CN106963746A - A kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions - Google Patents

A kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions Download PDF

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Publication number
CN106963746A
CN106963746A CN201710160949.1A CN201710160949A CN106963746A CN 106963746 A CN106963746 A CN 106963746A CN 201710160949 A CN201710160949 A CN 201710160949A CN 106963746 A CN106963746 A CN 106963746A
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sustained
spheres
release
release micro
microsolubility
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赖树挺
郑阳
曹付春
连远发
刘锋
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AC Pharmaceuticals Co Ltd
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AC Pharmaceuticals Co Ltd
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Priority to CN201710160949.1A priority Critical patent/CN106963746A/en
Publication of CN106963746A publication Critical patent/CN106963746A/en
Priority to PCT/CN2018/079173 priority patent/WO2018166502A1/en
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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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)

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  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a kind of slow releasing composition, and in particular to and a kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions.The present invention shipwreck it is molten/microsolubility pharmaceutical sustained release compositions include two or more release behaviors it is different shipwreck it is molten/microsolubility medicament slow-release microsphere.The slow releasing composition of the present invention is by the way that the different sustained-release micro-spheres of two or more release behaviors are combined, the shipwreck that so obtains is molten/sustained release phase of the slow releasing composition without obvious phase hangover or shorter of microsolubility medicine, and without phenomenon of burst release, with good sustained release performance, and effective blood drug concentration can be maintained within the time of several weeks or more, administration frequency is effectively reduced, facilitates the life and work of patient, is conducive to improving patient's administration compliance and convenience.

Description

A kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions
Technical field
The present invention relates to a kind of slow releasing composition, and in particular to and a kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions.
Background technology
At present, biodegradable polymer microballoon turns into one of important research field of novel Drug Delivery Systems, the administration System can regard the microballoons made from framework material such as PLA (PLA), poly lactic coglycolic acid (PLGA) as long-acting system The carrier of agent, human body or animal can be administered with muscle or hypodermic mode, being capable of Drug controlled release speed and release In the cycle, only can maintain effective drug concentration levels for a long time with single administration, can minimization treatment needed for medicine it is total Dosage, improves the compliance of drug therapy of patient.
Depot antipsychotics Risperidal Consta based on technological development disclosed in patent CN1137756 are (permanent Moral) using molecular weight about 100-150kDa PLGA as carrier, Risperidone is API, and drugloading rate is about 35-40%, every 2 weeks muscle note Penetrate once.Said preparation is prevented effectively from the peak valley concentration that medication is produced daily, but only has a small amount of insoluble drug release in the first day, then goes out Now grow of about the insoluble drug release deadtime of 3 weeks, therefore patient also needs to rely on oral administration general in 3 weeks after injecting the microballoon Obstruction-removing prescription type can be only achieved therapeutic effect, and Clinical practice is inconvenient, and patient compliance is poor.
The content of the invention
One kind is provided without the obvious hangover it is an object of the invention to overcome above-mentioned the deficiencies in the prior art part The sustained release phase of phase or shorter, without phenomenon of burst release, with good sustained release performance, and can be tieed up within the time more than several weeks The shipwreck of holding effective blood drug concentration is molten/microsolubility pharmaceutical sustained release compositions.
To achieve the above object, the technical scheme taken of the present invention is：A kind of shipwreck is molten/combination of microsolubility medicament slow release Thing, it include the different shipwreck of two or more release behaviors it is molten/microsolubility medicament slow-release microsphere.
The different shipwreck of above two above release behavior is molten/and microsolubility medicament slow-release microsphere refers to：The same time opens Begin carry out drug release experiment, pharmaceutical release time without intersect or intersect it is less but it is front and rear be mutually linked it is two or more not With release behavior shipwreck it is molten/microsolubility medicament slow-release microsphere.The slow releasing composition of the present invention is by the way that two or more releases are gone To be combined for different sustained-release micro-spheres, the shipwreck so obtained is molten/and the slow releasing composition of microsolubility medicine is without significantly releasing Put period of delay or the shorter sustained release phase, and without phenomenon of burst release, with good sustained release performance, and can several weeks or with On time in maintain effective blood drug concentration, effectively reduce administration frequency, facilitate the life and work of patient, be conducive to carrying High patient's administration compliance and convenience.
In the present invention, the sustained release refers to microballoon in vitro under release conditions, it is impossible to start to discharge medicine at once, or The medicine total amount discharged within a period of time of beginning is seldom, less than 10%, preferably smaller than 8%, more preferably less than 5%；It is described It is not more than 3 days compared with the time of brachydactylia sustained release without obvious delay acquisition time or sustained release phase, preferably no greater than 2 days, more Preferably no greater than 1 day.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the shipwreck is molten/micro- Soluble drug slow releasing composition include without obvious delay acquisition time or sustained release phase it is shorter, and pharmaceutical release time be 2-3 The sustained-release micro-spheres A in week and be the sustained-release micro-spheres B of 2-3 weeks with 2-3 week sustained release phase and pharmaceutical release time；Or including tool There are sustained-release micro-spheres C and the sustained-release micro-spheres A that 2-3 weeks sustained release phase and pharmaceutical release time are 4-5 weeks；Or including with 4 weeks sustained release phases and pharmaceutical release time for 4-5 weeks sustained-release micro-spheres E and without obvious delay acquisition time or sustained release phase Shorter and pharmaceutical release time is the sustained-release micro-spheres D of 4-5 weeks；Or including the sustained-release micro-spheres A, sustained-release micro-spheres B and be sustained micro- Ball E；Or including the sustained-release micro-spheres A, sustained-release micro-spheres C and with 5-6 weeks sustained release phase and pharmaceutical release time be 4 weeks with On sustained-release micro-spheres F.
The shipwreck that is made up of sustained-release micro-spheres A and sustained-release micro-spheres B is molten/microsolubility pharmaceutical sustained release compositions, it can persistently be released Put medicine 4-6 weeks；The shipwreck that is made up of sustained-release micro-spheres A and sustained-release micro-spheres C is molten/microsolubility pharmaceutical sustained release compositions, it can hold Continuous release medicine 6-7 weeks；The shipwreck that is made up of sustained-release micro-spheres D and sustained-release micro-spheres E is molten/microsolubility pharmaceutical sustained release compositions, it can With sustained release drugs about 8 weeks；The shipwreck that is made up of sustained-release micro-spheres A, sustained-release micro-spheres B and sustained-release micro-spheres E is molten/and microsolubility medicine delays Composition is released, it can be 8-9 weeks with sustained release drugs；The shipwreck being made up of sustained-release micro-spheres A, sustained-release micro-spheres C and sustained-release micro-spheres F Molten/microsolubility pharmaceutical sustained release compositions, it can be more than 9-10 weeks with sustained release drugs.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the sustained-release micro-spheres A, sustained-release micro-spheres B, sustained-release micro-spheres C, sustained-release micro-spheres D, sustained-release micro-spheres E and sustained-release micro-spheres F preparing raw material include following weight The component of part：Shipwreck is molten/30-60 parts of microsolubility medicine, 40-70 parts of slightly water-soluble polymer.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the sustained-release micro-spheres At least one of A, sustained-release micro-spheres B, sustained-release micro-spheres C, sustained-release micro-spheres D, sustained-release micro-spheres E, sustained-release micro-spheres F preparing raw material include Following components in parts by weight：Shipwreck is molten/35-55 parts of microsolubility medicine, 45-65 parts of slightly water-soluble polymer.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the shipwreck is molten/micro- Soluble drug include Risperidone, 9-hydroxy-risperidone, Aripiprazole, Iloperidone, according to a piperazine azoles, Ziprasidone, Anastrozole, more how Piperazine is neat, Olanzapine, naltrexone, haloperole, taxol, docetaxel, Entecavir or their derivative.It is used as the present invention The shipwreck is molten/the more preferably embodiments of microsolubility pharmaceutical sustained release compositions, the shipwreck is molten/and microsolubility medicine includes profit and trains Ketone, 9-hydroxy-risperidone, Aripiprazole, Iloperidone, donepezil, Olanzapine, according to a piperazine azoles, Entecavir or their derivative Thing.As shipwreck of the present invention it is molten/the more preferably embodiments of microsolubility pharmaceutical sustained release compositions, the shipwreck is molten/slightly soluble Property medicine include Risperidone, 9-hydroxy-risperidone, Aripiprazole, Iloperidone, according to a piperazine azoles or their derivative.Wherein, it is described Derivative include and be not limited to palmitic acid handkerchief stand piperazine ketone, lauroyl Aripiprazole, haloperidol decanoate, pamoic acid Olanzapine, Ziprasidone.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the slightly water-soluble Polymer is at least one in polyester, makrolon, polyacetals, polyanhydride, poly-hydroxy fatty acid, their copolymer or blend Kind.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the slightly water-soluble Polymer be polylactide (PLA), PGA (PGA), PLGA (PLGA), polycaprolactone (PCL), Their copolymer (such as PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG- with polyethylene glycol (PEG) PCL, PCL-PEG-PCL, PEG-PLA-PEG, PEG-PLGA-PEG), it is poly butyric, poly- hydroxypentanoic acid, poly- to dioxocyclohex It is ketone (PPDO), chitosan, alginic acid and its salt, polybutylcyanoacrylate, condensing model, poe, polyamide, polyphosphazene, poly- At least one of phosphate.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the slightly water-soluble Polymer be in polylactide (PLA), PLGA (PLGA), their copolymers with polyethylene glycol extremely Few one kind.As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, as of the present invention The preferred embodiment of risperidone slow-release composition, the insoluble drug slow releasing composition is polylactide (PLA), the third friendship At least one of ester-glycolide copolymer (PLGA).
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the slightly water-soluble The strand of polymer carries anion or cation group, or does not carry anion or cation group.Preferably, it is described Slightly water-soluble polymer has end carboxyl or end ester group.It is highly preferred that the slightly water-soluble polymer has end carboxyl.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the sustained-release micro-spheres A In, slightly water-soluble polymer is PLGA, and the weight average molecular weight of PLGA is 20000-40000Da, viscosity is that 0.23-0.42dL/g, wherein lactide and glycolide mol ratio are 70:30-80:20；Institute State in sustained-release micro-spheres B, slightly water-soluble polymer is PLGA, and the weight of PLGA is equal Molecular weight is 41000-100000Da, and viscosity is that 0.42-0.9dL/g, wherein lactide and glycolide mol ratio are 70:30- 80:20；In the sustained-release micro-spheres C, slightly water-soluble polymer is PLGA, and lactide coglycolide copolymerization The weight average molecular weight of thing is 35100-44900Da, and viscosity is 0.38-0.46dL/g, wherein lactide and glycolide mol ratio For 80:20-90:10；In the sustained-release micro-spheres D, slightly water-soluble polymer is PLGA, and lactide-second The weight average molecular weight of lactide copolymers is 20000-35000Da, and viscosity is 0.23-0.38dL/g, wherein lactide and glycolide Mol ratio be 80:20-90:10；In the sustained-release micro-spheres E, slightly water-soluble polymer is PLGA, and The weight average molecular weight of PLGA is 45000-65000Da, and viscosity is 0.38-0.58dL/g, wherein lactide Mol ratio with glycolide is 80:20-90:10；In the sustained-release micro-spheres F, slightly water-soluble polymer is that polylactide or third are handed over Ester-glycolide copolymer, and the weight average molecular weight of slightly water-soluble polymer is 20000-60000Da, viscosity is 0.23- 0.54dL/g, wherein lactide and glycolide mol ratio are 90:10-100:0.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, following (a)~(f) At least one of in：
(a) in the sustained-release micro-spheres A, the weight average molecular weight of PLGA is 20000-35000Da, is glued Spend for 0.23-0.38dL/g, wherein the mol ratio of lactide and glycolide is 75:25；
(b) in the sustained-release micro-spheres B, the weight average molecular weight of PLGA is 50000-900000Da, is glued Spend for 0.49-0.0.81dL/g, wherein the mol ratio of lactide and glycolide is 75:25；
(c) in the sustained-release micro-spheres C, the weight average molecular weight of PLGA is 38000-42000Da, is glued Spend for 0.40-0.43dL/g, wherein the mol ratio of lactide and glycolide is 85:15；
(d) in the sustained-release micro-spheres D, the weight average molecular weight of PLGA is 25000-30000Da, is glued Spend for 0.27-0.34dL/g, wherein the mol ratio of lactide and glycolide is 85:15；
(e) in the sustained-release micro-spheres E, the weight average molecular weight of PLGA is 45000-60000Da, is glued Spend for 0.42-0.54dL/g, wherein the mol ratio of lactide and glycolide is 85:15；
(f) in the sustained-release micro-spheres F, the weight average molecular weight of slightly water-soluble polymer is 25000-55000Da, and viscosity is 0.28-0.52dL/g。
Shipwreck of the present invention is molten/microsolubility pharmaceutical sustained release compositions in, the slightly water-soluble polymer is biodegradable, raw The compatible slightly water-soluble polymer of thing.The slightly water-soluble polymer can be single polymer, or a variety of polymerizations Mole when molecular weight of the mixture of thing, such as lactide and glycolide is identical but carries the different PLGA of group combination, third The combination for mole when carrying the PLGA that group is identical but molecular weight is different of lactide and glycolide, molecular weight and carry group phase With but the lactide PLGA different from the mol ratio of glycolide combination, molecular weight, carry group and lactide and glycolide Mol ratio different PLGA combination, PLGA and PLA combination etc..
Molecular weight used in this explanation is weight average molecular weight, is obtained by gel permeation chromatography (GPC) measurement Value；Used viscosity is that Ubbelohde viscometer measures obtained value.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the sustained-release micro-spheres A Also include release regulator, weight/mass percentage composition of the release regulator in the sustained-release micro-spheres A is 0.1-10%；It is preferred that Ground, weight/mass percentage composition of the release regulator in the sustained-release micro-spheres A is 0.5-8%；Preferably, the release regulation Weight/mass percentage composition of the agent in the sustained-release micro-spheres A is 1-6%.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the release regulation Agent is organic lipophilic material and/or organic hydrophilicity material.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the organic lipophilic Property material be at least one of aliphatic acid, fatty acid ester, grease；The organic hydrophilicity material is alcohols, carbohydrate, amino At least one of acid, albumen, polyvinylpyrrolidone.As shipwreck of the present invention it is molten/microsolubility pharmaceutical sustained release compositions Preferred embodiment, the organic lipophilic material be aliphatic acid；The organic hydrophilicity material is alcohols, polyvinyl pyrrole At least one of alkanone.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the aliphatic acid is At least one of oleic acid, stearic acid, laurate, myristic acid, palmitic acid, arachidic acid, mountain Yu acid, lignin acid；The alcohol Class is the polyethylene glycol (PEG) that molecular weight is 400-6000Da.The aliphatic acid be preferably but not limited to C12~C24 alkanoic acids and its Derivative, including but not limited to oleic acid, stearic acid, laurate, myristic acid, palmitic acid, arachidic acid, mountain Yu acid, lignin acid, It is preferred that stearic acid, mountain Yu acid.The alcohols is preferably but not limited to the polyethylene glycol (PEG) that molecular weight is 600-6000Da, such as PEG600, PEG1000, PEG2000, PEG4000, PEG6000, preferred molecular weight are 400~6000Da polyethylene glycol (PEG), more preferably molecular weight is 400~3000Da PEG.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the sustained-release micro-spheres Excipient is also included, weight/mass percentage composition of the excipient in the sustained-release micro-spheres is 0~8%.The sustained release of the present invention is micro- One or more excipient can be included in ball.Excipient can assign active medicine or the other features of particulate, for example, increase The life of particulate, the stability of active medicine or carrier, promotion active medicine from the controlled release in particulate or regulation active medicine The permeability of thing tissue.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the excipient bag Include buffer and antioxidant；
The buffer is at least one of inorganic acid, acylate, and the buffer is in the sustained-release micro-spheres Weight/mass percentage composition is 0~5%；Preferably, weight/mass percentage composition of the buffer in the sustained-release micro-spheres is 0~3%； Preferably, weight/mass percentage composition of the buffer in the sustained-release micro-spheres is 0~2%；
The antioxidant is butylated hydroxyarisol, dibutylphenol, tocopherol, isopropyl myristate, d-a Tocopherol acetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisol, butylatedhydroxyquinone, hydroxyl tonka-bean Element, Yoshinox BHT, amass wealth by heavy taxation sour fatty acid ester, the third hydroxybenzoate, trihydroxybutyrophenone, vitamin E, vitamin E- At least one of TPGS, ρ-hydroxybenzoate；Weight/mass percentage composition of the antioxidant in the sustained-release micro-spheres is 0 ~1%；Preferably, weight/mass percentage composition of the antioxidant in the sustained-release micro-spheres is 0~0.08%；Preferably, institute It is 0~0.05% to state weight/mass percentage composition of the antioxidant in the sustained-release micro-spheres.
It is described to amass wealth by heavy taxation sour fatty acid ester selected from such as ethyl ester, propyl ester, monooctyl ester, lauryl in the selection of the antioxidant, it is described ρ-hydroxybenzoate is selected from such as methyl esters, ethyl ester, propyl ester, butyl ester.The antioxidant is produced with effectively removing in implant Raw any free radical or the amount of peroxide are present in slow releasing composition.
Buffer of the present invention includes but is not limited to inorganic acid and acylate, such as carbonic acid, acetic acid, oxalic acid, citric acid, The salt of phosphoric acid, hydrochloric acid, including the sour calcium of calcium carbonate, calcium hydroxide, Pork and beans fringed pink, calcium oleate, calcium palmitate, calcium stearate, calcium phosphate, Calcium acetate, magnesium acetate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, carbonic acid The sour zinc of zinc, zinc hydroxide, zinc oxide, Pork and beans fringed pink, zinc oleate, zinc acetate, zinc chloride, zinc sulfate, zinc hydrogen sulfate, zinc carbonate, nitre Sour zinc, zinc gluconate, zinc palmitate, zinc stearate, trbasic zinc phosphate, sodium carbonate, sodium acid carbonate, sodium hydrogensulfite, thiosulfuric acid Sodium, Acetic acid-sodium acetate buffer salt, and combinations thereof.It is preferred that the zinc salt of inorganic acid and organic acid.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the shipwreck is molten/micro- When soluble drug slow releasing composition includes sustained-release micro-spheres A and sustained-release micro-spheres B, sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine eases up The weight ratio for releasing microballoon B reclaimed waters indissoluble/microsolubility medicine is 1~3：1~3；The shipwreck is molten/microsolubility pharmaceutical sustained release compositions During including sustained-release micro-spheres A and sustained-release micro-spheres C, sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine and sustained-release micro-spheres C reclaimed waters indissoluble/micro- The weight ratio of soluble drug is 1~3：2~5；The shipwreck is molten/and microsolubility pharmaceutical sustained release compositions are gentle including sustained-release micro-spheres D When releasing microballoon E, the weight ratio of sustained-release micro-spheres D reclaimed waters indissoluble/microsolubility medicine and sustained-release micro-spheres E reclaimed waters indissoluble/microsolubility medicine For 1：1；The shipwreck is molten/and microsolubility pharmaceutical sustained release compositions are when including sustained-release micro-spheres D and sustained-release micro-spheres F, sustained-release micro-spheres D reclaimed waters The weight ratio of indissoluble/microsolubility medicine and sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine is 5：4；The shipwreck is molten/microsolubility When pharmaceutical sustained release compositions include the sustained-release micro-spheres A, sustained-release micro-spheres B and sustained-release micro-spheres E, the sustained-release micro-spheres A, sustained-release micro-spheres The weight ratio of B and sustained-release micro-spheres E reclaimed waters indissoluble/microsolubility medicine is sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine：Sustained release is micro- Ball B reclaimed waters indissoluble/microsolubility medicine：Sustained-release micro-spheres E reclaimed waters indissoluble/microsolubility medicine=2：2：5；The shipwreck is molten/microsolubility When pharmaceutical sustained release compositions include the sustained-release micro-spheres A, sustained-release micro-spheres B and sustained-release micro-spheres F, the sustained-release micro-spheres A, sustained-release micro-spheres The weight ratio of B and sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine is sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine：Sustained release is micro- Ball B reclaimed waters indissoluble/microsolubility medicine：Sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine=1~3：1~3：2~5；The shipwreck When molten/microsolubility pharmaceutical sustained release compositions include the sustained-release micro-spheres A, sustained-release micro-spheres C and sustained-release micro-spheres F, the sustained-release micro-spheres The weight ratio of A, sustained-release micro-spheres C and sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine is sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine Thing：Sustained-release micro-spheres C reclaimed waters indissoluble/microsolubility medicine：Sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine=2：4：5~7.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the shipwreck is molten/micro- When soluble drug slow releasing composition includes sustained-release micro-spheres A and sustained-release micro-spheres B, sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine eases up The weight ratio for releasing microballoon B reclaimed waters indissoluble/microsolubility medicine is 1：1.
The shipwreck of the present invention is molten/and microsolubility pharmaceutical sustained release compositions are the different sustained-release micro-spheres of two or more release behaviors Combination, wherein the sustained-release micro-spheres of different release behaviors exist in certain proportion, the ratio is activity contained in microballoon The ratio of the quality of medicine, identical from the ratio of the deenergized period of the sustained-release micro-spheres of different release behaviors, deenergized period is longer Ratio shared by unit is bigger.Further, the ratio is also related to pharmaceutical properties or clinical administration, such as dosage In the clinical practice that need to be stepped up, the sustained-release micro-spheres unit discharged afterwards is bigger than the ratio shared by previous unit.Specific combination Mode can be according to practical situations flexible combination.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the sustained-release micro-spheres Preparation method comprise the following steps：
(1) by shipwreck it is molten/microsolubility medicine and slightly water-soluble polymer be dissolved in organic solvent, formed in oil phase；
(2) surfactant is dissolved in aqueous medium, forms outer aqueous phase；
(3) the interior oil phase for obtaining step (1) is added in outer aqueous phase, and emulsion is made, and then passes through solvent evaporation or molten Agent, which is extracted, solidifies the particulate in solution, collects particulate, washs and dries, obtains the sustained-release micro-spheres.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the step (1) In, the mass percent of slightly water-soluble polymer and organic solvent is 1~10%；In the step (2), the surfactant Weight/mass percentage composition in outer aqueous phase is 0.1~10%；In the step (3), the volume of the outer aqueous phase is the interior oil More than 60 times of phase volume.As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, it is described In step (1), the mass percent of slightly water-soluble polymer and organic solvent is 1.5-9%；In the step (2), the table Weight/mass percentage composition of the face activating agent in outer aqueous phase is 0.5-8%；In the step (3), the volume of the outer aqueous phase is institute State interior oil phase volume more than 80 times.As shipwreck of the present invention it is molten/sides of being preferable to carry out of microsolubility pharmaceutical sustained release compositions In formula, the step (1), the mass percent of slightly water-soluble polymer and organic solvent is 3-8.5%；In the step (2), Weight/mass percentage composition of the surfactant in outer aqueous phase is 1~7%；In the step (3), the volume of the outer aqueous phase It is more than 100 times of the interior oil phase volume.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the step (1) In, organic solvent is at least one of halogenated hydrocarbons, fatty acid ester, aromatic hydrocarbon；The halogenated hydrocarbons comprising dichloromethane, chloroform, Chloroethanes, tetrachloro-ethylene, trichloro ethylene, dichloroethanes, trichloroethanes, carbon tetrachloride, fluorohydrocarbon, chlorobenzene, Arcton 11；Institute State fatty acid ester and include ethyl acetate, butyl acetate；The aromatic hydrocarbon includes benzene,toluene,xylene, phenmethylol.It is described organic Solvent can dissolve simultaneously biodegradable, bio-compatible slightly water-soluble polymer and shipwreck it is molten/microsolubility medicine, low boiling point In water and water is not dissolved in or is insoluble in.The organic solvent can be single organic solvent, or miscible two kinds and with On organic solvent.The organic solvent be selected from halogenated hydrocarbons (such as dichloromethane, chloroform, chloroethanes, tetrachloro-ethylene, trichloro ethylene, Dichloroethanes, trichloroethanes, carbon tetrachloride, fluorohydrocarbon, chlorobenzene (single, double, triple substitution), Arcton 11 etc.), fatty acid ester (such as ethyl acetate, butyl acetate), aromatic hydrocarbon (such as benzene,toluene,xylene, phenmethylol), preferably halogenated aliphatic hydro carbons is molten Agent, more preferably dichloromethane, chloroform.The ratio of organic solvent is different by different pharmaceutical in the mixture, according to reality Situation is allocated.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the surface-active Agent is nonionic surfactant, and the nonionic surfactant includes polyoxyethylene aliphatic alcohol ether (Brij), poly- sorbic acid Ester (such as Tween 80, polysorbate60), polyoxyethylene fatty acid ester (OEO), castor oil derivatives, polyoxyethylene poly- the third two Alcohol copolymer, sucrose fatty ester, cithrol, polyoxyethylene sorbitol acid anhydride mono fatty acid ester, polyoxyethylene Sorbitan di fatty acid ester, polyoxyethylene glycerol mono fatty acid ester, polyoxyethylene glycerol di fatty acid ester, polyglycereol fat Acid esters, polypropylene glycol monoesters, aryl burn base Aethoxy Sklerol, Pluronic F68 (poloxamer), polyvinyl alcohol And its at least one of derivative, polyvinylpyrrolidone (PVP), polysaccharide (PVA).It is molten/micro- as shipwreck of the present invention The preferred embodiment of soluble drug slow releasing composition, the nonionic surfactant is PULLRONIC F68 copolymerization Thing, polyvinyl alcohol, polysorbate, PVP or polysaccharide.As shipwreck of the present invention it is molten/microsolubility medicine delay The preferred embodiment of composition is released, the nonionic surfactant is polyvinyl alcohol or polysaccharide.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, the polysaccharide includes Starch and starch derivatives, methylcellulose, ethyl cellulose, hydroxylated cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose Element, Arabic gum, chitosan derivatives, gellan gum, alginate derivatives, glucan derivative and amorphous cellulose, preferably hydroxyl Third methylcellulose, Chitosan-phospholipid complex, amylopectin or glucan and its derivative.
As shipwreck of the present invention it is molten/preferred embodiments of microsolubility pharmaceutical sustained release compositions, in the outer aqueous phase Also contain inorganic salts or organic salt；The inorganic salts be phosphoric acid, sulfuric acid, acetic acid, the sylvite of carbonic acid or sodium salt, Tris, MES, At least one of HEPES.The weight percent concentration of inorganic salts in aqueous is：0-5%, preferably 0.01-4%, it is more excellent Select 0.05-3%；PH scopes are 3-9, more preferably preferably 4-9,5.5-8.5.Contain inorganic salts or organic salt in outer aqueous phase, to drop Water-soluble actives are molten in humble ball solidification process oozes into aqueous phase, and its mechanism is active for the osmotic pressure or reduction for improving foreign minister Solubility of the material in foreign minister.
The method for forming uniform emulsion is identical with well-known emulsification method, using the dress for producing high shear force Put (such as magnetic stirring apparatus, mechanical agitator, high-shear homogenizer, Ultrasound Instrument, membrane emulsifier, Rotor-stator mixers, static mixed Clutch, high pressure homogenizer etc.) interior oil phase and outer aqueous phase are mixed, to form homogeneous latex emulsion.
In the slow releasing composition of the present invention, every kind of microballoon of composition has similar geometry particle diameter.The sustained-release micro-spheres are equal With the geometry particle diameter less than 200 μm.Typically, the particle size of the microballoon is about 10-200 μm, preferably 20-150 μm, more It is preferred that 30-150 μm.Microspherulite diameter size is by dynamic light scattering technique (such as laser diffractometry) or microtechnic (as scanned Electron microscopy) measure.
Herein when stated ranges, it is meant that contain the combination of any scope therein or scope.
When the slow releasing composition is administered in suspending agent form, suspension formulations can be made with appropriate decentralized medium in it Form.
The decentralized medium includes nonionic surfactant (or stabilizer), castor oil derivatives, fiber Plain thickener, sodium alginate, hyaluronic acid, dextrin, starch.Or it is selectable, can also be with other excipient such as isotonic agent (such as Sodium chloride, mannitol, glycerine, sorbierite, lactose, xylitol, maltose, galactolipin, sucrose, glucose etc.), pH adjusting agent (such as carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid or these sour salt, such as sodium carbonate, sodium acid carbonate), anti-corrosion Agent (such as p-hydroxybenzoate, propylparaben, phenmethylol, chlorobutanol, sorbic acid, boric acid) etc. is combined, system Solidified after into aqueous solution by methods such as freeze-drying, hypobaric drying method, spray drying, again dissolved solidfied material using preceding The decentralized medium of dispersion microsphere is obtained in distilled water for injection.
In addition, slow-release injected can also be obtained by following methods：Microballoon is scattered in vegetable oil (such as sesame oil and jade Rice bran oil) or vegetable oil added with phosphatide (such as lecithin) in, or be scattered in medium chain triglyceride, mixed with obtaining oiliness Suspension.
The slow releasing composition is the combination of the sustained-release micro-spheres of the different release behaviors of two kinds and the above, can be with mixture Form administration, the sustained-release micro-spheres of different release behaviors are present in same packing container simultaneously as a mixture, described Mixture is the physical mixture for two kinds or more of sustained-release micro-spheres being manufactured separately；Or two kinds or more be manufactured separately Sustained-release micro-spheres are placed in different packing containers or separate two or more by detachable interlayer and do not connect or part connected space Packing container in, remixed before administration；Or two kinds or more of the sustained-release micro-spheres prepared are respectively placed in individually packaging and held In device, it is administered simultaneously with individually unit or completes to deliver medicine to identical or different parts within 12h time difference.
The slow releasing composition that the present invention is obtained can be used for granular form, suspending agent form, implants form, injection dosage form Formula, adhesive form etc., it is possible to which oral or parenteral administration (give by intramuscular injection, hypodermic injection, percutaneous dosing, mucous membrane Medicine (in cheek, in intravaginal, rectum etc.)).
The composition of the present invention is sufficiently stable, can be with sustained release more than several weeks, and such as length is of about 4 weeks, such as length of about 8 It is all, such as long of about 12 weeks, or the longer time, it can be adjusted according to specific medicinal property or Treatment need.
Brief description of the drawings
Fig. 1 is the sustained-release micro-spheres of beasle dog injection embodiment 6 in the embodiment of the present invention 54 and the controlled release composition of embodiment 31 After thing, the concentration of Risperidone in its blood sample；
Fig. 2 is the sustained-release micro-spheres of beasle dog injection embodiment 6 in the embodiment of the present invention 54 and the controlled release composition of embodiment 47 After thing, the concentration of Risperidone in its blood sample.
Embodiment
To better illustrate the object, technical solutions and advantages of the present invention, below in conjunction with specific embodiments and the drawings pair The present invention is described further.
In following examples, the computational methods of microballoon carrying drug ratio are：Drug quality/microspheres quality in carrying drug ratio=microballoon × 100%；The computational methods of entrapment efficiency are：Drug quality/medicine feeding quality × 100% in envelop rate=microballoon.
Embodiment 1
A kind of sustained-release micro-spheres (sustained-release micro-spheres A) of the present embodiment, its without obvious delay acquisition time or sustained release phase compared with It is short, and pharmaceutical release time is 2-3 weeks, its preparing raw material includes following components in parts by weight：Slightly water-soluble/slightly soluble medicine 30 Part, 70 parts of slightly water-soluble polymer；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, The weight average molecular weight of the PLGA is 20kDa, and viscosity is that 0.23dL/g, wherein lactide and glycolide mol ratio are 70：30, It has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is：By shipwreck it is molten/microsolubility medicine and slightly water-soluble polymer In the dichloromethane for being dissolved in 10 times of quality, phase in the oil that must be clarified is dissolved；Then by phase solution in oil in mechanical agitation It is added under (1000rpm) in 100 times of the 2%PVA aqueous solution of oily internal phase volume, emulsification 10min obtains O/W emulsions；By this breast Liquid mechanical agitation (500rpm) about 6h solidifies microballoon；Finally it is collected by centrifugation microballoon, and with milli-Q water microballoon 5 times, freezing Dry, obtain sustained-release micro-spheres A.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 25-98 μm, and its carrying drug ratio is 27.60% after measured, Entrapment efficiency is 92.00%.
Embodiment 2
A kind of sustained-release micro-spheres (sustained-release micro-spheres A) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For 2 weeks, its preparing raw material included following components in parts by weight：Shipwreck is molten/35 parts of microsolubility medicine, slightly water-soluble polymer 65 Part；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the Weight-average molecular of the PLGA Measure as 25kDa, viscosity is that 0.28dL/g, wherein lactide and glycolide mol ratio are 75：25, it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 24-100 μm, and its carrying drug ratio is 31.94% after measured, Entrapment efficiency is 91.26%.
Embodiment 3
A kind of sustained-release micro-spheres (sustained-release micro-spheres A) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For 3 weeks, the preparing raw material of the sustained-release micro-spheres included following components in parts by weight：Shipwreck is molten/and 35 parts of microsolubility medicine, shipwreck be molten 55 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 30kDa, viscosity be 0.32dL/g, wherein lactide and glycolide mol ratio be 80：20, it has end Carboxyl.
Sustained-release micro-spheres A preparation method is same as Example 1 described in the present embodiment.
Gained sustained-release micro-spheres A profiles rounding, surface are smooth, and particle diameter is 20-95 μm, and its carrying drug ratio is 40.89% after measured, Entrapment efficiency is 90.86%.
Embodiment 4
A kind of sustained-release micro-spheres (sustained-release micro-spheres A) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For release 2 weeks, the preparing raw material of the sustained-release micro-spheres included following components in parts by weight：Shipwreck is molten/55 parts of microsolubility medicine, water 45 parts of slightly solubility polymer；The shipwreck is molten/and microsolubility medicine is lauroyl Aripiprazole, and the slightly water-soluble polymer is PLGA, the PLGA weight average molecular weight are 35kDa, and viscosity is that 0.38dL/g, wherein lactide and glycolide mol ratio are 75：25, it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 28-105 μm, and its carrying drug ratio is 50.05% after measured, Entrapment efficiency is 91.00%.
Embodiment 5
A kind of sustained-release micro-spheres (sustained-release micro-spheres A) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For release 3 weeks, the preparing raw material of the sustained-release micro-spheres included following components in parts by weight：Shipwreck is molten/60 parts of microsolubility medicine, water 40 parts of slightly solubility polymer；The shipwreck is molten/and microsolubility medicine is palmitic acid 9-hydroxy-risperidone, and the slightly water-soluble polymer is PLGA, the PLGA weight average molecular weight are 40kDa, and viscosity is that 0.42dL/g, wherein lactide and glycolide mol ratio are 80：20, it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 23-100 μm, and its carrying drug ratio is 54.25% after measured, Entrapment efficiency is 90.42%.
Embodiment 6
A kind of sustained-release micro-spheres (sustained-release micro-spheres B) of the present embodiment, it has 2 weeks sustained release phases and pharmaceutical release time For 2 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 30 parts of microsolubility medicine, shipwreck be molten 70 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 40kDa, viscosity be 0.42dL/g, wherein lactide and glycolide mol ratio be 70：30, it has end Ester group.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 25-99 μm, and its carrying drug ratio is 27.61% after measured, Entrapment efficiency is 92.03%.
Embodiment 7
A kind of sustained-release micro-spheres (sustained-release micro-spheres B) of the present embodiment, it has 2 weeks sustained release phases and pharmaceutical release time For 3 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 35 parts of microsolubility medicine, shipwreck be molten 65 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 50kDa, viscosity be 0.49dL/g, wherein lactide and glycolide mol ratio be 80：20, it has end Carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 24-96 μm, and its carrying drug ratio is 31.79% after measured, Entrapment efficiency is 90.82%.
Embodiment 8
A kind of sustained-release micro-spheres (sustained-release micro-spheres B) of the present embodiment, when it has about 2 week sustained release phase and insoluble drug release Between be 2 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/45 parts of microsolubility medicine, shipwreck 55 parts of soluble polymer；The shipwreck is molten/and microsolubility medicine is lauroyl Aripiprazole, and the slightly water-soluble polymer is PLGA, the slightly water-soluble polymer is PLGA, and the weight average molecular weight of the PLGA is 70kDa, and viscosity is 0.67dL/g, wherein The mol ratio of lactide and glycolide is 75：25, it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 30-108 μm, and its carrying drug ratio is 40.52% after measured, Entrapment efficiency is 90.05%.
Embodiment 9
A kind of sustained-release micro-spheres (sustained-release micro-spheres B) of the present embodiment, it has 3 weeks sustained release phases and pharmaceutical release time For 2 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 55 parts of microsolubility medicine, shipwreck be molten 45 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 90kDa, viscosity be 0.81dL/g, wherein lactide and glycolide mol ratio be 75：25, it has end Ester group.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 22-97 μm, and its carrying drug ratio is 49.94% after measured, Entrapment efficiency is 90.80%.
Embodiment 10
A kind of sustained-release micro-spheres (sustained-release micro-spheres B) of the present embodiment, it has 3 weeks sustained release phases and pharmaceutical release time For 2 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 60 parts of microsolubility medicine, shipwreck be molten 40 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is palmitic acid 9-hydroxy-risperidone, and the slightly water-soluble polymer is PLGA, The weight average molecular weight of the PLGA is 100kDa, and viscosity is that 0.90dL/g, wherein lactide and glycolide mol ratio are 80： 20, it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 26-107 μm, and its carrying drug ratio is 53.97% after measured, Entrapment efficiency is 89.95%.
Embodiment 11
A kind of sustained-release micro-spheres (sustained-release micro-spheres C) of the present embodiment, it has 2 weeks sustained release phases and pharmaceutical release time For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 30 parts of microsolubility medicine, shipwreck be molten 70 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 35.1kDa, viscosity be 0.38dL/g, wherein lactide and glycolide mol ratio be 80：20, it has Hold ester group.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 31-115 μm, and its carrying drug ratio is 26.85% after measured, Entrapment efficiency is 89.50%.
Embodiment 12
A kind of sustained-release micro-spheres (sustained-release micro-spheres C) of the present embodiment, it has 2 weeks sustained release phases and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 35 parts of microsolubility medicine, shipwreck be molten 65 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 38kDa, viscosity be 0.40dL/g, wherein lactide and glycolide mol ratio be 80：20, it has end Carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 27-106 μm, and its carrying drug ratio is 31.89% after measured, Entrapment efficiency is 91.10%.
Embodiment 13
A kind of sustained-release micro-spheres (sustained-release micro-spheres C) of the present embodiment, it has 3 weeks sustained release phases and pharmaceutical release time For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 45 parts of microsolubility medicine, shipwreck be molten 55 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 40kDa, viscosity be 0.41dL/g, wherein lactide and glycolide mol ratio be 85：15, it has end Carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 22-103 μm, and its carrying drug ratio is 40.75% after measured, Entrapment efficiency is 90.55%.
Embodiment 14
A kind of sustained-release micro-spheres (sustained-release micro-spheres C) of the present embodiment, it has 2 weeks sustained release phases and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 55 parts of microsolubility medicine, shipwreck be molten 45 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Aripiprazole, and the slightly water-soluble polymer is PLGA, described PLGA weight average molecular weight is 42kDa, and viscosity is that 0.43dL/g, wherein lactide and glycolide mol ratio are 85：15, it has There is end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 25-99 μm, and its carrying drug ratio is 50.23% after measured, Entrapment efficiency is 91.32%.
Embodiment 15
A kind of sustained-release micro-spheres (sustained-release micro-spheres C) of the present embodiment, it has 3 weeks sustained release phases and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 60 parts of microsolubility medicine, shipwreck be molten 40 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is 9-hydroxy-risperidone, and the slightly water-soluble polymer is PLGA, described PLGA weight average molecular weight is 44.9kDa, and viscosity is that 0.46dL/g, wherein lactide and glycolide mol ratio are 90：10, its With end ester group.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 28-95 μm, and its carrying drug ratio is 55.29% after measured, Entrapment efficiency is 92.15%.
Embodiment 16
A kind of sustained-release micro-spheres (sustained-release micro-spheres D) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 30 parts of microsolubility medicine, shipwreck be molten 70 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 20kDa, viscosity be 0.23dL/g, wherein lactide and glycolide mol ratio be 80：20, it has end Ester group.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 22-96 μm, and its carrying drug ratio is 27.60% after measured, Entrapment efficiency is 92.00%.
Embodiment 17
A kind of sustained-release micro-spheres (sustained-release micro-spheres D) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 35 parts of microsolubility medicine, shipwreck be molten 65 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Olanzapine, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 25kDa, viscosity be 0.27dL/g, wherein lactide and glycolide mol ratio be 85：15, it has end Carboxyl.The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 25-112 μm, and its carrying drug ratio is 32.07% after measured, Entrapment efficiency is 91.63%.
Embodiment 18
A kind of sustained-release micro-spheres (sustained-release micro-spheres D) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time About 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/45 parts of microsolubility medicine, shipwreck 55 parts of soluble polymer；The shipwreck is molten/and microsolubility medicine is Entecavir, and the slightly water-soluble polymer is PLGA, described PLGA weight average molecular weight is 28kDa, and viscosity is that 0.29dL/g, wherein lactide and glycolide mol ratio are 85：15, it has There is end ester group.The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 25-98 μm, and its carrying drug ratio is 40.90% after measured, Entrapment efficiency is 90.88%.
Embodiment 19
A kind of sustained-release micro-spheres (sustained-release micro-spheres D) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 55 parts of microsolubility medicine, shipwreck be molten 45 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 30kDa, viscosity be 0.34dL/g, wherein lactide and glycolide mol ratio be 85：15, it has end Carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 32-105 μm, and its carrying drug ratio is 50.63% after measured, Entrapment efficiency is 92.05%.
Embodiment 20
A kind of sustained-release micro-spheres (sustained-release micro-spheres D) of the present embodiment, it is without obvious phase hangover and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 60 parts of microsolubility medicine, shipwreck be molten 40 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the shipwreck Soluble polymer is PLGA, and the weight average molecular weight of the PLGA is 35kDa, and viscosity is 0.38dL/g, and wherein lactide is handed over second The mol ratio of ester is 90：10, it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 27-110 μm, and its carrying drug ratio is 54.40% after measured, Entrapment efficiency is 90.66%.
Embodiment 21
A kind of sustained-release micro-spheres (sustained-release micro-spheres E) of the present embodiment, it has 4 weeks sustained release phases and pharmaceutical release time For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 30 parts of microsolubility medicine, shipwreck be molten 70 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 45kDa, viscosity be 0.38dL/g, wherein lactide and glycolide mol ratio be 80：20, it has end Carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 35-100 μm, and its carrying drug ratio is 27.44% after measured, Entrapment efficiency is 91.45%.
Embodiment 22
A kind of sustained-release micro-spheres (sustained-release micro-spheres E) of the present embodiment, it has 4 weeks sustained release phases and pharmaceutical release time For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 35 parts of microsolubility medicine, shipwreck be molten 65 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Olanzapine, and the slightly water-soluble polymer is PLGA, the shipwreck Soluble polymer is PLGA, and the weight average molecular weight of the PLGA is 45kDa, and viscosity is 0.42dL/g, and wherein lactide is handed over second The mol ratio of ester is 85：15, it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 31-112 μm, and its carrying drug ratio is 31.76% after measured, Entrapment efficiency is 90.75%.
Embodiment 23
A kind of sustained-release micro-spheres (sustained-release micro-spheres E) of the present embodiment, it has about 4 weeks sustained release phases and pharmaceutical release times For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 45 parts of microsolubility medicine, shipwreck be molten 55 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Entecavir, and the slightly water-soluble polymer is PLGA, described PLGA weight average molecular weight is 50kDa, and viscosity is that 0.49dL/g, wherein lactide and glycolide mol ratio are 85：15, it has There is end ester group.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 24-95 μm, and its carrying drug ratio is 40.43% after measured, Entrapment efficiency is 89.85%.
Embodiment 24
A kind of sustained-release micro-spheres (sustained-release micro-spheres E) of the present embodiment, it has 4 weeks sustained release phases and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 55 parts of microsolubility medicine, shipwreck be molten 45 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is pamoic acid Olanzapine, and the slightly water-soluble polymer is PLGA, The weight average molecular weight of the PLGA is 55kDa, and viscosity is that 0.54dL/g, wherein lactide and glycolide mol ratio are 85：15, It has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 28-118 μm, and its carrying drug ratio is 49.69% after measured, Entrapment efficiency is 90.35%.
Embodiment 25
A kind of sustained-release micro-spheres (sustained-release micro-spheres E) of the present embodiment, it has 4 weeks sustained release phases and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 60 parts of microsolubility medicine, shipwreck be molten 40 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 60kDa, viscosity be 0.58dL/g, wherein lactide and glycolide mol ratio be 90：10, it has end Carboxyl.
The preparation method of the present embodiment sustained-release micro-spheres is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 28-120 μm, and its carrying drug ratio is 54.30% after measured, Entrapment efficiency is 90.50%.
Embodiment 26
A kind of sustained-release micro-spheres (sustained-release micro-spheres F) of the present embodiment, it has 5 weeks sustained release phases and pharmaceutical release time is 4 Week；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/30 parts of microsolubility medicine, slightly water-soluble 70 parts of polymer；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA's Weight average molecular weight is 20kDa, and viscosity is that 0.23dL/g, wherein lactide and glycolide mol ratio are 90：10, it has end carboxylic Base.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 26-103 μm, and its carrying drug ratio is 27.06% after measured, Entrapment efficiency is 90.20%.
Embodiment 27
A kind of sustained-release micro-spheres (sustained-release micro-spheres F) of the present embodiment, it has 6 weeks sustained release phases and pharmaceutical release time For 4 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 35 parts of microsolubility medicine, shipwreck be molten 65 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLGA, the PLGA Weight average molecular weight be 25kDa, viscosity be 0.28dL/g, wherein lactide and glycolide mol ratio be 95：5, it has end Carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 30-99 μm, and its carrying drug ratio is 31.94% after measured, Entrapment efficiency is 91.25%.
Embodiment 28
A kind of sustained-release micro-spheres (sustained-release micro-spheres F) of the present embodiment, it has 5 weeks sustained release phases and pharmaceutical release time For 5 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 45 parts of microsolubility medicine, shipwreck be molten 55 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLA, the PLA's Weight average molecular weight is 40kDa, and viscosity is 0.39dL/g, and it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 25-110 μm, and its carrying drug ratio is 40.34% after measured, Entrapment efficiency is 89.65%.
Embodiment 29
A kind of sustained-release micro-spheres (sustained-release micro-spheres F) of the present embodiment, it has 6 weeks sustained release phases and pharmaceutical release time For 6 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 55 parts of microsolubility medicine, shipwreck be molten 45 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is palmitic acid 9-hydroxy-risperidone, and the slightly water-soluble polymer is PLA, institute The weight average molecular weight for stating PLA is 55kDa, and viscosity is 0.52dL/g, and it has end carboxyl.
The preparation method of sustained-release micro-spheres described in the present embodiment is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 28-112 μm, and its carrying drug ratio is 50.68% after measured, Entrapment efficiency is 92.15%.
Embodiment 30
A kind of sustained-release micro-spheres (sustained-release micro-spheres F) of the present embodiment, it has 6 weeks sustained release phases and pharmaceutical release time For 7 weeks；The preparing raw material of the sustained-release micro-spheres includes following components in parts by weight：Shipwreck is molten/and 60 parts of microsolubility medicine, shipwreck be molten 40 parts of polymer of property；The shipwreck is molten/and microsolubility medicine is Risperidone, and the slightly water-soluble polymer is PLA, the PLA's Weight average molecular weight is 60kDa, and viscosity is 0.54dL/g, and it has end ester group.The preparation method of sustained-release micro-spheres described in the present embodiment It is same as Example 1.
Gained sustained-release micro-spheres profile rounding, surface are smooth, and particle diameter is 27-115 μm, and its carrying drug ratio is 53.38% after measured, Entrapment efficiency is 88.97%.
Embodiment 31
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the different Risperidone of 2 kinds of release behaviors The binary combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 1 and embodiment 6, and the sustained release of embodiment 1 The mass ratio of Risperidone is 1 in microballoon and the sustained-release micro-spheres of embodiment 6：1；The deenergized period of the slow releasing composition of the present embodiment is about For 4 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 1 and embodiment 6 is with occupation mode：2 kinds of microballoons are prepared respectively, then Mix, be packaged in a closed cillin bottle according to the above ratio, decentralized medium suspension is directly injected into when using, is then injected.
Embodiment 32
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, i.e., release microballoon by embodiment 2 and embodiment 7 and combine, and embodiment 2 and embodiment 7 Sustained-release micro-spheres in Risperidone mass ratio be 2：3；The deenergized period of the slow releasing composition of the present embodiment is about 5 weeks.Wherein, it is real The combination for applying the sustained-release micro-spheres of example 2 and embodiment 7 is with occupation mode：2 kinds of microballoons are prepared respectively, are then distinguished according to the above ratio It is packaged in two closed cillin bottles, decentralized medium suspension one of which microballoon is first injected when using, then extracts all mixed out again It is suspended, is then injected with another microballoon in another cillin bottle of suspension injection.
Embodiment 33
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, i.e. the sustained-release micro-spheres of embodiment 3 and embodiment 9 combine, and embodiment 3 and implement The mass ratio of Risperidone is 3 in the sustained-release micro-spheres of example 9：2；The deenergized period of the slow releasing composition of the present embodiment is about 5 weeks.Its In, combination and the occupation mode of the sustained-release micro-spheres of embodiment 3 and embodiment 9 are：2 kinds of microballoons are prepared respectively, then by above-mentioned ratio Example is packaged in two closed cillin bottles respectively, with 3 when using:The decentralized medium of 2 ratios is suspended two kinds of microballoons, Ran Houzai respectively All two kinds of suspensions are extracted out with same syringe, then injected.
Embodiment 34
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the sharp piperazine of handkerchief of 2 kinds of different release behaviors The binary combination of ketone sustained-release micro-spheres composition, i.e. the sustained-release micro-spheres of embodiment 5 and embodiment 10 are combined, and the sum of embodiment 5 The mass ratio of palmitic acid 9-hydroxy-risperidone is 1 in the sustained-release micro-spheres of embodiment 10：1；The release week of the slow releasing composition of the present embodiment Phase is about 6 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 5 and embodiment 10 is with occupation mode：2 kinds of microballoons are prepared respectively, Then mix, be packaged in a closed cillin bottle according to the above ratio, decentralized medium suspension is directly injected into when using, is then noted Penetrate.
Embodiment 35
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the A Li piperazines of 2 kinds of different release behaviors The binary combination of azoles sustained-release micro-spheres composition, i.e., combined by the Aripiprazole sustained-release micro-spheres of embodiment 4 and embodiment 8, and real The mass ratio for applying Aripiprazole in the sustained-release micro-spheres of example 4 and embodiment 8 is 1：1；The release week of the slow releasing composition of the present embodiment Phase is about 4 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 4 and embodiment 8 is with occupation mode：2 kinds of microballoons are prepared respectively, Then mix, be packaged in a closed cillin bottle according to the above ratio, decentralized medium suspension is directly injected into when using, is then noted Penetrate.
Embodiment 36
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 1 and embodiment 11, and embodiment 1 and reality The mass ratio for applying Risperidone in the sustained-release micro-spheres of example 11 is 1：2；The deenergized period of the slow releasing composition of the present embodiment is about 6 weeks. Wherein, the combination of the sustained-release micro-spheres of embodiment 1 and embodiment 11 is with occupation mode：2 kinds of microballoons are prepared respectively, then by above-mentioned Ratio is packaged in two closed cillin bottles respectively, with 1 when using:The decentralized medium of 2 ratios is suspended two kinds of microballoons respectively, then Two kinds of suspensions are extracted out respectively with two different syringes, be then successively injected in different parts again.
Embodiment 37
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 2 and embodiment 12, and embodiment 2 and reality The mass ratio for applying Risperidone in the sustained-release micro-spheres of example 12 is 2：5；The deenergized period of the slow releasing composition of the present embodiment is about 7 weeks. Wherein, the combination of the sustained-release micro-spheres of embodiment 2 and embodiment 12 is with occupation mode：2 kinds of microballoons are prepared respectively, then by above-mentioned Ratio is packaged in two closed cillin bottles respectively, with 2 when using:The decentralized medium of 5 ratios is suspended two kinds of microballoons respectively, wherein A kind of microsphere suspension is first injected, and another microsphere suspension is injected in different parts after 2 hours.
Embodiment 38
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 3 and embodiment 13, and embodiment 3 and reality The mass ratio for applying Risperidone in the sustained-release micro-spheres of example 13 is 3：4；The deenergized period of the slow releasing composition of the present embodiment is about 7 weeks. Wherein, the combination of the sustained-release micro-spheres of embodiment 3 and embodiment 13 is with occupation mode：2 kinds of microballoons are prepared respectively, then by above-mentioned Ratio is packaged in two closed cillin bottles respectively, with 3 when using:The decentralized medium of 4 ratios is suspended two kinds of microballoons respectively, wherein A kind of microsphere suspension is first injected, and another microsphere suspension is injected in same area after 8 hours.
Embodiment 39
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the A Li piperazines of 2 kinds of different release behaviors Azoles sustained-release micro-spheres composition binary combination, i.e., combined by embodiment 4 and the sustained-release micro-spheres of embodiment 14, and embodiment 4 delay The mass ratio for releasing Aripiprazole in the lauroyl Aripiprazole in microballoon and the sustained-release micro-spheres of embodiment 14 is 2：5；The present embodiment The deenergized period of slow releasing composition be about 7 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 4 and embodiment 14 and user Formula is：2 kinds of microballoons are prepared respectively, are then mixed according to the above ratio, are packaged in a closed cillin bottle, are directly injected into when using Decentralized medium is suspended, and then injects.
Embodiment 40
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the sharp piperazine of handkerchief of 2 kinds of different release behaviors The binary combination of ketone sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 5 and embodiment 15, and embodiment 5 Palmitic acid 9-hydroxy-risperidone in the sustained-release micro-spheres and mass ratio of 9-hydroxy-risperidone is 3 in the sustained-release micro-spheres of embodiment 15：5；This implementation The deenergized period of the slow releasing composition of example is about 8 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 5 and embodiment 15 is with using Mode is：2 kinds of microballoons are prepared respectively, are then mixed according to the above ratio, are packaged in a closed cillin bottle, are directly noted when using Enter decentralized medium suspension, then inject.
Embodiment 41
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, the i.e. sustained-release micro-spheres of embodiment 16 and embodiment 21 are combined, and embodiment 16 and reality The mass ratio for applying Risperidone in the sustained-release micro-spheres of example 21 is 1：1；The deenergized period of the slow releasing composition of the present embodiment is about 8 weeks. Wherein, the combination of the sustained-release micro-spheres of embodiment 16 and embodiment 21 is with occupation mode：2 kinds of microballoons are prepared respectively, then by upper Ratio mixing is stated, is packaged in a closed cillin bottle, decentralized medium suspension is directly injected into when using, is then injected.
Embodiment 42
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Olanzapine of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, the i.e. sustained-release micro-spheres of embodiment 17 and embodiment 22 are combined, and embodiment 17 and reality The mass ratio for applying Olanzapine in the sustained-release micro-spheres of example 22 is 1：1；The deenergized period of the slow releasing composition of the present embodiment is about 8 weeks. Wherein, the combination of the sustained-release micro-spheres of embodiment 17 and embodiment 22 is with occupation mode：2 kinds of microballoons are prepared respectively, then by upper Ratio mixing is stated, is packaged in a closed cillin bottle, decentralized medium suspension is directly injected into when using, is then injected.
Embodiment 43
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is 2 kinds of different release behaviors according to a piperazine The binary combination of azoles sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 18 and embodiment 23, and embodiment 18 Mass ratio with the Entecavir in the sustained-release micro-spheres of embodiment 23 is 1：1；The deenergized period of the slow releasing composition of the present embodiment About 9 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 18 and embodiment 23 is with occupation mode：2 kinds of microballoons are prepared respectively, Then mix, be packaged in a closed cillin bottle according to the above ratio, decentralized medium suspension is directly injected into when using, is then noted Penetrate.
Embodiment 44
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Olanzapine of 2 kinds of different release behaviors Sustained-release micro-spheres composition binary combination, i.e., combined by embodiment 17 and the sustained-release micro-spheres of embodiment 24, and embodiment 17 delay The mass ratio for releasing the Olanzapine in microballoon and the pamoic acid Olanzapine in the sustained-release micro-spheres of embodiment 24 is 4：5；The present embodiment The deenergized period of slow releasing composition be about 9 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 17 and embodiment 24 and user Formula is：2 kinds of microballoons are prepared respectively, are then mixed according to the above ratio, are packaged in a closed cillin bottle, are directly injected into when using Decentralized medium is suspended, and then injects.
Embodiment 45
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, the i.e. sustained-release micro-spheres of embodiment 19 and embodiment 26 are combined, and embodiment 19 and reality The mass ratio for applying Risperidone in the sustained-release micro-spheres of example 26 is 5：4；The deenergized period of the slow releasing composition of the present embodiment is about 9 weeks. Wherein, the combination of the sustained-release micro-spheres of embodiment 19 and embodiment 26 is with occupation mode：2 kinds of microballoons are prepared respectively, then by upper Ratio mixing is stated, is packaged in a closed cillin bottle, decentralized medium suspension is directly injected into when using, is then injected.
Embodiment 46
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 2 kinds of different release behaviors The binary combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 20 and embodiment 28, and the He of embodiment 20 The mass ratio of Risperidone is 5 in the sustained-release micro-spheres of embodiment 28：4；The deenergized period of the slow releasing composition of the present embodiment is about 9 Week.Wherein, the combination of the sustained-release micro-spheres of embodiment 20 and embodiment 28 is with occupation mode：2 kinds of microballoons are prepared respectively, are then pressed Aforementioned proportion is mixed, and is packaged in a closed cillin bottle, and decentralized medium suspension is directly injected into when using, is then injected.
Embodiment 47
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 3 kinds of different release behaviors The triple combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 1, embodiment 6 and embodiment 25, and is implemented The mass ratio of Risperidone is 2 in the sustained-release micro-spheres of example 1, embodiment 6 and embodiment 25：2：5；The slow releasing composition of the present embodiment Deenergized period is about 9 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 1, embodiment 6 and embodiment 25 and occupation mode are：Point 3 kinds of microballoons are not prepared, are then mixed according to the above ratio, be packaged in a closed cillin bottle, scattered Jie is directly injected into when using Matter is suspended, and then injects.
Embodiment 48
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, what its risperidone slow-release microsphere for being was constituted Triple combination, i.e., combined by the sustained-release micro-spheres of embodiment 2, embodiment 7 and embodiment 26, and embodiment 2, the and of embodiment 7 The mass ratio of Risperidone is 2 in the sustained-release micro-spheres of embodiment 26：3：4；The deenergized period of the slow releasing composition of the present embodiment is 9 Week.Wherein, the combination of the sustained-release micro-spheres of embodiment 2, embodiment 7 and embodiment 26 and occupation mode are：Prepare respectively 3 kinds it is micro- Ball, is then mixed according to the above ratio, is packaged in a closed cillin bottle, decentralized medium suspension is directly injected into when using, then Injection.
Embodiment 49
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 3 kinds of different release behaviors The triple combination of sustained-release micro-spheres composition, i.e. the sustained-release micro-spheres of embodiment 3, embodiment 9 and embodiment 28 are combined, and embodiment 3rd, the mass ratio of Risperidone is 3 in the sustained-release micro-spheres of embodiment 9 and embodiment 28：2：5；The slow releasing composition of the present embodiment is released The cycle of putting is about 10 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 3, embodiment 9 and embodiment 28 and occupation mode are：Point 3 kinds of microballoons are not prepared, are then mixed according to the above ratio, be packaged in a closed cillin bottle, scattered Jie is directly injected into when using Matter is suspended, and then injects.
Embodiment 50
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 3 kinds of different release behaviors The triple combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 1, embodiment 11 and embodiment 27, and real The mass ratio for applying Risperidone in the sustained-release micro-spheres of example 1, embodiment 11 and embodiment 27 is 2：4：5；The controlled release composition of the present embodiment The deenergized period of thing is about 11 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 1, embodiment 11 and embodiment 27 and user Formula is：3 kinds of microballoons are prepared respectively, are then mixed according to the above ratio, are packaged in a closed cillin bottle, are directly injected into when using Decentralized medium is suspended, and then injects.
Embodiment 51
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the palmitic acid of 3 kinds of different release behaviors 9-hydroxy-risperidone sustained-release micro-spheres composition triple combination, i.e., embodiment 5, embodiment 10 and embodiment 29 sustained-release micro-spheres combination and Into, and the mass ratio of palmitic acid 9-hydroxy-risperidone is 1 in the sustained-release micro-spheres of embodiment 5, embodiment 10 and embodiment 29：1：2；This reality The deenergized period for applying the slow releasing composition of example is about 12 weeks.Wherein, the sustained-release micro-spheres of embodiment 5, embodiment 10 and embodiment 29 Combination be with occupation mode：3 kinds of microballoons are prepared respectively, are then mixed according to the above ratio, are packaged in a closed cillin bottle, Decentralized medium suspension is directly injected into when using, is then injected.
Embodiment 52
A kind of shipwreck of the present embodiment is molten/microsolubility pharmaceutical sustained release compositions, it is the Risperidone of 3 kinds of different release behaviors The triple combination of sustained-release micro-spheres composition, i.e., combined by the sustained-release micro-spheres of embodiment 1, embodiment 11 and embodiment 30, and real The mass ratio for applying Risperidone in the sustained-release micro-spheres of example 1, embodiment 11 and embodiment 30 is 2：4：7；The controlled release composition of the present embodiment The deenergized period of thing is about 13 weeks.Wherein, the combination of the sustained-release micro-spheres of embodiment 1, embodiment 11 and embodiment 30 and user Formula is：3 kinds of microballoons are prepared respectively, are then mixed according to the above ratio, are packaged in a closed cillin bottle, are directly injected into when using Decentralized medium is suspended, and then injects.
Embodiment 53
The vitro release of sustained-release micro-spheres and slow releasing composition is determined, and method is as follows：
The slow releasing composition 20mg of sustained-release micro-spheres and embodiment 31-54 that precision weighs embodiment 1-30 puts 200mL centrifugations Guan Zhong, plus pH7.4PBS (contain 0.05% Tween 80,0.05% sodium azide) 50mL, are placed in 37 DEG C, 150rpm waters bath with thermostatic control shake Swing in device, be placed in after preset time point takes out 1mL release liquids, supplement equivalent fresh medium in thermostatic control oscillator vibration and continue to release Degree of putting tests (n=3).Take out liquid and release amount of medicine is detected using high performance liquid chromatography (HPLC), calculate release rate.As a result such as Shown in table 1-6.
The release in vitro rate of the embodiment 1-10 of table 1 sustained-release micro-spheres
The release in vitro rate of the embodiment 11-20 of table 2 sustained-release micro-spheres
The release in vitro rate of the embodiment 21-30 of table 3 sustained-release micro-spheres
The release in vitro rate of the embodiment 31-38 of table 4 slow releasing composition
The release in vitro rate of the embodiment 39-45 of table 5 slow releasing composition
The release in vitro rate of the embodiment 46-52 of table 6 slow releasing composition
The slow releasing composition that can be seen that the present invention from table 4-6 microsphere composition release in vitro data is relatively single Sustained-release micro-spheres substantially shorten, even eliminate the sustained release phase, and without phenomenon of burst release, patient is avoided or reduce injection clothes The trouble of oral ordinary preparation is still needed to after medicine；Meanwhile, by the slow releasing composition of the present invention, deenergized period is substantially than single sustained release Microballoon is long, essentially the superposition of the acquisition time of unit sustained-release micro-spheres, can substantially reduce administration frequency, for because of reasons such as work Can not frequently arrive hospital receive administration patient bring great convenience, dramatically increase to drug compliance and convenience.
The zoopery of embodiment 54
(1) take 12 weight in 10kg ± 0.5kg beasle dog, male and female half and half are equally divided into 2 groups, intramuscular injection is implemented The 1.2ml 0.5%CMC of the risperidone slow-release microsphere of example 6 and the slow releasing composition (containing Risperidone 18mg) of embodiment 31 are water-soluble The suspension of liquid, takes respectively at 1h, 6h, 12h, 1d, 7d, 14d, 21d, 28d, 35d, 42d, 49d and 56d in rabbit auricular vein Blood sample 1.5mL.The blood sample of all collections after 8000rpm centrifugations 10min in taking -70 DEG C of supernatant to freeze, then using ability Domain known method surveys the concentration of Risperidone in above-mentioned all blood samples, as a result sees Fig. 1.
(2) take 12 weight in 10kg ± 0.5kg beasle dog, male and female half and half are equally divided into 2 groups, intramuscular injection is implemented The risperidone slow-release microsphere (18mg containing Risperidone, was administered once every 2 weeks, totally 3 times) and the slow releasing composition of embodiment 47 of example 6 The suspension of the 1.2ml 0.5%CMC aqueous solution of (45mg containing Risperidone is administered once), respectively at 1h, 6h, 12h, 1d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 70d, 77d, 84d, 91d and 98d are in rabbit auricular vein blood sampling 1.5mL. The blood sample of all collections after 8000rpm centrifugations 10min in taking -70 DEG C of supernatant to freeze, then using means known in the art The concentration of Risperidone in above-mentioned all blood samples is surveyed, Fig. 2 is as a result seen.
By Fig. 1-2 it can be seen that, slow releasing composition microballoon of the invention shows good slow release effect, increases quickly after administration Concentration is healed, and without phenomenon of burst release, and need the time of similar 2 weeks to reach the unit sustained-release micro-spheres in combination To corresponding blood concentration, there is sustained release phenomenon, it is consistent with release in vitro behavior outcome.In Fig. 1, the combination of embodiment 31 Blood concentration after thing single-dose continues of about 35 days in the range of 2-7ng/mL, and the unit microballoon of embodiment 6 is due to early stage Substantially do not discharge, the blood concentration after single-dose continues about 28 days in the range of 2-14ng/mL, but slow releasing composition is given Blood concentration is smaller in longer time section fluctuation after medicine, and the blood concentration fluctuation of unit microballoon is obvious.It is real in Fig. 2 Apply the blood concentration after the composition single-dose of example 47 in the range of 2-7ng/mL continue of about 70 days, and the microballoon of embodiment 6 by Do not discharged substantially in early stage, the blood concentration after 3 administrations is continuously 63 days in the range of 2-13ng/mL.Although unit is micro- Ball can also be maintained at certain limit in certain period of time, but need to carry out multiple dosing.Comparatively, it is of the invention many First composition has more preferable action effect, quickly reaches therapeutic plasma concentrations after can injecting, and can maintain longer time, Mitigate side effect, administration dosage period can be extended, reduce administration frequency, so as to be conducive to improving sufferer compliance, convenience.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than the present invention is protected The limitation of scope is protected, although being explained in detail with reference to preferred embodiment to the present invention, one of ordinary skill in the art should Understand, technical scheme can be modified or equivalent substitution, without departing from the essence of technical solution of the present invention And scope.

Claims (10)

1. a kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：Including the different water of two or more release behaviors Indissoluble/microsolubility medicament slow-release microsphere.
2. shipwreck as claimed in claim 1 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：The shipwreck is molten/slightly soluble Property pharmaceutical sustained release compositions include without obvious delay acquisition time or sustained release phase it is shorter, and pharmaceutical release time be 2-3 weeks Sustained-release micro-spheres A and with the sustained-release micro-spheres B that 2-3 weeks sustained release phase and pharmaceutical release time are 2-3 weeks；
Or including with the sustained-release micro-spheres C and the sustained-release micro-spheres that 2-3 weeks sustained release phase and pharmaceutical release time are 4-5 weeks A；
Or including with 4 weeks sustained release phases and pharmaceutical release time for 4-5 weeks sustained-release micro-spheres E and release without obvious delay Put the phase or the sustained release phase is shorter and pharmaceutical release time is the sustained-release micro-spheres D of 4-5 weeks；
Or including the sustained-release micro-spheres A, sustained-release micro-spheres B and sustained-release micro-spheres E；
Or including the sustained-release micro-spheres A, sustained-release micro-spheres C and with 5-6 weeks sustained release phase and pharmaceutical release time be 4 weeks with On sustained-release micro-spheres F.
3. shipwreck as claimed in claim 2 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：The sustained-release micro-spheres A, Sustained-release micro-spheres B, sustained-release micro-spheres C, sustained-release micro-spheres D, sustained-release micro-spheres E and sustained-release micro-spheres F preparing raw material include following weight parts Component：Shipwreck is molten/30-60 parts of microsolubility medicine, 40-70 parts of slightly water-soluble polymer.
4. shipwreck as claimed in claim 3 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：The sustained-release micro-spheres A, Under at least one of sustained-release micro-spheres B, sustained-release micro-spheres C, sustained-release micro-spheres D, sustained-release micro-spheres E, sustained-release micro-spheres F preparing raw material include State the component of parts by weight：Shipwreck is molten/35-55 parts of microsolubility medicine, 45-65 parts of slightly water-soluble polymer.
5. shipwreck as described in claim 3 or 4 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：The shipwreck is molten/ Microsolubility medicine include Risperidone, 9-hydroxy-risperidone, Aripiprazole, Iloperidone, according to a piperazine azoles, Ziprasidone, Anastrozole, many Donepezil, Olanzapine, naltrexone, haloperole, taxol, docetaxel, Entecavir or their derivative.
6. shipwreck as described in claim 3 or 4 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：The slightly water-soluble Polymer is at least one of polylactide, PLGA, their copolymers with polyethylene glycol.
7. shipwreck as claimed in claim 6 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：The sustained-release micro-spheres A In, slightly water-soluble polymer is PLGA, and the weight average molecular weight of PLGA is 20000-40000Da, viscosity is that 0.23-0.42dL/g, wherein lactide and glycolide mol ratio are 70:30-80:20；Institute State in sustained-release micro-spheres B, slightly water-soluble polymer is PLGA, and the weight of PLGA is equal Molecular weight is 41000-100000Da, and viscosity is that 0.42-0.9dL/g, wherein lactide and glycolide mol ratio are 70:30- 80:20；In the sustained-release micro-spheres C, slightly water-soluble polymer is PLGA, and lactide coglycolide copolymerization The weight average molecular weight of thing is 35100-44900Da, and viscosity is 0.38-0.46dL/g, wherein lactide and glycolide mol ratio For 80:20-90:10；In the sustained-release micro-spheres D, slightly water-soluble polymer is PLGA, and lactide-second The weight average molecular weight of lactide copolymers is 20000-35000Da, and viscosity is 0.23-0.38dL/g, wherein lactide and glycolide Mol ratio be 80:20-90:10；In the sustained-release micro-spheres E, slightly water-soluble polymer is PLGA, and The weight average molecular weight of PLGA is 45000-65000Da, and viscosity is 0.38-0.58dL/g, wherein lactide Mol ratio with glycolide is 80:20-90:10；In the sustained-release micro-spheres F, slightly water-soluble polymer is that polylactide or third are handed over Ester-glycolide copolymer, and the weight average molecular weight of slightly water-soluble polymer is 20000-60000Da, viscosity is 0.23- 0.54dL/g, wherein lactide and glycolide mol ratio are 90:10-100:0.
8. shipwreck as claimed in claim 7 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：As follows in (a)~(f) At least one of：
(a) in the sustained-release micro-spheres A, the weight average molecular weight of PLGA is 20000-35000Da, and viscosity is 0.23-0.38dL/g, wherein lactide and glycolide mol ratio are 75:25；
(b) in the sustained-release micro-spheres B, the weight average molecular weight of PLGA is 50000-900000Da, and viscosity is 0.49-0.0.81dL/g, wherein lactide and glycolide mol ratio are 75:25；
(c) in the sustained-release micro-spheres C, the weight average molecular weight of PLGA is 38000-42000Da, and viscosity is 0.40-0.43dL/g, wherein lactide and glycolide mol ratio are 85:15；
(d) in the sustained-release micro-spheres D, the weight average molecular weight of PLGA is 25000-30000Da, and viscosity is 0.27-0.34dL/g, wherein lactide and glycolide mol ratio are 85:15；
(e) in the sustained-release micro-spheres E, the weight average molecular weight of PLGA is 45000-60000Da, and viscosity is 0.42-0.54dL/g, wherein lactide and glycolide mol ratio are 85:15；
(f) in the sustained-release micro-spheres F, the weight average molecular weight of slightly water-soluble polymer is 25000-55000Da, and viscosity is 0.28- 0.52dL/g。
9. shipwreck as described in any one of claim 3~8 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：The water When indissoluble/microsolubility pharmaceutical sustained release compositions include sustained-release micro-spheres A and sustained-release micro-spheres B, sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility The weight ratio of medicine and sustained-release micro-spheres B reclaimed waters indissoluble/microsolubility medicine is 1~3：1~3；The shipwreck is molten/and microsolubility medicine delays When releasing composition including sustained-release micro-spheres A and sustained-release micro-spheres C, in sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine and sustained-release micro-spheres C Shipwreck is molten/and the weight ratio of microsolubility medicine is 1~3：2~5；The shipwreck is molten/and microsolubility pharmaceutical sustained release compositions include sustained release During microballoon D and sustained-release micro-spheres E, sustained-release micro-spheres D reclaimed waters indissoluble/microsolubility medicine and sustained-release micro-spheres E reclaimed waters indissoluble/microsolubility medicine Weight ratio be 1：1；The shipwreck is molten/and microsolubility pharmaceutical sustained release compositions are when including sustained-release micro-spheres D and sustained-release micro-spheres F, sustained release The weight ratio of microballoon D reclaimed waters indissoluble/microsolubility medicine and sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine is 5：4；The shipwreck When molten/microsolubility pharmaceutical sustained release compositions include the sustained-release micro-spheres A, sustained-release micro-spheres B and sustained-release micro-spheres E, the sustained-release micro-spheres The weight ratio of A, sustained-release micro-spheres B and sustained-release micro-spheres E reclaimed waters indissoluble/microsolubility medicine is sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine Thing：Sustained-release micro-spheres B reclaimed waters indissoluble/microsolubility medicine：Sustained-release micro-spheres E reclaimed waters indissoluble/microsolubility medicine=2：2：5；The shipwreck When molten/microsolubility pharmaceutical sustained release compositions include the sustained-release micro-spheres A, sustained-release micro-spheres B and sustained-release micro-spheres F, the sustained-release micro-spheres The weight ratio of A, sustained-release micro-spheres B and sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine is sustained-release micro-spheres A reclaimed waters indissoluble/microsolubility medicine Thing：Sustained-release micro-spheres B reclaimed waters indissoluble/microsolubility medicine：Sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine=1~3：1~3：2~5； The shipwreck is molten/and microsolubility pharmaceutical sustained release compositions are when including the sustained-release micro-spheres A, sustained-release micro-spheres C and sustained-release micro-spheres F, described The weight ratio of sustained-release micro-spheres A, sustained-release micro-spheres C and sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine be sustained-release micro-spheres A reclaimed waters indissoluble/ Microsolubility medicine：Sustained-release micro-spheres C reclaimed waters indissoluble/microsolubility medicine：Sustained-release micro-spheres F reclaimed waters indissoluble/microsolubility medicine=2：4：5~ 7。
10. shipwreck as described in any one of claim 3~9 is molten/microsolubility pharmaceutical sustained release compositions, it is characterised in that：It is described The preparation method of sustained-release micro-spheres comprises the following steps：
(1) by shipwreck it is molten/microsolubility medicine and slightly water-soluble polymer be dissolved in organic solvent, formed in oil phase；
(2) surfactant is dissolved in aqueous medium, forms outer aqueous phase；
(3) the interior oil phase for obtaining step (1) is added in outer aqueous phase, and emulsion is made, and is then carried by solvent evaporation or solvent Taking solidifies the particulate in solution, collects particulate, washs and dries, obtains the sustained-release micro-spheres.
CN201710160949.1A 2017-03-17 2017-03-17 A kind of shipwreck is molten/microsolubility pharmaceutical sustained release compositions Pending CN106963746A (en)

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