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WO2018137631A1 - Sparingly water-soluble or slightly water-soluble drug sustained release composition and preparation method therefor - Google Patents

Sparingly water-soluble or slightly water-soluble drug sustained release composition and preparation method therefor Download PDF

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Publication number
WO2018137631A1
WO2018137631A1 PCT/CN2018/073901 CN2018073901W WO2018137631A1 WO 2018137631 A1 WO2018137631 A1 WO 2018137631A1 CN 2018073901 W CN2018073901 W CN 2018073901W WO 2018137631 A1 WO2018137631 A1 WO 2018137631A1
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Prior art keywords
water
release
insoluble
slightly soluble
soluble drug
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PCT/CN2018/073901
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French (fr)
Chinese (zh)
Inventor
刘锋
赖树挺
郑阳
曹付春
连远发
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广州帝奇医药技术有限公司
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Publication of WO2018137631A1 publication Critical patent/WO2018137631A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/5169—Proteins, e.g. albumin, gelatin

Definitions

  • the invention relates to a sustained-release pharmaceutical composition and a preparation method thereof, in particular to a water-insoluble/slightly soluble drug sustained-release composition and a preparation method thereof.
  • biodegradable polymer microspheres have become one of the important research fields of new drug delivery systems, such as polylactide (PLA), lactide-glycolide copolymer (PLGA), etc.
  • the microspheres prepared from the skeleton material can be used as a carrier for the long-acting preparation, and can be administered to the human body or the animal by intramuscular or subcutaneous injection, which can limit the drug release rate and release cycle, and can be effectively maintained for a long time by only one administration.
  • the concentration of the therapeutic drug can minimize the total dose of the drug required for the treatment, and can improve the patient's medication compliance.
  • the long-acting antipsychotic drug Risperidal Consta (Hengde) developed based on the technology disclosed in the patent CN1137756 uses PLGA with a molecular weight of about 150 kDa as a carrier and risperidone as an API, which is injected intramuscularly every 2 weeks.
  • the preparation is effective in avoiding the peak-to-valley concentration produced by daily medication, but only a small amount of drug is released on the first day, followed by a drug release stagnation period of about 3 weeks, so the patient needs to be within 3 weeks after the injection of the microsphere.
  • Oral administration of common dosage forms can achieve therapeutic effects, inconvenient clinical use, and poor patient compliance.
  • risperidone is a poorly water-soluble/slightly soluble drug
  • the initial drug release is small, resulting in a release stagnation period of the drug blood drug concentration, with drug loading.
  • the drug release stagnation period is gradually reduced.
  • the drug loading amount reaches a certain range, the drug is released after administration.
  • patent CN101653422 discloses a risperidone microsphere composition which can be released for several weeks, and eliminates the drug stagnation period by increasing the drug loading rate (45% or more), but the formulation stability is poor, and after long-term storage, the microspheres are in vivo. The release behavior will change significantly.
  • the ratio of hydrophobic component (LA) to hydrophilic component (GA) and molecular weight have a significant effect on the release of water-soluble drugs, and the proportion of hydrophilic components of PLGA.
  • risperidone microspheres which are immediately released into the body are prepared.
  • this polymer combination tends to cause surface collapse during radiation sterilization, because PLGAs with different monomer ratios and molecular weights have different degrees of degradation under irradiation; further, PLGAs with lower molecular weight and higher GA monomer ratio Degradation is more likely to occur during storage, which is not conducive to the preservation stability of the preparation. Meanwhile, PLGA excipients with lower molecular weight and higher proportion of GA components are more difficult to prepare and store, and the cost is relatively higher.
  • Patent CN104013578 adds isopropyl palmitate and butyl stearate to prepare paliperidone derivative sustained-release microspheres to change the structure of the microspheres and the crystalline state of the drug, so that the drug is closer to the core of the microsphere, and The formation of a dense shell structure on the surface of the sphere limits the diffusion of the drug. Although this method avoids the initial burst release phenomenon, it causes a delayed release of about 5 days, which is inconvenient for clinical use and poor patient compliance.
  • the object of the present invention is to overcome the above-mentioned deficiencies in the prior art and to provide a delayed release or burst release phenomenon after administration, capable of maintaining therapeutic blood concentration for several weeks or longer, and having good A water-insoluble/slightly soluble drug sustained-release composition that releases properties and better stability. Meanwhile, another object of the present invention is to provide a method for preparing the water-insoluble/slightly soluble drug sustained-release composition.
  • the technical solution adopted by the present invention is: a water-insoluble/slightly soluble drug sustained-release composition
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition comprises a release regulator .
  • the preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present invention comprises a non-solvent type preparation raw material and a solvent-type preparation raw material, wherein the non-solvent type preparation raw material comprises a release regulator, excluding a surfactant; the solvent type preparation raw material Includes aqueous media and organic solvents.
  • the preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present invention is added with a release regulating agent, which can effectively adjust the release of the water-insoluble/slightly soluble drug in the sustained-release composition.
  • the speed makes the water-insoluble/slightly soluble drug sustained-release composition of the invention have no obvious release delay period or burst release after administration, has good sustained-release properties, and can maintain stability for several weeks or more. It is released and has good stability and can maintain its release behavior after long-term storage.
  • the release regulator in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition, the release regulator has a mass percentage The content is from 0.1 to 10%.
  • the quality of the release modifier in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition The percentage is from 0.5 to 8%.
  • the release modifier has a mass percentage of 0.5 to 8%, which allows the sustained release composition to have a better sustained release effect and/or stability.
  • a more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention the quality of the release modifier in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition
  • the percentage is from 1 to 6%.
  • the release modifier has a mass percentage of from 1 to 6%, which allows the sustained release composition to have a better sustained release effect and/or stability.
  • the release modifier is an organic lipophilic substance and/or an organic hydrophilic substance.
  • the organic lipophilic substance is finally converted into carbon dioxide and water in the body, which can cause pores on the surface and inside of the microsphere, increase the permeability of the body fluid, and promote the dissolution of the water-insoluble/slightly soluble drug, thereby avoiding release after a period of time. Very slow release platform.
  • the organic hydrophilic substance can also produce fine pores on the surface and inside of the microspheres, and these pores can increase the permeability of the body fluid after the microspheres are injected into the body, and improve the dissolution rate of the water-insoluble/slightly soluble drug, which is greatly shortened or Avoid release stagnation, and also promote the transfer of degradation products inside the microsphere.
  • the sustained-release composition of the present invention not only avoids the initial burst release phenomenon but also avoids water-soluble/slightly soluble drugs due to the release of the organic lipophilic substance or the organic hydrophilic substance. Delayed release platform after first-day release when the molecular weight of the polymer is relatively large, maintaining the effective blood concentration, and also solving the delay of preparing long-period sustained-release microspheres by using PLGA with high molecular weight and high LA component as carrier The problem of release.
  • the organic hydrophilic substance when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is in the The mass percentage of the release modifier is 30% or more. In a more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is in the The mass percentage of the release regulator is 50% or more.
  • the release modifier when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is in the The mass percentage of the release regulator is 70% or more.
  • the organic lipophilic substance is at least one of a fatty acid, a fatty acid ester, and a fat; the organic hydrophilic substance is an alcohol At least one of a sugar, an amino acid, a protein, and polyvinylpyrrolidone.
  • the organic lipophilic substance is a fatty acid; and the organic hydrophilic substance is at least one of an alcohol and polyvinylpyrrolidone.
  • the fatty acid is preferably, but not limited to, a C12-C24 alkanoic acid and derivatives thereof, including but not limited to oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, lignin acid, preferably Stearic acid, behenic acid.
  • the alcohol is preferably, but not limited to, polyethylene glycol (PEG) having a molecular weight of 400-6000 Da, such as PEG 600, PEG 1000, PEG 2000, PEG 4000, PEG 6000, preferably PEG having a molecular weight of 400 to 4000 Da, more preferably PEG having a molecular weight of 400 to 3000 Da. .
  • the fatty acid is oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, woody At least one of the acids;
  • the alcohol is a polyethylene glycol having a molecular weight of 400 to 6000 Da.
  • a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention characterized in that the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition further comprises water-insoluble/slightly soluble Drugs and water insoluble polymers.
  • the poorly water-soluble polymer of the present invention is a biodegradable, biocompatible, water-insoluble polymer.
  • a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition, the water-insoluble/slightly soluble drug
  • the mass percentage is 25-60%, and the mass percentage of the poorly water-soluble polymer is 39.9-74.9%; preferably, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition,
  • the water-insoluble/slightly soluble drug has a mass percentage of 30 to 55%, and the water-insoluble polymer has a mass percentage of 44.9-69.9%; preferably, the water-insoluble/slightly soluble drug
  • the water-insoluble/slightly soluble drug has a mass percentage of 35 to 50%, and the water-insoluble polymer has a mass percentage of 49.9 to 64.9%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention includes, but is not limited to, risperidone, paliperidone, aripiprazole, and ipan At least one of ketone, epiliperazole, ziprasidone, anastrozole, donepezil, olanzapine, naltrexone, haloperidol, paclitaxel, entecavir, docetaxel, and derivatives thereof .
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention includes, but is not limited to, risperidone, paliperidone, aripiprazole, and y. At least one of phenyllicone, epiliperazole, donepezil, olanzapine, haloperidol, paclitaxel, entecavir, docetaxel, and derivatives thereof.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention includes, but is not limited to, risperidone, paliperidone, aripiprazole, and y. At least one of phenyllicone, entecavir, epiliperazole, and derivatives thereof.
  • the derivative includes, but is not limited to, paliperidone palmitate, aripiprazole lauroyl, haloperidol citrate, olanzapine pamoate, ziprasidone mesylate.
  • the poorly water-soluble polymer is a polyester, a polycarbonate, a polyacetal, a polyanhydride, a polyhydroxy fatty acid, and copolymerization thereof. At least one of a substance or a blend.
  • the poorly water-soluble polymer is polylactide (PLA), polyglycolide (PGA), lactide-B-crossing.
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are At least one of copolymers with polyethylene glycol.
  • the poorly water-soluble polymer is in a polylactide (PLA) or a lactide-glycolide copolymer (PLGA). At least one.
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are The weight average molecular weight of the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol in at least one of copolymers with polyethylene glycol Both are 25000-150000Da.
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of 30,000 to 125,000 Da. More preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of from 35,000 to 100,000 Da.
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are When at least one of copolymers with polyethylene glycol, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and the copolymer of polyethylene glycol have a viscosity 0.25-1.2 dL/g (test conditions were ⁇ 0.5% (w/v), CHCl3, 25 °C).
  • the polylactide (PLA), lactide-glycolide copolymer (PLGA), and their copolymers with polyethylene glycol have a viscosity of 0.3-1.0 dL/g (test conditions are -0.5) % (w/v), CHCl3, 25 ° C). More preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and the copolymer of these and polyethylene glycol have a viscosity of 0.35-0.9 dL/g (test condition is ⁇ 0.5% (w/v), CHCl3, 25 ° C).
  • the molecular chain of the poorly water-soluble polymer carries an anionic or cationic group or does not carry an anionic or cationic group.
  • the poorly water soluble polymer has a terminal carboxyl group or a terminal ester group. More preferably, the biodegradable and biocompatible water poorly soluble polymer has a terminal carboxyl group.
  • the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), In at least one of the copolymers with polyethylene glycol, the molar ratio of lactide to glycolide is from 100:0 to 50:50.
  • the poorly water-soluble polymer is at least one of polylactide (PLA), lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol, wherein The molar ratio of lactide to glycolide is from 100:0 to 65:35.
  • the poorly water-soluble polymer is at least one of a polylactide (PLA), a lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol, wherein The molar ratio of lactide to glycolide is from 100:0 to 75:25.
  • PLA polylactide
  • PLGA lactide-glycolide copolymer
  • molar ratio of lactide to glycolide is from 100:0 to 75:25.
  • the water-insoluble polymer may be a single polymer or a mixture of a plurality of polymers.
  • a molar ratio of lactide (LA) to glycolide (GA) and a combination of PLGA and PLA having the same molecular weight but different carrying groups molar ratio of lactide (LA) to glycolide (GA)
  • a combination of PLGA and PLA having the same molecular weight and the same carrier group but different molar ratio of lactide to glycolide, and
  • the difference in the percentage of glycolide is not more than 20%; the molecular weight, the carrier group and the combination of PLGA and PLA which are different in the molar ratio of lactide to glycolide, and the molecular weight difference is not more than 20kD
  • the molecular weight described above is a weight average molecular weight, which is a value obtained by gel permeation chromatography (GPC) measurement; the viscosity is a value obtained by an Ubbelohde viscometer measurement.
  • GPC gel permeation chromatography
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition further comprises an excipient, the shaping
  • the mass percentage of the agent in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition is 0 to 8%.
  • the water-insoluble/slightly soluble drug sustained release composition of the present invention may further comprise one or more excipients.
  • excipients can impart other characteristics to the active drug or microparticles, such as increasing the stability of the microparticles, active drug or carrier, promoting controlled release of the active drug from the microparticles, or modulating the permeability of the biological tissue of the active drug.
  • Excipients described in the present invention include, but are not limited to, antioxidants, buffers, and the like.
  • the excipient includes a buffer and an antioxidant
  • the buffering agent is at least one of an organic acid and a mineral acid salt, and the mass percentage of the buffering agent in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition is 0 to 5%; preferably, the buffering agent is in a non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition in a mass percentage of 0 to 3%; preferably, the buffering agent is The non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition has a mass percentage of 0 to 2%;
  • the antioxidants are tert-butyl-p-hydroxyanisole, dibutylphenol, tocopherol, isopropyl myristate, tocopheryl daacetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butyl Hydroxyguanidine, hydroxycoumarin, butylated hydroxytoluene, decanoic acid fatty acid ester, propyl hydroxybenzoate, hydroxybutanone, vitamin E, vitamin E-TPGS, ⁇ -hydroxybenzoate At least one; the antioxidant is in a non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition in a mass percentage of 0 to 1%; preferably, the antioxidant is in the The non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition has a mass percentage of 0 to 0.08%; more preferably, the antioxidant is sustained in the water-insoluble/slightly soluble drug.
  • the citric acid fatty acid ester is selected from, for example, ethyl ester, propyl ester, octyl ester, lauryl ester, and the ⁇ -hydroxy benzoate is selected from, for example, methyl ester, ethyl ester, propyl ester, and butyl. Ester and the like.
  • the antioxidant is present in the sustained release composition in an amount effective to remove any free radicals or peroxides produced within the implant.
  • the buffering agent of the present invention includes, but is not limited to, mineral acids and organic acid salts, such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate.
  • mineral acids and organic acid salts such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate.
  • the excipient is added in the inner oil phase.
  • the excipient is a very fine powder, its particle diameter is less than 0.5 ⁇ m, preferably the particle diameter is less than 0.1 ⁇ m, and more preferably the particle diameter is less than 0.05 ⁇ m.
  • the excipient solvent is suspended in the internal oil phase with the inner oil phase or with very small particles.
  • the water-insoluble/slightly soluble drug sustained-release composition is a microsphere or a microparticle.
  • the microspheres are usually used for injection administration, and the microparticles or microspheres can be inhaled into a syringe and injected through a fine needle.
  • the route of delivery is by injection using a fine needle, including subcutaneous, intramuscular, intraocular, and the like.
  • Passing a thin needle means that the needle has a diameter of at least 20 G (inner diameter 580 ⁇ m), generally between about 22 G (inner diameter 410 ⁇ m) and about 30 G (inner diameter 150 ⁇ m), or 30 G or more. It is advantageous to use a needle that is as thin as at least 24G, more advantageously a needle that is as thin as at least 26G.
  • the microspheres have a geometric particle diameter of less than 200 ⁇ m.
  • the microspheres have a particle size of from about 10 to 200 ⁇ m, preferably from 15 to 150 ⁇ m, more preferably from about 20 to 120 ⁇ m.
  • the particle size of the microspheres is measured by a dynamic light scattering method (for example, laser diffraction method) or a microscopic technique (such as scanning electron microscopy).
  • the present invention also provides a preparation method of the poorly water-soluble/slightly soluble drug sustained-release composition as described above.
  • the technical solution adopted by the present invention is as follows: a water-insoluble/slightly soluble solution as described above.
  • a method for preparing a drug sustained release composition comprising the steps of:
  • the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 1-18. %; in the steps (2a) and (2b), the mass percentage of the surfactant in the outer aqueous phase is 0.1 to 10%; in the steps (3a) and (3b), the outer water
  • the volume of the phase is more than 60 times the volume of the inner oil phase.
  • the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 1.5 to 12%; in the steps (2a) and (2b), the mass percentage of the surfactant in the external aqueous phase is 0.5 to 8%; in the steps (3a) and (3b), the outer The volume of the aqueous phase is more than 80 times the volume of the internal oil phase.
  • the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 3 to 10%; in the steps (2a) and (2b), the mass percentage of the surfactant in the outer aqueous phase is from 1 to 7%; in the steps (3a) and (3b), the outer The volume of the aqueous phase is more than 100 times the volume of the internal oil phase.
  • the mass percentage of the poorly water-soluble polymer in the organic solvent varies depending on the type of the polymer, the weight average molecular weight, and the type of the organic solvent, and usually the mass percentage thereof (water poorly soluble polymer mass / organic solvent mass) ⁇ 100%) is 1 to 18%.
  • the outer aqueous phase of the steps (2a) and (2b) contains a surfactant, and the surfactant can increase the organic phase.
  • Wetting properties improving the stability and shape of small liquid beads during emulsification, avoiding re-polymerization of small liquid beads, reducing the number of unencapsulated or partially encapsulated small spherical particles, thereby reducing the initial burst release of the drug during release .
  • the organic solvent in the steps (1a) and (1b) is a halogenated hydrocarbon, a fatty acid ester or an aromatic hydrocarbon.
  • the halogenated hydrocarbon comprises dichloromethane, chloroform, ethyl chloride, tetrachloroethylene, trichloroethylene, dichloroethane, trichloroethane, carbon tetrachloride, fluorocarbon, chlorobenzene (mono, di-, tri-substituted), trichlorofluoromethane;
  • the fatty acid ester comprises ethyl acetate, butyl acetate;
  • the aromatic hydrocarbon comprises benzene, toluene, xylene, benzyl alcohol.
  • the organic solvent can simultaneously dissolve a poorly water-soluble polymer, a poorly water-soluble/slightly soluble drug, a boiling point lower than water, and insoluble or poorly soluble in water.
  • the solvent may be a single organic solvent or a miscible two or more organic solvents.
  • a halogenated aliphatic hydrocarbon solvent is preferred, and at least one of dichloromethane and chloroform is more preferred.
  • the proportion of the organic solvent is different according to different drugs, and is formulated according to actual conditions.
  • the surfactant is an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, and a nonionic surface active agent.
  • At least one of a surfactant, a surface active biomolecule preferably, the surfactant is at least one of an anionic surfactant, a nonionic surfactant, and a surface active biomolecule; more preferably, the surface active
  • the agent is at least one of a nonionic surfactant and a surface active biomolecule
  • the cationic surfactant comprises benzalkonium chloride, cetyltrimethylammonium bromide, lauric acid dimethylbenzyl group Chloroammonium, acylcarnitine hydrochloride, alkylpyridine halide
  • the anionic surfactant comprises an alkyl sulfate (such as sodium lauryl sulfate, ammonium lauryl sulfate, sodium stearyl sulfate) Etc.), potassium laurate, sodium alginate, sodium polyacrylate and its derivatives, alkyl polyepoxyethylene sulfate, sodium dioctyl sulfosucc
  • the polysaccharide includes starch and starch derivatives, methyl cellulose, ethyl cellulose, hydroxy cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and arabic. Gum, chitosan derivative, gellan gum, alginic acid derivative, dextran derivative and amorphous cellulose, preferably hydroxypropyl cellulose, chitosan and its derivatives, amylopectin or dextran And its derivatives.
  • the outer aqueous phase further contains an inorganic salt or an organic salt; the inorganic salt is phosphoric acid, sulfuric acid, acetic acid, or carbonic acid. At least one of a potassium salt or a sodium salt, Tris, MES, HEPES; the inorganic salt or organic salt in the outer aqueous phase in a mass percentage of 0 to 5%.
  • the inorganic salt or the organic salt is contained in the outer aqueous phase in an amount of 0.01 to 4% by mass.
  • the inorganic salt or the organic salt is contained in an amount of 0.05 to 3% by mass in the external aqueous phase.
  • the pH of the outer aqueous phase ranges from 3 to 9; preferably, the pH of the outer aqueous phase ranges from 4 to 9; more preferably, The pH of the outer aqueous phase ranges from 5.5 to 8.5.
  • the water-soluble active substance in the solidification process of the microsphere can be reduced to the aqueous phase, and the mechanism is to increase the osmotic pressure of the external aqueous phase or reduce the active substance in the external water. Solubility in the phase.
  • the method of preparing the emulsion in the steps (3a) and (3b) is the same as the well-known emulsification method, and the production is high.
  • Shear force devices such as magnetic stirrers, mechanical stirrers, high-speed homogenizers, ultrasound systems, membrane emulsifiers, rotor-stator mixers, static mixers, high-pressure homogenizers, etc.
  • organic internal phase and aqueous external phase Mix to form a homogeneous emulsion.
  • the solvent is removed in the steps (3a) and (3b) by the following method:
  • the gas stream blows the surface of the liquid, and controls the contact area of the liquid phase with the gas phase, the rate of emulsion agitation and circulation (such as JP-A-9-221418) to accelerate the evaporation of the organic solvent, preferably the gas stream;
  • the organic solvent e.g., W00183594
  • W00183594 is rapidly evaporated from the hollow fiber membrane
  • the hollow fiber membrane is preferably, for example, a silicone rubber pervaporation film (particularly a pervaporation film prepared from polydimethylsiloxane).
  • the microspheres are separated by centrifugation, sieving or filtration in the steps (3a) and (3b).
  • the method of drying the microspheres in the steps (3a) and (3b) is not particularly limited, and examples thereof include heating, vacuum drying, freeze drying, vacuum drying, and combinations thereof.
  • microparticles or microspheres of the present invention may encapsulate a large amount of the active ingredient, depending on the type and content of the active ingredient, the dosage form, the duration of release, the subject to be administered, the route of administration, the purpose of administration, the target disease and symptoms, and the like. And choose it properly.
  • the dosage can be considered satisfactory as long as the active ingredient can be maintained in the active concentration of the drug for the desired duration in vivo.
  • microspheres When the microspheres are administered as a suspension, they may be in the form of a suspension formulation with a suitable dispersion medium.
  • the dispersion medium includes a nonionic surfactant (or stabilizer), a polyoxyethylene castor oil derivative, a cellulose thickener, sodium alginate, hyaluronic acid, dextrin, and starch. Alternatively, it may be combined with other excipients such as isotonic agents (such as sodium chloride, mannitol, glycerol, sorbitol, lactose, xylitol, maltose, galactose, sucrose, glucose, etc.), pH adjusters.
  • preservatives eg, parabens, propylparaben, benzyl alcohol
  • chlorobutanol e.g., chlorobutanol
  • sorbic acid boric acid, etc., etc.
  • sustained-release injections can also be obtained by dispersing microparticles or microspheres in vegetable oils such as sesame oil and corn oil or vegetable oils supplemented with phospholipids such as lecithin, or in medium chain triglycerides. To obtain an oily suspension.
  • microspheres obtained by the invention can be used in the form of granules, suspensions, implants, injections, adhesives, etc., and can be administered orally or parenterally (intramuscular injection, subcutaneous injection, menstrual injection). Dermal administration, mucosal administration (intracrine, intravaginal, rectal, etc.).
  • the risperidone sustained release composition of the present invention is sufficiently stable to be sustained for several weeks or more, such as up to about 2 weeks, such as up to about 4 weeks, such as up to about 8 weeks, such as up to about 12 weeks, such as long Up to about 24 weeks, such as up to about 48 weeks, or longer, can be adjusted for specific drug properties or treatment needs.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present invention is prepared by adding a release regulator which can effectively adjust the release rate of the water-insoluble/slightly soluble drug in the sustained-release composition. Therefore, the water-insoluble/slightly soluble drug sustained-release composition of the present invention has no obvious release delay period or burst release after administration, has good sustained release property, and can be stably released in a period of several weeks or more. Moreover, it has good stability and can maintain its release behavior after long-term storage.
  • the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention can rapidly and efficiently prepare the water-insoluble/slightly soluble drug sustained-release composition of the present invention.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: entecavir 25%, poorly water soluble polymer: PLGA 74.9%, release regulator: 0.1% mixture of stearic acid and PEG6000.
  • the molar ratio of lactide to glycolide in the PLGA is 90:10, the weight average molecular weight of the PLGA is 25 kDa, the viscosity is 0.24 dL/g, and the PLGA has a terminal ester group; In a mixture of fatty acid and PEG 6000, the mass percentage of the PEG 6000 in the release regulator is 70%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 60 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain entecavir sustained-release microspheres.
  • the entecavir sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 35-105 ⁇ m.
  • the drug loading rate is 22.54%, and the encapsulation efficiency of entecavir is 90.16%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: aripiprazole 27%, poorly water soluble polymer: PLGA 72.5%, release regulator: 0.5% mixture of behenic acid and PEG4000.
  • the mass percentage of the PEG 4000 in the release regulator is 60%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 65 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 9 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain aripiprazole sustained-release microspheres.
  • the aripiprazole sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 32-97 ⁇ m.
  • the drug loading rate is 24.09%, and the entrapment efficiency of aripiprazole is 89.22%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: risperidone 30%, poorly water soluble polymer: PLA 69.2%, release regulator: behenic acid 0.8%.
  • the PLA has a weight average molecular weight of 35 Da and a viscosity of 0.31 dL/g, and the PLGA has a terminal ester group.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 70 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain risperidone sustained release microspheres.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 31-95 ⁇ m.
  • the drug loading rate is 28.11%, and the risperidone encapsulation efficiency is 93.7%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: paliperidone palmitate 33%, poorly water soluble polymer: PLGA 66%, release regulator: 1% stearic acid.
  • the molar ratio of lactide to glycolide in the PLGA is 85:15
  • the weight average molecular weight of the PLGA is 40 kDa
  • the viscosity is 0.35 dL/g
  • the PLGA has a terminal ester group.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 75 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 15 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 7 times with ultrapure water to obtain paliperidone palmitate sustained release microspheres.
  • the sustained release microspheres of paliperidic palmitate obtained in this example have a round shape and a smooth surface, and the particle size is 32-90 ⁇ m.
  • the drug loading rate is 30.25%, and the encapsulation efficiency of paliperidone palmitate is 91.77%. .
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: risperidone 35%, poorly water soluble polymer: PLGA 63%, release regulator: 2% mixture of stearic acid and PEG3000.
  • the molar ratio of lactide to glycolide in the PLGA is 85:15
  • the weight average molecular weight of the PLGA is 50 kDa
  • the viscosity is 0.39 dL/g
  • the PLGA has a terminal carboxyl group
  • the hard fat In a mixture of acid and PEG3000
  • the mass percentage of the PEG 3000 in the release regulator is 30%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 80 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain risperidone sustained release microspheres.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 28-86 ⁇ m.
  • the drug-loading rate is 32.43%, and the encapsulation efficiency of risperidone is 90.08%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% Water-insoluble/slightly soluble drug: paliperidone palmitate 38%, poorly water-soluble polymer: PLGA 59%, release regulator: 3% mixture of lignin acid and PEG2000.
  • the molar ratio of lactide to glycolide in the PLGA is 75:25, the weight average molecular weight of the PLGA is 60 kDa, the viscosity is 0.55 dL/g, and the PLGA has a terminal carboxyl group; the lignin In a mixture of acid and PEG2000, the mass percentage of the PEG 2000 in the release modifier is 80%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 85 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 11 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 3 times with ultrapure water to obtain paliperidone palmitate sustained release microspheres.
  • the sustained release microspheres of paliperidic palmitate obtained in this example have a round shape and a smooth surface, and the particle size is 23-91 ⁇ m.
  • the drug loading rate is determined to be 34.29%, and the encapsulation efficiency of paliperidone palmitate is 90.23%. .
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: aripiprazole 40%, poorly water soluble polymer: PLGA 56%, release regulator: 4% mixture of arachidic acid and polyvinylpyrrolidone.
  • the molar ratio of lactide to glycolide in the PLGA is 75:25, the weight average molecular weight of the PLGA is 70 kDa, the viscosity is 0.60 dL/g, and the PLGA has a terminal ester group;
  • the polyvinylpyrrolidone is present in the release modifier in an amount of 80% by mass.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 90 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 12 minutes, and then stirred (500 rpm, 5 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain aripiprazole sustained-release microspheres.
  • the aripiprazole sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle diameter is 22-93 ⁇ m.
  • the drug loading rate is 35.33%, and the entrapment efficiency of aripiprazole is 88.33%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: paliperidone palmitate 42%, poorly water soluble polymer: PLA 53%, release regulator: PEG1200 5%.
  • the PLA is an equal mixture of PLA (100/0, 80 kDa, 0.65 dL/g, carboxyl end) and PLA (100/0, 80 kDa, 0.65 dL/g, ester base).
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 95 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain paliperidone palmitate sustained-release microspheres.
  • the sustained release microspheres of paliperidone palmitate obtained in this example have a round shape and a smooth surface, and the particle size is 20-87 ⁇ m.
  • the drug loading rate is 38.55%, and the encapsulation efficiency of paliperidone palmitate is 91.79%. .
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: olanzapine pamoate 44%, poorly water soluble polymer: PLGA 50%, release regulator: 6% mixture of behenic acid and PEG1000.
  • the mass percentage of the PEG 1000 in the release regulator is 90%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 100 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 4 times with ultrapure water to obtain olanzapine pamoate sustained release microspheres.
  • the olanzapine pamoate sustained-release microsphere obtained in this embodiment has a round shape and a smooth surface, and the particle diameter is 20-96 ⁇ m.
  • the drug loading rate is 38.02%, and the encapsulation efficiency of olanzapine pamoate is measured. 86.41%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : water-insoluble/slightly soluble drug: ziprasidone 50%, poorly water-soluble polymer: PLA 43%, release regulator: 7% mixture of palmitic acid and protein.
  • the PLA has a weight average molecular weight of 100 kDa and a viscosity of 0.81 dL/g, and the PLA has a terminal carboxyl group; and the mixture of palmitic acid and protein has a mass of the protein in the release regulator. The content of the fraction is 40%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 105 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (700 rpm, 4 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 6 times with ultrapure water to obtain ziprasidone sustained-release microspheres.
  • the ziprasidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and have a particle diameter of 27 to 91 ⁇ m.
  • the drug loading rate is 44.75%, and the encapsulation efficiency of ziprasidone is 89.5%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: anastrozole 55%, poorly water soluble polymer: PLGA 37%, release regulator: 8% mixture of myristic acid and amino acids.
  • the PLGA is a mixture of PLGA- and PLGA, the molar ratio of the PLGA-to-lactide to the glycolide is 85:15, and the weight average molecular weight of the PLGA-I is 125 kDa, and the viscosity is 0.94 dL/ g, and the PLGA has a terminal carboxyl group; the molar ratio of the lactide to the glycolide in the PLGA is 65:35, and the weight average molecular weight of the PLGA is 105 kDa and the viscosity is 0.75 dL/g, and
  • the PLGA dimer has a terminal carboxyl group; in the mixture of myristic acid and an amino acid, the amino acid has a mass percentage of 95% in the release regulator.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 110 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (400 rpm, 8 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain anastrozole acid sustained-release microspheres.
  • the anastrozole sustained-release microspheres obtained in this embodiment have a round shape and a smooth surface, and the particle size is 23-84 ⁇ m.
  • the drug loading rate is determined to be 45.42%, and the encapsulation efficiency of anastrozole is 87.35%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: donepezil 60%, poorly water soluble polymer: PLGA 29%, release regulator: 10% mixture of lauric acid and PEG600, antioxidant: trihydroxybutyroin 1%. .
  • the molar ratio of lactide to glycolide in the PLGA is 50:50, the weight average molecular weight of the PLGA is 150 kDa, the viscosity is 1.16 dL/g, and the PLGA has a terminal ester group; the laurel In a mixture of acid and PEG 600, the mass percentage of the PEG 600 in the release modifier is 50%.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the external aqueous phase, wherein the volume of the external aqueous phase is 120 times the volume of the internal oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (600 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to release the microspheres with donepezil.
  • the donepezil sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 20-81 ⁇ m.
  • the drug loading rate is 49.71%, and the encapsulation efficiency of donepezil is 90.38%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: risperidone 35%, poorly water soluble polymer: PLGA 63%, release regulator: PEG400 2%.
  • the molar ratio of lactide to glycolide in the PLGA is 75:25
  • the weight average molecular weight of the PLGA is 105 kDa
  • the viscosity is 0.83 dL/g
  • the PLGA has a terminal ester group.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 100 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 7 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain risperidone sustained release microspheres.
  • the risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 25-98 ⁇ m.
  • the drug-loading rate is 32.46%, and the encapsulation efficiency of risperidone is 92.74%.
  • the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: paliperidone 35%, poorly water soluble polymer: PLGA 63%, release regulator: PEG3000 2%.
  • the molar ratio of lactide to glycolide in the PLGA is 75:25
  • the weight average molecular weight of the PLGA is 105 kDa
  • the viscosity is 0.83 dL/g
  • the PLGA has a terminal ester group.
  • the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
  • the internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 90 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours).
  • the microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain paliperidone sustained-release microspheres.
  • the paliperidone sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle diameter is 29-100 ⁇ m.
  • the drug loading rate is 32.74%, and the encapsulation efficiency of paliperidone is 93.54%.
  • the water-insoluble/slightly soluble drug sustained-release microspheres prepared in Examples 1 to 14 were used as test groups 1 to 14, respectively, and the following two comparative examples were used as a control group:
  • Comparative Example 1 The preparation method was the same as in Example 1 of Patent CN1137756, in which risperidone 35%, PLGA (75/25, 105 kDa, 0.83 dL/g, ester base) 65% was charged.
  • the obtained risperidone sustained-release microspheres have a round shape and a particle size of 34-131 ⁇ m.
  • the drug loading rate is 31.95%, and the encapsulation efficiency of risperidone is 91.29%.
  • Comparative Example 2 The preparation method was the same as in Example 1 of Patent CN104013578, in which risperidone 35%, PLGA (75/25, 105 kDa, 0.83 dL/g, ester base) 65% was charged.
  • the obtained risperidone sustained-release microspheres have a round shape and a particle size of 25-118 ⁇ m.
  • the drug loading rate is 31.35%, and the risperidone encapsulation efficiency is 89.57%.
  • Test method accurately weighed 20 mg of each of the microspheres prepared in Examples 1-14 and Comparative Example 1-2 in a 200 mL centrifuge tube, and added pH 7.4 PBS (containing 0.05% Tween 80, 0.05% sodium azide) 50 mL. Place it in a 37 ° C, 150 rpm constant temperature water bath shaker, take 1 mL of the release solution at the preset time point, add an equal amount of fresh medium, and place it in a constant temperature water bath oscillator to continue the release test. The amount of drug released was determined by high performance liquid chromatography (HPLC), and the results are shown in Tables 1 and 2.
  • HPLC high performance liquid chromatography
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 0.05 0.10 0 0.20 0 0 0 0 0.5 0.45 0.44 0.17 0.52 0 0.37 0.21 0 1 0.78 0.73 0.39 1.32 0.40 1.25 1.02 0.20 2 1.23 1.11 0.95 1.64 0.90 3.59 4.30 0.40 7 12.89 12.05 4.97 15.84 11.89 19.63 19.56 3.50 14 29.65 26.93 16.42 37.05 25.72 47.39 45.21 13.40
  • the sustained release microspheres of the present invention have no burst effect, and the release rate on the first day is not more than 2%, and can be released in a near zero-order trend within 120 days, and has a significant sustained release effect.
  • there is no sudden release or a slow release of late release in the early stage indicating that there is no visible difference in the degradation rate of the polymer of the surface and core of these microspheres, indicating that the release modifier produces voids to cause internal degradation of the microspheres.
  • the acidic product is transported to the outside in time, avoiding or greatly reducing the phenomenon that the auto-catalytic degradation rate of the core polymer is accelerated, and effectively overcomes the disadvantages of the PLA or PLGA body degradation effect.
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 0.29 0.34 0 0.29 0 0.16 0.11 0.10 0.5 0.52 0.57 0.23 0.68 0.21 0.52 0.38 0.20 1 0.91 0.95 0.63 1.52 0.73 1.46 1.46 0.42 2 1.35 1.56 1.25 1.86 1.35 4.97 5.69 0.57 7 14.02 14.07 5.37 17.62 13.56 22.07 22.24 4.69 14 32.07 29.94 18.86 39.08 27.62 49.32 48.16 14.98 twenty one 65.09 61.04 38.67 63.31 48.22 88.64 85.32 27.14 28 94.98 86.06 56.72 83.02 66.98 99.16 97.87 39.49 35 100.00 97.13 70.91 93.38 84.26 100.00 100.00 49.97 42 100.00 100.00 81.91 100.00 94.06 100.00 100.00 61.14 49 100.00 89.08 100.00 100.00 70.25 56
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 0.16 0.39 0.11 0.41 0.05 0.21 0.23 0.21 0.5 0.63 0.67 0.39 0.82 0.32 0.76 0.51 0.32 1 1.24 1.26 0.84 1.73 0.84 1.68 1.59 0.53 2 1.59 1.74 1.42 2.03 1.50 5.06 5.87 0.78 7 15.26 14.25 5.66 19.67 15.06 23.58 24.43 5.06 14 33.42 31.24 20.16 42.06 29.13 50.85 49.17 15.49 twenty one 66.22 63.37 40.09 64.81 49.98 90.06 86.69 29.57 28 96.38 87.96 58.84 85.21 69.05 99.97 98.24 41.32 35 100.00 98.94 72.64 95.07 86.24 100.00 100.00 52.69 42 100.00 100.00 83.25 100.00 95.21 100.00 100.00 64.07 49 100.00 91.36 100.00 100.00 72.51 56 98
  • Example 2 Example 3
  • Example 4 Example 5
  • Example 6 Example 7
  • Example 8 0.04 3.12 3.30 1.15 3.37 3.68 3.12 3.18 1.25 0.25 5.32 5.90 3.68 5.94 4.63 5.32 5.30 3.4 0.5 9.80 8.60 4.64 15.26 3.15 9.86 9.81 4.00 1 8.56 7.85 3.15 12.85 8.90 18.82 19.45 3.24
  • the water-insoluble/slightly soluble sustained-release microspheres of the present invention showed a good sustained-release effect, and the blood concentration was increased soon after administration, while the comparative ratio required almost 2-3 weeks.
  • the time can reach 5ng/mL or more.
  • the blood concentration of the water-insoluble/slightly soluble sustained release microspheres of the present invention can last for more than 20 days in the range of 5-30 ng/mL; while Comparative Example 1 and Comparative Example 2 are about 21 days, lasting about 20 days.
  • the water-insoluble/slightly soluble sustained-release microspheres of the invention have better effects, can maintain a certain blood drug concentration for a long period of time, can delay the drug administration cycle, and reduce the burden and inconvenience of the patient.

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Abstract

Provided are a sparingly water-soluble/slightly water-soluble drug sustained release composition, wherein the non-solvent preparation raw materials of the sparingly water-soluble/slightly water-soluble drug sustained release composition comprise a release regulator. The release regulator is added to the preparation raw materials of the sparingly water-soluble/slightly water-soluble drug sustained release composition, and the release regulator is capable of effectively regulating the release rate of the sparingly water-soluble/slightly water-soluble drug in the sustained release composition, such that the sparingly water-soluble/slightly water-soluble drug sustained release composition has no obvious release delay period or burst release phenomenon after administration, has a good sustained release performance, can maintain a therapeutic blood drug concentration for several weeks or longer, has a relatively good stability, and can still preserve the release behaviour thereof after long-term storage. Also provided is a method for preparing the sparingly water-soluble/slightly water-soluble drug sustained release composition.

Description

水难溶或微溶性药物缓释组合物及其制备方法Water-insoluble or slightly soluble drug sustained-release composition and preparation method thereof 技术领域Technical field
本发明涉及一种缓释药物组合物及其制备方法，尤其是一种水难溶/微溶性药物缓释组合物及其制备方法。The invention relates to a sustained-release pharmaceutical composition and a preparation method thereof, in particular to a water-insoluble/slightly soluble drug sustained-release composition and a preparation method thereof.
背景技术Background technique
近十几年来，生物可降解聚合物微球已成为新型给药系统的重要研究领域之一，该给药系统将聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)等骨架材料制得的微球可以作为长效制剂的载体，对人体或动物能以肌肉或皮下注射的方式给药，能够限制药物释放速度及释放周期，仅用一次给药能够长时间维持有效的治疗药物浓度，能够极小化治疗所需的药物总给药量，能够提高患者的药物治疗依从性。In the past decade, biodegradable polymer microspheres have become one of the important research fields of new drug delivery systems, such as polylactide (PLA), lactide-glycolide copolymer (PLGA), etc. The microspheres prepared from the skeleton material can be used as a carrier for the long-acting preparation, and can be administered to the human body or the animal by intramuscular or subcutaneous injection, which can limit the drug release rate and release cycle, and can be effectively maintained for a long time by only one administration. The concentration of the therapeutic drug can minimize the total dose of the drug required for the treatment, and can improve the patient's medication compliance.
基于专利CN1137756公开的技术开发的长效抗精神病药Risperidal Consta(恒德)以分子量约150kDa的PLGA为载体，利培酮为API，每2周肌肉注射一次。该制剂有效避免每天服药产生的峰谷浓度，但在首日仅有少量的药物释放，随后出现长达约3周的药物释放停滞期，因此患者在注射该微球后的3周内还需要依靠口服给药普通剂型才能达到治疗效果，临床使用不方便，患者依从性差。The long-acting antipsychotic drug Risperidal Consta (Hengde) developed based on the technology disclosed in the patent CN1137756 uses PLGA with a molecular weight of about 150 kDa as a carrier and risperidone as an API, which is injected intramuscularly every 2 weeks. The preparation is effective in avoiding the peak-to-valley concentration produced by daily medication, but only a small amount of drug is released on the first day, followed by a drug release stagnation period of about 3 weeks, so the patient needs to be within 3 weeks after the injection of the microsphere. Oral administration of common dosage forms can achieve therapeutic effects, inconvenient clinical use, and poor patient compliance.
有研究者认为，由于利培酮为水难溶/微溶性药物，微球载药量较低时，初始药物释放很少，导致药物血药浓度出现一定时间的释放停滞期，随着载药量的提高，药物释放停滞期逐步减小，当载药量达到一定范围时，给药后即有药物释放。如专利CN101653422公开一种可以释放数周的利培酮微球组合物，通过提高载药率(45％以上)来消除释药停滞期，但制剂稳定性差，经长期贮存后，微球的体内释放行为会发生明显变化。Some researchers believe that because risperidone is a poorly water-soluble/slightly soluble drug, when the drug loading of the microsphere is low, the initial drug release is small, resulting in a release stagnation period of the drug blood drug concentration, with drug loading. When the amount is increased, the drug release stagnation period is gradually reduced. When the drug loading amount reaches a certain range, the drug is released after administration. For example, patent CN101653422 discloses a risperidone microsphere composition which can be released for several weeks, and eliminates the drug stagnation period by increasing the drug loading rate (45% or more), but the formulation stability is poor, and after long-term storage, the microspheres are in vivo. The release behavior will change significantly.
也有研究者认为，以PLGA为载体时，疏水性组分(LA)与亲水性组分(GA)的比例及分子量大小对水溶性药物的释放有显著的影响，PLGA亲水性组分比例越高(如LA:GA＝50:50)，分子量越小，药物溶出越快，可大大缩短释放停滞期。如专利CN 103338752以两种不同分子量及组分比例(55-110kDa，LA:GA＝65:35～90:10及4-35kDa，LA:GA＝50:50～75:25)的PLGA的混合物(重量比为70～90:10～30)作为载体制备进入体内立即释放的利培酮微球。然而，这种聚合物组合在辐射灭菌过程中易造成表面塌陷，因为不同单体比例及分子量的PLGA在辐射下降解程度不同；再者，由于分子量较低且GA单体比例较高的PLGA在存储过程中更容易发生降解，不利于制剂的保存稳定性；同时，分子量较低且GA组分比例较高的PLGA辅料的制备、存储难度较大，成本相对较高。Some researchers believe that when PLGA is used as a carrier, the ratio of hydrophobic component (LA) to hydrophilic component (GA) and molecular weight have a significant effect on the release of water-soluble drugs, and the proportion of hydrophilic components of PLGA. The higher (such as LA: GA = 50: 50), the smaller the molecular weight, the faster the drug is dissolved, which can greatly shorten the release stagnation period. For example, the patent CN 103338752 is a mixture of PLGA with two different molecular weights and component ratios (55-110 kDa, LA:GA=65:35-90:10 and 4-35 kDa, LA:GA=50:50-75:25). (Weight ratio: 70 to 90: 10 to 30) As a carrier, risperidone microspheres which are immediately released into the body are prepared. However, this polymer combination tends to cause surface collapse during radiation sterilization, because PLGAs with different monomer ratios and molecular weights have different degrees of degradation under irradiation; further, PLGAs with lower molecular weight and higher GA monomer ratio Degradation is more likely to occur during storage, which is not conducive to the preservation stability of the preparation. Meanwhile, PLGA excipients with lower molecular weight and higher proportion of GA components are more difficult to prepare and store, and the cost is relatively higher.
专利CN104013578添加棕榈酸异丙酯、硬脂酸丁酯制备帕潘立酮衍生物缓释微球，以改变微球的结构和药物晶态，使药物更趋近于微球核心，且使微球表面形成致密壳结构限制药物的扩散。此方法虽然避免了初期突释现象，但是造成了约5天的延迟释放，临床使用不方便，患者依从性差。Patent CN104013578 adds isopropyl palmitate and butyl stearate to prepare paliperidone derivative sustained-release microspheres to change the structure of the microspheres and the crystalline state of the drug, so that the drug is closer to the core of the microsphere, and The formation of a dense shell structure on the surface of the sphere limits the diffusion of the drug. Although this method avoids the initial burst release phenomenon, it causes a delayed release of about 5 days, which is inconvenient for clinical use and poor patient compliance.
发明内容Summary of the invention
本发明的目的在于克服上述现有技术中的不足之处而提供一种给药后无明显释放延迟期或突释现象、能够在数周或更长的时间内维持治疗血药浓度、具有良好释放性能和较好的稳 定性的水难溶/微溶性药物缓释组合物。同时，本发明的另一目的在于提供所述水难溶/微溶性药物缓释组合物的制备方法。SUMMARY OF THE INVENTION The object of the present invention is to overcome the above-mentioned deficiencies in the prior art and to provide a delayed release or burst release phenomenon after administration, capable of maintaining therapeutic blood concentration for several weeks or longer, and having good A water-insoluble/slightly soluble drug sustained-release composition that releases properties and better stability. Meanwhile, another object of the present invention is to provide a method for preparing the water-insoluble/slightly soluble drug sustained-release composition.
为实现上述目的，本发明采取的技术方案为：一种水难溶/微溶性药物缓释组合物，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含释放调节剂。本发明水难溶/微溶性药物缓释组合物的制备原料包括非溶剂型制备原料和溶剂型制备原料，其中，非溶剂型制备原料包含释放调节剂，不包括表面活性剂；溶剂型制备原料包括水性介质和有机溶剂。In order to achieve the above object, the technical solution adopted by the present invention is: a water-insoluble/slightly soluble drug sustained-release composition, and the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition comprises a release regulator . The preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present invention comprises a non-solvent type preparation raw material and a solvent-type preparation raw material, wherein the non-solvent type preparation raw material comprises a release regulator, excluding a surfactant; the solvent type preparation raw material Includes aqueous media and organic solvents.
本发明所述水难溶/微溶性药物缓释组合物的制备原料，加入了释放调节剂，所述释放调节剂能够有效调节水难溶/微溶性药物在所述缓释组合物中的释放速度，使得本发明的水难溶/微溶性药物缓释组合物给药后无明显释放延迟期或突释现象，具有良好的缓释性能，并能在数周或以上的时间内保持稳定的释放，而且具有较好的稳定性，在长时间存储后仍能够保持其释放行为。The preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present invention is added with a release regulating agent, which can effectively adjust the release of the water-insoluble/slightly soluble drug in the sustained-release composition. The speed makes the water-insoluble/slightly soluble drug sustained-release composition of the invention have no obvious release delay period or burst release after administration, has good sustained-release properties, and can maintain stability for several weeks or more. It is released and has good stability and can maintain its release behavior after long-term storage.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中，所述释放调节剂质量百分含量为0.1～10％。作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为0.5～8％。释放调节剂的质量百分含量为0.5～8％，可使所述缓释组合物具有更好的缓释效果和/或稳定性。作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为1～6％。所述释放调节剂的质量百分含量为1～6％，可使所述缓释组合物具有更好的缓释效果和/或稳定性。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition, the release regulator has a mass percentage The content is from 0.1 to 10%. A more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the quality of the release modifier in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition The percentage is from 0.5 to 8%. The release modifier has a mass percentage of 0.5 to 8%, which allows the sustained release composition to have a better sustained release effect and/or stability. A more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the quality of the release modifier in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition The percentage is from 1 to 6%. The release modifier has a mass percentage of from 1 to 6%, which allows the sustained release composition to have a better sustained release effect and/or stability.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述释放调节剂为有机亲油性物质和/或有机亲水性物质。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the release modifier is an organic lipophilic substance and/or an organic hydrophilic substance.
所述有机亲油性物质，在体内最终转化为二氧化碳和水，可使微球表面及内部产生孔道，增加体液的渗透性，促进水难溶/微溶性药物的溶出，从而避免出现释放一段时间后的极慢释放平台。The organic lipophilic substance is finally converted into carbon dioxide and water in the body, which can cause pores on the surface and inside of the microsphere, increase the permeability of the body fluid, and promote the dissolution of the water-insoluble/slightly soluble drug, thereby avoiding release after a period of time. Very slow release platform.
所述有机亲水性物质也可使微球表面及内部产生细微的孔道，这些孔道可以增加微球注射于体内后体液的渗透性，提高水难溶/微溶性药物的溶出速率，大大缩短或避免出现释放停滞期，同时也促进了微球内部降解产物的转移。The organic hydrophilic substance can also produce fine pores on the surface and inside of the microspheres, and these pores can increase the permeability of the body fluid after the microspheres are injected into the body, and improve the dissolution rate of the water-insoluble/slightly soluble drug, which is greatly shortened or Avoid release stagnation, and also promote the transfer of degradation products inside the microsphere.
本发明所述缓释组合物，由于含有通过加入有机亲油性物质和或有机亲水性物质的释放调节剂，不但可以避免初始突释现象，而且可以避免水难溶/微溶性药物因水溶性较差且聚合物分子量较大时而出现首日释放后的延迟释放平台，维持有效血药浓度，也解决了以高分子量及LA组分比例高的PLGA作为载体制备长周期缓释微球的延迟释放的问题。The sustained-release composition of the present invention not only avoids the initial burst release phenomenon but also avoids water-soluble/slightly soluble drugs due to the release of the organic lipophilic substance or the organic hydrophilic substance. Delayed release platform after first-day release when the molecular weight of the polymer is relatively large, maintaining the effective blood concentration, and also solving the delay of preparing long-period sustained-release microspheres by using PLGA with high molecular weight and high LA component as carrier The problem of release.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述释放调节剂由有机亲油性物质和有机亲水性物质组成时，所述有机亲水性物质在所述释放调节剂中的质量百分含量为30％以上。作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述释放调节剂由有机亲油性物质和有机亲水性物质组成时，所述有机亲水性物质在所述释放调节剂中的质量百分含量为50％以上。作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述释放调节剂由有机亲油性物质和有机亲水性物质组成时，所述有机亲水性物质在所述释放调节剂中的质量百分含量为70％以上。In a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is in the The mass percentage of the release modifier is 30% or more. In a more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is in the The mass percentage of the release regulator is 50% or more. In a more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is in the The mass percentage of the release regulator is 70% or more.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述有机亲油性物质为脂肪酸、脂肪酸酯、油脂中的至少一种；所述有机亲水性物质为醇、糖、氨基酸、蛋白、聚乙烯吡咯烷酮中的至少一种。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述有机亲油性物质为脂肪酸；所述有机亲水性物质为醇、聚乙烯吡咯烷酮中的至少一种。In a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the organic lipophilic substance is at least one of a fatty acid, a fatty acid ester, and a fat; the organic hydrophilic substance is an alcohol At least one of a sugar, an amino acid, a protein, and polyvinylpyrrolidone. In a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the organic lipophilic substance is a fatty acid; and the organic hydrophilic substance is at least one of an alcohol and polyvinylpyrrolidone.
所述脂肪酸优选但不限于C12～C24烷酸及其衍生物，包括但不限于油酸、硬脂酸、月桂酸、肉豆蔻酸、棕榈酸、花生酸、山俞酸、木质素酸，优选硬脂酸、山俞酸。所述醇优选但不限于分子量为400-6000Da的聚乙二醇(PEG)，如PEG600、PEG1000、PEG2000、PEG4000、PEG6000，优选分子量为400～4000Da的PEG，更优选分子量为400～3000Da的PEG。The fatty acid is preferably, but not limited to, a C12-C24 alkanoic acid and derivatives thereof, including but not limited to oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, lignin acid, preferably Stearic acid, behenic acid. The alcohol is preferably, but not limited to, polyethylene glycol (PEG) having a molecular weight of 400-6000 Da, such as PEG 600, PEG 1000, PEG 2000, PEG 4000, PEG 6000, preferably PEG having a molecular weight of 400 to 4000 Da, more preferably PEG having a molecular weight of 400 to 3000 Da. .
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述脂肪酸为油酸、硬脂酸、月桂酸、肉豆蔻酸、棕榈酸、花生酸、山俞酸、木质素酸中的至少一种；所述醇为分子量为400-6000Da的聚乙二醇。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the fatty acid is oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, behenic acid, woody At least one of the acids; the alcohol is a polyethylene glycol having a molecular weight of 400 to 6000 Da.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，其特征在于，所述水难溶/微溶性药物组合物的非溶剂型制备原料还包含水难溶/微溶性药物和水难溶性聚合物。A preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, characterized in that the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition further comprises water-insoluble/slightly soluble Drugs and water insoluble polymers.
本发明所述水难溶性聚合物为可生物降解、生物相容的水难溶性聚合物。The poorly water-soluble polymer of the present invention is a biodegradable, biocompatible, water-insoluble polymer.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物组合物的非溶剂型制备原料中，所述水难溶/微溶性药物的质量百分含量为25～60％，所述水难溶性聚合物的质量百分含量为39.9-74.9％；优选地，所述水难溶/微溶性药物组合物的非溶剂型制备原料中，所述水难溶/微溶性药物的质量百分含量为30～55％，所述水难溶性聚合物的质量百分含量为44.9-69.9％；优选地，所述水难溶/微溶性药物组合物的非溶剂型制备原料中，所述水难溶/微溶性药物的质量百分含量为35～50％，所述水难溶性聚合物的质量百分含量为49.9-64.9％。A preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition, the water-insoluble/slightly soluble drug The mass percentage is 25-60%, and the mass percentage of the poorly water-soluble polymer is 39.9-74.9%; preferably, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition, The water-insoluble/slightly soluble drug has a mass percentage of 30 to 55%, and the water-insoluble polymer has a mass percentage of 44.9-69.9%; preferably, the water-insoluble/slightly soluble drug In the non-solvent-type preparation raw material of the composition, the water-insoluble/slightly soluble drug has a mass percentage of 35 to 50%, and the water-insoluble polymer has a mass percentage of 49.9 to 64.9%.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物包括且不限于利培酮、帕利哌酮、阿立哌唑、伊潘立酮、依匹哌唑、齐拉西酮、阿那曲唑、多奈哌齐、奥氮平、纳曲酮、氟哌啶醇、紫杉醇、恩替卡韦、多西他赛、它们的衍生物中的至少一种。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the water-insoluble/slightly soluble drug includes, but is not limited to, risperidone, paliperidone, aripiprazole, and ipan At least one of ketone, epiliperazole, ziprasidone, anastrozole, donepezil, olanzapine, naltrexone, haloperidol, paclitaxel, entecavir, docetaxel, and derivatives thereof .
作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述水难溶/微溶性药物包括且不限于利培酮、帕利哌酮、阿立哌唑、伊潘立酮、依匹哌唑、多奈哌齐、奥氮平、氟哌啶醇、紫杉醇、恩替卡韦、多西他赛、它们的衍生物中的至少一种。As a more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the water-insoluble/slightly soluble drug includes, but is not limited to, risperidone, paliperidone, aripiprazole, and y. At least one of phenyllicone, epiliperazole, donepezil, olanzapine, haloperidol, paclitaxel, entecavir, docetaxel, and derivatives thereof.
作为本发明所述水难溶/微溶性药物缓释组合物的更优选实施方式，所述水难溶/微溶性药物包括且不限于利培酮、帕利哌酮、阿立哌唑、伊潘立酮、恩替卡韦、依匹哌唑、它们的衍生物中的至少一种。As a more preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the water-insoluble/slightly soluble drug includes, but is not limited to, risperidone, paliperidone, aripiprazole, and y. At least one of phenyllicone, entecavir, epiliperazole, and derivatives thereof.
其中，所述衍生物包括且不限于棕榈酸帕利哌酮、月桂酰阿立哌唑、癸酸氟哌啶醇、双羟萘酸奥氮平、甲磺酸齐拉西酮。Wherein, the derivative includes, but is not limited to, paliperidone palmitate, aripiprazole lauroyl, haloperidol citrate, olanzapine pamoate, ziprasidone mesylate.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚酯、聚碳酸酯、聚缩醛、聚酐、聚羟基脂肪酸、它们的共聚物或共混物中的至少一种。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the poorly water-soluble polymer is a polyester, a polycarbonate, a polyacetal, a polyanhydride, a polyhydroxy fatty acid, and copolymerization thereof. At least one of a substance or a blend.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、聚乙交酯(PGA)、丙交酯-乙交酯共聚物(PLGA)、聚己内酯(PCL)、它 们与聚乙二醇的共聚物(如PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA、PEG-PCL、PCL-PEG-PCL、PEG-PLA-PEG、PEG-PLGA-PEG)、聚羟基丁酸、聚羟基戊酸、聚对二氧环己酮(PPDO)、壳聚糖、海藻酸及其盐、聚氰基丙烯酸酯、聚酸酐、聚原酸酯、聚酰胺、聚磷腈、聚磷酸酯中的至少一种。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the poorly water-soluble polymer is polylactide (PLA), polyglycolide (PGA), lactide-B-crossing. Ester copolymer (PLGA), polycaprolactone (PCL), copolymers thereof with polyethylene glycol (such as PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA-PEG-PLA, PEG-PCL, PCL-PEG-PCL, PEG-PLA-PEG, PEG-PLGA-PEG), polyhydroxybutyric acid, polyhydroxyvaleric acid, polydioxanone (PPDO), chitosan, alginic acid and its salts, At least one of polycyanoacrylate, polyanhydride, polyorthoester, polyamide, polyphosphazene, polyphosphate.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物中的至少一种。作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)中的至少一种。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are At least one of copolymers with polyethylene glycol. As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the poorly water-soluble polymer is in a polylactide (PLA) or a lactide-glycolide copolymer (PLGA). At least one.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物中的至少一种时，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的重均分子量均为25000-150000Da。优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的重均分子量均为30000-125000Da。更优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的重均分子量均为35000-100000Da。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are The weight average molecular weight of the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol in at least one of copolymers with polyethylene glycol Both are 25000-150000Da. Preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of 30,000 to 125,000 Da. More preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and copolymers thereof with polyethylene glycol have a weight average molecular weight of from 35,000 to 100,000 Da.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物中的至少一种时，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的粘度均为0.25-1.2dL/g(测试条件为～0.5％(w/v)，CHCl3，25℃)。优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的粘度均为0.3-1.0dL/g(测试条件为～0.5％(w/v)，CHCl3，25℃)。更优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、它们与聚乙二醇的共聚物的粘度均为0.35-0.9dL/g(测试条件为～0.5％(w/v)，CHCl3，25℃)。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), and they are When at least one of copolymers with polyethylene glycol, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and the copolymer of polyethylene glycol have a viscosity 0.25-1.2 dL/g (test conditions were ~0.5% (w/v), CHCl3, 25 °C). Preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and their copolymers with polyethylene glycol have a viscosity of 0.3-1.0 dL/g (test conditions are -0.5) % (w/v), CHCl3, 25 ° C). More preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA), and the copolymer of these and polyethylene glycol have a viscosity of 0.35-0.9 dL/g (test condition is ~ 0.5% (w/v), CHCl3, 25 ° C).
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物的分子链携带阴离子或阳离子基团，或者不携带阴离子或阳离子基团。优选地，所述水难溶性聚合物具有端羧基或端酯基。更优选地，所述生物降解和生物相容的水难溶性聚合物具有端羧基。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the molecular chain of the poorly water-soluble polymer carries an anionic or cationic group or does not carry an anionic or cationic group. Preferably, the poorly water soluble polymer has a terminal carboxyl group or a terminal ester group. More preferably, the biodegradable and biocompatible water poorly soluble polymer has a terminal carboxyl group.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、其与聚乙二醇的共聚物中的至少一种时，其中的丙交酯与乙交酯的摩尔比为100:0～50:50。优选地，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、其与聚乙二醇的共聚物中的至少一种时，其中的丙交酯与乙交酯的摩尔比为100:0～65:35。更优选地，所述水难溶性聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)、其与聚乙二醇的共聚物中的至少一种时，其中的丙交酯与乙交酯的摩尔比为100:0～75:25。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the poorly water-soluble polymer is polylactide (PLA), lactide-glycolide copolymer (PLGA), In at least one of the copolymers with polyethylene glycol, the molar ratio of lactide to glycolide is from 100:0 to 50:50. Preferably, the poorly water-soluble polymer is at least one of polylactide (PLA), lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol, wherein The molar ratio of lactide to glycolide is from 100:0 to 65:35. More preferably, the poorly water-soluble polymer is at least one of a polylactide (PLA), a lactide-glycolide copolymer (PLGA), and a copolymer thereof with polyethylene glycol, wherein The molar ratio of lactide to glycolide is from 100:0 to 75:25.
本发明所述水难溶/微溶性药物缓释组合物中，所述水难溶性聚合物可以为单一的聚合物，也可以为多种聚合物的混合物。如，丙交酯(LA)与乙交酯(GA)的摩尔比及分子量相同但携带基团不同的PLGA和或PLA的组合；丙交酯(LA)与乙交酯(GA)的摩尔比及携带基团相同但分子量不同的PLGA和或PLA的组合，且分子量差别不大于20kDa；分子量及携带基团相同但丙交酯与乙交酯的摩尔比不同的PLGA和或PLA的组合，且乙交酯的百分 率差别不大于20％；分子量、携带基团及丙交酯与乙交酯的摩尔比均不同的PLGA和或PLA的组合，且分子量差别不大于20kDa、乙交酯的百分率差别不大于20％。In the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the water-insoluble polymer may be a single polymer or a mixture of a plurality of polymers. For example, a molar ratio of lactide (LA) to glycolide (GA) and a combination of PLGA and PLA having the same molecular weight but different carrying groups; molar ratio of lactide (LA) to glycolide (GA) And a combination of PLGA and PLA having the same group but different molecular weights, and having a molecular weight difference of not more than 20 kDa; a combination of PLGA and PLA having the same molecular weight and the same carrier group but different molar ratio of lactide to glycolide, and The difference in the percentage of glycolide is not more than 20%; the molecular weight, the carrier group and the combination of PLGA and PLA which are different in the molar ratio of lactide to glycolide, and the molecular weight difference is not more than 20kDa, the difference of the percentage of glycolide Not more than 20%.
上述所述的分子量为重均分子量，是通过凝胶渗透色谱仪(GPC)测量所获得的值；所述粘度是乌氏粘度计测量所获得的值。The molecular weight described above is a weight average molecular weight, which is a value obtained by gel permeation chromatography (GPC) measurement; the viscosity is a value obtained by an Ubbelohde viscometer measurement.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料还包含赋形剂，所述赋形剂在所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中的质量百分含量为0～8％。本发明的水难溶/微溶性药物缓释组合物中还可以包含一种或一种以上的赋形剂。赋形剂可以赋予活性药物或微粒其它特征，例如增加微粒、活性药物或载体的稳定性、促进活性药物从微粒中的可控释放、或调节活性药物的生物学组织的渗透性。本发明中所述的赋形剂包括但不限于抗氧化剂、缓冲剂等。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition further comprises an excipient, the shaping The mass percentage of the agent in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition is 0 to 8%. The water-insoluble/slightly soluble drug sustained release composition of the present invention may further comprise one or more excipients. The excipients can impart other characteristics to the active drug or microparticles, such as increasing the stability of the microparticles, active drug or carrier, promoting controlled release of the active drug from the microparticles, or modulating the permeability of the biological tissue of the active drug. Excipients described in the present invention include, but are not limited to, antioxidants, buffers, and the like.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述赋形剂包括缓冲剂和抗氧化剂；As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the excipient includes a buffer and an antioxidant;
所述缓冲剂为有机酸、无机酸盐中的至少一种，所述缓冲剂在所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中的质量百分含量为0～5％；优选地，所述缓冲剂在所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中的质量百分含量为0～3％；优选地，所述缓冲剂在所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中的质量百分含量为0～2％；The buffering agent is at least one of an organic acid and a mineral acid salt, and the mass percentage of the buffering agent in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition is 0 to 5%; preferably, the buffering agent is in a non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition in a mass percentage of 0 to 3%; preferably, the buffering agent is The non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition has a mass percentage of 0 to 2%;
所述抗氧化剂为叔丁基对羟基茴香醚、二丁基苯酚、生育酚、肉豆蔻酸异丙酯、d-a乙酸生育酚、抗坏血酸、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚、丁基化羟基醌、羟基香豆素、丁基化羟基甲苯、掊酸脂肪酸酯、丙羟基苯甲酸酯、三羟基苯丁酮、维生素E、维生素E-TPGS、ρ-羟基苯甲酸酯中的至少一种；所述抗氧化剂在所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中的质量百分含量为0～1％；优选地，所述抗氧化剂在所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中的质量百分含量为0～0.08％；更优选地，所述抗氧化剂在所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中的质量百分含量为0～0.05％。The antioxidants are tert-butyl-p-hydroxyanisole, dibutylphenol, tocopherol, isopropyl myristate, tocopheryl daacetate, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butyl Hydroxyguanidine, hydroxycoumarin, butylated hydroxytoluene, decanoic acid fatty acid ester, propyl hydroxybenzoate, hydroxybutanone, vitamin E, vitamin E-TPGS, ρ-hydroxybenzoate At least one; the antioxidant is in a non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition in a mass percentage of 0 to 1%; preferably, the antioxidant is in the The non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition has a mass percentage of 0 to 0.08%; more preferably, the antioxidant is sustained in the water-insoluble/slightly soluble drug. The non-solvent-type preparation material of the composition has a mass percentage of 0 to 0.05%.
所述抗氧化剂的选择中，所述掊酸脂肪酸酯选自如乙酯、丙酯、辛酯、月桂酯，所述ρ-羟基苯甲酸酯选自如甲酯、乙酯、丙酯、丁酯等。所述抗氧化剂以有效地清除植入物内产生的任何自由基或过氧化物的量存在于缓释组合物中。In the selection of the antioxidant, the citric acid fatty acid ester is selected from, for example, ethyl ester, propyl ester, octyl ester, lauryl ester, and the ρ-hydroxy benzoate is selected from, for example, methyl ester, ethyl ester, propyl ester, and butyl. Ester and the like. The antioxidant is present in the sustained release composition in an amount effective to remove any free radicals or peroxides produced within the implant.
本发明所述缓冲剂包括但不限于无机酸和有机酸盐，如碳酸、乙酸、草酸、柠檬酸、磷酸、盐酸的盐，包括碳酸钙、氢氧化钙、肉豆蘧酸钙、油酸钙、棕榈酸钙、硬脂酸钙、磷酸钙、醋酸钙、醋酸镁、碳酸镁、氢氧化镁、磷酸镁、肉豆蔻酸镁、油酸镁、棕榈酸镁、硬脂酸镁、碳酸锌、氢氧化锌、氧化锌、肉豆蘧酸锌、油酸锌、醋酸锌、氯化锌、硫酸锌、硫酸氢锌、碳酸锌、硝酸锌、葡萄糖酸锌、棕榈酸锌、硬脂酸锌、磷酸锌、碳酸钠、碳酸氢钠、亚硫酸氢钠、硫代硫酸钠、醋酸-醋酸钠缓冲盐，及它们的组合。优选无机酸和有机酸的锌盐。The buffering agent of the present invention includes, but is not limited to, mineral acids and organic acid salts, such as salts of carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, including calcium carbonate, calcium hydroxide, calcium myristate, calcium oleate. Calcium palmitate, calcium stearate, calcium phosphate, calcium acetate, magnesium acetate, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium myristate, magnesium oleate, magnesium palmitate, magnesium stearate, zinc carbonate, Zinc hydroxide, zinc oxide, zinc myristate, zinc oleate, zinc acetate, zinc chloride, zinc sulfate, zinc hydrogen sulfate, zinc carbonate, zinc nitrate, zinc gluconate, zinc palmitate, zinc stearate, Zinc phosphate, sodium carbonate, sodium hydrogencarbonate, sodium hydrogen sulfite, sodium thiosulfate, acetic acid-sodium acetate buffer salts, and combinations thereof. Preferred are zinc salts of inorganic acids and organic acids.
所述赋形剂在内油相时加入。当所述赋形剂为极细微的粉末时，其粒径小于0.5μm，优选为粒径小于0.1μm，更优选粒径小于0.05μm。所述赋形剂溶剂与内油相中或以极小颗粒混悬于内油相中。The excipient is added in the inner oil phase. When the excipient is a very fine powder, its particle diameter is less than 0.5 μm, preferably the particle diameter is less than 0.1 μm, and more preferably the particle diameter is less than 0.05 μm. The excipient solvent is suspended in the internal oil phase with the inner oil phase or with very small particles.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述水难溶/微溶性药物缓释组合物为微球或微粒。当所述水难溶/微溶性药物缓释组合物为微球时，微球通常用于注射给药，微粒或微球可以被吸入到注射器中，并通过细的针注射。优选的，递送途径是使用 细针进行注射，包括皮下、肌肉、眼内等。通过细的针意味着针至少为20G口径(内径580μm)，一般在大约22G(内径410μm)和大约30G(内径150μm)之间，或30G以上。有利的是使用细到至少24G的针头，更有利的是细到至少26G的针头。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the water-insoluble/slightly soluble drug sustained-release composition is a microsphere or a microparticle. When the water-insoluble/slightly soluble drug sustained-release composition is a microsphere, the microspheres are usually used for injection administration, and the microparticles or microspheres can be inhaled into a syringe and injected through a fine needle. Preferably, the route of delivery is by injection using a fine needle, including subcutaneous, intramuscular, intraocular, and the like. Passing a thin needle means that the needle has a diameter of at least 20 G (inner diameter 580 μm), generally between about 22 G (inner diameter 410 μm) and about 30 G (inner diameter 150 μm), or 30 G or more. It is advantageous to use a needle that is as thin as at least 24G, more advantageously a needle that is as thin as at least 26G.
作为本发明所述水难溶/微溶性药物缓释组合物的优选实施方式，所述微球的几何粒径小于200μm。典型地，所述微球的粒径大约为10～200μm，优选15～150μm，更优选大约20～120μm。微球粒径大小通过动态光散射方法(例如激光衍射法)、或显微技术(如扫描电镜法)来测量。As a preferred embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the microspheres have a geometric particle diameter of less than 200 μm. Typically, the microspheres have a particle size of from about 10 to 200 μm, preferably from 15 to 150 μm, more preferably from about 20 to 120 μm. The particle size of the microspheres is measured by a dynamic light scattering method (for example, laser diffraction method) or a microscopic technique (such as scanning electron microscopy).
另外，本发明还提供一种如上所述水难溶/微溶性药物缓释组合物的制备方法，为实现此目的，本发明采取的技术方案为：一种如上所述水难溶/微溶性药物缓释组合物的制备方法，包括以下步骤：In addition, the present invention also provides a preparation method of the poorly water-soluble/slightly soluble drug sustained-release composition as described above. To achieve the object, the technical solution adopted by the present invention is as follows: a water-insoluble/slightly soluble solution as described above. A method for preparing a drug sustained release composition, comprising the steps of:
(1a)将所述非溶剂型制备原料溶于有机溶剂中，形成内油相；(1a) dissolving the non-solvent-type preparation raw material in an organic solvent to form an internal oil phase;
(2a)将表面活性剂溶于水性介质中，形成外水相；(2a) dissolving the surfactant in an aqueous medium to form an external aqueous phase;
(3a)将步骤(1a)得到的内油相加入到外水相中，制成乳液，然后通过溶剂蒸发或溶剂提取使溶液中的微粒硬化，收集微粒，洗涤并干燥，得水难溶/微溶性药物缓释微球；(3a) adding the internal oil phase obtained in the step (1a) to the external aqueous phase to prepare an emulsion, and then hardening the particles in the solution by solvent evaporation or solvent extraction, collecting the particles, washing and drying to obtain water insoluble/ Slightly soluble drug sustained release microspheres;
或者or
(1b)将所述非溶剂型制备原料所含的除释放调节剂外的其余各物质溶于有机溶剂中，形成内油相；(1b) dissolving the remaining substances contained in the non-solvent-type preparation raw material in addition to the release modifier in an organic solvent to form an internal oil phase;
(2b)将释放调节剂和表面活性剂溶于水性介质中，形成外水相；(2b) dissolving the release modifier and the surfactant in an aqueous medium to form an external aqueous phase;
(3b)将步骤(1b)得到的内油相加入到外水相中，制成乳液，然后通过溶剂蒸发或溶剂提取使溶液中的微粒硬化，收集微粒，洗涤并干燥，得水难溶/微溶性药物缓释微球。(3b) adding the internal oil phase obtained in the step (1b) to the external aqueous phase to prepare an emulsion, and then hardening the particles in the solution by solvent evaporation or solvent extraction, collecting the particles, washing and drying to obtain water insoluble/ A slightly soluble drug sustained release microsphere.
作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的优选实施方式，所述步骤(1a)和(1b)中水难溶性聚合物与有机溶剂的质量百分比为1～18％；所述步骤(2a)和(2b)中，所述表面活性剂在外水相中的质量百分含量为0.1～10％；所述步骤(3a)和(3b)中，所述外水相的体积是所述内油相体积的60倍以上。作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的更优选实施方式，所述步骤(1a)和(1b)中水难溶性聚合物与有机溶剂的质量百分比为1.5～12％；所述步骤(2a)和(2b)中，所述表面活性剂在外水相中的质量百分含量为0.5～8％；所述步骤(3a)和(3b)中，所述外水相的体积是所述内油相体积的80倍以上。作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的更优选实施方式，所述步骤(1a)和(1b)中水难溶性聚合物与有机溶剂的质量百分比为3～10％；所述步骤(2a)和(2b)中，所述表面活性剂在外水相中的质量百分含量为1～7％；所述步骤(3a)和(3b)中，所述外水相的体积是所述内油相体积的100倍以上。As a preferred embodiment of the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 1-18. %; in the steps (2a) and (2b), the mass percentage of the surfactant in the outer aqueous phase is 0.1 to 10%; in the steps (3a) and (3b), the outer water The volume of the phase is more than 60 times the volume of the inner oil phase. As a more preferred embodiment of the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 1.5 to 12%; in the steps (2a) and (2b), the mass percentage of the surfactant in the external aqueous phase is 0.5 to 8%; in the steps (3a) and (3b), the outer The volume of the aqueous phase is more than 80 times the volume of the internal oil phase. As a more preferred embodiment of the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the mass percentage of the poorly water-soluble polymer and the organic solvent in the steps (1a) and (1b) is 3 to 10%; in the steps (2a) and (2b), the mass percentage of the surfactant in the outer aqueous phase is from 1 to 7%; in the steps (3a) and (3b), the outer The volume of the aqueous phase is more than 100 times the volume of the internal oil phase.
所述水难溶性聚合物在有机溶剂中的质量百分含量依据聚合物的类型、重均分子量以及有机溶剂的类型而变化，通常其质量百分含量(水难溶性聚合物质量/有机溶剂质量×100％)为1～18％。The mass percentage of the poorly water-soluble polymer in the organic solvent varies depending on the type of the polymer, the weight average molecular weight, and the type of the organic solvent, and usually the mass percentage thereof (water poorly soluble polymer mass / organic solvent mass) ×100%) is 1 to 18%.
本发明所述水难溶/微溶性药物缓释组合物的制备方法中，所述步骤(2a)和(2b)的外水相中含有表面活性剂，所述表面活性剂可以增加有机相的湿润性质、提高乳化过程中小液珠的稳定性及形状，避免小液珠重新聚合、减少未包封的或部分包封的小球颗粒的数量，从而减少了药物在释放过程中的初始突释。In the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the outer aqueous phase of the steps (2a) and (2b) contains a surfactant, and the surfactant can increase the organic phase. Wetting properties, improving the stability and shape of small liquid beads during emulsification, avoiding re-polymerization of small liquid beads, reducing the number of unencapsulated or partially encapsulated small spherical particles, thereby reducing the initial burst release of the drug during release .
作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的优选实施方式，所述步骤(1a)和(1b)中的有机溶剂为卤代烃、脂肪酸酯、芳香烃中的至少一种；所述卤代烃包含二氯甲烷、氯仿、氯乙烷、四氯乙烯、三氯乙烯、二氯乙烷、三氯乙烷、四氯化碳、氟烃、氯代苯(单、双、三取代)、三氯氟甲烷；所述脂肪酸酯包含乙酸乙酯、乙酸丁酯；所述芳香烃包含苯、甲苯、二甲苯、苯甲醇。所述有机溶剂可以同时溶解水难溶性聚合物、水难溶/微溶性药物，沸点低于水且不溶于或难溶于水。所述溶剂可以为单一的有机溶剂，也可以为混溶的两种及以上的有机溶剂。上述所述有机溶剂的选择中，优选卤代脂肪烃类溶剂，更优选二氯甲烷、氯仿中的至少一种。所述内油相中，有机溶剂的用量比例按照不同药物有所不同，根据实际情况调配。As a preferred embodiment of the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the organic solvent in the steps (1a) and (1b) is a halogenated hydrocarbon, a fatty acid ester or an aromatic hydrocarbon. At least one; the halogenated hydrocarbon comprises dichloromethane, chloroform, ethyl chloride, tetrachloroethylene, trichloroethylene, dichloroethane, trichloroethane, carbon tetrachloride, fluorocarbon, chlorobenzene (mono, di-, tri-substituted), trichlorofluoromethane; the fatty acid ester comprises ethyl acetate, butyl acetate; the aromatic hydrocarbon comprises benzene, toluene, xylene, benzyl alcohol. The organic solvent can simultaneously dissolve a poorly water-soluble polymer, a poorly water-soluble/slightly soluble drug, a boiling point lower than water, and insoluble or poorly soluble in water. The solvent may be a single organic solvent or a miscible two or more organic solvents. Among the above-mentioned selection of the organic solvent, a halogenated aliphatic hydrocarbon solvent is preferred, and at least one of dichloromethane and chloroform is more preferred. In the internal oil phase, the proportion of the organic solvent is different according to different drugs, and is formulated according to actual conditions.
作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的优选实施方式，所述表面活性剂为阴离子表面活性剂、阳离子表面活性剂、两性离子表面活性剂、非离子表面活性剂、表面活性生物分子中的至少一种；优选地，所述表面活性剂为阴离子表面活性剂、非离子表面活性剂、表面活性生物分子中的至少一种；更优选地，所述表面活性剂为非离子表面活性剂、表面活性生物分子中的至少一种；所述阳离子表面活性剂包括苯扎氯胺、溴化十六烷基三甲基铵、月桂酸基二甲基苯甲基氯铵、酰基肉毒碱盐酸盐、烷基吡啶卤化物；所述阴离子表面活性剂包括烷基硫酸盐(如十二烷基硫酸钠、十二烷基硫酸铵、十八烷基硫酸钠等)、月桂酸钾、藻酸钠、聚丙烯酸钠及其衍生物、烷基聚环氧乙烯硫酸酯、丁二酸二辛基磺酸钠、磷脂、甘油酯、羧甲基纤维素钠、油酸钠、硬脂酸钠、胆酸和其他胆汁酸(如胆酸、脱氧胆酸、甘氨胆酸、牛黄胆酸、甘氨脱氧胆酸)的钠盐；所述非离子表面活性剂包括聚氧乙烯脂肪醇醚、聚山梨酸酯(如吐温80、吐温60等)、聚氧乙烯脂肪酸酯、聚氧乙烯蓖麻油衍生物、聚氧乙烯聚丙二醇共聚物、蔗糖脂肪酸酯、聚乙二醇脂肪酸酯、聚氧乙烯山梨糖醇酐单脂肪酸酯、聚氧乙烯山梨糖醇酐二脂肪酸酯、聚氧乙烯甘油单脂肪酸酯、聚氧乙烯甘油二脂肪酸酯、聚甘油脂肪酸酯、聚丙二醇单酯、芳基烧基聚醚醇、聚氧乙烯-聚氧丙烯共聚物(泊洛沙姆)、聚乙烯醇及其衍生物、聚乙烯吡咯烷酮和多糖，优选泊洛沙姆、聚乙烯醇、聚山梨酸酯、聚乙烯吡咯烷酮和多糖，更优选聚乙烯醇、多糖；所述表面活性生物分子包括聚氨基酸(如聚天冬氨酸、聚谷氨酸或它们的类似物)、肽(如碱性肽)、蛋白质(如明胶、酪蛋白、白蛋白、水蛭素、淀粉羟乙基酶等，优选白蛋白)。As a preferred embodiment of the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the surfactant is an anionic surfactant, a cationic surfactant, a zwitterionic surfactant, and a nonionic surface active agent. At least one of a surfactant, a surface active biomolecule; preferably, the surfactant is at least one of an anionic surfactant, a nonionic surfactant, and a surface active biomolecule; more preferably, the surface active The agent is at least one of a nonionic surfactant and a surface active biomolecule; the cationic surfactant comprises benzalkonium chloride, cetyltrimethylammonium bromide, lauric acid dimethylbenzyl group Chloroammonium, acylcarnitine hydrochloride, alkylpyridine halide; the anionic surfactant comprises an alkyl sulfate (such as sodium lauryl sulfate, ammonium lauryl sulfate, sodium stearyl sulfate) Etc.), potassium laurate, sodium alginate, sodium polyacrylate and its derivatives, alkyl polyepoxyethylene sulfate, sodium dioctyl sulfosuccinate, phospholipids, glycerides, sodium carboxymethylcellulose, a sodium salt of sodium, sodium stearate, cholic acid, and other bile acids (eg, cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid); the nonionic surfactant includes Polyoxyethylene fatty alcohol ether, polysorbate (such as Tween 80, Tween 60, etc.), polyoxyethylene fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene polypropylene glycol copolymer, sucrose fatty acid ester , polyethylene glycol fatty acid ester, polyoxyethylene sorbitan mono fatty acid ester, polyoxyethylene sorbitan di fatty acid ester, polyoxyethylene glycerin mono fatty acid ester, polyoxyethylene glycerin di fatty acid ester , polyglycerol fatty acid esters, polypropylene glycol monoesters, aryl alkyl polyether alcohols, polyoxyethylene-polyoxypropylene copolymers (poloxamers), polyvinyl alcohol and its derivatives, polyvinylpyrrolidone and polysaccharides, Preferred are poloxamers, polyvinyl alcohols, polysorbates, polyvinylpyrrolidone and polysaccharides, more preferably polyvinyl alcohols, polysaccharides; the surface active biomolecules include polyamino acids (eg polyaspartic acid, polyglutamic acid) Or their analogs), peptides (such as basic peptides), proteins (such as , Casein, albumin, hirudin, enzymes hydroxyethyl starch, preferably albumin).
上述所述非离子表面活性剂的选择中，所述多糖包括淀粉和淀粉衍生物、甲基纤维素、乙基纤维素、羟基纤维素、羟丙基纤维素、羟丙甲基纤维素、阿拉伯胶、壳聚糖衍生物、结冷胶、藻酸衍生物、葡聚糖衍生物和非晶态纤维素，优选羟丙纤维素、壳聚糖及其衍生物、支链淀粉或葡聚糖及其衍生物。In the selection of the above nonionic surfactant, the polysaccharide includes starch and starch derivatives, methyl cellulose, ethyl cellulose, hydroxy cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and arabic. Gum, chitosan derivative, gellan gum, alginic acid derivative, dextran derivative and amorphous cellulose, preferably hydroxypropyl cellulose, chitosan and its derivatives, amylopectin or dextran And its derivatives.
作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的优选实施方式，所述外水相中还含有无机盐或有机盐；所述无机盐为磷酸、硫酸、乙酸、碳酸的钾盐或钠盐、Tris、MES、HEPES中的至少一种；所述无机盐或有机盐在所述外水相中的质量百分含量为0～5％。作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的更优选实施方式，所述无机盐或有机盐在所述外水相中的质量百分含量为0.01～4％。作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的更优选实施方式，述无机盐或有机盐在所述外水相中的质量百分含量为0.05～3％。当所述外水相含有无机盐或有机盐时，所述外水相的pH值范围为3～9；优选地， 所述外水相的pH值范围为4～9；更优选地，所述外水相的pH值范围为5.5～8.5。In a preferred embodiment of the method for preparing a water-insoluble/slightly soluble drug sustained-release composition according to the present invention, the outer aqueous phase further contains an inorganic salt or an organic salt; the inorganic salt is phosphoric acid, sulfuric acid, acetic acid, or carbonic acid. At least one of a potassium salt or a sodium salt, Tris, MES, HEPES; the inorganic salt or organic salt in the outer aqueous phase in a mass percentage of 0 to 5%. In a more preferred embodiment of the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the inorganic salt or the organic salt is contained in the outer aqueous phase in an amount of 0.01 to 4% by mass. As a more preferred embodiment of the method for producing a water-insoluble/slightly soluble drug sustained-release composition of the present invention, the inorganic salt or the organic salt is contained in an amount of 0.05 to 3% by mass in the external aqueous phase. When the outer aqueous phase contains an inorganic salt or an organic salt, the pH of the outer aqueous phase ranges from 3 to 9; preferably, the pH of the outer aqueous phase ranges from 4 to 9; more preferably, The pH of the outer aqueous phase ranges from 5.5 to 8.5.
当所述外水相中还含有无机盐或有机盐时，可以降低微球固化过程中水溶性活性物质溶渗至水相中，其机理为提高外水相的渗透压或降低活性物质在外水相中的溶解度。When the external aqueous phase further contains an inorganic salt or an organic salt, the water-soluble active substance in the solidification process of the microsphere can be reduced to the aqueous phase, and the mechanism is to increase the osmotic pressure of the external aqueous phase or reduce the active substance in the external water. Solubility in the phase.
作为本发明所述水难溶/微溶性药物缓释组合物的制备方法的优选实施方式，所述步骤(3a)和(3b)中制成乳液的方法与众所周知的乳化方法相同，采用产生高剪切力的装置(如磁力搅拌器、机械搅拌器、高速均质机、超声仪、膜乳化器、转子-定子混合器、静态混合器、高压均质机等)将有机内相与水性外相混合，以形成均匀乳液。As a preferred embodiment of the preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the method of preparing the emulsion in the steps (3a) and (3b) is the same as the well-known emulsification method, and the production is high. Shear force devices (such as magnetic stirrers, mechanical stirrers, high-speed homogenizers, ultrasound systems, membrane emulsifiers, rotor-stator mixers, static mixers, high-pressure homogenizers, etc.) with organic internal phase and aqueous external phase Mix to form a homogeneous emulsion.
优选地，所述步骤(3a)和(3b)中采用以下方法将溶剂除去：Preferably, the solvent is removed in the steps (3a) and (3b) by the following method:
(A)通过加热、减压(或联合加热)和减压蒸去有机溶剂；(A) the organic solvent is distilled off by heating, reduced pressure (or combined heating), and reduced pressure;
(B)气流鼓吹液体表面，并控制液相与气相的接触面积、乳液搅拌和循环的速率(如JP-A-9-221418)加速有机溶剂的蒸发，所述气流优选氮气；(B) the gas stream blows the surface of the liquid, and controls the contact area of the liquid phase with the gas phase, the rate of emulsion agitation and circulation (such as JP-A-9-221418) to accelerate the evaporation of the organic solvent, preferably the gas stream;
(C)用空心纤维薄膜快速蒸去有机溶剂(如W00183594)，空心纤维薄膜优选是例如硅橡胶全蒸发薄膜(特别是由聚二甲基硅氧烷制备的全蒸发薄膜)。(C) The organic solvent (e.g., W00183594) is rapidly evaporated from the hollow fiber membrane, and the hollow fiber membrane is preferably, for example, a silicone rubber pervaporation film (particularly a pervaporation film prepared from polydimethylsiloxane).
优选地，所述步骤(3a)和(3b)中通过离心、过筛或过滤的方式将微球予以分离。Preferably, the microspheres are separated by centrifugation, sieving or filtration in the steps (3a) and (3b).
所述步骤(3a)和(3b)中干燥微球的方法没有特别限定，例如可举出加热、减压干燥、冷冻干燥、真空干燥和它们的组合。The method of drying the microspheres in the steps (3a) and (3b) is not particularly limited, and examples thereof include heating, vacuum drying, freeze drying, vacuum drying, and combinations thereof.
本发明的微粒或微球体可以包封大量的活性成分，剂量可依据活性成分的类型与含量、剂型、释放持续时间、给药受试者、给药途径、给药目的、靶标疾病及症状等而适当地选择。然而，只要活性成分可于活体内维持在药物有效浓度达预期的持续时间，则该剂量可认为是令人满意的。The microparticles or microspheres of the present invention may encapsulate a large amount of the active ingredient, depending on the type and content of the active ingredient, the dosage form, the duration of release, the subject to be administered, the route of administration, the purpose of administration, the target disease and symptoms, and the like. And choose it properly. However, the dosage can be considered satisfactory as long as the active ingredient can be maintained in the active concentration of the drug for the desired duration in vivo.
当微球以悬浮剂形式给药时，其可与适当的分散介质制成混悬液制剂形式。When the microspheres are administered as a suspension, they may be in the form of a suspension formulation with a suitable dispersion medium.
所述分散介质包括非离子表面活性剂(或稳定剂)、聚氧乙烯蓖麻油衍生物、纤维素增稠剂、海藻酸钠、透明质酸、糊精、淀粉。或可选择的，还可以与其他赋形剂如等渗剂(如氯化钠、甘露醇、甘油、山梨醇、乳糖、木糖醇、麦芽糖、半乳糖、蔗糖、葡萄糖等)、pH调节剂(例如碳酸、醋酸、草酸、柠檬酸、磷酸、盐酸或这些酸的盐，例如碳酸钠、碳酸氢钠等)、防腐剂(例如对羟基苯甲酸酯、对羟基苯甲酸丙酯、苯甲醇、氯代丁醇、山梨酸、硼酸等)等结合，制成水性溶液后通过冷冻干燥法、减压干燥法、喷雾干燥等方法固化，使用前再将固化物溶解于注射用蒸馏水中获得分散微球的分散介质。The dispersion medium includes a nonionic surfactant (or stabilizer), a polyoxyethylene castor oil derivative, a cellulose thickener, sodium alginate, hyaluronic acid, dextrin, and starch. Alternatively, it may be combined with other excipients such as isotonic agents (such as sodium chloride, mannitol, glycerol, sorbitol, lactose, xylitol, maltose, galactose, sucrose, glucose, etc.), pH adjusters. (eg, carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid or salts of these acids, such as sodium carbonate, sodium bicarbonate, etc.), preservatives (eg, parabens, propylparaben, benzyl alcohol) , chlorobutanol, sorbic acid, boric acid, etc., etc., are combined into an aqueous solution, and then solidified by freeze drying, vacuum drying, spray drying, etc., and the cured product is dissolved in distilled water for injection to obtain dispersion before use. A dispersion medium of microspheres.
此外，缓释注射剂也可通过下述方法获得：将微粒或微球分散于植物油(诸如芝麻油及玉米油)或添加有磷脂(诸如卵磷脂)的植物油中，或者分散于中链甘油三酯中，以获得油性混悬液。In addition, sustained-release injections can also be obtained by dispersing microparticles or microspheres in vegetable oils such as sesame oil and corn oil or vegetable oils supplemented with phospholipids such as lecithin, or in medium chain triglycerides. To obtain an oily suspension.
本发明获得的微球可用于颗粒剂形式、悬浮剂形式、埋植剂形式、注射剂形式、粘附剂形式等等，并可以口服或非胃肠道给药(肌内注射、皮下注射、经皮给药、粘膜给药(颊内、阴道内、直肠内等)。The microspheres obtained by the invention can be used in the form of granules, suspensions, implants, injections, adhesives, etc., and can be administered orally or parenterally (intramuscular injection, subcutaneous injection, menstrual injection). Dermal administration, mucosal administration (intracrine, intravaginal, rectal, etc.).
本发明的利培酮缓释组合物足够稳定，可以持续释放数周以上，诸如长达约2周、诸如长达约4周、诸如长达约8周、诸如长达约12周、诸如长达约24周、诸如长达约48周，或更长时间，可根据具体药物特性或治疗需求进行调节。The risperidone sustained release composition of the present invention is sufficiently stable to be sustained for several weeks or more, such as up to about 2 weeks, such as up to about 4 weeks, such as up to about 8 weeks, such as up to about 12 weeks, such as long Up to about 24 weeks, such as up to about 48 weeks, or longer, can be adjusted for specific drug properties or treatment needs.
本发明的水难溶/微溶性药物缓释组合物，制备过程中加入了释放调节剂，所述释放调节 剂能够有效调节水难溶/微溶性药物在所述缓释组合物中的释放速度，使得本发明的水难溶/微溶性药物缓释组合物给药后无明显释放延迟期或突释现象，具有良好的缓释性能，并能在数周或以上的时间内稳定的释放，而且具有较好的稳定性，在长时间存储后仍能够保持其释放行为。本发明所述水难溶/微溶性药物缓释组合物的制备方法，能够快速高效制备得到本发明的水难溶/微溶性药物缓释组合物。The water-insoluble/slightly soluble drug sustained-release composition of the present invention is prepared by adding a release regulator which can effectively adjust the release rate of the water-insoluble/slightly soluble drug in the sustained-release composition. Therefore, the water-insoluble/slightly soluble drug sustained-release composition of the present invention has no obvious release delay period or burst release after administration, has good sustained release property, and can be stably released in a period of several weeks or more. Moreover, it has good stability and can maintain its release behavior after long-term storage. The preparation method of the water-insoluble/slightly soluble drug sustained-release composition of the present invention can rapidly and efficiently prepare the water-insoluble/slightly soluble drug sustained-release composition of the present invention.
具体实施方式detailed description
为更好的说明本发明的目的、技术方案和优点，下面将结合附图和具体实施例对本发明作进一步说明。The present invention will be further described with reference to the accompanying drawings and specific embodiments.
实施例1Example 1
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：恩替卡韦25％、水难溶性聚合物：PLGA 74.9％、释放调节剂：硬脂酸和PEG6000的混合物0.1％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: entecavir 25%, poorly water soluble polymer: PLGA 74.9%, release regulator: 0.1% mixture of stearic acid and PEG6000.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为90：10，所述PLGA的重均分子量为25kDa、粘度为0.24dL/g，且所述PLGA具有端酯基；所述硬脂酸和PEG6000的混合物中，所述PEG6000在所述释放调节剂中的质量百分含量为70％。Wherein the molar ratio of lactide to glycolide in the PLGA is 90:10, the weight average molecular weight of the PLGA is 25 kDa, the viscosity is 0.24 dL/g, and the PLGA has a terminal ester group; In a mixture of fatty acid and PEG 6000, the mass percentage of the PEG 6000 in the release regulator is 70%.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯甲烷中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为12％；(1) dissolving the poorly water-soluble polymer in an organic solvent dichloromethane, and then adding a water-insoluble/slightly soluble drug and a release modifier, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer The mass percentage with the organic solvent is 12%;
(2)将表面活性剂PVA溶于水中，制得浓度为0.1％的PVA水溶液，即得外水相；(2) dissolving the surfactant PVA in water to obtain a PVA aqueous solution having a concentration of 0.1%, that is, obtaining an external aqueous phase;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的60倍，乳化10min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得恩替卡韦缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 60 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain entecavir sustained-release microspheres.
本实施例所得恩替卡韦缓释微球外形圆整、表面光滑，粒径为35～105μm，经测定其载药率为22.54％，恩替卡韦包封率为90.16％。The entecavir sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 35-105 μm. The drug loading rate is 22.54%, and the encapsulation efficiency of entecavir is 90.16%.
实施例2Example 2
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：阿立哌唑27％、水难溶性聚合物：PLGA 72.5％、释放调节剂：山俞酸和PEG4000的混合物0.5％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: aripiprazole 27%, poorly water soluble polymer: PLGA 72.5%, release regulator: 0.5% mixture of behenic acid and PEG4000.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为95：5，所述PLGA的重均分子量为30kDa、粘度为0.29dL/g，且所述PLGA具有端酯基；所述山俞酸和PEG4000的混合物中，所述PEG4000在所述释放调节剂中的质量百分含量为60％。Wherein the molar ratio of lactide to glycolide in the PLGA is 95:5, the weight average molecular weight of the PLGA is 30 kDa, the viscosity is 0.29 dL/g, and the PLGA has a terminal ester group; In a mixture of succinic acid and PEG 4000, the mass percentage of the PEG 4000 in the release regulator is 60%.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯乙烷中，然后加入水难溶/微溶性药物、释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为11％；(1) dissolving the poorly water-soluble polymer in an organic solvent of dichloroethane, then adding a water-insoluble/slightly soluble drug, releasing a regulator, and dissolving to obtain an internal oil phase; wherein the water is poorly soluble in polymerization The mass percentage of the substance to the organic solvent is 11%;
(2)将表面活性剂PVA和无机盐磷酸钾溶于水中，即得外水相，其中所述PVA在所述外水相中的质量浓度为0.5％，所述磷酸钾在所述外水相中的质量浓度为0.01％；(2) dissolving the surfactant PVA and the inorganic salt potassium phosphate in water to obtain an outer aqueous phase, wherein the mass concentration of the PVA in the outer aqueous phase is 0.5%, and the potassium phosphate is in the outer water. The mass concentration in the phase is 0.01%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的65倍，乳化9min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用 超纯水洗涤微球5次，得阿立哌唑缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 65 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 9 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain aripiprazole sustained-release microspheres.
本实施例所得阿立哌唑缓释微球外形圆整、表面光滑，粒径为32～97μm，经测定其载药率为24.09％，阿立哌唑包封率为89.22％。The aripiprazole sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 32-97 μm. The drug loading rate is 24.09%, and the entrapment efficiency of aripiprazole is 89.22%.
实施例3Example 3
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：利培酮30％、水难溶性聚合物：PLA 69.2％、释放调节剂：山俞酸0.8％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: risperidone 30%, poorly water soluble polymer: PLA 69.2%, release regulator: behenic acid 0.8%.
其中，所述PLA的重均分子量为35Da、粘度为0.31dL/g，且所述PLGA具有端酯基。Wherein the PLA has a weight average molecular weight of 35 Da and a viscosity of 0.31 dL/g, and the PLGA has a terminal ester group.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂甲苯中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为10％；(1) dissolving the poorly water-soluble polymer in an organic solvent toluene, and then adding a water-insoluble/slightly soluble drug and a release regulator to dissolve to obtain an internal oil phase; wherein the water-insoluble polymer and the organic The mass percentage of the solvent is 10%;
(2)将表面活性剂PVP和无机盐硫酸钠溶于水中，即得外水相，其中所述PVP在所述外水相中的质量浓度为1％，所述硫酸钠在所述外水相中的质量浓度为0.05％；(2) dissolving the surfactant PVP and the inorganic salt sodium sulfate in water to obtain an outer aqueous phase, wherein the mass concentration of the PVP in the outer aqueous phase is 1%, and the sodium sulfate is in the outer water The mass concentration in the phase is 0.05%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的70倍，乳化10min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得利培酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 70 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain risperidone sustained release microspheres.
本实施例所得利培酮缓释微球外形圆整、表面光滑，粒径为31～95μm，经测定其载药率为28.11％，利培酮包封率为93.7％。The risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 31-95 μm. The drug loading rate is 28.11%, and the risperidone encapsulation efficiency is 93.7%.
实施例4Example 4
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：棕榈酸帕利哌酮33％、水难溶性聚合物：PLGA 66％、释放调节剂：硬脂酸1％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: paliperidone palmitate 33%, poorly water soluble polymer: PLGA 66%, release regulator: 1% stearic acid.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为85：15，所述PLGA的重均分子量为40kDa、粘度为0.35dL/g，且所述PLGA具有端酯基。Wherein, the molar ratio of lactide to glycolide in the PLGA is 85:15, the weight average molecular weight of the PLGA is 40 kDa, the viscosity is 0.35 dL/g, and the PLGA has a terminal ester group.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂苯甲醇中，然后加入水难溶/微溶性药物、释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为9％；(1) dissolving the poorly water-soluble polymer in an organic solvent, benzyl alcohol, and then adding a water-insoluble/slightly soluble drug, a release regulator, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer and the water-insoluble polymer The mass percentage of the organic solvent is 9%;
(2)将表面活性剂甲基纤维素和无机盐乙酸钾溶于水中，即得外水相，其中所述甲基纤维素在所述外水相中的质量浓度为2％，所述乙酸钾在所述外水相中的质量浓度为1％；(2) dissolving the surfactant methylcellulose and the inorganic salt potassium acetate in water to obtain an external aqueous phase, wherein the methyl cellulose has a mass concentration of 2% in the outer aqueous phase, the acetic acid The mass concentration of potassium in the outer aqueous phase is 1%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的75倍，乳化15min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球7次，得棕榈酸帕利哌酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 75 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 15 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 7 times with ultrapure water to obtain paliperidone palmitate sustained release microspheres.
本实施例所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为32～90μm，经测定其载药率为30.25％，棕榈酸帕利哌酮包封率为91.77％。The sustained release microspheres of paliperidic palmitate obtained in this example have a round shape and a smooth surface, and the particle size is 32-90 μm. The drug loading rate is 30.25%, and the encapsulation efficiency of paliperidone palmitate is 91.77%. .
实施例5Example 5
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：利培酮35％、水难溶性聚合物：PLGA 63％、释放调节剂：硬脂酸和PEG3000的混合物2％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: risperidone 35%, poorly water soluble polymer: PLGA 63%, release regulator: 2% mixture of stearic acid and PEG3000.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为85：15，所述PLGA的重均分子量为50kDa、粘度为0.39dL/g，且所述PLGA具有端羧基；所述硬脂酸和PEG3000的混合物中，所述PEG3000在所述释放调节剂中的质量百分含量为30％。Wherein the molar ratio of lactide to glycolide in the PLGA is 85:15, the weight average molecular weight of the PLGA is 50 kDa, the viscosity is 0.39 dL/g, and the PLGA has a terminal carboxyl group; the hard fat In a mixture of acid and PEG3000, the mass percentage of the PEG 3000 in the release regulator is 30%.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂氯仿中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为8％；(1) dissolving the poorly water-soluble polymer in an organic solvent, chloroform, and then adding a water-insoluble/slightly soluble drug and a release modifier, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer and the organic The mass percentage of the solvent is 8%;
(2)将表面活性剂PVA溶于水中，即得外水相，其中所述PVA在所述外水相中的质量浓度为3％；(2) The surfactant PVA is dissolved in water, that is, the outer aqueous phase is obtained, wherein the mass concentration of the PVA in the outer aqueous phase is 3%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的80倍，乳化10min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得利培酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 80 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain risperidone sustained release microspheres.
本实施例所得利培酮缓释微球外形圆整、表面光滑，粒径为28～86μm，经测定其载药率为32.43％，利培酮包封率为90.08％。The risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 28-86 μm. The drug-loading rate is 32.43%, and the encapsulation efficiency of risperidone is 90.08%.
实施例6Example 6
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：棕榈酸帕利哌酮38％、水难溶性聚合物：PLGA 59％、释放调节剂：木质素酸和PEG2000的混合物3％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% Water-insoluble/slightly soluble drug: paliperidone palmitate 38%, poorly water-soluble polymer: PLGA 59%, release regulator: 3% mixture of lignin acid and PEG2000.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为75：25，所述PLGA的重均分子量为60kDa、粘度为0.55dL/g，且所述PLGA具有端羧基；所述木质素酸和PEG2000的混合物中，所述PEG2000在所述释放调节剂中的质量百分含量为80％。Wherein the molar ratio of lactide to glycolide in the PLGA is 75:25, the weight average molecular weight of the PLGA is 60 kDa, the viscosity is 0.55 dL/g, and the PLGA has a terminal carboxyl group; the lignin In a mixture of acid and PEG2000, the mass percentage of the PEG 2000 in the release modifier is 80%.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯甲烷中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为7％；(1) dissolving the poorly water-soluble polymer in an organic solvent dichloromethane, and then adding a water-insoluble/slightly soluble drug and a release modifier, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer The mass percentage with the organic solvent is 7%;
(2)将表面活性剂白蛋白溶于水中，即得外水相，其中所述白蛋白在所述外水相中的质量浓度为4％，所述碳酸钠在所述外水相中的质量浓度为2％；(2) dissolving the surfactant albumin in water to obtain an external aqueous phase, wherein the albumin has a mass concentration of 4% in the outer aqueous phase, and the sodium carbonate is in the outer aqueous phase. The mass concentration is 2%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的85倍，乳化11min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球3次，得棕榈酸帕利哌酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 85 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 11 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 3 times with ultrapure water to obtain paliperidone palmitate sustained release microspheres.
本实施例所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为23～91μm，经测定其载药率为34.29％，棕榈酸帕利哌酮包封率为90.23％。The sustained release microspheres of paliperidic palmitate obtained in this example have a round shape and a smooth surface, and the particle size is 23-91 μm. The drug loading rate is determined to be 34.29%, and the encapsulation efficiency of paliperidone palmitate is 90.23%. .
实施例7Example 7
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：阿立哌唑40％、水难溶性聚合物：PLGA 56％、释放调节剂：花生酸和聚乙烯吡咯烷酮的混合物4％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: aripiprazole 40%, poorly water soluble polymer: PLGA 56%, release regulator: 4% mixture of arachidic acid and polyvinylpyrrolidone.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为75：25，所述PLGA的重均分子量为70kDa、粘度为0.60dL/g，且所述PLGA具有端酯基；所述花生酸和聚乙烯吡咯烷酮的混合物中，所述聚乙烯吡咯烷酮在所述释放调节剂中的质量百分含量为80％。Wherein the molar ratio of lactide to glycolide in the PLGA is 75:25, the weight average molecular weight of the PLGA is 70 kDa, the viscosity is 0.60 dL/g, and the PLGA has a terminal ester group; In a mixture of an acid and polyvinylpyrrolidone, the polyvinylpyrrolidone is present in the release modifier in an amount of 80% by mass.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于体积比为8:2的二氯甲烷/苯甲醇中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为6％；(1) dissolving the poorly water-soluble polymer in methylene chloride/benzyl alcohol in a volume ratio of 8:2, and then adding a water-insoluble/slightly soluble drug and a release regulator, and dissolving to obtain an internal oil phase; The mass percentage of the poorly water-soluble polymer to the organic solvent is 6%;
(2)将表面活性剂胆酸溶于水中，即得外水相，其中所述胆酸在所述外水相中的质量浓度为5％；(2) The surfactant bile acid is dissolved in water, that is, the outer aqueous phase is obtained, wherein the mass concentration of the bile acid in the outer aqueous phase is 5%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的90倍，乳化12min得O/W乳液，然后搅拌(500rpm，5h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得阿立哌唑缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 90 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 12 minutes, and then stirred (500 rpm, 5 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain aripiprazole sustained-release microspheres.
本实施例所得阿立哌唑缓释微球外形圆整、表面光滑，粒径为22～93μm，经测定其载药率为35.33％，阿立哌唑包封率为88.33％。The aripiprazole sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle diameter is 22-93 μm. The drug loading rate is 35.33%, and the entrapment efficiency of aripiprazole is 88.33%.
实施例8Example 8
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：棕榈酸帕利哌酮42％、水难溶性聚合物：PLA 53％、释放调节剂：PEG1200 5％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: paliperidone palmitate 42%, poorly water soluble polymer: PLA 53%, release regulator: PEG1200 5%.
其中，所述PLA为PLA(100/0、80kDa，0.65dL/g，羧基端)和PLA(100/0、80kDa，0.65dL/g，酯基端)的等比例混合物。Wherein, the PLA is an equal mixture of PLA (100/0, 80 kDa, 0.65 dL/g, carboxyl end) and PLA (100/0, 80 kDa, 0.65 dL/g, ester base).
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯乙烷中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为5％；(1) dissolving the poorly water-soluble polymer in an organic solvent, dichloroethane, and then adding a water-insoluble/slightly soluble drug and a release modifier, and dissolving to obtain an internal oil phase; wherein the water is poorly soluble in polymerization The mass percentage of the substance to the organic solvent is 5%;
(2)将表面活性剂PVA溶于水溶液中，即得外水相，其中所述PVA在所述外水相中的质量浓度为6％；(2) The surfactant PVA is dissolved in an aqueous solution, that is, an external aqueous phase is obtained, wherein the mass concentration of the PVA in the external aqueous phase is 6%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的95倍，乳化10min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得棕榈酸帕利哌酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 95 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain paliperidone palmitate sustained-release microspheres.
本实施例所得棕榈酸帕利哌酮缓释微球外形圆整、表面光滑，粒径为20～87μm，经测定其载药率为38.55％，棕榈酸帕利哌酮包封率为91.79％。The sustained release microspheres of paliperidone palmitate obtained in this example have a round shape and a smooth surface, and the particle size is 20-87 μm. The drug loading rate is 38.55%, and the encapsulation efficiency of paliperidone palmitate is 91.79%. .
实施例9Example 9
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：奥氮平双羟萘酸盐44％、水难溶性聚合物：PLGA 50％、释放调节剂：山俞酸和PEG1000的混合物6％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: olanzapine pamoate 44%, poorly water soluble polymer: PLGA 50%, release regulator: 6% mixture of behenic acid and PEG1000.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为65：35，所述PLGA的重均分子量为90kDa、粘度为0.7dL/g，且所述PLGA具有端羧基；所述山俞酸和PEG1000的混合物中，所述PEG1000在所述释放调节剂中的质量百分含量为90％。Wherein the molar ratio of lactide to glycolide in the PLGA is 65:35, the weight average molecular weight of the PLGA is 90 kDa, the viscosity is 0.7 dL/g, and the PLGA has a terminal carboxyl group; In a mixture of an acid and PEG 1000, the mass percentage of the PEG 1000 in the release regulator is 90%.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂氯仿中，然后加入水难溶/微溶性药物、释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为4％；(1) dissolving the poorly water-soluble polymer in an organic solvent chloroform, then adding a water-insoluble/slightly soluble drug, releasing a regulator, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer and the organic The mass percentage of the solvent is 4%;
(2)将表面活性剂PVA溶于水中，即得外水相，其中所述PVA在所述外水相中的质量浓度为7％；(2) The surfactant PVA is dissolved in water, that is, the outer aqueous phase is obtained, wherein the mass concentration of the PVA in the outer aqueous phase is 7%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的100倍，乳化10min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球4次，得奥氮平双羟萘酸缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 100 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 4 times with ultrapure water to obtain olanzapine pamoate sustained release microspheres.
本实施例所得奥氮平双羟萘酸缓释微球外形圆整、表面光滑，粒径为20～96μm，经测定其载药率为38.02％，奥氮平双羟萘酸包封率为86.41％。The olanzapine pamoate sustained-release microsphere obtained in this embodiment has a round shape and a smooth surface, and the particle diameter is 20-96 μm. The drug loading rate is 38.02%, and the encapsulation efficiency of olanzapine pamoate is measured. 86.41%.
实施例10Example 10
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：齐拉西酮50％、水难溶性聚合物：PLA 43％、释放调节剂：棕榈酸和蛋白的混合物7％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : water-insoluble/slightly soluble drug: ziprasidone 50%, poorly water-soluble polymer: PLA 43%, release regulator: 7% mixture of palmitic acid and protein.
其中，所述PLA的重均分子量为100kDa、粘度为0.81dL/g，且所述PLA具有端羧基；所述棕榈酸和蛋白的混合物中，所述蛋白在所述释放调节剂中的质量百分含量为40％。Wherein the PLA has a weight average molecular weight of 100 kDa and a viscosity of 0.81 dL/g, and the PLA has a terminal carboxyl group; and the mixture of palmitic acid and protein has a mass of the protein in the release regulator. The content of the fraction is 40%.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯甲烷中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为3.5％；(1) dissolving the poorly water-soluble polymer in an organic solvent dichloromethane, and then adding a water-insoluble/slightly soluble drug and a release modifier, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer The mass percentage with the organic solvent is 3.5%;
(2)将表面活性剂藻酸钾溶于水中，即得外水相，其中所述藻酸钾在所述外水相中的质量浓度为8％；(2) The surfactant potassium alginate is dissolved in water to obtain an external aqueous phase, wherein the mass concentration of the potassium alginate in the outer aqueous phase is 8%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的105倍，乳化10min得O/W乳液，然后搅拌(700rpm，4h)将微球固化，离心收集微球，并用超纯水洗涤微球6次，得齐拉西酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 105 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (700 rpm, 4 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 6 times with ultrapure water to obtain ziprasidone sustained-release microspheres.
本实施例所得齐拉西酮缓释微球外形圆整、表面光滑，粒径为27～91μm，经测定其载药率为44.75％，齐拉西酮包封率为89.5％。The ziprasidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and have a particle diameter of 27 to 91 μm. The drug loading rate is 44.75%, and the encapsulation efficiency of ziprasidone is 89.5%.
实施例11Example 11
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：阿那曲唑55％、水难溶性聚合物：PLGA 37％、释放调节剂：肉豆蔻酸和氨基酸的混合物8％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: anastrozole 55%, poorly water soluble polymer: PLGA 37%, release regulator: 8% mixture of myristic acid and amino acids.
其中，所述PLGA为PLGA一和PLGA二的混合物，所述PLGA一中丙交酯与乙交酯的摩尔比为85：15，所述PLGA一的重均分子量为125kDa、粘度为0.94dL/g，且所述PLGA一具有端羧基；所述PLGA二中丙交酯与乙交酯的摩尔比为65:35，所述PLGA二的重均分子量为105kDa、粘度为0.75dL/g，且所述PLGA二具有端羧基；所述肉豆蔻酸和氨基酸的混合物中，所述氨基酸在所述释放调节剂中的质量百分含量为95％。Wherein, the PLGA is a mixture of PLGA- and PLGA, the molar ratio of the PLGA-to-lactide to the glycolide is 85:15, and the weight average molecular weight of the PLGA-I is 125 kDa, and the viscosity is 0.94 dL/ g, and the PLGA has a terminal carboxyl group; the molar ratio of the lactide to the glycolide in the PLGA is 65:35, and the weight average molecular weight of the PLGA is 105 kDa and the viscosity is 0.75 dL/g, and The PLGA dimer has a terminal carboxyl group; in the mixture of myristic acid and an amino acid, the amino acid has a mass percentage of 95% in the release regulator.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯甲烷中，然后加入水难溶/微溶性药物和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为3％；(1) dissolving the poorly water-soluble polymer in an organic solvent dichloromethane, and then adding a water-insoluble/slightly soluble drug and a release modifier, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer The mass percentage with the organic solvent is 3%;
(2)将表面活性剂泊洛沙姆溶于水中，即得外水相，其中所述泊洛沙姆在所述外水相中的质量浓度为9％；(2) The surfactant poloxamer is dissolved in water to obtain an external aqueous phase, wherein the mass concentration of the poloxamer in the external aqueous phase is 9%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的110倍，乳化10min得O/W乳液，然后搅拌(400rpm，8h)将微球固化，离心收集微球，并 用超纯水洗涤微球5次，得阿那曲唑酸缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 110 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (400 rpm, 8 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain anastrozole acid sustained-release microspheres.
本实施例所得阿那曲唑缓释微球外形圆整、表面光滑，粒径为23～84μm，经测定其载药率为45.42％，阿那曲唑包封率为87.35％。The anastrozole sustained-release microspheres obtained in this embodiment have a round shape and a smooth surface, and the particle size is 23-84 μm. The drug loading rate is determined to be 45.42%, and the encapsulation efficiency of anastrozole is 87.35%.
实施例12Example 12
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：多奈哌齐60％、水难溶性聚合物：PLGA 29％、释放调节剂：月桂酸和PEG600的混合物10％、抗氧化剂：三羟基苯丁酮1％。。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: donepezil 60%, poorly water soluble polymer: PLGA 29%, release regulator: 10% mixture of lauric acid and PEG600, antioxidant: trihydroxybutyroin 1%. .
其中，所述PLGA中丙交酯与乙交酯的摩尔比为50：50，所述PLGA的重均分子量为150kDa、粘度为1.16dL/g，且所述PLGA具有端酯基；所述月桂酸和PEG600的混合物中，所述PEG600在所述释放调节剂中的质量百分含量为50％。Wherein the molar ratio of lactide to glycolide in the PLGA is 50:50, the weight average molecular weight of the PLGA is 150 kDa, the viscosity is 1.16 dL/g, and the PLGA has a terminal ester group; the laurel In a mixture of acid and PEG 600, the mass percentage of the PEG 600 in the release modifier is 50%.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂四氯乙烯中，然后加入水难溶/微溶性药物、和抗氧化剂和释放调节剂，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为3％；(1) dissolving the poorly water-soluble polymer in an organic solvent of tetrachloroethylene, then adding a water-insoluble/slightly soluble drug, and an antioxidant and a release regulator, and dissolving to obtain an internal oil phase; wherein the water The mass percentage of the poorly soluble polymer to the organic solvent is 3%;
(2)将表面活性剂羧甲基纤维素钠溶于水中，即得外水相，其中所述羧甲基纤维素钠在所述外水相中的质量浓度为10％；(2) The surfactant sodium carboxymethylcellulose is dissolved in water to obtain an external aqueous phase, wherein the mass concentration of the sodium carboxymethylcellulose in the external aqueous phase is 10%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的120倍，乳化10min得O/W乳液，然后搅拌(600rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得多奈哌齐缓释微球。(3) The internal oil phase obtained in the step (1) is added to the external aqueous phase, wherein the volume of the external aqueous phase is 120 times the volume of the internal oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (600 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to release the microspheres with donepezil.
本实施例所得多奈哌齐缓释微球外形圆整、表面光滑，粒径为20～81μm，经测定其载药率为49.71％，多奈哌齐包封率为90.38％。The donepezil sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle size is 20-81 μm. The drug loading rate is 49.71%, and the encapsulation efficiency of donepezil is 90.38%.
实施例13Example 13
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：利培酮35％、水难溶性聚合物：PLGA 63％、释放调节剂：PEG400 2％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: risperidone 35%, poorly water soluble polymer: PLGA 63%, release regulator: PEG400 2%.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为75：25，所述PLGA的重均分子量为105kDa、粘度为0.83dL/g，且所述PLGA具有端酯基。Wherein, the molar ratio of lactide to glycolide in the PLGA is 75:25, the weight average molecular weight of the PLGA is 105 kDa, the viscosity is 0.83 dL/g, and the PLGA has a terminal ester group.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯甲烷中，然后加入水难溶性药物，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为5％；(1) dissolving the poorly water-soluble polymer in an organic solvent dichloromethane, and then adding a poorly water-soluble drug, and dissolving to obtain an internal oil phase; wherein the mass percentage of the poorly water-soluble polymer and the organic solvent is 5%;
(2)将表面活性剂壳聚糖溶于水中，然后加入释放调节剂溶解混匀，即得外水相，其中所述壳聚糖在所述外水相中的质量浓度为1％；(2) The surfactant chitosan is dissolved in water, and then added to the release regulator to dissolve and mix, that is, the outer aqueous phase is obtained, wherein the mass concentration of the chitosan in the outer aqueous phase is 1%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的100倍，乳化10min得O/W乳液，然后搅拌(500rpm，7h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得利培酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 100 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 7 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain risperidone sustained release microspheres.
本实施例所得利培酮缓释微球外形圆整、表面光滑，粒径为25～98μm，经测定其载药率为32.46％，利培酮包封率为92.74％。The risperidone sustained-release microspheres obtained in the present embodiment have a round shape and a smooth surface, and the particle diameter is 25-98 μm. The drug-loading rate is 32.46%, and the encapsulation efficiency of risperidone is 92.74%.
实施例14Example 14
本发明水难溶/微溶性药物缓释组合物的一种实施例，本实施例所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含以下质量百分含量的组分：水难溶/微溶性药物：帕利哌酮35％、水难溶性聚合物：PLGA 63％、释放调节剂：PEG3000 2％。An embodiment of the water-insoluble/slightly soluble drug sustained-release composition of the present invention, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition of the present embodiment comprises the following components by mass% : poorly water soluble / slightly soluble drugs: paliperidone 35%, poorly water soluble polymer: PLGA 63%, release regulator: PEG3000 2%.
其中，所述PLGA中丙交酯与乙交酯的摩尔比为75：25，所述PLGA的重均分子量为105kDa、粘度为0.83dL/g，且所述PLGA具有端酯基。Wherein, the molar ratio of lactide to glycolide in the PLGA is 75:25, the weight average molecular weight of the PLGA is 105 kDa, the viscosity is 0.83 dL/g, and the PLGA has a terminal ester group.
本实施例所述水难溶/微溶性药物缓释组合物采用以下方法制备而成：The water-insoluble/slightly soluble drug sustained-release composition of the present embodiment is prepared by the following method:
(1)将所述水难溶性聚合物溶于有机溶剂二氯甲烷中，然后加入水难溶/微溶性药物，溶解后得到内油相；其中，所述水难溶性聚合物与有机溶剂的质量百分比为5％；(1) dissolving the poorly water-soluble polymer in an organic solvent dichloromethane, and then adding a water-insoluble/slightly soluble drug, and dissolving to obtain an internal oil phase; wherein the water-insoluble polymer and the organic solvent are The mass percentage is 5%;
(2)将表面活性剂羟丙甲纤维素溶于水中，然后加入释放调节剂溶解混匀，即得外水相，其中所述羟丙甲纤维素在所述外水相中的质量浓度为1％；(2) dissolving the surfactant hypromellose in water, then adding a release regulator to dissolve and mix, that is, obtaining an external aqueous phase, wherein the mass concentration of the hypromellose in the outer aqueous phase is 1%;
(3)将步骤(1)得到的内油相加入到外水相中，其中所述外水相体积是内油相体积的90倍，乳化10min得O/W乳液，然后搅拌(500rpm，6h)将微球固化，离心收集微球，并用超纯水洗涤微球5次，得帕利哌酮缓释微球。(3) The internal oil phase obtained in the step (1) is added to the outer aqueous phase, wherein the outer aqueous phase volume is 90 times the volume of the inner oil phase, and the O/W emulsion is obtained by emulsification for 10 minutes, and then stirred (500 rpm, 6 hours). The microspheres were solidified, the microspheres were collected by centrifugation, and the microspheres were washed 5 times with ultrapure water to obtain paliperidone sustained-release microspheres.
本实施例所得帕利哌酮缓释微球外形圆整、表面光滑，粒径为29～100μm，经测定其载药率为32.74％，帕利哌酮包封率为93.54％。The paliperidone sustained-release microspheres obtained in this example have a round shape and a smooth surface, and the particle diameter is 29-100 μm. The drug loading rate is 32.74%, and the encapsulation efficiency of paliperidone is 93.54%.
实施例15Example 15
本发明水难溶/微溶性药物缓释组合物的体外释放度测定Determination of in vitro release of the poorly water soluble/slightly soluble drug sustained release composition of the present invention
分别采用实施例1～14制备得到的水难溶/微溶性药物缓释微球作为试验组1～14，采用以下两个对比例作为对照组：The water-insoluble/slightly soluble drug sustained-release microspheres prepared in Examples 1 to 14 were used as test groups 1 to 14, respectively, and the following two comparative examples were used as a control group:
对比例1：制备方法同专利CN1137756中实施例1，其中投料：利培酮35％、PLGA(75/25，105kDa，0.83dL/g，酯基端)65％。所得利培酮缓释微球外形圆整，粒径为34～131μm，经测定其载药率为31.95％，利培酮包封率为91.29％。Comparative Example 1: The preparation method was the same as in Example 1 of Patent CN1137756, in which risperidone 35%, PLGA (75/25, 105 kDa, 0.83 dL/g, ester base) 65% was charged. The obtained risperidone sustained-release microspheres have a round shape and a particle size of 34-131 μm. The drug loading rate is 31.95%, and the encapsulation efficiency of risperidone is 91.29%.
对比例2：制备方法同专利CN104013578中实施例1，其中投料：利培酮35％、PLGA(75/25，105kDa，0.83dL/g，酯基端)65％。所得利培酮缓释微球外形圆整，粒径为25～118μm，经测定其载药率为31.35％，利培酮包封率为89.57％。Comparative Example 2: The preparation method was the same as in Example 1 of Patent CN104013578, in which risperidone 35%, PLGA (75/25, 105 kDa, 0.83 dL/g, ester base) 65% was charged. The obtained risperidone sustained-release microspheres have a round shape and a particle size of 25-118 μm. The drug loading rate is 31.35%, and the risperidone encapsulation efficiency is 89.57%.
测试方法：精密称取实施例1-14及对比例1-2制备的微球各20mg置于200mL离心管中，加pH7.4PBS(含0.05％吐温80，0.05％叠氮化钠)50mL，置于37℃、150rpm恒温水浴振荡器中，在预设时间点取出1mL释放液，补充等量新鲜介质后置于恒温水浴振荡器中继续释放度试验。取出液采用高效液相色谱法(HPLC)检测药物释放量，结果如表1和表2所示。Test method: accurately weighed 20 mg of each of the microspheres prepared in Examples 1-14 and Comparative Example 1-2 in a 200 mL centrifuge tube, and added pH 7.4 PBS (containing 0.05% Tween 80, 0.05% sodium azide) 50 mL. Place it in a 37 ° C, 150 rpm constant temperature water bath shaker, take 1 mL of the release solution at the preset time point, add an equal amount of fresh medium, and place it in a constant temperature water bath oscillator to continue the release test. The amount of drug released was determined by high performance liquid chromatography (HPLC), and the results are shown in Tables 1 and 2.
表1缓释微球的体外释放数据Table 1 In vitro release data of sustained release microspheres
时间/天Time/day 实施例1Example 1 实施例2Example 2 实施例3Example 3 实施例4Example 4 实施例5Example 5 实施例6Example 6 实施例7Example 7 实施例8Example 8
0.040.04 0.050.05 0.100.10 00 0.200.20 00 00 00 00
0.50.5 0.450.45 0.440.44 0.170.17 0.520.52 00 0.370.37 0.210.21 00
11 0.780.78 0.730.73 0.390.39 1.321.32 0.400.40 1.251.25 1.021.02 0.200.20
22 1.231.23 1.111.11 0.950.95 1.641.64 0.900.90 3.593.59 4.304.30 0.400.40
77 12.8912.89 12.0512.05 4.974.97 15.8415.84 11.8911.89 19.6319.63 19.5619.56 3.503.50
1414 29.6529.65 26.9326.93 16.4216.42 37.0537.05 25.7225.72 47.3947.39 45.2145.21 13.4013.40
21twenty one 63.2063.20 57.4757.47 36.3236.32 60.2160.21 45.6245.62 86.3486.34 82.7682.76 24.9824.98
2828 93.1893.18 83.8783.87 54.4154.41 78.7278.72 64.2664.26 97.1597.15 95.3495.34 37.2937.29
3535 99.3299.32 95.1395.13 68.6368.63 90.1490.14 81.1681.16 100.00100.00 100.00100.00 47.0847.08
4242 100.00100.00 99.7299.72 79.4479.44 99.0099.00 90.5090.50 100.00100.00 100.00100.00 58.2158.21
4949 100.00100.00 100.00100.00 87.2987.29 100.00100.00 100.00100.00 -- -- 67.7567.75
5656 -- 100.00100.00 93.6093.60 100.00100.00 100.00100.00 -- -- 76.7376.73
6363 -- -- 100.00100.00 -- -- -- -- 83.7483.74
7777 -- -- 100.00100.00 -- -- -- -- 96.4896.48
9191 -- -- -- -- -- -- -- 100.00100.00
105105 -- -- -- -- -- -- -- 100.00100.00
表2缓释微球的体外释放数据Table 2 In vitro release data of sustained release microspheres
Figure PCTCN2018073901-appb-000001
Figure PCTCN2018073901-appb-000001
从表1和表2可以看出，本发明的缓释微球没有突释效应，首日释放率不超过2％，而且能在120天内以接近零级趋势释放，具有明显的缓释效果，而且没有出现突释或者前期释放缓慢后期释放加剧的现象，说明这些微球表层和芯部的聚合物的降解速率没有出现可见的差别，说明了其中的释放调节剂产生空隙使得微球内部降解产生的酸性产物及时传送至外部，避免或大大减少出现芯部聚合物自催化降解速度加快的现象，有效的克服了PLA或PLGA体降解效应的弊端。It can be seen from Table 1 and Table 2 that the sustained release microspheres of the present invention have no burst effect, and the release rate on the first day is not more than 2%, and can be released in a near zero-order trend within 120 days, and has a significant sustained release effect. Moreover, there is no sudden release or a slow release of late release in the early stage, indicating that there is no visible difference in the degradation rate of the polymer of the surface and core of these microspheres, indicating that the release modifier produces voids to cause internal degradation of the microspheres. The acidic product is transported to the outside in time, avoiding or greatly reducing the phenomenon that the auto-catalytic degradation rate of the core polymer is accelerated, and effectively overcomes the disadvantages of the PLA or PLGA body degradation effect.
从表1和表2中实施例与对比例的对比可以看出，本发明的微球相对对比例明显缩短了 延迟释放期，而且没有突释现象，说明本发明通过加入释放调节剂能够明显的改善缓释微球的释放行为，大大缩短微球的释放迟滞期，使病人避免或减少注射服药后仍需口服普通制剂，显著增加给药依从性和便利性。From the comparison of the examples in Table 1 and Table 2 with the comparative examples, it can be seen that the relative proportion of the microspheres of the present invention is significantly shortened by the delayed release period, and there is no burst release phenomenon, indicating that the present invention can be apparent by adding a release modifier. Improve the release behavior of the sustained-release microspheres, greatly shorten the release lag period of the microspheres, and enable the patient to avoid or reduce the need to take oral common preparations after the injection, significantly increasing the compliance and convenience of administration.
实施例16Example 16
本发明水难溶/微溶性药物缓释微球的稳定性效果试验Stability test of water-insoluble/slightly soluble drug sustained-release microspheres of the present invention
根据中国药典(2015版四部)9001原料药物与制剂稳定性试验指导原则，需要在冰箱(4-8℃)保存的对温度敏感的药物的加速试验，在25℃±2℃、相对湿度60％±10％的条件下进行，时间为6个月。将实施例1～14和对比例1～2的微球置于25℃±2℃、相对湿度60％±10％的药品稳定性试验箱中考察加速稳定性，分别于第30天、第90天和第180天取样(n＝3)测释放行为，释放行为测定方法同实施例15。结果如表3～8所示。实施例1～14和对比例的微球第0天的释放行为见表1和表2。According to the Chinese Pharmacopoeia (2015 edition four) 9001 raw material drugs and preparation stability test guidelines, the need for accelerated test of temperature-sensitive drugs stored in the refrigerator (4-8 ° C), at 25 ° C ± 2 ° C, relative humidity 60% Performed under ±10% conditions for 6 months. The microspheres of Examples 1 to 14 and Comparative Examples 1 and 2 were placed in a drug stability test chamber at 25 ° C ± 2 ° C and a relative humidity of 60% ± 10% to investigate the acceleration stability on the 30th day and the 90th, respectively. The release behavior was measured at day and day 180 (n=3), and the release behavior was measured in the same manner as in Example 15. The results are shown in Tables 3-8. The release behavior of the microspheres of Examples 1 to 14 and Comparative Examples on Day 0 is shown in Tables 1 and 2.
表3第30天加速稳定性样品的体外释放数据In vitro release data of accelerated stability samples on day 30 of Table 3
Figure PCTCN2018073901-appb-000002
Figure PCTCN2018073901-appb-000002
表4第30天加速稳定性样品的体外释放数据In vitro release data of accelerated stability samples on day 30 of Table 4
Figure PCTCN2018073901-appb-000003
Figure PCTCN2018073901-appb-000003
Figure PCTCN2018073901-appb-000004
Figure PCTCN2018073901-appb-000004
表5第90天加速稳定性样品的体外释放数据In vitro release data of accelerated stability samples on day 90 of Table 5.
时间/天Time/day 实施例1Example 1 实施例2Example 2 实施例3Example 3 实施例4Example 4 实施例5Example 5 实施例6Example 6 实施例7Example 7 实施例8Example 8
0.040.04 0.290.29 0.340.34 00 0.290.29 00 0.160.16 0.110.11 0.100.10
0.50.5 0.520.52 0.570.57 0.230.23 0.680.68 0.210.21 0.520.52 0.380.38 0.200.20
11 0.910.91 0.950.95 0.630.63 1.521.52 0.730.73 1.461.46 1.461.46 0.420.42
22 1.351.35 1.561.56 1.251.25 1.861.86 1.351.35 4.974.97 5.695.69 0.570.57
77 14.0214.02 14.0714.07 5.375.37 17.6217.62 13.5613.56 22.0722.07 22.2422.24 4.694.69
1414 32.0732.07 29.9429.94 18.8618.86 39.0839.08 27.6227.62 49.3249.32 48.1648.16 14.9814.98
21twenty one 65.0965.09 61.0461.04 38.6738.67 63.3163.31 48.2248.22 88.6488.64 85.3285.32 27.1427.14
2828 94.9894.98 86.0686.06 56.7256.72 83.0283.02 66.9866.98 99.1699.16 97.8797.87 39.4939.49
3535 100.00100.00 97.1397.13 70.9170.91 93.3893.38 84.2684.26 100.00100.00 100.00100.00 49.9749.97
4242 100.00100.00 100.00100.00 81.9181.91 100.00100.00 94.0694.06 100.00100.00 100.00100.00 61.1461.14
4949   100.00100.00 89.0889.08 100.00100.00 100.00100.00     70.2570.25
5656     96.0796.07         79.0379.03
6363     100.00100.00         85.4185.41
7777               98.9498.94
9191               100.00100.00
105105               100.00100.00
表6第90天加速稳定性样品的体外释放数据Table 6 In vitro release data of accelerated stability samples on day 90
Figure PCTCN2018073901-appb-000005
Figure PCTCN2018073901-appb-000005
Figure PCTCN2018073901-appb-000006
Figure PCTCN2018073901-appb-000006
表7第180天加速稳定性样品的体外释放数据In vitro release data of accelerated stability samples on day 180 of Table 7
时间/天Time/day 实施例1Example 1 实施例2Example 2 实施例3Example 3 实施例4Example 4 实施例5Example 5 实施例6Example 6 实施例7Example 7 实施例8Example 8
0.040.04 0.160.16 0.390.39 0.110.11 0.410.41 0.050.05 0.210.21 0.230.23 0.210.21
0.50.5 0.630.63 0.670.67 0.390.39 0.820.82 0.320.32 0.760.76 0.510.51 0.320.32
11 1.241.24 1.261.26 0.840.84 1.731.73 0.840.84 1.681.68 1.591.59 0.530.53
22 1.591.59 1.741.74 1.421.42 2.032.03 1.501.50 5.065.06 5.875.87 0.780.78
77 15.2615.26 14.2514.25 5.665.66 19.6719.67 15.0615.06 23.5823.58 24.4324.43 5.065.06
1414 33.4233.42 31.2431.24 20.1620.16 42.0642.06 29.1329.13 50.8550.85 49.1749.17 15.4915.49
21twenty one 66.2266.22 63.3763.37 40.0940.09 64.8164.81 49.9849.98 90.0690.06 86.6986.69 29.5729.57
2828 96.3896.38 87.9687.96 58.8458.84 85.2185.21 69.0569.05 99.9799.97 98.2498.24 41.3241.32
3535 100.00100.00 98.9498.94 72.6472.64 95.0795.07 86.2486.24 100.00100.00 100.00100.00 52.6952.69
4242 100.00100.00 100.00100.00 83.2583.25 100.00100.00 95.2195.21 100.00100.00 100.00100.00 64.0764.07
4949   100.00100.00 91.3691.36 100.00100.00 100.00100.00     72.5172.51
5656     98.2798.27   100.00-100.00-     81.6581.65
6363     100.00100.00         87.1687.16
7777     100.00100.00         100.00100.00
9191               100.00100.00
表8第180天加速稳定性样品的体外释放数据Table 8 In vitro release data of accelerated stability samples on day 180
Figure PCTCN2018073901-appb-000007
Figure PCTCN2018073901-appb-000007
Figure PCTCN2018073901-appb-000008
Figure PCTCN2018073901-appb-000008
对比表1～8可以看出，本发明所得微球在加速稳定性测定环境下，释放行为没有显著的改变，而对比例的样品随着放置时间增加，其释放行为发生了明显的变化，具体体现为释放时间提前，由14-21天开始释放提前至2-14天开始释放。如果按照市售产品(恒德)的给药方法，由于药物提前释放，叠加口服给药的剂量，会导致病人血液中的血液浓度增加。对于利培酮等抗精神病药物，血液浓度增加将会导致较为严重的副反应，对病人的治疗、生活和工作造成不可忽视的影响。Comparing Tables 1 to 8, it can be seen that the release behavior of the microspheres obtained by the present invention in the accelerated stability measurement environment is not significantly changed, and the release behavior of the sample of the comparative example changes significantly with the increase of the placement time. It is reflected that the release time is advanced, and the release begins from 14-21 days and is released from 2-14 days in advance. According to the administration method of the commercially available product (Hengde), due to the early release of the drug, the dose of the oral administration is superimposed, which causes an increase in the blood concentration in the blood of the patient. For antipsychotic drugs such as risperidone, an increase in blood concentration will lead to more serious side effects, which may have a negligible effect on the treatment, life and work of patients.
实施例17Example 17
本发明水难溶/微溶性药物缓释组合物的动物试验Animal test of the water-insoluble/slightly soluble drug sustained-release composition of the invention
取重量为2.0kg-3.0kg的新西兰大耳白兔，每组6只(随机分组)，雌雄各半，每组分别肌肉注射含有实施例1～14和对比例1-2制备的微球的1.2ml含0.5％CMC-Na的生理盐水溶液的混悬液，每剂量的混悬液中的缓释微球的水难溶/微溶性药物含量为18mg，分别于第0.04d，0.25d，0.5d，1d，3d，7d，14d，21d，28d，35d，42d，49d，56d，63d，77d，84d，91d，98d，105d，112d和119d于兔耳缘静脉取血5mL。所有采集的血样均于8000rpm离心10min后取上清液-70℃冻存，然后采用本领域已知方法检测上述所有血样中水难溶/微溶性药物的血药浓度，取平均值。结果见表9和10所示。New Zealand white rabbits weighing 2.0kg-3.0kg, each group of 6 (randomized groups), male and female, each group were intramuscularly injected with microspheres prepared in Examples 1-14 and Comparative Examples 1-2. 1.2ml suspension of physiological saline solution containing 0.5% CMC-Na, the water-insoluble/slightly soluble drug content of the sustained-release microspheres in each suspension is 18 mg, respectively at 0.04d, 0.25d, 0.5d, 1d, 3d, 7d, 14d, 21d, 28d, 35d, 42d, 49d, 56d, 63d, 77d, 84d, 91d, 98d, 105d, 112d and 119d were taken 5 mL from the rabbit ear vein. All collected blood samples were centrifuged at 8000 rpm for 10 min, and the supernatant was frozen at -70 ° C, and then the blood concentration of the water-insoluble/slightly soluble drug in all the blood samples was measured by a method known in the art, and averaged. The results are shown in Tables 9 and 10.
表9血药浓度结果(ng/ml)Table 9 blood concentration results (ng/ml)
时间/天Time/day 实施例1Example 1 实施例2Example 2 实施例3Example 3 实施例4Example 4 实施例5Example 5 实施例6Example 6 实施例7Example 7 实施例8Example 8
0.040.04 3.123.12 3.303.30 1.151.15 3.373.37 3.683.68 3.123.12 3.183.18 1.251.25
0.250.25 5.325.32 5.905.90 3.683.68 5.945.94 4.634.63 5.325.32 5.305.30 3.43.4
0.50.5 9.809.80 8.608.60 4.644.64 15.2615.26 3.153.15 9.869.86 9.819.81 4.004.00
11 8.568.56 7.857.85 3.153.15 12.8512.85 8.908.90 18.8218.82 19.4519.45 3.243.24
77 15.0515.05 14.2014.20 8.938.93 19.2019.20 15.5415.54 29.1529.15 30.1430.14 8.118.11
1414 30.8030.80 28.5028.50 15.5015.50 24.5524.55 20.6820.68 17.6117.61 15.6015.60 15.1615.16
21twenty one 19.1019.10 21.7021.70 20.6020.60 17.2217.22 25.7525.75 5.205.20 6.526.52 14.4114.41
2828 7.607.60 11.8011.80 23.7023.70 10.8410.84 19.9019.90 0.970.97 0.560.56 18.7418.74
3535 2.202.20 5.245.24 16.9016.90 5.125.12 13.8413.84 0.050.05 00 15.2015.20
4242 0.740.74 2.612.61 13.8213.82 1.011.01 8.448.44 00   26.0726.07
4949 0.120.12 0.550.55 10.4610.46 0.140.14 4.324.32     16.4816.48
5656 00 0.130.13 6.326.32 00 0.510.51     14.6014.60
6363   00 1.411.41   0.250.25     12.4112.41
7070     0.250.25   00     7.357.35
7777     00         5.125.12
8484               0.980.98
9191               00
表10血药浓度结果(ng/ml)Table 10 blood concentration results (ng / ml)
Figure PCTCN2018073901-appb-000009
Figure PCTCN2018073901-appb-000009
由表9和表10可看到，本发明的水难溶/微溶性缓释微球显示出良好的缓释效果，给药后很快增加血药浓度，而对比例需要差不多2-3周的时间才能达到5ng/mL以上。本发明水难溶/微溶性缓释微球的血药浓度在5-30ng/mL范围内能够持续达20天以上；而对比例1和对比例2约为21天，持续约20天。本发明的水难溶/微溶性缓释微球具有更好的作用效果，能在较长的时间内保持一定的血药浓度，可延迟给药周期，减轻病患的负担与不便。As can be seen from Tables 9 and 10, the water-insoluble/slightly soluble sustained-release microspheres of the present invention showed a good sustained-release effect, and the blood concentration was increased soon after administration, while the comparative ratio required almost 2-3 weeks. The time can reach 5ng/mL or more. The blood concentration of the water-insoluble/slightly soluble sustained release microspheres of the present invention can last for more than 20 days in the range of 5-30 ng/mL; while Comparative Example 1 and Comparative Example 2 are about 21 days, lasting about 20 days. The water-insoluble/slightly soluble sustained-release microspheres of the invention have better effects, can maintain a certain blood drug concentration for a long period of time, can delay the drug administration cycle, and reduce the burden and inconvenience of the patient.
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。It should be noted that the above embodiments are only intended to illustrate the technical solutions of the present invention and are not intended to limit the scope of the present invention, although the present invention will be described in detail with reference to the preferred embodiments, The technical solutions of the present invention may be modified or equivalently substituted without departing from the spirit and scope of the technical solutions of the present invention.

Claims (12)

  1. 一种水难溶/微溶性药物缓释组合物，其特征在于，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料包含释放调节剂。A water-insoluble/slightly soluble drug sustained-release composition, characterized in that the non-solvent-type preparation material of the water-insoluble/slightly soluble drug sustained-release composition comprises a release regulator.
  2. 如权利要求1所述的水难溶/微溶性药物缓释组合物，其特征在于，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为0.1～10％；优选地，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为0.5～8％；优选地，所述水难溶/微溶性药物缓释组合物的非溶剂型制备原料中，所述释放调节剂的质量百分含量为1～6％。The water-insoluble/slightly soluble drug sustained-release composition according to claim 1, wherein in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition, the release regulator The mass percentage is 0.1 to 10%; preferably, the non-solvent preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition, the release modifier has a mass percentage of 0.5 to 8%; Preferably, in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble drug sustained-release composition, the release regulator has a mass percentage of 1 to 6%.
  3. 如权利要求1所述的水难溶/微溶性药物缓释组合物，其特征在于，所述释放调节剂为有机亲油性物质和/或有机亲水性物质。The water-insoluble/slightly soluble drug sustained-release composition according to claim 1, wherein the release modifier is an organic lipophilic substance and/or an organic hydrophilic substance.
  4. 如权利要求3所述的水难溶/微溶性药物缓释组合物，其特征在于，所述释放调节剂由有机亲油性物质和有机亲水性物质组成时，所述有机亲水性物质在所述释放调节剂中的质量百分含量为30％以上；优选地，所述释放调节剂由有机亲油性物质和有机亲水性物质组成时，所述有机亲水性物质在所述释放调节剂中的质量百分含量为50％以上；优选地，所述释放调节剂由有机亲油性物质和有机亲水性物质组成时，所述有机亲水性物质在所述释放调节剂中的质量百分含量为70％以上。The water-insoluble/slightly soluble drug sustained-release composition according to claim 3, wherein when the release regulating agent is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is The mass percentage of the release regulator is 30% or more; preferably, when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the organic hydrophilic substance is regulated in the release The mass percentage in the agent is 50% or more; preferably, when the release modifier is composed of an organic lipophilic substance and an organic hydrophilic substance, the quality of the organic hydrophilic substance in the release regulator The percentage is 70% or more.
  5. 如权利要求3或4所述的水难溶/微溶性药物缓释组合物，其特征在于，所述有机亲油性物质为脂肪酸、脂肪酸酯、油脂中的至少一种；所述有机亲水性物质为醇、糖、氨基酸、蛋白、聚乙烯吡咯烷酮中的至少一种。The water-insoluble/slightly soluble drug sustained-release composition according to claim 3 or 4, wherein the organic lipophilic substance is at least one of a fatty acid, a fatty acid ester, and a fat; the organic hydrophilic The substance is at least one of an alcohol, a sugar, an amino acid, a protein, and polyvinylpyrrolidone.
  6. 如权利要求5所述的水难溶/微溶性药物缓释组合物，其特征在于，所述脂肪酸为油酸、硬脂酸、月桂酸、肉豆蔻酸、棕榈酸、花生酸、山俞酸、木质素酸中的至少一种；所述醇为分子量为400-6000Da的聚乙二醇。The water-insoluble/slightly soluble drug sustained-release composition according to claim 5, wherein the fatty acid is oleic acid, stearic acid, lauric acid, myristic acid, palmitic acid, arachidic acid, and behenic acid. At least one of lignin acids; the alcohol is a polyethylene glycol having a molecular weight of 400 to 6000 Da.
  7. 如权利要求1～6任一项所述的水难溶/微溶性药物缓释组合物，其特征在于，所述水难溶/微溶性药物组合物的非溶剂型制备原料还包含水难溶/微溶性药物和水难溶性聚合物；所述水难溶/微溶性药物组合物的非溶剂型制备原料中，所述水难溶/微溶性药物的质量百分含量为25～60％，所述水难溶性聚合物的质量百分含量为39.9-74.9％；优选地，所述水难溶/微溶性药物组合物的非溶剂型制备原料中，所述水难溶/微溶性药物的质量百分含量为30～55％，所述水难溶性聚合物的质量百分含量为44.9-69.9％；优选地，所述水难溶/微溶性药物组合物的非溶剂型制备原料中，所述水难溶/微溶性药物的质量百分含量为35～50％，所述水难溶性聚合物的质量百分含量为49.9-64.9％。The poorly water-soluble/slightly soluble drug sustained-release composition according to any one of claims 1 to 6, wherein the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition further comprises water-insoluble a slightly soluble drug and a poorly water-soluble polymer; in the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition, the water-insoluble/slightly soluble drug has a mass percentage of 25 to 60%, The water-insoluble polymer has a mass percentage of 39.9-74.9%; preferably, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition, the water-insoluble/slightly soluble drug The mass percentage is 30 to 55%, and the water-insoluble polymer has a mass percentage of 44.9-69.9%; preferably, the non-solvent-type preparation raw material of the water-insoluble/slightly soluble pharmaceutical composition, The water-insoluble/slightly soluble drug has a mass percentage of 35 to 50%, and the water-insoluble polymer has a mass percentage of 49.9 to 64.9%.
  8. 如权利要求7所述的水难溶/微溶性药物缓释组合物，其特征在于，所述水难溶/微溶性药物包括利培酮、帕利哌酮、阿立哌唑、伊潘立酮、依匹哌唑、齐拉西酮、阿那曲唑、多奈哌齐、奥氮平、纳曲酮、氟哌啶醇、紫杉醇、恩替卡韦、多西他赛、它们的衍生物中的至少一种。The poorly water-soluble/slightly soluble drug sustained-release composition according to claim 7, wherein the water-insoluble/slightly soluble drug comprises risperidone, paliperidone, aripiprazole, and ipilide. At least one of a ketone, epiliperazole, ziprasidone, anastrozole, donepezil, olanzapine, naltrexone, haloperidol, paclitaxel, entecavir, docetaxel, and derivatives thereof.
  9. 如权利要求7所述的水难溶/微溶性药物缓释组合物，其特征在于，所述水难溶性聚合物为聚丙交酯、丙交酯-乙交酯共聚物及它们与聚乙二醇的共聚物中的至少一种。The water-insoluble/slightly soluble drug sustained-release composition according to claim 7, wherein the poorly water-soluble polymer is a polylactide, a lactide-glycolide copolymer, and a polyethylene glycol thereof. At least one of the copolymers of alcohols.
  10. 如权利要求9所述的利培酮缓释组合物，其特征在于，所述水难溶性聚合物为聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物中的至少一种，且其中丙交酯与乙交 酯的摩尔比为100:0～65:35；优选地，其中丙交酯与乙交酯的摩尔比为100:0～70:30；更优选地，其中丙交酯与乙交酯的摩尔比为100:0～75:25。The risperidone sustained-release composition according to claim 9, wherein the poorly water-soluble polymer is a polylactide, a lactide-glycolide copolymer, and a copolymer thereof with polyethylene glycol. At least one of them, and wherein the molar ratio of lactide to glycolide is from 100:0 to 65:35; preferably, the molar ratio of lactide to glycolide is from 100:0 to 70:30; More preferably, the molar ratio of lactide to glycolide is from 100:0 to 75:25.
  11. 如权利要求9或10所述的利培酮缓释组合物，其特征在于，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的重均分子量均为25000-150000Da；优选地，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的重均分子量均为30000-125000Da；更优选地，所述聚丙交酯、丙交酯-乙交酯共聚物、它们与聚乙二醇的共聚物的重均分子量均为35000-100000Da。The risperidone sustained-release composition according to claim 9 or 10, wherein the polylactide, lactide-glycolide copolymer, and a copolymer of polyethylene glycol have a weight average molecular weight Each of 25000-150000Da; preferably, the polylactide, lactide-glycolide copolymer, and copolymers thereof with polyethylene glycol have a weight average molecular weight of 30,000-125000Da; more preferably, The polylactide, lactide-glycolide copolymer, and copolymers thereof with polyethylene glycol have a weight average molecular weight of from 35,000 to 100,000 Da.
  12. 如权利要求1～11任一项所述的水难溶/微溶性药物缓释组合物，其特征在于，所述水难溶/微溶性药物缓释组合物的制备方法包括以下步骤：The water-insoluble/slightly soluble drug sustained-release composition according to any one of claims 1 to 11, wherein the preparation method of the water-insoluble/slightly soluble drug sustained-release composition comprises the following steps:
    (1a)将所述非溶剂型制备原料溶于有机溶剂中，形成内油相；(1a) dissolving the non-solvent-type preparation raw material in an organic solvent to form an internal oil phase;
    (2a)将表面活性剂溶于水性介质中，形成外水相；(2a) dissolving the surfactant in an aqueous medium to form an external aqueous phase;
    (3a)将步骤(1a)得到的内油相加入到外水相中，制成乳液，然后通过溶剂蒸发或溶剂提取使溶液中的微粒硬化，收集微粒，洗涤并干燥，得水难溶/微溶性药物缓释微球；(3a) adding the internal oil phase obtained in the step (1a) to the external aqueous phase to prepare an emulsion, and then hardening the particles in the solution by solvent evaporation or solvent extraction, collecting the particles, washing and drying to obtain water insoluble/ Slightly soluble drug sustained release microspheres;
    或者or
    (1b)将所述非溶剂型制备原料所含的除释放调节剂外的其余各物质溶于有机溶剂中，形成内油相；(1b) dissolving the remaining substances contained in the non-solvent-type preparation raw material in addition to the release modifier in an organic solvent to form an internal oil phase;
    (2b)将释放调节剂和表面活性剂溶于水性介质中，形成外水相；(2b) dissolving the release modifier and the surfactant in an aqueous medium to form an external aqueous phase;
    (3b)将步骤(1b)得到的内油相加入到外水相中，制成乳液，然后通过溶剂蒸发或溶剂提取使溶液中的微粒硬化，收集微粒，洗涤并干燥，得水难溶/微溶性药物缓释微球。(3b) adding the internal oil phase obtained in the step (1b) to the external aqueous phase to prepare an emulsion, and then hardening the particles in the solution by solvent evaporation or solvent extraction, collecting the particles, washing and drying to obtain water insoluble/ A slightly soluble drug sustained release microsphere.
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