WO2024037536A1 - 包含伐尼克兰的缓释制剂及其制备方法 - Google Patents

包含伐尼克兰的缓释制剂及其制备方法 Download PDF

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WO2024037536A1
WO2024037536A1 PCT/CN2023/113099 CN2023113099W WO2024037536A1 WO 2024037536 A1 WO2024037536 A1 WO 2024037536A1 CN 2023113099 W CN2023113099 W CN 2023113099W WO 2024037536 A1 WO2024037536 A1 WO 2024037536A1
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Prior art keywords
varenicline
sustained
lactide
polylactide
release
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PCT/CN2023/113099
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English (en)
French (fr)
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刘代春
曲伟
颜携国
尹述贵
张涛
陈泽琴
付晓芳
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 WO2024037536A1 publication Critical patent/WO2024037536A1/zh

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    • 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
    • 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
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse

Definitions

  • the present invention relates to the field of pharmaceutical preparations, and in particular to sustained-release preparations containing varenicline and preparation methods thereof.
  • Nicotine dependence is a chronic and highly relapsing disease, the essence of which is nicotine dependence. Nicotine is contained in the smoke produced by burning cigarettes, cigars, pipes, and smokeless tobacco. Smoking is a quick and effective way to absorb nicotine into the body. Nicotine is a psychoactive substance that can make some people feel "euphoric" after use. It can temporarily improve some individuals' work performance and cognitive abilities, extend their attention span, and reduce negative emotions such as anxiety and depression. .
  • Tobacco dependence often manifests itself in two aspects: physical dependence and psychological dependence.
  • Physical dependence is characterized by a series of unbearable symptoms and signs that smokers will experience after stopping smoking, which are called withdrawal symptoms, including craving for smoking, anxiety, depression, restlessness, headache, increased salivary gland secretion, and inattention. Concentration, sleep disturbances, increased blood pressure and heart rate, etc.
  • Mental dependence is also called psychological dependence, commonly known as “heart addiction”, which manifests as a strong subjective desire to smoke. If a tobacco dependent smokes again after experiencing withdrawal symptoms, they will feel satisfied and euphoric, and their body and mind will tend to be relaxed and peaceful, making it more difficult to quit smoking.
  • Varenicline is a new smoking cessation drug that is a partial agonist of nicotine acetylcholine receptors. After combining with nicotine acetylcholine receptors, varenicline acts as an agonist, stimulating the release of dopamine in the brain, which can alleviate withdrawal symptoms after quitting smoking. On the other hand, its antagonistic properties can prevent nicotine from interacting with nicotine acetylcholine receptors. Combined, reduces the euphoria of smoking. Varenicline tartrate tablets were applied for marketing by Pfizer on May 10, 2006, with the trade name Available in two specifications: 0.5mg and 1.0mg.
  • varenicline 7,8,9,10-tetrahydro-6,10-methylene-6H-pyrazino[2,3-h][3]benzazepine
  • the chemical structure is as follows:
  • Varenicline has a unique bitter taste, which is bitter and burning, and may cause discomfort when swallowed. Even if varenicline is prepared into salt, the problem of this bitter taste remains unresolved. Therefore, oral administration of varenicline tartrate tablets can Cause nausea in patients to some extent.
  • CN108463252A provides a method containing varenicline or a pharmaceutically acceptable salt thereof as an active ingredient, and both a carboxyl-containing anionic polymer and an amino-containing cationic polymer as Pharmaceutical formulations of bitter taste masking agents for oral administration.
  • WO2007/01296 also provides a transdermal composition containing varenicline or its pharmaceutically acceptable salt or prodrug form, wherein varenicline can be slowly released through the skin layer.
  • varenicline can be slowly released through the skin layer.
  • US20190350844A1 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 liquid, microemulsion, and in-situ gelling, subcutaneous/muscular injection or subcutaneous implantation 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 Dosing batches improve patient compliance and reduce the risk of adverse reactions. Since 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.
  • the existing technology has the following shortcomings: 1) Ordinary oral tablets containing varenicline or its pharmaceutically acceptable salts have a unique bitter taste, that is, bitter and burning taste, and the patient's compliance with taking the medicine is difficult. Sex will be poor, often causing nausea and other adverse reactions. 2) Although the use of oral tablets with bitter taste masking agents or the development of transdermal patches can reduce or even avoid the irritation of swallowing, patients are not willing to quit smoking and may stop taking the medicine on their own, leading to relapse.
  • Storage-type sustained-release preparations such as microspheres, oily solutions, liposomes, suspensions, microemulsions, and in-situ gels prepared by conventional processes have good solubility in Varenicline or its pharmaceutically acceptable saline solution. There is a burst release phenomenon, the blood concentration fluctuates greatly, and the risk of adverse reactions is high.
  • type 2 organic solvents are often used, resulting in residual organic solvents and an increase in the number of drugs. side effects.
  • the present invention provides a sustained-release preparation containing varenicline and a preparation method thereof.
  • the sustained-release preparation can solve the bitter taste and swallowing irritation of oral administration, reduce the irritation of administration, and increase the patient's comfort. Compliance can also eliminate the problem of sudden or delayed release, and can be released stably for a long time. At the same time, it can avoid daily administration, reduce patient pain, reduce the risk of adverse reactions, and improve the success rate of smoking cessation.
  • the invention provides a sustained-release preparation, which contains 20-60 parts by weight of active drugs and 40-80 parts of biodegradable polymers; the active drug is varenicline free base, or its pharmaceutically acceptable Acceptable salts, including but not limited to varenicline tartrate, varenicline salicylate, varenicline sulfate, varenicline fumarate, varenicline oxalate, varenicline hydrochloride, varenicline hydrobromide, citron One or more of varenicline acid, varenicline maleate, varenicline succinate, and varenicline phosphate.
  • the active drug is varenicline free base, or its pharmaceutically acceptable Acceptable salts, including but not limited to varenicline tartrate, varenicline salicylate, varenicline sulfate, varenicline fumarate, varenicline oxalate, varenicline hydrochloride, varenicline hydrobromide, citron One or more of vare
  • the sustained-release preparation contains, by weight, 30-60 parts of active drug and 40-70 parts of biodegradable polymer; preferably 35-60 parts of active drug and 40-60 parts of biodegradable polymer. 65 servings. More preferably, it is 45-60 parts and 40-55 parts of biodegradable polymer.
  • the sustained-release agent includes, by weight percentage: 30-60% active drug and 40-70% biodegradable polymer; preferably 45-60% and biodegradable polymer 40-55%.
  • the biodegradable polymer includes polylactide (PLA), polyglycolide, lactide-co-glycolide (PLGA), polycaprolactone (PCL), and polylactide, polyethylene One or more of lactide, lactide-glycolide copolymer, or copolymer of polycaprolactone and polyethylene glycol (PEG).
  • PLA polylactide
  • PLA polyglycolide
  • PLA lactide-co-glycolide
  • PCL polycaprolactone
  • PEG polyethylene glycol
  • the biodegradable polymer is at least one of polylactide, lactide-glycolide copolymer, and a copolymer of polylactide or lactide-glycolide copolymer and polyethylene glycol.
  • Preferred is polylactide and/or lactide-glycolide copolymer; further preferred is polylactide or lactide-glycolide copolymer with a molar ratio of 50-95:5-50; further preferred is polypropylene Lactide or lactide-glycolide copolymer with a molar ratio of 50-85:15-50.
  • the weight average molecular weight (Mw) of the polylactide or lactide-glycolide copolymer is 7000-150000 Da; preferably, the weight average molecular weight of the polylactide or lactide-glycolide copolymer is is 9000-120000Da.
  • the intrinsic viscosity of the polylactide and lactide-glycolide copolymer is 0.1-2.5dL/g. More preferably, the intrinsic viscosity of the polylactide and lactide-glycolide copolymer is 0.2-1.2dL/g. Wherein, the intrinsic viscosity is measured using an Ubbelohde viscometer.
  • the molecular chain of the polylactide or lactide-glycolide copolymer 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 is an alkyl ester group or a carboxyl group.
  • the dosage form of the sustained-release preparation includes granular, cylindrical or rod-shaped; preferably cylindrical or rod-shaped; further preferably cylindrical or rod-shaped with an aspect ratio of 10-50:1; even more preferably long-diameter Cylindrical or rod-shaped with a ratio of 15-40:1; more preferably, cylindrical or rod-shaped with an aspect ratio of 20-30:1.
  • the sustained-release preparation when the sustained-release preparation is cylindrical or rod-shaped, it has a length of no more than 6cm and a diameter of no more than 3mm; more preferably, when the sustained-release preparation is cylindrical or rod-shaped, it has a length of no more than 6cm. The length is 5cm and the diameter is no more than 2.5mm; more preferably, when the sustained-release preparation is cylindrical or rod-shaped, it has a length no more than 3.5cm and a diameter no more than 1.5mm.
  • the biodegradable polymer of the implant of the present invention can biodegrade 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 biodegrade into carbon dioxide and water in the body, has good biocompatibility, and can be a single polymer or a mixture of multiple polymers.
  • the dosage form of the sustained-release preparation is an implant.
  • the present invention also provides a method for preparing the above-mentioned implant, which includes the following steps:
  • Active drugs and biodegradable polymers are mixed, freeze-pulverized, dried, and sieved to obtain a mixture
  • step (1) The mixture obtained in step (1) is melt-extruded, cooled, molded, and pelletized to obtain a preliminary sustained-release preparation
  • step (3) The preliminary sustained-release preparation obtained in step (2) is heated and passivated or coated to obtain it.
  • the freezing and grinding temperature in step (1) is -70°C to -30°C; preferably, the freezing and grinding temperature in step (1) is -70°C, -50°C or -30°C.
  • the drying in step (1) controls moisture by heating, and the moisture range is 0.05-5.0%; more preferably, the moisture range is 0.1-3.0%; more preferably, the moisture range is 0.1-2.0%.
  • the particle size is no larger than 20, 40 or 60 mesh.
  • the treatment temperature of the heat passivation in step (3) is 80-130°C, and the time is 5-60 min; preferably, the treatment temperature of the heat passivation is 90-120°C, and the time is 10-45 min. ; Further preferably, the heat passivation treatment temperature is 100-115°C and the time is 15-30min.
  • the coating liquid used in the coating process in step (3) is a sustained-release composition and an organic solvent;
  • the sustained-release composition includes polylactide, polyglycolide, lactide-glycolide Copolymers, polycaprolactone, and polylactide, polyethylene One or more of lactide, lactide-glycolide copolymer, or copolymer of polycaprolactone and polyethylene glycol; preferably, the weight proportion of the sustained-release composition in the coating solution is 2-30%; further preferably, the weight proportion of the sustained-release composition in the coating liquid is 5-15%;
  • the organic solvent includes dimethyl sulfoxide, methanol, acetone, acetonitrile, dichloro One or more of methane, chloroform, tetrahydrofuran, and ethyl acetate; preferably, the organic solvent is ethyl acetate and/or dichloromethane.
  • the intrinsic viscosity of the polylactide (PLA) and lactide-glycolide copolymer (PLGA) is 0.1-2.5dL/g; preferably, the polylactide (PLA), lactide-glycolide copolymer (PLGA)
  • the intrinsic viscosity of lactide copolymer (PLGA) is 0.2-1.2dL/g.
  • the molecular chain of polylactide (PLA) or lactide-glycolide copolymer (PLGA) carries anionic or cationic groups, or does not carry anionic or cationic groups; preferably, the polylactide (PLA), lactide glycolide copolymer (PLGA) end-capping group is alkyl ester group or carboxyl group.
  • the sustained-release composition in step (3) is polylactide (PLA) and/or lactide-glycolide copolymer (PLGA).
  • varenicline or its pharmaceutically acceptable salts adsorbed on the outer surface and distributed in the gaps can form a dense layer with the biodegradable polymer.
  • the protective film can not only solve the bitter taste and swallowing irritation of oral administration, reduce the irritation of administration, and increase patient compliance, but also eliminate the problem of sudden or delayed release, and can be released stably and in a long-term manner, which is the same as the original tartaric acid.
  • the treatment plan for Nicolan Tablets is to gradually increase the dosage and avoid daily dosing.
  • the sustained-release polymer is biodegradable in the human body and does not require surgical removal after the release of the subcutaneously implanted drug, thus avoiding the pain of another surgery for the patient.
  • no organic solvents are used in the preparation method of the implant of the present invention, or Class 3 organic solvents with lower toxicity are used, which further reduces the risk of adverse reactions.
  • it is implanted subcutaneously, making it difficult for patients to stop taking the medicine on their own and relapse, which improves the effectiveness of smoking cessation. Success rate.
  • Figure 1 is an SEM image of the varenicline implant morphology of Comparative Example 1;
  • Figure 2 is an SEM image of the varenicline implant morphology of Example 1;
  • Figure 3 is a cross-sectional SEM image of the varenicline implant of Example 14;
  • Figure 4 is an SEM image of varenicline microspheres of Comparative Example 5;
  • Figure 5 is a comparative chart of the in vitro cumulative release of varenicline implants in Examples 1, 4, 13, 14, 15, and 16;
  • Figure 6 is a comparative chart of the in vitro cumulative release of varenicline implants of Comparative Examples 1-7.
  • the varenicline prescription accounts for 25% (W/W)
  • the polylactic acid (PLA) accounts for 75% (W/W), of which the polylactic acid (PLA)
  • the weight average molecular weight is 20kDa
  • the intrinsic viscosity is 0.27dL/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 85°C, the screw speed is 100RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 90° C. for 10 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.5 mm and an aspect ratio of 30.
  • the varenicline prescription accounts for 30% (W/W)
  • the polylactic acid (PLA) accounts for 70% (W/W), of which the polylactic acid (PLA)
  • the weight average molecular weight is 40kDa
  • the intrinsic viscosity is 0.50dL/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 110°C, the screw speed is 120RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 2.5mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 115°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 23.
  • the varenicline prescription accounts for 50% (W/W)
  • the polylactic acid (PLA) accounts for 50% (W/W), of which the polylactic acid (PLA)
  • the weight average molecular weight is 120kDa
  • the intrinsic viscosity is 0.95dL/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 140°C, the screw speed is 100RPM, and the outlet pressure is less than 50Bar), and then pelletized to obtain the diameter. It is a 3.0mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 130°C for 15 minutes, and then cooled to room temperature to obtain an implant with a diameter of 3.0 mm and an aspect ratio of 20.
  • the varenicline prescription accounts for 30% (W/W)
  • the lactide-glycolide copolymer (PLGA) accounts for 70% (W/W)
  • the weight average molecular weight of PLGA is 15kDa
  • the intrinsic viscosity is 0.16dL/g
  • the molar ratio is 50:50, 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 80°C, the screw speed is 80RPM, and the outlet pressure is less than 20Bar), and then pelletized to obtain the diameter. It is a 1.7mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 85°C for 30 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.7 mm and an aspect ratio of 24.
  • the varenicline prescription accounts for 45% (W/W)
  • the lactide-glycolide copolymer (PLGA) accounts for 55% (W/W)
  • the weight average molecular weight of PLGA is 30kDa
  • the intrinsic viscosity is 0.36dL/g
  • the 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 100°C, the screw speed is 150RPM, and the outlet pressure is less than 50Bar), 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 105°C for 20 minutes, and then cooled to room temperature to obtain an implant with a diameter of 2.0 mm and an aspect ratio of 22.
  • the varenicline prescription accounts for 55% (W/W)
  • the lactide-glycolide copolymer (PLGA) accounts for 45% (W/W)
  • the weight average molecular weight of PLGA is 140kDa
  • the intrinsic viscosity is 0.87dL/g
  • the molar ratio is 85:15
  • 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 130°C, the screw speed is 100RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.3mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 120°C for 30 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.3 mm and an aspect ratio of 25.
  • varenicline prescription accounts for 40% (W/W)
  • PCL polycaprolactone
  • W/W 60%
  • the molecular weight is 80kDa
  • the intrinsic viscosity is 0.68dL/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 100RPM, and the outlet pressure is less than 30Bar), 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 85°C for 45 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.6 mm and an aspect ratio of 22.
  • varenicline prescription accounts for 30% (W/W)
  • PLA-PEG-PLA accounts for 70% (W/W)
  • PLA-PEG-PLA The weight average molecular weight is 100kDa, the PEG mass percentage is 4%, and the intrinsic viscosity is 0.82dL/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 150RPM, 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 15 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 varenicline prescription accounts for 30% (W/W)
  • the polylactic acid (PLA) accounts for 70% (W/W), of which the polylactic acid (PLA)
  • the weight average molecular weight is 80kDa
  • the intrinsic viscosity is 0.74dL/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 130°C, the screw speed is 100RPM, and the outlet pressure is less than 40Bar), and then pelletized to obtain the diameter. It is a 1.0mm 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 80kDa, carboxyl end-capped), the organic solvent is ethyl acetate, and vacuum dried at 40°C for 24 hours , an implant with a diameter of 1.0 mm and an aspect ratio of 25 was obtained.
  • the coating liquid is 10% polylactic acid (PLA weight average molecular weight is 80kDa, carboxyl end-capped)
  • the organic solvent is ethyl acetate
  • the varenicline prescription accounts for 50% (W/W)
  • the polylactic acid (PLA) accounts for 50% (W/W), of which the polylactic acid (PLA)
  • the weight average molecular weight is 120kDa
  • the intrinsic viscosity is 0.91dL/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 135°C, the screw speed is 150RPM, and the outlet pressure is less than 60Bar), and then pelletized to obtain the diameter. It is a 2.0mm cylindrical implant;
  • step 3 Coat the implant obtained in step 2), wherein the coating liquid is 5% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped), the organic solvent is ethyl acetate, and vacuum dried at 35°C After 48 hours, the implant with a diameter of 2.0 mm and an aspect ratio of 23 was obtained.
  • the coating liquid is 5% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped)
  • the organic solvent is ethyl acetate
  • the varenicline tartrate prescription accounts for 50% (W/W)
  • polylactic acid (PLA) accounts for 50% (W/W)
  • PVA polylactic acid
  • the weight average molecular weight is 60kDa, the intrinsic viscosity is 0.63dL/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 100°C, the screw speed is 100RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 90° C. for 15 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.5 mm and an aspect ratio of 23.
  • the raw and auxiliary material components for the preparation of the implant described in this example accounts for 55% (W/W), and the lactide-glycolide copolymer (PLGA) accounts for 45% (W/W).
  • the weight average molecular weight of PLGA is 140kDa, the intrinsic viscosity is 0.88dL/g, the molar ratio is 85:15, 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 130°C, the screw speed is 100RPM, and the outlet pressure is less than 50Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 120°C for 35 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.5 mm and an aspect ratio of 21.
  • varenicline hydrochloride prescription accounts for 50% (W/W)
  • lactide glycolide copolymer (PLGA) accounts for 50% (W/W)
  • the weight average molecular weight of PLGA is 80kDa
  • the intrinsic viscosity is 0.78dL/g
  • the molar ratio is 60:40, and it is end-capped by alkyl ester.
  • 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 140°C, the screw speed is 100RPM, and the outlet pressure is less than 50Bar), 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 140°C for 15 minutes, and then cooled to room temperature to obtain an implant with a diameter of 2.5 mm and an aspect ratio of 23.
  • the varenicline tartrate prescription accounts for 60% (W/W)
  • the lactide-glycolide copolymer (PLGA) accounts for 40% (W/W).
  • the weight average molecular weight of PLGA is 20kDa
  • the intrinsic viscosity is 0.27dL/g
  • the molar ratio is 50:50, 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 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 3 Coat the implant obtained in step 2), wherein the coating liquid is 5% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped), the organic solvent is ethyl acetate, and vacuum dried at 35°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 5% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped)
  • the organic solvent is ethyl acetate
  • the varenicline prescription accounts for 25% (W/W)
  • the polylactic acid (PLA) accounts for 75% (W/W)
  • the polylactic acid (PLA) The weight average molecular weight is 130kDa, the intrinsic viscosity is 1.45dL/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 85°C, the screw speed is 100RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant;
  • step 2) The implant obtained in step 2) is heated and passivated at 90° C. for 10 minutes, and then cooled to room temperature to obtain an implant with a diameter of 1.5 mm and an aspect ratio of 30.
  • the varenicline tartrate prescription accounts for 60% (W/W)
  • the lactide-glycolide copolymer (PLGA) accounts for 40% (W/W).
  • the weight average molecular weight of PLGA is 8kDa
  • the intrinsic viscosity is 0.17dL/g
  • the molar ratio is 50:50, 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 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 3 Coat the implant obtained in step 2), wherein the coating liquid is 5% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped), the organic solvent is ethyl acetate, and vacuum dried at 35°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 5% polylactic acid (PLA weight average molecular weight is 120kDa, alkyl ester group end-capped)
  • the organic solvent is ethyl acetate
  • the varenicline prescription accounts for 25% (W/W)
  • the polylactic acid (PLA) accounts for 75% (W/W)
  • the polylactic acid (PLA) The weight average molecular weight is 20kDa, the intrinsic viscosity is 0.27dL/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 85°C, the screw speed is 100RPM, and the outlet pressure is less than 30Bar), and then pelletized to obtain the diameter. It is a 1.5mm cylindrical implant.
  • the raw and auxiliary material components for the preparation of the implant described in this comparative example accounts for 30% (W/W), and the lactide-glycolide copolymer (PLGA) accounts for 70% (W/W), wherein
  • the weight average molecular weight of PLGA is 15kDa, the intrinsic viscosity is 0.16dL/g, the molar ratio is 50:50, 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 80°C, the screw speed is 80RPM, and the outlet pressure is less than 20Bar), and then pelletized to obtain the diameter. It is a 1.7mm cylindrical implant.
  • varenicline hydrochloride prescription accounts for 50% (W/W)
  • lactide glycolide copolymer (PLGA) accounts for 50% (W/W)
  • the weight average molecular weight of PLGA is 80kDa
  • the intrinsic viscosity is 0.78dL/g
  • the molar ratio is 60:40, and it is end-capped by alkyl ester.
  • 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 140°C, the screw speed is 100RPM, and the outlet pressure is less than 50Bar), and then pelletized to obtain the diameter. It is a 2.5mm cylindrical implant.
  • the varenicline tartrate prescription accounts for 60% (W/W)
  • the lactide-glycolide copolymer (PLGA) accounts for 40% (W/W)
  • the weight average molecular weight of PLGA is 20kDa
  • the intrinsic viscosity is 0.27dL/g
  • the molar ratio is 50:50, 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 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 Weigh 10.0g varenicline and 15.0g polylactic acid (PLA, intrinsic viscosity 0.85), add 80.00g methylene chloride, 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.
  • a peristaltic pump 2000ml/min
  • a syringe pump to inject the oil phase into the inner cavity of the high shear homogenizer at 50ml/min.
  • a single emulsion under high shear forming a single emulsion under high shear.
  • a magnetic stirrer 500RPM
  • the particles are sieved through a sieve to obtain the varenicline microspheres (see Figure 4 for details).
  • the raw and auxiliary materials for the preparation of the implant described in this comparative example only replace the polylactic acid (PLA) in Example 1 with polyvinylpyrrolidone (PVP K12), and the other components remain unchanged, that is, the varenicline prescription accounts for 25 %(W/W), polyvinylpyrrolidine Ketone (PVP K12) is 75% (W/W).
  • the preparation method of the implant described in this comparative example is the same as that of Example 1.
  • the raw and auxiliary materials for the preparation of the implant described in this comparative example include varenicline tartrate prescription accounting for 70% (W/W), lactide glycolide copolymer (PLGA) accounting for 30% (W/W),
  • the weight average molecular weight of PLGA is 20kDa
  • the intrinsic viscosity is 0.27dL/g
  • the molar ratio is 50:50
  • the preparation method of the implant described in this comparative example is the same as that of Example 14. 1. Determination of drug loading capacity of implants
  • Drug loading (drug weight contained in the implant/total weight of the implant) ⁇ 100%
  • the drug loading capacity of the implant is close to the theoretical drug loading capacity, while the drug loading capacity of the microspheres is slightly lower than the theoretical drug loading capacity. This may be due to varenicline free base It is partially dissolved in water during the emulsification process, resulting in content loss.
  • the RSDs of the drug loading capacity of the implants are all small, ranging from 0.02 to 0.09%, which shows that under the hot melt extrusion process conditions, the content uniformity of each section of the implant prepared is good, and is slightly better than the drug loading capacity of the microspheres. RSD.
  • the implants obtained in Comparative Examples 1-4 were further processed by thermal passivation or coating processes, corresponding to Example 1, Example 4, Example 13 and Example 14.
  • the drug loading capacity of the latter was almost the same as that of the former. , which also shows that the thermal passivation or coating process of the implant obtained by hot melt extrusion has no effect on the drug loading capacity.
  • Example 1 The implants of Example 1, Example 4, Example 13, Example 14, Example 15, Example 16, Comparative Examples 1-4, Comparative Examples 6-7, and the microorganism of Comparative Example 5 were For each example, 6 samples (30 mg) were weighed and placed in a 100 ml Erlenmeyer flask. The release medium was 50 ml phosphate buffer pH 7.4. The test was carried out using a 37 ⁇ 0.5°C constant temperature water bath oscillator with a rotation speed of 50 RPM.
  • Comparative analysis of the in vitro release results of the implant of Example 1, the implant of Comparative Example 1, and the microspheres of Comparative Example 5 showed that both Comparative Example 1 and Comparative Example 5 had burst release, and the implant was better than the microspheres in terms of drug release cycle. About 1 month; while the implant of Example 1 has no burst release or delayed release phenomenon, the release rate is stable, the fluctuation is small, and the drug release cycle is extended, about 1.5 months. This is because after the hot-melt extrusion process, further thermal passivation treatment can form a dense protective film on the outer surface of the implant (see Figure 1 and Figure 2), blocking the adhesion to the outer surface of the implant. Drug particles are released quickly.
  • Comparative analysis of the in vitro release results of the implant of Example 4 and the implant of Comparative Example 2, and the in vitro release results of the implant of Example 13 and Comparative Example 3 shows that the first results of Comparative Example 2 and Comparative Example 3 are
  • the daily release degree is 15-20%, while the first-day release degree of Example 4 and Example 13 is less than 10%. That is, after the hot melt extrusion process, further thermal passivation treatment can form a dense protective film on the outer surface of the implant, blocking the rapid release of drug particles attached to the outer surface of the implant.
  • Example 4 and Example 13 prolonged drug release by about 2 weeks compared to Comparative Example 2 and Comparative Example 3 respectively.
  • Comparative analysis of the in vitro release results of the implant of Example 14 and the implant of Comparative Example 4 showed that the first-day release of Comparative Example 4 was approximately 20%, while the first-day release of Example 14 was approximately 10%. That is, after the hot melt extrusion process, further coating treatment can form a dense protective film on the outer surface of the implant (see Figure 3), blocking the rapid release of drug particles attached to the outer surface of the implant. In addition, under the same drug loading and dosage conditions, Example 14 extended drug release by about 10 days compared to Comparative Example 4.
  • Example 15 uses PLA with a weight average molecular weight of 13kDa and an intrinsic viscosity of 1.45dL/g. The drug is released slowly in the early stage, and the cumulative drug release amount in 15 days is about 10%, because the weight average molecular weight of PLA exceeds 12kDa and the intrinsic viscosity exceeds 1.2dL/g. g, After hot melt extrusion and dispersion with varenicline, there is a relatively delayed release phenomenon.
  • Example 16 uses PLGA with a weight average molecular weight of 8kDa and an intrinsic viscosity of 0.17dL/g. The drug release rate is relatively fast, with more than 80% released in 20 days. Because the biodegradable polymer has a low molecular weight and a small intrinsic viscosity, it is easy to Hydrolysis or self-degradation leads to rapid dissolution/dissolution of varenicline.

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Abstract

本发明提供了包含伐尼克兰的缓释制剂及其制备方法，涉及药物制剂领域，该缓释制剂包含活性药物20-60份和可生物降解聚合物40-80份；其中，活性药物为伐尼克兰游离碱，或其药学上可接受盐，包括但不限于酒石酸伐尼克兰、水杨酸伐尼克兰、硫酸伐尼克兰、富马酸伐尼克兰、草酸伐尼克兰、盐酸伐尼克兰、氢溴酸伐尼克兰、枸橼酸伐尼克兰、马来酸伐尼克兰、琥珀酸伐尼克兰、磷酸伐尼克兰中的一种或多种。该缓释制剂能解决口服给药的苦味和吞咽刺激性，降低给药刺激性，增加患者的依从性，还能消除突释或迟释问题，可长效稳定地释放，同时能够避免每天给药，减少患者痛苦，降低不良反应风险，提高戒烟成功率。

Description

包含伐尼克兰的缓释制剂及其制备方法
本发明要求于2022年08月15日提交中国专利局、申请号为202210976295.0、发明名称为“包含伐尼克兰的缓释制剂及其制备方法”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，具体涉及包含伐尼克兰的缓释制剂及其制备方法。
背景技术
烟草依赖是一种慢性高复发性疾病,其本质是尼古丁依赖。卷烟、雪茄、烟斗燃烧所产生的烟雾以及无烟烟草中均含有尼古丁，吸烟是将尼古丁摄入身体的迅速、有效的方式。尼古丁是一种具有精神活性的物质，使用后可使部分人产生“欣快”感，并可暂时改善一些个体的工作表现和认知能力、延长注意力集中时间、减轻焦虑和抑郁等不良情绪。
烟草依赖常表现为躯体依赖和心理依赖两个方面。躯体依赖表现为，在停止吸烟后，吸烟者将会产生一系列不易忍受的症状和体征，称之为戒断症状，包括吸烟渴求、焦虑、抑郁、不安、头痛、唾液腺分泌增加、注意力不集中、睡眠障碍、血压升高和心率加快等。精神依赖又称心理依赖，俗称“心瘾”，表现为主观上强烈渴求吸烟。烟草依赖者出现戒断症状后若再吸烟，会产生满足和欣快感，躯体和精神趋于松弛和宁静，使戒烟更加困难。
伐尼克兰是一种新型戒烟药物，为尼古丁乙酰胆碱受体的部分激动剂。伐尼克兰与尼古丁乙酰胆碱受体结合后，一方面发挥激动剂的作用，刺激脑内释放多巴胺，可缓解戒烟后的戒断症状；另一方面，它的拮抗特性可以阻止尼古丁与尼古丁乙酰胆碱受体结合，减少吸烟的欣快感。酒石酸伐尼克兰片于2006年5月10日由辉瑞申请上市，商品名为有0.5mg和1.0mg两个规格。第1～3日0.5mg，每日1次；第4～7日0.5mg，每日2次；第8日～治疗结束1mg，每日2次；患者应服用本品治疗12周。伐尼克兰化学名称为7,8,9,10-四氢-6,10-亚甲基-6H-吡嗪并[2,3-h][3]苯并氮杂化学结构如下：
由于伐尼克兰具有独特的苦味，即苦涩和灼烈口感，并且在吞咽时可能引起不适感。即使将伐尼克兰制备成盐，这种苦味的问题仍然无法解决。因此，口服酒石酸伐尼克兰片，可 一定程度地引起患者的恶心。为掩盖这种独特的苦味和吞咽时的刺激性，CN108463252A提供了包含伐尼克兰或其药学上可接受的盐作为活性成分，以及含羧基的阴离子聚合物和含氨基的阳离子聚合物两者作为苦味掩蔽剂的口服施用的药物制剂。
另外，为了减少给药频次和吞咽刺激性，WO2007/01296还提供了包含伐尼克兰或其药学上可接受的盐或前药形式的透皮组合物，其中伐尼克兰经由皮肤层缓慢释放可以减少恶心的发生，并提高患者对药物的依从性和更大患者群的需求。但是，如果患者在治疗过程中失去了戒烟的动力和意愿，则可轻易地撕下伐尼克兰透皮贴剂而停止治疗，导致复吸。因此，伐尼克兰透皮贴剂对于戒烟治疗仍不是最理想的。
US20190350844A1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/肌肉注射或者皮下植入，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。
综合而言，现有技术存在以下缺点：1)包含伐尼克兰或其药学上可接受盐制成的普通口服片，因原料药具有独特的苦味，即苦涩和灼烈口感，患者服药的顺应性将较差，常引起恶心等不良反应。2)采用苦味掩蔽剂的口服片或者开发透皮贴剂，虽能减小甚至避免吞咽刺激性，但是患者戒烟意愿不强，可自行停药，导致复吸。3)常规工艺制备的微球、油性溶液、脂质体、混悬液、微乳液、原位胶凝等储库式缓释制剂，因伐尼克兰或其药学上可接受盐水溶性好，存在突释现象，血药浓度波动大，不良反应发生风险高。4)微球、油性溶液、脂质体、混悬液、微乳液、原位胶凝等储库式缓释制剂制备工艺中，经常会使用2类有机溶剂，从而导致有机溶剂残留，增加药物的副作用。
针对现有技术存在的问题，寻找一种能够解决上述问题的包含伐尼克兰的缓释制剂及其制备方法十分必要。
发明内容
本发明针对现有技术存在的问题，提供了包含伐尼克兰的缓释制剂及其制备方法，该缓释制剂能解决口服给药的苦味和吞咽刺激性，降低给药刺激性，增加患者的依从性，还能消除突释或迟释问题，可长效稳定地释放，同时能够避免每天给药，减少患者痛苦，降低不良反应风险，提高戒烟成功率。
为实现上述目的，本发明采用的技术方案如下：
本发明涉及的缩写以及英文含义如表1所示：
本发明提供了一种缓释制剂，按重量份数计，包含活性药物20-60份和可生物降解聚合物40-80份；所述活性药物为伐尼克兰游离碱，或其药学上可接受盐，包括但不限于酒石酸伐尼克兰、水杨酸伐尼克兰、硫酸伐尼克兰、富马酸伐尼克兰、草酸伐尼克兰、盐酸伐尼克兰、氢溴酸伐尼克兰、枸橼酸伐尼克兰、马来酸伐尼克兰、琥珀酸伐尼克兰、磷酸伐尼克兰中的一种或多种。
进一步地，所述的缓释制剂，按重量份数计，包含活性药物30-60份和可生物降解聚合物40-70份；优选为活性药物35-60份和可生物降解聚合物40-65份。更进一步优选为45-60份和可生物降解聚合物40-55份。
在一些具体的实施方式中，所述的缓释剂，按重量百分比计，包括：活性药物30-60％和可生物降解聚合物40-70％；优选为45-60％和可生物降解聚合物40-55％。
进一步地，所述可生物降解聚合物包括聚丙交酯(PLA)，聚乙交酯，丙交酯乙交酯共聚物(PLGA)，聚己内酯(PCL)，以及聚丙交酯、聚乙交酯、丙交酯乙交酯共聚物或聚己内酯和聚乙二醇(PEG)的共聚物中的一种或多种。
进一步地，所述可生物降解聚合物为聚丙交酯，丙交酯乙交酯共聚物，以及聚丙交酯或丙交酯乙交酯共聚物与聚乙二醇的共聚物中的至少一种；优选为聚丙交酯和/或丙交酯乙交酯共聚物；进一步优选为聚丙交酯或摩尔比为50-95：5-50的丙交酯乙交酯共聚物；更进一步优选为聚丙交酯或摩尔比为50-85：15-50的丙交酯乙交酯共聚物。
进一步地，所述聚丙交酯或丙交酯乙交酯共聚物的重均分子量(Mw)为7000-150000Da；优选地，所述聚丙交酯或丙交酯乙交酯共聚物的重均分子量为9000-120000Da。
进一步地，所述聚丙交酯、丙交酯乙交酯共聚物的特性黏度为0.1-2.5dL/g。更优选地，所述聚丙交酯、丙交酯乙交酯共聚物的特性黏度为0.2-1.2dL/g。其中，所述特性黏度采用乌氏粘度计测定。
进一步地，所述聚丙交酯、丙交酯乙交酯共聚物的分子链携带阴离子或阳离子基团，或者不携带阴离子或阳离子基团。更优选地，所述聚丙交酯(PLA)、丙交酯乙交酯共聚物封端基团为烷酯基或者羧基。
进一步地，所述缓释制剂的剂型包括颗粒状、圆柱状或棒状；优选为圆柱状或棒状；进一步优选为长径比为10-50：1的圆柱状或棒状；更进一步优选为长径比为15-40：1的圆柱状或棒状；更进一步优选为长径比为20-30：1的圆柱状或棒状。
进一步地，当所述缓释制剂为圆柱状或棒状时，其具有不大于6cm的长度，不大于3mm的直径；更优选地，所述缓释制剂为圆柱状或棒状时，其具有不大于5cm的长度，不大于2.5mm的直径；更优选地，所述缓释制剂为圆柱状或棒状时，其具有不大于3.5cm的长度，不大于1.5mm的直径。
进一步地，本发明所述植入剂的可生物降解聚合物，可在体内生物降解为二氧化碳和水，生物相容性好，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，所述缓释制剂的剂型为植入剂。
本发明还提供了上述的植入剂的制备方法，包括以下步骤：
(1)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)得到的混合物熔融挤出、冷却成型、切粒，得到初成型缓释制剂；
(3)将步骤(2)得到的初成型缓释制剂进行加热钝化或包衣，即得。
进一步地，步骤(1)中冷冻粉碎温度为-70℃～-30℃；优选地，步骤(1)中冷冻粉碎温度为-70℃、-50℃或-30℃。
进一步地，步骤(1)中所述干燥通过加热控制水分，水分范围为0.05-5.0％；更优选地，水分范围为0.1-3.0％；更优选地，水分范围为0.1-2.0％。
进一步地，步骤(1)中所述冷冻粉碎后，粒径不大于20、40或60目。
进一步地，步骤(3)中所述加热钝化的处理温度为80-130℃，时间为5-60min；优选地，所述加热钝化的处理温度为90-120℃，时间为10-45min；进一步优选地，所述加热钝化的处理温度为100-115℃，时间为15-30min。
进一步地，步骤(3)中所述包衣过程中使用的包衣液为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，聚己内酯，以及聚丙交酯、聚乙 交酯、丙交酯乙交酯共聚物或聚己内酯和聚乙二醇的共聚物中的一种或多种；优选地，所述缓释组合物在包衣液中的重量占比为2-30％；进一步优选地，所述缓释组合物在包衣液中的重量占比为5-15％；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；优选地，所述有机溶剂为乙酸乙酯和/或二氯甲烷。
进一步地，所述聚丙交酯(PLA)、丙交酯乙交酯共聚物(PLGA)的特性黏度为0.1-2.5dL/g；优选地，所述聚丙交酯(PLA)、丙交酯乙交酯共聚物(PLGA)的特性黏度为0.2-1.2dL/g。
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；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。
优选地，步骤(3)中所述缓释组合物为聚丙交酯(PLA)和/或丙交酯乙交酯共聚物(PLGA)。
本发明所取得的技术效果是：
采用本发明的热熔挤出，以及热钝化或者包衣处理工艺，可使吸附在外表面和分布在空隙内的伐尼克兰或其药学上可接受盐与可生物降解聚合物形成一层致密的保护膜，不仅能解决口服给药的苦味和吞咽刺激性，降低给药刺激性，增加患者的依从性，还能消除突释或迟释问题，可长效稳定地释放，与原研酒石酸伐尼克兰片逐步提高给药剂量的治疗方案一致，并避免每天给药。另外，缓释聚合物为可人体内生物降解，皮下植入药物释放结束后无需手术取出，避免患者再次手术的痛苦。更进一步，本发明的植入剂制备方法中未使用有机溶剂，或者使用毒性更低的3类有机溶剂，进一步降低不良反应风险，同时皮下埋植，患者难以自行停药而复吸，提高戒烟成功率。
附图说明
图1为对比例1的伐尼克兰植入剂形态SEM图；
图2为实施例1的伐尼克兰植入剂形态SEM图；
图3为实施例14的伐尼克兰植入剂横切面SEM图；
图4为对比例5的伐尼克兰微球SEM图；
图5为实施例1、4、13、14、15、16的伐尼克兰植入剂体外累计释放对比图；
图6为对比例1-7的伐尼克兰植入剂体外累计释放对比图。
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：伐尼克兰处方占比25％(W/W)，聚乳酸(PLA)为75％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.27dL/g，烷酯基封端。
1)将6.0g伐尼克兰和18.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制3.5％，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85℃，螺杆转速100RPM，出料口压力小于30Bar)，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90℃加热钝化处理10min，冷却至室温，得到所述的直径为1.5mm，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：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40kDa，特性黏度为0.50dL/g，烷酯基封端。
1)将4.5g伐尼克兰和10.5g聚乳酸(PLA)混合，-50℃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110℃，螺杆转速120RPM，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115℃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23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：伐尼克兰处方占比50％(W/W)，聚乳酸(PLA)为50％(W/W)，其中聚乳酸(PLA)的重均分子量为120kDa，特性黏度为0.95dL/g，烷酯基封端。
1)将10.0g伐尼克兰和10.0g聚乳酸(PLA)混合，-60℃冷冻粉碎，水分控制1.4％，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140℃，螺杆转速100RPM，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130℃加热钝化处理15min，冷却至室温，得到所述的直径为3.0mm，长径比为20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：伐尼克兰处方占比30％(W/W)，丙交酯乙交酯共聚物(PLGA)为70％(W/W)，其中PLGA的重均分子量为15kDa，特性黏度为0.16dL/g，摩尔比为50:50，烷酯基封端。
1)将4.5g伐尼克兰和10.5g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制3.2％，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80℃，螺杆转速80RPM，出料口压力小于20Bar)，切粒，得到直径为1.7mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行85℃加热钝化处理30min，冷却至室温，得到所述的直径为1.7mm，长径比为24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：伐尼克兰处方占比45％(W/W)，丙交酯乙交酯共聚物(PLGA)为55％(W/W)，其中PLGA的重均分子量为30kDa，特性黏度为0.36dL/g，摩尔比为75:25，羧基封端。
1)将9.0g伐尼克兰和11.0g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制2.5％，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150RPM，出料口压力小于50Bar)，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105℃加热钝化处理20min，冷却至室温，得到所述的直径为2.0mm，长径比为22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：伐尼克兰处方占比55％(W/W)，丙交酯乙交酯共聚物(PLGA)为45％(W/W)，其中PLGA的重均分子量为140kDa，特性黏度为0.87dL/g，摩尔比为85:15，烷酯基封端。
1)将16.5g伐尼克兰和13.5g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制1.0％，过筛收集不大于60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130℃，螺杆转速100RPM，出料口压力小于40Bar)，切粒，得到直径为1.3mm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30min，冷却至室温，得到所述的直径为1.3mm，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：伐尼克兰处方占比40％(W/W)，聚己内酯(PCL)为60％(W/W)，其中PCL的重均分子量为80kDa，特性黏度为0.68dL/g，烷酯基封端。
1)将12.0g伐尼克兰和18.0g聚己内酯(PCL)混合，-40℃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90℃，螺杆转速100RPM，出料口压力小于30Bar)，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85℃加热钝化处理45min，冷却至室温，得到所述的直径为1.6mm，长径比为22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：伐尼克兰处方占比30％(W/W)，PLA-PEG-PLA为70％(W/W)，其中PLA-PEG-PLA的重均分子量为100kDa，PEG质量百分比为4％，特性黏度为0.82dL/g。
1)将15.0g伐尼克兰和35.0g PLA-PEG-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95℃，螺杆转速150RPM，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15min，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：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80kDa，特性黏度为0.74dL/g，羧基封端。
1)将4.5g伐尼克兰和10.5g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130℃，螺杆转速100RPM，出料口压力小于40Bar)，切粒，得到直径为1.0mm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80kDa，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1.0mm，长径比为25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：伐尼克兰处方占比50％(W/W)，聚乳酸(PLA)为50％(W/W)，其中聚乳酸(PLA)的重均分子量为120kDa，特性黏度为0.91dL/g，烷酯基封端。
1)将15.0g伐尼克兰和15.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制0.8％，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135℃，螺杆转速150RPM，出料口压力小于60Bar)，切粒，得到直径为2.0mm圆柱状植入剂；
3)将步骤2)所得的植入剂进行包衣，其中包衣液为5％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，35℃真空干燥48小时，得到所述的直径为2.0mm，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：酒石酸伐尼克兰处方占比50％(W/W)，聚乳酸(PLA)为50％(W/W)，其中聚乳酸(PLA)的重均分子量为60kDa，特性黏度为0.63dL/g，烷酯基封端。
1)将8.0g酒石酸伐尼克兰和8.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制1.2％，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30Bar)，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90℃加热钝化处理15min，冷却至室温，得到所述的直径为1.5mm，长径比为23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：酒石酸伐尼克兰处方占比55％(W/W)，丙交酯乙交酯共聚物(PLGA)为45％(W/W)，其中PLGA的重均分子量为140kDa，特性黏度为0.88dL/g，摩尔比为85:15，羧基封端。
1)将16.5g伐尼克兰和13.5g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制0.6％，过筛收集不大于60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130℃，螺杆转速100RPM，出料口压力小于50Bar)，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120℃加热钝化处理35min，冷却至室温，得到所述的直径为1.5mm，长径比为21的植入剂。
实施例13：
本实施例所述植入剂的制备原辅料组分：盐酸伐尼克兰处方占比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80kDa，特性黏度为0.78dL/g，摩尔比为60:40，烷酯封端。
1)将20.0g伐尼克兰和20.0g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制0.8％，过筛收集不大于60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140℃，螺杆转速100RPM，出料口压力小于50Bar)，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140℃加热钝化处理15min，冷却至室温，得到所述的直径为2.5mm，长径比为23的植入剂。
实施例14：
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60％(W/W)，丙交酯乙交酯共聚物(PLGA)为40％(W/W)，其中PLGA的重均分子量为20kDa，特性黏度为0.27dL/g，摩尔比为50:50，羧基封端。
1)将18.0g伐尼克兰和12.0g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制1.0％，过筛收集不大于60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5％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，35℃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15：
本实施例所述植入剂的制备原辅料组分：伐尼克兰处方占比25％(W/W)，聚乳酸(PLA)为75％(W/W)，其中聚乳酸(PLA)的重均分子量为130kDa，特性黏度为1.45dL/g，烷酯基封端。
1)将6.0g伐尼克兰和18.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制3.5％，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85℃，螺杆转速100RPM，出料口压力小于30Bar)，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90℃加热钝化处理10min，冷却至室温，得到所述的直径为1.5mm，长径比为30的植入剂。
实施例16：
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60％(W/W)，丙交酯乙交酯共聚物(PLGA)为40％(W/W)，其中PLGA的重均分子量为8kDa，特性黏度为0.17dL/g，摩尔比为50:50，羧基封端。
1)将18.0g伐尼克兰和12.0g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制1.0％，过筛收集不大于60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5％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，35℃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。
对比例1
本对比例所述植入剂的制备原辅料组分：伐尼克兰处方占比25％(W/W)，聚乳酸(PLA)为75％(W/W)，其中聚乳酸(PLA)的重均分子量为20kDa，特性黏度为0.27dL/g，烷酯基封端。
1)将6.0g伐尼克兰和18.0g聚乳酸(PLA)混合，-40℃冷冻粉碎，水分控制3.5％，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85℃，螺杆转速100RPM，出料口压力小于30Bar)，切粒，得到直径为1.5mm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：伐尼克兰处方占比30％(W/W)，丙交酯乙交酯共聚物(PLGA)为70％(W/W)，其中PLGA的重均分子量为15kDa，特性黏度为0.16dL/g，摩尔比为50:50，烷酯基封端。
1)将4.5g伐尼克兰和10.5g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制3.2％，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80℃，螺杆转速80RPM，出料口压力小于20Bar)，切粒，得到直径为1.7mm圆柱状植入剂。
对比例3：
本对比例所述植入剂的制备原辅料组分：盐酸伐尼克兰处方占比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80kDa，特性黏度为0.78dL/g，摩尔比为60:40，烷酯封端。
1)将20.0g伐尼克兰和20.0g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制0.8％，过筛收集不大于60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140℃，螺杆转速100RPM，出料口压力小于50Bar)，切粒，得到直径为2.5mm圆柱状植入剂。
对比例4：
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60％(W/W)，丙交酯乙交酯共聚物(PLGA)为40％(W/W)，其中PLGA的重均分子量为20kDa，特性黏度为0.27dL/g，摩尔比为50:50，羧基封端。
1)将18.0g伐尼克兰和12.0g丙交酯乙交酯共聚物(PLGA)混合，-30℃冷冻粉碎，水分控制1.0％，过筛收集不大于60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。
对比例5
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)油相配制：称取10.0g伐尼克兰，以及15.0g聚乳酸(PLA，特性黏度0.85)，加入80.00g二氯甲烷，涡旋摇荡使其充分溶解，作为油相。
3)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。
4)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，得到所述的伐尼克兰微球(详见图4)。
对比例6
本对比例所述植入剂的制备原辅料组分仅将实施例1中的聚乳酸(PLA)替换为聚乙烯吡咯烷酮(PVP K12)，其他组分不变，即伐尼克兰处方占比25％(W/W)，聚乙烯吡咯烷 酮(PVP K12)为75％(W/W)。但本对比例所述植入剂的制备方法同实施例1。
对比例7
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70％(W/W)，丙交酯乙交酯共聚物(PLGA)为30％(W/W)，其中PLGA的重均分子量为20kDa，特性黏度为0.27dL/g，摩尔比为50:50，羧基封端。但本对比例所述植入剂的制备方法同实施例14。一、植入剂载药量的测定
实施例1-16和对比例1-7，随机取样各6份，采用高效液相色谱法检测各个样品的含量，检测波长：237nm，流速：1ml/min，柱温：35℃，进样量：20μl，色谱柱：Kromasil 100-5-C18 4.6×250mm，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2植入剂和微球的载药量

由表2中各样品的载药量检测结果可知，植入剂的载药量与理论载药量接近，而微球载药量稍低于理论载药量，这可能因为伐尼克兰游离碱在乳化过程中部分溶于水中而导致含量损耗。植入剂载药量的RSD均较小，为0.02～0.09％，这表明热熔挤出工艺条件下，所制备的各段植入剂含量均一性好，并且略优于微球载药量的RSD。另外，对比例1-4所得植入剂进一步采用热钝化或者包衣工艺处理，对应得到实施例1、实施例4、实施例13和实施例14，后者载药量和前者均几乎一致，这也说明对热熔挤出所得植入剂进行热钝化或包衣工艺，对载药量无影响。
二、体外释放度考察
测定方法：将实施例1、实施例4、实施例13、实施例14、实施例15、实施例16，对比例1-4、对比例6-7的植入剂，以及对比例5的微球，每个实例均称取6个样品(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5-6)和平均日释放率(详见表3-4)。
表3体外平均累计释放度(％)

表4体外平均累计释放度(％)

对比分析实施例1植入剂、对比例1植入剂、对比例5微球的体外释放结果，对比例1和对比例5均存在突释，并且植入剂优于微球，药物释放周期约1个月；而实施例1植入剂无突释，也无延迟释放现象，释放速率平稳，波动小，药物释放周期延长，约1.5个月。这是因为热熔挤出工艺后，进一步采用热钝化处理，可使植入剂外表面形成一层致密的保护膜，见图1、图2)，阻滞附着在植入剂外表面的药物颗粒快速释放。
对比分析实施例4植入剂、对比例2植入剂的体外释放结果，以及实施例13植入剂、对比例3植入剂的体外释放结果可知，对比例2和对比例3的第一天释放度在15～20％，而实施例4和实施例13的第一天释放度为10％以下。即热熔挤出工艺后，进一步采用热钝化处理，可使植入剂外表面形成一层致密的保护膜，阻滞附着在植入剂外表面的药物颗粒快速释放。另外，在相同载药量和考察剂量条件下，实施例4、实施例13分别比对比例2、对比例3延长药物释放2周左右。
对比分析实施例14植入剂、对比例4植入剂的体外释放结果，对比例4的第一天释放度约为20％，而实施例14的第一天释放度约为10％。即热熔挤出工艺后，进一步采用包衣处理，可使植入剂外表面形成一层致密的保护膜(见图3)，阻滞附着在植入剂外表面的药物颗粒快速释放。另外，在相同载药量和考察剂量条件下，实施例14比对比例4延长药物释放10天左右。
对比例6中仅将本发明中可生物降解聚合物更换为聚乙烯吡咯烷酮，采用热熔挤出制备伐尼克兰缓释制剂，体外溶出度考察时发生严重的突释，对该药物的阻滞效果明显差于本发明中可生物降解聚合物。
对比例7中仅提高载药量至70％，采用热熔挤出制备伐尼克兰缓释制剂，体外溶出度考察时发生严重的突释，整个周期内释放速率升高，说明伐尼克兰和可生物降解聚合物占比控制在合适的范围内，才能避免突释或迟释问题，维持稳定的药物释放速率。
实施例15采用重均分子量为13kDa、特性黏度为1.45dL/g的PLA，前期药物释放缓慢，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， 将与伐尼克兰热熔挤出分散后，相对而言有迟释现象。实施例16采用重均分子量8kDa、特性黏度为0.17dL/g的PLGA，药物释放速率相对较快，20天释放80％以上，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，导致伐尼克兰溶出/溶蚀较快。
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. 一种伐尼克兰的缓释制剂，其特征在于：按重量份数计，包含活性药物20-60份和可生物降解聚合物40-80份；所述活性药物为伐尼克兰游离碱，或其药学上可接受盐，包括但不限于酒石酸伐尼克兰、水杨酸伐尼克兰、硫酸伐尼克兰、富马酸伐尼克兰、草酸伐尼克兰、盐酸伐尼克兰、氢溴酸伐尼克兰、枸橼酸伐尼克兰、马来酸伐尼克兰、琥珀酸伐尼克兰、磷酸伐尼克兰中的一种或多种。
  2. 根据权利要求1所述的缓释制剂，其特征在于：按重量份数计，包含活性药物30-60份和可生物降解聚合物40-70份；优选为活性药物35-60份和可生物降解聚合物40-65份；更进一步优选为45-60份和可生物降解聚合物40-55份。
  3. 根据权利要求1所述的缓释制剂，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，以及聚丙交酯、聚乙交酯、丙交酯乙交酯共聚物或聚己内酯和聚乙二醇的共聚物中的一种或多种。
  4. 根据权利要求3所述的缓释制剂，其特征在于：所述可生物降解聚合物为聚丙交酯，丙交酯乙交酯共聚物，以及聚丙交酯或丙交酯乙交酯共聚物与聚乙二醇的共聚物中的至少一种；优选为聚丙交酯和/或丙交酯乙交酯共聚物；进一步优选为聚丙交酯或摩尔比为50-95：5-50的丙交酯乙交酯共聚物；更进一步优选为聚丙交酯或摩尔比为50-85：15-50的丙交酯乙交酯共聚物。
  5. 根据权利要求4所述的缓释制剂，其特征在于：所述聚丙交酯或丙交酯乙交酯共聚物的重均分子量为7000-150000Da；优选地，所述聚丙交酯或丙交酯乙交酯共聚物的重均分子量为9000-120000Da。
  6. 根据权利要求4所述的缓释制剂，其特征在于：所述聚丙交酯、丙交酯乙交酯共聚物的特性黏度为0.1-2.5dL/g；优选地，所述聚丙交酯、丙交酯乙交酯共聚物的特性黏度为0.2-1.2dL/g。
  7. 根据权利要求4所述的缓释制剂，所述聚丙交酯、丙交酯乙交酯共聚物的分子链携带阴离子或阳离子基团，或者不携带阴离子或阳离子基团；优选地，所述聚丙交酯、丙交酯乙交酯共聚物封端基团为烷酯基或者羧基。
  8. 根据权利要求1-7任一项所述的缓释制剂的制备方法，其特征在于，所述缓释制剂的剂型为植入剂；所述植入剂的制备方法包括以下步骤：
    (1)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)得到的混合物熔融挤出、冷却成型、切粒，得到初成型缓释制剂；
    (3)将步骤(2)得到的初成型缓释制剂进行加热钝化或包衣，即得。
  9. 根据权利要求8所述的制备方法，其特征在于：步骤(3)中所述加热钝化的处理温度为80-130℃，时间为5-60min；优选地，所述加热钝化的处理温度为90-120℃，时间为10-45min；进一步优选地，所述加热钝化的处理温度为100-115℃，时间为15-30min。
  10. 根据权利要求8所述的制备方法，其特征在于：步骤(3)中所述包衣过程中使用的包衣液为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，聚己内酯，聚丙交酯、聚乙交酯、丙交酯乙交酯共聚物或聚己内酯和聚乙二醇的共聚物中的一种或多种；优选地，所述缓释组合物在包衣液中的重量占比为2-30％；进一步优选地，所述缓释组合物在包衣液中的重量占比为5-15％；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；优选地，所述有机溶剂为乙酸乙酯和/或二氯甲烷。
PCT/CN2023/113099 2022-08-15 2023-08-15 包含伐尼克兰的缓释制剂及其制备方法 WO2024037536A1 (zh)

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