性成分的示例性实例包括但不限于抗高血压药、降血脂药、口服抗糖尿病药、非甾体抗炎药、β受体拮抗剂、钙离子通道阻滞剂、5-羟色胺再摄取抑制剂、抗精神病药和抗菌药。
在某些实施方案中，能够用于本公开的抗高血压药的示例性实例包括但不限于交感神经药物，例如利血平、地舍平、美索舍平、美卡拉明和潘必定；血管扩张药物，例如肼屈嗪、双肼屈嗪、托屈嗪、布屈嗪、米诺地尔、吡那地尔和硝普钠；影响肾素-血管紧张素-醛固酮***药物，例如依那克仑、雷米克仑、阿利克仑、替普罗肽、卡托普利、马来酸依那普利和氯沙坦；以及钙离子通道阻滞剂，例如硝苯地平、盐酸尼卡地平、尼群地平、非洛地平、依拉地平、苯磺酸氨氯地平、西尼地平、拉西地平、氯维地平、地尔硫卓、盐酸维拉帕米和苄普地尔。
在某些实施方案中，能够用于本公开的降血脂药的示例性实例包括但不限于烟酸、阿西莫司、烟酸肌醇酯、氯贝特、洛伐他汀、普伐他汀、执伐他汀、阿伐他汀、普罗布考、考来烯胺、考来替泊、地维烯胺、非诺贝特、泛硫乙胺、亚油酸和Omega-3脂肪酸。
在某些实施方案中，能够用于本公开的口服抗糖尿病药的示例性实例包括但不限于胰岛素及其类似物，例如普通胰岛素、门冬胰岛素、 赖脯胰岛素和甘精胰岛素；胰岛素分泌促进剂，例如氨磺丁脲、甲苯磺丁脲、格列吡嗪、格列美脲和瑞格列奈；胰岛素增敏剂，例如盐酸二甲双胍；α-葡萄糖苷酶抑制剂，例如伏格列波糖和米格列醇；二肽基肽酶-4-抑制剂，例如磷酸西格列汀。
在某些实施方案中，能够用于本公开的非甾体抗炎药的示例性实例包括但不限于吲哚美辛、双氯芬酸钠、布洛芬、萘普生、吡咯昔康、美洛昔康、塞来昔布和艾瑞昔布。
在某些实施方案中，能够用于本公开的β受体拮抗剂的示例性实例包括但不限于***、吲哚洛尔、噻吗洛尔、美托洛尔、阿替洛尔、倍他洛尔、比索洛尔、拉贝洛尔、卡维洛尔和阿尔马尔。
在某些实施方案中，能够用于本公开的钙离子通道阻滞剂的示例性实例包括但不限于硝苯地平、盐酸尼卡地平、尼群地平、非洛地平、依拉地平、苯磺酸氨氯地平、西尼地平、拉西地平、氯维地平、地尔硫卓、盐酸维拉帕米和苄普地尔。
在某些实施方案中，能够用于本公开的5-羟色胺再摄取抑制剂的示例性实例包括但不限于氟西汀、舍曲林、帕罗西汀、西酞普兰和氟伏沙明。
在某些实施方案中，能够用于本公开的抗精神病药的示例性实例包括但不限于盐酸氯丙嗪、奋乃静、癸氟奋乃静、氯普噻吨、费哌啶醇和舒必利。
在某些实施方案中，能够用于本公开的抗菌药的示例性实例包括但不限于合成抗菌药，例如磺胺甲噁唑、甲氧苄啶、诺氟沙星、环丙沙星、左氧氟沙星和利奈唑胺；以及抗生素药，例如青霉素、头孢菌素C、克拉维酸和舒巴坦。
在某些实施方案中，能够用于本公开的药物活性成分的示例性实例包括但不限于盐酸哌唑嗪、盐酸苯丙醇胺、甲磺酸多沙唑嗪、盐酸维拉帕米、盐酸奥昔布宁、伊拉地平、帕利哌酮、马来酸氯苯那敏、格列吡嗪、硝苯地平、盐酸伪麻黄碱、硫酸伪麻黄碱、硫酸铝、卡马西平、醋酸亮丙瑞林、枸橼酸舒芬太尼和盐酸哌甲酯。
在某些实施方案中，药物活性成分选自甲磺酸多沙唑嗪、帕利哌 酮、硝苯地平、盐酸奥昔布宁和格列吡嗪。
除上述所列举的活性药物之外，本公开所披露的制剂技术显然也可用于其他的活性药物成分，通过本领域的常规方法调整优化，使渗透泵制剂达到与本公开实施例中相同或相似的效果，即药物稳定释放。
在某些实施方案中，渗透泵控释片剂直径约为5-15mm。
在某些实施方案中，渗透泵控释片剂直径约为8mm。
在某些实施方案中，渗透泵控释片剂直径约为9mm。
在某些实施方案中，渗透泵控释片剂直径约为10mm。
在某些实施方案中，渗透泵控释片剂直径约为11mm。
在某些实施方案中，渗透泵控释片剂直径约为12mm。
在某些实施方案中，渗透泵控释片剂的硬度约为15-30Kg。
在某些实施方案中，渗透泵控释片剂的硬度约为15-20Kg。
在某些实施方案中，渗透泵控释片剂的硬度约为18-23Kg。
在某些实施方案中，渗透泵控释片剂的硬度约为20-25Kg。
在某些实施方案中，渗透泵控释片剂的硬度约为23-28Kg。
在某些实施方案中，本公开提供的原位致孔法制备的渗透泵控释片剂，可在简化生产工艺，提高生产效率的同时，保证产品稳定的释药行为。
另一方面，本公开涉及用于制备渗透泵控释片剂的压片机，所述压片机的冲头内表面带有突起物，所述突起物用于形成所述片剂的释药孔道，所述突起物的端面具有凹陷部。
在某些实施方案中，压片机的冲头内表面带有圆柱形或棱柱形突起物。
在某些实施方案中，压片机的上冲头内表面带有圆柱形或棱柱形突起物。
在某些实施方案中，能够用于本公开的棱柱形的示例性实例包括但不限于三棱柱形、四棱柱形和五棱柱形。
在某些实施方案中，能够用于本公开的凹陷部的示例性实例包括但不限于球缺形、圆柱形、圆锥形、棱柱形、棱锥形和其他形状的凹陷。
在某些实施方案中，圆柱形或棱柱形突起物的高度可调。
再一方面，本公开涉及制备渗透泵控释片剂的方法，其包括：
(1)压制片芯，并在压制的过程中形成通道，从而得到具有至少一个释药孔道的片芯；以及
(2)对所述片芯进行包衣，从而得到所述渗透泵控释片剂。
在某些实施方案中，包衣增重约为1-30％。
在某些实施方案中，包衣增重约为3-10％。
在某些实施方案中，包衣增重约为8-15％。
在某些实施方案中，包衣增重约为10-17％。
在某些实施方案中，包衣增重约为13-20％。
在某些实施方案中，包衣增重约为18-25％。
在某些实施方案中，包衣增重约为23-30％。
在某些实施方案中，在压制片芯之前还包括：
分别混合片芯各层中除润滑剂外的其余各组分，最后向各层中加入润滑剂，混合均匀。
在某些实施方案中，使用包衣液对所述片芯进行包衣。
在某些实施方案中，包衣液的配制包括以下步骤：
1)将包衣膜中的半透膜材料和增塑剂溶于有机溶剂中，制得有机溶液；
2)将致孔剂溶于水中，制得水溶液；以及
3)将水溶液加入有机溶液中，搅拌，如果有，再加入抗粘剂，搅拌，制得所述包衣液。
在某些实施方案中，能够用于本公开的有机溶剂的示例性实例包括但不限于甲醇、乙醇、异丙醇、二氯甲烷、丙酮、上述有机溶剂的水溶液及其混合物。
在某些实施方案中，能够用于本公开的有机溶剂的水溶液的示例性实例包括但不限于乙醇水溶液、甲醇水溶液、异丙醇水溶液及其混合物。
在某些实施方案中，本公开的渗透泵控释制剂可为单室或多室。
在某些实施方案中，本公开的渗透泵控释制剂为二室。
在某些实施方案中，本公开的渗透泵控释制剂为三室。
在某些实施方案中，本领域技术人员可以根据公知教导选择合适的渗透泵控释制剂结构类型。
影响渗透泵控释制剂药物释放速率的因素主要包括衣膜厚度、衣膜通透系数、包衣膜内外的渗透压差和药物溶解度4个参数，释药孔大小也对药物释放有一定影响。衣膜厚度直接影响水分渗入片芯的速度，进而影响膜内药物溶解，高分子材料溶胀；衣膜厚度要能承受膜内促渗剂产生的高渗透压，保证衣膜不变形、不破裂，进而保证释药的安全稳定。衣膜材料、包衣液处方组成、包衣膜制备工艺直接影响衣膜通透系数，可通过向衣膜处方中加入水溶性增塑剂或致孔剂来增大衣膜对水分的通透性。根据药物分子的性质选择合适的处方组成属于本领域公知常识。
除上述所列举的活性药物之外，本公开所披露的制剂技术显然也可用于其他的活性药物成分，通过本领域的常规方法调整优化，使渗透泵制剂达到与本公开实施例中相同或相似的效果，即药物稳定释放。
在某些实施方案中，进行合适的体外或体内测定来确定本公开渗透泵控释制剂的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常，足以实现预防或治疗效果的本公开渗透泵控释制剂的有效量为约0.001mg/kg体重/天至约10,000mg/kg体重/天。合适的情况下，剂量为约0.01mg/kg体重/天至约1000mg/kg体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg宿主体重，更通常为0.1至500mg/kg宿主体重。示例性的治疗方案为每两天一次或每周一次或每月一次给药。通常多次给予所述制剂，单次剂量之间的间隔可以是每天、每周、每月或每年。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。
采用现有的原位致孔技术，在包衣机上无法得到预期的理想结果，所得渗透泵制剂释药行为极其不稳定。本公开的发明人认为可能是流化床与包衣机的固液相对运动状态不一样所致，流化床中的喷雾与固体核芯同向运动，而包衣机中的喷雾垂直喷洒在固体核芯上，后者增加了喷雾与固体核芯的接触面积和喷雾的冲击力度，故使包衣液渗入释药孔道形成连续或不规律的包衣膜。即使流化床可制备出符合预期的渗透泵控释制剂，但流化床中的物料运动原理为压缩空气从物料下部吹入，物料完全借助风力成流化状态，这对有相当质量和密度的物料，如片剂，在大规模的生产中是难以实现的。
本公开的发明人经过大量探索性试验，发现一种新的原位致孔制备渗透泵控释制剂的方法，该制备方法在压制制剂核芯过程中形成特殊释药孔道，该释药孔道连通片芯内部至片剂外表面，且片芯内部在释药孔道底端具有凸起部，该凸起部使包衣液在包衣过程中无法在释药孔道中形成连续的包衣膜，可在提高生产效率的同时，保证产品有正常、稳定的释药行为。
又一方面，本公开涉及改善药物在个体内释放的方法，其包括对需要所述方法的个体给予渗透泵控释片剂，其中所述渗透泵控释片剂包括片芯和包衣膜，所述包衣膜包覆在所述片芯的外表面上，其中所述片剂具有至少一个释药孔道，所述释药孔道连通所述片芯至所述片剂外表面，所述释药孔道的底端处具有凸起部。
在某些实施方案中，每天2次给予渗透泵控释片剂。
在某些实施方案中，每天1次给予渗透泵控释片剂。
在某些实施方案中，每2天1次给予渗透泵控释片剂。
下面将结合实施例对本公开的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本公开，而不应视为限定本公开的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
实施例
实施例1：帕利哌酮渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000006
(2)半透膜
Figure PCTCN2018096611-appb-000007
制备过程如下：
1)制备片芯：分别按照阻滞层、含药层、助推层的处方量，称取除硬脂酸以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个突起物，所述突起物为2mm高、底面边长为2mm的正四棱柱，且正四棱柱的端面带有0.7mm深、底 面直径为1mm的圆锥形凹陷，控制压片硬度为23-28kg。
制成的片芯带有一个底面边长为2mm、深2mm的正四棱柱形释药孔道，且含药层在释药孔道的底端处具有一高0.7mm、底面直径为1mm的圆锥形凸起部。
2)包半透膜：
a.包衣液的配制：聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将醋酸纤维素和邻苯二甲酸酯溶于丙酮中，再加入聚乙二醇4000水溶液，搅拌均匀，得包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在8-15％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为6mg的帕利哌酮渗透泵控释片。制得的片剂在所述圆锥形凸起处没有形成连续的包衣。
实施例2：帕利哌酮渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000008
(2)半透膜
Figure PCTCN2018096611-appb-000009
Figure PCTCN2018096611-appb-000010
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除山嵛酸甘油酯以外的物料，过30目筛，置于V型混合机中预混后，再加山嵛酸甘油酯，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个3mm高、底面边长为1.82mm的正三棱柱，且正三棱柱的端面带有1.05mm深、底面边长为1.6mm的正三棱锥形凹陷，控制压片硬度为20-25kg。
制成的片芯带有一个底面边长为1.82mm、深3mm的正三棱柱形释药孔道，且含药层在释药孔道的底端处具有一高1.05mm、底面边长为1.6mm的正三棱锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇400溶于水中，得聚乙二醇400水溶液。将乙基纤维素和甘油酯溶于乙醇中，再加入聚乙二醇400水溶液，搅拌均匀，得包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在3-10％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为6mg的帕利哌酮渗透泵控释片。制得的片剂在所述正三棱锥形凸起处没有形成连续的包衣。
实施例3：盐酸奥昔布宁渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000011
Figure PCTCN2018096611-appb-000012
(2)半透膜
Figure PCTCN2018096611-appb-000013
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.5mm高、底面直径为2.5mm的圆柱体，且圆柱体的端面带有1mm深、底面边长为2mm的正四棱锥形凹陷，控制压片硬度为20-25kg。
制成的片芯带有一个直径为2.5mm、深2.5mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高1mm、底面边长为2mm的正四棱锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将醋酸纤维素和邻苯二甲酸酯溶于丙酮中，再加入聚乙二醇 4000水溶液，搅拌均匀，得包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在23-30％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为15mg的奥昔布宁渗透泵控释片。制得的片剂在所述正四棱锥形凸起处没有形成连续的包衣。
实施例4：盐酸奥昔布宁渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000014
(2)半透膜
Figure PCTCN2018096611-appb-000015
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸 镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.3mm高、底面直径为1.9mm的圆柱体，且圆柱体的端面带有0.9mm深、底面边长为1.2mm的正三棱锥形凹陷，控制压片硬度为18-23kg。
制成的片芯带有一个直径为1.9mm、深2.3mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高0.9mm、底面边长为1.2mm的正三棱锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将聚氯乙烯和邻苯二甲酸酯溶于丙酮中，再加入聚乙二醇4000水溶液，搅拌均匀，得包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在10-17％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为15mg的奥昔布宁渗透泵控释片。制得的片剂在所述正三棱锥形凸起处没有形成连续的包衣。
实施例5：格列吡嗪渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000016
Figure PCTCN2018096611-appb-000017
(2)半透膜
Figure PCTCN2018096611-appb-000018
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.7mm高、底面直径为3mm的圆柱体，且圆柱体的端面带有1.2mm深、底面直径为2mm的圆锥形凹陷，控制压片硬度为15-20kg。
制成的片芯带有一个直径为3mm、深2.7mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高1.2mm、底面直径为2mm的圆锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将醋酸纤维素溶于丙酮中，再加入聚乙二醇4000水溶液，搅拌均匀，搅拌下加入滑石粉，搅拌使之分散均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在18-25％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为10mg的格列吡嗪渗透泵控释片。制得的片剂在所述圆锥形凸起处没有形成连续的包衣。
实施例6：格列吡嗪渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000019
(2)半透膜
Figure PCTCN2018096611-appb-000020
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.85mm高、底面直径为2.12mm的圆柱体，且圆柱体的端面带有0.95mm深、底面直径为1.6mm的圆锥形凹陷，控制压片硬度为18-23kg。
制成的片芯带有一个直径为2.12mm、深2.85mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高0.95mm、底面直径为1.6mm的圆锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将醋酸纤维素溶于丙酮中，再加入聚乙二醇4000水溶液，搅拌均匀，搅拌下加入滑石粉，搅拌使之分散均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在13-20％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为10mg的格列吡嗪渗透泵控释片。制得的片剂在所述圆锥形凸起处没有形成连续的包衣。
实施例7：硝苯地平渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000021
(2)半透膜
Figure PCTCN2018096611-appb-000022
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.25mm高、底面直径为2.5mm的圆柱体，且圆柱体的端面带有0.85mm深、底面直径为1.62mm的圆锥形凹陷，控制压片硬度为23-28kg。
制成的片芯带有一个直径为2.5mm、深2.25mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高0.85mm、底面直径为1.62mm的圆锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇600溶于水中，得聚乙二醇600水溶液。将醋酸纤维素和苯甲酸酯溶于乙醇中，再加入聚乙二醇600水溶液，搅拌均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在10-17％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为90mg的硝苯地平渗透泵控释片。制得的片剂在所述圆锥形凸起处没有形成连续的包衣。
实施例8：硝苯地平渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000023
Figure PCTCN2018096611-appb-000024
(2)半透膜
Figure PCTCN2018096611-appb-000025
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.6mm高、底面直径为2.25mm的圆柱体，且圆柱体的端面带有1.1mm深、底面直径为2mm的圆锥形凹陷，控制压片硬度为20-25kg。
制成的片芯带有一个直径为2.25mm、深2.6mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高1.1mm、底面直径为2mm的圆锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将醋酸纤维素和邻苯二甲酸酯溶于丙酮中，再加入聚乙二醇4000水溶液，搅拌均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在18-25％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为90mg的硝苯地平渗透泵控释片。制得的片剂在所述圆锥形凸起处没有形成连续的包衣。
实施例9：硝苯地平渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000026
(2)半透膜
Figure PCTCN2018096611-appb-000027
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.5mm高、底面直径为1.56mm的圆柱体，且圆柱体的端面带有1.3mm深、底面直径为1mm的圆锥形凹陷，控制压片硬度为20-25kg。
制成的片芯带有一个直径为1.56mm、深2.5mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高1.3mm、底面直径为1mm的圆锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇600溶于水中，得聚乙二醇600水溶液。将醋酸纤维素和苯甲酸酯溶于乙醇中，再加入聚乙二醇600水溶液，搅拌均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在10-17％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为90mg的硝苯地平渗透泵控释片。制得的片剂在所述圆锥形凸起处没有形成连续的包衣。
实施例10：甲磺酸多沙唑嗪渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000028
(2)半透膜
Figure PCTCN2018096611-appb-000029
Figure PCTCN2018096611-appb-000030
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.9mm高、底面长为2.7mm、底面宽为2mm的四棱柱，且四棱柱的端面带有1.5mm深、底面长为2mm、底面宽为1mm的四棱锥形凹陷，控制压片硬度为23-28kg。
制成的片芯带有一个底面长为2.7mm、底面宽为2mm、深2.9mm的四棱柱形释药孔道，且含药层在释药孔道的底端处具有一高1.5mm、底面长为2mm、底面宽为1mm的四棱锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将醋酸纤维素溶于丙酮中，再加入聚乙二醇4000水溶液，搅拌均匀，搅拌下加入滑石粉，搅拌使之分散均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在13-20％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为8mg的甲磺酸多沙唑嗪渗透泵控释片。制得的片剂在所述四棱锥形凸起处没有形成连续的包衣。
实施例11：甲磺酸多沙唑嗪渗透泵控释片的制备
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000031
Figure PCTCN2018096611-appb-000032
(2)半透膜
Figure PCTCN2018096611-appb-000033
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片。冲头采用直径为8mm的浅凹形圆形冲头，冲头表面带有1个2.1mm高、底面直径为2.15mm的圆柱体，且圆柱体的端面带有1.2mm深、底面长为1.9mm、底面宽为1.5mm的四棱锥形凹陷，控制压片硬度为23-28kg。
制成的片芯带有一个直径为2.15mm、深2.1mm的圆柱形释药孔道，且含药层在释药孔道的底端处具有一高1.2mm、底面长为1.9mm、底面宽为1.5mm的四棱锥形凸起部。
2)包半透膜：
a.包衣液的配制：将聚乙二醇4000溶于水中，得聚乙二醇4000水溶液。将醋酸纤维素溶于丙酮中，再加入聚乙二醇4000水溶液，搅拌均匀，搅拌下加入滑石粉，搅拌使之分散均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在18-25％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为8mg的甲磺酸多沙唑嗪渗透泵控释 片。制得的片剂在所述四棱锥形凸起处没有形成连续的包衣。
对比实施例1参照US5,654,005所述方法制备格列吡嗪渗透泵片
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000034
(2)半透膜
Figure PCTCN2018096611-appb-000035
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片，冲头采用直径为8mm的浅凹形圆形冲，冲头表面带有1个2.7mm高、底面直径为3mm的圆柱体，控制压片硬度为15-20kg。制成的片芯带有一个直径为3mm、深2.7mm的圆柱形释药孔道，含药层在释药孔道的底端处没有凸起部。
2)包半透膜：
a.包衣液的配制：同实施例5。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在5-15％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为10mg的格列吡嗪渗透泵控释片。
对比实施例2参照US5,654,005所述方法制备格列吡嗪渗透泵片
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000036
(2)半透膜
Figure PCTCN2018096611-appb-000037
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片，冲头采用直径为8mm的浅凹形圆形冲，冲头表面带有1个2.7mm高、底面直径为3mm的圆锥 体，控制压片硬度为15-20kg。制成的片芯带有一个底面直径为3mm、深2.7mm的倒圆锥形释药孔道。
2)包半透膜：
a.包衣液的配制：同实施例5。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在5-15％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为10mg的格列吡嗪渗透泵控释片。
对比实施例3参照US5,654,005所述方法制备硝苯地平渗透泵片
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000038
(2)半透膜
Figure PCTCN2018096611-appb-000039
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片，冲头采用直径为8mm的浅凹形圆形冲，冲头表面带有1个2.25mm高、底面直径为2.5mm的圆柱体，控制压片硬度为23-28kg。制成的片芯带有一个直径为2.5mm、深2.25mm的圆柱形释药孔道，含药层在释药孔道的底端处没有凸起部。
2)包半透膜：
a.包衣液的配制：同实施例7。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在5-15％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为90mg的硝苯地平渗透泵控释片。
对比实施例4参照US5,654,005所述方法制备硝苯地平渗透泵片
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000040
(2)半透膜
Figure PCTCN2018096611-appb-000041
Figure PCTCN2018096611-appb-000042
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片，冲头采用直径为8mm的浅凹形圆形冲，冲头表面带有1个2.25mm高、底面直径为2.50mm的圆锥体，控制压片硬度为23-28kg。制成的片芯带有一个底面直径为2.50mm、深2.25mm的倒圆锥形释药孔道。
2)包半透膜：
a.包衣液的配制：同实施例7。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在5-15％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为90mg的硝苯地平渗透泵控释片。
对比实施例5参照US5,654,005所述方法制备硝苯地平渗透泵片
处方组成：
(1)片芯
Figure PCTCN2018096611-appb-000043
Figure PCTCN2018096611-appb-000044
(2)半透膜
Figure PCTCN2018096611-appb-000045
制备过程如下：
1)制备片芯：分别按照含药层、助推层的处方量，称取除硬脂酸镁以外的物料，过30目筛，置于V型混合机中预混后，再加硬脂酸镁，混合均匀，即得到每一层的混合物料。将不同层的混合物料分别置于多层压片机的不同料斗中，压制成片，冲头采用直径为8mm的浅凹形圆形冲，冲头表面带有1个1.30mm高、底面直径为2.70mm的圆柱体，控制压片硬度为23-28kg。制成的片芯带有一个底面直径为2.70mm、深1.30mm的圆柱形释药孔道。
2)包半透膜：
a.包衣液的配制：将聚乙二醇600溶于水中，得聚乙二醇600水溶液。将醋酸纤维素和苯甲酸酯溶于乙醇中，再加入聚乙二醇600水溶液，搅拌均匀，得到包衣液。
b.包衣：将片芯置于包衣机中，调节包衣机转速5-15rpm、喷液速度150-500ml/min、进风温度25-50℃、雾化压力0.1-0.4MPa，控制片温度在15-30℃，控制包衣增重约在10-17％。包衣后在40℃下保温干燥约2h。
上述制备方法可得到规格为90mg的硝苯地平渗透泵控释片。制得的片剂在所述圆锥形凸起处没有形成连续的包衣。
实验例1帕利哌酮渗透泵控释片释放行为测试试验
待测样品：
实施例1和2制备得到的6mg规格的帕利哌酮渗透泵控释片；
市售帕利哌酮渗透泵控释片作为对照(商品名：
Figure PCTCN2018096611-appb-000046
规格：6mg)；
每种样品设置6个平行样。
释放度实验采用天大天发溶出仪和安捷伦HPLC测定。
释放度测定：
采用美国药典USP35中Apparatus II法(搅拌桨)，转速50rpm，水浴温度(37.0±0.5)℃，溶出介质为pH1.0模拟胃液(配制方法参考《美国药典USP40-NF35》，Volume 1，Test Solutions)500mL进行释放度测定。将待测样品置于沉降篮中，投入溶出杯中，分别于1h，2h，4h，6h，8h，12h，18h，20h，22h，24h取样10mL，用0.45μm微孔滤膜过滤，同时补充同温度的溶出介质10mL，取滤液进行HPLC测定。分别计算帕利哌酮在不同溶出时间的累积释放度，如表1所示，绘出累积溶出曲线，如图5所示。
结果显示，实施例1和2制得的帕利哌酮渗透泵控释片与市售的帕利哌酮渗透泵控释片
Figure PCTCN2018096611-appb-000047
体外释药行为基本一致，且根据RSD结果，两者释药稳定性基本一致。
表1 自制帕利哌酮渗透泵控释片与
Figure PCTCN2018096611-appb-000048
累积释放度(n＝6)
Figure PCTCN2018096611-appb-000049
Figure PCTCN2018096611-appb-000050
实验例2盐酸奥昔布宁渗透泵控释片释放行为测试试验
待测样品：
实施例3和4制备得到的15mg规格的盐酸奥昔布宁渗透泵控释片；
市售盐酸奥昔布宁渗透泵控释片作为对照(商品名：
Figure PCTCN2018096611-appb-000051
XL，规格：15mg)；
每种样品设置6个平行样。
释放度实验采用天大天发溶出仪和安捷伦HPLC测定。
释放度测定：
采用美国药典USP35中Apparatus II法(搅拌桨)，转速50rpm，水浴温度(37.0±0.5)℃，溶出介质为含0.5％十二烷基硫酸钠(SLS)的pH6.8磷酸缓冲液900mL。将待测样品投入溶出杯中，分别于2h，4h，8h，12h，16h，20h，24h取样5mL，用0.45μm微孔滤膜过滤，同时补充同温度的溶出介质5mL，取滤液进行HPLC测定。分别计算奥昔布宁在不同溶出时间的累积释放度，如表2所示，绘出累积释放曲线，如图6所示。
结果显示，实施例3和4制得的盐酸奥昔布宁渗透泵控释片与市售的盐酸奥昔布宁渗透泵控释片
Figure PCTCN2018096611-appb-000052
XL体外释药行为基本一致，且根据RSD结果，两者释药稳定性基本一致。
表2 自制盐酸奥昔布宁渗透泵控释片与
Figure PCTCN2018096611-appb-000053
XL累积释放度(n＝6)
Figure PCTCN2018096611-appb-000054
Figure PCTCN2018096611-appb-000055
实验例3格列吡嗪渗透泵控释片释放行为测试试验
待测样品：
实施例5和6制备得到的10mg规格的格列吡嗪渗透泵控释片；
市售格列吡嗪渗透泵控释片作为对照(商品名：
Figure PCTCN2018096611-appb-000056
XL，规格：10mg)；
每种样品设置6个平行样。
释放度实验采用天大天发溶出仪和安捷伦HPLC测定。
释放度测定：
采用美国药典USP35中Apparatus II法(搅拌桨)，转速50rpm，水浴温度(37.0±0.5)℃，溶出介质为不含胰酶的pH7.5模拟肠液(配制方法参考《美国药典USP40-NF35》，Volume 1，Test Solutions)900mL。
将待测样品投入溶出杯中，分别于2h，4h，6h，8h，12h，16h，20h，24h取样5mL，用0.45μm微孔滤膜过滤，同时补充同温度的溶出介质5mL，取滤液进行HPLC测定。分别计算格列吡嗪在不同溶出时间的累积释放度，如表3所示，绘出累积释放曲线，如图7所示。
结果显示，实施例5和6制得的格列吡嗪渗透泵控释片与市售的格列吡嗪渗透泵控释片
Figure PCTCN2018096611-appb-000057
XL体外释药行为基本一致，且根据RSD结果，两者释药稳定性基本一致。
表3 自制格列吡嗪渗透泵控释片与
Figure PCTCN2018096611-appb-000058
XL累积释放度(n＝6)
Figure PCTCN2018096611-appb-000059
实验例4硝苯地平渗透泵控释片释放行为测试试验
待测样品：
实施例7和8制备得到的90mg规格的硝苯地平渗透泵控释片；
市售硝苯地平渗透泵控释片作为对照(商品名：
Figure PCTCN2018096611-appb-000060
XL，规格：90mg)；
每种样品设置6个平行样。
释放度实验采用天大天发溶出仪和安捷伦HPLC测定。
释放度测定：
采用美国药典USP35中Apparatus II法(搅拌桨)，转速100rpm，水浴温度(37.0±0.5)℃，溶出介质为含1％十二烷基硫酸钠(SLS)的pH6.8磷酸缓冲液900mL进行释放度测定。将待测样品投入溶出杯中，分别于2，4，8，12，16，20，24h取样5mL，用0.45μm微孔滤膜过滤，同时补充同温度的溶出介质5mL，去续滤液进行HPLC测定。分别计算硝苯地平在不同溶出时间的累积释放度，如表4所示，绘出累积释放曲线，如图8所示。
结果显示，实施例7和8制得的硝苯地平渗透泵控释片与市售的硝苯地平渗透泵控释片
Figure PCTCN2018096611-appb-000061
XL体外释药行为基本一致，且根 据RSD结果，两者释药稳定性基本一致。
表4 自制硝苯地平渗透泵控释片与
Figure PCTCN2018096611-appb-000062
XL累积释放度(n＝6)
Figure PCTCN2018096611-appb-000063
实验例5硝苯地平渗透泵控释片释放行为测试试验
待测样品：
实施例9制备得到的90mg规格的硝苯地平渗透泵控释片；每种样品设置6个平行样。
释放度测定：方法同实验例4
分别计算硝苯地平在不同溶出时间的累积释放度，如表5所示，绘出累积释放曲线，如图16所示。由表5和图16可以看出，实施例9制得的硝苯地平渗透泵控释片体外累积释放度的RSD较小，样品间累积释放度波动小。
表5 硝苯地平渗透泵片释放累积释放度(n＝6)
Figure PCTCN2018096611-appb-000064
Figure PCTCN2018096611-appb-000065
实验例6甲磺酸多沙唑嗪渗透泵控释片释放行为测试试验
待测样品：
实施例10和11制备得到的8mg规格的甲磺酸多沙唑嗪渗透泵控释片；
市售甲磺酸多沙唑嗪渗透泵控释片作为对照(商品名：
Figure PCTCN2018096611-appb-000066
XL，规格：8mg)；
每种样品设置6个平行样。
释放度实验采用天大天发溶出仪和安捷伦HPLC测定。
释放度测定：
采用美国药典USP35中Apparatus II法(搅拌桨)，转速75rpm，水浴温度(37.0±0.5)℃，溶出介质为不含胰酶的pH7.5模拟肠液(配制方法参考《美国药典USP40-NF35》，Volume 1，Test Solutions)900mL。
将待测样品投入溶出杯中，分别于1h，2h，4h，6h，8h，12h，16h取样5mL，用0.45μm微孔滤膜过滤，同时补充同温度的溶出介质5mL，取滤液进行HPLC测定。分别计算多沙唑嗪在不同溶出时间的累积释放度，如表6所示，绘出累积释放曲线，如图9所示。
结果显示，实施例10和11制得的甲磺酸多沙唑嗪渗透泵控释片与市售的甲磺酸多沙唑嗪渗透泵控释片
Figure PCTCN2018096611-appb-000067
XL体外释药行为基本一致，且根据RSD结果，两者释药稳定性基本一致。
表6 自制甲磺酸多沙唑嗪渗透泵控释片与
Figure PCTCN2018096611-appb-000068
XL累积释放度(n＝6)
Figure PCTCN2018096611-appb-000069
Figure PCTCN2018096611-appb-000070
实验例7相同处方不同方法制备的格列吡嗪渗透泵片的释放行为比较
待测样品：
实施例5、对比实施例1和2制备得到的10mg规格的格列吡嗪渗透泵控释片；每种样品设置6个平行样。
释放度测定：方法同实验例3
分别计算格列吡嗪在不同溶出时间的累积释放度，如表7所示，绘出累积释放曲线，如图10所示。由表7和图10可以看出，与对比实施例1和2制得的格列吡嗪渗透泵片相比，实施例5制得的格列吡嗪渗透泵片体外累积释放度的RSD较小，释药行为更稳定。
对实施例5、对比实施例1和2的6个平行样品分别绘制累积释放曲线，如图11-13所示。结果进一步显示了，实施例5制备的格列吡嗪渗透泵片，样品间累积释放度波动小，释放行为更为稳定，对比实施例1和2制备的格列吡嗪渗透泵片，样品间累积释放度波动较大，释放行为很不稳定。
表7 不同方法制备的格列吡嗪渗透泵片累积释放度(n＝6)
Figure PCTCN2018096611-appb-000071
Figure PCTCN2018096611-appb-000072
实验例8相同处方不同方法制备的硝苯地平渗透泵片的释放行为比较
待测样品：
实施例7、对比实施例3和4制备得到的10mg规格的硝苯地平渗透泵控释片；每种样品设置6个平行样。
释放度测定：方法同实验例4
分别计算硝苯地平在不同溶出时间的累积释放度，如表8所示，绘出累积释放曲线，如图13所示。由表8和图14可以看出，与对比实施例3和4制得的硝苯地平渗透泵控释片相比，实施例7制得的硝苯地平渗透泵控释片体外累积释放度的RSD较小，释药行为更稳定。
对实施例7、对比实施例3和4的6个平行样品分别绘制累积释放曲线，如图15、图17-18所示。结果进一步显示了，实施例7制备的硝苯地平渗透泵控释片，样品间累积释放度波动小，释放行为更为稳定，对比实施例3和4制备的硝苯地平渗透泵控释片，样品间累积释放度波动较大，释放行为很不稳定。
表8 不同方法制备的硝苯地平渗透泵片释放累积释放度(n＝6)
Figure PCTCN2018096611-appb-000073
Figure PCTCN2018096611-appb-000074
实验例9硝苯地平渗透泵控释片释放行为测试试验
待测样品：
对比实施例5制备得到的90mg规格的硝苯地平渗透泵控释片；每种样品设置6个平行样。
释放度测定：方法同实验例4
分别计算硝苯地平在不同溶出时间的累积释放度，如表9所示，绘出累积释放曲线，如图19所示。
对实施例9、对比实施例5的6个平行样品分别绘制累积释放曲线，如图16、图19所示。结果进一步显示了，实施例9制备的硝苯地平渗透泵控释片，样品间累积释放度波动小，释放行为更为稳定，对比实施例5制备的硝苯地平渗透泵控释片，样品间累积释放度波动较大，释放行为很不稳定。
表9 不同方法制备的硝苯地平渗透泵片释放累积释放度(n＝6)
Figure PCTCN2018096611-appb-000075
Figure PCTCN2018096611-appb-000076
以上实验表明本公开的渗透泵控释制剂具有稳定的释药行为，并且本公开的渗透泵控释制剂在片芯压制过程中即形成特殊释药孔道，阻碍了包衣过程中包衣液在释药孔道底部形成连续包衣膜，使该制备方法可适用于多种制剂包衣设备，及范围更宽的工艺参数条件，增加了生产效率和方法的实用性的同时，保证产品有稳定的释药行为。
在本公开中，诸如第一和第二等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来，而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。
尽管本公开的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本公开的保护范围之内。本公开的全部范围由所附权利要求及其任何等同物给出。

Claims (22)

  1. 渗透泵控释片剂，其包括片芯和包衣膜，所述包衣膜包覆在所述片芯的外表面上，其中所述片剂具有至少一个释药孔道，所述释药孔道连通所述片芯至所述片剂外表面，所述释药孔道的底端处具有凸起部。
  2. 如权利要求1所述的渗透泵控释片剂，其中所述凸起部的底面积不大于所述释药孔道的横截面，优选所述凸起部具有0.5-3.0mm的高度，更优选0.6-2.0mm的高度，更优选0.7-1.5mm的高度。
  3. 如权利要求1或2所述的渗透泵控释片剂，所述凸起部具有0.5-2.9mm的最大横向长度，优选0.7-2.5mm的最大横向长度，更优选1.0-2.0mm的最大横向长度。
  4. 如权利要求1-3中任一权利要求所述的渗透泵控释片剂，其中所述释药孔道横截面的最大横向长度为1.00-3.00mm，优选1.40-2.50mm，更优选1.70-2.20mm，更优选1.95mm。
  5. 如权利要求1-4中任一权利要求所述的渗透泵控释片剂，其中所述释药孔道的深度为1.00-3.00mm，优选2.05-2.95mm，更优选2.25-2.75mm，更优选2.50mm。
  6. 如权利要求1-5中任一权利要求所述的渗透泵控释片剂，其中所述凸起部为圆柱形、球缺形、圆锥形、棱柱形或棱锥形，优选所述棱锥形为三棱锥、四棱锥或五棱锥。
  7. 如权利要求1-6中任一权利要求所述的渗透泵控释片剂，其中所述凸起部的高度不小于释药孔道横截面的最大横向长度的50％。
  8. 如权利要求1-7中任一权利要求所述的渗透泵控释片剂，其中 所述释药孔道横截面为圆形、正方形、长方形、三角形或多边形。
  9. 如权利要求1-8中任一权利要求所述的渗透泵控释片剂，其中所述片芯为单层或多层，优选单层、双层或三层。
  10. 如权利要求1-9中任一权利要求所述的渗透泵控释片剂，其中所述片芯包括至少一含药层，优选所述含药层包含药物活性成分、促渗透聚合物以及任选地其他药物可接受的辅料。
  11. 如权利要求1-9中任一权利要求所述的渗透泵控释片剂，其中所述片芯为双层，优选所述双层的第一层为含药层，并且第二层为助推层，更优选所述含药层包含药物活性成分、促渗透聚合物以及任选地其他药物可接受的辅料，更优选所述助推层包括促渗透聚合物、促渗透剂以及任选地其他药物可接受的辅料。
  12. 如权利要求1-9中任一权利要求所述的渗透泵控释片剂，其中所述片芯为三层，优选所述三层的第一层为阻滞层，第二层为含药层，并且第三层为助推层，更优选所述含药层包含药物活性成分、促渗透聚合物以及任选地其他药物可接受的辅料，更优选所述助推层包括促渗透聚合物、促渗透剂以及任选地其他药物可接受的辅料，更优选所述阻滞层包含促渗透聚合物、促渗透剂以及任选地其他药物可接受的辅料。
  13. 如权利要求10-12中任一权利要求所述的渗透泵控释片剂，其中所述药物活性成分选自抗高血压药、降血脂药、口服抗糖尿病药、非甾体抗炎药、β受体拮抗剂、钙离子通道阻滞剂、5-羟色胺再摄取抑制剂、抗精神病药和抗菌药。
  14. 如权利要求10-13中任一权利要求所述的渗透泵控释片剂，其中所述药物活性成分选自盐酸哌唑嗪、盐酸苯丙醇胺、甲磺酸多沙 唑嗪、盐酸维拉帕米、盐酸奥昔布宁、伊拉地平、帕利哌酮、马来酸氯苯那敏、格列吡嗪、硝苯地平、盐酸伪麻黄碱、硫酸伪麻黄碱、硫酸铝、卡马西平、醋酸亮丙瑞林、枸橼酸舒芬太尼和盐酸哌甲酯；优选所述药物活性成分选自硝苯地平和卡马西平。
  15. 如权利要求10-14中任一权利要求所述的渗透泵控释片剂，其中所述促渗透聚合物选自聚氧乙烯、聚乙烯吡咯烷酮、聚丙烯酸、羟丙甲纤维素、聚羟基甲基丙烯酸烷烃酯类及其混合物。
  16. 如权利要求11-15中任一权利要求所述的渗透泵控释片剂，其中所述促渗透剂选自氯化钠、氯化镁、硫酸镁、硫酸钠、硫酸钾、酒石酸、乳糖、甘露醇、尿素及其混合物。
  17. 如权利要求10-16中任一权利要求所述的渗透泵控释片剂，其还包含润滑剂，优选所述润滑剂选自硬脂酸镁、硬脂酸、山嵛酸甘油酯及其混合物。
  18. 如权利要求1-17中任一权利要求所述的渗透泵控释片剂，所述包衣膜包含半透膜材料，任选地还包含致孔剂、增塑剂、抗粘剂和/或其他药物可接受的辅料，优选所述半透膜材料选自醋酸纤维素、醋酸纤维素水分散体、乙基纤维素、聚氯乙烯、聚碳酸酯、乙烯醇-乙烯基乙酸酯、乙烯-丙烯聚合物及其混合物，优选所述致孔剂选自丙三醇、山梨醇、聚乙二醇400、聚乙二醇600、聚乙二醇1000、聚乙二醇1500、聚乙二醇4000、羟丙甲纤维素、聚乙烯醇及其混合物，优选所述增塑剂选自邻苯二甲酸酯、甘油酯、琥珀酸酯、苯甲酸酯、磷酸酯、己二酸酯和酒石酸酯及其混合物，优选抗粘剂选自滑石粉、微粉硅胶、单硬脂酸甘油酯、硬脂酸镁、二氧化钛及其混合物。
  19. 用于制备渗透泵控释片剂的压片机，所述压片机的冲头内表面带有突起物，所述形突起物用于形成所述片剂的释药孔道，所述突 起的端面具有凹陷部，
    优选所述凹陷部为球缺形、圆柱形、圆锥形、棱柱形或棱锥形，
    优选所述压片机的上冲头内表面带有圆柱形或棱柱形突起物。
  20. 制备渗透泵控释片剂的方法，其包括：
    (1)压制片芯，并在压制的过程中形成通道，从而得到具有至少一个释药孔道的片芯；以及
    (2)对所述片芯进行包衣，从而得到所述渗透泵控释片剂。
  21. 如权利要求20所述的方法，其中步骤(2)中包衣增重为1-30％。
  22. 改善药物在个体内释放的方法，其包括对需要所述方法的个体给予权利要求1-18中任一权利要求所述的渗透泵控释片剂。
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CN110623933B (zh) * 2019-06-15 2022-07-01 德州德药制药有限公司 一种盐酸二甲双胍控释片及其制备方法
CN110327306B (zh) * 2019-06-15 2022-03-08 德州德药制药有限公司 一种伊拉地平控释片及其制备方法
CN114425879A (zh) * 2020-10-28 2022-05-03 上海复星星泰医药科技有限公司 一种用于制备包芯片的压片机、包芯片及其制备方法
CN114601811A (zh) * 2020-12-08 2022-06-10 南京星银药业集团有限公司 一种硝苯地平双层渗透泵控释片及其制备方法

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