CN106822042A - A kind of risperidone slow-release composition and preparation method thereof - Google Patents
A kind of risperidone slow-release composition and preparation method thereof Download PDFInfo
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- CN106822042A CN106822042A CN201710052701.3A CN201710052701A CN106822042A CN 106822042 A CN106822042 A CN 106822042A CN 201710052701 A CN201710052701 A CN 201710052701A CN 106822042 A CN106822042 A CN 106822042A
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- risperidone
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
Abstract
The present invention relates to a kind of slow releasing composition and preparation method thereof, a kind of risperidone slow-release composition and preparation method thereof is disclosed.The non-solvent preparing raw material of risperidone slow-release composition of the invention includes Risperidone, slightly water-soluble polymer and release regulator, and the release regulator includes organic lipophilicity substance；The preparation method of risperidone slow-release composition of the invention is comprised the following steps：(1) the non-solvent preparing raw material is dissolved in organic solvent, forms interior oil phase；(2) surfactant is dissolved in aqueous medium, forms outer water phase；(3) the interior oil phase that step (1) is obtained is added in outer water phase, is made emulsion, microsphere hardening, the collection particulate in solution is then made by solvent evaporation or solvent extraction, washed and dry, obtain risperidone slow-release microsphere.Risperidone slow-release composition of the invention is sufficiently stable, can be adjusted according to specific medicinal property or Treatment need with sustained release more than several weeks.
Description
Technical field
The present invention relates to a kind of slow releasing composition and preparation method thereof, especially a kind of risperidone slow-release composition and its system
Preparation Method.
Background technology
In recent ten years, biodegradable polymer microballoon has turned into one of important research field of novel Drug Delivery Systems,
The delivery system can be as by microballoons obtained in framework material such as PLA (PLA), poly lactic coglycolic acids (PLGA)
The carrier of durative action preparation, can be administered to human body or animal with muscle or hypodermic mode, can limit drug releasing rate
And deenergized period, only can for a long time maintain effective medicine concentration with single administration, can minimization treatment needed for
The total dosage of medicine, it is possible to increase the compliance of drug therapy of patient.
Depot antipsychotics Risperidal Consta based on technological development disclosed in patent CN1137756 are (permanent
Moral) with the PLGA of molecular weight about 150kDa as carrier, Risperidone is API, every intramuscular injection in 2 weeks is once.Said preparation is prevented effectively from
The peak valley concentration that medication is produced daily, but only have a small amount of insoluble drug release in the first day, then there is the insoluble drug release up to about 3 weeks
Deadtime, thus 3 weeks after the microballoon is injected of patient it is interior also need to be can be only achieved by oral administration general formulation control curative effect
Really, Clinical practice is inconvenient, and patient compliance is poor.
There is researcher to think, due to Risperidone be shipwreck it is molten/microsolubility medicine, when microballoon drugloading rate is relatively low, initial drug
Release is little, causes medicine blood concentration the release deadtime of certain hour occur, and with the raising of drugloading rate, insoluble drug release stops
Demurrage progressively reduces, and when drugloading rate reaches certain limit, has insoluble drug release after administration.As patent CN101653422 is disclosed
A kind of Risperidone microsphere composition that can discharge several weeks, drug release deadtime is eliminated by improving carrying drug ratio (more than 45%),
But preparation stability is poor, after storing for a long time, the internal release behavior of microballoon can occur significant change.
Also there is researcher to think, during with PLGA as carrier, the ratio of hydrophobic components (LA) and hydrophilic component (GA) and
Release of the molecular size range to water soluble drug has significant impact, PLGA hydrophilic component ratios (such as LA higher:GA=50:
50), molecular weight is smaller, and drug-eluting is faster, is substantially shorter release deadtime.If patent CN 103338752 is with two kinds of differences
Molecular weight and monomer ratio (55-110kDa, LA:GA=65:35~90:10 and 4-35kDa, LA:GA=50:50~75:25)
PLGA mixture (weight ratio be 70~90:10~30) micro- into the Risperidone for discharging immediately in vivo as carrier preparation
Ball.However, this combination of polymers easily causes surface during radiation sterilization collapse, because different monomers ratio and molecular weight
PLGA palliating degradation degree is different under the radiation；Furthermore, because molecular weight is relatively low and GA monomer ratios PLGA higher was being stored
It is easier to degrade in journey, is unfavorable for the storage stability of preparation；Meanwhile, molecular weight is relatively low and GA component ratios are higher
The preparation of PLGA auxiliary materials, storage difficulty are larger, and cost is of a relatively high.
The content of the invention
Nothing substantially release after a kind of administration is provided it is an object of the invention to overcome above-mentioned the deficiencies in the prior art part
Period of delay or phenomenon of burst release, can within several weeks or longer time maintaining treatment blood concentration, with good release performance
With the risperidone slow-release composition of preferable stability.Meanwhile, another object of the present invention is to provide the risperidone slow-release
The preparation method of composition.
To achieve the above object, the technical scheme taken of the present invention is：A kind of risperidone slow-release composition, the Risperidone
The non-solvent preparing raw material of slow releasing composition includes Risperidone, slightly water-soluble polymer and release regulator, and the release is adjusted
Section agent includes organic lipophilicity substance.The preparing raw material of risperidone slow-release composition of the present invention include non-solvent preparing raw material and
Solvent-borne type preparing raw material.Wherein, the non-solvent preparing raw material includes Risperidone, slightly water-soluble polymer and release regulation
Agent, not including surfactant；The solvent-borne type preparing raw material includes aqueous medium and organic solvent.
Contain release regulator in the non-solvent preparing raw material of risperidone slow-release composition of the present invention, and it is described
Release regulator includes organic lipophilicity substance, and carbon dioxide and water can be eventually converted into vivo, makes microsphere surface and inside
Duct is produced, increases the permeability of body fluid, promote the dissolution of Risperidone.
As the preferred embodiment of risperidone slow-release composition of the present invention, the risperidone slow-release composition it is non-
In solvent-borne type preparing raw material, the weight/mass percentage composition of the release regulator is 0.1~10%；Preferably, the Risperidone delays
Release in the non-solvent preparing raw material of composition, the weight/mass percentage composition of the release regulator is 0.5~8%；Preferably, institute
State in the non-solvent preparing raw material of risperidone slow-release composition, the weight/mass percentage composition of the release regulator is 1~6%.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the organic lipophilic material is fat
At least one in acid, fatty acid ester, grease.As the more preferably implementation method of risperidone slow-release composition of the present invention,
The organic lipophilic material is aliphatic acid.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the aliphatic acid is preferably but not limited to
C12~C24 alkanoic acids and its derivative, including but not limited to oleic acid, stearic acid, laurate, myristic acid, palmitic acid, arachidic acid,
Mountain Yu acid, lignin acid, preferably stearic acid, mountain Yu acid.
As the preferred embodiment of risperidone slow-release composition of the present invention, the risperidone slow-release composition it is non-
In solvent-borne type preparing raw material, the weight/mass percentage composition of the Risperidone is 25~60%, the quality of the slightly water-soluble polymer
Percentage composition is 39.9-74.9%；Preferably, in the non-solvent preparing raw material of the risperidone slow-release composition, the profit
The weight/mass percentage composition for training ketone is 30~55%, and the weight/mass percentage composition of the slightly water-soluble polymer is 44.9-69.9%；It is excellent
Selection of land, in the non-solvent preparing raw material of the risperidone slow-release composition, the weight/mass percentage composition of the Risperidone for 35~
50%, the weight/mass percentage composition of the slightly water-soluble polymer is 44.9-69.9%.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly-
At least one in ester, makrolon, polyacetals, polyanhydride, poly-hydroxy fatty acid, their copolymer or blend.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
Lactide (PLA), PGA (PGA), PLGA (PLGA), polycaprolactone (PCL), they and poly- second two
Alcohol copolymer (such as PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PEG-PCL,
PEG-PLA-PEG, PEG-PLGA-PEG), poly butyric, poly- hydroxypentanoic acid, PPDO (PPDO), shitosan,
In alginic acid and its salt, polybutylcyanoacrylate, condensing model, poe, polyamide, polyphosphazene, polyphosphate at least one
Kind.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
At least one in lactide (PLA), PLGA (PLGA), their copolymers with polyethylene glycol.As this
The preferred embodiment of the risperidone slow-release composition is invented, the insoluble drug slow releasing composition is polylactide
(PLA), at least one in PLGA (PLGA).
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
It is described during at least one in lactide (PLA), PLGA (PLGA), their copolymers with polyethylene glycol
Polylactide (PLA), PLGA (PLGA), they are equal with the weight average molecular weight of the copolymer of polyethylene glycol
It is 25000-150000Da.Preferably, the polylactide (PLA), PLGA (PLGA), they with it is poly-
The weight average molecular weight of the copolymer of ethylene glycol is 30000-125000Da.It is highly preferred that the polylactide (PLA), the third friendship
Ester-glycolide copolymer (PLGA), the weight average molecular weight of their copolymers with polyethylene glycol are 30000-100000Da.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
It is described during at least one in lactide (PLA), PLGA (PLGA), their copolymers with polyethylene glycol
Polylactide (PLA), PLGA (PLGA), the viscosity of their copolymers with polyethylene glycol are 0.30-
(test condition is~0.5% (w/v), CHCl to 1.15dL/g3, 25 DEG C).Preferably, the polylactide (PLA), lactide-
Glycolide copolymer (PLGA), the viscosity of their copolymers with polyethylene glycol be 0.37-0.95dL/g (test condition for~
0.5% (w/v), CHCl3, 25 DEG C).It is highly preferred that the polylactide (PLA), PLGA (PLGA),
They are 0.37-0.809dL/g with the viscosity of the copolymer of polyethylene glycol, and (test condition is~0.5% (w/v), CHCl3,
25℃)。
As the preferred embodiment of risperidone slow-release composition of the present invention, the molecule of the slightly water-soluble polymer
Chain carries anion or cation group, or does not carry anion or cation group.Preferably, the slightly water-soluble polymerization
Thing has end carboxyl or end ester group.It is highly preferred that the slightly water-soluble polymer has end carboxyl.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the slightly water-soluble polymer is poly- third
It is therein during at least one in lactide (PLA), PLGA (PLGA), its copolymer with polyethylene glycol
Lactide is 100 with the mol ratio of glycolide:0~65:35.Preferably, it is described can slightly water-soluble polymer be polylactide
(PLA), during at least one in PLGA (PLGA), its copolymer with polyethylene glycol, therein third hands over
Ester is 100 with the mol ratio of glycolide:0~70:30.It is highly preferred that the slightly water-soluble polymer be polylactide (PLA),
During at least one in PLGA (PLGA), its copolymer with polyethylene glycol, lactide therein and second
The mol ratio of lactide is 100:0~75:25.
In risperidone slow-release composition of the present invention, the slightly water-soluble polymer is biodegradable, bio-compatible water
Slightly solubility polymer.The slightly water-soluble polymer can be single polymer, or the mixture of multiple polymers.
Such as, lactide and glycolide mole when molecular weight is identical but carries the combination of group different PLGA and/or PLA；Lactide
From the combination for mole when carrying group is identical but molecular weight is different PLGA and/or PLA of glycolide, and molecular weight difference is not
More than 20kDa；The group of molecular weight and the carrying PLGA that group is identical but lactide is different from the mol ratio of glycolide and/or PLA
Close, and the percentage difference of glycolide is not more than 20%；The mol ratio of molecular weight, carrying group and lactide and glycolide is not
The combination of same PLGA and/or PLA, and molecular weight difference is not more than 20kDa, the percentage difference of glycolide is not more than 20%.
Molecular weight described above is weight average molecular weight, is measured by gel permeation chromatograph (GPC) and is obtained
Value；The viscosity is that Ubbelohde viscometer measures obtained value.
As the preferred embodiment of risperidone slow-release composition of the present invention, the risperidone slow-release composition it is non-
Solvent-borne type preparing raw material also includes excipient, non-solvent preparing raw material of the excipient in the risperidone slow-release composition
In weight/mass percentage composition be 0~8%.In risperidone slow-release composition of the invention, one or more can also be included
Excipient.Excipient can assign active medicine or particulate further feature, for example, increase the steady of particulate, active medicine or carrier
Qualitative, promotion active medicine is from the controlled release in particulate or the permeability of the biological organization of regulation active medicine.The present invention
Described in excipient include but is not limited to antioxidant, buffer etc..
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the excipient includes buffer and resists
Oxidant.
The buffer is at least one in organic acid, inorganic acid salt, and the buffer is in the risperidone slow-release group
Weight/mass percentage composition in the non-solvent preparing raw material of compound is 0~5%.
The antioxidant is butylated hydroxyarisol, dibutylphenol, tocopherol, isopropyl myristate, d-a
Tocopherol acetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol, butylatedhydroxyquinone, hydroxyl tonka-bean
Element, Yoshinox BHT, amass wealth by heavy taxation sour fatty acid ester, the third hydroxybenzoate, trihydroxybutyrophenone, vitamin E, vitamin E-
At least one in TPGS, ρ-hydroxybenzoate；Non-solvent of the antioxidant in the risperidone slow-release composition
Weight/mass percentage composition in preparing raw material is 0~1%.
It is described to amass wealth by heavy taxation sour fatty acid ester selected from such as ethyl ester, propyl ester, monooctyl ester, lauryl in the selection of the antioxidant, it is described
ρ-hydroxybenzoate is selected from such as methyl esters, ethyl ester, propyl ester, butyl ester.The antioxidant is produced with effectively removing in implant
Raw any free radical or the amount of peroxide are present in slow releasing composition.
Buffer of the present invention includes but is not limited to inorganic acid and acylate, such as carbonic acid, acetic acid, oxalic acid, citric acid,
The salt of phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, Pork and beans fringed pink acid calcium, calcium oleate, calcium palmitate, calcium stearate, calcium phosphate,
Calcium acetate, magnesium acetate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, carbonic acid
Zinc, zinc hydroxide, zinc oxide, Pork and beans fringed pink acid zinc, zinc oleate, zinc acetate, zinc chloride, zinc sulfate, zinc hydrogen sulfate, zinc carbonate, nitre
Sour zinc, zinc gluconate, zinc palmitate, zinc stearate, trbasic zinc phosphate, sodium carbonate, sodium acid carbonate, sodium hydrogensulfite, thiosulfuric acid
Sodium, Acetic acid-sodium acetate buffer salt, and combinations thereof.It is preferred that the zinc salt of inorganic acid and organic acid.
The excipient is added in interior oil phase.When the excipient is imperceptible powder, its particle diameter is less than 0.5 μ
M, preferably particle diameter are less than 0.1 μm, and more preferably particle diameter is less than 0.05 μm.In the excipient solvent and interior oil phase or with minimum
Grain is suspended in interior oil phase.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the risperidone slow-release composition is micro-
Ball or particulate.When the risperidone slow-release composition is microballoon, microballoon is generally used for drug administration by injection, and particulate or microballoon can be by
It is drawn into syringe, and is injected by thin pin.Preferably, route of delivery is injected using fine needle, including subcutaneous, flesh
Meat, intraocular etc..Pin at least 20G bores (580 μm of internal diameter) are meaned by thin pin, typically at about 22G (410 μm of internal diameter)
Between about 30G (150 μm of internal diameter), or more than 30G.Advantageously using thin at least syringe needle of 24G, it is more advantageous to thin
To at least syringe needle of 26G.
Used as the preferred embodiment of risperidone slow-release composition of the present invention, the geometry particle diameter of the microballoon is less than
200μm.Typically, the particle diameter of the microballoon is about 10~200 μm, preferably 15~150 μm, more preferably from about 20~120 μm.
Microspherulite diameter size is surveyed by dynamic light scattering method (such as laser diffractometry) or microtechnic (such as ESEM method)
Amount.
In addition, the present invention also provides a kind of preparation side that can be simply efficiently prepared above-mentioned risperidone slow-release composition
Method, in order to achieve this, the technical scheme that this hair is taken is：A kind of preparation method of risperidone slow-release composition as described above,
Comprise the following steps：
(1) the non-solvent preparing raw material is dissolved in organic solvent, forms interior oil phase；
(2) surfactant is dissolved in aqueous medium, forms outer water phase；
(3) the interior oil phase that step (1) is obtained is added in outer water phase, is made emulsion, then evaporated or molten by solvent
Microsphere hardening, the collection particulate made in solution is extracted in agent, is washed and is dried, and obtains risperidone slow-release microsphere.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, in the step (1),
Slightly water-soluble polymer is 1~18% with the mass percent of organic solvent；In the step (2), the surfactant exists
Weight/mass percentage composition in outer water phase is 0.1~10%；In the step (3), the volume of the outer water phase is the interior oil phase
More than 60 times of volume.It is described as the more preferably implementation method of the preparation method of risperidone slow-release composition of the present invention
Slightly water-soluble polymer and the mass percent of organic solvent are 1.5~9% in step (1)；In the step (2), the table
Weight/mass percentage composition of the face activating agent in outer water phase is 0.5~8%；In the step (3), the volume of the outer water phase is institute
State interior oil phase volume more than 80 times.As the more preferably embodiment party of the preparation method of risperidone slow-release composition of the present invention
Formula, slightly water-soluble polymer and the mass percent of organic solvent are 3~8.5% in the step (1)；In the step (2),
Weight/mass percentage composition of the surfactant in outer water phase is 1~7%；In the step (3), the volume of the outer water phase
It is more than 100 times of the interior oil phase volume.
Type, the Weight-average molecular of slightly water-soluble polymer weight/mass percentage composition foundation polymer in organic solvent
The type of amount and organic solvent and change, usual its weight/mass percentage composition (slightly water-soluble of biodegradable and bio-compatible
Polymer quality/organic solvent quality × 100%) is 1~18%.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, in the step (1)
Organic solvent be at least one in halogenated hydrocarbons, fatty acid ester, aromatic hydrocarbon；The halogenated hydrocarbons includes dichloromethane, chloroform, chlorine
Ethane, tetrachloro-ethylene, trichloro ethylene, dichloroethanes, trichloroethanes, carbon tetrachloride, fluorohydrocarbon, chlorobenzene, Arcton 11；It is described
Fatty acid ester includes ethyl acetate, butyl acetate；The aromatic hydrocarbon includes benzene,toluene,xylene, phenmethylol.
The organic solvent can simultaneously dissolve slightly water-soluble polymer and Risperidone, boiling point less than water and insoluble in or it is difficult
Water is dissolved in, the organic solvent can be single organic solvent, or two kinds miscible and the organic solvent of the above.Institute
State organic solvent and be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, chloroethanes, tetrachloro-ethylene, trichloro ethylene, dichloroethanes, three chloroethenes
Alkane, carbon tetrachloride, fluorohydrocarbon, chlorobenzene (single, double, triple substitution), Arcton 11 etc.), fatty acid ester (such as ethyl acetate, acetic acid
Butyl ester etc.), aromatic hydrocarbon (such as benzene,toluene,xylene, phenmethylol), preferably halogenated aliphatic hydro carbons solvent, more preferably dichloromethane
Alkane, chloroform.To press different pharmaceutical different for the ratio of organic solvent in the mixture, is allocated according to actual conditions.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, the surfactant
It is anion surfactant, cationic surfactant, zwitterionic surfactant, nonionic surfactant, surface
At least one in active biomolecule；The cationic surfactant includes BZK, cetyltrimethylammonium base
Ammonium, bay acidic group dimethyl benzyl oronain, acylcarnitines hydrochloride, alky pyridinium halides；The anionic surface is lived
Property agent include alkyl sulfate, potassium laurate, mosanom, Sodium Polyacrylate and its derivative, alkyl Pluronic F-127 sulfuric ester,
Dioctyl sodium sulfosuccinate, phosphatide, glyceride, sodium carboxymethylcellulose, enuatrol, odium stearate, cholic acid and other bile
The sodium salt of acid；The nonionic surfactant includes polyoxyethylene aliphatic alcohol ether, polysorbate, polyoxyethylene fatty acid
Ester, castor oil derivatives, polyoxyethylene polypropylene glycol copolymers, sucrose fatty ester, cithrol,
Polyoxyethylene sorbitol acid anhydride mono fatty acid ester, polyoxyethylene sorbitol acid anhydride di fatty acid ester, polyoxyethylene glycerol monoester fat
Acid esters, polyoxyethylene glycerol di fatty acid ester, polyglyceryl fatty acid ester, polypropylene glycol monoesters, aryl burn base Aethoxy Sklerol, polyoxy second
Alkene-poiyoxypropylene copolymer, polyvinyl alcohol and its derivative, polyvinylpyrrolidone and polysaccharide；The Surface active biological point
Attached bag includes polyaminoacid, peptide, protein.
The surfactant (or stabilizer) can increase the wetting properties of organic phase, improve small liquid pearl in emulsion process
Stability and shape, it is to avoid small liquid pearl regroups, it is non-encapsulated to reduce or the quantity of the small spherical particles of part encapsulating so that
Reduce initial burst of the medicine during release.
The surfactant (or stabilizer) is anion surfactant, cationic surfactant, amphion
Live on surfactant, nonionic surfactant or compound as Surface active biological molecule, preferred anionic surface
Property agent, nonionic surfactant (or stabilizer) or Surface active biological molecule, more preferably nonionic surfactant
(or stabilizer) or Surface active biological molecule.
The cationic surfactant includes but is not limited to quaternary ammonium compound such as benzalkonium chloride, cetyltrimethylammonium
Base ammonium, bay acidic group dimethyl benzyl oronain, acylcarnitines hydrochloride or alky pyridinium halides.
The anion surfactant includes but is not limited to lauryl sodium sulfate, ammonium lauryl sulfate, octadecane
The alkyl sulfates such as base sodium sulphate, potassium laurate, mosanom, Sodium Polyacrylate and its derivative, alkyl Pluronic F-127 sulfuric acid
Ester, dioctyl sodium sulfosuccinate, phosphatide, glyceride, sodium carboxymethylcellulose, enuatrol, odium stearate, cholic acid and other courages
The sodium salt of juice acid (such as cholic acid, deoxycholic acid, glycocholic acid, taurocholate, glycodesoxycholic acid).
The nonionic surfactant includes but is not limited to polyoxyethylene aliphatic alcohol ether (Brij), polysorbate
(such as Tween 80, polysorbate60), polyoxyethylene fatty acid ester (OEO), castor oil derivatives, polyoxyethylene polypropylene glycol
Copolymer, sucrose fatty ester, cithrol, polyoxyethylene sorbitol acid anhydride mono fatty acid ester, polyoxyethylene mountain
Pears sugar alcohol acid anhydride di fatty acid ester, polyoxyethylene glycerol mono fatty acid ester, polyoxyethylene glycerol di fatty acid ester, polyglycerol fatty acid
Ester, polypropylene glycol monoesters, aryl burn base Aethoxy Sklerol, Pluronic F68 (poloxamer), polyvinyl alcohol
(PVA) and its derivative, PVP (PVP) and polysaccharide, preferred poloxamer, polyvinyl alcohol, polysorbate, poly-
Ethylene ratio pyrrolidone and polysaccharide, more preferably polyvinyl alcohol, polysaccharide.
The polysaccharide includes starch and starch derivatives, methylcellulose, ethyl cellulose, hydroxylated cellulose, hydroxypropyl
Cellulose, HPMC, Arabic gum, chitosan derivatives, gellan gum, alginate derivatives, glucan derivative and
Amorphous cellulose, preferably Hydroxypropyl methylcellulose, Chitosan-phospholipid complex, amylopectin or glucan and its derivative.
Surface active biological molecule includes polyaminoacid (such as poly-aspartate or polyglutamic acid or their analog), peptide
(such as basic peptide), protein (such as gelatin, casein, albumin, hirudin, hetastarch, preferably albumin).
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, the surfactant
Mass percentage concentration in outer water phase is 0.1~10%；Preferably, quality percentage of the surfactant in outer water phase
Concentration is 0.5~8%；It is highly preferred that mass percentage concentration of the surfactant in outer water phase is 1~7%.
As the preferred embodiment of the preparation method of risperidone slow-release composition of the present invention, in the outer water phase also
Contain inorganic salts or organic salt；The inorganic salts are phosphoric acid, sulfuric acid, acetic acid, the sylvite of carbonic acid or sodium salt, Tris, MES, HEPES
In at least one；The weight/mass percentage composition of the inorganic salts or organic salt in the outer water phase is 0~5%.Further,
Inorganic salts or organic salt can also be contained in the outer water phase, water-soluble actives are molten to be oozed to water to reduce in microballoon solidification process
Xiang Zhong, its mechanism is to improve the osmotic pressure of foreign minister or reduce solubility of the active material in foreign minister.The inorganic salts include but
It is not limited to water miscible phosphoric acid, sulfuric acid, acetic acid, the sylvite of carbonic acid or sodium salt, Tris, MES, HEPES or their any mixing
Thing, its weight percent concentration in the aqueous solution is：0-5%, preferably 0.01-4%, more preferably 0.05-3%.PH scopes are
3-9, preferably 4-9, more preferably 5.5-8.5.
The method for being made emulsion is identical with well-known emulsification method, using the device for producing high shear force (such as
Magnetic stirring apparatus, mechanical agitator, high-shear homogenizer, Ultrasound Instrument, membrane emulsifier, Rotor-stator mixers, static mixer,
High pressure homogenizer etc.) by it is organic it is interior mix with external aqueous phase, to form homogeneous latex emulsion.
Solvent evaporation can apply following methods in the step (3)：
(A) organic solvent is boiled off by heating, decompression (or combined heat) and decompression；
(B) air-flow advertises liquid surface, and controls the speed of liquid phase and the contact area, emulsion stirring and circulation of gas phase
(such as JP-A-9-221418) accelerates the evaporation of organic solvent, the preferred nitrogen of air-flow；
(C) organic solvent (such as W00183594) is quickly boiled off with hollow fiber membrane, hollow fiber membrane is preferably for example
Silicon rubber pervaporation film (the pervaporation film for particularly being prepared by dimethyl silicone polymer).
Microballoon obtained in the step (3) is separated by way of centrifugation, sieving or filtering.
The method of dry microspheres is not particularly limited in the step (3), for example, can enumerate heating, drying under reduced pressure, freezing
Dry, be vacuum dried and combinations thereof.
Particulate of the invention or microballoon can encapsulate substantial amounts of active component, dosage can according to the type of active component with contain
Amount, formulation, release duration, administration subject, method of administration, administration purpose, targeted condition and symptom etc. and suitably select
Select.However, as long as active component can reach the expected duration in medicine effective concentration is in vivo maintained, then the dosage can be recognized
To be gratifying.
When microballoon is administered in suspending agent form, it can be made suspension formulations form with appropriate decentralized medium.
The decentralized medium includes nonionic surfactant (or stabilizer), castor oil derivatives, fiber
Plain thickener, sodium alginate, hyaluronic acid, dextrin, starch.Or it is selectable, can also be with other excipient such as isotonic agent (such as
Sodium chloride, mannitol, glycerine, sorbierite, lactose, xylitol, maltose, galactolipin, sucrose, glucose etc.), pH adjusting agent
(such as carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid or these sour salt, such as sodium carbonate, sodium acid carbonate etc.), anti-corrosion
Agent (such as p-hydroxybenzoate, propylparaben, phenmethylol, chlorobutanol, sorbic acid, boric acid etc.) etc. is combined,
Solidified by methods such as freeze-drying, hypobaric drying method, spray drying after being made aqueous solution, using preceding again that solidfied material is molten
Solution obtains the decentralized medium of dispersion microsphere in distilled water for injection.
Additionally, slow-release injected can also be obtained by following methods：Particulate or microballoon are scattered in vegetable oil (such as sesame
Oil and corn oil) or be added with the vegetable oil of phosphatide (such as lecithin), or be scattered in medium chain triglyceride, to obtain
Oil-based suspension.
The microballoon that the present invention is obtained can be used for granular form, suspending agent form, implants form, injection form, viscous
Attached dosage form formula etc., it is possible to oral or parenteral administration (intramuscular injection, hypodermic injection, percutaneous dosing, mucosa delivery (cheek
In interior, intravaginal, rectum etc.)).
Risperidone slow-release composition of the invention is sufficiently stable, can with sustained release more than several weeks, such as up to about 2 weeks,
Such as it is up to about 4 weeks, is such as up to about 8 weeks, is such as up to about 12 weeks, or the longer time, can be carried out according to specific Treatment need
Regulation.
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiment to the present invention
It is described further.
In following examples, the computational methods of microballoon carrying drug ratio are：Drug quality/microspheres quality in carrying drug ratio=microballoon ×
100%；The computational methods of entrapment efficiency are：Medicine actual mass/medicine feeding quality × 100% in envelop rate=microballoon.
Embodiment 1
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 25%, slightly water-soluble polymer：PLA 74.9%,
Release regulator：Stearic acid 0.1%.Wherein, the weight average molecular weight of the PLA is 30kDa, and viscosity is 0.27dL/g, and described
PLA has ester group end.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 10%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is PVA and potassium phosphate is soluble in water, outer water phase is formed, quality percentages of the PVA in the outer water phase contains
It is 0.1% to measure, and weight/mass percentage composition of the potassium phosphate in the outer water phase is 0.01%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
60 times of the interior oil phase, emulsification is made emulsion, then by this solution 6 hours of mechanical agitation at 500 rpm, microballoon is consolidated
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 20~94 μm, after measured its
Carrying drug ratio is 2294%, and Risperidone envelop rate is 91.76%.
Embodiment 2
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 30%, slightly water-soluble polymer：PLA 69.5%,
Release regulator：Mountain Yu acid 0.5%.Wherein, by the PLA at ester group end, (weight average molecular weight is 40kDa to the PLA, and viscosity is
0.35dL/g) PLA (weight average molecular weight is 40kDa, and viscosity is 0.35dL/g) with c-terminus is constituted, the PLA and carboxylic at ester group end
The mass ratio of the PLA of cardinal extremity is：70:69.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in chloroform, the slightly water-soluble polymer is with the mass percent of chloroform
9.5%, Risperidone and release regulator are subsequently adding, it is uniformly dissolved, form interior oil phase；
(2) it is Hydroxypropyl methylcellulose and sodium phosphate is soluble in water, outer water phase is formed, the Hydroxypropyl methylcellulose is described outer
Weight/mass percentage composition in water phase is 0.5%, and weight/mass percentage composition of the sodium phosphate in the outer water phase is 0.05%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
65 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 27~100 μm, after measured
Its carrying drug ratio is 27.60%, and Risperidone envelop rate is 92.0%.
Embodiment 3
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLA 64.2%,
Release regulator：Mountain Yu acid thing 0.8%.Wherein, the weight average molecular weight of the PLA is 35kDa, and viscosity is 0.32dL/g, and institute
Stating PLA has c-terminus.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and tetrachloro-ethylene
Percentage is 9%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is albumin is soluble in water, form outer water phase, weight/mass percentage composition of the albumin in the outer water phase
It is 1%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
70 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 29~96 μm, after measured its
Carrying drug ratio is 32.38%, and Risperidone envelop rate is 92.5%.
Embodiment 4
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLGA64%, releases
Put conditioning agent：Lignin acid 1%.Wherein, in the PLGA, the mol ratio of lactide and glycolide is 95:5, the PLGA's
Weight average molecular weight is 40kDa, and viscosity is 0.36dL/g, and the PLA has ester group end.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 9%, is subsequently adding Risperidone, release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is polysorbate is soluble in water, form outer water phase, quality of the polysorbate in the outer water phase
Percentage composition is 2%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
75 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 30~100 μm, after measured
Its carrying drug ratio is 31.99%, and Risperidone envelop rate is 91.40%.
Embodiment 5
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLGA 63%, releases
Put conditioning agent：Stearic acid 2%.Wherein, the mol ratio of lactide and glycolide is 85 in the PLGA:15, the weight of the PLGA
Average molecular weight is 45kDa, and viscosity is 0.39dL/g, and the PLA has ester group end.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in ethyl acetate, the quality of the slightly water-soluble polymer and ethyl acetate
Percentage is 8.5%, is subsequently adding Risperidone, release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is benzalkonium chloride is soluble in water, form outer water phase, quality percentage of the benzalkonium chloride in the outer water phase
Content is 3%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
80 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 30~110 μm, after measured
Its carrying drug ratio is 32.50%, and Risperidone envelop rate is 92.86%.
Embodiment 6
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 40%, slightly water-soluble polymer：PLA 57%, releases
Put conditioning agent：Stearic acid 3%.Wherein, in the PLA it is mixture with c-terminus PLA and with ester group end PLA, and its
In to have c-terminus PLA and mass ratio with ester group end PLA be 37:20, it is described with c-terminus PLA and with ester group end
The weight average molecular weight of PLA is 55kDa, and viscosity is 0.47dL/g.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dimethylbenzene, the quality percentage of the slightly water-soluble polymer and dimethylbenzene
Than being 8%, Risperidone, release regulator are subsequently adding, be uniformly dissolved, form interior oil phase；
(2) it is potassium laurate is soluble in water, form outer water phase, quality percentage of the potassium laurate in the outer water phase
Content is 4%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
85 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 27~118 μm, after measured
Its carrying drug ratio is 37.30%, and Risperidone envelop rate is 93.25%.
Embodiment 7
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 40%, slightly water-soluble polymer：PLGA 56%, releases
Put conditioning agent：Arachidic acid 4%,.Wherein, lactide and the mol ratio of glycolide are 85 in the PLGA:15, the weight of the PLGA
Average molecular weight is 65kDa, and viscosity is 0.57dL/g, and the PLGA has c-terminus.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality percentage of the slightly water-soluble polymer and chloroform
Than being 7.5%, Risperidone, release regulator are subsequently adding, be uniformly dissolved, form interior oil phase；
(2) it is poloxamer is soluble in water, form outer water phase, quality percentage of the poloxamer in the outer water phase
Content is 5%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
90 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 27~104 μm, after measured
Its carrying drug ratio is 38.1%, and Risperidone envelop rate is 95.25%.
Embodiment 8
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 40%, slightly water-soluble polymer：PLGA 55%, releases
Put conditioning agent：Arachidic acid 5%.Wherein, lactide and the mol ratio of glycolide are 75 in the PLGA:25, the weight of the PLGA
Average molecular weight is 75kDa, and viscosity is 0.66dL/g, and the PLGA has ester group end.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in phenmethylol, the quality percentage of the slightly water-soluble polymer and phenmethylol
Than being 6%, Risperidone, release regulator are subsequently adding, be uniformly dissolved, form interior oil phase；
(2) it is PVP and sodium sulphate is soluble in water, outer water phase is formed, quality percentages of the PVP in the outer water phase contains
It is 6% to measure, and weight/mass percentage composition of the sodium sulphate in the outer water phase is 3%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
100 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 28~107 μm, after measured
Its carrying drug ratio is 36.40%, and Risperidone envelop rate is 91.00%.
Embodiment 9
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 45%, slightly water-soluble polymer：PLGA 46%, releases
Put conditioning agent：Mountain Yu acid 6%, excipient：Buffer zinc stearate 2%, antioxidant vitamin E 1%.Wherein, the PLGA
It is the PLGA with c-terminus and the mixture of the PLGA with ester group end, and the PLGA with c-terminus and with ester group end
The mass ratio of PLGA is 2:1；Lactide and the mol ratio of glycolide are 85 in the PLGA with c-terminus:15, divide equally again
Son amount is 85kDa, and viscosity is 0.71dL/g；Lactide and the mol ratio of glycolide are 75 in the PLGA with ester group end:
25, weight average molecular weight is 70kDa, and viscosity is 0.56dL/g.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 5%, is subsequently adding Risperidone, release regulator and excipient, is uniformly dissolved, and forms interior oil phase；
(2) it is starch and potassium acetate is soluble in water, form outer water phase, quality percentage of the starch in the outer water phase
Content is 7%, and weight/mass percentage composition of the potassium acetate in the outer water phase is 4%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
105 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 21~98 μm, after measured its
Carrying drug ratio is 41.60%, and Risperidone envelop rate is 92.44%.
Embodiment 10
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 50%, slightly water-soluble polymer：PLGA 43%, releases
Put conditioning agent：Palmitic acid 7%.Wherein, lactide and the mol ratio of glycolide are 80 in the PLGA:20, the weight of the PLGA
Average molecular weight is 100kDa, and viscosity is 0.81dL/g, and the PLGA has ester group end.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality percentage of the slightly water-soluble polymer and chloroform
Than being 4%, Risperidone, release regulator are subsequently adding, be uniformly dissolved, form interior oil phase；
(2) shitosan is dissolved in the Tris aqueous solution, forms outer water phase, quality of the shitosan in the outer water phase
Percentage composition is 8%, and weight/mass percentage compositions of the Tris in the outer water phase is 1.5%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
95 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 25~99 μm, after measured its
Carrying drug ratio is 46.15%, and Risperidone envelop rate is 92.30%.
Embodiment 11
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 55%, slightly water-soluble polymer：PLGA36%, releases
Put conditioning agent：Myristic acid 8%, excipient：Buffer zinc nitrate 1%.Wherein, the PLGA is that PLGA (with second hand over by lactide
The mol ratio of ester is 70:30th, weight average molecular weight be 125kDa, viscosity be 0.5dL/g, with c-terminus) and PLGA (lactide and
The mol ratio of glycolide is 85:15th, weight average molecular weight be 125kDa, viscosity be 0.79dL/g, with c-terminus) mixture.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and dichloromethane
Percentage is 3.5%, is subsequently adding Risperidone, release regulator and excipient, is uniformly dissolved, and forms interior oil phase；
(2) gelatin is dissolved in the MES aqueous solution, forms outer water phase, quality percentage of the gelatin in the outer water phase
Content is 9%, and weight/mass percentage compositions of the MES in the outer water phase is 2.5%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
80 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 30~114 μm, after measured
Its carrying drug ratio is 49.83%, and Risperidone envelop rate is 90.60%.
Embodiment 12
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 60%, slightly water-soluble polymer：PLGA30%, releases
Put conditioning agent：Laurate 10%.Wherein, in the PLGA, the mol ratio of lactide and glycolide is 65:35, the PLGA's
Weight average molecular weight is 150kDa, and viscosity is 1.2dL/g, and the PLA has c-terminus.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in trichloroethanes, the quality of the slightly water-soluble polymer and trichloroethanes
Percentage is 3.5%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is polyvinyl alcohol is soluble in water, form outer water phase, quality percentage of the polyvinyl alcohol in the outer water phase
Content is 10%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
100 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 38~125 μm, after measured
Its carrying drug ratio is 53.50%, and Risperidone envelop rate is 89.17%.
Embodiment 13
A kind of embodiment of risperidone slow-release composition of the present invention, risperidone slow-release composition described in the present embodiment it is non-molten
Component of the formulation preparing raw material comprising following weight/mass percentage composition：Risperidone 35%, slightly water-soluble polymer：PLGA61%, releases
Put conditioning agent：Mountain Yu acid 4%.Wherein, in the PLGA, the mol ratio of lactide and glycolide is 75:25, the weight of the PLGA
Average molecular weight is 100kDa, and viscosity is 0.80dL/g, and the PLA has ester group end.
Risperidone slow-release composition is prepared from using following preparation method described in the present embodiment：
(1) slightly water-soluble polymer is dissolved in dichloromethane, the quality of the slightly water-soluble polymer and butyl acetate
Percentage is 4%, is subsequently adding Risperidone and release regulator, is uniformly dissolved, and forms interior oil phase；
(2) it is ethyl cellulose is soluble in water, form outer water phase, quality of the ethyl cellulose in the outer water phase
Percentage composition is 4%；
(3) the interior oil phase that step (1) is obtained is added in step (2) the outer water phase of gained, the volume of the outer water phase is
105 times of the interior oil phase, emulsification is made emulsion, and then by this solution, 6 hours of mechanical agitation consolidate microballoon at 500 rpm
Change, be collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freeze-drying obtains risperidone slow-release microsphere.
Gained risperidone slow-release microsphere profile rounding, surface are smooth in the present embodiment, and particle diameter is 20~88 μm, after measured its
Carrying drug ratio is 32.50%, and Risperidone envelop rate is 92.86%.
Embodiment 14
The vitro release of poorly water soluble drugs slow releasing composition of the present invention is determined
Poorly water soluble drugs sustained-release micro-spheres that embodiment 1~13 prepares are respectively adopted as test group 1~13, use
Following four comparative example is as a control group：
Comparative example 1, preparation method with embodiment 1 in patent CN1137756, wherein feeding intake：Risperidone 35%, PLGA (75/
25,100kDa, 0.79dL/g, ester group end) 65%.Gained risperidone slow-release microsphere profile rounding, particle diameter is 30-127 μm, through surveying
Fixed its carrying drug ratio is 31.15%, and Risperidone envelop rate is 89.00%.
Comparative example 2, preparation method is with the embodiment of the present invention 5, wherein feeding intake：Risperidone 35%, without release regulator, profit
Training ketone 35%, 65%.Gained risperidone slow-release microsphere profile rounding, surface are smooth, and particle diameter is 28-86 μm, and it carries medicine after measured
Rate is 31.53%, and Risperidone envelop rate is 90.08%.
Comparative example 3, preparation method is with the embodiment of the present invention 6, wherein feeding intake：Without release regulator, Risperidone 40%, water
Slightly solubility polymer 60%.Gained risperidone slow-release microsphere profile rounding, surface are smooth, and particle diameter is 23-91 μm, after measured its load
Medicine rate is 36.09%, and Risperidone envelop rate is 90.23%.
Comparative example 4, preparation method is with the embodiment of the present invention 7, wherein feeding intake：Without release regulator, Risperidone 40%, water
Slightly solubility polymer 60%.Gained risperidone slow-release microsphere profile rounding, surface are smooth, and particle diameter is 22-93 μm, after measured its load
Medicine rate is 36.84%, and Risperidone envelop rate is 92.10%.
Method of testing：Each 20mg of microballoon that precision weighs embodiment 1-14 and comparative example 1-2 preparations puts 200mL centrifuge tubes
In, plus pH7.4PBS (containing 0.05% Tween 80,0.05% sodium azide) 50mL, it is placed in 37 DEG C, 150rpm waters bath with thermostatic control vibration
In device, 1mL release liquids are taken out in Preset Time point, be placed in after supplement equivalent fresh medium in thermostatic control oscillator vibration and continue to discharge
Degree experiment.Take out liquid and release amount of medicine is detected using high performance liquid chromatography (HPLC), as a result as shown in Table 1 and Table 2.
The release in vitro data of the sustained-release micro-spheres of table 1
The release in vitro data of the sustained-release micro-spheres of table 2
As can be seen from Table 1 and Table 2, sustained-release micro-spheres of the invention do not have burst effect, and first day release rate is no more than 2%,
And in 4-12 weeks to approach the release of zero level trend, with obvious slow release effect, and can be released or preceding without occurring dashing forward
Phase discharges the phenomenon of slow later stage release aggravation, illustrates that the degradation rate of the polymer of these microballoon top layers and core does not occur
Visible difference, illustrates that release regulator therein produces space so that the acid product that the degraded of microballoon inside is produced is passed in time
Deliver to outside, it is to avoid or greatly reduce the phenomenon for the quickening of core polymer self-catalysis degradation speed occur, effectively overcome PLA
Or the drawbacks of PLGA body degradation effects.
Embodiment can be seen that microballoon relative contrast example substantially contracting of the invention with the contrast of comparative example from Tables 1 and 2
Short sustained release phase, and without phenomenon of burst release, illustrate of the invention can significantly improve slow by adding release regulator
The release behavior of microballoon is released, the release lag phase of microballoon is greatly shortened, makes patient avoid or reduce injection oral common after taking medicine
Preparation, dramatically increases to drug compliance and convenience.
Embodiment 15
The stabilizing effect experiment of poorly water soluble drugs sustained-release micro-spheres of the present invention.
According to Chinese Pharmacopoeia (2015 editions four) 9001 material medicines and preparation stability test direction principle, it is necessary in ice
(4-8 DEG C) accelerated test of the thermally sensitive medicine of preservation of case, in 25 DEG C ± 2 DEG C, the bar of relative humidity 60% ± 10%
Carried out under part, the time is 6 months.The microballoon of embodiment 1~13 and comparative example 1~4 is placed in 25 DEG C ± 2 DEG C, relative humidity
Accelerated stability is investigated in 60% ± 10% testing chamber for medicine stability, was sampled respectively at the 30th day, the 90th day and the 180th day
(n=3) release behavior is surveyed, release behavior assay method is with embodiment 14.Result is as shown in table 3~8.Embodiment 1~13 and right
The microballoon release behavior of the 0th day of ratio 1~4 is shown in Tables 1 and 2.
The 30th day release in vitro data of accelerated stability sample of table 3
The 30th day release in vitro data of accelerated stability sample of table 4
The 90th day release in vitro data of accelerated stability sample of table 5
The 90th day release in vitro data of accelerated stability sample of table 6
The 180th day release in vitro data of accelerated stability sample of table 7
The 180th day release in vitro data of accelerated stability sample of table 8
Contrast table 3~8 can be seen that thus obtained microsphere of the present invention under accelerated stability determination of the environment, and release behavior does not have
It is obvious to change, and the sample of comparative example increases with standing time, its release behavior there occurs obvious change, embody
For release time shifts to an earlier date, release was advanced to and starts within 2-14 days release by 14-21 days.If according to commercially available prod (permanent moral)
Medication, because medicine discharges in advance, is superimposed the dosage being administered orally, and the haemoconcentration in patient blood can be caused to increase.
For this kind of antipsychotic drug of the poorly water soluble drugs such as Risperidone, haemoconcentration increase will cause to produce more serious pair anti-
Should, treatment, live and work to patient cause very important influence.
Embodiment 16
The animal experiment of poorly water soluble drugs slow releasing composition of the present invention
Take New Zealand large ear rabbit of the weight in 2.0kg-3.0kg, every 6 one group (random packet), male and female half and half, every group
Intramuscular injection respectively contains the physiology salts of the 1.2ml containing 0.5%CMC-Na of microballoon prepared by embodiment 1~13 and comparative example 1~4
The suspension of the aqueous solution, the poorly water soluble drugs content of the sustained-release micro-spheres in suspension per dosage is 18mg, respectively at the
0.04d, 0.25d, 0.5d, 1d, 3d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 77d, 84d, 91d and 98d in
Rabbit auricular vein takes blood 5mL.The blood sample of all collections takes -70 DEG C of supernatant and freezes after 8000rpm is centrifuged 10min, then
The blood concentration of poorly water soluble drugs in above-mentioned all blood samples is detected using means known in the art, is averaged.The results are shown in Table 9
With table 10.
The blood concentration result (ng/ml) of table 9
The blood concentration result (ng/ml) of table 10
Be can be seen that by table 9 and table 10, Risperidone microballoon of the invention shows good slow release effect, increases quickly after administration
Concentration is healed, and comparative example needs the time of similar 2-4 weeks to can be only achieved more than 5ng/mL respective concentrations, with release in vitro
Behavior is identical with similar.The blood concentration of sustained-release micro-spheres of the invention can last up to about 20-60 in the range of 5-30ng/mL
My god；And comparative example lasts about 20-28 days.Illustrate that Risperidone microballoon of the invention has more preferable action effect, can be more long
Time in keep certain blood concentration, administration dosage period can be extended, mitigate side effect, improve sufferer compliance.
It is last to should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than the present invention is protected
The limitation of scope is protected, although being explained in detail to the present invention with reference to preferred embodiment, one of ordinary skill in the art should
Understand, technical scheme can be modified or equivalent, without deviating from the essence of technical solution of the present invention
And scope.
Claims (10)
1. a kind of risperidone slow-release composition, it is characterised in that the non-solvent preparing raw material of the risperidone slow-release composition
Comprising Risperidone, slightly water-soluble polymer and release regulator, the release regulator includes organic lipophilicity substance.
2. risperidone slow-release composition as claimed in claim 1, it is characterised in that the risperidone slow-release composition it is non-molten
In formulation preparing raw material, the weight/mass percentage composition of the release regulator is 0.1~10%；Preferably, the risperidone slow-release
In the non-solvent preparing raw material of composition, the weight/mass percentage composition of the release regulator is 0.5~8%；Preferably, it is described
In the non-solvent preparing raw material of risperidone slow-release composition, the weight/mass percentage composition of the release regulator is 1~6%.
3. risperidone slow-release composition as claimed in claim 1 or 2, it is characterised in that the organic lipophilic material is fat
At least one in fat acid, fatty acid ester, grease.
4. risperidone slow-release composition as claimed in claim 3, it is characterised in that the aliphatic acid is oleic acid, stearic acid, the moon
At least one in cinnamic acid, myristic acid, palmitic acid, arachidic acid, mountain Yu acid, lignin acid.
5. the risperidone slow-release composition as described in any one of Claims 1 to 4, it is characterised in that the risperidone slow-release group
In the non-solvent preparing raw material of compound, the weight/mass percentage composition of the Risperidone is 25~60%, the slightly water-soluble polymerization
The weight/mass percentage composition of thing is 39.9-74.9%；Preferably, the non-solvent preparing raw material of the risperidone slow-release composition
In, the weight/mass percentage composition of the Risperidone is 30~55%, and the weight/mass percentage composition of the slightly water-soluble polymer is 44.9-
69.9%；Preferably, in the non-solvent preparing raw material of the risperidone slow-release composition, the quality percentage of the Risperidone contains
It is 35~50% to measure, and the weight/mass percentage composition of the slightly water-soluble polymer is 44.9-69.9%.
6. risperidone slow-release composition as claimed in claim 5, it is characterised in that the slightly water-soluble polymer is poly- third to hand over
At least one in ester, PLGA and their copolymers with polyethylene glycol.
7. risperidone slow-release composition as claimed in claim 6, it is characterised in that the polylactide, lactide coglycolide
Copolymer, the weight average molecular weight of their copolymers with polyethylene glycol are 25000-150000Da；Preferably, described poly- third hand over
Ester, PLGA, the weight average molecular weight of their copolymers with polyethylene glycol are 30000-125000Da；
It is highly preferred that the polylactide, PLGA, their weight average molecular weight with the copolymer of polyethylene glycol
It is 30000-100000Da.
8. risperidone slow-release composition as claimed in claims 6 or 7, it is characterised in that the polylactide, lactide-second
Lactide copolymers, the viscosity of their copolymers with polyethylene glycol are 0.30-1.15dL/g；Preferably, the polylactide,
PLGA, the viscosity of their copolymers with polyethylene glycol are 0.37-0.95dL/g；It is highly preferred that institute
State polylactide, PLGA, the viscosity of their copolymers with polyethylene glycol and be 0.37-0.80dL/g.
9. risperidone slow-release composition as claimed in claim 6, it is characterised in that the slightly water-soluble polymer is poly- third to hand over
At least one in ester, PLGA, its copolymer with polyethylene glycol, and wherein lactide and glycolide
Mol ratio be 100:0~65:35；Preferably, wherein lactide and the mol ratio of glycolide is 100:0~70:30；More preferably
Ground, wherein lactide are 100 with the mol ratio of glycolide:0~75:25.
10. the risperidone slow-release composition as described in any one of claim 1~9, it is characterised in that the risperidone slow-release group
The preparation method of compound is comprised the following steps：
(1) the non-solvent preparing raw material is dissolved in organic solvent, forms interior oil phase；
(2) surfactant is dissolved in aqueous medium, forms outer water phase；
(3) the interior oil phase that step (1) is obtained is added in outer water phase, is made emulsion, then evaporated by solvent or solvent is carried
Microsphere hardening, the collection particulate made in solution is taken, is washed and is dried, obtain risperidone slow-release microsphere.
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| CN201710052701.3A CN106822042A (en) | 2017-01-24 | 2017-01-24 | A kind of risperidone slow-release composition and preparation method thereof |
| PCT/CN2018/073899 WO2018137629A1 (en) | 2017-01-24 | 2018-01-24 | Risperidone sustained release composition and preparation method therefor |
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| CN201710052701.3A CN106822042A (en) | 2017-01-24 | 2017-01-24 | A kind of risperidone slow-release composition and preparation method thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018137629A1 (en) * | 2017-01-24 | 2018-08-02 | 广州帝奇医药技术有限公司 | Risperidone sustained release composition and preparation method therefor |
| WO2018137631A1 (en) * | 2017-01-24 | 2018-08-02 | 广州帝奇医药技术有限公司 | Sparingly water-soluble or slightly water-soluble drug sustained release composition and preparation method therefor |
| CN111278429A (en) * | 2017-11-01 | 2020-06-12 | 韩国化学研究院 | Microsphere sustained-release injection containing escitalopram and preparation method thereof |
| CN115006354A (en) * | 2022-06-16 | 2022-09-06 | 北京阳光诺和药物研究股份有限公司 | Risperidone-blended PLGA (polylactic-co-glycolic acid) sustained-release microspheres and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB201904771D0 (en) * | 2019-04-04 | 2019-05-22 | Orexo Ab | New pharmaceutical compositions |
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| CN1625391A (en) * | 2002-02-01 | 2005-06-08 | 株式会社太平洋 | Cyclosporin-containing sustained release pharmaceutical composition |
| CN101541313A (en) * | 2006-10-05 | 2009-09-23 | 万能药生物有限公司 | Novel injectable depot compositions and process of preparation of such compositions |
| CN103338752A (en) * | 2011-04-25 | 2013-10-02 | 山东绿叶制药有限公司 | Risperidone sustained release microsphere composition |
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| DK1660039T3 (en) * | 2003-07-18 | 2017-01-16 | Oakwood Laboratories L L C | PREVENTION OF REDUCTION OF THE POLYMER MOLECULE WEIGHT, THE PREPARATION OF PURPOSES AND GELING IN POLYMER COMPOSITIONS |
| CN101292960B (en) * | 2006-04-29 | 2011-02-09 | 中国人民解放军军事医学科学院毒物药物研究所 | Sustained-release microsphere containing risperidone and preparation method thereof |
| CN106822042A (en) * | 2017-01-24 | 2017-06-13 | 广州帝奇医药技术有限公司 | A kind of risperidone slow-release composition and preparation method thereof |
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2017
- 2017-01-24 CN CN201710052701.3A patent/CN106822042A/en active Pending
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2018
- 2018-01-24 WO PCT/CN2018/073899 patent/WO2018137629A1/en active Application Filing
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|---|---|---|---|---|
| CN1625391A (en) * | 2002-02-01 | 2005-06-08 | 株式会社太平洋 | Cyclosporin-containing sustained release pharmaceutical composition |
| CN101541313A (en) * | 2006-10-05 | 2009-09-23 | 万能药生物有限公司 | Novel injectable depot compositions and process of preparation of such compositions |
| CN103338752A (en) * | 2011-04-25 | 2013-10-02 | 山东绿叶制药有限公司 | Risperidone sustained release microsphere composition |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018137629A1 (en) * | 2017-01-24 | 2018-08-02 | 广州帝奇医药技术有限公司 | Risperidone sustained release composition and preparation method therefor |
| WO2018137631A1 (en) * | 2017-01-24 | 2018-08-02 | 广州帝奇医药技术有限公司 | Sparingly water-soluble or slightly water-soluble drug sustained release composition and preparation method therefor |
| CN111278429A (en) * | 2017-11-01 | 2020-06-12 | 韩国化学研究院 | Microsphere sustained-release injection containing escitalopram and preparation method thereof |
| CN115006354A (en) * | 2022-06-16 | 2022-09-06 | 北京阳光诺和药物研究股份有限公司 | Risperidone-blended PLGA (polylactic-co-glycolic acid) sustained-release microspheres and preparation method thereof |
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| WO2018137629A1 (en) | 2018-08-02 |
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