WO2018137629A1 - 一种利培酮缓释组合物及其制备方法 - Google Patents

一种利培酮缓释组合物及其制备方法 Download PDF

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Publication number
WO2018137629A1
WO2018137629A1 PCT/CN2018/073899 CN2018073899W WO2018137629A1 WO 2018137629 A1 WO2018137629 A1 WO 2018137629A1 CN 2018073899 W CN2018073899 W CN 2018073899W WO 2018137629 A1 WO2018137629 A1 WO 2018137629A1
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Prior art keywords
risperidone
release
release composition
sustained
solvent
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PCT/CN2018/073899
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English (en)
French (fr)
Inventor
刘锋
赖树挺
郑阳
曹付春
连远发
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广州帝奇医药技术有限公司
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Publication of WO2018137629A1 publication Critical patent/WO2018137629A1/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
    • A61K9/0002—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to a sustained release composition and a preparation method thereof, in particular to a risperidone sustained release composition and a preparation method thereof.
  • the drug delivery system is made of matrix materials such as polylactic acid (PLA) and lactic acid-glycolic acid copolymer (PLGA).
  • PLA polylactic acid
  • PLGA lactic acid-glycolic acid copolymer
  • the microspheres can be used as a carrier for long-acting preparations, and can be administered to humans or animals by intramuscular or subcutaneous injection, which can limit the release rate and release cycle of the drug, and can maintain an effective therapeutic drug concentration for a long time with only one administration.
  • the ability to minimize the total dose of the drug required for treatment can improve the patient's medication compliance.
  • the long-acting antipsychotic drug Risperidal Consta (Hengde) developed based on the technology disclosed in the patent CN1137756 uses PLGA with a molecular weight of about 150 kDa as a carrier and risperidone as an API, which is injected intramuscularly every 2 weeks.
  • 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.
  • risperidone is a poorly water-soluble/slightly soluble drug
  • the initial drug release is small, resulting in a release stagnation period of the drug blood drug concentration, with drug loading.
  • the drug release stagnation period is gradually reduced.
  • the drug loading amount reaches a certain range, the drug is released after administration.
  • patent CN101653422 discloses a risperidone microsphere composition which can be released for several weeks, and eliminates the drug stagnation period by increasing the drug loading rate (45% or more), but the formulation stability is poor, and after long-term storage, the microspheres are in vivo. The release behavior will change significantly.
  • the ratio of hydrophobic component (LA) to hydrophilic component (GA) and molecular weight have a significant effect on the release of water-soluble drugs, and the proportion of hydrophilic components of PLGA.
  • risperidone microspheres which are immediately released into the body are prepared.
  • this polymer combination tends to cause surface collapse during radiation sterilization, because PLGAs with different monomer ratios and molecular weights have different degrees of degradation under irradiation; further, PLGAs with lower molecular weight and higher GA monomer ratio Degradation is more likely to occur during storage, which is not conducive to the preservation stability of the preparation. Meanwhile, PLGA excipients with lower molecular weight and higher proportion of GA components are more difficult to prepare and store, and the cost is relatively higher.
  • the object of the present invention is to overcome the above-mentioned deficiencies of the prior art and to provide a delayed release or burst release phenomenon after administration, capable of maintaining therapeutic blood concentration for several weeks or longer, and having good A risperidone sustained release composition that releases properties and better stability. Meanwhile, another object of the present invention is to provide a method for preparing the risperidone sustained-release composition.
  • the technical solution adopted by the present invention is: a risperidone sustained-release composition
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition comprises risperidone, a poorly water-soluble polymer and a release A modulating agent comprising an organic lipophilic substance.
  • the preparation raw materials of the risperidone sustained-release composition of the present invention include a non-solvent-type preparation raw material and a solvent-type preparation raw material.
  • the non-solvent-type preparation raw material comprises risperidone, a poorly water-soluble polymer and a release regulator, excluding a surfactant
  • the solvent-type preparation raw material comprises an aqueous medium and an organic solvent.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present invention contains a release regulator, and the release regulator comprises an organic lipophilic substance, which can be finally converted into carbon dioxide and water in the body to make the surface of the microsphere and Internal pores are created to increase the permeability of body fluids and promote the dissolution of risperidone.
  • the release modifier in the non-solvent-type preparation raw material of the risperidone sustained-release composition, has a mass percentage of 0.1 to 10%;
  • the release modifier in the non-solvent-type preparation raw material of the risperidone sustained-release composition, has a mass percentage of 0.5 to 8%; preferably, the risperidone sustained-release composition is not In the solvent-based preparation raw material, the release regulator has a mass percentage of 1 to 6%.
  • the organic lipophilic substance is at least one of a fatty acid, a fatty acid ester, and a fat.
  • the organic lipophilic substance is a fatty acid.
  • the fatty acid is preferably, but not limited to, a C12-C24 alkanoic acid and a derivative thereof, including but not limited to oleic acid, stearic acid, lauric acid, and nutmeg. Acid, palmitic acid, arachidic acid, behenic acid, lignin acid, preferably stearic acid, behenic acid.
  • the risperidone sustained-release composition of the present invention in the non-solvent-type preparation raw material of the risperidone sustained-release composition, the risperidone has a mass percentage of 25 to 60%.
  • the water-insoluble polymer has a mass percentage of 39.9-74.9%; preferably, the non-solvent-type preparation raw material of the risperidone sustained-release composition has a mass percentage of the risperidone of 30 ⁇ 55%, the mass percentage of the poorly water-soluble polymer is 44.9-69.9%; preferably, the mass of the risperidone is 100% in the non-solvent preparation raw material of the risperidone sustained-release composition The content of the fraction is 35 to 50%, and the mass percentage of the poorly water-soluble polymer is 44.9 to 6.9%.
  • the poorly water-soluble polymer is a polyester, a polycarbonate, a polyacetal, a polyanhydride, a polyhydroxy fatty acid, a copolymer or a blend thereof. At least one of the substances.
  • the poorly water-soluble polymer is polylactide (PLA), polyglycolide (PGA), lactide-glycolide copolymer (PLGA), polycaprolactone (PCL), their copolymers with polyethylene glycol (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 its salts, polycyanoacrylate At least one of an ester, a polyanhydride, a polyorthoester, a polyamide, a polyphosphazene, and a polyphosphate.
  • PLA-PEG polyglycolide
  • PGA lactide-glycolide copolymer
  • PCL polycaprolactone
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are combined with polyethylene glycol. At least one of the copolymers of alcohols.
  • the poorly soluble drug sustained-release composition is at least one of polylactide (PLA) and lactide-glycolide copolymer (PLGA).
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are combined with polyethylene glycol.
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of 25,000- 150000Da.
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of 30,000 to 125,000 Da. More preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of from 3,000 to 100,000 Da.
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are combined with polyethylene glycol.
  • PLA polylactide
  • PLGA lactide-glycolide copolymer
  • the copolymer of them and polyethylene glycol have a viscosity of 0.30-1.15 dL. /g (test conditions were ⁇ 0.5% (w/v), CHCl3, 25 °C).
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a viscosity of 0.37-0.95 dL/g (test conditions are -0.5) % (w/v), CHCl3, 25 ° C). More preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and the copolymer of these and polyethylene glycol have a viscosity of 0.37-0.809 dL/g (test condition is ⁇ 0.5% (w/v), CHCl3, 25 ° C).
  • 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 is polylactide (PLA), lactide-glycolide copolymer (PLGA), and polyethylene
  • the molar ratio of lactide to glycolide is from 100:0 to 65:35.
  • the water-insoluble polymer is at least one of polylactide (PLA), lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol, wherein The molar ratio of lactide to glycolide is from 100:0 to 70:30.
  • the poorly water-soluble polymer is at least one of a polylactide (PLA), a lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol, wherein The molar ratio of lactide to glycolide is from 100:0 to 75:25.
  • PLA polylactide
  • PLGA lactide-glycolide copolymer
  • molar ratio of lactide to glycolide is from 100:0 to 75:25.
  • 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.
  • a molar ratio of lactide to glycolide and a combination of PLGA and PLA having the same molecular weight but different carrying groups; a molar ratio of lactide to glycolide and PLGA and or the same molecular weight but different molecular weights Combination of PLA, and molecular weight difference is not more than 20kDa; combination of PLGA and PLA with the same molecular weight and the same carrier group but different molar ratio of lactide to glycolide, and the difference of the percentage of glycolide is not more than 20%; molecular weight The carrier group and the combination of PLGA and PLA having different molar ratios of lactide to glycolide, and the difference in molecular weight is not more than 20 kDa, and the difference in the percentage of glycolide is not more than 20%.
  • the molecular weight described above is a weight average molecular weight, which is a value obtained by gel permeation chromatography (GPC) measurement; the viscosity is a value obtained by Ubbelohde viscometer measurement.
  • GPC gel permeation chromatography
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition further comprises an excipient which is slow in the risperidone
  • the non-solvent-type preparation raw material of the release composition has a mass percentage of 0 to 8%.
  • the risperidone sustained release composition of the present invention may further comprise one or more excipients.
  • 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.
  • Excipients described in the present invention include, but are not limited to, antioxidants, buffers, and the like.
  • the excipient includes a buffer and an antioxidant.
  • the buffering agent is at least one of an organic acid and a mineral acid salt, and the buffering agent is contained in an amount of 0 to 5% by mass in the non-solvent-type preparation raw material of the risperidone sustained-release composition.
  • 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 antioxidant is in a non-solvent-type preparation raw material of the risperidone sustained-release composition in a mass percentage of 0 to 1%.
  • 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 excipient is added in the inner oil phase.
  • the excipient is a very fine powder, its particle diameter is less than 0.5 ⁇ m, preferably the particle diameter is less than 0.1 ⁇ m, and more preferably the particle diameter is less than 0.05 ⁇ m.
  • the excipient solvent is suspended in the internal oil phase with the inner oil phase or with very small particles.
  • the risperidone sustained-release composition is a microsphere or a microparticle.
  • the microspheres are usually used for administration by injection, and the microparticles or microspheres can be inhaled into a syringe and injected through a fine needle.
  • the route of delivery is by injection using a fine needle, including subcutaneous, intramuscular, intraocular, and the like.
  • Passing a thin needle means that the needle has a diameter of at least 20 G (inner diameter 580 ⁇ m), generally between about 22 G (inner diameter 410 ⁇ m) and about 30 G (inner diameter 150 ⁇ m), or 30 G or more. It is advantageous to use a needle that is as thin as at least 24G, more advantageously a needle that is as thin as at least 26G.
  • the microspheres have a geometric particle diameter of less than 200 ⁇ m.
  • the microspheres have a particle size of from about 10 to 200 ⁇ m, preferably from 15 to 150 ⁇ m, more preferably from about 20 to 120 ⁇ m.
  • the particle size of the microspheres is measured by a dynamic light scattering method (for example, laser diffraction method) or a microscopic technique (such as scanning electron microscopy).
  • the present invention also provides a preparation method capable of preparing the above-mentioned risperidone sustained-release composition simply and efficiently, and in order to achieve the object, the technical solution adopted by the present invention is: a risperidone sustained-release composition as described above
  • the preparation method comprises the following steps:
  • step (3) adding the internal oil phase obtained in the step (1) to the external aqueous phase to prepare an emulsion, and then hardening the particles in the solution by solvent evaporation or solvent extraction, collecting the particles, washing and drying to obtain risperidone Release the microspheres.
  • the mass percentage of the poorly water-soluble polymer and the organic solvent is 1 to 18%; the step (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 and the organic solvent in the step (1) is 1.5 to 9%; the step (2) The mass percentage of the surfactant in the outer aqueous phase is 0.5 to 8%; in the step (3), the volume of the outer aqueous phase is 80 times or more the volume of the inner oil phase.
  • a more preferred embodiment of the preparation method of the risperidone sustained-release composition of the present invention wherein the mass percentage of the poorly water-soluble polymer and the organic solvent in the step (1) is from 3 to 8.5%; the step (2) The mass percentage of the surfactant in the outer aqueous phase is from 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 mass percentage of the poorly water-soluble polymer in the organic solvent varies depending on the type of the polymer, the weight average molecular weight, and the type of the organic solvent, and usually the mass percentage thereof (biodegradable and biocompatible water is difficult)
  • the mass of the soluble polymer / the mass of the organic solvent ⁇ 100%) is 1 to 18%.
  • the organic solvent in the step (1) is at least one of a halogenated hydrocarbon, a fatty acid ester, and an aromatic hydrocarbon;
  • the hydrocarbon includes methylene chloride, 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 poorly water-soluble polymer and risperidone, has a boiling point lower than water and is insoluble or poorly soluble in water, and the organic solvent may be a single organic solvent or a miscible two or The above organic solvent.
  • 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 an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, a nonionic surfactant, and a surface active agent.
  • the cationic surfactant comprises benzalkonium chloride, cetyltrimethylammonium bromide, lauric acid dimethylbenzylammonium chloride, acylcarnitine hydrochloride An alkyl pyridine halide;
  • the anionic surfactant comprises an alkyl sulfate, potassium laurate, sodium alginate, sodium polyacrylate and its derivatives, alkyl polyepoxyethylene sulfate, dioctyl succinate Sodium sulfonate, phospholipids, glycerides, sodium carboxymethylcellulose, sodium oleate, sodium stearate, sodium salts of cholic acid and other bile acids;
  • the nonionic surfactants include polyoxyethylene fatty alcohol ethers, Polysorbate, polyoxyethylene fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene polypropylene glycol copolymer, sucrose fatty acid ester, polyethylene glycol fatty acid ester, poly
  • the surfactant (or stabilizer) can increase the wetting property of the organic phase, improve the stability and shape of the small liquid bead during the emulsification process, avoid re-polymerization of the small liquid bead, and reduce the unencapsulated or partially encapsulated small spherical particles.
  • the amount of the drug thereby reducing the initial burst of the drug during the release process.
  • the surfactant is an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, a nonionic surfactant or a surface active biomolecule, preferably an anionic surfactant, nonionic A surfactant (or stabilizer) or a surface active biomolecule, more preferably a nonionic surfactant (or stabilizer) or a surface active biomolecule.
  • the cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, lauric dimethylbenzylammonium chloride, acylcarnitine hydrochloride or Alkylpyridine halide.
  • the anionic surfactants include, but are not limited to, sodium lauryl sulfate, ammonium lauryl sulfate, sodium stearyl sulfate, alkyl sulfate, potassium laurate, sodium alginate, sodium polyacrylate, and derivatives thereof. , alkyl polyethylene oxide sulfate, sodium dioctyl sulfonate, phospholipids, glycerides, sodium carboxymethyl cellulose, sodium oleate, sodium stearate, cholic acid and other bile acids (eg The sodium salt of cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, and glycodeoxycholic acid.
  • the nonionic surfactants include, but are not limited to, polyoxyethylene fatty alcohol ethers (benzazole), polysorbates (such as Tween 80, Tween 60), polyoxyethylene fatty acid esters (OEO), polyoxygen Ethylene 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 glycerol di-fatty acid ester, polyglycerin fatty acid ester, polypropylene glycol monoester, aryl alkyl polyether alcohol, polyoxyethylene-polyoxypropylene copolymer (Polo Sigma), polyvinyl alcohol (PVA) and its derivatives, polyvinylpyrrolidone (PVP) and polysaccharides, preferably poloxamer, polyviny
  • the polysaccharide includes starch and starch derivatives, methyl cellulose, ethyl cellulose, hydroxy cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, gum arabic, chitosan derivatives, gellan gum, Alginic acid derivatives, dextran derivatives and amorphous cellulose, preferably hypromellose, chitosan and derivatives thereof, amylopectin or dextran and derivatives thereof.
  • Surface active biomolecules include polyamino acids (such as polyaspartic acid or polyglutamic acid or their analogs), peptides (such as basic peptides), proteins (such as gelatin, casein, albumin, hirudin, starch hydroxyl Ethylase or the like, preferably albumin).
  • polyamino acids such as polyaspartic acid or polyglutamic acid or their analogs
  • peptides such as basic peptides
  • proteins such as gelatin, casein, albumin, hirudin, starch hydroxyl Ethylase or the like, preferably albumin).
  • the surfactant has a mass concentration of 0.1 to 10% in the external aqueous phase; preferably, the surfactant is in the external water.
  • the mass percent concentration in the phase is from 0.5 to 8%; more preferably, the surfactant has a mass percent concentration in the outer aqueous phase of from 1 to 7%.
  • 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 inorganic salt or organic salt in the outer aqueous phase in a mass percentage of 0 to 5%.
  • the outer aqueous phase may further contain an inorganic salt or an organic salt to reduce the infiltration of the water-soluble active substance into the aqueous phase during the curing process of the microsphere, and the mechanism is to increase the osmotic pressure of the external phase or reduce the active material in the external phase.
  • the inorganic salt includes, but is not limited to, water-soluble phosphoric acid, sulfuric acid, acetic acid, potassium or sodium carbonate of carbonic acid, Tris, MES, HEPES or any mixture thereof, and the concentration by weight in aqueous solution is 0-5%. Preferably, it is from 0.01 to 4%, more preferably from 0.05 to 3%.
  • the pH ranges from 3 to 9, preferably from 4 to 9, more preferably from 5.5 to 8.5.
  • the method for preparing the emulsion is the same as the well-known emulsification method, and the device for generating high shear force (such as a magnetic stirrer, a mechanical stirrer, a high-speed homogenizer, an ultrasonic machine, a membrane emulsifier, a rotor-stator mixer, A static mixer, a high pressure homogenizer, etc.) mixes the organic internal phase with an aqueous external phase to form a uniform emulsion.
  • the device for generating high shear force such as a magnetic stirrer, a mechanical stirrer, a high-speed homogenizer, an ultrasonic machine, a membrane emulsifier, a rotor-stator mixer, A static mixer, a high pressure homogenizer, etc.
  • the solvent evaporation in the step (3) can be applied to the following method:
  • the gas stream blows the surface of the liquid, and controls the contact area of the liquid phase with the gas phase, the rate of emulsion agitation and circulation (such as JP-A-9-221418) to accelerate the evaporation of the organic solvent, preferably the gas stream;
  • the organic solvent e.g., W00183594
  • W00183594 is rapidly evaporated from the hollow fiber membrane
  • the hollow fiber membrane is preferably, for example, a silicone rubber pervaporation film (particularly a pervaporation film prepared from polydimethylsiloxane).
  • microspheres obtained in the step (3) are separated by centrifugation, sieving or filtration.
  • the method of drying the microspheres in the step (3) is not particularly limited, and examples thereof include heating, vacuum drying, freeze drying, vacuum drying, and combinations thereof.
  • microparticles or microspheres of the present invention may encapsulate a large amount of active ingredients, depending on the type and content of the active ingredient, the dosage form, the duration of release, the subject to be administered, the route of administration, the purpose of administration, the target disease and symptoms, and the like. And choose it properly.
  • the dosage can be considered satisfactory as long as the active ingredient can be maintained in the active concentration of the drug for the desired duration in vivo.
  • microspheres When the microspheres are administered as a suspension, they may be in the form of a suspension formulation 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 eg, parabens, propylparaben, benzyl alcohol
  • chlorobutanol e.g., chlorobutanol
  • sorbic acid boric acid, etc., etc.
  • sustained-release injections can also be obtained by dispersing microparticles or microspheres in vegetable oils such as sesame oil and corn oil or vegetable oils supplemented with phospholipids such as lecithin, or in medium chain triglycerides. To obtain an oily suspension.
  • microspheres obtained by the invention can be used in the form of granules, suspensions, implants, injections, adhesives, etc., and can be administered orally or parenterally (intramuscular injection, subcutaneous injection, menstrual injection). Dermal administration, mucosal administration (intracrine, intravaginal, rectal, etc.)).
  • the risperidone sustained release composition of the present invention is sufficiently stable to be sustained for several weeks or more, such as up to about 2 weeks, such as up to about 4 weeks, such as up to about 8 weeks, such as up to about 12 weeks, or more For a long time, it can be adjusted according to the specific treatment needs.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 25%, water Insoluble polymer: PLA 74.9%, release regulator: stearic acid 0.1%.
  • the PLA has a weight average molecular weight of 30 kDa, a viscosity of 0.27 dL/g, and the PLA has an ester group end.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 20-94 ⁇ m.
  • the drug-loading rate is 2294%, and the encapsulation efficiency of risperidone is 91.76%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass: risperidone 30%, water Poorly soluble polymer: PLA 69.5%, release regulator: kaempferic acid 0.5%.
  • the PLA consists of PLA at the ester end (weight average molecular weight: 40 kDa, viscosity: 0.35 dL/g) and carboxy terminal PLA (weight average molecular weight: 40 kDa, viscosity: 0.35 dL/g), PLA and carboxyl groups at the ester end
  • the mass ratio of the PLA at the end is: 70:69.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 27-100 ⁇ m.
  • the drug loading rate is 27.60%, and the risperidone encapsulation efficiency is 92.0%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass: risperidone 35%, water Insoluble polymer: PLA 64.2%, release regulator: sulphate 0.8%.
  • the PLA has a weight average molecular weight of 35 kDa, a viscosity of 0.32 dL/g, and the PLA has a carboxyl terminal.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 29-96 ⁇ m.
  • the drug-loading rate is 32.38%, and the risperidone encapsulation efficiency is 92.5%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass: risperidone 35%, water Insoluble polymer: PLGA 64%, release regulator: 1% lignin.
  • risperidone 35% water Insoluble polymer
  • PLGA 64% water Insoluble polymer
  • release regulator 1% lignin.
  • the molar ratio of lactide to glycolide is 95:5
  • the weight average molecular weight of the PLGA is 40 kDa
  • the viscosity 0.36 dL/g
  • the PLA has an ester group end.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 30-100 ⁇ m.
  • the drug-loading rate is 31.99%, and the encapsulation efficiency of risperidone is 91.40%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass: risperidone 35%, water Insoluble polymer: PLGA 63%, release regulator: 2% stearic acid.
  • risperidone 35% water Insoluble polymer
  • PLGA 63% water Insoluble polymer
  • release regulator 2% stearic acid.
  • the molar ratio of lactide to glycolide in the PLGA is 85:15
  • the weight average molecular weight of the PLGA is 45 kDa
  • the viscosity is 0.39 dL/g
  • the PLA has an ester group end.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 30-110 ⁇ m.
  • the drug-loading rate is 32.50%, and the encapsulation efficiency of risperidone is 92.86%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 40%, water Insoluble polymer: PLA 57%, release regulator: 3% stearic acid.
  • the PLA is a mixture having a carboxyl terminal PLA and an ester terminal PLA, and wherein the mass ratio of the carboxyl terminal PLA and the ester terminal PLA is 37:20, the carboxyl terminal PLA and the ester group
  • the terminal PLA had a weight average molecular weight of 55 kDa and a viscosity of 0.47 dL/g.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 27-118 ⁇ m.
  • the drug loading rate is 37.30%, and the risperidone encapsulation efficiency is 93.25%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 40%, water Insoluble polymer: PLGA 56%, release regulator: 4% arachidic acid.
  • risperidone 40% water Insoluble polymer
  • PLGA 56% water Insoluble polymer
  • release regulator: 4% arachidic acid a component that controls the risperidone sustained-release composition of the present embodiment.
  • the molar ratio of lactide to glycolide in the PLGA is 85:15
  • the weight average molecular weight of the PLGA is 65 kDa
  • the viscosity is 0.57 dL/g
  • the PLGA has a carboxyl terminal.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 27-104 ⁇ m.
  • the drug loading rate is 38.1%, and the risperidone encapsulation efficiency is 95.25%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 40%, water Insoluble polymer: PLGA 55%, release regulator: 5% peanut acid.
  • risperidone 40% water Insoluble polymer
  • PLGA 55% water Insoluble polymer
  • release regulator: 5% peanut acid a molar ratio of lactide to glycolide in the PLGA is 75:25
  • the weight average molecular weight of the PLGA is 75 kDa
  • the viscosity is 0.66 dL/g
  • the PLGA has an ester end.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 28-107 ⁇ m.
  • the drug loading rate is 36.40%, and the risperidone encapsulation efficiency is 91.00%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 45%, water Insoluble polymer: PLGA 46%, release regulator: 6% of behenic acid, excipient: buffer 2% zinc stearate, antioxidant vitamin E 1%.
  • the PLGA is a mixture of a PLGA having a carboxyl terminal and a PLGA having an ester terminal, and a mass ratio of a PLGA having a carboxyl terminal to a PLGA having an ester terminal is 2:1; and the lactide having a carboxyl terminal is lactide and B
  • the molar ratio of lactide is 85:15, the weight average molecular weight is 85 kDa, and the viscosity is 0.71 dL/g; the molar ratio of lactide to glycolide in the PLGA having ester terminal is 75:25, and the weight average molecular weight is 70kDa, viscosity 0.56dL / g.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 21 to 98 ⁇ m.
  • the drug loading rate is 41.60%, and the risperidone encapsulation efficiency is 92.44%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 50%, water Insoluble polymer: PLGA 43%, release regulator: 7% palmitic acid.
  • risperidone 50% water Insoluble polymer
  • PLGA 43% water Insoluble polymer
  • release regulator 7% palmitic acid.
  • the molar ratio of lactide to glycolide in the PLGA is 80:20
  • the weight average molecular weight of the PLGA is 100 kDa
  • the viscosity is 0.81 dL/g
  • the PLGA has an ester group end.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and have a particle diameter of 25 to 99 ⁇ m.
  • the drug loading rate is determined to be 46.15%, and the risperidone encapsulation efficiency is 92.30%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 55%, water Insoluble polymer: PLGA 36%, release regulator: 8% myristic acid, excipient: buffer zinc nitrate 1%.
  • the PLGA is PLGA (the molar ratio of lactide to glycolide is 70:30, the weight average molecular weight is 125 kDa, the viscosity is 0.5 dL/g, having a carboxyl terminal), and PLGA (lactide and glycolide) A mixture having a molar ratio of 85:15, a weight average molecular weight of 125 kDa, a viscosity of 0.79 dL/g, and a carboxyl terminal.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and have a particle diameter of 30 to 114 ⁇ m.
  • the drug loading rate is determined to be 49.83%, and the risperidone encapsulation efficiency is 90.60%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass percent: risperidone 60%, water Insoluble polymer: PLGA 30%, release regulator: 10% lauric acid.
  • risperidone 60% water Insoluble polymer
  • PLGA 30% water Insoluble polymer
  • the molar ratio of lactide to glycolide is 65:35
  • the weight average molecular weight of the PLGA is 150 kDa
  • the viscosity is 1.2 dL/g
  • the PLA has a carboxyl terminal.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 38-125 ⁇ m.
  • the drug-loading rate is determined to be 53.50%, and the risperidone encapsulation efficiency is 89.17%.
  • the non-solvent-type preparation raw material of the risperidone sustained-release composition of the present embodiment comprises the following components by mass: risperidone 35%, water Insoluble polymer: PLGA 61%, release regulator: 4% of behenic acid.
  • risperidone 35% water Insoluble polymer
  • PLGA 61% water Insoluble polymer
  • release regulator 4% of behenic acid.
  • the molar ratio of lactide to glycolide is 75:25
  • the weight average molecular weight of the PLGA is 100 kDa
  • the viscosity is 0.80 dL/g
  • the PLA has an ester group end.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 20-88 ⁇ m.
  • the drug-loading rate is 32.50%, and the encapsulation efficiency of risperidone is 92.86%.
  • the water-insoluble drug sustained-release microspheres prepared in Examples 1 to 13 were used as test groups 1 to 13, respectively, and the following four comparative examples were used as a control group:
  • Comparative Example 1 the preparation method was the same as in Example 1 of Patent CN1137756, in which risperidone 35%, PLGA (75/25, 100 kDa, 0.79 dL/g, ester base) 65% was charged.
  • the obtained risperidone sustained-release microspheres have a round shape and a particle size of 30-127 ⁇ m.
  • the drug loading rate is 31.15%, and the risperidone encapsulation efficiency is 89.00%.
  • Example 2 Comparative Example 2, the preparation method was the same as Example 5 of the present invention, in which: risperidone 35%, no release regulator, risperidone 35%, 65%.
  • the obtained risperidone sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 28-86 ⁇ m.
  • the drug loading rate is 31.53%, and the encapsulation efficiency of risperidone is 90.08%.
  • Comparative Example 3 was prepared in the same manner as in Example 6 of the present invention, wherein the feed was: no release modifier, 40% risperidone, and 60% water-insoluble polymer.
  • the obtained risperidone sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 23-91 ⁇ m.
  • the drug loading rate is 36.09%, and the encapsulation efficiency of risperidone is 90.23%.
  • Example 4 the preparation method was the same as in Example 7 of the present invention, wherein the feed was: no release modifier, 40% risperidone, and 60% water-insoluble polymer.
  • the obtained risperidone sustained-release microspheres have a round shape and a smooth surface, and the particle diameter is 22-93 ⁇ m.
  • the drug loading rate is 36.84%, and the risperidone encapsulation efficiency is 92.10%.
  • Test method accurately weighed 20 mg of the microspheres prepared in Examples 1-14 and Comparative Examples 1-2 into a 200 mL centrifuge tube, and added pH 7.4 PBS (containing 0.05% Tween 80, 0.05% sodium azide) 50 mL. Place it in a 37 ° C, 150 rpm constant temperature water bath shaker, take 1 mL of the release solution at the preset time point, add an equal amount of fresh medium, and place it in a constant temperature water bath oscillator to continue the release test. The amount of drug released was determined by high performance liquid chromatography (HPLC), and the results are shown in Tables 1 and 2.
  • HPLC high performance liquid chromatography
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 0.15 0.10 0.17 0.14 0 0 0 0.17 0.5 0.50 0.39 0.39 0.69 0.34 0.21 0.50 0.50 1 1.03 0.75 0.95 1.18 0.59 0.65 1.30 1.65 2 1.85 1.32 3.88 2.73 1.73 1.39 3.70 3.46 7 14.00 11.85 16.42 16.70 12.00 6.73 19.79 20.73 14 27.80 25.35 34.32 36.95 26.59 19.08 39.04 46.70 twenty one 46.33 40.80 49.55 56.37 45.20 32.11 60.33 73.82 28 67.50 60.50 68.63 76.55 63.15 46.65 74.42 96.78 35 89.18 80.87 87.24 90.14 79.76 62.99 87.56 100.00 42 98.86 92.53 97.33 98.25 91.50 75.14 96.24 100.00 49 100.00 98.
  • the sustained-release microspheres of the present invention have no burst effect, and the release rate on the first day is not more than 2%, and can be released in a near zero-order trend within 4-12 weeks, which is obviously slow.
  • the acidic products produced by internal degradation are transported to the outside in time, avoiding or greatly reducing the phenomenon that the auto-catalytic degradation rate of the core polymer is accelerated, effectively overcoming the disadvantages of PLA or PLGA body degradation effects.
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 0.12 0.08 0.18 0.13 0.03 0 0.02 0.16 0.5 0.48 0.37 0.40 0.69 0.37 0.30 0.45 0.48 1 1.03 0.75 0.98 1.17 0.66 0.99 1.39 1.66 2 1.84 1.33 3.87 2.74 1.71 1.68 3.69 3.46 7 14.25 11.80 16.40 16.72 12.46 7.58 20.32 20.78 14 27.76 25.34 34.35 36.98 28.72 19.77 39.55 46.79 twenty one 46.35 41.00 49.65 56.40 46.92 33.66 61.39 73.85 28 67.52 60.51 68.66 76.53 66.43 46.94 74.80 96.80 35 89.15 80.86 86.95 90.00 81.89 64.07 88.21 100.00 42 98.00 92.34 97.35 97.93 92.63 77.08 95.90 100.00 49 100.00 98.15
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 0.17 0.13 0.20 0.19 0.12 0.01 0.07 0.20 0.5 0.55 0.42 0.44 0.72 0.44 0.46 0.64 0.56 1 1.16 0.78 1.01 1.20 0.80 1.21 1.55 1.70 2 1.90 1.40 3.96 2.79 1.95 2.02 3.93 3.59 7 14.51 12.03 16.55 16.80 13.80 8.33 22.18 20.96 14 28.00 26.00 34.49 37.21 29.99 20.70 42.76 48.00 twenty one 47.28 41.75 50.20 56.75 49.31 35.59 63.00 74.30 28 68.42 61.44 69.15 77.05 69.20 49.31 77.31 98.05 35 90.00 81.87 87.83 90.65 84.16 66.44 90.32 100.00 42 99.90 93.12 98.72 99.00 94.49 80.00 97.20 100.00 49 100.00 99.21 100.00 100.00 100.00
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 0.21 0.24 0.24 0.22 0.30 0.05 0.13 0.26 0.5 0.64 0.56 0.50 0.79 0.66 0.73 0.86 0.62 1 1.27 0.88 1.13 1.25 0.99 1.63 2.12 1.79 2 2.16 1.5 4.09 2.85 2.31 3.07 4.91 3.71 7 15.06 12.51 16.84 17.00 15.37 11.25 25.30 21.45 14 29.31 26.71 35.50 37.82 33.39 25.25 47.10 49.12 twenty one 48.65 42.30 51.12 57.16 52.96 39.65 66.65 75.75 28 70.13 62.66 70.04 77.89 72.22 54.51 83.43 99.83 35 91.75 82.89 89.46 91.74 88.15 69.15 96.09 100.00
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.4 5.35 4.17 4.54 5.11 1.26 1.18 1.59 5.26 0.25 2.14 1.75 1.49 3.28 2.48 2.75 4.15 2.34 0.5 3.46 2.54 2.75 4.51 5.45 4.86 6.45 5.96 1 2.89 3.09 8.65 5.87 7.8 6.54 10.98 8.28 7 12.25 10.32 14.46 15.24 15.54 9.45 17.04 18.11 14 18.74 16.26 20.66 21.3 19.49 14.10 23.19 26.16 twenty one 24.55 22.49 23.04 24.79 21.28 18.04 21.78 21.24 28 22.36 23.15 20.27 19.46 17.72 20.39 13.72 13.07 35 15.42 17.17 12.54 11.5 10.53 16.18 7.53 6.32 42 7.19 10.36 5.67 4.86 6.33 11.06 3.33 1.45 49 1.50 5.28 1.28 1.05 1.39 7.53 0.89 0.15 56 0 0.85 0 0 0.33 3.62 0 0 63 0 0 2.53 70 0.89
  • the risperidone microspheres of the present invention showed a good sustained release effect, and the blood concentration was increased very quickly after administration, and the comparative ratio took approximately 2-4 weeks to reach 5 ng/ The corresponding concentration above mL is similar to the in vitro release behavior.
  • the blood concentration of the sustained release microspheres of the present invention can last for about 20-60 days in the range of 5-30 ng/mL; while the comparative example lasts for about 20-28 days. It is illustrated that the risperidone microsphere of the present invention has a better effect, can maintain a certain blood drug concentration for a long period of time, can prolong the administration cycle, reduce side effects, and improve patient compliance.

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Abstract

一种缓释组合物及其制备方法，非溶剂型制备原料包含利培酮、水难溶性聚合物和释放调节剂，所述释放调节剂包含有机亲油性物质，制备方法包括以下步骤:（1）将非溶剂型制备原料溶于有机溶剂中，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硬化，收集微粒，洗涤并干燥。

Description

一种利培酮缓释组合物及其制备方法 技术领域
本发明涉及一种缓释组合物及其制备方法，尤其是一种利培酮缓释组合物及其制备方法。
背景技术
近十几年来，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，能够限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治疗药物浓度，能够极小化治疗所需的药物总给药量，能够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150kDa的PLGA为载体，利培酮为API，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。
有研究者认为，由于利培酮为水难溶/微溶性药物，微球载药量较低时，初始药物释放很少，导致药物血药浓度出现一定时间的释放停滞期，随着载药量的提高，药物释放停滞期逐步减小，当载药量达到一定范围时，给药后即有药物释放。如专利CN101653422公开一种可以释放数周的利培酮微球组合物，通过提高载药率(45％以上)来消除释药停滞期，但制剂稳定性差，经长期贮存后，微球的体内释放行为会发生明显变化。
也有研究者认为，以PLGA为载体时，疏水性组分(LA)与亲水性组分(GA)的比例及分子量大小对水溶性药物的释放有显著的影响，PLGA亲水性组分比例越高(如LA:GA＝50:50)，分子量越小，药物溶出越快，可大大缩短释放停滞期。如专利CN 103338752以两种不同分子量及单体比例(55-110kDa，LA:GA＝65:35～90:10及4-35kDa，LA:GA＝50:50～75:25)的PLGA的混合物(重量比为70～90:10～30)作为载体制备进入体内立即释放的利培酮微球。然而，这种聚合物组合在辐射灭菌过程中易造成表面塌陷，因为不同单体比例及分子量的PLGA在辐射下降解程度不同；再者，由于分子量较低且GA单体比例较高的PLGA在存储过程中更容易发生降解，不利于制剂的保存稳定性；同时，分子量较低且GA组分比例较高的PLGA辅料的制备、存储难度较大，成本相对较高。
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给药后无明显释放延迟期 或突释现象、能够在数周或更长的时间内维持治疗血药浓度、具有良好的释放性能和较好的稳定性的利培酮缓释组合物。同时，本发明的另一目的在于提供所述利培酮缓释组合物的制备方法。
为实现上述目的，本发明采取的技术方案为：一种利培酮缓释组合物，所述利培酮缓释组合物的非溶剂型制备原料包含利培酮、水难溶性聚合物和释放调节剂，所述释放调节剂包含有机亲油性物质。本发明利培酮缓释组合物的制备原料包括非溶剂型制备原料和溶剂型制备原料。其中，所述非溶剂型制备原料包含利培酮、水难溶性聚合物和释放调节剂，不包括表面活性剂；所述溶剂型制备原料包括水性介质和有机溶剂。
本发明所述利培酮缓释组合物的非溶剂型制备原料中含有释放调节剂，而且所述释放调节剂包含有机亲油性物质，在体内可最终转化为二氧化碳和水，使微球表面及内部产生孔道，增加体液的渗透性，促进利培酮的溶出。
作为本发明所述利培酮缓释组合物的优选实施方式，所述利培酮缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为0.1～10％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为0.5～8％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为1～6％。
作为本发明所述利培酮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。作为本发明所述利培酮缓释组合物的更优选实施方式，所述有机亲油性物质为脂肪酸。
作为本发明所述利培酮缓释组合物的优选实施方式，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。
作为本发明所述利培酮缓释组合物的优选实施方式，所述利培酮缓释组合物的非溶剂型制备原料中，所述利培酮的质量百分含量为25～60％，所述水难溶性聚合物的质量百分含量为39.9-74.9％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述利培酮的质量百分含量为30～55％，所述水难溶性聚合物的质量百分含量为44.9-69.9％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述利培酮的质量百分含量为35～50％，所述水难溶性聚合物的质量百分含量为44.9-69.9％。
作为本发明所述利培酮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。
作为本发明所述利培酮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。
作为本发明所述利培酮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。
作为本发明所述利培酮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时，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的重均分子量均为25000-150000Da。优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的重均分子量均为30000-125000Da。更优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的重均分子量均为30000-100000Da。
作为本发明所述利培酮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时，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的粘度均为0.30-1.15dL/g(测试条件为～0.5％(w/v)，CHCl3，25℃)。优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的粘度均为0.37-0.95dL/g(测试条件为～0.5％(w/v)，CHCl3，25℃)。更优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的粘度均为0.37-0.809dL/g(测试条件为～0.5％(w/v)，CHCl3，25℃)。
作为本发明所述利培酮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。
作为本发明所述利培酮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)、其与聚乙二醇的共聚物中的至少一种时，其中的丙交酯与乙交酯的摩尔比为100:0～65:35。优选地，所述可水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、其与聚乙二醇的共聚物中的至少一种时，其中的丙交酯与乙交酯的摩尔比为100:0～70:30。更优选地，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)、其与聚乙二醇的共聚物中的至少一种时，其中的丙交酯与乙交酯的摩尔比为100:0～75:25。
本发明利培酮缓释组合物中，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和或PLA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和或PLA的组合，且分子量差别不大于 20kDa；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和或PLA的组合，且乙交酯的百分率差别不大于20％；分子量、携带基团及丙交酯与乙交酯的摩尔比均不同的PLGA和或PLA的组合，且分子量差别不大于20kDa、乙交酯的百分率差别不大于20％。
上述所述的的分子量为重均分子量，是通过凝胶渗透色谱仪(GPC)测量所获得的值；所述粘度是乌氏粘度计测量所获得的值。
作为本发明所述利培酮缓释组合物的优选实施方式，所述利培酮缓释组合物的非溶剂型制备原料还包含赋形剂，所述赋形剂在所述利培酮缓释组合物的非溶剂型制备原料中的质量百分含量为0～8％。本发明的利培酮缓释组合物中，还可以包含一种或一种以上的赋形剂。赋形剂可以赋予活性药物或微粒其它特征，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。本发明中所述的赋形剂包括但不限于抗氧化剂、缓冲剂等。
作为本发明所述利培酮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。
所述缓冲剂为有机酸、无机酸盐中的至少一种，所述缓冲剂在所述利培酮缓释组合物的非溶剂型制备原料中的质量百分含量为0～5％。
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利培酮缓释组合物的非溶剂型制备原料中的质量百分含量为0～1％。
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。
所述赋形剂在内油相时加入。当所述赋形剂为极细微的粉末时，其粒径小于0.5μm，优选为粒径小于0.1μm，更优选粒径小于0.05μm。所述赋形剂溶剂与内油相中或以极小颗粒混悬于内油相中。
作为本发明所述利培酮缓释组合物的优选实施方式，所述利培酮缓释组合物为微球或微粒。当所述利培酮缓释组合物为微球时，微球通常用于注射给药，微粒或微球可以被吸入到 注射器中，并通过细的针注射。优选的，递送途径是使用细针进行注射，包括皮下、肌肉、眼内等。通过细的针意味着针至少为20G口径(内径580μm)，一般在大约22G(内径410μm)和大约30G(内径150μm)之间，或30G以上。有利的是使用细到至少24G的针头，更有利的是细到至少26G的针头。
作为本发明所述利培酮缓释组合物的优选实施方式，所述微球的几何粒径小于200μm。典型地，所述微球的粒径大约为10～200μm，优选15～150μm，更优选大约20～120μm。微球粒径大小通过动态光散射方法(例如激光衍射法)、或显微技术(如扫描电镜法)来测量。
另外，本发明还提供一种能够简单高效制备得到上述利培酮缓释组合物的制备方法，为实现此目的，本发采取的技术方案为：一种如上所述利培酮缓释组合物的制备方法，包括以下步骤：
(1)将所述非溶剂型制备原料溶于有机溶剂中，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硬化，收集微粒，洗涤并干燥，得利培酮缓释微球。
作为本发明所述利培酮缓释组合物的制备方法的优选实施方式，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1～18％；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。作为本发明所述利培酮缓释组合物的制备方法的更优选实施方式，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。作为本发明所述利培酮缓释组合物的制备方法的更优选实施方式，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。
所述水难溶性聚合物在有机溶剂中的质量百分含量依据聚合物的类型、重均分子量以及有机溶剂的类型而变化，通常其质量百分含量(可生物降解和生物相容的水难溶性聚合物质量/有机溶剂质量×100％)为1～18％。
作为本发明所述利培酮缓释组合物的制备方法的优选实施方式，所述步骤(1)中的有机溶剂为卤代烃、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水难溶性聚合物和利培酮，沸点低于水且不溶于或难溶于水，所述有机溶剂可以为单一的有机溶剂，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。
作为本发明所述利培酮缓释组合物的制备方法的优选实施方式，所述表面活性剂为阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂、非离子表面活性剂、表面活性生物分子中的至少一种；所述阳离子表面活性剂包括苯扎氯胺、溴化十六烷基三甲基铵、月桂酸基二甲基苯甲基氯铵、酰基肉毒碱盐酸盐、烷基吡啶卤化物；所述阴离子表面活性剂包括烷基硫酸盐、月桂酸钾、藻酸钠、聚丙烯酸钠及其衍生物、烷基聚环氧乙烯硫酸酯、丁二酸二辛基磺酸钠、磷脂、甘油酯、羧甲基纤维素钠、油酸钠、硬脂酸钠、胆酸和其他胆汁酸的钠盐；所述非离子表面活性剂包括聚氧乙烯脂肪醇醚、聚山梨酸酯、聚氧乙烯脂肪酸酯、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、聚乙烯醇及其衍生物、聚乙烯吡咯烷酮和多糖；所述表面活性生物分子包括聚氨基酸、肽、蛋白质。
所述表面活性剂(或稳定剂)可以增加有机相的湿润性质、提高乳化过程中小液珠的稳定性及形状，避免小液珠重新聚合、减少未包封的或部分包封的小球颗粒的数量，从而减少了药物在释放过程中的初始突释。
所述表面活性剂(或稳定剂)为阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂、非离子性表面活性剂或表面活性生物分子这样的化合物，优选阴离子表面活性剂、非离子性表面活性剂(或稳定剂)或表面活性生物分子，更优选非离子性表面活性剂(或稳定剂)或表面活性生物分子。
所述阳离子表面活性剂包括但不限于季铵化合物如苯扎氯铵、溴化十六烷基三甲基铵、月桂酸基二甲基苯甲基氯铵、酰基肉毒碱盐酸盐或烷基吡啶卤化物。
所述阴离子表面活性剂包括但不限于十二烷基硫酸钠、十二烷基硫酸铵、十八烷基硫酸钠等烷基硫酸盐、月桂酸钾、藻酸钠、聚丙烯酸钠及其衍生物、烷基聚环氧乙烯硫酸酯、丁二酸二辛基磺酸钠、磷脂、甘油酯、羧甲基纤维素钠、油酸钠、硬脂酸钠、胆酸和其它胆汁酸(如胆酸、脱氧胆酸、甘氨胆酸、牛磺胆酸、甘氨脱氧胆酸)的钠盐。
所述非离子性表面活性剂包括但不限于聚氧乙烯脂肪醇醚(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、聚乙烯比咯烷酮(PVP)和多糖，优选泊洛沙姆、聚乙烯醇、聚山梨酸酯、聚乙烯比咯烷酮和多糖，更优选聚乙烯醇、多糖。
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。
表面活性生物分子包括聚氨基酸(如聚天冬氨酸或聚谷氨酸或它们的类似物)、肽(如碱性肽)、蛋白质(如明胶、酪蛋白、白蛋白、水蛭素、淀粉羟乙基酶等，优选白蛋白)。
作为本发明所述利培酮缓释组合物的制备方法的优选实施方式，所述表面活性剂在外水相中的质量百分浓度为0.1～10％；优选地，所述表面活性剂在外水相中的质量百分浓度为0.5～8％；更优选地，所述表面活性剂在外水相中的质量百分浓度为1～7％。
作为本发明所述利培酮缓释组合物的制备方法的优选实施方式，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；所述无机盐或有机盐在所述外水相中的质量百分含量为0～5％。进一步的，所述外水相中还可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。所述无机盐包括但不限于水溶性的磷酸、硫酸、乙酸、碳酸的钾盐或钠盐、Tris、MES、HEPES或它们的任意混合物，其于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。
所述制成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)将有机内相与水性外相混合，以形成均匀乳液。
所述步骤(3)中溶剂蒸发可以应用下述方法：
(A)通过加热、减压(或联合加热)和减压蒸去有机溶剂；
(B)气流鼓吹液体表面，并控制液相与气相的接触面积、乳液搅拌和循环的速率(如JP-A-9-221418)加速有机溶剂的蒸发，所述气流优选氮气；
(C)用空心纤维薄膜快速蒸去有机溶剂(如W00183594)，空心纤维薄膜优选是例如硅橡胶全蒸发薄膜(特别是由聚二甲基硅氧烷制备的全蒸发薄膜)。
所述步骤(3)中所获得的微球通过离心、过筛或过滤的方式予以分离。
所述步骤(3)中干燥微球的方法没有特别限定，例如可举出加热、减压干燥、冷冻干燥、真空干燥和它们的组合。
本发明的微粒或微球可以包封大量的活性成分，剂量可依据活性成分的类型与含量、剂型、释放持续时间、给药受试者、给药途径、给药目的、靶标疾病及症状等而适当地选择。 然而，只要活性成分可于活体内维持在药物有效浓度达预期的持续时间，则该剂量可认为是令人满意的。
当微球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(例如对羟基苯甲酸酯、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：将微粒或微球分散于植物油(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。
本发明获得的微球可用于颗粒剂形式、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))。
本发明的利培酮缓释组合物足够稳定，可以持续释放数周以上，诸如长达约2周、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，可根据具体治疗需求进行调节。
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＝微球中药物实际质量/药物投料质量×100％。
实施例1
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮25％，水难溶性聚合物：PLA 74.9％，释放调节剂：硬脂酸0.1％。其中，所述PLA的重均分子量为30kDa，粘度为0.27dL/g，且所述PLA具有酯基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与二氯甲烷的质量百分比为10％，然后加入利培酮和释放调节剂，溶解均匀，形成内油相；
(2)将PVA和磷酸钾溶于水中，形成外水相，所述PVA在所述外水相中的质量百分含量为0.1％，所述磷酸钾在所述外水相中的质量百分含量为0.01％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的60倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时，将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为20～94μm，经测定其载药率为2294％，利培酮包封率为91.76％。
实施例2
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮30％，水难溶性聚合物：PLA 69.5％，释放调节剂：山俞酸0.5％。其中，所述PLA由酯基端的PLA(重均分子量为40kDa，粘度为0.35dL/g)和羧基端的PLA(重均分子量为40kDa，粘度为0.35dL/g)组成，酯基端的PLA与羧基端的PLA的质量比为：70:69。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于氯仿中，所述水难溶性聚合物与氯仿的质量百分比为9.5％，然后加入利培酮和释放调节剂，溶解均匀，形成内油相；
(2)将羟丙甲纤维素和磷酸钠溶于水中，形成外水相，所述羟丙甲纤维素在所述外水相中的质量百分含量为0.5％，所述磷酸钠在所述外水相中的质量百分含量为0.05％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的65倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为27～100μm，经测定其载药率为27.60％，利培酮包封率为92.0％。
实施例3
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮35％，水难溶性聚合物：PLA 64.2％，释放调节剂：山俞酸物0.8％。其中，所述PLA的重均分子量为35kDa，粘度为0.32dL/g，且所述PLA具有羧基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与四氯乙烯的质量百分比为9％，然后加入利培酮和释放调节剂，溶解均匀，形成内油相；
(2)将白蛋白溶于水中，形成外水相，所述白蛋白在所述外水相中的质量百分含量为1％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的70倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为29～96μm，经测定其载药率为32.38％，利培酮包封率为92.5％。
实施例4
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮35％，水难溶性聚合物：PLGA 64％，释放调节剂：木质素酸1％。其中，所述PLGA中，丙交酯和乙交酯的摩尔比为95:5，所述PLGA的重均分子量为40kDa，粘度为0.36dL/g，且所述PLA具有酯基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与二氯甲烷的质量百分比为9％，然后加入利培酮、释放调节剂，溶解均匀，形成内油相；
(2)将聚山梨酸酯溶于水中，形成外水相，所述聚山梨酸酯在所述外水相中的质量百分含量为2％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的75倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为30～100μm，经测定其载药率为31.99％，利培酮包封率为91.40％。
实施例5
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮35％，水难溶性聚合物：PLGA 63％，释放调节剂：硬脂酸2％。其中，所述PLGA中丙交酯和乙交酯的摩尔比为85:15，所述PLGA的重均分子量为45kDa，粘度为0.39dL/g，且所述PLA具有酯基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于乙酸乙酯中，所述水难溶性聚合物与乙酸乙酯的质量百分比为8.5％，然后加入利培酮、释放调节剂，溶解均匀，形成内油相；
(2)将苯扎氯铵溶于水中，形成外水相，所述苯扎氯铵在所述外水相中的质量百分含量为3％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的80倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为30～110μm，经测定其载药率为32.50％，利培酮包封率为92.86％。
实施例6
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮40％，水难溶性聚合物：PLA 57％，释放调节剂：硬脂酸3％。其中，所述PLA中为具有羧基端PLA和具有酯基端PLA的混合物，且其中具有羧基端PLA和具有酯基端PLA的质量比为37:20，所述具有羧基端PLA和具有酯基端PLA的重均分子量均为55kDa，粘度均为0.47dL/g。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二甲苯中，所述水难溶性聚合物与二甲苯的质量百分比为8％，然后加入利培酮、释放调节剂，溶解均匀，形成内油相；
(2)将月桂酸钾溶于水中，形成外水相，所述月桂酸钾在所述外水相中的质量百分含量为4％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的85倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为27～118μm，经测定其载药率为37.30％，利培酮包封率为93.25％。
实施例7
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮40％，水难溶性聚合物：PLGA 56％，释放调节剂：花生酸4％，。其中，所述PLGA中丙交酯与乙交酯的摩尔比为85:15，所述PLGA的重均分子量为65kDa，粘度为0.57dL/g，且所述PLGA具有羧基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与氯仿的质量百分比为7.5％，然后加入利培酮、释放调节剂，溶解均匀，形成内油相；
(2)将泊洛沙姆溶于水中，形成外水相，所述泊洛沙姆在所述外水相中的质量百分含量为5％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的90倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为27～104μm，经测定其载药率为38.1％，利培酮包封率为95.25％。
实施例8
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮40％，水难溶性聚合物：PLGA 55％，释放调节剂：花生酸5％。其中，所述PLGA中丙交酯与乙交酯的摩尔比为75:25，所述PLGA的重均分子量为75kDa，粘度为0.66dL/g，且所述PLGA具有酯基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于苯甲醇中，所述水难溶性聚合物与苯甲醇的质量百分比为6％，然后加入利培酮、释放调节剂，溶解均匀，形成内油相；
(2)将PVP和硫酸钠溶于水中，形成外水相，所述PVP在所述外水相中的质量百分含量为6％，所述硫酸钠在所述外水相中的质量百分含量为3％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的100倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为28～107μm，经测定其载药率为36.40％，利培酮包封率为91.00％。
实施例9
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮45％，水难溶性聚合物：PLGA 46％，释放调节剂：山俞酸6％，赋形剂：缓冲剂硬脂酸锌2％、抗氧化剂维生素E 1％。其中，所述PLGA为具有羧基端的PLGA和具有酯基端的PLGA的混合物，且具有羧基端的PLGA和具有酯基端的PLGA的质量比为2:1；所述具有羧基端的PLGA中丙交酯与乙交酯的摩尔比为85:15，重均分子量为85kDa，粘度为0.71dL/g；所述具有酯基端的PLGA中丙交酯与乙交酯的摩尔比为75:25，重均分子量为70kDa，粘度为0.56dL/g。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与二氯甲烷的质量百分比为5％，然后加入利培酮、释放调节剂和赋形剂，溶解均匀，形成内油相；
(2)将淀粉和乙酸钾溶于水中，形成外水相，所述淀粉在所述外水相中的质量百分含量为7％，所述乙酸钾在所述外水相中的质量百分含量为4％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的105倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为21～98μm，经测定其载药率为41.60％，利培酮包封率为92.44％。
实施例10
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮50％，水难溶性聚合物：PLGA 43％，释放调节剂：棕榈酸7％。其中，所述PLGA中丙交酯与乙交酯的摩尔比为80:20，所述PLGA的重均分子量为100kDa，粘度为0.81dL/g，且所述PLGA具有酯基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与氯仿的质量百分比为4％，然后加入利培酮、释放调节剂，溶解均匀，形成内油相；
(2)将壳聚糖溶于Tris水溶液中，形成外水相，所述壳聚糖在所述外水相中的质量百分含量为8％，所述Tris在所述外水相中的质量百分含量为1.5％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的95倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为25～99μm，经测定其载药率为46.15％，利培酮包封率为92.30％。
实施例11
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮55％，水难溶性聚合物：PLGA 36％，释放调节剂：肉豆蔻酸8％，赋形剂：缓冲剂硝酸锌1％。其中，所述PLGA为PLGA(丙交酯与乙交酯的摩尔比为70:30、重均分子量为125kDa、粘度为0.5dL/g，具有羧基端)和PLGA(丙交酯与乙交酯的摩尔比为85:15、重均分子量为125kDa、粘度为0.79dL/g，具有羧基端)的混合物。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与二氯甲烷的质量百分比为3.5％，然后加入利培酮、释放调节剂和赋形剂，溶解均匀，形成内油相；
(2)将明胶溶于MES水溶液中，形成外水相，所述明胶在所述外水相中的质量百分含量为9％，所述MES在所述外水相中的质量百分含量为2.5％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的80倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为30～114μm，经测定其载药率为49.83％，利培酮包封率为90.60％。
实施例12
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮60％，水难溶性聚合物：PLGA 30％，释放调节剂：月桂酸10％。其中，所述PLGA中，丙交酯和乙交酯的摩尔比为65:35，所述PLGA的重均分子量为150kDa，粘度为1.2dL/g，且所述PLA具有羧基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于三氯乙烷中，所述水难溶性聚合物与三氯乙烷的质量百分比为3.5％，然后加入利培酮和释放调节剂，溶解均匀，形成内油相；
(2)将聚乙烯醇溶于水中，形成外水相，所述聚乙烯醇在所述外水相中的质量百分含量为10％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的100倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为38～125μm，经测定其载药率为53.50％，利培酮包封率为89.17％。
实施例13
本发明利培酮缓释组合物的一种实施例，本实施例所述利培酮缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：利培酮35％，水难溶性聚合物：PLGA61％，释放调节剂：山俞酸4％。其中，所述PLGA中，丙交酯和乙交酯的摩尔比为75:25，所述PLGA的重均分子量为100kDa，粘度为0.80dL/g，且所述PLA具有酯基端。
本实施例所述利培酮缓释组合物采用以下制备方法制备而成：
(1)将水难溶性聚合物溶于二氯甲烷中，所述水难溶性聚合物与乙酸丁酯的质量百分比为4％，然后加入利培酮和释放调节剂，溶解均匀，形成内油相；
(2)将乙基纤维素溶于水中，形成外水相，所述乙基纤维素在所述外水相中的质量百分含量为4％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外水相中，所述外水相的体积是所述内油相的105倍，乳化制成乳液，然后将此溶液在500rpm下机械搅拌6个小时将微球固化，离心收集微球，并用超纯水洗涤微球5次，冷冻干燥，得利培酮缓释微球。
本实施例中所得利培酮缓释微球外形圆整、表面光滑，粒径为20～88μm，经测定其载药率为32.50％，利培酮包封率为92.86％。
实施例14
本发明水难溶性药物缓释组合物的体外释放度测定
分别采用实施例1～13制备得到的水难溶性药物缓释微球作为试验组1～13，采用以下四个对比例作为对照组：
对比例1，制备方法同专利CN1137756中实施例1，其中投料：利培酮35％、PLGA(75/25，100kDa，0.79dL/g，酯基端)65％。所得利培酮缓释微球外形圆整，粒径为30-127μm，经测定其载药率为31.15％，利培酮包封率为89.00％。
对比例2，制备方法同本发明实施例5，其中投料：利培酮35％、不含释放调节剂，利培酮35％、65％。所得利培酮缓释微球外形圆整、表面光滑，粒径为28-86μm，经测定其载药率为31.53％，利培酮包封率为90.08％。
对比例3，制备方法同本发明实施例6，其中投料：不含释放调节剂，利培酮40％、水难溶性聚合物60％。所得利培酮缓释微球外形圆整、表面光滑，粒径为23-91μm，经测定其载药率为36.09％，利培酮包封率为90.23％。
对比例4，制备方法同本发明实施例7，其中投料：不含释放调节剂，利培酮40％、水难溶性聚合物60％。所得利培酮缓释微球外形圆整、表面光滑，粒径为22-93μm，经测定其载药率为36.84％，利培酮包封率为92.10％。
测试方法：精密称取实施例1-14及对比例1-2制备的微球各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。取出液采用高效液相色谱法(HPLC)检测药物释放量，结果如表1和表2所示。
表1缓释微球的体外释放数据
时间/天 实施例1 实施例2 实施例3 实施例4 实施例5 实施例6 实施例7 实施例8
0.04 0.15 0.10 0.17 0.14 0 0 0 0.17
0.5 0.50 0.39 0.39 0.69 0.34 0.21 0.50 0.50
1 1.03 0.75 0.95 1.18 0.59 0.65 1.30 1.65
2 1.85 1.32 3.88 2.73 1.73 1.39 3.70 3.46
7 14.00 11.85 16.42 16.70 12.00 6.73 19.79 20.73
14 27.80 25.35 34.32 36.95 26.59 19.08 39.04 46.70
21 46.33 40.80 49.55 56.37 45.20 32.11 60.33 73.82
28 67.50 60.50 68.63 76.55 63.15 46.65 74.42 96.78
35 89.18 80.87 87.24 90.14 79.76 62.99 87.56 100.00
42 98.86 92.53 97.33 98.25 91.50 75.14 96.24 100.00
49 100.00 98.05 100.20 100.00 100.00 87.00 100.00  
56 100.00 100.00 100.00 100.00 100.00 96.48 100.00  
63   100.00       100.00    
70           100.00    
表2缓释微球的体外释放数据
Figure PCTCN2018073899-appb-000001
从表1和表2可以看出，本发明的缓释微球没有突释效应，首日释放率不超过2％，而且能在4-12周内以接近零级趋势释放，具有明显的缓释效果，而且没有出现突释或者前期释放缓慢后期释放加剧的现象，说明这些微球表层和芯部的聚合物的降解速率没有出现可见的差别，说明了其中的释放调节剂产生空隙使得微球内部降解产生的酸性产物及时传送至外部，避免或大大减少出现芯部聚合物自催化降解速度加快的现象，有效的克服了PLA或PLGA体降解效应的弊端。
从表1和表2中实施例与对比例的对比可以看出，本发明的微球相对对比例明显缩短了延迟释放期，而且没有突释现象，说明本发明通过加入释放调节剂能够明显的改善缓释微球的释放行为，大大缩短微球的释放迟滞期，使病人避免或减少注射服药后口服普通制剂，显著增加给药依从性和便利性。
实施例15
本发明水难溶性药物缓释微球的稳定性效果试验。
根据中国药典(2015版四部)9001原料药物与制剂稳定性试验指导原则，需要在冰箱(4-8℃)保存的对温度敏感的药物的加速试验，在25℃±2℃、相对湿度60％±10％的条件下进行，时间为6个月。将实施例1～13和对比例1～4的微球置于25℃±2℃、相对湿度60％±10％的药品稳定性试验箱中考察加速稳定性，分别于第30天、第90天和第180天取样(n＝3)测释放行为，释放行为测定方法同实施例14。结果如表3～8所示。实施例1～13和对比例1～4的微球第0天的释放行为见表1和表2。
表3第30天加速稳定性样品的体外释放数据
时间/天 实施例1 实施例2 实施例3 实施例4 实施例5 实施例6 实施例7 实施例8
0.04 0.12 0.08 0.18 0.13 0.03 0 0.02 0.16
0.5 0.48 0.37 0.40 0.69 0.37 0.30 0.45 0.48
1 1.03 0.75 0.98 1.17 0.66 0.99 1.39 1.66
2 1.84 1.33 3.87 2.74 1.71 1.68 3.69 3.46
7 14.25 11.80 16.40 16.72 12.46 7.58 20.32 20.78
14 27.76 25.34 34.35 36.98 28.72 19.77 39.55 46.79
21 46.35 41.00 49.65 56.40 46.92 33.66 61.39 73.85
28 67.52 60.51 68.66 76.53 66.43 46.94 74.80 96.80
35 89.15 80.86 86.95 90.00 81.89 64.07 88.21 100.00
42 98.00 92.34 97.35 97.93 92.63 77.08 95.90 100.00
49 100.00 98.15 100.00 100.00 100.00 87.28 100.30  
56 10000 100.00 100.00 100.00 100.00 97.73 100.00  
63   100.00       100.00    
70           100.00    
表4第30天加速稳定性样品的体外释放数据
Figure PCTCN2018073899-appb-000002
Figure PCTCN2018073899-appb-000003
表5第90天加速稳定性样品的体外释放数据
时间/天 实施例1 实施例2 实施例3 实施例4 实施例5 实施例6 实施例7 实施例8
0.04 0.17 0.13 0.20 0.19 0.12 0.01 0.07 0.20
0.5 0.55 0.42 0.44 0.72 0.44 0.46 0.64 0.56
1 1.16 0.78 1.01 1.20 0.80 1.21 1.55 1.70
2 1.90 1.40 3.96 2.79 1.95 2.02 3.93 3.59
7 14.51 12.03 16.55 16.80 13.80 8.33 22.18 20.96
14 28.00 26.00 34.49 37.21 29.99 20.70 42.76 48.00
21 47.28 41.75 50.20 56.75 49.31 35.59 63.00 74.30
28 68.42 61.44 69.15 77.05 69.20 49.31 77.31 98.05
35 90.00 81.87 87.83 90.65 84.16 66.44 90.32 100.00
42 99.90 93.12 98.72 99.00 94.49 80.00 97.20 100.00
49 100.00 99.21 100.00 100.00 100.00 91.30 100.00  
56 100.000 100.00 100.00 100.00 100.00 99.88 100.00  
63   100.00       100.18    
70           100.00    
表6第90天加速稳定性样品的体外释放数据
Figure PCTCN2018073899-appb-000004
表7第180天加速稳定性样品的体外释放数据
时间/天 实施例1 实施例2 实施例3 实施例4 实施例5 实施例6 实施例7 实施例8
0.04 0.21 0.24 0.24 0.22 0.30 0.05 0.13 0.26
0.5 0.64 0.56 0.50 0.79 0.66 0.73 0.86 0.62
1 1.27 0.88 1.13 1.25 0.99 1.63 2.12 1.79
2 2.16 1.5 4.09 2.85 2.31 3.07 4.91 3.71
7 15.06 12.51 16.84 17.00 15.37 11.25 25.30 21.45
14 29.31 26.71 35.50 37.82 33.39 25.25 47.10 49.12
21 48.65 42.30 51.12 57.16 52.96 39.65 66.65 75.75
28 70.13 62.66 70.04 77.89 72.22 54.51 83.43 99.83
35 91.75 82.89 89.46 91.74 88.15 69.15 96.09 100.00
42 100.00 94.35 100.00 100.00 97.60 84.43 100.00 100.00
49 100.00 100.00 100.00 100.00 100.00 96.16 100.00  
56   100.00     100.00 100.00    
63           100.00    
表8第180天加速稳定性样品的体外释放数据
Figure PCTCN2018073899-appb-000005
对比表3～8可以看出，本发明所得微球在加速稳定性测定环境下，释放行为没有明显的改变，而对比例的样品随着放置时间增加，其释放行为发生了明显的变化，具体体现为释放时间提前，由14-21天开始释放提前至2-14天开始释放。如果按照市售产品(恒德)的给药方法，由于药物提前释放，叠加口服给药的剂量，会导致病人血液中的血液浓度增加。对于利培酮等水难溶性药物这类抗精神病药，血液浓度增加将会导致产生较为严重的副反应，对病人的治疗、生活和工作造成不可忽视的影响。
实施例16
本发明水难溶性药物缓释组合物的动物试验
取重量在2.0kg-3.0kg的新西兰大耳白兔，每6只一组(随机分组)，雌雄各半，每组分别肌肉注射含有实施例1～13和对比例1～4制备的微球的1.2ml含0.5％CMC-Na的生理盐水溶液的混悬液，每剂量的混悬液中的缓释微球的水难溶性药物含量为18mg，分别于第0.04d，0.25d，0.5d，1d，3d，7d，14d，21d，28d，35d，42d，49d，56d，63d，77d，84d，91d和98d于兔耳缘静脉取血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检测上述所有血样中水难溶性药物的血药浓度，取平均值。结果见表9和表10。
表9血药浓度结果(ng/ml)
时间/d 实施例1 实施例2 实施例3 实施例4 实施例5 实施例6 实施例7 实施例8
0.4 5.35 4.17 4.54 5.11 1.26 1.18 1.59 5.26
0.25 2.14 1.75 1.49 3.28 2.48 2.75 4.15 2.34
0.5 3.46 2.54 2.75 4.51 5.45 4.86 6.45 5.96
1 2.89 3.09 8.65 5.87 7.8 6.54 10.98 8.28
7 12.25 10.32 14.46 15.24 15.54 9.45 17.04 18.11
14 18.74 16.26 20.66 21.3 19.49 14.10 23.19 26.16
21 24.55 22.49 23.04 24.79 21.28 18.04 21.78 21.24
28 22.36 23.15 20.27 19.46 17.72 20.39 13.72 13.07
35 15.42 17.17 12.54 11.5 10.53 16.18 7.53 6.32
42 7.19 10.36 5.67 4.86 6.33 11.06 3.33 1.45
49 1.50 5.28 1.28 1.05 1.39 7.53 0.89 0.15
56 0 0.85 0 0 0.33 3.62 0 0
63   0     0 2.53    
70           0.89    
77           0    
84                
表10血药浓度结果(ng/ml)
Figure PCTCN2018073899-appb-000006
Figure PCTCN2018073899-appb-000007
由表9和表10可看见，本发明的利培酮微球显示出良好的缓释效果，给药后很快增加血药浓度，而对比例需要差不多2-4周的时间才能达到5ng/mL以上相应浓度，与体外释放行为相同具有相似。本发明的缓释微球的血药浓度在5-30ng/mL范围内能够持续达约20-60天；而对比例持续约20-28天。说明了本发明的利培酮微球具有更好的作用效果，能在较长的时间内保持一定的血药浓度，可延长给药给药周期，减轻副作用，提高病患依从性。
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. 一种利培酮缓释组合物，其特征在于，所述利培酮缓释组合物的非溶剂型制备原料包含利培酮、水难溶性聚合物和释放调节剂，所述释放调节剂包含有机亲油性物质。
  2. 如权利要求1所述的利培酮缓释组合物，其特征在于，所述利培酮缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为0.1～10％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为0.5～8％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为1～6％。
  3. 如权利要求1或2所述的利培酮缓释组合物，其特征在于，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。
  4. 如权利要求3所述的利培酮缓释组合物，其特征在于，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。
  5. 如权利要求1～4任一项所述的利培酮缓释组合物，其特征在于，所述利培酮缓释组合物的非溶剂型制备原料中，所述利培酮的质量百分含量为25～60％，所述水难溶性聚合物的质量百分含量为39.9-74.9％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述利培酮的质量百分含量为30～55％，所述水难溶性聚合物的质量百分含量为44.9-69.9％；优选地，所述利培酮缓释组合物的非溶剂型制备原料中，所述利培酮的质量百分含量为35～50％，所述水难溶性聚合物的质量百分含量为44.9-69.9％。
  6. 如权利要求5所述的利培酮缓释组合物，其特征在于，所述水难溶性聚合物为聚丙交酯、丙交酯-乙交酯共聚物及它们与聚乙二醇的共聚物中的至少一种。
  7. 如权利要求6所述的利培酮缓释组合物，其特征在于，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的重均分子量均为25000-150000Da；优选地，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的重均分子量均为30000-125000Da；更优选地，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的重均分子量均为30000-100000Da。
  8. 如权利要求6或7所述的利培酮缓释组合物，其特征在于，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的粘度均为0.30-1.15dL/g；优选地，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的粘度均为0.37-0.95dL/g；更优选地，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的粘度均为0.37-0.80dL/g。
  9. 如权利要求6所述的利培酮缓释组合物，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、其与聚乙二醇的共聚物中的至少一种，且其中丙交酯与乙交酯的摩尔比为100:0～65:35；优选地，其中丙交酯与乙交酯的摩尔比为100:0～70:30；更优选地，其中丙交酯与乙交酯的摩尔比为100:0～75:25。
  10. 如权利要求1～9任一项所述的利培酮缓释组合物，其特征在于，所述利培酮缓释组合物的制备方法包括以下步骤：
    (1)将所述非溶剂型制备原料溶于有机溶剂中，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硬化，收集微粒，洗涤并干燥，得利培酮缓释微球。
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