WO2018137628A1 - 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法 - Google Patents

帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法 Download PDF

Info

Publication number
WO2018137628A1
WO2018137628A1 PCT/CN2018/073898 CN2018073898W WO2018137628A1 WO 2018137628 A1 WO2018137628 A1 WO 2018137628A1 CN 2018073898 W CN2018073898 W CN 2018073898W WO 2018137628 A1 WO2018137628 A1 WO 2018137628A1
Authority
WO
WIPO (PCT)
Prior art keywords
paliperidone
sustained
release composition
derivative
solvent
Prior art date
Application number
PCT/CN2018/073898
Other languages
English (en)
French (fr)
Inventor
刘锋
赖树挺
曹付春
郑阳
连远发
Original Assignee
广州帝奇医药技术有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 广州帝奇医药技术有限公司 filed Critical 广州帝奇医药技术有限公司
Publication of WO2018137628A1 publication Critical patent/WO2018137628A1/zh

Links

Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/0002—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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats

Definitions

  • the invention relates to a water-insoluble/slightly soluble drug sustained-release composition and a preparation method thereof, in particular to a sustained-release composition of paliperidone and a derivative thereof and a preparation method of the sustained-release composition.
  • Patent CN201110059685 discloses a method for preparing spherical particles of poorly soluble drugs, dissolving a poorly soluble drug (such as paliperidone palmitate, paclitaxel) in a lipophilic solvent to prepare a dispersed phase, and then adding to the dispersed phase An emulsion is formed in the mutually soluble continuous phase, the lipophilic solvent in the dispersed phase is removed, a drug fine particle suspension is obtained, the continuous phase is washed away, and spherical particles having a particle diameter of 2 to 50 ⁇ m are collected.
  • a poorly soluble drug such as paliperidone palmitate, paclitaxel
  • the spherical particles prepared by the method have a large difference in specific surface area due to different particle diameters, resulting in a large difference in the dissolution rate of the particles, and the large-sized particles are significantly slower to dissolve than the small-sized particles. Therefore, if the blood concentration fluctuation is to be small, the molar ratio of the particles of different particle diameters must be strictly controlled, so that the amount of the drug dissolved per unit time fluctuates within a small range, and the preparation is difficult.
  • the drug delivery system is made of matrix materials such as polylactic acid (PLA) and polylactic acid-glycolic acid copolymer (PLGA).
  • PLA polylactic acid
  • PLGA polylactic acid-glycolic acid copolymer
  • the obtained 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 prepare a drug release rate and a release cycle, and can maintain an effective therapeutic drug concentration for a long time with only one administration.
  • the minimization of the total dose of the drug required for treatment can improve the patient's medication compliance.
  • Patent CN104013578 prepares paliperidone derivative sustained-release microspheres by adding isopropyl palmitate and butyl stearate to change the structure of the microspheres and the crystalline state of the drug, so that the drug is closer to the core of the microsphere, and The formation of a dense shell structure on the surface of the microspheres limits the diffusion of the drug. Although this method avoids the initial burst release phenomenon, it causes a delayed release period of about 5 days or more, which is inconvenient for clinical use and poor patient compliance. At the same time, the technology allows the drug to accumulate in the core, similar to the preparation of drug particles of different particle sizes in the patent CN201110059685, as well as the effect of particle size on the dissolution rate.
  • the object of the present invention is to overcome the above-mentioned deficiencies of the prior art and to provide a stable release therapeutic phase or a burst release phenomenon after administration, capable of maintaining a stable therapeutic blood concentration for several weeks or more, and having good A sustained release composition of paliperidone and its derivatives with improved release properties and better stability. Meanwhile, another object of the present invention is to provide a method for producing the sustained release composition.
  • the technical solution adopted by the present invention is: a sustained-release composition of paliperidone and a derivative thereof, wherein the non-solvent preparation raw material of the sustained-release composition comprises paliperidone or paclitaxel A ketone derivative, the raw material for which the sustained-release composition is prepared further contains a poorly water-soluble polymer.
  • the preparation materials for the sustained-release composition of the present invention include a non-solvent-type preparation raw material and a solvent-type preparation raw material. Among them, the non-solvent type preparation material contains paliperidone or paliperidone derivative, and further contains a poorly water-soluble polymer, but it does not include a surfactant.
  • the poorly water-soluble polymer serves as a carrier of paliperidone or a derivative thereof.
  • the paliperidone derivative includes, but is not limited to, paliperidone palmitate.
  • a preferred embodiment of the sustained release composition of paliperidone and a derivative thereof according to the present invention wherein the paliperidone or paliperidone derivative is a non-solvent-type preparation raw material of the sustained-release composition
  • the mass percentage is 35-70%, and the water-insoluble polymer has a mass percentage of 30-65%; preferably, the non-solvent preparation raw material of the sustained-release composition, the Parley
  • the mass percentage of the piperazine or paliperidone derivative is 40 to 65%, and the mass percentage of the poorly water-soluble polymer is 35 to 60%; more preferably, the non-sustained composition is not
  • the paliperidone or paliperidone derivative has a mass percentage of 40 to 60%
  • the water-insoluble polymer has a mass percentage of 40 to 60%.
  • the poorly water-soluble polymer is a polyester, a polycarbonate, a polyacetal, a polyanhydride, a polyhydroxy fatty acid, or a At least one of the copolymer or blend.
  • the poorly water-soluble polymer is polylactide (PLA), polyglycolide (PGA), lactide- Glycolide copolymer (PLGA), polycaprolactone (PCL) and 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 or At least one of a salt, a polycyanoacrylate, 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 at least one of them and a copolymer of polyethylene glycol.
  • the poorly soluble drug sustained release composition is a polylactide (PLA), a lactide-glycolide copolymer ( At least one of PLGA).
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA). And at least one of their copolymers with polyethylene glycol, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and the copolymer of polyethylene glycol
  • the average molecular weight is 25000-100000Da; preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and their copolymers with polyethylene glycol have a weight average molecular weight of 25000- More preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of 25,000 to 80,000 Da.
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA). And at least one of their copolymers with polyethylene glycol, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and the copolymer of polyethylene glycol have a viscosity 0.25-0.80 dL/g (test conditions are -0.5% (w/v), CHCl3, 25 ° C); preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA) The viscosity of their copolymer with polyethylene glycol is 0.30-0.70 dL/g (test conditions are -0.5% (w/v), CHCl3, 25 ° C); more preferably, the polylactide (PLA) ), lactide-glycolide copolymer (PLA), lactide-glycolide copolymer (PLA), lactide-glycoli
  • 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.
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA). And at least one of a copolymer thereof and polyethylene glycol, wherein a molar ratio of lactide to glycolide is from 100:0 to 75:25; preferably, the water-insoluble polymer is polyacrylic acid
  • 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 100:0 ⁇ 80:20; more preferably, 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.
  • the molar ratio of lactide to glycolide is 100:0 ⁇ 80:20
  • 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 sustained release composition further comprises a release regulator.
  • the release modifier in the non-solvent-type preparation raw material of the sustained-release composition, has a mass percentage of 0.1 to 10%; preferably, in the non-solvent-type preparation raw material of the sustained-release composition, the release modifier has a mass percentage of 0.5 to 8%; preferably, the non-solvent preparation of the sustained-release composition In the raw material, the release modifier has a mass percentage of from 1 to 6%.
  • the release regulator is at least one of an organic lipophilic substance and an organic hydrophilic substance.
  • the sustained release composition of paliperidone and a derivative thereof according to the present invention is added with a release regulator, and the release regulator comprises at least one of an organic lipophilic substance and an organic hydrophilic substance.
  • the organic lipophilic substance is finally converted into carbon dioxide and water in the body, which can cause pores on the surface and inside of the microsphere, increase the permeability of the body fluid, and promote the dissolution of paliperidone or its derivative, thereby avoiding release after a period of time. Very slow release platform.
  • the organic hydrophilic substance can also produce fine pores on the surface and inside of the microspheres, which can increase the permeability of the body fluid after the microspheres are injected into the body, and promote the dissolution of paliperidone or its derivatives, which is greatly shortened or The initial release-free phenomenon is avoided to release the stagnation period, and the transfer of degradation products inside the microsphere is also promoted.
  • the sustained release composition of paliperidone and its derivative of the present invention can avoid the initial burst phenomenon and avoid the phenomenon that the preparation raw material contains an organic lipophilic substance, an organic hydrophilic substance or a combination thereof.
  • the delayed release platform after the first day of release is released, the blood concentration is maintained, and the PLGA with high molecular weight and LA component ratio is also solved.
  • the carrier prepares the problem of delayed release of long-period sustained-release microspheres.
  • the release regulator is an organic lipophilic substance and an organic hydrophilic substance, and the organic hydrophilic substance is in the
  • the mass percentage of the release modifier is 30% or more; preferably, the mass percentage of the organic hydrophilic substance in the release regulator is 50% or more; preferably, the organic hydrophilicity
  • the mass percentage of the substance in the release regulator is 70% or more.
  • the organic lipophilic substance is at least one of a fatty acid, a fatty acid ester, and a fat; the organic hydrophilic substance It is at least one of an alcohol, a sugar, an amino acid, a protein, and polyvinylpyrrolidone.
  • the organic lipophilic substance is a fatty acid; and the organic hydrophilic substance is at least at least one of an alcohol and a polyvinylpyrrolidone.
  • the fatty acid is oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, and salicylic acid.
  • At least one of lignin acids; the alcohol is a polyethylene glycol having a molecular weight of 400 to 6000 Da.
  • the fatty acid is preferably, but not limited to, a C12-C24 alkanoic acid or a derivative 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 to 4000 Da, more preferably PEG having a molecular weight of 400 to 3000 Da.
  • the non-solvent-type preparation raw material of the sustained-release composition further comprises an excipient in which the excipient is
  • the non-solvent-type preparation raw material of the release composition has a mass percentage of 0 to 8%.
  • the sustained release composition of paliperidone and its derivative 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; and the buffer is at least one of an organic acid and a mineral acid salt.
  • the antioxidant is tert-butyl-p-hydroxyanisole, dibutylphenol, tocopherol, isopropyl myristate, tocopheryl daacetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, Butylated hydroxyindole, hydroxycoumarin, butylated hydroxytoluene, decanoic acid fatty acid ester, propyl hydroxybenzoate, hydroxybutanone, vitamin E, vitamin E-TPGS, ⁇ -hydroxybenzoic acid At least one of the esters.
  • 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 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 excipient is added at the internal 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 phase with the inner phase or with very small particles.
  • the 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 simply and efficiently preparing an upper sustained-release composition.
  • the technical solution adopted by the present invention is: a sustained-release composition of paliperidone and a derivative thereof
  • the preparation method comprises the following steps:
  • the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 1 to 10%; the step (2a) And (2b), the mass percentage of the surfactant in the external phase is 0.1 to 10%; in the steps (3a) and (3b), the volume of the external phase is the volume of the internal phase 60 times or more.
  • the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 1.5 to 9%; the step (2a) And (2b), the mass percentage of the surfactant in the outer aqueous phase is 0.5 to 8%; in the steps (3a) and (3b), the volume of the outer aqueous phase is the inner More than 80 times the volume of the oil phase.
  • the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 3 to 8.5%; 2a) and (2b), the mass percentage of the surfactant in the outer aqueous phase is from 1 to 7%; in the steps (3a) and (3b), the volume of the outer aqueous phase is the 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 steps (1a) and (1b) 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; in the steps (2a) and (2b), the nonaqueous solvent is hydrophilic.
  • an aqueous solvent wherein the hydrophilic nonaqueous solvent is at least one selected from the group consisting of a polyol, a polyol derivative, and a hydrophilic high molecular polymer; preferably, the polyol is ethylene glycol or propylene glycol. At least one of glycerin, pentaerythritol, sorbitan, a fatty acid ester thereof, and a derivative of the fatty acid ester thereof; the hydrophilic high molecular polymer is polyethylene glycol, polyoxyethylene fatty alcohol ether , polyoxyethylene alkyl phenol ether, polyoxyethylene fatty acid ester, polyoxyethylene castor oil, their Derivative or polyvinylpyrrolidone. More preferably, the nonaqueous solvent having hydrophilicity is at least one of ethylene glycol, polyethylene glycol, and glycerin; more preferably, the hydrophilic nonaqueous solvent is glycerin.
  • the organic solvent may simultaneously dissolve a poorly water-soluble polymer, paliperidone or a derivative thereof, and a release regulator having a boiling point lower than water and insoluble or poorly soluble in water, and the organic solvent may be a single organic solvent. It may also be 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 molar ratio of the organic solvent in the mixture is different according to different drugs, and is formulated according to actual conditions.
  • the nonaqueous solvent is not miscible with the lipophilic solvent in the dispersed phase, and is preferably a hydrophilic nonaqueous solvent.
  • the hydrophilic nonaqueous solvent is selected from the group consisting of a polyol or a derivative thereof, a hydrophilic high molecular polymer, or any mixture thereof.
  • a preferred embodiment of the method for preparing a sustained-release composition according to the present invention wherein the surfactant is at least one of an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, and a nonionic surfactant;
  • the cationic surfactant comprises benzalkonium chloride, cetyltrimethylammonium bromide, lauric acid dimethylbenzylammonium chloride, acylcarnitine hydrochloride, alkylpyridine halide;
  • the anionic surfactants include alkyl sulfates, potassium laurate, sodium alginate, sodium polyacrylate or derivatives thereof, alkyl polyethylene oxide sulfate, sodium dioctyl sulfosuccinate, phospholipids, glycerides a sodium salt of sodium carboxymethylcellulose, sodium oleate, sodium stearate, cholic acid and other bile acids; said nonionic surfactant comprising polyoxyethylene
  • 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).
  • 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 or 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.
  • sodium lauryl sulfate ammonium lauryl sulfate, sodium stearyl sulfate, alkyl sulfate, potassium laurate, sodium alginate, sodium polyacrylate or derivatives thereof.
  • 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 glycerol 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) or 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 or derivatives thereof, amylopectin or dextran or derivatives thereof.
  • 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 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 steps (3a) and (3b) are separated by centrifugation, sieving or filtration.
  • the method of drying the microspheres in the steps (3a) and (3b) 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 sustained release composition of paliperidone and its derivatives 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 Approximately 12 weeks, such as up to about 24 weeks, such as up to about 48 weeks, or longer, may be adjusted depending on the particular drug properties or treatment needs.
  • the non-solvent-type preparation raw material of the sustained release composition of the present embodiment comprises the following mass percent component: paliperidone 35%, poorly water soluble polymer: PLA 64.9%, release regulator: PEG800 0.1%.
  • the PLA has a weight average molecular weight of 20 kDa, a viscosity of 0.25 dL/g, and the PLA has an ester group end.
  • the volume of the external phase is 60 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone sustained-release microspheres.
  • the paliperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 32-124 ⁇ m.
  • the drug loading rate is 31.58%, and the encapsulation efficiency of paliperidone is 90.22%.
  • the non-solvent-type preparation raw material of the sustained release composition of the present embodiment comprises the following mass percent component: paliperidone 40%, poorly water-soluble polymer: PLA 59.5%, release regulator: 0.5% of behenic 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 295:300, the carboxyl terminal PLA and the ester terminal PLA has a weight average molecular weight of 20 kDa and a viscosity of 0.25 dL/g.
  • the internal phase obtained in the step (1) is added to the external phase obtained in the step (2), the volume of the external phase is 65 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone sustained-release microspheres.
  • the paliperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 29 to 112 ⁇ m.
  • the drug loading rate is 36.25%, and the encapsulation efficiency of paliperidone is 90.63%.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 45%, poorly water soluble polymer: PLA 55%.
  • the PLA has a weight average molecular weight of 25 kDa, a viscosity of 0.28 dL/g, and the PLA has a carboxyl terminal.
  • the volume of the external phase is 70 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 28-105 ⁇ m.
  • the drug loading rate is 41.18%, and the encapsulation efficiency of paliperidone palmitate is 91.51. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 45%, poorly water soluble polymer: PLGA 55%.
  • the PLGA is PLGA (the molar ratio of lactide to glycolide is 95:5, the weight average molecular weight is 25 kDa, the viscosity is 0.28 dL/g, having an ester end), and the PLGA (lactide and ethylene glycol)
  • the mixture had a molar ratio of 85:15, a weight average molecular weight of 25 kDa, a viscosity of 0.29 dL/g, and an ester base, and a mass ratio of 250:300.
  • the internal phase obtained in the step (1) is added to the external phase obtained in the step (2), the volume of the external phase is 75 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the sustained release microspheres of paliperidone palmitate obtained in this example have a round shape and a smooth surface, and the particle size is 33-110 ⁇ m.
  • the drug loading rate is determined to be 41.13%, and the encapsulation efficiency of paliperidone palmitate is 91.40. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 50%, poorly water soluble polymer: PLGA 49%, release regulator: 1% mixture of stearic acid and PEG400.
  • palmitate Piperketone 50% poorly water soluble polymer: PLGA 49%
  • release regulator 1% mixture of stearic acid and PEG400.
  • the mass percentage in the conditioner is 50%.
  • the volume of the external phase is 80 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the sustained release microspheres of paliperidone palmitate obtained in this example have a round shape and a smooth surface, and the particle diameter is 29-119 ⁇ m.
  • the drug loading rate is 45.95%, and the encapsulation efficiency of paliperidone palmitate is 91.90. %.
  • the non-solvent-type preparation raw material of the sustained release composition of the present embodiment comprises the following components by mass: palmitase Risperidone 50%, poorly water soluble polymer: PLA 47%, release regulator: 3% mixture of stearic acid and PEG600.
  • 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 1:1, the carboxyl terminal PLA and the ester group
  • the viscosity of the terminal PLA is 0.38 dL/g
  • the weight average molecular weight of the carboxy terminal PLA is 40 kDa
  • the weight average molecular weight of the ester terminal PLA is 38 kDa
  • PEG 600 is in the release regulator.
  • the mass percentage in the medium is 60%.
  • the internal phase obtained in the step (1) is added to the external phase obtained in the step (2), the volume of the external phase is 85 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 25-110 ⁇ m.
  • the drug loading rate is 46.10%, and the encapsulation efficiency of paliperidone palmitate is 92.20. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 55%, poorly water soluble polymer: PLGA 45%.
  • palmitate Piperketone 55% poorly water soluble polymer
  • PLGA 45% poorly water soluble polymer
  • the molar ratio of lactide to glycolide in the PLGA is 85:15
  • the weight average molecular weight of the PLGA is 50 kDa
  • the viscosity is 0.44 dL/g
  • the PLGA has a carboxyl end.
  • the volume of the external phase is 90 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate 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 50.85%, and the encapsulation efficiency of paliperidone palmitate is 92.45. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 55%, poorly water soluble polymer: PLGA 45%.
  • palmitate Piperketone 55% poorly water soluble polymer
  • PLGA 45% poorly water soluble polymer
  • the molar ratio of lactide to glycolide in the PLGA is 75:25
  • the weight average molecular weight of the PLGA is 60 kDa
  • the viscosity is 0.55 dL/g
  • the PLGA has an ester group end.
  • the volume of the external phase is 100 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 35-120 ⁇ m.
  • the drug loading rate is determined to be 50.40%, and the encapsulation efficiency of paliperidone palmitate is 91.64. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 60%, poorly water soluble polymer: PLGA 34%, release modifier: 6% mixture of palmitic acid and PEG 1000.
  • 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 20:14; 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 70 kDa, and the viscosity is 0.60 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 65 kDa, viscosity was 0.56 dL/g; of the release regulator, the mass percentage of PEG 1000 in the release regulator was 30%.
  • the internal phase obtained in the step (1) is added to the external phase obtained in the step (2), the volume of the external phase is 105 times that of the internal phase, emulsified to prepare an emulsion, and then the solution is mechanically stirred at 500 rpm.
  • the microspheres were solidified for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 25-104 ⁇ m.
  • the drug loading rate is determined to be 54.23%, and the encapsulation efficiency of paliperidone palmitate is 90.38. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 60%, poorly water soluble polymer: PLGA 40%.
  • the PLGA is composed of PLGA (the molar ratio of lactide to glycolide is 80:20, the weight average molecular weight is 80 kDa, the viscosity is 0.65 dL/g, having an ester end), and PLGA (lactide and B)
  • the lactide had a molar ratio of 70:30, a weight average molecular weight of 72 kDa, a viscosity of 0.60 dL/g, and a mixture having an ester group end, and the mass ratio was 1:1.
  • the volume of the external phase is 95 times that of the internal phase, emulsified to form an emulsion, and then the solution is mechanically placed at 500 rpm.
  • the microspheres were solidified by stirring for 6 hours, and the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 25-99 ⁇ m.
  • the drug loading rate is 54.75%, and the encapsulation efficiency of paliperidone palmitate is 91.13. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperazine 65%, poorly water soluble polymer: PLGA 26%, release regulator: 8% mixture of myristic acid and PEG 1500, excipient: buffer zinc nitrate 1%.
  • the PLGA is PLGA (the molar ratio of lactide to glycolide is 75:25, the weight average molecular weight is 90 kDa, the viscosity is 0.70 dL/g, having a carboxyl terminal), and the PLGA (lactide and glycolide) a molar ratio of 85:15, a weight average molecular weight of 80 kDa, a viscosity of 0.65 dL/g, having a carboxyl terminal), and a mass ratio of 1:1; in the release regulator, PEG 1500 is at the release modifier The mass percentage in the medium is 90%.
  • the internal phase obtained in the step (1) is added to the external phase obtained in the step (2), the volume of the external phase is 80 times that of the internal oil phase, emulsified to prepare an emulsion, and then the solution is mechanical at 500 rpm.
  • the microspheres were solidified by stirring for 6 hours, and the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 33-126 ⁇ m.
  • the drug loading rate is 58.64%, and the encapsulation efficiency of paliperidone palmitate is 90.21. %.
  • the non-solvent-type preparation raw material of the sustained-release composition of the present embodiment comprises the following mass percent component: palmitate Piperketone 70%, poorly water soluble polymer: PLGA 20%, release regulator: lauric acid 10%.
  • palmitate Piperketone 70% poorly water soluble polymer: PLGA 20%
  • release regulator: lauric acid 10% a mass percent component
  • 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 PLGA has a carboxyl terminal.
  • the volume of the external aqueous phase is 100 times that of the internal phase, emulsified to form an emulsion, and then the solution is at 500 rpm.
  • the microspheres were solidified by mechanical stirring for 6 hours, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water, and lyophilized to obtain paliperidone palmitate sustained-release microspheres.
  • the paliperidone palmitate sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle diameter is 29-110 ⁇ m.
  • the drug loading rate is 63.50%, and the encapsulation efficiency of paliperidone palmitate is 90.71. %.
  • the water-insoluble drug sustained-release microspheres prepared in Examples 1 to 12 were used as test groups 1 to 12, respectively, and the following two comparative examples were used as a control group:
  • the preparation method is the same as that of Patent CN104013578.
  • the drug is paliperidone palmitate
  • the polymer is PLGA (75/25, 60 kDa, 0.55 dL/g, ester base)
  • the regulator is butyl stearate.
  • the obtained paliperidone palmitate sustained-release microspheres have a round shape and a particle size of 27-125 ⁇ m.
  • the drug loading rate was determined to be 26.50%, and the encapsulation efficiency of paliperidone palmitate was 88.33%.
  • Comparative Example 2 was prepared in the same manner as in Example 14 of Patent CN104013578.
  • the drug is paliperidone palmitate
  • the polymer is PLGA (75/25, 40 kDa, 0.38 dL/g, ester base)
  • the regulator is butyl stearate.
  • the obtained paliperidone palmitate sustained-release microspheres have a round shape and a particle size of 25-122 ⁇ m.
  • the drug loading rate was determined to be 26.48%, and the encapsulation efficiency of paliperidone palmitate was 88.27%.
  • Test method Weigh accurately 20 mg of each of the microspheres prepared in Examples 1-12 and Comparative Example 1-2 into a 200 mL centrifuge tube, and add 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 0.04 0 0.05 0.11 0 0.12 0 0 0.5 0.39 0.35 0.50 0.21 0.70 0.14 0.20 1 0.75 1.14 1.30 0.65 1.59 0.63 0.53 2 1.32 3.05 3.70 1.99 4.08 3.35 2.35 7 11.85 14.22 17.79 8.73 16.53 12.98 9.98 14 25.35 33.04 37.25 20.08 37.67 21.45 23.25 twenty one 42.80 50.30 56.33 34.81 60.45 34.29 42.10
  • Example 11 Example 12 Comparative example 1 Comparative example 2 0.04 0 0.19 0 0.10 0.17 0 0 0.5 0.17 0.48 0.10 0.55 0.98 0.19 0.5 1 1.05 1.60 0.78 1.95 2.28 0.55 1.00 2 1.98 3.55 1.52 8.26 5.46 1.27 2.50 7 8.46 20.53 6.35 24.66 29.73 5.38 4.34 14 24.73 37.67 15.24 48.36 56.67 37.3 45.15 twenty one 47.70 51.75 24.55 78.82 78.82 62.25 70.30 28 73.82 64.80 39.64 97.01 94.78 78.48 86.27 35 97.78 78.19 50.36 100.00 100.00 86.19 95.45 42 100.00 87.49 63.45 100.00 100.00 94.60 100.00 49 100.00 96.64 77.00 100.00 100.00 56 100.00 85.49 100.00 63 100.00 95.26 70 100.00 77 100.00
  • the sustained release microspheres of the present invention have no burst effect, and the release rate on the first day is not more than 2.5%, and can be released in a near zero-order trend within 5-10 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.
  • the microspheres of the present invention have no significant delayed release period relative to the comparative example, and there is no burst release phenomenon, and the slope of the release curve is significantly smaller than the comparative example, indicating The invention can obviously improve the release behavior of the sustained release microspheres by adding a release regulator, greatly shorten the release lag period of the microspheres, the drug release rate is gentle, reduce the side effects caused by the fluctuation of the blood drug concentration, and enable the patient to avoid or reduce the injection medication. Oral administration is still required after oral administration, significantly increasing drug compliance and convenience.
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7 0.04 0 0.03 0.10 0 0.1 0 0 0.5 0.39 0.35 0.49 0.20 0.68 0.15 0.19 1 0.77 1.13 1.31 0.63 1.60 0.60 0.53 2 1.30 3.06 3.68 2.00 4.06 3.28 2.36 7 11.85 14.20 17.80 8.75 16.55 13.02 9.95 14 25.38 33.06 37.28 20.06 37.68 21.50 23.18 twenty one 42.84 50.33 56.30 34.80 60.44 34.36 42.47 28 61.55 66.39 70.65 47.70 76.05 43.95 55.70 35 82.85 81.85 79.55 66.02 87.25 56.55 70.67 42 93.50 91.25 89.25 78.15 96.02 67.83 81.85 49 99.12 97.33 95.35 89.05 100.00 75.94 91.39 56 100.00 100.00 100.00 97.00 10
  • Example 11 Example 12 Comparative example 1 Comparative example 2 0.04 0 0.15 0 0.11 0.15 0.12 0.18 0.5 0.20 0.48 0.11 0.56 0.95 0.35 0.55 1 0.98 1.62 0.75 1.93 2.26 1.21 1.27 2 2.05 3.56 1.50 8.25 5.49 2.56 2.73 7 8.49 20.50 6.36 24.67 29.70 6.42 5.79 14 24.68 37.68 15.25 48.5 56.69 39.16 43.63 twenty one 47.83 51.80 24.52 78.89 78.85 63.10 68.39 28 73.69 64.79 39.65 97.00 94.70 78.66 87.56 35 97.75 78.18 50.40 100.00 100.00 87.35 96.76 42 100.00 87.50 93.39 100.00 100.00 95.40 100.00 49 100.00 96.60 77.20 100.00 100.00 56 100.00 85.56 63 100.00 95.25 70 100.00 77 100.00
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7 0.04 0.05 0.06 0.13 0 0.13 0.01 0.02 0.5 0.43 0.38 0.52 0.23 0.72 0.17 0.23 1 0.80 1.17 1.34 0.66 1.65 0.70 0.56 2 1.39 3.11 3.75 2.06 4.15 3.56 2.47 7 11.87 14.25 17.87 8.80 16.82 13.25 10.13 14 25.45 33.85 37.95 20.24 37.96 21.77 23.32 twenty one 43.02 50.96 56.90 34.92 60.89 34.99 43.09 28 61.96 66.98 70.88 47.86 76.49 44.44 56.45 35 83.10 89.02 80.00 66.75 87.73 59.30 71.45 42 93.88 91.80 90.13 78.66 96.59 68.36 82.58 49 98.55 98.00 95.40 89.63 100.00 76.67 94.03 56 100.00 100.00 100.00 100.00 96.
  • Example 11 Example 12 Comparative example 1 Comparative example 2 0.04 0 0.19 0.03 0.13 0.18 0.30 0.44 0.5 0.25 0.53 0.17 0.58 0.99 0.62 0.87 1 1.04 1.67 0.82 2.01 2.31 1.69 1.58 2 2.18 3.77 1.59 8.36 5.53 3.24 3.51 7 8.60 20.55 6.75 24.75 29.75 13.86 12.24 14 24.94 38.28 15.63 48.69 57.15 44.30 50.47 twenty one 48.16 52.34 24.96 79.10 79.20 67.66 75.16 28 74.56 65.12 40.6 97.63 94.89 82.79 91.72 35 98.35 78.9 51.37 100.00 100.00 92.48 100.00 42 100.00 88.00 64.09 100.00 100.00 99.09 100.00 49 100.00 96.98 78.15 100.00 56 100.00 86.52 63 100.00 96.30 70 100.00 77 100.00
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7 0.04 0.12 0.08 0.17 0.04 0.16 0.05 0.05 0.5 0.50 0.40 0.55 0.27 0.77 0.21 0.31 1 0.83 1.20 1.38 0.70 1.73 0.76 0.62 2 1.44 3.17 3.86 2.11 4.22 3.84 0.61 7 11.95 14.78 18.12 8.87 17.09 13.81 10.22 14 25.56 34.25 38.44 20.57 38.16 22.27 23.46 twenty one 43.59 51.14 57.22 35.02 61.25 35.60 44.13 28 62.34 67.63 70.15 48.00 77.28 45.35 57.15 35 84.13 89.68 80.75 67.14 88.30 64.43 72.11 42 94.25 92.12 90.88 79.10 97.22 79.05 83.36
  • Example 11 Example 12 Comparative example 1 Comparative example 2 0.04 0.08 0.22 0.03 0.13 0.2 0.96 1.08 0.5 0.29 0.55 0.17 0.61 1.06 1.85 2.52 1 1.18 1.73 0.82 2.15 2.35 3.14 4.66 2 2.32 3.85 1.59 8.50 5.62 6.97 7.45 7 8.73 20.63 6.75 24.96 29.91 23.10 20.76 14 25.34 38.95 15.63 49.12 57.80 50.52 56.33 twenty one 49.03 53.15 24.96 79.86 79.88 72.31 81.59 28 75.12 65.98 40.6 98.25 94.78 86.57 96.24 35 98.55 79.33 51.37 100.00 100.00 97.12 100.00 42 100.00 88.79 64.09 100.00 100.00 100.00 100.00 49 100.00 97.45 78.15 100.00 56 100.00 86.52 63 100.00 96.30 70 100.00 77 100.00
  • a suspension of physiological saline solution containing 0.5% CMC-Na, the water-insoluble drug content of the sustained release microspheres in each suspension is 18 mg, respectively at 0.04d, 0.5d, 1d, 7d, 14d , 21d, 28d, 35d, 42d, 49d, 56d, 63d, 77d, 84d, 91d and 98d were taken 1.5 mL of blood samples from the rabbit ear vein.
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7 0.4 0.96 1.15 2.31 0.55 2.45 0.66 0.56 0.5 3.15 2.68 3.65 1.59 4.20 1.10 1.48 1 2.34 4.89 5.15 2.85 7.26 2.18 2.64 7 8.56 13.20 14.68 6.24 17.39 11.58 10.15 14 17.48 25.71 26.93 14.59 28.48 17.60 18.00 twenty one 25.6 22.98 23.20 19.46 24.25 20.55 26.15 28 22.12 18.26 16.58 18.10 15.23 18.65 21.18 35 15.25 12.25 11.6 18.75 8.19 17.45 15.55 42 9.14 8.56 8.44 12.50 3.15 12.78 9.59 49 3.45 3.86 4.50 7.59 0 8.96 5.03 56 0.23 0.39 1.25 2.33 5.05 1.32 63 0 0 0 0.15 1.63 0 70 0 0 0
  • Example 12 Comparative example 1 Comparative example 2 0.4 0.75 2.30 0.38 0.96 1.55 0.59 0.75 0.5 1.17 1.95 0.91 2.35 3.47 0.35 0.89 1 3.58 5.29 2.10 4.66 5.8 0 0.55 7 8.45 18.35 6.34 17.35 20.00 2.25 1.78 14 19.79 24.18 12.55 27.48 29.55 20.35 24.20 twenty one 28.89 20.70 16.25 17.25 15.30 29.03 28.16 28 20.35 17.25 19.5 6.12 3.12 16.18 12.58 35 10.25 12.17 22.15 1.15 0.30 6.35 3.43 42 2.59 6.58 18.23 0 0 2.11 0.05 49 0.23 2.55 14.30 0 0 0
  • the poorly soluble drug microspheres of the present invention showed a good sustained release effect, and the blood drug concentration was increased soon after administration, while the comparative example 1-2 was hardly released within 7 days, and in vitro. The release behavior is consistent. Therefore, the sustained-release microsphere of the present invention has a better therapeutic effect and is advantageous for improving patient compliance.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种帕利哌酮及其衍生物的缓释组合物及其制备方法，原料包含帕利哌酮或帕利哌酮衍生物及水难溶性聚合物。所述缓释组合物具有良好的缓释性能，稳定性。

Description

帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法 技术领域
本发明涉及一种水难溶/微溶性药物缓释组合物及其制备方法，尤其是一种帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法。
背景技术
很多水难溶/微溶性药物制成的普通剂型的生物利用度较低，将其开发为长效缓释剂型是一个理想的选择，可降低因频繁给药造成的需要浓度波动和提高患者的顺应性。
专利CN201110059685公开了一种难溶性药物球形颗粒的制备方法，将难溶性药物(如帕潘立酮棕榈酸酯、紫杉醇)溶于亲脂性溶剂中制得分散相，然后加入到与该分散相不互溶的连续相中形成乳剂，除去分散相中的所述亲脂性溶剂，得到药物细微颗粒混悬剂，洗涤除去连续相、收集得到具有2～50微米的粒径的球形颗粒。该方法制备的球形颗粒，由于粒径不同的而比表面积相差较大，造成了这些颗粒的溶解速度存在较大的差别，大粒径颗粒明显比小粒径颗粒溶解得慢。因此如果要使血药浓度波动较小，就必须严格控制不同粒径的颗粒的摩尔比，以使单位时间内溶解的药物量在一个较小的范围内波动，制备难度较高。
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)、聚乳酸-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。
专利CN104013578通过添加棕榈酸异丙酯、硬脂酸丁酯制备帕潘立酮衍生物缓释微球，以改变微球的结构和药物晶态，使药物更趋近于微球核心，且使微球表面形成致密壳结构限制药物的扩散。此方法虽然避免了初期突释现象，但是造成了约5天及以上的延迟释放期，临床使用不方便，患者依从性差。同时，该技术使药物于核心中聚集，与专利CN201110059685中制备不同粒径药物颗粒类似，同样存在颗粒大小对溶解速度的影响。
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、能够在数周或以上的时间内维持稳定的治疗血药浓度、具有良好的释放性能和较好的稳定性的帕利哌酮及其衍生物的缓释组合物。同时，本发明的另一目的在于提供所述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：一种帕利哌酮及其衍生物的缓释组合物，所述缓释组合物的非溶剂型制备原料包含帕利哌酮或帕利哌酮衍生物，所述缓释组合物的制 备原料还包含水难溶性聚合物。本发明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。其中非溶剂型制备原料包含帕利哌酮或帕利哌酮衍生物，还包含水难溶性聚合物，但其不包括表面活性剂。
本发明的帕利哌酮及其衍生物的缓释组合物中，水难溶性聚合物作为帕利哌酮或其衍生物的载体。
作为本发明所述帕利哌酮及其衍生物的缓释组合物的优选实施方式，所述帕利哌酮衍生物包括但不限于棕榈酸帕利哌酮。
作为本发明所述帕利哌酮及其衍生物的缓释组合物的优选实施方式，所述缓释组合物的非溶剂型制备原料中，所述帕利哌酮或帕利哌酮衍生物的质量百分含量为35～70％，所述水难溶性聚合物的质量百分含量为30-65％；优选地，所述缓释组合物的非溶剂型制备原料中，所述帕利哌酮或帕利哌酮衍生物的质量百分含量为40～65％，所述水难溶性聚合物的质量百分含量为35-60％；更优选地，所述缓释组合物的非溶剂型制备原料中，所述帕利哌酮或帕利哌酮衍生物的质量百分含量为40～60％，所述水难溶性聚合物的质量百分含量为40-60％。
作为本发明所述帕利哌酮及其衍生物的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。
作为本发明所述帕利哌酮及其衍生物的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)及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、海藻酸或其盐、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。
作为本发明所述帕利哌酮及其衍生物的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。作为本发明所述帕利哌酮及其衍生物的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。
作为本发明所述帕利哌酮及其衍生物的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25000-100000Da；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25000-90000Da；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25000-80000Da。
作为本发明所述帕利哌酮及其衍生物的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0.25-0.80dL/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0.30-0.70dL/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0.30-0.65dL/g(测试条件为～0.5％(w/v)，CHCl3，25℃)。
作为本发明所述帕利哌酮及其衍生物的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。
作为本发明所述帕利哌酮及其衍生物的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，且其中丙交酯与乙交酯的摩尔比为100:0～75:25；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，其中丙交酯与乙交酯的摩尔比为100:0～80:20；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，其中丙交酯与乙交酯的摩尔比为100:0～85:15。
本发明帕利哌酮及其衍生物的缓释组合物中，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。
作为本发明所述帕利哌酮及其衍生物的缓释组合物的优选实施方式，所述缓释组合物还包含释放调节剂。
作为本发明所述帕利哌酮及其衍生物的缓释组合物的优选实施方式，所述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％。
作为本发明所述帕利哌酮及其衍生物的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、有机亲水性物质中的至少一种。
本发明所述帕利哌酮及其衍生物的缓释组合物，加入了释放调节剂，而且所述释放调节剂包含有机亲油性物质、有机亲水性物质中的至少一种。所述有机亲油性物质在体内最终转化为二氧化碳和水，可使微球表面及内部产生孔道，增加体液的渗透性，促进帕利哌酮或其衍生物的溶出，从而避免出现释放一段时间后的极慢释放平台。所述有机亲水性物质也可使微球表面及内部产生细微的孔道，这些孔道可以增加微球注射于体内后体液的渗透性，促进帕利哌酮或其衍生物的溶出，大大缩短或避免了初期无释放的现象释放停滞期，同时也促进了微球内部降解产物的转移。
因此，本发明所述帕利哌酮及其衍生物的缓释组合物，由于制备原料含有有机亲油性物质、有机亲水性物质或它们的组合，不但可以避免初始突释现象，而且可以避免帕利哌酮或其衍生物因水溶性较差且聚合物分子量较大时而出现首日释放后的延迟释放平台，维持血药浓度，也解决了以高分子量及LA组分比例高的PLGA作为载体制备长周期缓释微球的延迟释放的问题。
作为本发明所述帕利哌酮及其衍生物的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有机亲水性物质，所述有机亲水性物质在所述释放调节剂中的质量百分含量为30％以上；优选地，所述有机亲水性物质在所述释放调节剂中的质量百分含量为50％以上；优选地，所述有机亲水性物质在所述释放调节剂中的质量百分含量为70％以上。
作为本发明所述帕利哌酮及其衍生物的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、糖、氨基酸、蛋白、聚乙烯吡咯烷酮中的至少一种。作为本发明所述帕利哌酮及其衍生物的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；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。
作为本发明所述帕利哌酮及其衍生物的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；所述醇为分子量为400-6000Da的聚乙二醇。所述脂肪酸优选但不限于C12～C24烷酸或其衍生物，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400～4000Da的聚乙二醇(PEG)，更优选分子量为400～3000Da的PEG。
作为本发明所述帕利哌酮及其衍生物的缓释组合物的优选实施方式，所述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％。本发明的帕利哌酮及其衍生物的缓释组合物中，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。
作为本发明所述帕利哌酮及其衍生物的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。
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。
所述赋形剂在内相时加入。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相中或以极小颗粒混悬于内油相中。
作为本发明所述帕利哌酮及其衍生物的缓释组合物的优选实施方式，所述缓释组合物为微球或微粒。当所述帕利哌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。
作为本发明所述帕利哌酮及其衍生物的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：一种帕利哌酮及其衍生物的缓释组合物的制备方法，其包括以 下步骤：
(1a)将所述缓释组合物的非溶剂型制备原料所含的各物质溶于有机溶剂中，形成内相；
(2a)将表面活性剂溶于水溶剂或者非水溶剂中，形成外相；
(3a)将步骤(1a)得到的内相加入到外相中，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，得帕利哌酮或其衍生物的缓释微球；
或者
(1b)将所述缓释组合物的非溶剂型制备原料所含的除释放调节剂外的其余各物质溶于有机溶剂中，形成内相；
(2b)将释放调节剂和表面活性剂溶于水溶剂或者非水溶剂中，形成外相；
(3b)将步骤(1b)得到的内相加入到外相中，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，得帕利哌酮或其衍生物的缓释微球。
作为本发明所述缓释组合物的制备方法的优选实施方式，所述步骤(1a)和(1b)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(2a)和(2b)中，所述表面活性剂在外相中的质量百分含量为0.1～10％；所述步骤(3a)和(3b)中，所述外相的体积是所述内相体积的60倍以上。作为本发明所述释组合物的制备方法的更优选实施方式，所述步骤(1a)和(1b)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(2a)和(2b)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(3a)和(3b)中，所述外水相的体积是所述内油相体积的80倍以上。作为本发明所述缓释组合物的制备方法的更优选实施方式，所述步骤(1a)和(1b)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(2a)和(2b)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(3a)和(3b)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％。
作为本发明所述缓释组合物的制备方法的优选实施方式，所述步骤(1a)和(1b)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；所述步骤(2a)和(2b)中，非水溶剂为具有亲水性的非水溶剂，所述具有亲水性的非水溶剂选自多元醇、多元醇衍生物、亲水性高分子聚合物中的至少一种；优选地，所述多元醇为乙二醇、丙二醇、甘油、季戊四醇、失水山梨醇、它们的脂肪酸酯、它们的脂肪酸酯的衍生物中的至少一种；所述亲水性高分子聚合物为聚乙二醇、聚氧乙烯脂肪醇醚、聚氧乙烯烷基酚醚、聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油、它们的衍生物或聚乙烯吡咯烷酮。更优选地，所述具 有亲水性的非水溶剂为乙二醇、聚乙二醇和甘油中的至少一种；更优选地，所述具有亲水性的非水溶剂为甘油。
所述有机溶剂可以同时溶解水难溶性聚合物、帕利哌酮或其衍生物以及释放调节剂，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摩尔比按不同药物有所不同，根据实际情况调配。所述非水溶剂不与所述分散相中的亲脂性溶剂互溶，优选为具有亲水性的非水溶剂。所述具有亲水性的非水溶剂选自多元醇或其衍生物、亲水性高分子聚合物或它们的任意混合物。
作为本发明所述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、聚丙烯酸钠或其衍生物、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(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)衍生物、聚乙烯吡咯烷酮(PVP)和多糖。
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)。
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、聚丙烯酸钠或其衍生物、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)或其衍生物、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、壳聚糖或其衍生物、支链淀粉或葡聚糖或其衍生物。
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(3a)和(3b)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(3a)和(3b)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(3a)和(3b)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))。
本发明的帕利哌酮及其衍生物的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、诸如长达约24周、诸如长达约48周，或更长时间，可根据具体药物特性或治疗需求进行调节。
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
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：帕利哌酮35％，水难溶性聚合物：PLA 64.9％，释放调节剂：PEG800 0.1％。其中，所述PLA的重均分子量为20kDa，粘度为0.25dL/g，且所述PLA具有酯基端。
本实施例所述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％，然后加入帕利哌酮和释放调节剂，溶解均匀，形成内相；
(2)将PVA溶于水中，形成外相，所述PVA在所述外相中的质量百分含量为0.1％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得帕利哌酮缓释微球。
本实施例中所得帕利哌酮缓释微球外形圆整、表面光滑，粒径为32～124μm，经测定其载药率为31.58％，帕利哌酮包封率为90.22％。
实施例2
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：帕利哌酮40％，水难溶性聚合物：PLA 59.5％，释放调节剂：山俞酸0.5％。其中，所述PLA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295:300，所述具有羧基端PLA和具有酯基端PLA的重均分子量均为20kDa，粘度均为0.25dL/g。
本实施例所述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10％，然后加入帕利哌酮和释放调节剂，溶解均匀，形成内相；
(2)将羟丙甲纤维素溶于水中，形成外相，所述羟丙甲纤维素在所述外相中的质量百分含量为0.5％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得帕利哌酮缓释微球。
本实施例中所得帕利哌酮缓释微球外形圆整、表面光滑，粒径为29～112μm，经测定其载药率为36.25％，帕利哌酮包封率为90.63％。
实施例3
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮45％，水难溶性聚合物：PLA55％。其中，所述PLA的重均分子量为25kDa，粘度为0.28dL/g，且所述PLA具有羧基端。
本实施例所述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9.5％，然后加入棕榈酸帕利哌酮，溶解均匀，形成内相；
(2)将白蛋白溶于水中，形成外相，所述白蛋白在所述外相中的质量百分含量为1％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为28～105μm，经测定其载药率为41.18％，棕榈酸帕利哌酮包封率为91.51％。
实施例4
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮45％，水难溶性聚合物：PLGA55％。其中，所述PLGA为PLGA(丙交酯与乙交酯的摩尔比为95:5、重均分子量为25kDa、粘度为0.28dL/g，具有酯基端)和PLGA(丙交酯与乙交酯的摩尔比为85:15、重均分子量为 25kDa、粘度为0.29dL/g，具有酯基端)的混合物，且质量比为250:300。
本实施例所述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9.5％，然后加入棕榈酸帕利哌酮，溶解均匀，形成内相；
(2)将聚山梨酸酯溶于水中，形成外相，所述聚山梨酸酯在所述外相中的质量百分含量为2％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为33～110μm，经测定其载药率为41.13％，棕榈酸帕利哌酮包封率为91.40％。
实施例5
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮50％，水难溶性聚合物：PLGA49％，释放调节剂：硬脂酸和PEG400的混合物1％。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30kDa，粘度为0.32dL/g；所述释放调节剂中，PEG400在所述释放调节剂中的质量百分含量为50％。
本实施例所述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9％，然后加入棕榈酸帕利哌酮，溶解均匀，形成内相；
(2)将释放调节剂、苯扎氯铵溶于水中，形成外相，所述苯扎氯铵在所述外相中的质量百分含量为3％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为29～119μm，经测定其载药率为45.95％，棕榈酸帕利哌酮包封率为91.90％。
实施例6
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕帕利哌酮50％，水难溶性聚合物：PLA 47％，释放调节剂：硬脂酸和PEG600的混合物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1:1，所述具有羧基端PLA和具有酯基端PLA的粘度均为0.38dL/g，具有羧基端PLA的重均分子 量均为40kDa，具有酯基端PLA的重均分子量均为38kDa；所述释放调节剂中，PEG600在所述释放调节剂中的质量百分含量为60％。
本实施例所述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体积比为8:2的二氯甲烷/二甲苯中，所述水难溶性聚合物与有机溶剂的质量百分比为8.5％，然后加入棕榈酸帕利哌酮、释放调节剂，溶解均匀，形成内相；
(2)将月桂酸钾溶于水中，形成外相，所述月桂酸钾在所述外相中的质量百分含量为4％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为25～110μm，经测定其载药率为46.10％，棕榈酸帕利哌酮包封率为92.20％。
实施例7
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮55％，水难溶性聚合物：PLGA45％。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50kDa，粘度为0.44dL/g，且所述PLGA具有羧基端。
本实施例所述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8％，然后加入棕榈酸帕利哌酮，溶解均匀，形成内相；
(2)将泊洛沙姆溶于水中，形成外相，所述泊洛沙姆在所述外相中的质量百分含量为5％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌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50.85％，棕榈酸帕利哌酮包封率为92.45％。
实施例8
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮55％，水难溶性聚合物：PLGA45％。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60kDa，粘度为0.55dL/g，且所述PLGA具有酯基端。
本实施例所述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7％，然后加入棕榈酸帕利哌酮，溶解均匀，形成内相；
(2)将PVP溶于水中，形成外相，所述PVP在所述外相中的质量百分含量为6％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为35～120μm，经测定其载药率为50.40％，棕榈酸帕利哌酮包封率为91.64％。
实施例9
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮60％，水难溶性聚合物：PLGA34％，释放调节剂：棕榈酸和PEG1000的混合物6％。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20:14；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70kDa，粘度为0.60dL/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65kDa，粘度为0.56dL/g；所述释放调节剂中，PEG1000在所述释放调节剂中的质量百分含量为30％。
本实施例所述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6％，然后加入棕榈酸帕利哌酮、释放调节剂，溶解均匀，形成内相；
(2)将淀粉溶于水中，形成外相，所述淀粉在所述外相中的质量百分含量为7％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为25～104μm，经测定其载药率为54.23％，棕榈酸帕利哌酮包封率为90.38％。
实施例10
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮60％，水难溶性聚合物：PLGA40％。其中，所述PLGA为由PLGA(丙交酯与乙交酯的摩尔比为80:20，重均分子量为80kDa，粘度为0.65dL/g，具有酯基端)和PLGA(丙交酯与乙交酯的摩尔比为70:30，重均分子量为72kDa，粘度为0.60dL/g，具有酯基端)组成的混合物，且质量比为1:1。
本实施例所述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5％，然后加入棕榈酸帕利哌酮，溶解均匀，形成内相；
(2)将壳聚糖溶于水中，形成外相，所述壳聚糖在所述外相中的质量百分含量为8％；
(3)将步骤(1)得到的内油相加入到步骤(2)所得外相中，所述外相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌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54.75％，棕榈酸帕利哌酮包封率为91.13％。
实施例11
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮65％，水难溶性聚合物：PLGA26％，释放调节剂：肉豆蔻酸和PEG1500的混合物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75:25、重均分子量为90kDa、粘度为0.70dL/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80kDa、粘度为0.65dL/g，具有羧基端)的混合物，且质量比为1:1；所述释放调节剂中，PEG1500在所述释放调节剂中的质量百分含量为90％。
本实施例所述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4％，然后加入棕榈酸帕利哌酮、释放调节剂和赋形剂，溶解均匀，形成内相；
(2)将明胶S溶于溶液中，形成外相，所述明胶在所述外相中的质量百分含量为9％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为33～126μm，经测定其载药率为58.64％，棕榈酸帕利哌酮包封率为90.21％。
实施例12
本发明帕利哌酮及其衍生物的缓释组合物的一种实施例，本实施例所述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：棕榈酸帕利哌酮70％，水难溶性聚合物：PLGA20％，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75:25，所述PLGA的重均分子量为100kDa，粘度为0.80dL/g，且所述PLGA具有羧基端。
本实施例所述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％，然后加入棕榈酸帕利哌酮和释放调节剂，溶解均匀，形成内相；
(2)将聚乙烯醇溶于水中，形成外相，所述聚乙烯醇在所述外相中的质量百分含量为10％；
(3)将步骤(1)得到的内相加入到步骤(2)所得外相中，所述外水相的体积是所述内相的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，得棕榈酸帕利哌酮缓释微球。
本实施例中所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为29～110μm，经测定其载药率为63.50％，棕榈酸帕利哌酮包封率为90.71％。
实施例13
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1～12制备得到的水难溶性药物缓释微球作为试验组1～12，采用以下两个对比例作为对照组：
对比例1，制备方法同专利CN104013578实施例7。其中，药物为棕榈酸帕利哌酮，聚合物为PLGA(75/25，60kDa，0.55dL/g，酯基端)，调节剂为硬脂酸丁酯。所得棕榈酸帕利哌酮缓释微球外形圆整，粒径为27-125μm，经测定其载药率为26.50％，棕榈酸帕利哌酮包封率为88.33％。
对比例2，制备方法同专利CN104013578实施例14。其中，药物为棕榈酸帕利哌酮，聚合物为PLGA(75/25，40kDa，0.38dL/g，酯基端)，调节剂为硬脂酸丁酯。所得棕榈酸帕利哌酮缓释微球外形圆整，粒径为25-122μm，经测定其载药率为26.48％，棕榈酸帕利哌酮包封率为88.27％。
测试方法：精密称取实施例1-12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
0.04 0 0.05 0.11 0 0.12 0 0
0.5 0.39 0.35 0.50 0.21 0.70 0.14 0.20
1 0.75 1.14 1.30 0.65 1.59 0.63 0.53
2 1.32 3.05 3.70 1.99 4.08 3.35 2.35
7 11.85 14.22 17.79 8.73 16.53 12.98 9.98
14 25.35 33.04 37.25 20.08 37.67 21.45 23.25
21 42.80 50.30 56.33 34.81 60.45 34.29 42.10
28 61.50 66.42 70.66 47.65 76.09 44.08 55.39
35 82.87 81.89 79.56 65.99 87.20 56.09 70.20
42 93.53 91.27 89.24 78.14 96.37 67.75 81.85
49 99.05 97.30 95.30 89.00 100.00 75.73 91.32
56 100.00 100.00 100.00 96.48 100.00 87.30 98.60
63 100.00 100.00 100.00 100.00   96.66 100.00
70       100.00   100.00 100.00
77           100.00  
表2缓释微球的体外释放数据
时间/天 实施例8 实施例9 实施例10 实施例11 实施例12 对比例1 对比例2
0.04 0 0.19 0 0.10 0.17 0 0
0.5 0.17 0.48 0.10 0.55 0.98 0.19 0.5
1 1.05 1.60 0.78 1.95 2.28 0.55 1.00
2 1.98 3.55 1.52 8.26 5.46 1.27 2.50
7 8.46 20.53 6.35 24.66 29.73 5.38 4.34
14 24.73 37.67 15.24 48.36 56.67 37.3 45.15
21 47.70 51.75 24.55 78.82 78.82 62.25 70.30
28 73.82 64.80 39.64 97.01 94.78 78.48 86.27
35 97.78 78.19 50.36 100.00 100.00 86.19 95.45
42 100.00 87.49 63.45 100.00 100.00 94.60 100.00
49 100.00 96.64 77.00     100.00 100.00
56   100.00 85.49     100.00  
63   100.00 95.26        
70     100.00        
77     100.00        
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2.5％，而且能在5-10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没有明显的延迟释放期，而且没有突释现象，而且释放曲线斜率明显比对比例小，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，药物释放速度平缓，减少血药浓度波动造成的副作用，并使病人避免或减少注射服药后仍需口服普通制剂，显著增加给药依从性和便利性。
实施例14
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1～12和对比例1～2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13。结果如表3～8所示。实施例1～12和对比例1～2的微球第0天的释放行为见表1和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
0.04 0 0.03 0.10 0 0.1 0 0
0.5 0.39 0.35 0.49 0.20 0.68 0.15 0.19
1 0.77 1.13 1.31 0.63 1.60 0.60 0.53
2 1.30 3.06 3.68 2.00 4.06 3.28 2.36
7 11.85 14.20 17.80 8.75 16.55 13.02 9.95
14 25.38 33.06 37.28 20.06 37.68 21.50 23.18
21 42.84 50.33 56.30 34.80 60.44 34.36 42.47
28 61.55 66.39 70.65 47.70 76.05 43.95 55.70
35 82.85 81.85 79.55 66.02 87.25 56.55 70.67
42 93.50 91.25 89.25 78.15 96.02 67.83 81.85
49 99.12 97.33 95.35 89.05 100.00 75.94 91.39
56 100.00 100.00 100.00 97.00 100.00 87.21 99.20
63 100.00 100.00 100.00 100.00   96.53 100.00
70       100.00   100.00 100.00
77           100.00  
表4第30天加速稳定性样品的体外释放数据
时间/天 实施例8 实施例9 实施例10 实施例11 实施例12 对比例1 对比例2
0.04 0 0.15 0 0.11 0.15 0.12 0.18
0.5 0.20 0.48 0.11 0.56 0.95 0.35 0.55
1 0.98 1.62 0.75 1.93 2.26 1.21 1.27
2 2.05 3.56 1.50 8.25 5.49 2.56 2.73
7 8.49 20.50 6.36 24.67 29.70 6.42 5.79
14 24.68 37.68 15.25 48.5 56.69 39.16 43.63
21 47.83 51.80 24.52 78.89 78.85 63.10 68.39
28 73.69 64.79 39.65 97.00 94.70 78.66 87.56
35 97.75 78.18 50.40 100.00 100.00 87.35 96.76
42 100.00 87.50 93.39 100.00 100.00 95.40 100.00
49 100.00 96.60 77.20     100.00 100.00
56   100.00 85.56        
63   100.00 95.25        
70     100.00        
77     100.00        
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
0.04 0.05 0.06 0.13 0 0.13 0.01 0.02
0.5 0.43 0.38 0.52 0.23 0.72 0.17 0.23
1 0.80 1.17 1.34 0.66 1.65 0.70 0.56
2 1.39 3.11 3.75 2.06 4.15 3.56 2.47
7 11.87 14.25 17.87 8.80 16.82 13.25 10.13
14 25.45 33.85 37.95 20.24 37.96 21.77 23.32
21 43.02 50.96 56.90 34.92 60.89 34.99 43.09
28 61.96 66.98 70.88 47.86 76.49 44.44 56.45
35 83.10 89.02 80.00 66.75 87.73 59.30 71.45
42 93.88 91.80 90.13 78.66 96.59 68.36 82.58
49 98.55 98.00 95.40 89.63 100.00 76.67 94.03
56 100.00 100.00 100.00 96.28 100.00 88.32 100.00
63 100.00 100.00 100.00 100.00   97.25 100.00
70       100.00   100.00  
77           100.00  
表6第90天加速稳定性样品的体外释放数据
时间/天 实施例8 实施例9 实施例10 实施例11 实施例12 对比例1 对比例2
0.04 0 0.19 0.03 0.13 0.18 0.30 0.44
0.5 0.25 0.53 0.17 0.58 0.99 0.62 0.87
1 1.04 1.67 0.82 2.01 2.31 1.69 1.58
2 2.18 3.77 1.59 8.36 5.53 3.24 3.51
7 8.60 20.55 6.75 24.75 29.75 13.86 12.24
14 24.94 38.28 15.63 48.69 57.15 44.30 50.47
21 48.16 52.34 24.96 79.10 79.20 67.66 75.16
28 74.56 65.12 40.6 97.63 94.89 82.79 91.72
35 98.35 78.9 51.37 100.00 100.00 92.48 100.00
42 100.00 88.00 64.09 100.00 100.00 99.09 100.00
49 100.00 96.98 78.15     100.00  
56   100.00 86.52        
63   100.00 96.30        
70     100.00        
77     100.00        
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
0.04 0.12 0.08 0.17 0.04 0.16 0.05 0.05
0.5 0.50 0.40 0.55 0.27 0.77 0.21 0.31
1 0.83 1.20 1.38 0.70 1.73 0.76 0.62
2 1.44 3.17 3.86 2.11 4.22 3.84 0.61
7 11.95 14.78 18.12 8.87 17.09 13.81 10.22
14 25.56 34.25 38.44 20.57 38.16 22.27 23.46
21 43.59 51.14 57.22 35.02 61.25 35.60 44.13
28 62.34 67.63 70.15 48.00 77.28 45.35 57.15
35 84.13 89.68 80.75 67.14 88.30 64.43 72.11
42 94.25 92.12 90.88 79.10 97.22 79.05 83.36
49 100.00 98.32 95.46 90.20 100.00 77.19 95.15
56 100.00 100.00 100.00 97.36 100.00 89.21 100.00
63   100.00 100.00 100.00   97.40 100.00
70       100.00   100.00  
77           100.00  
表8第180天加速稳定性样品的体外释放数据
时间/天 实施例8 实施例9 实施例10 实施例11 实施例12 对比例1 对比例2
0.04 0.08 0.22 0.03 0.13 0.2 0.96 1.08
0.5 0.29 0.55 0.17 0.61 1.06 1.85 2.52
1 1.18 1.73 0.82 2.15 2.35 3.14 4.66
2 2.32 3.85 1.59 8.50 5.62 6.97 7.45
7 8.73 20.63 6.75 24.96 29.91 23.10 20.76
14 25.34 38.95 15.63 49.12 57.80 50.52 56.33
21 49.03 53.15 24.96 79.86 79.88 72.31 81.59
28 75.12 65.98 40.6 98.25 94.78 86.57 96.24
35 98.55 79.33 51.37 100.00 100.00 97.12 100.00
42 100.00 88.79 64.09 100.00 100.00 100.00 100.00
49 100.00 97.45 78.15     100.00  
56   100.00 86.52        
63   100.00 96.30        
70     100.00        
77     100.00        
对比表1～8可以看出，本发明所得微球在加速稳定性测定环境下，随着时间的增加释放行为变化不明显，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，具体体现为释放迟滞期缩短、首释放时间提前，由约7天开始释放提前至第1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大幅增加。对于抗精神病药，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。另外，对比例样品而且释放速度也随放置时间增加而加快，释放周期缩短，释放行为发生改变。
实施例15
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1～12和对比例制备的微球的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，0.5d，1d，7d，14d，21d，28d，35d，42d，49d，56d，63d，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
0.4 0.96 1.15 2.31 0.55 2.45 0.66 0.56
0.5 3.15 2.68 3.65 1.59 4.20 1.10 1.48
1 2.34 4.89 5.15 2.85 7.26 2.18 2.64
7 8.56 13.20 14.68 6.24 17.39 11.58 10.15
14 17.48 25.71 26.93 14.59 28.48 17.60 18.00
21 25.6 22.98 23.20 19.46 24.25 20.55 26.15
28 22.12 18.26 16.58 18.10 15.23 18.65 21.18
35 15.25 12.25 11.6 18.75 8.19 17.45 15.55
42 9.14 8.56 8.44 12.50 3.15 12.78 9.59
49 3.45 3.86 4.50 7.59 0 8.96 5.03
56 0.23 0.39 1.25 2.33   5.05 1.32
63 0 0 0 0.15   1.63 0
70       0   0  
表10血药浓度结果(ng/ml)
时间/d 实施例8 实施例9 实施例10 实施例11 实施例12 对比例1 对比例2
0.4 0.75 2.30 0.38 0.96 1.55 0.59 0.75
0.5 1.17 1.95 0.91 2.35 3.47 0.35 0.89
1 3.58 5.29 2.10 4.66 5.8 0 0.55
7 8.45 18.35 6.34 17.35 20.00 2.25 1.78
14 19.79 24.18 12.55 27.48 29.55 20.35 24.20
21 28.89 20.70 16.25 17.25 15.30 29.03 28.16
28 20.35 17.25 19.5 6.12 3.12 16.18 12.58
35 10.25 12.17 22.15 1.15 0.30 6.35 3.43
42 2.59 6.58 18.23 0 0 2.11 0.05
49 0.23 2.55 14.30     0 0
56 0 0 7.25        
63     3.32        
70     0.14        
77     0        
由表9和表10可看见，本发明的难溶性药物微球显示出良好的缓释效果，给药后很快增加血药浓度，而对比例1-2在7天内几乎没有释放，与体外释放行为一致。由此，说明本发明的缓释微球具有更好的治疗效果，有利于提高病患依从性。
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. 一种帕利哌酮及其衍生物的缓释组合物，其特征在于，所述缓释组合物的非溶剂型制备原料包含帕利哌酮或帕利哌酮衍生物，所述缓释组合物的制备原料还包含水难溶性聚合物。
  2. 如权利要求1所述的帕利哌酮及其衍生物的缓释组合物，其特征在于，所述缓释组合物的非溶剂型制备原料中，所述帕利哌酮或帕利哌酮衍生物的质量百分含量为35～70％，所述水难溶性聚合物的质量百分含量为30-65％；优选地，所述缓释组合物的非溶剂型制备原料中，所述帕利哌酮或帕利哌酮衍生物的质量百分含量为40～65％，所述水难溶性聚合物的质量百分含量为35-60％。
  3. 如权利要求1或2所述的帕利哌酮或及其衍生物的缓释组合物，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。
  4. 如权利要求3所述的帕利哌酮及其衍生物的缓释组合物，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20000-100000Da；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25000-90000Da；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25000-80000Da。
  5. 如权利要求3或4所述的帕利哌酮及其衍生物的缓释组合物，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0.25-0.80dL/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0.30-0.70dL/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0.30-0.65dL/g。
  6. 如权利要求3所述的帕利哌酮及其衍生物的缓释组合物，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100:0～75:25；优选地，其中丙交酯与乙交酯的摩尔比为100:0～80:20；更优选地，其中丙交酯与乙交酯的摩尔比为100:0～85:15。
  7. 如权利要求1～6任一项所述的帕利哌酮及其衍生物的缓释组合物，其特征在于，所述缓释组合物的非溶剂型制备原料还包含释放调节剂，所述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％。
  8. 如权利要求7所述的帕利哌酮及其衍生物的缓释组合物，其特征在于，所述释放调 节剂为有机亲油性物质、有机亲水性物质中的至少一种。
  9. 如权利要求8所述的帕利哌酮及其衍生物的缓释组合物，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；所述有机亲水性物质为醇、糖、氨基酸、蛋白、聚乙烯吡咯烷酮中的至少一种。
  10. 如权利要求1～9任一项所述的帕利哌酮及其衍生物的缓释组合物，其特征在于，所述缓释组合物的制备方法包括以下步骤：
    (1a)将所述缓释组合物的非溶剂型制备原料所含的各物质溶于有机溶剂中，形成内相；
    (2a)将表面活性剂溶于水溶剂或者非水溶剂中，形成外相；
    (3a)将步骤(1a)得到的内相加入到外相中，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，得帕利哌酮或其衍生物的缓释微球；
    或者
    (1b)将所述缓释组合物的非溶剂型制备原料所含的除释放调节剂外的其余各物质溶于有机溶剂中，形成内相；
    (2b)将释放调节剂和表面活性剂溶于水溶剂或者非水溶剂中，形成外相；
    (3b)将步骤(1b)得到的内相加入到外相中，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，得帕利哌酮或其衍生物的缓释微球。
PCT/CN2018/073898 2017-01-24 2018-01-24 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法 WO2018137628A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710052729.7A CN106727589A (zh) 2017-01-24 2017-01-24 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法
CN201710052729.7 2017-01-24

Publications (1)

Publication Number Publication Date
WO2018137628A1 true WO2018137628A1 (zh) 2018-08-02

Family

ID=58942589

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/073898 WO2018137628A1 (zh) 2017-01-24 2018-01-24 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法

Country Status (2)

Country Link
CN (1) CN106727589A (zh)
WO (1) WO2018137628A1 (zh)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116270486A (zh) * 2017-01-24 2023-06-23 广州帝奇医药技术有限公司 水难溶或微溶性药物缓释组合物及其制备方法
CN106727589A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法
CN107213136B (zh) * 2017-06-07 2021-06-01 广州帝奇医药技术有限公司 一种长效缓释药物制剂及其制备方法
CN112545995B (zh) * 2018-05-16 2024-02-23 珠海市丽珠微球科技有限公司 一种阿立哌唑缓释微球及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102614132A (zh) * 2012-03-16 2012-08-01 中国医药集团总公司四川抗菌素工业研究所 帕利哌酮缓释微丸
CN102784111A (zh) * 2011-05-17 2012-11-21 山东绿叶制药有限公司 一种多巴胺受体激动剂类药物的缓释制剂
CN106727589A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101292960B (zh) * 2006-04-29 2011-02-09 中国人民解放军军事医学科学院毒物药物研究所 含利培酮的缓释微球及其制备方法
ES2855349T3 (es) * 2011-04-25 2021-09-23 Shan Dong Luye Pharm Co Ltd Composición de risperidona de microesferas de liberación controlada
CN103126997B (zh) * 2011-12-01 2016-08-03 中国人民解放军军事医学科学院毒物药物研究所 含利培酮及其类似物的缓释微球及其制备方法
WO2016199170A2 (en) * 2015-06-10 2016-12-15 Cipla Limited Paliperidone palmitate particles and compositions thereof
CN105560192A (zh) * 2016-01-07 2016-05-11 万全万特制药江苏有限公司 一种棕榈酸帕利哌酮长效微球注射液的制备方法
CN106038569A (zh) * 2016-05-26 2016-10-26 湖南赛沃药业有限公司 一种帕利哌酮植入剂及其制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102784111A (zh) * 2011-05-17 2012-11-21 山东绿叶制药有限公司 一种多巴胺受体激动剂类药物的缓释制剂
CN102614132A (zh) * 2012-03-16 2012-08-01 中国医药集团总公司四川抗菌素工业研究所 帕利哌酮缓释微丸
CN106727589A (zh) * 2017-01-24 2017-05-31 广州帝奇医药技术有限公司 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法

Also Published As

Publication number Publication date
CN106727589A (zh) 2017-05-31

Similar Documents

Publication Publication Date Title
WO2018137627A1 (zh) 阿立哌唑及其衍生物的缓释组合物与该缓释组合物的制备方法
WO2018137631A1 (zh) 水难溶或微溶性药物缓释组合物及其制备方法
WO2018166502A1 (zh) 一种水难溶/微溶性药物缓释组合物
Giri et al. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery
Ansary et al. Biodegradable poly (D, L-lactic-co-glycolic acid)-based micro/nanoparticles for sustained release of protein drugs-A review
WO2018137629A1 (zh) 一种利培酮缓释组合物及其制备方法
JP5345141B2 (ja) コア／シェル構造を有するマイクロスフェア
WO2018223894A1 (zh) 一种长效缓释药物制剂及其制备方法
RU2464972C2 (ru) Композиции с замедленным высвобождением, включающие октреотид и два или более сополимера полилактида и гликолида
WO2018137628A1 (zh) 帕利哌酮及其衍生物的缓释组合物与该缓释组合物的制备方法
Zhang et al. Design of controlled release PLGA microspheres for hydrophobic fenretinide
US7691412B2 (en) Prolonged release biodegradable microspheres and method for preparing same
JP2010505819A (ja) デポ型注射剤組成物とその調製方法
US11723868B2 (en) Biodegradable polymer microsphere compositions for parenteral administration
CN112972388B (zh) 卡利拉嗪释放制剂
Patel et al. Biodegradable polymers: Emerging excipients for the pharmaceutical and medical device industries
WO2018137630A1 (zh) 利培酮缓释组合物及其制备方法
JP6047111B2 (ja) ゾル−ゲル転移の性質を有する高分子を用いた微小球体の製造方法及びこれにより製造された微小球体
WO2016089309A1 (en) Method of preparing hollow microparticles and hollow microparticles prepared thereof
JP7266220B2 (ja) エスシタロプラムを含む微粒球状徐放出注射剤及びその製造方法
AU2007263004A1 (en) Sustained release formulations of aromatase inhibitors
CN115554269A (zh) 一种平稳释放氟维司群的微球及制备方法
Rhodes et al. Formulation of Depot Delivery Systems
Tamani Towards a better understanding of the drug release mechanisms in PLGA microparticles
Schutzman Mechanistic Evaluation of Early Phases of Drug Release From Polymer Microparticles Prepared by Atomization Techniques

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18745059

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18745059

Country of ref document: EP

Kind code of ref document: A1