WO2018166502A1 - 一种水难溶/微溶性药物缓释组合物 - Google Patents

一种水难溶/微溶性药物缓释组合物 Download PDF

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Publication number
WO2018166502A1
WO2018166502A1 PCT/CN2018/079173 CN2018079173W WO2018166502A1 WO 2018166502 A1 WO2018166502 A1 WO 2018166502A1 CN 2018079173 W CN2018079173 W CN 2018079173W WO 2018166502 A1 WO2018166502 A1 WO 2018166502A1
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sustained
release
water
insoluble
microsphere
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PCT/CN2018/079173
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English (en)
French (fr)
Inventor
赖树挺
郑阳
曹付春
连远发
刘锋
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广州帝奇医药技术有限公司
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Publication of WO2018166502A1 publication Critical patent/WO2018166502A1/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
    • A61K9/48—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
    • 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
    • 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)

Definitions

  • the present invention relates to a sustained release composition, and in particular to a water insoluble/slightly soluble drug sustained release composition.
  • biodegradable polymer microspheres have become one of the important research fields of new drug delivery systems, which use microspheres made of matrix materials such as polylactic acid (PLA) and lactic acid-glycolic acid copolymer (PLGA). It can be used as a carrier for long-acting preparations, and can be administered to humans or animals by intramuscular or subcutaneous injection. It can control the release rate and release cycle of the drug, and can maintain an effective drug treatment concentration for a long time with only one administration. The total dose of the drug required for the treatment is improved, and the patient's medication compliance is improved.
  • PLA polylactic acid
  • PLGA lactic acid-glycolic acid copolymer
  • Risperidal Consta (Hengde), a long-acting antipsychotic drug developed based on the technology disclosed in the patent CN1137756, uses PLGA with a molecular weight of about 100-150 kDa as a carrier, and risperidone as an API.
  • the drug loading is about 35-40%, muscles every 2 weeks. Inject once.
  • the preparation is effective in avoiding the peak-to-valley concentration produced by daily medication, but only a small amount of drug is released on the first day, followed by a drug release stagnation period of about 3 weeks, so the patient needs to be within 3 weeks after the injection of the microsphere.
  • Oral administration of common dosage forms can achieve therapeutic effects, inconvenient clinical use, and poor patient compliance.
  • the object of the present invention is to overcome the above-mentioned deficiencies of the prior art and to provide an insignificant release delay period or a shorter delayed release period, no burst release phenomenon, good sustained release performance, and can be used for several weeks or more.
  • a water-insoluble/slightly soluble drug sustained-release composition that maintains an effective blood concentration for a period of time.
  • the technical solution adopted by the present invention is: a water-insoluble/slightly soluble drug sustained-release composition comprising two or more water-insoluble/slightly soluble drug sustained-release microspheres having different release behaviors.
  • the above two kinds of water-insoluble/slightly soluble drug sustained-release microspheres with different release behaviors refer to: drug release experiments started at the same time, and the drug release time has no cross or crossover, but two or more types are connected before and after. Water-soluble/slightly soluble drug sustained-release microspheres with different release behaviors.
  • the sustained-release composition of the present invention has no significant release delay period or short delay by combining two or more sustained-release microspheres having different release behaviors, and the thus obtained water-insoluble/slightly soluble drug sustained-release composition has no obvious release delay or short delay. Release period, no burst release, good sustained release performance, and can maintain effective blood concentration in a few weeks or more, effectively reducing the frequency of administration, facilitating the life and work of patients, and improving Patient administration compliance and convenience.
  • the delayed release means that the microspheres cannot start releasing the drug immediately under the condition of in vitro release, or the total amount of the drug released in the initial period of time is small, less than 10%, preferably less than 8%, more preferably less than 5%; the absence of a significant delayed release period or a shorter delayed release period means that the delayed release is not more than 3 days, preferably no more than 2 days, more preferably no more than 1 day.
  • the water-insoluble/slightly soluble drug sustained-release composition includes no significant delayed release period or a delayed delayed release period, and the drug Sustained release microspheres A with a release time of 2-3 weeks and sustained release microspheres B with a 2-3 week delayed release period and a drug release time of 2-3 weeks; or a drug with a 2-3 week delayed release period Sustained-release microspheres C with a release time of 4-5 weeks and the sustained-release microspheres A; or sustained-release microspheres E with a 4-week delayed release period and a drug release time of 4-5 weeks and no significant delay a sustained release microsphere D having a shorter release period or a delayed release period and a drug release time of 4-5 weeks; or comprising the sustained release microsphere A, sustained release microsphere B and sustained release microsphere E; or Sustained-release microspheres A, sustained-release microspheres C, and sustained-release microspheres F having a delayed release
  • a water-insoluble/slightly soluble drug sustained-release composition consisting of sustained-release microspheres A and sustained-release microspheres B, which can continuously release drugs for 4-6 weeks; consists of sustained-release microspheres A and sustained-release microspheres C A poorly water-soluble/slightly soluble drug sustained-release composition, which can continuously release a drug for 6-7 weeks; a water-insoluble/slightly soluble drug sustained-release composition composed of sustained-release microspheres D and sustained-release microspheres E, which can Sustained release of the drug for about 8 weeks; a water-insoluble/slightly soluble drug sustained-release composition consisting of sustained-release microspheres A, sustained-release microspheres B and sustained-release microspheres E, which can continuously release the drug for 8-9 weeks; A water-insoluble/slightly soluble drug sustained-release composition comprising sustained-release microspheres A, sustained-release microspheres C and sustained-release microspheres F, which can continuously release the drug for 9-10 weeks or more.
  • the sustained release microsphere A, the sustained release microsphere B, the sustained release microsphere C, the sustained release microsphere D, and the sustained release micro each include the following components by weight: 30-60 parts of the poorly water-soluble/slightly soluble drug, and 40-70 parts of the poorly water-soluble polymer.
  • the sustained release microsphere A, the sustained release microsphere B, the sustained release microsphere C, the sustained release microsphere D, and the sustained release micro includes the following components by weight: 35-55 parts of a poorly water-soluble/slightly soluble drug, and 45-65 parts of a poorly water-soluble polymer.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention includes risperidone, paliperidone, aripiprazole, iloperidone, Epiprazole, ziprasidone, anastrozole, donepezil, olanzapine, naltrexone, haloperidol, paclitaxel, docetaxel, entecavir or derivatives thereof.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention includes risperidone, paliperidone, aripiprazole, and iloperidone. , donepezil, olanzapine, epidiperazole, entecavir, or derivatives thereof.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention includes risperidone, paliperidone, aripiprazole, and iloperidone. , epiliperazole, or their derivatives. Wherein, the derivative includes, but is not limited to, paliperidone palmitate, aripiprazole lauroyl, haloperidol citrate, olanzapine pamoate, ziprasidone mesylate.
  • the poorly water-soluble polymer is a polyester, a polycarbonate, a polyacetal, a polyanhydride, a polyhydroxy fatty acid, and copolymerization thereof. At least one of a substance or a blend.
  • the poorly water-soluble polymer is polylactide (PLA), polyglycolide (PGA), lactide-B-crossing.
  • Ester copolymer (PLGA), polycaprolactone (PCL), their copolymer with polyethylene glycol (PEG) (such as PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG -PCL, PCL-PEG-PCL, PEG-PLA-PEG, PEG-PLGA-PEG), polyhydroxybutyric acid, polyhydroxyvaleric acid, polydioxanone (PPDO), chitosan, alginic acid and At least one of a salt, a polycyanoacrylate, a polyanhydride, a polyorthoester, a polyamide, a polyphosphazene, and a polyphosphate.
  • PEG polyethylene glycol
  • PPDO polydioxanone
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are At least one of copolymers with polyethylene glycol.
  • PLA polylactide
  • PLGA lactide-glycolide copolymer
  • the poorly soluble drug sustained-release composition is polypropylene At least one of an ester (PLA), a lactide-glycolide copolymer (PLGA).
  • the molecular chain of the poorly water-soluble polymer carries an anionic or cationic group or does not carry an anionic or cationic group.
  • the poorly water soluble polymer has a terminal carboxyl group or a terminal ester group. More preferably, the poorly water-soluble polymer has a terminal carboxyl group.
  • the poorly water-soluble polymer in the sustained-release microsphere A, is a lactide-glycolide copolymer, and lactide - the glycolide copolymer has a weight average molecular weight of 20000-40000 Da and a viscosity of 0.23-0.42 dL/g, wherein the molar ratio of lactide to glycolide is 70:30-80:20;
  • the poorly water-soluble polymer is a lactide-glycolide copolymer, and the lactide-glycolide copolymer has a weight average molecular weight of 41,000 to 100,000 Da and a viscosity of 0.42 to 0.9 dL/g.
  • the molar ratio of the ester to the glycolide is 70:30-80:20; in the sustained-release microsphere C, the poorly water-soluble polymer is a lactide-glycolide copolymer, and the lactide-glycolide The copolymer has a weight average molecular weight of 35100-44900Da, a viscosity of 0.38-0.46dL/g, wherein the molar ratio of lactide to glycolide is 80:20-90:10; in the sustained release microsphere D, water
  • the poorly soluble polymer is a lactide-glycolide copolymer, and the lactide-glycolide copolymer has a weight average molecular weight of 20,000 to 35,000 Da and a viscosity of 0.23 to 0.38 dL/g, wherein lactide and B.
  • the molar ratio of ester is 80:20-90:10
  • the poorly water-soluble polymer is a lactide-glycolide copolymer
  • the lactide-glycolide copolymer has a weight average molecular weight of 45,000 to 65,000 Da and a viscosity of 0.38 to 0.58 dL.
  • the poorly water-soluble polymer is polylactide or lactide-glycolide copolymerization
  • the water-insoluble polymer has a weight average molecular weight of 20,000 to 60,000 Da and a viscosity of 0.23 to 0.54 dL/g, wherein the molar ratio of lactide to glycolide is from 90:10 to 100:0.
  • the lactide-glycolide copolymer has a weight average molecular weight of 20,000 to 35,000 Da and a viscosity of 0.23 to 0.38 dL/g, wherein the molar ratio of lactide to glycolide At 75:25;
  • the lactide-glycolide copolymer has a weight average molecular weight of 50,000 to 900,000 Da and a viscosity of 0.49 to 0.081 lL/g, wherein the molar of lactide and glycolide The ratio is 75:25;
  • the lactide-glycolide copolymer has a weight average molecular weight of 38,000-42000 Da and a viscosity of 0.40-0.43 dL/g, wherein the molar ratio of lactide to glycolide 85:15;
  • the lactide-glycolide copolymer has a weight average molecular weight of 25,000 to 30,000 Da and a viscosity of 0.27 to 0.34 dL/g, wherein the molar ratio of lactide to glycolide 85:15;
  • the lactide-glycolide copolymer has a weight average molecular weight of 45,000 to 60,000 Da and a viscosity of 0.42 to 0.54 dL/g, wherein the molar ratio of lactide to glycolide 85:15;
  • the water-insoluble polymer has a weight average molecular weight of 25,000 to 55,000 Da and a viscosity of 0.28 to 0.52 dL/g.
  • the poorly water-soluble polymer is a biodegradable, biocompatible water-insoluble polymer.
  • the poorly water-soluble polymer may be a single polymer or a mixture of a plurality of polymers, such as a molar ratio of lactide to glycolide and a combination of PLGA having the same molecular weight but different carrying groups.
  • Combination, molecular weight, carrier group of PLGA with the same molar ratio of ester to glycolide and PLGA with the same carrier group but different molecular weight, molecular weight and the same carrier group but different molar ratio of lactide to glycolide A combination of PLGA in which the molar ratio of lactide to glycolide is different, a combination of PLGA and PLA, and the like.
  • the molecular weight used in the present specification is a weight average molecular weight, which is a value obtained by gel permeation chromatography (GPC) measurement; the viscosity used is a value obtained by an Ubbelohde viscometer measurement.
  • GPC gel permeation chromatography
  • the sustained-release microsphere A further comprises a release regulator, the quality of the release modifier in the sustained-release microsphere A The percentage is 0.1-10%; preferably, the release modifier has a mass percentage in the sustained release microsphere A of 0.5-8%; preferably, the release regulator is in the sustained release The mass percentage in the microsphere A is 1-6%.
  • the release modifier is an organic lipophilic substance and/or an organic hydrophilic substance.
  • the organic lipophilic substance is at least one of a fatty acid, a fatty acid ester, and a fat; the organic hydrophilic substance is an alcohol At least one of a class, a saccharide, an amino acid, a protein, and polyvinylpyrrolidone.
  • the organic lipophilic substance is a fatty acid; and the organic hydrophilic substance is at least one of an alcohol and polyvinylpyrrolidone.
  • the fatty acid is oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, woody At least one of the acids;
  • the alcohol is polyethylene glycol (PEG) having a molecular weight of 400 to 6000 Da.
  • the fatty acid is preferably, but not limited to, a C12-C24 alkanoic acid and derivatives thereof, including but not limited to oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, lignin acid, preferably Stearic acid, behenic acid.
  • the alcohols are preferably, but not limited to, polyethylene glycol (PEG) having a molecular weight of 600-6000 Da, such as PEG 600, PEG 1000, PEG 2000, PEG 4000, PEG 6000, preferably polyethylene glycol (PEG) having a molecular weight of 400-6000 Da, more preferably PEG having a molecular weight of 400 to 3000 Da.
  • the sustained-release microspheres further comprise an excipient, and the mass percentage of the excipient in the sustained-release microspheres The content is 0 to 8%.
  • One or more excipients may be included in the sustained release microspheres of the present invention.
  • the excipients can impart other characteristics to the active drug or microparticles, such as increasing the stability of the microparticles, active drug or carrier, promoting controlled release of the active drug from the microparticles, or modulating the permeability of the biological tissue of the active drug.
  • the excipient includes a buffer and an antioxidant
  • the buffering agent is at least one of a mineral acid and an organic acid salt, and the mass percentage of the buffering agent in the sustained-release microsphere is 0 to 5%; preferably, the buffering agent is in the The mass percentage of the slow release microspheres is 0 to 3%; preferably, the mass percentage of the buffer in the sustained release microspheres is 0 to 2%;
  • the antioxidants are tert-butyl-p-hydroxyanisole, dibutylphenol, tocopherol, isopropyl myristate, tocopheryl daacetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butyl Hydroxyguanidine, hydroxycoumarin, butylated hydroxytoluene, decanoic acid fatty acid ester, propyl hydroxybenzoate, hydroxybutanone, vitamin E, vitamin E-TPGS, ⁇ -hydroxybenzoate
  • At least one of the antioxidants; the mass percentage of the antioxidant in the sustained release microspheres is 0 to 1%; preferably, the mass percentage of the antioxidant in the sustained release microspheres is 0 ⁇ 0.08%;
  • the antioxidant is present in the sustained release microspheres in an amount of from 0 to 0.05% by mass.
  • the citric acid fatty acid ester is selected from, for example, ethyl ester, propyl ester, octyl ester, lauryl ester, and the ⁇ -hydroxy benzoate is selected from, for example, methyl ester, ethyl ester, propyl ester, and butyl. Ester and the like.
  • the antioxidant is present in the sustained release composition in an amount effective to remove any free radicals or peroxides produced within the implant.
  • the buffering agent of the present invention includes, but is not limited to, mineral acids and organic acid salts, such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate.
  • mineral acids and organic acid salts such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate.
  • the water-insoluble/slightly soluble drug sustained-release composition comprises sustained-release microspheres A and sustained-release microspheres B, and sustained release.
  • the weight ratio of the water-insoluble/slightly soluble drug in the microsphere A to the poorly soluble/slightly soluble drug in the sustained-release microsphere B is from 1 to 3:1 to 3; the water-insoluble/slightly soluble drug sustained-release composition
  • the weight ratio of the water-insoluble/slightly soluble drug in the slow-release microsphere A to the water-insoluble/slightly soluble drug in the sustained-release microsphere C is 1 to 3:2.
  • the water-insoluble/slightly soluble drug sustained-release composition comprises sustained-release microspheres D and sustained-release microspheres E, the water-insoluble/slightly soluble drug and the sustained-release microspheres E in the sustained-release microsphere D
  • the weight ratio of the water-insoluble/slightly soluble drug is 1:1; when the water-insoluble/slightly soluble drug sustained-release composition comprises the sustained-release microsphere D and the sustained-release microsphere F, the water in the sustained-release microsphere D is difficult.
  • the weight ratio of the poorly soluble/slightly soluble drug to the slow-dissolving microsphere F in the water-insoluble/slightly soluble drug is 5:4;
  • the water-insoluble/slightly soluble drug sustained-release composition includes the sustained-release microsphere A, When the microsphere B and the sustained release microsphere E are released, the slowing
  • the water-insoluble/slightly soluble drug sustained-release composition includes the sustained-release microsphere A, sustained release When the microsphere B and the sustained release microsphere F, the weight ratio of the water-insoluble/slightly
  • the water-insoluble/slightly soluble drug sustained-release composition comprises sustained-release microspheres A and sustained-release microspheres B, and sustained release.
  • the weight ratio of the water-insoluble/slightly soluble drug in the microsphere A to the water-insoluble/slightly soluble drug in the sustained-release microsphere B was 1:1.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention is a combination of two or more sustained release microspheres having different release behaviors, wherein the sustained release microspheres with different release behaviors exist in a certain ratio, and the ratio is microspheres.
  • the ratio of the mass of the active drug contained in the drug is the same as the ratio of the release cycle of the sustained-release microspheres with different release behaviors, and the proportion of the cells having a longer release period is larger. Further, the ratio is also related to the nature of the drug or the clinical administration method. For a clinical application in which the dose needs to be gradually increased, the sustained release microsphere unit released later is larger than the previous unit.
  • the specific combination can be flexibly combined according to the actual application.
  • the method for preparing the sustained-release microspheres comprises the following steps:
  • the mass percentage of the poorly water-soluble polymer to the organic solvent is 1 to 10%; 2), the mass percentage of the surfactant in the outer aqueous phase is 0.1 to 10%; in the step (3), the volume of the outer aqueous phase is 60 times or more the volume of the inner oil phase .
  • the mass percentage of the poorly water-soluble polymer to the organic solvent is 1.5-9%; 2), the mass percentage of the surfactant in the outer aqueous phase is 0.5-8%; in the step (3), the volume of the outer aqueous phase is more than 80 times the volume of the inner oil phase .
  • the mass percentage of the poorly water-soluble polymer to the organic solvent is 3-8.5%; 2), the mass percentage of the surfactant in the outer aqueous phase is 1 to 7%; in the step (3), the volume of the outer aqueous phase is more than 100 times the volume of the inner oil phase .
  • the organic solvent is at least one of a halogenated hydrocarbon, a fatty acid ester, and an aromatic hydrocarbon;
  • the halogenated hydrocarbon comprises dichloromethane, chloroform, ethyl chloride, tetrachloroethylene, trichloroethylene, dichloroethane, trichloroethane, carbon tetrachloride, fluorocarbon, chlorobenzene, trichlorofluoromethane;
  • the fatty acid ester comprises ethyl acetate and butyl acetate;
  • the aromatic hydrocarbon comprises benzene, toluene, xylene, benzyl alcohol.
  • the organic solvent can simultaneously dissolve the biodegradable, biocompatible water-insoluble polymer and the water-insoluble/slightly soluble drug, having a boiling point lower than water and being insoluble or poorly soluble in water.
  • the organic solvent may be a single organic solvent or a miscible two or more organic solvents.
  • the organic solvent is selected from the group consisting of halogenated hydrocarbons (such as dichloromethane, chloroform, ethyl chloride, tetrachloroethylene, trichloroethylene, dichloroethane, trichloroethane, carbon tetrachloride, fluorocarbons, chlorobenzenes).
  • the aliphatic hydrocarbon solvent is more preferably dichloromethane or chloroform.
  • the proportion of the organic solvent in the mixture varies according to different drugs, and is formulated according to actual conditions.
  • the surfactant is a nonionic surfactant, and the nonionic surfactant comprises a polyoxyethylene fatty alcohol ether.
  • polysorbate such as Tween 80, Tween 60
  • polyoxyethylene fatty acid ester OEO
  • polyoxyethylene castor oil derivative polyoxyethylene polypropylene glycol copolymer, sucrose fatty acid ester, polyethylene Glycol fatty acid ester, polyoxyethylene sorbitan mono-fatty acid ester, polyoxyethylene sorbitan di-fatty acid ester, polyoxyethylene glycerin mono-fatty acid ester, polyoxyethylene glycerin di-fatty acid ester, polyglycerin Fatty acid esters, polypropylene glycol monoesters, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxamers), polyvinyl alcohols (PVA) and their
  • the nonionic surfactant is a polyoxyethylene-polyoxypropylene copolymer, polyvinyl alcohol, polysorbate, polyethylene. Pyrrolidone or polysaccharide.
  • the nonionic surfactant is polyvinyl alcohol or a polysaccharide.
  • the polysaccharide includes starch and starch derivatives, methyl cellulose, ethyl cellulose, hydroxy cellulose, hydroxypropyl cellulose. , hydroxypropylmethylcellulose, gum arabic, chitosan derivatives, gellan gum, alginic acid derivatives, dextran derivatives and amorphous cellulose, preferably hypromellose, chitosan and Derivatives, amylopectin or dextran and derivatives thereof.
  • the outer aqueous phase further contains an inorganic salt or an organic salt;
  • the inorganic salt is a potassium salt of phosphoric acid, sulfuric acid, acetic acid or carbonic acid. Or at least one of sodium salt, Tris, MES, HEPES.
  • the concentration by weight of the inorganic salt in the aqueous solution is from 0 to 5%, preferably from 0.01 to 4%, more preferably from 0.05 to 3%; the pH is in the range of from 3 to 9, preferably from 4 to 9, more preferably from 5.5 to 8.5.
  • the outer aqueous phase contains an inorganic salt or an organic salt to reduce the infiltration of the water-soluble active substance into the aqueous phase during the solidification of the microsphere.
  • the mechanism is to increase the osmotic pressure of the external phase or reduce the solubility of the active material in the external phase.
  • the method of forming a uniform emulsion is the same as the well-known emulsification method, using a device that generates high shear force (such as a magnetic stirrer, a mechanical stirrer, a high speed homogenizer, an ultrasound machine, a membrane emulsifier, a rotor-stator mixer). , static mixer, high pressure homogenizer, etc.)
  • a device that generates high shear force such as a magnetic stirrer, a mechanical stirrer, a high speed homogenizer, an ultrasound machine, a membrane emulsifier, a rotor-stator mixer.
  • static mixer high pressure homogenizer, etc.
  • each of the microspheres composed has a similar geometric particle size.
  • the sustained release microspheres each have a geometric particle size of less than 200 ⁇ m.
  • the microspheres have a particle size of from about 10 to about 200 ⁇ m, preferably from about 20 to about 150 ⁇ m, more preferably from about 30 to about 150 ⁇ m.
  • the size of the microspheres is measured by dynamic light scattering techniques (such as laser diffraction) or microscopic techniques (such as scanning electron microscopy).
  • sustained release composition When administered as a suspension, it can be formulated as a suspension with a suitable dispersion medium.
  • the dispersion medium includes a nonionic surfactant (or stabilizer), a polyoxyethylene castor oil derivative, a cellulose thickener, sodium alginate, hyaluronic acid, dextrin, and starch. Alternatively, it may be combined with other excipients such as isotonic agents (such as sodium chloride, mannitol, glycerol, sorbitol, lactose, xylitol, maltose, galactose, sucrose, glucose, etc.), pH adjusters.
  • preservatives such as parabens, propylparaben, benzyl alcohol
  • chlorobutanol sorbic acid, boric acid, etc., etc.
  • a sustained release injection can also be obtained by dispersing the microspheres in a vegetable oil such as sesame oil and corn oil or a vegetable oil to which a phospholipid such as lecithin is added, or dispersing in a medium chain triglyceride to Obtain an oily suspension.
  • a vegetable oil such as sesame oil and corn oil or a vegetable oil to which a phospholipid such as lecithin is added, or dispersing in a medium chain triglyceride to Obtain an oily suspension.
  • the sustained release composition is a combination of two or more sustained release microspheres with different release behaviors, and can be administered in the form of a mixture, and the sustained release microspheres with different release behaviors are simultaneously present in the same packaging container in the form of a mixture.
  • the mixture is a physical mixture of two or more sustained release microspheres prepared separately; or two or more sustained release microspheres prepared separately are placed in different packaging containers or separated by a removable compartment Two or more packaging containers that are not connected or partially connected to each other, are mixed before administration; or two or more sustained-release microspheres prepared are separately placed in separate packaging containers, or administered simultaneously in separate units or at 12h Dosing is administered to the same or different sites within the time difference.
  • the sustained-release composition obtained by the present invention can be used in the form of granules, suspensions, implants, injections, adhesives, and the like, and can be administered orally or parenterally (intramuscular injection, subcutaneous injection). , transdermal administration, mucosal administration (intracrine, intravaginal, rectal, etc.)).
  • compositions of the present invention are sufficiently stable to be sustained for more than a few weeks, such as up to about 4 weeks, such as up to about 8 weeks, such as up to about 12 weeks, or longer, depending on the particular pharmaceutical properties or therapeutic needs. Adjustment.
  • Example 1 is a concentration of risperidone in a blood sample of the sustained release microsphere of Example 6 and the sustained release composition of Example 31 in the beagle dog according to Example 54 of the present invention
  • Figure 2 is a graph showing the concentration of risperidone in a blood sample of the sustained release microsphere of Example 6 and the sustained release composition of Example 47 in the beagle dog of Example 54 of the present invention.
  • the sustained release microsphere (sustained release microsphere A) of the present embodiment has no obvious delayed release period or a delayed release period, and the drug release time is 2-3 weeks, and the preparation raw materials include the following parts by weight.
  • Components 30 parts of poorly water-soluble/slightly soluble drugs, 70 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the PLGA
  • the weight average molecular weight is 20 kDa, the viscosity is 0.23 dL/g, and the molar ratio of lactide to glycolide is 70:30, which has a terminal carboxyl group.
  • the method for preparing the sustained-release microspheres of the present embodiment is: dissolving the water-insoluble/slightly soluble drug and the poorly water-soluble polymer in 10 times of methylene chloride to dissolve the clarified oil internal phase;
  • the internal phase solution was added to a 100% 2% PVA aqueous solution in an oil internal phase volume under mechanical stirring (1000 rpm), and emulsified for 10 minutes to obtain an O/W emulsion; the emulsion was mechanically stirred (500 rpm) for about 6 hours to cure the microspheres;
  • the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain a sustained release microsphere A.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 25-98 ⁇ m.
  • the drug loading rate is 27.60%, and the drug encapsulation efficiency is 92.00%.
  • the sustained release microsphere (sustained release microsphere A) of the present embodiment has no obvious release delay period and the drug release time is 2 weeks, and the preparation raw material comprises the following components by weight: water insoluble/ 35 parts of slightly soluble drug, 65 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the poorly water-soluble polymer is PLGA, and the weight average molecular weight of the PLGA is 25 kDa, and the viscosity is 0.28 dL/g, wherein the molar ratio of lactide to glycolide is 75:25, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 24-100 ⁇ m.
  • the drug loading rate is 31.94%, and the drug encapsulation efficiency is 91.26%.
  • the sustained release microsphere (sustained release microsphere A) of the present embodiment has no obvious release delay period and the drug release time is 3 weeks, and the preparation material of the sustained release microspheres includes the following weight groups. Points: 35 parts of water-insoluble/slightly soluble drug, 55 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 30 kDa, the viscosity is 0.32 dL/g, and the molar ratio of lactide to glycolide is 80:20, which has a terminal carboxyl group.
  • the preparation method of the sustained release microsphere A of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microsphere A has a round shape and a smooth surface, and has a particle diameter of 20-95 ⁇ m.
  • the drug loading rate is determined to be 40.89%, and the drug encapsulation efficiency is 90.86%.
  • the sustained release microsphere (sustained release microsphere A) of the present embodiment has no obvious release delay period, and the drug release time is released for 2 weeks, and the preparation raw material of the sustained release microsphere includes the following parts by weight.
  • Component 55 parts of water-insoluble/slightly soluble drug, 45 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is lauroyl aripiprazole, and the water-insoluble polymer is PLGA, PLGA has a weight average molecular weight of 35 kDa and a viscosity of 0.38 dL/g, wherein the molar ratio of lactide to glycolide is 75:25, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 28-105 ⁇ m.
  • the drug loading rate is 50.05%, and the drug encapsulation efficiency is 91.00%.
  • the sustained release microsphere (sustained release microsphere A) of the present embodiment has no obvious release delay period, and the drug release time is released for 3 weeks, and the preparation raw material of the sustained release microsphere comprises the following parts by weight Component: 60 parts of water-insoluble/slightly soluble drug, 40 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is paliperidone palmitate, and the water-insoluble polymer is PLGA, PLGA has a weight average molecular weight of 40 kDa and a viscosity of 0.42 dL/g, wherein the molar ratio of lactide to glycolide is 80:20, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 23-100 ⁇ m.
  • the drug loading rate is 54.25%, and the drug encapsulation efficiency is 90.42%.
  • the sustained release microsphere (sustained release microsphere B) of the present embodiment has a delayed release period of 2 weeks and a drug release time of 2 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 30 parts of water-insoluble/slightly soluble drug, 70 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 40 kDa, the viscosity is 0.42 dL/g, and the molar ratio of lactide to glycolide is 70:30, which has a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 25-99 ⁇ m.
  • the drug loading rate is 27.61%, and the drug encapsulation efficiency is 92.03%.
  • the sustained release microsphere (sustained release microsphere B) of the present embodiment has a delayed release period of 2 weeks and a drug release time of 3 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 35 parts of water-insoluble/slightly soluble drug, 65 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the poorly water-soluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 50 kDa, the viscosity is 0.49 dL/g, and the molar ratio of lactide to glycolide is 80:20, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 24-96 ⁇ m.
  • the drug loading rate is determined to be 31.79%, and the drug encapsulation efficiency is 90.82%.
  • the sustained release microsphere (sustained release microsphere B) of the embodiment has a delayed release period of about 2 weeks and a drug release time of 2 weeks; and the preparation raw material of the sustained release microsphere comprises the following parts by weight Component: 45 parts of water-insoluble/slightly soluble drug, 55 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is lauroyl aripiprazole, and the water-insoluble polymer is PLGA,
  • the poorly water-soluble polymer is PLGA having a weight average molecular weight of 70 kDa and a viscosity of 0.67 dL/g, wherein the molar ratio of lactide to glycolide is 75:25, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 30-108 ⁇ m.
  • the drug loading rate is determined to be 40.52%, and the drug encapsulation efficiency is 90.05%.
  • the sustained release microsphere (sustained release microsphere B) of the present embodiment has a delayed release period of 3 weeks and a drug release time of 2 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 55 parts of water-insoluble/slightly soluble drug, 45 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 90 kDa, the viscosity is 0.81 dL/g, and the molar ratio of lactide to glycolide is 75:25, which has a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 22-97 ⁇ m.
  • the drug loading rate is 49.94%, and the drug encapsulation efficiency is 90.80%.
  • the sustained release microsphere (sustained release microsphere B) of the present embodiment has a delayed release period of 3 weeks and a drug release time of 2 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 60 parts of water-insoluble/slightly soluble drug, 40 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is paliperidone palmitate, the poorly water-soluble polymer is PLGA, and the PLGA The weight average molecular weight is 100 kDa, the viscosity is 0.90 dL/g, and the molar ratio of lactide to glycolide is 80:20, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 26-107 ⁇ m.
  • the drug loading rate is 53.97%, and the drug encapsulation efficiency is 89.95%.
  • the sustained release microsphere (sustained release microsphere C) of the embodiment has a delayed release period of 2 weeks and a drug release time of 4 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 30 parts of water-insoluble/slightly soluble drug, 70 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight was 35.1 kDa, the viscosity was 0.38 dL/g, and the molar ratio of lactide to glycolide was 80:20, which had a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 31-115 ⁇ m.
  • the drug loading rate is determined to be 26.85%, and the drug encapsulation efficiency is 89.50%.
  • the sustained release microsphere (sustained release microsphere C) of the embodiment has a delayed release period of 2 weeks and a drug release time of 5 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 35 parts of water-insoluble/slightly soluble drug, 65 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the poorly water-soluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 38 kDa, the viscosity is 0.40 dL/g, and the molar ratio of lactide to glycolide is 80:20, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 27-106 ⁇ m.
  • the drug loading rate is 31.89%, and the drug encapsulation efficiency is 91.10%.
  • the sustained release microsphere (sustained release microsphere C) of the present embodiment has a delayed release period of 3 weeks and a drug release time of 4 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 45 parts of water-insoluble/slightly soluble drug, 55 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 40 kDa, the viscosity is 0.41 dL/g, and the molar ratio of lactide to glycolide is 85:15, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 22-103 ⁇ m.
  • the drug loading rate is determined to be 40.75%, and the drug encapsulation efficiency is 90.55%.
  • the sustained release microsphere (sustained release microsphere C) of the embodiment has a delayed release period of 2 weeks and a drug release time of 5 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 55 parts of water-insoluble/slightly soluble drug, 45 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is aripiprazole, the water-insoluble polymer is PLGA, and the weight of the PLGA The average molecular weight is 42 kDa, the viscosity is 0.43 dL/g, and the molar ratio of lactide to glycolide is 85:15, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 25-99 ⁇ m.
  • the drug loading rate is determined to be 50.23%, and the drug encapsulation efficiency is 91.32%.
  • the sustained release microsphere (sustained release microsphere C) of the embodiment has a delayed release period of 3 weeks and a drug release time of 5 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 60 parts of water-insoluble/slightly soluble drug, 40 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is paliperidone, the water-insoluble polymer is PLGA, and the weight of the PLGA The average molecular weight was 44.9 kDa, the viscosity was 0.46 dL/g, and the molar ratio of lactide to glycolide was 90:10, which had a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 28-95 ⁇ m.
  • the drug loading rate is 55.29%, and the drug encapsulation efficiency is 92.15%.
  • the sustained release microsphere (sustained release microsphere D) of the present embodiment has no obvious release delay period and the drug release time is 4 weeks; and the preparation material of the sustained release microspheres includes the following weight groups. Points: 30 parts of water-insoluble/slightly soluble drug, 70 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 20 kDa, the viscosity is 0.23 dL/g, and the molar ratio of lactide to glycolide is 80:20, which has a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 22-96 ⁇ m.
  • the drug loading rate is 27.60%, and the drug encapsulation efficiency is 92.00%.
  • the sustained release microsphere (sustained release microsphere D) of the present embodiment has no obvious release delay period and the drug release time is 4 weeks; and the preparation material of the sustained release microspheres includes the following weight groups. Points: 35 parts of water-insoluble/slightly soluble drug, 65 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is olanzapine, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 25 kDa, the viscosity is 0.27 dL/g, and the molar ratio of lactide to glycolide is 85:15, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 25-112 ⁇ m.
  • the drug loading rate is 32.07%, and the drug encapsulation efficiency is 91.63%.
  • the sustained release microsphere (sustained release microsphere D) of the present embodiment has no obvious release delay period and the drug release time is about 4 weeks; and the preparation raw material of the sustained release microsphere includes the following parts by weight Component: 45 parts of water-insoluble/slightly soluble drug, 55 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is entecavir, the poorly water-soluble polymer is PLGA, and the weight average molecular weight of the PLGA It has a viscosity of 0.29 dL/g of 28 kDa, wherein the molar ratio of lactide to glycolide is 85:15, which has a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 25-98 ⁇ m.
  • the drug loading rate is determined to be 40.90%, and the drug encapsulation efficiency is 90.88%.
  • the sustained release microsphere (sustained release microsphere D) of the present embodiment has no obvious release delay period and the drug release time is 5 weeks; and the preparation material of the sustained release microsphere includes the following weight group Points: 55 parts of water-insoluble/slightly soluble drug, 45 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 30 kDa, the viscosity is 0.34 dL/g, and the molar ratio of lactide to glycolide is 85:15, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 32-105 ⁇ m.
  • the drug loading rate is determined to be 50.63%, and the drug encapsulation efficiency is 92.05%.
  • the sustained release microsphere (sustained release microsphere D) of the present embodiment has no obvious release delay period and the drug release time is 5 weeks; and the preparation material of the sustained release microsphere includes the following weight group Points: 60 parts of water-insoluble/slightly soluble drug, 40 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the poorly water-soluble polymer is PLGA, and the water is poorly soluble in polymerization.
  • the material is PLGA, and the PLGA has a weight average molecular weight of 35 kDa and a viscosity of 0.38 dL/g, wherein the molar ratio of lactide to glycolide is 90:10, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 27-110 ⁇ m.
  • the drug loading rate is determined to be 54.40%, and the drug encapsulation efficiency is 90.66%.
  • the sustained release microsphere (sustained release microsphere E) of the present embodiment has a delayed release period of 4 weeks and a drug release time of 4 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 30 parts of water-insoluble/slightly soluble drug, 70 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 45 kDa, the viscosity is 0.38 dL/g, and the molar ratio of lactide to glycolide is 80:20, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 35-100 ⁇ m.
  • the drug loading rate is determined to be 27.44%, and the drug encapsulation efficiency is 91.45%.
  • the sustained release microsphere (sustained release microsphere E) of the present embodiment has a delayed release period of 4 weeks and a drug release time of 4 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 35 parts of water-insoluble/slightly soluble drug, 65 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is olanzapine, the poorly water-soluble polymer is PLGA, and the water is poorly soluble in polymerization.
  • the material is PLGA, and the PLGA has a weight average molecular weight of 45 kDa and a viscosity of 0.42 dL/g, wherein the molar ratio of lactide to glycolide is 85:15, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 31-112 ⁇ m.
  • the drug loading rate is determined to be 31.76%, and the drug encapsulation efficiency is 90.75%.
  • the present embodiment is a sustained release microsphere (sustained release microsphere E) having a delayed release period of about 4 weeks and a drug release time of 4 weeks; and the preparation material of the sustained release microspheres includes the following weight groups. Points: 45 parts of water-insoluble/slightly soluble drug, 55 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is entecavir, the water-insoluble polymer is PLGA, and the weight average molecular weight of the PLGA is 50 kDa, viscosity 0.49 dL/g, wherein the molar ratio of lactide to glycolide is 85:15, which has a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 24-95 ⁇ m.
  • the drug loading rate is determined to be 40.43%, and the drug encapsulation efficiency is 89.85%.
  • the sustained release microsphere (sustained release microsphere E) of the embodiment has a delayed release period of 4 weeks and a drug release time of 5 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 55 parts of water-insoluble/slightly soluble drug, 45 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is olanzapine pamoate, and the water-insoluble polymer is PLGA,
  • the PLGA has a weight average molecular weight of 55 kDa and a viscosity of 0.54 dL/g, wherein the molar ratio of lactide to glycolide is 85:15, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 28-118 ⁇ m.
  • the drug loading rate is determined to be 49.69%, and the drug encapsulation efficiency is 90.35%.
  • the sustained release microsphere (sustained release microsphere E) of the embodiment has a delayed release period of 4 weeks and a drug release time of 5 weeks; and the preparation raw material of the sustained release microsphere comprises the following weight group Points: 60 parts of water-insoluble/slightly soluble drug, 40 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 60 kDa, the viscosity is 0.58 dL/g, and the molar ratio of lactide to glycolide is 90:10, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of this embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 28-120 ⁇ m.
  • the drug-loading rate is determined to be 54.30%, and the drug encapsulation efficiency is 90.50%.
  • the present embodiment is a sustained-release microsphere (sustained-release microsphere F) having a 5-week delayed release period and a drug release time of 4 weeks; and the preparation material of the sustained-release microspheres comprises the following components by weight 30 parts of water-insoluble/slightly soluble drug, 70 parts of poorly water-soluble polymer; the poorly water-soluble/slightly soluble drug is risperidone, the poorly water-soluble polymer is PLGA, and the weight average molecular weight of the PLGA It is 20 kDa and has a viscosity of 0.23 dL/g, wherein the molar ratio of lactide to glycolide is 90:10, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 26-103 ⁇ m.
  • the drug loading rate is determined to be 27.06%, and the drug encapsulation efficiency is 90.20%.
  • the sustained release microsphere (sustained release microsphere F) of the present embodiment has a 6-week delayed release period and a drug release time of 4 weeks; and the preparation material of the sustained-release microspheres includes the following weight groups Points: 35 parts of water-insoluble/slightly soluble drug, 65 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the poorly water-soluble polymer is PLGA, and the weight average of the PLGA The molecular weight is 25 kDa, the viscosity is 0.28 dL/g, and the molar ratio of lactide to glycolide is 95:5, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 30-99 ⁇ m.
  • the drug loading rate is 31.94%, and the drug encapsulation efficiency is 91.25%.
  • the sustained release microsphere (sustained release microsphere F) of the present embodiment has a 5-week delayed release period and a drug release time of 5 weeks; and the preparation material of the sustained-release microspheres includes the following weight groups Points: 45 parts of water-insoluble/slightly soluble drug, 55 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLA, and the weight of the PLA is It has a molecular weight of 40 kDa and a viscosity of 0.39 dL/g, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 25-110 ⁇ m.
  • the drug loading rate is determined to be 40.34%, and the drug encapsulation efficiency is 89.65%.
  • the sustained release microsphere (sustained release microsphere F) of the present embodiment has a 6-week delayed release period and a drug release time of 6 weeks; and the preparation material of the sustained-release microspheres includes the following weight groups. Points: 55 parts of water-insoluble/slightly soluble drug, 45 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is paliperidone palmitate, the poorly water-soluble polymer is PLA, the PLA The weight average molecular weight is 55 kDa and the viscosity is 0.52 dL/g, which has a terminal carboxyl group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 28-112 ⁇ m.
  • the drug loading rate is 50.68%, and the drug encapsulation efficiency is 92.15%.
  • the sustained release microsphere (sustained release microsphere F) of the present embodiment has a 6-week delayed release period and a drug release time of 7 weeks; and the preparation material of the sustained-release microspheres includes the following weight groups. Points: 60 parts of water-insoluble/slightly soluble drug, 40 parts of poorly water-soluble polymer; the water-insoluble/slightly soluble drug is risperidone, the water-insoluble polymer is PLA, and the weight of the PLA is The molecular weight is 60 kDa and the viscosity is 0.54 dL/g, which has a terminal ester group.
  • the preparation method of the sustained release microspheres of the present embodiment is the same as that of the first embodiment.
  • the obtained sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 27-115 ⁇ m.
  • the drug loading rate is 53.38%, and the drug encapsulation efficiency is 88.97%.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two risperidone sustained-release microspheres having different release behaviors, that is, the slowing of Examples 1 and 6.
  • the release microspheres are combined, and the mass ratio of the sustained release microspheres of Example 1 to the risperidone in the sustained release microspheres of Example 6 is 1:1; the release period of the sustained release composition of the present embodiment is about 4 weeks.
  • the combination and use manners of the sustained-release microspheres of Example 1 and Example 6 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, which is explained by Example 2 and Example 7.
  • the balls were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 2 and Example 7 was 2:3; the release period of the sustained release composition of the present example was about 5 weeks.
  • the combination and use mode of the sustained release microspheres of Example 2 and Example 7 are as follows: two kinds of microspheres are separately prepared, and then packaged in two sealed vials according to the above ratios, and the dispersion medium is firstly suspended during use. One of the microspheres is then pumped out of the other suspension into another vial and suspended with another microsphere and then injected.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, that is, sustained release of Example 3 and Example 9.
  • the microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 3 and Example 9 was 3:2; the release period of the sustained release composition of this example was about 5 weeks.
  • the combination and use mode of the sustained release microspheres of Example 3 and Example 9 are as follows: two kinds of microspheres are prepared separately, and then packaged in two sealed vials according to the above ratio, and used in a ratio of 3:2.
  • the dispersion medium was suspended with two kinds of microspheres, and then all the two suspensions were taken out in the same syringe and then injected.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of paliperidone sustained-release microspheres, that is, the slowing of Example 5 and Example 10.
  • the release microspheres are combined, and the mass ratio of paliperidic palmitate in the sustained release microspheres of Example 5 and Example 10 is 1:1; the release period of the sustained release composition of the present embodiment is about 6 week.
  • the combination and use mode of the sustained release microspheres of Example 5 and Example 10 are as follows: two kinds of microspheres are separately prepared, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of aripiprazole sustained-release microspheres, that is, from Example 4 and Example 8.
  • the aripiprazole sustained-release microspheres are combined, and the mass ratio of aripiprazole in the sustained-release microspheres of Example 4 and Example 8 is 1:1; the release period of the sustained-release composition of the present embodiment is about For 4 weeks.
  • the combination and use mode of the sustained release microspheres of Example 4 and Example 8 are as follows: two kinds of microspheres are prepared separately, and then mixed according to the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, that is, the slowing of Examples 1 and 11.
  • the release microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 1 and Example 11 was 1:2; the release period of the sustained release composition of the present example was about 6 weeks.
  • the combination and use manner of the sustained release microspheres of Example 1 and Example 11 are as follows: two kinds of microspheres are prepared separately, and then packaged in two sealed vials according to the above ratio, and used in a ratio of 1:2.
  • the two kinds of microspheres were suspended in the dispersion medium, and then the two suspensions were separately extracted by two different syringes, and then injected into different parts.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, that is, the slowing of Examples 2 and 12.
  • the release microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 2 and Example 12 was 2:5; the release period of the sustained release composition of the present example was about 7 weeks.
  • the combination and use mode of the sustained release microspheres of Example 2 and Example 12 are as follows: two kinds of microspheres are prepared separately, and then packaged in two sealed vials according to the above ratio, and used in a ratio of 2:5. Two kinds of microspheres were suspended in the dispersion medium. One of the microsphere suspensions was injected first, and the other microsphere suspension was injected into different parts after 2 hours.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, that is, the slowing of Examples 3 and 13.
  • the release microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 3 and Example 13 was 3:4; the release period of the sustained release composition of the present example was about 7 weeks.
  • the combination and use manners of the sustained release microspheres of Example 3 and Example 13 are as follows: two kinds of microspheres are separately prepared, and then packaged in two sealed vials in the above ratio, and used in a ratio of 3:4. Two kinds of microspheres were suspended in the dispersion medium, one of which was injected first, and the other was sprayed to the same site 8 hours later.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of aripiprazole sustained-release microspheres, that is, slowed by Example 4 and Example 14.
  • the microspheres are combined, and the mass ratio of lauroyl aripiprazole in the sustained release microspheres of Example 4 to the aripiprazole in the sustained release microspheres of Example 14 is 2:5;
  • the release period of the sustained release composition is about 7 weeks.
  • the combination and use mode of the sustained release microspheres of Example 4 and Example 14 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of paliperidone sustained-release microspheres, that is, by the embodiment 5 and the embodiment 15.
  • the sustained release microspheres are combined, and the mass ratio of paliperidone palmitate in the sustained release microspheres of Example 5 to paliperidone in the sustained release microspheres of Example 15 is 3:5; this embodiment
  • the release profile of the sustained release composition is about 8 weeks.
  • the combination and use mode of the sustained release microspheres of Example 5 and Example 15 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, that is, sustained release of Example 16 and Example 21.
  • the microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 16 and Example 21 was 1:1; the release period of the sustained release composition of this example was about 8 weeks.
  • the combination and use manners of the sustained release microspheres of Example 16 and Example 21 are as follows: two kinds of microspheres are separately prepared, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of olanzapine sustained-release microspheres, that is, sustained release of Example 17 and Example 22.
  • the microspheres were combined, and the mass ratio of olanzapine in the sustained release microspheres of Example 17 and Example 22 was 1:1; the release period of the sustained release composition of this example was about 8 weeks.
  • the combination and use mode of the sustained release microspheres of Example 17 and Example 22 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of epopirazole sustained-release microspheres, that is, by the embodiment 18 and the embodiment 23.
  • the sustained release microspheres were combined, and the mass ratio of entecavir in the sustained release microspheres of Example 18 and Example 23 was 1:1; the release period of the sustained release composition of the present example was about 9 weeks.
  • the combination and use mode of the sustained release microspheres of Example 18 and Example 23 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of olanzapine sustained-release microspheres, that is, sustained release from Example 17 and Example 24.
  • the microspheres were combined, and the mass ratio of olanzapine in the sustained-release microspheres of Example 17 to olanzapine of the sustained-release microspheres of Example 24 was 4:5; The release period of the release composition is about 9 weeks.
  • the combination and use manners of the sustained-release microspheres of Example 17 and Example 24 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, that is, sustained release of Example 19 and Example 26.
  • the microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 19 and Example 26 was 5:4; the release period of the sustained release composition of this example was about 9 weeks.
  • the combination and use manner of the sustained release microspheres of Example 19 and Example 26 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a binary combination of two different release behaviors of risperidone sustained-release microspheres, that is, the slowening of Example 20 and Example 28.
  • the release microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 20 and Example 28 was 5:4; the release period of the sustained release composition of the present example was about 9 weeks.
  • the combination and use manners of the sustained release microspheres of Example 20 and Example 28 are as follows: two kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected into the dispersion medium during use. And then inject.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a ternary combination of three different release behaviors of risperidone sustained-release microspheres, namely, Example 1, Example 6 and implementation
  • the sustained release microspheres of Example 25 were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 1, Example 6 and Example 25 was 2:2:5; the sustained release composition of the present example
  • the release cycle is approximately 9 weeks.
  • the combination and use manners of the sustained release microspheres of the first embodiment, the sixth embodiment and the second embodiment are as follows: three kinds of microspheres are separately prepared, and then mixed in the above ratio, packaged in a closed vial, and directly injected during use. The dispersion medium is suspended and then injected.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a ternary combination of risperidone sustained-release microspheres, that is, sustained release from Example 2, Example 7 and Example 26.
  • the microspheres were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 2, Example 7 and Example 26 was 2:3:4; the release period of the sustained release composition of the present example was 9 week.
  • the combination and use manners of the sustained release microspheres of the second embodiment, the seventh embodiment and the second embodiment are as follows: three kinds of microspheres are separately prepared, and then mixed in the above ratio, packaged in a closed vial, and directly injected during use. The dispersion medium is suspended and then injected.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a ternary combination of three different release behaviors of risperidone sustained-release microspheres, that is, Example 3, Example 9 and Examples
  • the sustained release microspheres of 28 were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 3, Example 9 and Example 28 was 3:2:5; the sustained release composition of the present example The release cycle is approximately 10 weeks.
  • the combination and use manners of the sustained release microspheres of Example 3, Example 9 and Example 28 are as follows: three kinds of microspheres are prepared separately, and then mixed according to the above ratio, packaged in a closed vial, and directly injected during use. The dispersion medium is suspended and then injected.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a ternary combination of three different release behaviors of risperidone sustained-release microspheres, namely, Example 1, Example 11 and implementation
  • the sustained release microspheres of Example 27 were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 1, Example 11 and Example 27 was 2:4:5; the sustained release composition of the present example The release cycle is approximately 11 weeks.
  • the combination and use manners of the sustained release microspheres of the first embodiment, the embodiment 11 and the embodiment 27 are as follows: three kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected during use. The dispersion medium is suspended and then injected.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a ternary combination of three different release behaviors of paliperidone palmitate sustained-release microspheres, that is, Example 5 and Example 10 And the sustained release microspheres of Example 29 were combined, and the mass ratio of paliperidone palmitate in the sustained release microspheres of Example 5, Example 10 and Example 29 was 1:1:2; The release period of the sustained release composition is about 12 weeks.
  • the combination and use manners of the sustained release microspheres of Example 5, Example 10 and Example 29 are as follows: three kinds of microspheres are separately prepared, and then mixed in the above ratio, packaged in a closed vial, and directly injected during use. The dispersion medium is suspended and then injected.
  • a water-insoluble/slightly soluble drug sustained-release composition of the present embodiment which is a ternary combination of three different release behaviors of risperidone sustained-release microspheres, namely, Example 1, Example 11 and implementation
  • the sustained release microspheres of Example 30 were combined, and the mass ratio of risperidone in the sustained release microspheres of Example 1, Example 11 and Example 30 was 2:4:7; the sustained release composition of the present example The release cycle is approximately 13 weeks.
  • the combination and use manners of the sustained release microspheres of the first embodiment, the embodiment 11 and the embodiment 30 are as follows: three kinds of microspheres are prepared separately, and then mixed in the above ratio, packaged in a closed vial, and directly injected during use. The dispersion medium is suspended and then injected.
  • sustained release microspheres and sustained release compositions are determined as follows:
  • the sustained release composition of the present invention significantly shortens or even eliminates the delayed release period relative to a single sustained release microsphere, and has no burst release phenomenon, so that the patient can avoid Or reducing the trouble of taking the oral preparation after the injection, and at the same time, by the sustained-release composition of the invention, the release period is obviously longer than the single sustained-release microsphere, and the deposition period of the unit sustained release microsphere is basically superimposed, which can greatly Reducing the frequency of administration is extremely convenient for patients who cannot be frequently administered to the hospital due to work or the like, and significantly increases the compliance and convenience of administration.
  • Example 12 beagle dogs weighing 10 kg ⁇ 0.5 kg, male and female, divided into 2 groups, intramuscularly injected with risperidone sustained-release microspheres of Example 6 and the sustained-release composition of Example 31 ( A suspension of 1.2 ml of 0.5% CMC aqueous solution containing risperidone 18 mg) at 1 h, 6 h, 12 h, 1 d, 7 d, 14 d, 21 d, 28 d, 35 d, 42 d, 49 d and 56 d in rabbit ear vein Take a blood sample of 1.5 mL.
  • the sustained-release composition microsphere of the present invention exhibits a good sustained-release effect, and the blood drug concentration is increased soon after administration, and there is no burst release phenomenon, and the unit is released in combination. It takes about 2 weeks for the microspheres to reach the corresponding blood concentration, and there is a delayed release, which is consistent with the in vitro release behavior.
  • the blood concentration of the composition of Example 31 after a single administration was maintained in the range of 2-7 ng/mL for about 35 days, while the unit microsphere of Example 6 was substantially not released in the previous period, single administration.
  • the blood concentration in the range of 2-14 ng/mL lasted for about 28 days, but the blood concentration of the sustained-release composition fluctuated less during a longer period of time, and the blood concentration fluctuation of the unit microspheres was compared. obvious.
  • the blood concentration of the composition of Example 47 after a single administration was maintained in the range of 2-7 ng/mL for about 70 days, while the microsphere of Example 6 was substantially not released in the early stage, after 3 administrations.
  • the plasma concentration continued for 63 days in the range of 2-13 ng/mL.
  • the unit microspheres can also remain within a certain range for a certain period of time, multiple administrations are required.
  • the multi-component composition of the present invention has a better effect, can achieve therapeutic blood concentration quickly after injection, can maintain a long time, reduce side effects, can prolong the administration cycle, and reduce administration. Frequency, which is conducive to improving patient compliance and convenience.

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Abstract

一种水难溶/微溶性药物缓释组合物，其包括两种以上释放行为不同的水难溶/微溶性药物缓释微球，缓释聚合物为聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物中的至少一种。

Description

一种水难溶/微溶性药物缓释组合物 技术领域
本发明涉及一种缓释组合物，具体涉及一种水难溶/微溶性药物缓释组合物。
背景技术
目前，生物可降解聚合物微球已成为新型给药系统的重要研究领域之一，该给药系统将聚乳酸(PLA)、乳酸-羟基乙酸共聚物(PLGA)等骨架材料制得的微球可以作为长效制剂的载体，对人体或动物能以肌肉或皮下注射的方式给药，能够控制药物释放速度及释放周期，仅用一次给药能够长时间维持有效的药物治疗浓度，能够极小化治疗所需的药物总给药量，提高患者的药物治疗依从性。
基于专利CN1137756公开的技术开发的长效抗精神病药Risperidal Consta(恒德)以分子量约100-150kDa的PLGA为载体，利培酮为API，载药量约为35-40％，每2周肌肉注射一次。该制剂有效避免每天服药产生的峰谷浓度，但在首日仅有少量的药物释放，随后出现长达约3周的药物释放停滞期，因此患者在注射该微球后的3周内还需要依靠口服给药普通剂型才能达到治疗效果，临床使用不方便，患者依从性差。
发明内容
本发明的目的在于克服上述现有技术的不足之处而提供一种无明显的释放延迟期或较短的延迟释放期、没有突释现象、具有良好的缓释性能，并能在数周以上的时间内维持有效血药浓度的水难溶/微溶性药物缓释组合物。
为实现上述目的，本发明采取的技术方案为：一种水难溶/微溶性药物缓释组合物，其包括两种以上释放行为不同的水难溶/微溶性药物缓释微球。
上述两种以上释放行为不同的水难溶/微溶性药物缓释微球指的是：同一时间开始进行药物释放实验，药物释放时间无交叉或交叉较少、但前后相互衔接的两种以上的不同释放行为的水难溶/微溶性药物缓释微球。本发明的缓释组合物通过将两种以上释放行为不同的缓释微球组合在一起，这样得到的水难溶/微溶性药物的缓释组合物无明显的释放延迟期或较短的延迟释放期，并且没有突释现象，具有良好的缓释性能，并能在数周或以上的时间内维持有效血药浓度，有效的降低了给药频率，方便患者的生活与工作，有利于提高患者给药顺应性和便利性。
本发明中，所述延迟释放指微球在体外释放条件下，不能马上开始释放药物，或者在开始的一段时间内释放的药物总量很少，小于10％，优选小于8％，更优选小于5％；所述无明显的延迟释放期或延迟释放期较短指延迟释放的时间不大于3天，优选不大于2天，更优选不大于1天。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物缓释组合物包括无明显的延迟释放期或延迟释放期较短，且药物释放时间为2-3周的缓释微球A和具有2-3周延迟释放期且药物释放时间为2-3周的缓释微球B；或者包括具有2-3周延迟释放期且药物释放时间为4-5周的缓释微球C和所述缓释微球A；或者包括具有4周延迟释放期且药物释放时间为4-5周的缓释微球E和无明显的延迟释放期或延迟释放期较短且药物释放时间为4-5周的缓释微球D；或者包括所述缓释微球A、缓释微球B和缓释微球E；或者包括所述缓释微球A、缓释微球C和具有5-6周延迟释放期且药物释放时间为4周以上的缓释微球F。
由缓释微球A和缓释微球B组成的水难溶/微溶性药物缓释组合物，其可以持续释放药 物4-6周；由缓释微球A和缓释微球C组成的水难溶/微溶性药物缓释组合物，其可以持续释放药物6-7周；由缓释微球D和缓释微球E组成的水难溶/微溶性药物缓释组合物，其可以持续释放药物约8周；由缓释微球A、缓释微球B和缓释微球E组成的水难溶/微溶性药物缓释组合物，其可以持续释放药物8-9周；由缓释微球A、缓释微球C和缓释微球F组成的水难溶/微溶性药物缓释组合物，其可以持续释放药物9-10周以上。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述缓释微球A、缓释微球B、缓释微球C、缓释微球D、缓释微球E和缓释微球F的制备原料均包括下述重量份的组分：水难溶/微溶性药物30-60份，水难溶性聚合物40-70份。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述缓释微球A、缓释微球B、缓释微球C、缓释微球D、缓释微球E、缓释微球F中的至少一种的制备原料包括下述重量份的组分：水难溶/微溶性药物35-55份，水难溶性聚合物45-65份。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物包括利培酮、帕利哌酮、阿立哌唑、伊潘立酮、依匹哌唑、齐拉西酮、阿那曲唑、多奈哌齐、奥氮平、纳曲酮、氟哌啶醇、紫杉醇、多西他赛、恩替卡韦或它们的衍生物。作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述水难溶/微溶性药物包括利培酮、帕利哌酮、阿立哌唑、伊潘立酮、多奈哌齐、奥氮平、依匹哌唑、恩替卡韦、或它们的衍生物。作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述水难溶/微溶性药物包括利培酮、帕利哌酮、阿立哌唑、伊潘立酮、依匹哌唑、或它们的衍生物。其中，所述衍生物包括且不限于棕榈酸帕立哌酮、月桂酰阿立哌唑、癸酸氟哌啶醇、双羟萘酸奥氮平、甲磺酸齐拉西酮。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚酯、聚碳酸酯、聚缩醛、聚酐、聚羟基脂肪酸、它们的共聚物或共混物中的至少一种。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、聚乙交酯(PGA)、丙交酯-乙交酯共聚物(PLGA)、聚己内酯(PCL)、它们与聚乙二醇(PEG)的共聚物(如PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA、PEG-PCL、PCL-PEG-PCL、PEG-PLA-PEG、PEG-PLGA-PEG)、聚羟基丁酸、聚羟基戊酸、聚对二氧环己酮(PPDO)、壳聚糖、海藻酸及其盐、聚氰基丙烯酸酯、聚酸酐、聚原酸酯、聚酰胺、聚磷腈、聚磷酸酯中的至少一种。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物中的至少一种。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，作为本发明所述利培酮缓释组合物的优选实施方式，所述难溶性药物缓释组合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)中的至少一种。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物的分子链携带阴离子或阳离子基团，或者不携带阴离子或阳离子基团。优选地，所述水难溶性聚合物具有端羧基或端酯基。更优选地，所述水难溶性聚合物具有端羧基。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述缓释微球A中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为20000-40000Da，粘度为0.23-0.42dL/g，其中丙交酯与乙交酯的摩尔比为70:30-80:20；所述缓释微球B中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子 量为41000-100000Da，粘度为0.42-0.9dL/g，其中丙交酯与乙交酯的摩尔比为70:30-80:20；所述缓释微球C中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为35100-44900Da，粘度为0.38-0.46dL/g，其中丙交酯与乙交酯的摩尔比为80:20-90:10；所述缓释微球D中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为20000-35000Da，粘度为0.23-0.38dL/g，其中丙交酯与乙交酯的摩尔比为80:20-90:10；所述缓释微球E中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为45000-65000Da，粘度为0.38-0.58dL/g，其中丙交酯与乙交酯的摩尔比为80:20-90:10；所述缓释微球F中，水难溶性聚合物为聚丙交酯或丙交酯-乙交酯共聚物，且水难溶性聚合物的重均分子量为20000-60000Da，粘度为0.23-0.54dL/g，其中丙交酯与乙交酯的摩尔比为90:10-100:0。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，如下(a)～(f)中的至少一项：
(a)所述缓释微球A中，丙交酯-乙交酯共聚物的重均分子量为20000-35000Da，粘度为0.23-0.38dL/g，其中丙交酯与乙交酯的摩尔比为75:25；
(b)所述缓释微球B中，丙交酯-乙交酯共聚物的重均分子量为50000-900000Da，粘度为0.49-0.0.81dL/g，其中丙交酯与乙交酯的摩尔比为75:25；
(c)所述缓释微球C中，丙交酯-乙交酯共聚物的重均分子量为38000-42000Da，粘度为0.40-0.43dL/g，其中丙交酯与乙交酯的摩尔比为85:15；
(d)所述缓释微球D中，丙交酯-乙交酯共聚物的重均分子量为25000-30000Da，粘度为0.27-0.34dL/g，其中丙交酯与乙交酯的摩尔比为85:15；
(e)所述缓释微球E中，丙交酯-乙交酯共聚物的重均分子量为45000-60000Da，粘度为0.42-0.54dL/g，其中丙交酯与乙交酯的摩尔比为85:15；
(f)所述缓释微球F中，水难溶性聚合物的重均分子量为25000-55000Da，粘度为0.28-0.52dL/g。
本发明水难溶/微溶性药物缓释组合物中，所述水难溶性聚合物为可生物降解、生物相容的水难溶性聚合物。所述水难溶性聚合物可以为单一的聚合物，也可以为多种聚合物的混合物,如丙交酯与乙交酯的摩尔比及分子量相同但携带基团不同的PLGA的组合、丙交酯与乙交酯的摩尔比及携带基团相同但分子量不同的PLGA的组合、分子量及携带基团相同但丙交酯与乙交酯的摩尔比不同的PLGA的组合、分子量、携带基团及丙交酯与乙交酯的摩尔比均不同的PLGA的组合、PLGA与PLA的组合等。
本说明中所使用的分子量为重均分子量，是通过凝胶渗透色谱(GPC)测量所获得的值；所使用的粘度是乌氏粘度计测量所获得的值。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述缓释微球A还包括释放调节剂，所述释放调节剂在所述缓释微球A中的质量百分含量为0.1-10％；优选地，所述释放调节剂在所述缓释微球A中的质量百分含量为0.5-8％；优选地，所述释放调节剂在所述缓释微球A中的质量百分含量为1-6％。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述释放调节剂为有机亲油性物质和/或有机亲水性物质。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述有机亲油性物质为脂肪酸、脂肪酸酯、油脂中的至少一种；所述有机亲水性物质为醇类、糖类、氨基酸、蛋白、 聚乙烯吡咯烷酮中的至少一种。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述有机亲油性物质为脂肪酸；所述有机亲水性物质为醇类、聚乙烯吡咯烷酮中的至少一种。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述脂肪酸为油酸、硬脂酸、月桂酸、肉豆蔻酸、棕榈酸、花生酸、山俞酸、木质素酸中的至少一种；所述醇类为分子量为400-6000Da的聚乙二醇(PEG)。所述脂肪酸优选但不限于C12～C24烷酸及其衍生物，包括但不限于油酸、硬脂酸、月桂酸、肉豆蔻酸、棕榈酸、花生酸、山俞酸、木质素酸，优选硬脂酸、山俞酸。所述醇类优选但不限于分子量为600-6000Da的聚乙二醇(PEG)，如PEG600、PEG1000、PEG2000、PEG4000、PEG6000，优选分子量为400～6000Da的聚乙二醇(PEG)，更优选分子量为400～3000Da的PEG。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述缓释微球还包含赋形剂，所述赋形剂在所述缓释微球中的质量百分含量为0～8％。本发明的缓释微球中可以包含一种或多种赋形剂。赋形剂可以赋予活性药物或微粒其它的特征，例如增加微粒、活性药物或载体的稳定性、促进活性药物从微粒中的可控释放、或调节活性药物的生物学组织的渗透性。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述赋形剂包括缓冲剂和抗氧化剂；
所述缓冲剂为无机酸、有机酸盐中的至少一种，所述缓冲剂在所述缓释微球中的质量百分含量为0～5％；优选地，所述缓冲剂在所述缓释微球中的质量百分含量为0～3％；优选地，所述缓冲剂在所述缓释微球中的质量百分含量为0～2％；
所述抗氧化剂为叔丁基对羟基茴香醚、二丁基苯酚、生育酚、肉豆蔻酸异丙酯、d-a乙酸生育酚、抗坏血酸、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚、丁基化羟基醌、羟基香豆素、丁基化羟基甲苯、掊酸脂肪酸酯、丙羟基苯甲酸酯、三羟基苯丁酮、维生素E、维生素E-TPGS、ρ-羟基苯甲酸酯中的至少一种；所述抗氧化剂在所述缓释微球中的质量百分含量为0～1％；优选地，所述抗氧化剂在所述缓释微球中的质量百分含量为0～0.08％；优选地，所述抗氧化剂在所述缓释微球中的质量百分含量为0～0.05％。
所述抗氧化剂的选择中，所述掊酸脂肪酸酯选自如乙酯、丙酯、辛酯、月桂酯，所述ρ-羟基苯甲酸酯选自如甲酯、乙酯、丙酯、丁酯等。所述抗氧化剂以有效地清除植入物内产生的任何自由基或过氧化物的量存在于缓释组合物中。
本发明所述缓冲剂包括但不限于无机酸和有机酸盐，如碳酸、乙酸、草酸、柠檬酸、磷酸、盐酸的盐，包括碳酸钙、氢氧化钙、肉豆蘧酸钙、油酸钙、棕榈酸钙、硬脂酸钙、磷酸钙、醋酸钙、醋酸镁、碳酸镁、氢氧化镁、磷酸镁、肉豆蔻酸镁、油酸镁、棕榈酸镁、硬脂酸镁、碳酸锌、氢氧化锌、氧化锌、肉豆蘧酸锌、油酸锌、醋酸锌、氯化锌、硫酸锌、硫酸氢锌、碳酸锌、硝酸锌、葡萄糖酸锌、棕榈酸锌、硬脂酸锌、磷酸锌、碳酸钠、碳酸氢钠、亚硫酸氢钠、硫代硫酸钠、醋酸-醋酸钠缓冲盐，及它们的组合。优选无机酸和有机酸的锌盐。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物缓释组合物包括缓释微球A和缓释微球B时，缓释微球A中水难溶/微溶性药物和缓释微球B中水难溶/微溶性药物的重量比为1～3：1～3；所述水难溶/微溶性药物缓释组合物包括缓释微球A和缓释微球C时，缓释微球A中水难溶/微溶性药物和缓释微球C中水难溶/微溶性药物的重量比为1～3：2～5；所述水难溶/微溶性药物缓释组合物包括缓释微球D和缓释微球E 时，缓释微球D中水难溶/微溶性药物和缓释微球E中水难溶/微溶性药物的重量比为1：1；所述水难溶/微溶性药物缓释组合物包括缓释微球D和缓释微球F时，缓释微球D中水难溶/微溶性药物和缓释微球F中水难溶/微溶性药物的重量比为5：4；所述水难溶/微溶性药物缓释组合物包括所述缓释微球A、缓释微球B和缓释微球E时，所述缓释微球A、缓释微球B和缓释微球E中水难溶/微溶性药物的重量比为缓释微球A中水难溶/微溶性药物：缓释微球B中水难溶/微溶性药物：缓释微球E中水难溶/微溶性药物＝2：2：5；所述水难溶/微溶性药物缓释组合物包括所述缓释微球A、缓释微球B和缓释微球F时，所述缓释微球A、缓释微球B和缓释微球F中水难溶/微溶性药物的重量比为缓释微球A中水难溶/微溶性药物：缓释微球B中水难溶/微溶性药物：缓释微球F中水难溶/微溶性药物＝1～3：1～3：2～5；所述水难溶/微溶性药物缓释组合物包括所述缓释微球A、缓释微球C和缓释微球F时，所述缓释微球A、缓释微球C和缓释微球F中水难溶/微溶性药物的重量比为缓释微球A中水难溶/微溶性药物：缓释微球C中水难溶/微溶性药物：缓释微球F中水难溶/微溶性药物＝2：4：5～7。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物缓释组合物包括缓释微球A和缓释微球B时，缓释微球A中水难溶/微溶性药物和缓释微球B中水难溶/微溶性药物的重量比为1：1。
本发明的水难溶/微溶性药物缓释组合物为两种以上释放行为不同的缓释微球的组合，其中不同释放行为的缓释微球以一定的比例存在，所述比例为微球中所含有的活性药物的质量的比例，与不同释放行为的缓释微球的释放周期的比例相同，释放周期越长的单元所占的比例越大。进一步的，所述比例还与药物性质或临床给药方法相关，如对于剂量需逐步增加的临床应用中，后释放的缓释微球单元比前一单元所占的比例要大。具体组合方式可根据实际应用情况灵活组合。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述缓释微球的制备方法包括以下步骤：
(1)将水难溶/微溶性药物和水难溶性聚合物溶于有机溶剂中，形成内油相；
(2)将表面活性剂溶于水性介质中，形成外水相；
(3)将步骤(1)得到的内油相加入到外水相中，制成乳液，然后通过溶剂蒸发或溶剂提取使溶液中的微粒固化，收集微粒，洗涤并干燥，得所述缓释微球。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述步骤(1)中，水难溶性聚合物与有机溶剂的质量百分比为1～10％；所述步骤(2)中，所述表面活性剂在外水相中的质量百分含量为0.1～10％；所述步骤(3)中，所述外水相的体积是所述内油相体积的60倍以上。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述步骤(1)中，水难溶性聚合物与有机溶剂的质量百分比为1.5-9％；所述步骤(2)中，所述表面活性剂在外水相中的质量百分含量为0.5-8％；所述步骤(3)中，所述外水相的体积是所述内油相体积的80倍以上。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述步骤(1)中，水难溶性聚合物与有机溶剂的质量百分比为3-8.5％；所述步骤(2)中，所述表面活性剂在外水相中的质量百分含量为1～7％；所述步骤(3)中，所述外水相的体积是所述内油相体积的100倍以上。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述步骤(1)中，有机溶剂为卤代烃、脂肪酸酯、芳香烃中的至少一种；所述卤代烃包含二氯甲烷、氯仿、氯乙烷、四氯乙烯、三氯乙烯、二氯乙烷、三氯乙烷、四氯化碳、氟烃、氯代苯、三氯氟甲烷； 所述脂肪酸酯包含乙酸乙酯、乙酸丁酯；所述芳香烃包含苯、甲苯、二甲苯、苯甲醇。所述有机溶剂可以同时溶解可生物降解、生物相容的水难溶性聚合物和水难溶/微溶性药物，沸点低于水且不溶于或难溶于水。所述有机溶剂可为单一的有机溶剂，也可以为混溶的两种及以上的有机溶剂。所述有机溶剂选自卤代烃(如二氯甲烷、氯仿、氯乙烷、四氯乙烯、三氯乙烯、二氯乙烷、三氯乙烷、四氯化碳、氟烃、氯代苯(单、双、三取代)、三氯氟甲烷等)、脂肪酸酯(如乙酸乙酯、乙酸丁酯等)、芳香烃(如苯、甲苯、二甲苯、苯甲醇等)，优选卤代脂肪烃类溶剂，更优选二氯甲烷、氯仿。所述混合物中有机溶剂的比例按不同药物有所不同，根据实际情况调配。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述表面活性剂为非离子表面活性剂，所述非离子表面活性剂包括聚氧乙烯脂肪醇醚(苄泽)、聚山梨酸酯(如吐温80、吐温60)、聚氧乙烯脂肪酸酯(OEO)、聚氧乙烯蓖麻油衍生物、聚氧乙烯聚丙二醇共聚物、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯、聚氧乙烯山梨糖醇酐单脂肪酸酯、聚氧乙烯山梨糖醇酐二脂肪酸酯、聚氧乙烯甘油单脂肪酸酯、聚氧乙烯甘油二脂肪酸酯、聚甘油脂肪酸酯、聚丙二醇单酯、芳基烧基聚醚醇、聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆)、聚乙烯醇(PVA)及其衍生物、聚乙烯吡咯烷酮(PVP)、多糖中的至少一种。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述非离子表面活性剂为聚氧乙烯-聚氧丙烯共聚物、聚乙烯醇、聚山梨酸酯、聚乙烯比咯烷酮或多糖。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述非离子表面活性剂为聚乙烯醇或多糖。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述多糖包括淀粉和淀粉衍生物、甲基纤维素、乙基纤维素、羟基纤维素、羟丙基纤维素、羟丙甲基纤维素、阿拉伯胶、壳聚糖衍生物、结冷胶、藻酸衍生物、葡聚糖衍生物和非晶态纤维素，优选羟丙甲纤维素、壳聚糖及其衍生物、支链淀粉或葡聚糖及其衍生物。
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述外水相中还含有无机盐或有机盐；所述无机盐为磷酸、硫酸、乙酸、碳酸的钾盐或钠盐、Tris、MES、HEPES中的至少一种。无机盐在水溶液中的重量百分比浓度为：0-5％，优选0.01-4％，更优选0.05-3％；pH范围为3-9，优选4-9，更优选5.5-8.5。外水相中含有无机盐或有机盐，以降低微球固化过程中水溶性活性物质溶渗至水相中，其机理为提高外相的渗透压或降低活性物质在外相中的溶解度。
所述形成均匀的乳液的方法与众所周知的乳化方法相同，采用产生高剪切力的装置(如磁力搅拌器、机械搅拌器、高速均质机、超声仪、膜乳化器、转子-定子混合器、静态混合器、高压均质机等)将内油相和外水相混合，以形成均匀乳液。
本发明的缓释组合物中，组成的每种微球具有相似的几何粒径。所述缓释微球均具有小于200μm的几何粒径。典型地，所述微球的粒径大小约为10-200μm，优选20-150μm，更优选30-150μm。微球粒径大小通过动态光散射技术(例如激光衍射法)、或显微技术(如扫描电镜法)来测量。
在本文中当陈述范围时，意味着包含了其中的任何范围或范围的组合。
当所述缓释组合物以悬浮剂形式给药时，其可与适当的分散介质制成混悬液制剂形式。
所述分散介质包括非离子表面活性剂(或稳定剂)、聚氧乙烯蓖麻油衍生物、纤维素增稠剂、海藻酸钠、透明质酸、糊精、淀粉。或可选择的，还可以与其他赋形剂如等渗剂(如氯化钠、甘露醇、甘油、山梨醇、乳糖、木糖醇、麦芽糖、半乳糖、蔗糖、葡萄糖等)、pH 调节剂(例如碳酸、醋酸、草酸、柠檬酸、磷酸、盐酸或这些酸的盐，例如碳酸钠、碳酸氢钠等)、防腐剂(如对羟基苯甲酸酯、对羟基苯甲酸丙酯、苯甲醇、氯代丁醇、山梨酸、硼酸等)等结合，制成水性溶液后通过冷冻干燥法、减压干燥法、喷雾干燥等方法固化，使用前再将固化物溶解于注射用蒸馏水中获得分散微球的分散介质。
此外，缓释注射剂也可通过下述方法获得：将微球分散于植物油(诸如芝麻油及玉米油)或添加有磷脂(诸如卵磷脂)的植物油中，或者分散于中链甘油三酯中，以获得油性混悬液。
所述缓释组合物为两种及以上的不同释放行为的缓释微球的组合，可以以混合物的形式给药，不同释放行为的缓释微球以混合物的形式同时存在于同一包装容器中，所述混合物为单独制备的两种或以上的缓释微球的物理混合物；或者单独制备的两种或以上的缓释微球置于不同的包装容器中或由可拆除的隔层隔开两个以上不连通或部分连通空间的包装容器中，给药前再混合；或者制备的两种或以上的缓释微球分别置于单独的包装容器中，以单独单元同时给药或在12h的时间差内完成给药于相同或者不同部位。
本发明获得的缓释组合物可用于颗粒剂形式、悬浮剂形式、埋植剂形式、注射剂形式、粘附剂形式等等，并可以口服或非胃肠道给药(肌内注射、皮下注射、经皮给药、粘膜给药(颊内、阴道内、直肠内等))。
本发明的组合物足够稳定，可以持续释放数周以上，诸如长达约4周、诸如长达约8周、诸如长达约12周，或更长时间，可根据具体药物特性或治疗需求进行调节。
附图说明
图1为本发明实施例54中比格犬注射实施例6的缓释微球和实施例31的缓释组合物后，其血样中利培酮的浓度；
图2为本发明实施例54中比格犬注射实施例6的缓释微球和实施例47的缓释组合物后，其血样中利培酮的浓度。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面将结合具体实施例和附图对本发明作进一步说明。
以下实施例中，微球载药率的计算方法为：载药率＝微球中药物质量/微球质量×100％；药物包封率的计算方法为：包封率＝微球中药物质量/药物投料质量×100％。
实施例1
本实施例的一种缓释微球(缓释微球A)，其无明显的延迟释放期或延迟释放期较短，且药物释放时间为2-3周，其制备原料包括下述重量份的组分：水难溶性/微溶药物30份、水难溶性聚合物70份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为20kDa，粘度为0.23dL/g，其中丙交酯与乙交酯的摩尔比为70：30，其具有端羧基。
本实施例所述缓释微球的制备方法为：将水难溶/微溶性药物和水难溶性聚合物溶于10倍质量的二氯甲烷中，溶解得澄清的油内相；然后将油内相溶液在机械搅拌(1000rpm)下加入到油内相体积的100倍的2％PVA水溶液中，乳化10min得O/W乳液；将此乳液机械搅拌(500rpm)约6h将微球固化；最后离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得缓释微球A。
所得缓释微球外形圆整、表面光滑，粒径为25-98μm，经测定其载药率为27.60％，药物 包封率为92.00％。
实施例2
本实施例的一种缓释微球(缓释微球A)，其无明显的释放延迟期且药物释放时间为2周的，其制备原料包括下述重量份的组分：水难溶/微溶性药物35份、水难溶性聚合物65份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为25kDa，粘度为0.28dL/g，其中丙交酯与乙交酯的摩尔比为75：25，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为24-100μm，经测定其载药率为31.94％，药物包封率为91.26％。
实施例3
本实施例的一种缓释微球(缓释微球A)，其无明显的释放延迟期、且药物释放时间为3周，所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物35份、水难溶性聚合物55份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为30kDa，粘度为0.32dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端羧基。
本实施例所述缓释微球A的制备方法与实施例1相同。
所得缓释微球A外形圆整、表面光滑，粒径为20-95μm，经测定其载药率为40.89％，药物包封率为90.86％。
实施例4
本实施例的一种缓释微球(缓释微球A)，其无明显的释放延迟期、且药物释放时间为释放2周，所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物55份、水难溶性聚合物45份；所述水难溶/微溶性药物为月桂酰阿立哌唑，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为35kDa，粘度为0.38dL/g，其中丙交酯与乙交酯的摩尔比为75：25，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为28-105μm，经测定其载药率为50.05％，药物包封率为91.00％。
实施例5
本实施例的一种缓释微球(缓释微球A)，其无明显的释放延迟期、且药物释放时间为释放3周，所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物60份、水难溶性聚合物40份；所述水难溶/微溶性药物为棕榈酸帕利哌酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为40kDa，粘度为0.42dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为23-100μm，经测定其载药率为54.25％，药物包封率为90.42％。
实施例6
本实施例的一种缓释微球(缓释微球B)，其具有2周延迟释放期、且药物释放时间为2周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物30份、水难溶性聚合物70份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA 的重均分子量为40kDa，粘度为0.42dL/g，其中丙交酯与乙交酯的摩尔比为70：30，其具有端酯基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为25-99μm，经测定其载药率为27.61％，药物包封率为92.03％。
实施例7
本实施例的一种缓释微球(缓释微球B)，其具有2周延迟释放期、且药物释放时间为3周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物35份、水难溶性聚合物65份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为50kDa，粘度为0.49dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为24-96μm，经测定其载药率为31.79％，药物包封率为90.82％。
实施例8
本实施例的一种缓释微球(缓释微球B)，其具有约2周延迟释放期、且药物释放时间为2周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物45份、水难溶性聚合物55份；所述水难溶/微溶性药物为月桂酰阿立哌唑，所述水难溶性聚合物为PLGA，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为70kDa，粘度为0.67dL/g，其中丙交酯与乙交酯的摩尔比为75：25，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为30-108μm，经测定其载药率为40.52％，药物包封率为90.05％。
实施例9
本实施例的一种缓释微球(缓释微球B)，其具有3周延迟释放期、且药物释放时间为2周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物55份、水难溶性聚合物45份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA,所述PLGA的重均分子量为90kDa，粘度为0.81dL/g，其中丙交酯与乙交酯的摩尔比为75：25，其具有端酯基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为22-97μm，经测定其载药率为49.94％，药物包封率为90.80％。
实施例10
本实施例的一种缓释微球(缓释微球B)，其具有3周延迟释放期、且药物释放时间为2周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物60份、水难溶性聚合物40份；所述水难溶/微溶性药物为棕榈酸帕利哌酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为100kDa，粘度为0.90dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为26-107μm，经测定其载药率为53.97％，药 物包封率为89.95％。
实施例11
本实施例的一种缓释微球(缓释微球C)，其具有2周延迟释放期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物30份、水难溶性聚合物70份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA,所述PLGA的重均分子量为35.1kDa，粘度为0.38dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端酯基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为31-115μm，经测定其载药率为26.85％，药物包封率为89.50％。
实施例12
本实施例的一种缓释微球(缓释微球C)，其具有2周延迟释放期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物35份、水难溶性聚合物65份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为38kDa，粘度为0.40dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为27-106μm，经测定其载药率为31.89％，药物包封率为91.10％。
实施例13
本实施例的一种缓释微球(缓释微球C)，其具有3周延迟释放期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物45份、水难溶性聚合物55份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为40kDa，粘度为0.41dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为22-103μm，经测定其载药率为40.75％，药物包封率为90.55％。
实施例14
本实施例的一种缓释微球(缓释微球C)，其具有2周延迟释放期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物55份、水难溶性聚合物45份；所述水难溶/微溶性药物为阿立哌唑，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为42kDa，粘度为0.43dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为25-99μm，经测定其载药率为50.23％，药物包封率为91.32％。
实施例15
本实施例的一种缓释微球(缓释微球C)，其具有3周延迟释放期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物60份、水难溶性 聚合物40份；所述水难溶/微溶性药物为帕利哌酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为44.9kDa，粘度为0.46dL/g，其中丙交酯与乙交酯的摩尔比为90：10，其具有端酯基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为28-95μm，经测定其载药率为55.29％，药物包封率为92.15％。
实施例16
本实施例的一种缓释微球(缓释微球D)，其无明显的释放延迟期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物30份、水难溶性聚合物70份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为20kDa，粘度为0.23dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端酯基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为22-96μm，经测定其载药率为27.60％，药物包封率为92.00％。
实施例17
本实施例的一种缓释微球(缓释微球D)，其无明显的释放延迟期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物35份、水难溶性聚合物65份；所述水难溶/微溶性药物为奥氮平，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为25kDa，粘度为0.27dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端羧基。本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为25-112μm，经测定其载药率为32.07％，药物包封率为91.63％。
实施例18
本实施例的一种缓释微球(缓释微球D)，其无明显的释放延迟期、且药物释放时间约为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物45份、水难溶性聚合物55份；所述水难溶/微溶性药物为恩替卡韦，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为28kDa，粘度为0.29dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端酯基。本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为25-98μm，经测定其载药率为40.90％，药物包封率为90.88％。
实施例19
本实施例的一种缓释微球(缓释微球D)，其无明显的释放延迟期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物55份、水难溶性聚合物45份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为30kDa，粘度为0.34dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为32-105μm，经测定其载药率为50.63％，药物包封率为92.05％。
实施例20
本实施例的一种缓释微球(缓释微球D)，其无明显的释放延迟期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物60份、水难溶性聚合物40份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为35kDa，粘度为0.38dL/g，其中丙交酯与乙交酯的摩尔比为90：10，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为27-110μm，经测定其载药率为54.40％，药物包封率为90.66％。
实施例21
本实施例的一种缓释微球(缓释微球E)，其具有4周延迟释放期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物30份、水难溶性聚合物70份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为45kDa，粘度为0.38dL/g，其中丙交酯与乙交酯的摩尔比为80：20，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为35-100μm，经测定其载药率为27.44％，药物包封率为91.45％。
实施例22
本实施例的一种缓释微球(缓释微球E)，其具有4周延迟释放期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物35份、水难溶性聚合物65份；所述水难溶/微溶性药物为奥氮平，所述水难溶性聚合物为PLGA，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为45kDa，粘度为0.42dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为31-112μm，经测定其载药率为31.76％，药物包封率为90.75％。
实施例23
本实施例一种缓释微球(缓释微球E)，其具有约4周延迟释放期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物45份、水难溶性聚合物55份；所述水难溶/微溶性药物为恩替卡韦，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为50kDa，粘度为0.49dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端酯基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为24-95μm，经测定其载药率为40.43％，药物包封率为89.85％。
实施例24
本实施例的一种缓释微球(缓释微球E)，其具有4周延迟释放期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物55份、水难溶性聚合物45份；所述水难溶/微溶性药物为双羟萘酸奥氮平，所述水难溶性聚合物为PLGA，所 述PLGA的重均分子量为55kDa，粘度为0.54dL/g，其中丙交酯与乙交酯的摩尔比为85：15，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为28-118μm，经测定其载药率为49.69％，药物包封率为90.35％。
实施例25
本实施例的一种缓释微球(缓释微球E)，其具有4周延迟释放期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物60份、水难溶性聚合物40份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为60kDa，粘度为0.58dL/g，其中丙交酯与乙交酯的摩尔比为90：10，其具有端羧基。
本实施例缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为28-120μm，经测定其载药率为54.30％，药物包封率为90.50％。
实施例26
本实施例一种缓释微球(缓释微球F)，其具有5周延迟释放期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物30份、水难溶性聚合物70份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为20kDa，粘度为0.23dL/g，其中丙交酯与乙交酯的摩尔比为90：10，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为26-103μm，经测定其载药率为27.06％，药物包封率为90.20％。
实施例27
本实施例的一种缓释微球(缓释微球F)，其具有6周延迟释放期、且药物释放时间为4周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物35份、水难溶性聚合物65份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLGA，所述PLGA的重均分子量为25kDa，粘度为0.28dL/g，其中丙交酯与乙交酯的摩尔比为95：5，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为30-99μm，经测定其载药率为31.94％，药物包封率为91.25％。
实施例28
本实施例的一种缓释微球(缓释微球F)，其具有5周延迟释放期、且药物释放时间为5周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物45份、水难溶性聚合物55份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLA，所述PLA的重均分子量为40kDa，粘度为0.39dL/g，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为25-110μm，经测定其载药率为40.34％，药物包封率为89.65％。
实施例29
本实施例的一种缓释微球(缓释微球F)，其具有6周延迟释放期、且药物释放时间为6周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物55份、水难溶性聚合物45份；所述水难溶/微溶性药物为棕榈酸帕利哌酮，所述水难溶性聚合物为PLA，所述PLA的重均分子量为55kDa，粘度为0.52dL/g，其具有端羧基。
本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为28-112μm，经测定其载药率为50.68％，药物包封率为92.15％。
实施例30
本实施例的一种缓释微球(缓释微球F)，其具有6周延迟释放期、且药物释放时间为7周；所述缓释微球的制备原料包括下述重量份的组分：水难溶/微溶性药物60份、水难溶性聚合物40份；所述水难溶/微溶性药物为利培酮，所述水难溶性聚合物为PLA，所述PLA的重均分子量为60kDa，粘度为0.54dL/g，其具有端酯基。本实施例所述缓释微球的制备方法与实施例1相同。
所得缓释微球外形圆整、表面光滑，粒径为27-115μm，经测定其载药率为53.38％，药物包封率为88.97％。
实施例31
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种释放行为不同的利培酮缓释微球组成的二元组合，即由实施例1和实施例6的缓释微球组合而成，且实施例1的缓释微球和实施例6的缓释微球中利培酮的质量比为1：1；本实施例的缓释组合物的释放周期约为4周。其中，实施例1和实施例6的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例32
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即由实施例2和实施例7释微球组合而成，且实施例2和实施例7的缓释微球中利培酮的质量比为2：3；本实施例的缓释组合物的释放周期约为5周。其中，实施例2和实施例7的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例分别封装于两个密闭西林瓶中，使用时先注入分散介质混悬其中一种微球，然后再抽出全部混悬液注入另一西林瓶中与另一种微球混悬，然后注射。
实施例33
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即实施例3和实施例9的缓释微球组合而成，且实施例3的和实施例9的缓释微球中利培酮的质量比为3：2；本实施例的缓释组合物的释放周期约为5周。其中，实施例3和实施例9的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例分别封装于两个密闭西林瓶中，使用时以3:2比例的分散介质分别混悬两种微球，然后再以同一个注射器抽出全部两种混悬液，然后注射。
实施例34
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的帕利哌酮缓释微球组成的二元组合，即实施例5和实施例10的缓释微球组合而成，且实施例5的和实施例10的缓释微球中棕榈酸帕利哌酮的质量比为1：1；本实施例的缓释组合物的释放周期约为6 周。其中，实施例5和实施例10的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例35
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的阿立哌唑缓释微球组成的二元组合，即由实施例4和实施例8的阿立哌唑缓释微球组合而成，且实施例4和实施例8的缓释微球中阿立哌唑的质量比为1：1；本实施例的缓释组合物的释放周期约为4周。其中，实施例4和实施例8的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例36
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即由实施例1和实施例11的缓释微球组合而成，且实施例1和实施例11的缓释微球中利培酮的质量比为1：2；本实施例的缓释组合物的释放周期约为6周。其中，实施例1和实施例11的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例分别封装于两个密闭西林瓶中，使用时以1:2比例的分散介质分别混悬两种微球，然后再以不同的两个注射器分别抽出两种混悬液，然后先后注射于不同部位。
实施例37
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即由实施例2和实施例12的缓释微球组合而成，且实施例2和实施例12的缓释微球中利培酮的质量比为2：5；本实施例的缓释组合物的释放周期约为7周。其中，实施例2和实施例12的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例分别封装于两个密闭西林瓶中，使用时以2:5比例的分散介质分别混悬两种微球，其中一种微球混悬液先注射，另一种微球混悬液2小时后注射于不同部位。
实施例38
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即由实施例3和实施例13的缓释微球组合而成，且实施例3和实施例13的缓释微球中利培酮的质量比为3：4；本实施例的缓释组合物的释放周期约为7周。其中，实施例3和实施例13的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例分别封装于两个密闭西林瓶中，使用时以3:4比例的分散介质分别混悬两种微球，其中一种微球混悬液先注射，另一种微球混悬液8小时后注射于相同部位。
实施例39
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的阿立哌唑缓释微球组成的二元组合，即由实施例4和实施例14缓释微球组合而成，且实施例4的缓释微球中的月桂酰阿立哌唑和实施例14的缓释微球中阿立哌唑的质量比为2：5；本实施例的缓释组合物的释放周期约为7周。其中，实施例4和实施例14的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例40
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的帕利哌酮缓释微球组成的二元组合，即由实施例5和实施例15的缓释微球组合而成，且实施例5的缓释微球中的棕榈酸帕利哌酮和实施例15的缓释微球中帕利哌酮的质量比为3：5；本实施例的缓 释组合物的释放周期约为8周。其中，实施例5和实施例15的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例41
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即实施例16和实施例21的缓释微球组合而成，且实施例16和实施例21的缓释微球中利培酮的质量比为1：1；本实施例的缓释组合物的释放周期约为8周。其中，实施例16和实施例21的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例42
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的奥氮平缓释微球组成的二元组合，即实施例17和实施例22的缓释微球组合而成，且实施例17和实施例22的缓释微球中奥氮平的质量比为1：1；本实施例的缓释组合物的释放周期约为8周。其中，实施例17和实施例22的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例43
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的依匹哌唑缓释微球组成的二元组合，即由实施例18和实施例23的缓释微球组合而成，且实施例18和实施例23的缓释微球中的恩替卡韦的质量比为1：1；本实施例的缓释组合物的释放周期约为9周。其中，实施例18和实施例23的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例44
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的奥氮平缓释微球组成的二元组合，即由实施例17和实施例24缓释微球组合而成，且实施例17的缓释微球中的奥氮平和实施例24的缓释微球中的双羟萘酸奥氮平的质量比为4：5；本实施例的缓释组合物的释放周期约为9周。其中，实施例17和实施例24的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例45
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即实施例19和实施例26的缓释微球组合而成，且实施例19和实施例26的缓释微球中利培酮的质量比为5：4；本实施例的缓释组合物的释放周期约为9周。其中，实施例19和实施例26的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例46
本实施例的一种水难溶/微溶性药物缓释组合物，其为2种不同释放行为的利培酮缓释微球组成的二元组合，即由实施例20和实施例28的缓释微球组合而成，且实施例20和实施例28的缓释微球中利培酮的质量比为5：4；本实施例的缓释组合物的释放周期约为9周。其中，实施例20和实施例28的缓释微球的组合与使用方式为：分别制备2种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例47
本实施例的一种水难溶/微溶性药物缓释组合物，其为3种不同释放行为的利培酮缓释微球组成的三元组合，即由实施例1、实施例6和实施例25的缓释微球组合而成，且实施例1、实施例6和实施例25的缓释微球中利培酮的质量比为2：2：5；本实施例的缓释组合物的释放周期约为9周。其中，实施例1、实施例6和实施例25的缓释微球的组合与使用方式为：分别制备3种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例48
本实施例的一种水难溶/微溶性药物缓释组合物，其为的利培酮缓释微球组成的三元组合，即由实施例2、实施例7和实施例26的缓释微球组合而成，且实施例2、实施例7和实施例26的缓释微球中利培酮的质量比为2：3：4；本实施例的缓释组合物的释放周期为9周。其中，实施例2、实施例7和实施例26的缓释微球的组合与使用方式为：分别制备3种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例49
本实施例的一种水难溶/微溶性药物缓释组合物，其为3种不同释放行为的利培酮缓释微球组成的三元组合，即实施例3、实施例9和实施例28的缓释微球组合而成，且实施例3、实施例9和实施例28的缓释微球中利培酮的质量比为3：2：5；本实施例的缓释组合物的释放周期约为10周。其中，实施例3、实施例9和实施例28的缓释微球的组合与使用方式为：分别制备3种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例50
本实施例的一种水难溶/微溶性药物缓释组合物，其为3种不同释放行为的利培酮缓释微球组成的三元组合，即由实施例1、实施例11和实施例27的缓释微球组合而成，且实施例1、实施例11和实施例27的缓释微球中利培酮的质量比为2：4：5；本实施例的缓释组合物的释放周期约为11周。其中，实施例1、实施例11和实施例27的缓释微球的组合与使用方式为：分别制备3种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例51
本实施例的一种水难溶/微溶性药物缓释组合物，其为3种不同释放行为的棕榈酸帕利哌酮缓释微球组成的三元组合，即实施例5、实施例10和实施例29的缓释微球组合而成，且实施例5、实施例10和实施例29的缓释微球中棕榈酸帕利哌酮的质量比为1：1：2；本实施例的缓释组合物的释放周期约为12周。其中，实施例5、实施例10和实施例29的缓释微球的组合与使用方式为：分别制备3种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入分散介质混悬，然后注射。
实施例52
本实施例的一种水难溶/微溶性药物缓释组合物，其为3种不同释放行为的利培酮缓释微球组成的三元组合，即由实施例1、实施例11和实施例30的缓释微球组合而成，且实施例1、实施例11和实施例30的缓释微球中利培酮的质量比为2：4：7；本实施例的缓释组合物的释放周期约为13周。其中，实施例1、实施例11和实施例30的缓释微球的组合与使用方式为：分别制备3种微球，然后按上述比例混合，封装于一个密闭西林瓶中，使用时直接注入 分散介质混悬，然后注射。
实施例53
缓释微球及缓释组合物的体外释放度测定，方法如下：
精密称取实施例1-30的缓释微球及实施例31-54的缓释组合物20mg置200mL离心管中，加pH7.4PBS(含0.05％吐温80，0.05％叠氮化钠)50mL，置于37℃、150rpm恒温水浴振荡器中，在预设时间点取出1mL释放液，补充等量新鲜介质后置于恒温水浴振荡器中继续释放度试验(n＝3)。取出液采用高效液相色谱法(HPLC)检测药物释放量，计算释放率。结果如表1-6所示。
表1 实施例1-10的缓释微球的体外释放率
Figure PCTCN2018079173-appb-000001
表2 实施例11-20的缓释微球的体外释放率
Figure PCTCN2018079173-appb-000002
Figure PCTCN2018079173-appb-000003
表3 实施例21-30的缓释微球的体外释放率
Figure PCTCN2018079173-appb-000004
表4 实施例31-38的缓释组合物的体外释放率
Figure PCTCN2018079173-appb-000005
Figure PCTCN2018079173-appb-000006
表5 实施例39-45的缓释组合物的体外释放率
Figure PCTCN2018079173-appb-000007
表6 实施例46-52的缓释组合物的体外释放率
Figure PCTCN2018079173-appb-000008
Figure PCTCN2018079173-appb-000009
从表4-6的微球组合物体外释放数据可以看出，本发明的缓释组合物相对单一的缓释微球明显缩短、甚至消除了延迟释放期，而且没有突释现象，使病人避免或减少注射服药后仍需口服普通制剂的麻烦；同时，通过本发明的缓释组合物，释放周期明显比单一缓释微球长，基本为单元缓释微球的释放期的叠加，可以大大降低给药频率，对于因工作等原因无法频繁到医院接受给药的病人带来极大的方便，显著增加给药依从性和便利性。
实施例54动物实验
(1)取12只重量在10kg±0.5kg的比格犬，雌雄各半，平均分为2组，肌肉注射实施例6的利培酮缓释微球和实施例31的缓释组合物(均含利培酮18mg)的1.2ml 0.5％CMC水溶液的混悬液，分别于第1h，6h，12h，1d，7d，14d，21d，28d，35d，42d，49d和56d于兔耳缘静脉取血样1.5mL。所有采集的血样均于8000rpm离心10min后取上清液-70℃冻存，然后采用本领域已知方法测上述所有血样中利培酮的浓度，结果见图1。
(2)取12只重量在10kg±0.5kg的比格犬，雌雄各半，平均分为2组，肌肉注射实施例6的利培酮缓释微球(含利培酮18mg，每隔2周给药1次，共3次)和实施例47的缓释组合物(含利培酮45mg，给药1次)的1.2ml 0.5％CMC水溶液的混悬液，分别于第1h，6h，12h，1d，7d，14d，21d，28d，35d，42d，49d，56d，63d，70d，77d，84d、91d和98d于兔耳缘静脉取血样1.5mL。所有采集的血样均于8000rpm离心10min后取上清液-70℃冻存，然后采用本领域已知方法测上述所有血样中利培酮的浓度，结果见图2。
由图1-2可看到，本发明的缓释组合物微球显示出良好的缓释效果，给药后很快增加血药浓度，而且没有突释现象，而对组合中的单元缓释微球需要差不多2周的时间才能达到相应血药浓度，存在延迟释放现象，与体外释放行为结果相一致。图1中，实施例31的组合物单次给药后的血药浓度在2-7ng/mL范围内持续达约35天，而实施例6单元微球由于前期基本没有释放，单次给药后的血药浓度在2-14ng/mL范围内持续约为28天，但缓释组合物给药后血药浓度在较长的时间段波动较小，而单元微球的血药浓度波动比较明显。图2中，实施例47组合物单次给药后的血药浓度在2-7ng/mL范围内持续达约70天，而实施例6微球由于前期基本没有释放，3次给药后的血药浓度在2-13ng/mL范围内持续为63天。虽然单元微球也能在一定时间段内保持在一定范围，但是却需要进行多次给药。相对而言，本发明的多元组合物具有更好的作用效果，能够注射后很快达到治疗血药浓度，并能维持较长的时间，减轻副作用，可延长给药给药周期，降低给药频率，从而有利于提高病患依从性、便利性。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。

Claims (10)

  1. 一种水难溶/微溶性药物缓释组合物，其特征在于：包括两种以上释放行为不同的水难溶/微溶性药物缓释微球。
  2. 如权利要求1所述的水难溶/微溶性药物缓释组合物，其特征在于：所述水难溶/微溶性药物缓释组合物包括无明显的延迟释放期或延迟释放期较短，且药物释放时间为2-3周的缓释微球A和具有2-3周延迟释放期且药物释放时间为2-3周的缓释微球B；
    或者包括具有2-3周延迟释放期且药物释放时间为4-5周的缓释微球C和所述缓释微球A；
    或者包括具有4周延迟释放期且药物释放时间为4-5周的缓释微球E和无明显的延迟释放期或延迟释放期较短且药物释放时间为4-5周的缓释微球D；
    或者包括所述缓释微球A、缓释微球B和缓释微球E；
    或者包括所述缓释微球A、缓释微球C和具有5-6周延迟释放期且药物释放时间为4周以上的缓释微球F。
  3. 如权利要求2所述的水难溶/微溶性药物缓释组合物，其特征在于：所述缓释微球A、缓释微球B、缓释微球C、缓释微球D、缓释微球E和缓释微球F的制备原料均包括下述重量份的组分：水难溶/微溶性药物30-60份，水难溶性聚合物40-70份。
  4. 如权利要求3所述的水难溶/微溶性药物缓释组合物，其特征在于：所述缓释微球A、缓释微球B、缓释微球C、缓释微球D、缓释微球E、缓释微球F中的至少一种的制备原料包括下述重量份的组分：水难溶/微溶性药物35-55份，水难溶性聚合物45-65份。
  5. 如权利要求3或4所述的水难溶/微溶性药物缓释组合物，其特征在于：所述水难溶/微溶性药物包括利培酮、帕利哌酮、阿立哌唑、伊潘立酮、依匹哌唑、齐拉西酮、阿那曲唑、多奈哌齐、奥氮平、纳曲酮、氟哌啶醇、紫杉醇、多西他赛、恩替卡韦或它们的衍生物。
  6. 如权利要求3或4所述的水难溶/微溶性药物缓释组合物，其特征在于：所述水难溶性聚合物为聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物中的至少一种。
  7. 如权利要求6所述的水难溶/微溶性药物缓释组合物，其特征在于：所述缓释微球A中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为20000-40000Da，粘度为0.23-0.42dL/g，其中丙交酯与乙交酯的摩尔比为70:30-80:20；所述缓释微球B中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为41000-100000Da，粘度为0.42-0.9dL/g，其中丙交酯与乙交酯的摩尔比为70:30-80:20；所述缓释微球C中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为35100-44900Da，粘度为0.38-0.46dL/g，其中丙交酯与乙交酯的摩尔比为80:20-90:10；所述缓释微球D中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为20000-35000Da，粘度为0.23-0.38dL/g，其中丙交酯与乙交酯的摩尔比为80:20-90:10；所述缓释微球E中，水难溶性聚合物为丙交酯-乙交酯共聚物，且丙交酯-乙交酯共聚物的重均分子量为45000-65000Da，粘度为0.38-0.58dL/g，其中丙交酯与乙交酯的摩尔比为80:20-90:10；所述缓释微球F中，水难溶性聚合物为聚丙交酯或丙交酯-乙交酯共聚物，且水难溶性聚合物的重均分子量为20000-60000Da，粘度为0.23-0.54dL/g，其中丙交酯与乙交酯的摩尔比为90:10-100:0。
  8. 如权利要求7所述的水难溶/微溶性药物缓释组合物，其特征在于：如下(a)～(f)中的至少一项：
    (a)所述缓释微球A中，丙交酯-乙交酯共聚物的重均分子量为20000-35000Da，粘度为0.23-0.38dL/g，其中丙交酯与乙交酯的摩尔比为75:25；
    (b)所述缓释微球B中，丙交酯-乙交酯共聚物的重均分子量为50000-900000Da，粘度为0.49-0.0.81dL/g，其中丙交酯与乙交酯的摩尔比为75:25；
    (c)所述缓释微球C中，丙交酯-乙交酯共聚物的重均分子量为38000-42000Da，粘度为0.40-0.43dL/g，其中丙交酯与乙交酯的摩尔比为85:15；
    (d)所述缓释微球D中，丙交酯-乙交酯共聚物的重均分子量为25000-30000Da，粘度为0.27-0.34dL/g，其中丙交酯与乙交酯的摩尔比为85:15；
    (e)所述缓释微球E中，丙交酯-乙交酯共聚物的重均分子量为45000-60000Da，粘度为0.42-0.54dL/g，其中丙交酯与乙交酯的摩尔比为85:15；
    (f)所述缓释微球F中，水难溶性聚合物的重均分子量为25000-55000Da，粘度为0.28-0.52dL/g。
  9. 如权利要求3～8任一项所述的水难溶/微溶性药物缓释组合物，其特征在于：所述水难溶/微溶性药物缓释组合物包括缓释微球A和缓释微球B时，缓释微球A中水难溶/微溶性药物和缓释微球B中水难溶/微溶性药物的重量比为1～3：1～3；所述水难溶/微溶性药物缓释组合物包括缓释微球A和缓释微球C时，缓释微球A中水难溶/微溶性药物和缓释微球C中水难溶/微溶性药物的重量比为1～3：2～5；所述水难溶/微溶性药物缓释组合物包括缓释微球D和缓释微球E时，缓释微球D中水难溶/微溶性药物和缓释微球E中水难溶/微溶性药物的重量比为1：1；所述水难溶/微溶性药物缓释组合物包括缓释微球D和缓释微球F时，缓释微球D中水难溶/微溶性药物和缓释微球F中水难溶/微溶性药物的重量比为5：4；所述水难溶/微溶性药物缓释组合物包括所述缓释微球A、缓释微球B和缓释微球E时，所述缓释微球A、缓释微球B和缓释微球E中水难溶/微溶性药物的重量比为缓释微球A中水难溶/微溶性药物：缓释微球B中水难溶/微溶性药物：缓释微球E中水难溶/微溶性药物＝2：2：5；所述水难溶/微溶性药物缓释组合物包括所述缓释微球A、缓释微球B和缓释微球F时，所述缓释微球A、缓释微球B和缓释微球F中水难溶/微溶性药物的重量比为缓释微球A中水难溶/微溶性药物：缓释微球B中水难溶/微溶性药物：缓释微球F中水难溶/微溶性药物＝1～3：1～3：2～5；所述水难溶/微溶性药物缓释组合物包括所述缓释微球A、缓释微球C和缓释微球F时，所述缓释微球A、缓释微球C和缓释微球F中水难溶/微溶性药物的重量比为缓释微球A中水难溶/微溶性药物：缓释微球C中水难溶/微溶性药物：缓释微球F中水难溶/微溶性药物＝2：4：5～7。
  10. 如权利要求3～9任一项所述的水难溶/微溶性药物缓释组合物，其特征在于：所述缓释微球的制备方法包括以下步骤：
    (1)将水难溶/微溶性药物和水难溶性聚合物溶于有机溶剂中，形成内油相；
    (2)将表面活性剂溶于水性介质中，形成外水相；
    (3)将步骤(1)得到的内油相加入到外水相中，制成乳液，然后通过溶剂蒸发或溶剂提取使溶液中的微粒固化，收集微粒，洗涤并干燥，得所述缓释微球。
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