WO2024037535A1 - 一种长效缓控释植入剂的制备方法 - Google Patents

一种长效缓控释植入剂的制备方法 Download PDF

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WO2024037535A1
WO2024037535A1 PCT/CN2023/113096 CN2023113096W WO2024037535A1 WO 2024037535 A1 WO2024037535 A1 WO 2024037535A1 CN 2023113096 W CN2023113096 W CN 2023113096W WO 2024037535 A1 WO2024037535 A1 WO 2024037535A1
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Prior art keywords
pla
implant
preparation
peg
plga
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PCT/CN2023/113096
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English (en)
French (fr)
Inventor
刘代春
曲伟
颜携国
尹述贵
张涛
陈泽琴
付晓芳
罗静玲
张璇
邱心敏
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深圳善康医药科技股份有限公司
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Publication of WO2024037535A1 publication Critical patent/WO2024037535A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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

Definitions

  • the invention relates to the field of pharmaceutical preparations, and in particular to a preparation method of a long-acting sustained-release implant.
  • Long-acting sustained-release injections are usually administered via subcutaneous or intramuscular injection, forming a drug reservoir at the injection site to exert a long-acting release effect. It can sustainably release drugs over several days to months. Its advantages include reduced dosing frequency, simplified drug treatment regimens, smaller pharmacokinetic fluctuations, and fewer adverse reactions. However, there are some limitations in its application, such as the need for medical administration, possible dose burst release, and variations between different preparations. Because of these clinical or pharmaceutical development challenges, in the past 30 years, only more than 20 long-acting sustained-release injection chemicals have been on the market, mainly used in antipsychotics, hormone therapy, detoxification and other fields. According to the release mechanism, it can be roughly divided into three categories: 1 Sustained release of raw materials.
  • the raw materials generally have poor water solubility and exert a sustained release effect through the slow dissolution and release of the raw materials.
  • the mechanism of self-aggregation and sustained release of drugs is that the raw materials aggregate in the body to form a gel-like drug reservoir to exert a long-lasting release effect.
  • the release mechanism is that the excipients slowly and continuously diffuse or degrade at the administration site, thereby achieving long-term release of the raw material.
  • nanocrystal/microcrystalline suspension injection or in-situ gel injection technology are mainly used; while for the third release mechanism, microspheres, in-situ gel or hot melt extrusion are mainly used to produce implants. Injection.
  • Hot melt extrusion technology also known as melt extrusion technology, refers to a technology that uniformly mixes drugs and carrier excipients in a molten state and extrudes them at a certain pressure, speed and shape.
  • This technology allows drugs to be dispersed in the carrier in the form of molecules, amorphous or metastable states, which can improve the dissolution and bioavailability of poorly soluble drugs.
  • It is a new formulation technology that has developed rapidly in recent years. It is used in the preparation of buffered drugs. It has outstanding advantages in controlled release preparations and drug delivery systems, and has low cost, simple process, good reproducibility and high production efficiency. It has broad development prospects in the field of pharmaceutical research and development.
  • Thermoplastic sustained-release polymers and water-soluble drugs are hot-melt extruded to form implants, and the drug particles are evenly distributed in the polymer matrix.
  • the molten drug-laden material coats the drug particles. Therefore, the size and surface of the pore structure formed are primarily a function of the size and surface area of the drug particles.
  • the polymer matrix consists of closed and open pore structures. In a closed pore structure, the drug particles are completely wrapped/enclosed by the polymer matrix, whereas in an open pore structure, the drug particles are exposed Exposed to the fluid medium in which the implant is placed.
  • the invention discloses a new long-acting implant preparation method, which uses coating or thermal passivation technology to control the sudden release of drugs at the initial stage of drug administration, maintain stable drug release, and achieve zero-level drug release or first-level drug release.
  • drug target. Medications include varenicline, buprenorphine, donepezil, triamcinolone acetonide, octreotide, leuprolide, goserelin, exenatide, or pharmaceutically acceptable salts thereof.
  • CN111714442 mixes active pharmaceutical ingredients and polylactic acid glycolic acid copolymer, dissolves them in a first solvent, performs hot melt extrusion, thereby obtaining a first extrudate, and immerses the first extrudate in a second solvent, thereby The implant was obtained.
  • This method uses organic solvents many times, the intermediate products need to be dried, the process is complex, and the risk of organic solvent residues is high.
  • US20190350844 provides microspheres, implants, oily solutions, liposomes, and suspensions composed of varenicline or its pharmaceutically acceptable derivatives and one or more biodegradable or non-biodegradable carriers.
  • Long-acting reservoir compositions such as liquids, microemulsions, and in-situ gels can be injected subcutaneously or intramuscularly or implanted, which can effectively prevent patients from stopping treatment on their own.
  • the dosage regimen of once every three days to once every six months can reduce the dosage of drug batches to improve patient compliance and reduce the risk of adverse reactions.
  • varenicline belongs to BCS category I and has good water solubility, the above dosage forms usually have a burst release phenomenon after administration, which brings certain safety risks to patients.
  • CN102755627 Mix acetic acid and ethanol to prepare a mixed solvent, then dissolve a pharmaceutically acceptable carrier and goserelin in the mixed solvent, and then freeze-dry to remove the solvent to prepare particles or fine powder, and then the particles are Or the fine powder is placed in a hot melt extruder, extruded into strips, and cut into cylinders.
  • This technology uses a lot of organic solvents, and the removal of organic solvents through freeze-drying has a long production cycle and high energy consumption.
  • CN106580868 discloses that a poorly water-soluble/slightly soluble drug and a release regulator are dissolved in an organic solvent, a poorly water-soluble polymer is added, and then the organic solvent is removed to obtain a solid mixture, which is extruded and cut in a hot-melt extruder. Get the implant.
  • adding release regulators to the prescription can adjust the drug release rate to a certain extent, for implants, only a few of the release regulators can be used for injection. The more complex the formulation, the higher the risk of injection.
  • a large amount of organic solvents are used to dissolve drugs and release regulators, making it difficult to control organic solvent residues in implants.
  • the present invention provides a preparation method of a long-acting sustained-release implant.
  • the preparation method is safe, has low energy consumption, has a short cycle and is easy to control. It ensures the sustained release of the implant while Can prevent sudden release.
  • the invention provides a method for preparing an implant, which includes the following steps:
  • step (2) The mixture obtained in step (1) is melted, extruded, cooled, formed, and pelletized to obtain a shaped solid;
  • step (3) The shaped solid obtained in step (2) is heated, passivated or coated, and dried to obtain an implant.
  • the weight ratio of the active drug and biodegradable polymer is 30-65:35-70; preferably 35-60:40-65.
  • the active drugs include varenicline, buprenorphine, donepezil, triamcinolone acetonide, octreotide, leuprolide, goserelin, exenatide, or pharmaceutically acceptable salts thereof.
  • the biodegradable polymer includes polylactide, polyglycolide, lactide-glycolide copolymer, polycaprolactone, PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA - One or more of PEG-PLA, PCL-PEG-PCL; preferably polylactide, lactide-glycolide copolymer, PLA-PEG, PLGA-PEG, PLGA-PEG-PLGA, PLA- PEG-PLA; further preferably polylactide and/or lactide-glycolide copolymer.
  • the molecular chain of the polylactide (PLA) or lactide-glycolide copolymer (PLGA) carries anionic or cationic groups, or does not carry anionic or cationic groups. More preferably, the end-capping group of the polylactide (PLA) or lactide-glycolide copolymer (PLGA) is an alkyl ester group or a carboxyl group. More preferably, when the biodegradable polymer is at least one of polylactide (PLA) and lactide-glycolide copolymer (PLGA), the molar ratio of lactide to glycolide is 100:0 to 50:50.
  • the biodegradable polymer is at least one of polylactide (PLA) and lactide-glycolide copolymer (PLGA)
  • the molar ratio of lactide to glycolide is 100:0 to 75:25.
  • the biodegradable polymer described in the present invention can be biodegraded into carbon dioxide and water in the body, has good biocompatibility, and can be a single polymer or a mixture of multiple polymers.
  • a PLGA combination with the same molar ratio and molecular weight of lactide and glycolide, but different end groups a PLGA combination with the same molar ratio and end groups of lactide and glycolide, but different molecular weights
  • a PLGA combination with different molar ratios, end groups and molecular weights of lactide and glycolide can be biodegraded into carbon dioxide and water in the body, has good biocompatibility, and can be a single polymer or a mixture of multiple polymers.
  • a PLGA combination with the same molar ratio and molecular weight of lactide and glycolide, but different end groups a PL
  • the temperature of freezing and grinding in step (1) is -70°C to -20°C, preferably -50°C to -25°C.
  • the particle size of the freeze-pulverized mixture described in step (1) is no larger than 20 mesh, preferably no larger than 40 mesh, and further preferably no larger than 60 mesh.
  • the temperature of the heating passivation described in step (3) is 70-150°C, and the time is 2-60 minutes; preferably, the The temperature of the heating passivation is 90-140°C, and the time is 5-30 minutes; further preferably, the temperature of the heating passivation is 95-130°C, and the time is 8-30 minutes.
  • the coating liquid used for coating in step (3) includes a sustained-release composition and an organic solvent; the sustained-release composition includes polylactide, polyglycolide, and lactide-glycolide copolymer.
  • the sustained-release composition includes polylactide and/or lactide-glycolide ester copolymer.
  • the weight proportion of the sustained-release composition in the coating liquid is 3-30%; preferably 6-25%.
  • the weight average molecular weight of the polylactide and lactide-glycolide copolymer is 7000-150000 Da, and the intrinsic viscosity is 0.1-2.5dL/g; preferably, the polylactide, lactide
  • the weight average molecular weight of the ester-glycolide copolymer is 9000-120000Da, and the intrinsic viscosity is 0.2-1.2dL/g.
  • the organic solvent includes one or more of dimethyl sulfoxide, methanol, acetone, acetonitrile, dichloromethane, chloroform, tetrahydrofuran, and ethyl acetate; preferably ethyl acetate and/or dichloromethane.
  • Methyl chloride preferably ethyl acetate and/or dichloromethane.
  • step (3) is specifically air drying at room temperature for 2-4 days, or vacuum drying at 30-45°C for 18-72 hours. Preferably, vacuum drying is performed at 35-40°C for 24-48 hours.
  • the present invention also provides implants prepared by the above preparation method.
  • the implant is in the shape of granules, cylinders or thin rods; preferably, it is in the shape of cylindrical or thin rods.
  • the implant when the implant is cylindrical or thin rod-shaped, it has a length of no more than 6cm and a diameter of no more than 3mm.
  • the implant when the implant is in the shape of a cylinder or a thin rod, it has a length of no more than 5cm and a diameter of no more than 2.5mm. More preferably, when the implant is in the shape of a cylinder or a thin rod, it has a length of no more than 3.5cm and a diameter of no more than 2.0mm.
  • the implant when the implant is in the shape of a cylinder or a thin rod, its aspect ratio is (10-50):1.
  • its aspect ratio is (15-40):1.
  • the implant when the implant is in the shape of a cylinder or a thin rod, its aspect ratio is (20-30):1.
  • the present invention thermally passivates implants of water-soluble drugs, especially BCS Class 1 and BCS Class 3 drugs, including some polypeptide drugs with acceptable thermal stability.
  • the method of the present invention can be used in implants.
  • a protective film is formed on the outer surface of the implant to block the rapid release of drug particles attached to the outer surface of the implant, thereby controlling the burst release phenomenon, reducing blood drug fluctuations, and improving the safety of long-acting sustained-release preparations.
  • the present invention adopts the methods of melt extrusion and coating/passivation, and adopts the dual sustained and controlled release mode of skeleton type and membrane control. Different from the dual membrane controlled sustained release, the skeleton type and membrane control work synergistically to achieve The implant can ensure sustained release while preventing sudden release.
  • Figure 1 is an SEM image of the sample morphology of Comparative Example 1;
  • Figure 2 is an SEM image of the sample morphology of Example 1;
  • Figure 3 is an SEM image of the sample morphology of Example 2.
  • Figure 4 is an SEM image of the sample morphology of Example 3.
  • Figure 5 is an SEM image of the sample morphology of Comparative Example 2.
  • Figure 6 is an SEM image of the sample morphology of Example 4.
  • Figure 7 is an SEM image of the sample morphology of Example 5.
  • Figure 8 is an SEM image of the sample morphology of Example 6
  • Figure 9 is an SEM image of the sample morphology of Comparative Example 8.
  • Figure 10 is a graph showing the in vitro release degree of the samples of each example.
  • Figure 11 is a graph showing the in vitro release degree of each comparative example sample.
  • the varenicline tartrate prescription accounts for 30% (W/W)
  • polylactic acid (PLA) accounts for 70% (W/W), of which polylactic acid (PLA)
  • the weight average molecular weight is 20kDa, and the intrinsic viscosity is 0.20dL/g. Alkyl ester group end-capped.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 95°C, the screw speed is 100RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.6mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 95°C for 30 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.6 mm and an aspect ratio of 30.
  • the varenicline tartrate prescription accounts for 30% (W/W)
  • polylactic acid (PLA) accounts for 70% (W/W), of which polylactic acid (PLA)
  • the weight average molecular weight is 20kDa
  • the intrinsic viscosity is 0.20dL/g
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 95°C, the screw speed is 100RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.6mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 110° C. for 20 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.6 mm and an aspect ratio of 30.
  • the varenicline tartrate prescription accounts for 30% (W/W)
  • polylactic acid (PLA) accounts for 70% (W/W), of which polylactic acid (PLA)
  • the weight average molecular weight is 20kDa
  • the intrinsic viscosity is 0.20dL/g
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 95°C, the screw speed is 100RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.6mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 120°C for 10 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.6 mm and an aspect ratio of 30.
  • buprenorphine hydrochloride prescription accounts for 50% (W/W)
  • lactide-glycolide copolymer (PLGA) accounts for 50% (W/W) )
  • the weight average molecular weight of PLGA is 100kDa
  • the intrinsic viscosity is 0.82dL/g
  • the component molar ratio is 75:25
  • the carboxyl group is terminated.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 125°C, the screw speed is 150RPM, and the outlet pressure is less than 50Bar), and then pelletized to obtain the diameter. It is a 3.0mm cylindrical implant;
  • step 2) Coat the implant obtained in step 2), wherein the coating liquid is 6% polylactic acid (PLA weight average molecular weight is 120kDa, carboxyl end-capped), the organic solvent is ethyl acetate, and vacuum dried at 40°C for 24 hours , an implant with a diameter of 3.0 mm and an aspect ratio of 25 was obtained.
  • the coating liquid is 6% polylactic acid (PLA weight average molecular weight is 120kDa, carboxyl end-capped)
  • the organic solvent is ethyl acetate
  • buprenorphine hydrochloride prescription accounts for 50% (W/W)
  • PLGA accounts for 50% (W/W)
  • the weight average molecular weight of PLGA is 100kDa
  • the intrinsic viscosity is 0.82dL/g
  • the component molar ratio is 75:25, and it is carboxyl-terminated.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 125°C, the screw speed is 150RPM, and the outlet pressure is less than 50Bar), and then pelletized to obtain the diameter. It is a 3.0mm cylindrical implant;
  • step 2) Coat the implant obtained in step 2), wherein the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 120kDa, carboxyl end-capped), the organic solvent is ethyl acetate, and vacuum dried at 40°C for 24 hours , an implant with a diameter of 3.0 mm and an aspect ratio of 25 was obtained.
  • the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 120kDa, carboxyl end-capped)
  • the organic solvent is ethyl acetate
  • buprenorphine hydrochloride prescription accounts for 50% (W/W)
  • PLGA accounts for 50% (W/W)
  • the weight average molecular weight of PLGA is 100kDa
  • the intrinsic viscosity is 0.82dL/g
  • the component molar ratio is 75:25, and it is carboxyl-terminated.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 125°C, the screw speed is 150RPM, and the outlet pressure is less than 50Bar), and then pelletized to obtain the diameter. It is a 3.0mm cylindrical implant;
  • step 2) Coat the implant obtained in step 2), wherein the coating liquid is 25% polylactic acid (PLA weight average molecular weight is 120kDa, carboxyl end-capped), the organic solvent is ethyl acetate, and vacuum dried at 40°C for 24 hours , an implant with a diameter of 3.0 mm and an aspect ratio of 25 was obtained.
  • the coating liquid is 25% polylactic acid (PLA weight average molecular weight is 120kDa, carboxyl end-capped)
  • the organic solvent is ethyl acetate
  • donepezil prescription accounts for 60% (W/W)
  • PLGA accounts for 40% (W/W)
  • the weight average molecular weight of PLGA is 40kDa and the intrinsic viscosity is 0.32 dL/g, molar ratio 85:15, carboxyl end-capped.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 120°C, the screw speed is 120RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 2.0mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 125°C for 25 minutes, and then cooled to room temperature to obtain an implant with a diameter of 2.0 mm and an aspect ratio of 24.
  • triamcinolone acetonide hydrochloride prescription accounts for 65% (W/W), PLA-PEG-PLA is 35% (W/W), in which the weight average molecular weight of PLA-PEG-PLA is 12kDa, the mass percentage of PEG is 5%, and the intrinsic viscosity is 0.12dL/g.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 90°C, the screw speed is 80RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 2.5mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 90°C for 20 minutes, and then cooled to room temperature to obtain an implant with a diameter of 2.5 mm and an aspect ratio of 25.
  • the raw and auxiliary material components for the preparation of the implant described in this example the prescription of octreotide acetate accounts for 40% (W/W), and the polylactic acid (PLA) accounts for 60% (W/W), of which the weight of polylactic acid (PLA) The average molecular weight is 20kDa, the intrinsic viscosity is 0.16dL/g, and it is end-capped with an alkyl ester group.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 90°C, the screw speed is 160RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.2mm cylindrical implant;
  • step 2) Coat the implant obtained in step 2), in which the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 20kDa, carboxyl end-capped), the organic solvent is dichloromethane, and the coating is vacuum dried at 25°C for 24 hours. , an implant with a diameter of 1.2 mm and an aspect ratio of 20 was obtained.
  • the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 20kDa, carboxyl end-capped)
  • the organic solvent is dichloromethane
  • the goserelin acetate prescription accounts for 45% (W/W)
  • PLGA accounts for 55% (W/W)
  • the intrinsic viscosity is 0.22dL/g, and it is end-capped with alkyl ester group.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 95°C, the screw speed is 150RPM, and the outlet pressure is less than 60Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant;
  • step 3 Coat the implant obtained in step 2), wherein the coating liquid is 15% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped), the organic solvent is ethyl acetate, and vacuum dried at 25°C After 48 hours, the implant with a diameter of 1.5 mm and an aspect ratio of 23 was obtained.
  • the coating liquid is 15% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped)
  • the organic solvent is ethyl acetate
  • the raw and auxiliary material components for the preparation of the implant described in this example accounts for 40% (W/W), and PLGA accounts for 60% (W/W).
  • the weight average molecular weight of PLGA is 25kDa.
  • the characteristics The viscosity is 0.24dL/g, the molar ratio is 75:25, and the alkyl ester group is end-capped.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 100°C, the screw speed is 100RPM, and the outlet pressure is less than 20Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant;
  • step 2) Coat the implant obtained in step 2), wherein the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped), the organic solvent is methylene chloride, and vacuum dried at 25°C After 48 hours, the implant with a diameter of 1.5 mm and an aspect ratio of 21 was obtained.
  • the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped)
  • the organic solvent is methylene chloride
  • the raw and auxiliary material components for the preparation of the implant described in this example the prescription of octreotide acetate accounts for 40% (W/W), and the polylactic acid (PLA) accounts for 60% (W/W), of which the weight of polylactic acid (PLA) The average molecular weight is 8kDa, the intrinsic viscosity is 0.10dL/g, and it is end-capped with an alkyl ester group.
  • the preparation method of the implant described in this example is the same as that in Example 9.
  • the raw and auxiliary material components for the preparation of the implant described in this example the prescription of octreotide acetate accounts for 40% (W/W), and the polylactic acid (PLA) accounts for 60% (W/W), of which the weight of polylactic acid (PLA) The average molecular weight is 130kDa, the intrinsic viscosity is 1.48dL/g, and it is end-capped with an alkyl ester group.
  • the preparation method of the implant described in this example is the same as that in Example 9.
  • the raw and auxiliary material components for the preparation of the implant described in this comparative example accounts for 30% (W/W), and polylactic acid (PLA) accounts for 70% (W/W), of which polylactic acid (PLA)
  • the weight average molecular weight is 20kDa, the intrinsic viscosity is 0.20dL/g, and it is end-capped with an alkyl ester group.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 95°C, the screw speed is 100RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.6mm cylindrical implant.
  • buprenorphine hydrochloride prescription accounts for 50% (W/W)
  • lactide-glycolide copolymer (PLGA) accounts for 50% (W/W) )
  • the weight average molecular weight of PLGA is 100kDa
  • the intrinsic viscosity is 0.82dL/g
  • the component molar ratio is 75:25
  • the carboxyl group is terminated.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 125°C, the screw speed is 150RPM, and the outlet pressure is less than 50Bar), and then pelletized to obtain the diameter. It is a 3.0mm cylindrical implant.
  • donepezil prescription accounts for 60% (W/W)
  • PLGA accounts for 40% (W/W)
  • the weight average molecular weight of PLGA is 40kDa and the intrinsic viscosity is 0.32 dL/g, molar ratio 85:15, carboxyl end-capped.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 120°C, the screw speed is 120RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 2.0mm cylindrical implant.
  • triamcinolone acetonide hydrochloride prescription accounts for 65% (W/W), PLA-PEG-PLA is 35% (W/W), in which the weight average molecular weight of PLA-PEG-PLA is 12kDa, the mass percentage of PEG is 5%, and the intrinsic viscosity is 0.12dL/g.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 90°C, the screw speed is 80RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 2.5mm cylindrical implant.
  • the raw and auxiliary material components for the preparation of the implant described in this example the prescription of octreotide acetate accounts for 40% (W/W), and the polylactic acid (PLA) accounts for 60% (W/W), of which the weight of polylactic acid (PLA) The average molecular weight is 20kDa, the intrinsic viscosity is 0.16dL/g, and it is end-capped with an alkyl ester group.
  • step 5 Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 90°C, the screw speed is 160RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.2mm cylindrical implant.
  • the raw and auxiliary material components for the preparation of the implant described in this example accounts for 45% (W/W), and PLGA accounts for 55% (W/W), in which the weight average molecular weight of PLGA is 30kDa.
  • the intrinsic viscosity is 0.22dL/g, and it is end-capped with alkyl ester group.
  • step 2) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 95°C, the screw speed is 150RPM, and the outlet pressure is less than 60Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant.
  • exenatide prescription accounts for 40% (W/W)
  • PLGA accounts for 60% (W/W)
  • the weight average molecular weight of PLGA is 25kDa, and the characteristics
  • the viscosity is 0.24dL/g, the molar ratio is 75:25, alkyl ester Base capped.
  • step 1) Place the raw and auxiliary material mixture obtained in step 1) into a hot melt extruder for melt extrusion (the temperature of the mixing and melting zone is set to 100°C, the screw speed is 100RPM, and the outlet pressure is less than 20Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant.
  • Oil phase preparation Add 80.00g methylene chloride to the internal water phase and 14.0g polylactic acid (PLA, intrinsic viscosity 0.20dL/g), vortex and shake to fully dissolve, as the oil phase.
  • PVA polylactic acid
  • Emulsification Use a peristaltic pump (2000ml/min) to inject the external water phase into the inner cavity of the high shear homogenizer (2000RPM), and then use a syringe pump to inject the oil phase into the inner cavity of the high shear homogenizer at 50ml/min. , forming a single emulsion under high shear. Stir the emulsion with a magnetic stirrer (500RPM), heat to 38°C and continue stirring for 20 hours. Evaporate the methylene chloride and keep in ice bath for 1 hour. Then filter and collect the filter residue to obtain microspheres.
  • the particles are sieved through a sieve to obtain the varenicline tartrate microspheres (see Figure 9 for details).
  • the raw and auxiliary material components for preparing the implant described in this comparative example are the same as those in Example 4.
  • the preparation method is the same as that in Example 4 except that the concentration of the coating liquid is 3%.
  • the raw and auxiliary material components for preparing the implant described in this comparative example are the same as those in Example 4.
  • the preparation method is the same as that in Example 4 except that the concentration of the coating liquid is 35%.
  • octreotide acetate prescription accounts for 40% (W/W), polylactic acid (PLA) It is 60% (W/W), in which the weight average molecular weight of polylactic acid (PLA) is 20kDa, the intrinsic viscosity is 0.16dL/g, and the alkyl ester group is end-capped.
  • step 2) Compress the raw and auxiliary material mixture obtained in step 1) into tablets, with a punching diameter of 6mm and a tablet weight of approximately 75mg;
  • step 2) Coat the tablets obtained in step 2), in which the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 20kDa, carboxyl end-capped), the organic solvent is dichloromethane, and the coating liquid is vacuum dried at 25°C for 24 hours. An implant with a diameter of 1.2 mm and an aspect ratio of 20 was obtained.
  • the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 20kDa, carboxyl end-capped)
  • the organic solvent is dichloromethane
  • Drug loading (weight of drug contained in the implant/total weight of the implant)*100%
  • Determination method Weigh 6 portions (30mg) of each implant prepared in Examples 1-13, Comparative Examples 1-5 and Comparative Examples 8-11, place them in a 100ml Erlenmeyer flask, and release the medium.
  • the pH of 50ml phosphate buffer solution is 7.4, and the test is carried out using a constant temperature water bath shaker at 37 ⁇ 0.5°C, with a rotation speed of 50RPM.
  • the thermal passivation treatment can significantly control the burst release phenomenon of water-soluble drugs in the initial stage, resulting in zero-order release throughout the sustained release cycle of the drug. Avoid adverse reactions that may occur in patients due to sudden drug release.
  • the thermal passivation temperature can be selected according to the hot melt extrusion temperature required for the implant. It is usually not lower than the hot melt extrusion temperature, but should not be too high, otherwise it may cause the implant to melt twice due to excessive temperature, resulting in Severe deformation. Thermal passivation time needs to be selected comprehensively in combination with the thermal passivation temperature. That is, the time required at different thermal passivation temperatures will vary, depending on the release control of the final product.
  • coating the implant can significantly reduce the release rate of the water-soluble drug in the initial stage, making it zero-order throughout the sustained release cycle of the drug. Release to avoid adverse reactions in patients that may occur due to sudden drug release.
  • the composition of the coating liquid can be determined according to the required controlled release rate. Generally, biodegradable polymers with low molecular weight/intrinsic viscosity will control release faster than those with high molecular weight. Linear biodegradable polymers will control release faster than multi-branched star-shaped ones. Controlled release is faster. Hydrophobic-capped biodegradable polymers will release faster than hydrophilic-capped biodegradable polymers.
  • PEG-modified biodegradable polymers will release faster than unmodified ones. Low concentration control will release faster than high concentration control. Release faster.
  • the in vitro release of Comparative Example 9 and Comparative Example 10 shows that if the concentration of the coating liquid is too low, there will be no obvious controlled release effect; if the concentration of the coating liquid is too high, the drug release will be seriously blocked, resulting in delayed release, which is not suitable for rapid release. Effective water-soluble drug varieties.
  • varenicline tartrate microspheres undergo severe burst release, and the drug is completely released in about 20 days.
  • the implant prepared by the hot melt extrusion process can be certain The degree of burst release is reduced, but the release amount on the first day is still large (>20%).
  • a dense controlled release film is formed on the outer surface of the implant, and the channels for drug dissolution/diffusion are significantly reduced (see Figures 1 to 8), thus avoiding sudden release and reducing the risk of drug release.
  • the initial release rate is controlled within the expected range, which is very suitable for the development of long-acting sustained-release implants for BCS Class 1 or BCS Class 3 drugs.
  • Example 12 uses PLA with a weight average molecular weight of 8 kDa and an intrinsic viscosity of 0.10 dL/g.
  • the drug release rate is faster than that of Example 9 because the biodegradable polymer has a low molecular weight and a small intrinsic viscosity and is easily hydrolyzed or degraded by itself. , resulting in faster dissolution/dissolution of octreotide acetate; but less than that of Comparative Example 5, indicating that coating can control early burst release to a certain extent.
  • Example 13 uses PLA with a weight average molecular weight of 130kDa and an intrinsic viscosity of 1.48dL/g. Compared with Example 9 and Comparative Example 5, the early release of the drug is significantly slower, and the cumulative drug release in 15 days is about 10%, because PLA is heavy. The average molecular weight exceeds 12kDa, the intrinsic viscosity exceeds 1.2dL/g, and there are many hydrophobic groups, making it more difficult for water to enter the pores in the matrix. The drug is firmly bound in PLA, and there is a relatively delayed release phenomenon.
  • Example 9 adopts hot melt extrusion and coating process, and Comparative Example 5 adopts uncoated process.
  • the early release of Comparative Example 5 is controlled to a certain extent. As the release time is extended, The drug is released quickly, and the release period is obviously shorter than that of the Example 9 sample. This shows that, first of all, the coating process can form a film-controlled sustained-release effect. This is because as the outer coating of the implant degrades, the porosity of the membrane increases and there is less resistance to drug release from the membrane pores, resulting in an increase in the release rate.
  • Example 9 adopts hot-melt extrusion and coating processes
  • Comparative Example 11 adopts tableting and coating processes. Since hot-melt extrusion can form a skeleton-type sustained-release structure, The release period of the core prepared by hot melt extrusion is longer than that of the tablet core obtained by compression. Therefore, in order to extend the sustained release cycle of drugs, hot melt extrusion and coating/passivation processes can be used to achieve dual sustained and controlled release effects, making the blood drug concentration more stable and extending the drug release cycle.

Abstract

一种长效缓控释植入剂的制备方法，涉及药物制剂领域，该长效缓控释植入剂的制备方法包括以下步骤：(1)将活性药物和可生物降解聚合物混合，冷冻粉碎，干燥，过筛，得到混合物；(2)将步骤(1)得到的混合物经熔融挤出、冷却成型、切粒，得到成型固体；(3)将步骤(2)得到的成型固体经加热钝化或包衣，干燥，得到植入剂。该制备方法安全、能耗低、周期短且易控制，在保证植入剂缓释的同时能够防止突释。

Description

一种长效缓控释植入剂的制备方法
本发明要求于2022年08月15日提交中国专利局、申请号为202210981508.9、发明名称为“一种长效缓控释植入剂的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在申请中。
技术领域
本发明涉及药物制剂领域，具体涉及一种长效缓控释植入剂的制备方法。
背景技术
长效缓控释注射剂，通常经皮下或肌内注射等途径给药，在注射位点形成药物储库发挥长效释放作用。它能够在几天至几个月内持续释放药物，其优点是降低给药频率、简化药物治疗方案、药动学波动较小、不良反应更少。但其应用存在一些局限性，如需就医给药、可能存在剂量突释、不同制剂间的变异等。正因为存在这些临床或者药学开发方面的挑战，近30多年以来，只有20多种长效缓控释注射剂化学药品上市，主要用于抗精神病、激素治疗和戒毒等领域。按照释放机制，大致可分为3类：①原料药缓释，其原料药一般水溶性较差，通过原料药缓慢的溶解和释放发挥缓释作用。②药物自凝集缓释，其机制是原料药在体内凝集形成凝胶状药物储库发挥长效释放作用。③辅料缓释，其释放机制是辅料在给药部位缓慢持续扩散或降解，进而实现原料药长效释放。对于前两种机制，主要采用纳米晶/微晶混悬型注射液或者原位凝胶注射技术；而对于第三种释放机制，主要通过微球、原位凝胶或者热熔挤出生产植入剂。
热熔挤出技术(HME)，又称为熔融挤出技术，指将药物与载体辅料在熔融状态下进行均匀混合，并以一定的压力、速度和形状挤出的一种技术。该技术使药物以分子、无定形态或亚稳定态等形式分散在载体中，可以提高难溶性药物溶出度、改善生物利用度，是近年来快速发展的一项新的制剂技术，在制备缓控释制剂和药物传递系统中表现出突出的优势，且成本低廉、工艺简单、重现性好、生产效率高，在医药研发领域具有广阔的开发前景。
热塑性的缓控释聚合物与水溶性药物，经热熔挤出制成植入剂，药物颗粒均匀分布在聚合物基质中。在挤出过程中，熔融的载药材料会包裹药物颗粒。因此，形成的孔结构的尺寸和表面主要是药物颗粒的尺寸和表面积的函数。聚合物基质由封闭和开放的孔结构组成。在封闭的孔结构中，药物颗粒被聚合物基质完全包裹/封闭，而在开放的孔结构中，药物颗粒暴 露于放置植入剂的流体介质中。因此，在植入剂给药起始阶段，暴露在外表面以及在开放的孔结构中的药物颗粒会快速释放，导致明显的剂量倾泻效应。该突释现象，对于水溶性好的药物更加明显，可能会给患者带来一定的安全性风险。本发明公开一种新的长效植入剂制备方法，即采用包衣或者热钝化工艺，可控制给药起始阶段药物突释，维持药物平稳释放，达到零级释药或者一级释药目标。药物包括伐尼克兰、丁丙诺啡、多奈哌齐、曲安奈德、奥曲肽、亮丙瑞林、戈舍瑞林、艾塞那肽，或其药学上可接受盐。
CN111714442将活性药物成分与聚乳酸羟基乙酸共聚物混合，溶于第一溶剂中，进行热熔挤出，从而得到第一挤出物，将所述第一挤出物浸入第二溶剂中，从而得到所述植入剂。该方法多次使用有机溶剂，中间产品需要干燥，工艺复杂，有机溶剂残留风险较高。
US20190350844提供了伐尼克兰或其药学上可接受的衍生物，以及一种或多种可生物降解或非可生物降解载体所组成的微球、植入物、油性溶液、脂质体、混悬液、微乳液、原位胶凝等长效储库组合物，皮下/肌肉注射或植入，可有效防止患者自行停止治疗，三天一次到每六个月一次的给药方案，可减少给药批次，提高患者的依从性和降低不良反应风险。由于伐尼克兰属于BCS I类，水溶性好，上述剂型在给药后通常存在突释现象，给患者带来一定的安全性风险。
CN102755627将乙酸和乙醇混合制成混合溶剂，然后将药学上可接受的载体和戈舍瑞林溶解于所述混合溶剂中，然后冷冻干燥去除溶剂，制得颗粒或细粉，再将所述颗粒或细粉置于热熔挤出机中，挤压成条状物，切割成圆柱状物。该技术使用较多有机溶剂，且通过冷冻干燥法去除有机溶剂生产周期长，能耗较大。
CN106580868公开将水难溶/微溶性药物和释放调节剂溶于有机溶剂中，在加入水难溶性聚合物，然后除去有机溶剂，得到固体混合物，进行热熔挤出机中进行挤出、切割，得到植入剂。处方中增加释放调节剂，虽然可在一定程度上调节药物释放速率，但是对于植入剂而言，释放调节剂中只有少数可用于注射，处方组成越复杂，注射风险更高。并且使用大量有机溶剂用于溶解药物和释放调节剂，植入剂中有机溶剂残留控制难度大。
针对现有技术中存在的问题，寻找一种安全、能耗低、周期短且易控制的长效缓控释植入剂的制备方法十分必要。
发明内容
本发明针对现有技术存在的问题，提供了一种长效缓控释植入剂的制备方法，该制备方法安全、能耗低、周期短且易控制，在保证植入剂缓释的同时能够防止突释。
为实现上述目的，本发明采用的技术方案如下：
本发明提供了一种植入剂的制备方法，包括以下步骤：
(1)将活性药物和可生物降解聚合物混合，冷冻粉碎，干燥，过筛，得到混合物；
(2)将步骤(1)得到的混合物经熔融挤出、冷却成型、切粒，得到成型固体；
(3)将步骤(2)得到的成型固体经加热钝化或包衣，干燥，得到植入剂。
进一步地，所述活性药物和可生物降解聚合物的重量比为30-65:35-70；优选为35-60:40-65。
进一步地，所述活性药物包括伐尼克兰、丁丙诺啡、多奈哌齐、曲安奈德、奥曲肽、亮丙瑞林、戈舍瑞林、艾塞那肽，或其药学上可接受盐。
进一步地，所述可生物降解聚合物包括聚丙交酯、聚乙交酯、丙交酯-乙交酯共聚物、聚己内酯、PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA、PCL-PEG-PCL中的一种或多种；优选为聚丙交酯、丙交酯-乙交酯共聚物、PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA；进一步优选为聚丙交酯和/或丙交酯-乙交酯共聚物。
进一步地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)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。更优选地，所述聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)封端基团为烷酯基或者羧基。更优选地，所述可生物降解聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)中的至少一种时，其中丙交酯与乙交酯的摩尔比为100:0至50:50。更优选地，所述可生物降解聚合物为聚丙交酯(PLA)、丙交酯-乙交酯共聚物(PLGA)中的至少一种时，其中丙交酯与乙交酯的摩尔比为100:0至75:25。
进一步地，作为本发明所述的可生物降解聚合物，可在体内生物降解为二氧化碳和水，生物兼容性好，可以为单一的聚合物，也可以是多种聚合物组成的混合物。比如，丙交酯与乙交酯的摩尔比和分子量均相同，但端基不同的PLGA组合；丙交酯与乙交酯的摩尔比和端基相同，但分子量不同的PLGA组合；丙交酯与乙交酯的分子量和端基相同，但摩尔比不同的PLGA组合；丙交酯与乙交酯的摩尔比、端基和分子量均不同的PLGA组合。
进一步地，步骤(1)中所述冷冻粉碎的温度为-70℃～-20℃优选为-50℃～-25℃。
步骤(1)中所述冷冻粉碎后的混合物的粒径不大于20目，优选为不大于40目，进一步优选为不大于60目。
进一步地，步骤(3)中所述加热钝化的温度为70-150℃，时间为2-60min；优选地，所 述加热钝化的温度为90-140℃，时间为5-30min；进一步优选地，所述加热钝化的温度为95-130℃，时间为8-30min。
进一步地，步骤(3)中所述包衣使用的包衣液包括缓释组合物和有机溶剂；所述缓释组合物包括聚丙交酯、聚乙交酯、丙交酯-乙交酯共聚物、PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA的一种或多种；优选地，所述缓释组合物包括聚丙交酯和/或丙交酯-乙交酯共聚物。
进一步地，所述包衣液中缓释组合物重量占比为3-30％；优选为6-25％。
进一步地，所述聚丙交酯、丙交酯-乙交酯共聚物的重均分子量均为7000-150000Da，特性粘度均为0.1-2.5dL/g；优选地，所述聚丙交酯、丙交酯-乙交酯共聚物的重均分子量均为9000-120000Da，特性粘度均为0.2-1.2dL/g。
进一步地，所述有机溶剂包括二甲基亚砜、甲醇、丙酮、乙腈、二氯甲烷、三氯甲烷、四氢呋喃、乙酸乙酯中的一种或多种；优选为乙酸乙酯和/或二氯甲烷。
进一步地，步骤(3)中所述干燥具体为室温晾干2-4天，或者30-45℃真空干燥18-72小时。优选为35-40℃真空干燥24-48小时。
进一步地，本发明还提供了上述的制备方法制备得到的植入剂。
进一步地，所述植入剂为颗粒状、圆柱状或细棒状；优选为圆柱状或细棒状。
进一步地，当所述植入剂为圆柱状或细棒状时，其具有不大于6cm的长度，不大于3mm的直径。优选地，所述植入剂为圆柱状或细棒状时，其具有不大于5cm的长度，不大于2.5mm的直径。更优选地，所述植入剂为圆柱状或细棒状时，其具有不大于3.5cm的长度，不大于2.0mm的直径。
进一步地，当所述植入剂为圆柱状或细棒状时，其长径比为(10-50)：1。优选地，所述植入剂为圆柱状或细棒状时，其长径比为(15-40)：1。更优选地，所述植入剂为圆柱状或细棒状时，其长径比为(20-30)：1。
本发明所取得的技术效果是：
1.本发明通过对水溶性药物的植入剂进行热钝化，尤其是BCS 1类和BCS 3类药物，包括部分热稳定性尚可的多肽类药物同样适用，本发明的方法能够在植入剂外表面形成一层保护膜，阻滞附着在植入剂外表面的药物颗粒快速释放，从而控制突释现象，使血药波动减小，提高长效缓控释制剂安全性。
2.本发明采用熔融挤出与包衣/钝化的方法，采用骨架型和膜控的双重缓控释方式，不同于双重膜控缓释，骨架型和膜控二者协同性作用从而能够使植入剂在保证缓释的同时防止突 释。
附图说明
图1为对比例1样品形态SEM图；
图2为实施例1样品形态SEM图；
图3为实施例2样品形态SEM图；
图4为实施例3样品形态SEM图；
图5为对比例2样品形态SEM图；
图6为实施例4样品形态SEM图；
图7为实施例5样品形态SEM图；
图8为实施例6样品形态SEM图；
图9为对比例8样品形态SEM图；
图10为各实施例样品的体外释放度考察图；
图11为各对比例样品的体外释放度考察图。
具体实施方式
以下通过特定的具体实例说明本发明的实施方式，本领域技术人员可由本说明书所揭露的内容轻易地了解本发明的其他优点与功效。本发明还可以通过另外不同的具体实施方式加以实施或应用，本说明书中的各项细节也可以基于不同观点与应用，在没有背离本发明的精神下进行各种修饰或改变。
在进一步描述本发明具体实施方式之前，应理解，本发明的保护范围不局限于下述特定的具体实施方案；还应当理解，本发明实施例中使用的术语是为了描述特定的具体实施方案，而不是为了限制本发明的保护范围。
当实施例给出数值范围时，应理解，除非本发明另有说明，每个数值范围的两个端点以及两个端点之间任何一个数值均可选用。除非另外定义，本文中使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同意义。
值得说明的是，本发明中使用的原料均为普通市售产品，因此对其来源不做具体限定。
实施例1：
本实施例所述植入剂的制备原辅料组分：酒石酸伐尼克兰处方占比30％(W/W)，聚乳酸(PLA)为70％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.20dL/g， 烷酯基封端。
1)将9.0g酒石酸伐尼克兰和21.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定95℃，螺杆转速100RPM，出料口压力小于40Bar)，切粒，得到直径为1.6mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行95℃加热钝化处理30min，冷却至室温，得到所述的直径为1.6mm，长径比为30的植入剂。
实施例2：
本实施例所述植入剂的制备原辅料组分：酒石酸伐尼克兰处方占比30％(W/W)，聚乳酸(PLA)为70％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.20dL/g，烷酯基封端。
1)将9.0g酒石酸伐尼克兰和21.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制3.7％，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定95℃，螺杆转速100RPM，出料口压力小于40Bar)，切粒，得到直径为1.6mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行110℃加热钝化处理20min，冷却至室温，得到所述的直径为1.6mm，长径比为30的植入剂。
实施例3
本实施例所述植入剂的制备原辅料组分：酒石酸伐尼克兰处方占比30％(W/W)，聚乳酸(PLA)为70％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.20dL/g，烷酯基封端。
1)将9.0g酒石酸伐尼克兰和21.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制3.7％，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定95℃，螺杆转速100RPM，出料口压力小于40Bar)，切粒，得到直径为1.6mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行120℃加热钝化处理10min，冷却至室温，得到所述的直径为1.6mm，长径比为30的植入剂。
实施例4：
本实施例所述植入剂的制备原辅料组分：盐酸丁丙诺啡处方占比50％(W/W)，丙交酯-乙交酯共聚物(PLGA)为50％(W/W)，其中PLGA的重均分子量为100kDa，特性黏度为0.82dL/g，组分摩尔比75:25，羧基封端。
1)将10.0g盐酸丁丙诺啡和10.0g PLGA混合，-60℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定125℃，螺杆转速150RPM，出料口压力小于50Bar)，切粒，得到直径为3.0mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行包衣，其中包衣液为6％聚乳酸(PLA重均分子量为120kDa，羧基封端)，有机溶剂为乙酸乙酯，40℃真空干燥24小时，得到所述的直径为3.0mm，长径比为25的植入剂。
实施例5：
本实施例所述植入剂的制备原辅料组分：盐酸丁丙诺啡处方占比50％(W/W)，PLGA为50％(W/W)，其中PLGA的重均分子量为100kDa，特性黏度为0.82dL/g，组分摩尔比75:25，羧基封端。
1)将10.0g盐酸丁丙诺啡和10.0g PLGA混合，-60℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定125℃，螺杆转速150RPM，出料口压力小于50Bar)，切粒，得到直径为3.0mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行包衣，其中包衣液为10％聚乳酸(PLA重均分子量为120kDa，羧基封端)，有机溶剂为乙酸乙酯，40℃真空干燥24小时，得到所述的直径为3.0mm，长径比为25的植入剂。
实施例6：
本实施例所述植入剂的制备原辅料组分：盐酸丁丙诺啡处方占比50％(W/W)，PLGA为50％(W/W)，其中PLGA的重均分子量为100kDa，特性黏度为0.82dL/g，组分摩尔比75:25，羧基封端。
1)将10.0g盐酸丁丙诺啡和10.0g PLGA混合，-60℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定125℃，螺杆转速150RPM，出料口压力小于50Bar)，切粒，得到直径为3.0mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行包衣，其中包衣液为25％聚乳酸(PLA重均分子量为120kDa，羧基封端)，有机溶剂为乙酸乙酯，40℃真空干燥24小时，得到所述的直径为3.0mm，长径比为25的植入剂。
实施例7：
本实施例所述植入剂的制备原辅料组分：多奈哌齐处方占比60％(W/W)，PLGA为40％(W/W)，其中PLGA的重均分子量为40kDa，特性黏度为0.32dL/g，摩尔比为85:15，羧基封端。
1)将24.0g多奈哌齐和16.0g PLGA混合，-30℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定120℃，螺杆转速120RPM，出料口压力小于30Bar)，切粒，得到直径为2.0mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行125℃加热钝化处理25min，冷却至室温，得到所述的直径为2.0mm，长径比为24的植入剂。
实施例8：
本实施例所述植入剂的制备原辅料组分：盐酸曲安奈德处方占比65％(W/W)， PLA-PEG-PLA为35％(W/W)，其中PLA-PEG-PLA的重均分子量为12kDa，PEG质量百分比为5％，特性黏度为0.12dL/g。
1)将26.0g盐酸曲安奈德和14.0g PLA-PEG-PLA混合，-40℃冷冻粉碎，水分控制5.0％，过筛收集不大于40目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定90℃，螺杆转速80RPM，出料口压力小于30Bar)，切粒，得到直径为2.5mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行90℃加热钝化处理20min，冷却至室温，得到所述的直径为2.5mm，长径比为25的植入剂。
实施例9：
本实施例所述植入剂的制备原辅料组分：醋酸奥曲肽处方占比40％(W/W)，聚乳酸(PLA)为60％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.16dL/g，烷酯基封端。
1)将12.0g醋酸奥曲肽和18g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制2.0％，过筛收集不大于40目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定90℃，螺杆转速160RPM，出料口压力小于40Bar)，切粒，得到直径为1.2mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行包衣，其中包衣液为10％聚乳酸(PLA重均分子量为20kDa，羧基封端)，有机溶剂为二氯甲烷，25℃真空干燥24小时，得到所述的直径为1.2mm，长径比为20的植入剂。
实施例10：
本实施例所述植入剂的制备原辅料组分：醋酸戈舍瑞林处方占比45％(W/W)，PLGA为55％(W/W)，其中PLGA的重均分子量为30kDa，特性黏度为0.22dL/g，烷酯基封端。1)将13.5g醋酸戈舍瑞林和16.5g PLGA混合，-40℃冷冻粉碎，水分控制1.0％，过筛收集
不大于40目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定95℃，螺杆转速150RPM，出料口压力小于60Bar)，切粒，得到直径为1.5mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行包衣，其中包衣液为15％聚乳酸(PLA重均分子量为120kDa，烷酯基封端)，有机溶剂为乙酸乙酯，25℃真空干燥48小时，得到所述的直径为1.5mm，长径比为23的植入剂。
实施例11：
本实施例所述植入剂的制备原辅料组分：艾塞那肽处方占比40％(W/W)，PLGA为60％(W/W)，其中PLGA的重均分子量为25kDa，特性黏度为0.24dL/g，摩尔比为75:25，烷酯基封端。
1)将12.0g艾塞那肽和18.0g PLGA混合，-30℃冷冻粉碎，水分控制1.5％，过筛收集不大于40目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定100℃，螺杆转速100RPM，出料口压力小于20Bar)，切粒，得到直径为1.5mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行包衣，其中包衣液为10％聚乳酸(PLA重均分子量为120kDa，烷酯基封端)，有机溶剂为二氯甲烷，25℃真空干燥48小时，得到所述的直径为1.5mm，长径比为21的植入剂。
实施例12
本实施例所述植入剂的制备原辅料组分：醋酸奥曲肽处方占比40％(W/W)，聚乳酸(PLA)为60％(W/W)，其中聚乳酸(PLA)的重均分子量为8kDa，特性黏度为0.10dL/g，烷酯基封端。本实施例所述植入剂的制备方法同实施例9。
实施例13
本实施例所述植入剂的制备原辅料组分：醋酸奥曲肽处方占比40％(W/W)，聚乳酸(PLA)为60％(W/W)，其中聚乳酸(PLA)的重均分子量为130kDa，特性黏度为1.48dL/g，烷酯基封端。本实施例所述植入剂的制备方法同实施例9。
对比例1
本对比例所述植入剂的制备原辅料组分：酒石酸伐尼克兰处方占比30％(W/W)，聚乳酸(PLA)为70％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.20dL/g，烷酯基封端。
1)将9.0g酒石酸伐尼克兰和21.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定95℃，螺杆转速100RPM，出料口压力小于40Bar)，切粒，得到直径为1.6mm圆柱状植入剂。
对比例2：
本对比例所述植入剂的制备原辅料组分：盐酸丁丙诺啡处方占比50％(W/W)，丙交酯-乙交酯共聚物(PLGA)为50％(W/W)，其中PLGA的重均分子量为100kDa，特性黏度为0.82dL/g，组分摩尔比75:25，羧基封端。
1)将10.0g盐酸丁丙诺啡和10.0g PLGA混合，-60℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定125℃，螺杆转速150RPM，出料口压力小于50Bar)，切粒，得到直径为3.0mm圆柱状植入剂。
对比例3：
本实施例所述植入剂的制备原辅料组分：多奈哌齐处方占比60％(W/W)，PLGA为40％(W/W)，其中PLGA的重均分子量为40kDa，特性黏度为0.32dL/g，摩尔比为85:15，羧基封端。
1)将24.0g多奈哌齐和16.0g PLGA混合，-30℃冷冻粉碎，过筛收集不大于20目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定120℃，螺杆转速120RPM，出料口压力小于30Bar)，切粒，得到直径为2.0mm圆柱状植入剂。
对比例4：
本实施例所述植入剂的制备原辅料组分：盐酸曲安奈德处方占比65％(W/W)， PLA-PEG-PLA为35％(W/W)，其中PLA-PEG-PLA的重均分子量为12kDa，PEG质量百分比为5％，特性黏度为0.12dL/g。
1)将26.0g盐酸曲安奈德和14.0g PLA-PEG-PLA混合，-40℃冷冻粉碎，水分控制5.0％，过筛收集不大于40目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定90℃，螺杆转速80RPM，出料口压力小于30Bar)，切粒，得到直径为2.5mm圆柱状植入剂。
对比例5：
本实施例所述植入剂的制备原辅料组分：醋酸奥曲肽处方占比40％(W/W)，聚乳酸(PLA)为60％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.16dL/g，烷酯基封端。
4)将12.0g醋酸奥曲肽和18g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制2.0％，过筛收集不大于40目的颗粒；
5)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定90℃，螺杆转速160RPM，出料口压力小于40Bar)，切粒，得到直径为1.2mm圆柱状植入剂。
对比例6：
本实施例所述植入剂的制备原辅料组分：醋酸戈舍瑞林处方占比45％(W/W)，PLGA为55％(W/W)，其中PLGA的重均分子量为30kDa，特性黏度为0.22dL/g，烷酯基封端。
1)将13.5g醋酸戈舍瑞林和16.5g PLGA混合，-40℃冷冻粉碎，水分控制1.0％，过筛收集不大于40目的颗粒；
2)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定95℃，螺杆转速150RPM，出料口压力小于60Bar)，切粒，得到直径为1.5mm圆柱状植入剂。
对比例7：
本实施例所述植入剂的制备原辅料组分：艾塞那肽处方占比40％(W/W)，PLGA为60％(W/W)，其中PLGA的重均分子量为25kDa，特性黏度为0.24dL/g，摩尔比为75:25，烷酯 基封端。
3)将12.0g艾塞那肽和18.0g PLGA混合，-30℃冷冻粉碎，水分控制1.5％，过筛收集不大于40目的颗粒；
4)将步骤1)所得的原辅料混合物置于热熔挤出机中进行熔融挤出(混合熔融区域温度设定100℃，螺杆转速100RPM，出料口压力小于20Bar)，切粒，得到直径为1.5mm圆柱状植入剂。
对比例8
酒石酸伐尼克兰微球制备：
1)外水相配制：称取50.00g聚乙烯醇(PVA，24/88)和400.00g氯化钠，加入5000ml水中，持续搅拌，使其充分溶解，待温度降至室温后，用100目筛网过滤，作为外水相。
2)内水相配制：称取6.0g酒石酸伐尼克兰，溶于24ml水。
3)油相配制：将内水相以及14.0g聚乳酸(PLA，特性黏度0.20dL/g)，加入80.00g二氯甲烷，涡旋摇荡使其充分溶解，作为油相。
4)乳化：用蠕动泵(2000ml/min)将外水相注入高剪切均质机内腔(2000RPM)，然后油相用注射泵以50ml/min推注进入高剪切均质机内腔，在高剪切作用下形成单乳。用磁力搅拌器(500RPM)搅拌乳液，加热至38℃继续搅拌20小时，挥发二氯甲烷，冰浴1h，然后过滤，收集滤渣得微球。
5)真空冷冻干燥，或其他形式干燥，除去残留溶剂和水分，水分＜2.1％。过筛网进行颗粒筛分，得到所述的酒石酸伐尼克兰微球(详见图9)。
对比例9
本对比例所述植入剂的制备原辅料组分同实施例4，制备方法除包衣液浓度为3％外，其他步骤均同实施例4。
对比例10
本对比例所述植入剂的制备原辅料组分同实施例4，制备方法除包衣液浓度为35％外，其他步骤均同实施例4。
对比例11：
本对比例所述片剂的制备原辅料组分：醋酸奥曲肽处方占比40％(W/W)，聚乳酸(PLA) 为60％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.16dL/g，烷酯基封端。
1)将12.0g醋酸奥曲肽和18g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制2.0％，过筛收集不大于40目的颗粒；
2)将步骤1)所得的原辅料混合物进行压片，冲膜直径6mm，片重约为75mg；
3)将步骤2)所得的片剂进行包衣，其中包衣液为10％聚乳酸(PLA重均分子量为20kDa，羧基封端)，有机溶剂为二氯甲烷，25℃真空干燥24小时，得到所述的直径为1.2mm，长径比为20的植入剂。
一、植入剂载药量的测定
实施例1-13和对比例1-11制备的样品，每个样品各取6份，采用本技术领域中常规的高效液相色谱法检测其含量和有关物质，载药量的计算方法如下：
载药量＝(植入剂中所含药物重/植入剂总重)*100％
表1植入剂载药量和总杂

由表1中各样品的载药量和有关物质检测结果可知，植入剂实际载药量与理论载药量非常接近，高于微球载药量，即热熔挤出工艺对原辅料几乎无损耗。通过热钝化处理后含量无变化，但进行包衣工艺，因包衣层具有一定厚度，导致载药量不同程度降低，由每个品种的包衣组成和包衣厚度等决定。另外，实施例和对比例所制备样品的总杂均较低，两者无明显差异，说明热钝化或者包衣工艺对水溶性药物植入剂的杂质无影响。
二、体外释放度考察
测定方法：将实施例1-13，对比例1-5和对比例8-11所制备的植入剂，每个样品均称取6份(30mg)，置于100ml锥形瓶中，释放介质为50ml磷酸盐缓冲液pH7.4，采用37±0.5℃恒温水浴振荡器考察，转速为50RPM。在预设时间点取样(第1天和第3天取样并更换介质后，每3或4天取样一次并更换介质，直至第90天取样，整个释放过程均保持满足漏槽条件)，样品含量采用高效液相色谱法检测，计算平均累计释放曲线(详见图10-11)和平均日释放率(详见表2)。
表2实施例体外平均累计释放度(％)

表3对比例体外平均累计释放度(％)

通过分析实施例1-3和对比例1所制备样品体外释放度考察结果，热钝化处理可明显控制水溶性药物起始阶段的突释现象，使整个药物缓释周期内呈零级释放，避免因药物突释可能造成患者发生不良反应。热钝化温度可根据植入剂所需热熔挤出温度进行选择，通常不低于热熔挤出温度，但不宜过高，否则可能导致植入剂因温度过高而二次熔融，发生严重形变。热钝化时间需结合热钝化温度进行综合选择，即不同热钝化温度下所需时间会有所差异，可视最终产品的释放度控制而定。
通过分析实施例4-6和对比例2所制备样品体外释放度考察结果，对植入剂进行包衣可显著降低水溶性药物起始阶段的释放速度，使整个药物缓释周期内呈零级释放，避免因药物突释可能造成患者发生不良反应。包衣液组成可根据所需控制释放速度而定，通常低分子量/特性黏度的可生物降解聚合物会比高分子量控制释放更快，直线型的可生物降解聚合物会比多支链星形控制释放更快，疏水性封端的可生物降解聚合物会比亲水性封端控制释放更快，PEG修饰的可生物降解聚合物会比未修饰的控制释放更快，低浓度比高浓度控制释放更快。对比例9和对比例10体外释放度表明，包衣液浓度过低将导致无明显控制释放效果；包衣液浓度过高，则严重阻滞药物释放，从而产生迟释现象，不适合需快速起效的水溶性药物品种。
通过分析实施例1-3，对比例1，对比例8体外释放度，酒石酸伐尼克兰微球发生严重突释，20天左右，药物完全释放，热熔挤出工艺制备的植入剂可一定程度减小突释，但第一天释放量仍较大(＞20％)。但是通过热钝化或者包衣工艺，使植入剂外表面形成一层致密的控释膜，药物溶解/扩散的孔道显著减少(见图1至图8)，从而避免突释，可将起始释放速度控制在预期的范围内，非常适合BCS 1类或者BCS 3类药物开发成长效缓控释植入剂。
实施例12采用重均分子量为8kDa、特性黏度为0.10dL/g的PLA，药物释放速率快于实施例9，因为该可生物降解聚合物分子量低，特性黏度也较小，容易水解或者自身降解，导致醋酸奥曲肽溶出/溶蚀较快；但是小于对比例5，说明包衣可一定程度控制前期突释。
实施例13采用重均分子量为130kDa、特性黏度为1.48dL/g的PLA，相对于实施例9和对比例5，药物前期释放明显减缓，15天药物累计释放量为10％左右，因为PLA重均分子量超过12kDa，特性黏度超过1.2dL/g，疏水基团较多，水分更难以进入基质中的孔道，药物被牢固地束缚在PLA中，相对而言有迟释现象。
通过分析对比例5、实施例9体外释放度，实施例9采用热熔挤出和包衣工艺，对比例5采用未包衣工艺，对比例5前期释放得到一定控制，随着释放时间延长，药物加快释放，释放周期明显小于实施例9样品。这说明，首先，包衣工艺能形成膜控型缓释效果。这是因为随着植入剂外层包衣膜的降解，膜的孔隙率增加，药物从膜孔释放的阻力更小，从而导致释放速率增加。通过分析对比例11、实施例9体外释放度，实施例9采用热熔挤出和包衣工艺，对比例11采用压片和包衣工艺，由于热熔挤出可形成骨架型缓释结构，热熔挤出制备的药芯释放周期长于压片所得的片芯释放周期。因此，为延长药物缓释周期，采用热熔挤出和包衣/钝化工艺，可达到双重缓控释效果，使血药浓度更加平稳，并延长药物释放周期。
本发明中的缩写以及英文含义详见表4。
表4缩写以及英文含义
最后应当说明的是，以上内容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，本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换，均不脱离本发明技术方案的实质和范围。

Claims (10)

  1. 一种植入剂的制备方法，其特征在于：包括以下步骤：
    (1)将活性药物和可生物降解聚合物混合，冷冻粉碎，干燥，过筛，得到混合物；
    (2)将步骤(1)得到的混合物经熔融挤出、冷却成型、切粒，得到成型固体；
    (3)将步骤(2)得到的成型固体经加热钝化或包衣，干燥，得到植入剂。
  2. 根据权利要求1所述的制备方法，其特征在于：所述活性药物和可生物降解聚合物的重量比为30-65:35-70；优选为35-60:40-65。
  3. 根据权利要求1所述的制备方法，其特征在于：所述活性药物包括伐尼克兰、丁丙诺啡、多奈哌齐、曲安奈德、奥曲肽、亮丙瑞林、戈舍瑞林、艾塞那肽，或其药学上可接受盐。
  4. 根据权利要求1所述的制备方法，其特征在于：所述可生物降解聚合物包括聚丙交酯、聚乙交酯、丙交酯-乙交酯共聚物、聚己内酯、PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA、PCL-PEG-PCL中的一种或多种；优选为聚丙交酯、丙交酯-乙交酯共聚物、PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA；进一步优选为聚丙交酯和/或丙交酯-乙交酯共聚物。
  5. 根据权利要求1所述的制备方法，其特征在于：步骤(1)中所述冷冻粉碎的温度为-70℃～-20℃优选为-50℃～-25℃。
  6. 根据权利要求1所述的制备方法，其特征在于：步骤(3)中所述加热钝化的温度为70-150℃，时间为2-60min；优选地，所述加热钝化的温度为90-140℃，时间为5-30min；进一步优选地，所述加热钝化的温度为95-130℃，时间为8-30min。
  7. 根据权利要求1所述的制备方法，其特征在于：步骤(3)中所述包衣使用的包衣液包括缓释组合物和有机溶剂；所述缓释组合物包括聚丙交酯、聚乙交酯、丙交酯-乙交酯共聚物、PLA-PEG、PLGA-PEG、PLGA-PEG-PLGA、PLA-PEG-PLA的一种或多种；优选地，所述缓释组合物包括聚丙交酯和/或丙交酯-乙交酯共聚物。
  8. 根据权利要求7所述的制备方法，其特征在于：所述包衣液中缓释组合物重量占比为3-30％；优选为6-25％。
  9. 根据权利要求4或7所述的制备方法，其特征在于：所述聚丙交酯、丙交酯-乙交酯共聚物的重均分子量均为7000-150000Da，特性粘度均为0.1-2.5dL/g；优选地，所述聚丙交酯、丙交酯-乙交酯共聚物的重均分子量均为9000-120000Da，特性粘度均为0.2-1.2dL/g。
  10. 如权利要求1-9任一项所述的制备方法制备得到的植入剂。
PCT/CN2023/113096 2022-08-15 2023-08-15 一种长效缓控释植入剂的制备方法 WO2024037535A1 (zh)

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