WO2018137631A1 - Composition à libération prolongée de médicament peu soluble dans l'eau ou légèrement soluble dans l'eau et son procédé de préparation - Google Patents

Composition à libération prolongée de médicament peu soluble dans l'eau ou légèrement soluble dans l'eau et son procédé de préparation Download PDF

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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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water
release
insoluble
slightly soluble
soluble drug
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PCT/CN2018/073901
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English (en)
Chinese (zh)
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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/fr

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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

L'invention concerne une composition à libération prolongée de médicament peu soluble dans l'eau/légèrement soluble dans l'eau, les matières premières de préparation sans solvant de la composition à libération prolongée de médicament peu soluble dans l'eau/légèrement soluble dans l'eau comprenant un régulateur de libération. Le régulateur de libération est ajouté aux matières premières de préparation de la composition à libération prolongée de médicament peu soluble dans l'eau/légèrement soluble dans l'eau, et le régulateur de libération est capable de réguler efficacement le taux de libération du médicament peu soluble dans l'eau/légèrement soluble dans l'eau dans la composition à libération prolongée, de telle sorte que la composition à libération prolongée de médicament peu soluble dans l'eau/légèrement soluble dans l'eau n'a pas de période de retard de libération évidente ou un phénomène de libération initiale rapide à très court terme (également bien connu sous l'anglicisme « burst release ») après l'administration, a une bonne performance de libération prolongée, peut maintenir une concentration de médicament thérapeutique dans le sang pendant plusieurs semaines ou plus, a une stabilité relativement bonne, et peut encore préserver son comportement de libération après un stockage à long terme. L'invention concerne également un procédé de préparation de la composition à libération prolongée de médicament peu soluble dans l'eau/légèrement soluble dans l'eau.
PCT/CN2018/073901 2017-01-24 2018-01-24 Composition à libération prolongée de médicament peu soluble dans l'eau ou légèrement soluble dans l'eau et son procédé de préparation WO2018137631A1 (fr)

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