WO2022095203A1 - 一种纳曲酮和利培酮复方缓释组合物 - Google Patents

一种纳曲酮和利培酮复方缓释组合物 Download PDF

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WO2022095203A1
WO2022095203A1 PCT/CN2020/135369 CN2020135369W WO2022095203A1 WO 2022095203 A1 WO2022095203 A1 WO 2022095203A1 CN 2020135369 W CN2020135369 W CN 2020135369W WO 2022095203 A1 WO2022095203 A1 WO 2022095203A1
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soluble polymer
naltrexone
risperidone
water
release
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PCT/CN2020/135369
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English (en)
French (fr)
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颜携国
严福乔
刘国辉
王实强
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深圳善康医疗健康产业有限公司
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Priority to US18/314,047 priority Critical patent/US20240016744A1/en
Priority to CN202080105731.6A priority patent/CN116710097A/zh
Priority to EP20960660.7A priority patent/EP4233844A4/en
Publication of WO2022095203A1 publication Critical patent/WO2022095203A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • 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
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the invention relates to a preparation method of a preparation, in particular to a compound sustained-release composition of naltrexone and risperidone, and a preparation method and application thereof.
  • Naltrxone is a pure opioid receptor antagonist, which has blocking effect on ⁇ -, ⁇ -, ⁇ -opioid receptors. It can block the effect of re-addiction, thereby weakening the positive reinforcement and negative reinforcement, and plays a good auxiliary role in preventing relapse. Its chemical structure is as follows:
  • Risperidone has a good effect on positive and negative symptoms and their accompanying emotional symptoms (such as anxiety, depression, etc.). Also reduces affective symptoms associated with schizophrenia. For patients with effective treatment in the acute phase, this product can continue to exert its clinical efficacy in the maintenance phase. Its chemical structure is as follows:
  • Microcapsules microcapsules
  • dispersing or adsorbing drugs in macromolecular compounds encapsulating drugs into microcapsules
  • Microspheres usually have the size of ⁇ m units, so that they can be injected into the muscle or subcutaneously of humans or animals.
  • Microsphere dosage forms can be made into various drug release rates, thereby controlling the drug delivery time. Therefore, only one administration can maintain the effective therapeutic concentration of the drug for a long time, minimize the total administration amount of the drug required for the treatment, and improve the compliance of the patient to the drug treatment.
  • naltrexone which has been proven to have good effects in improving opioid relapse control and alcohol addiction, but it cannot achieve good results in the treatment of new drug addiction, especially methamphetamines.
  • the direct effect of drug addiction treatment is not ideal.
  • the technical problem to be solved by the present invention is to provide a naltrexone sustained-release microsphere preparation that can effectively prolong the action time of the naltrexone and risperidone compound in vivo, and reduce the administration frequency of naltrexone and risperidone.
  • An object of the present invention is to provide a compound sustained-release composition of naltrexone and risperidone, which, in parts by weight, comprises the following components:
  • the risperidone sustained-release microspheres are prepared by W 1 /O/W 2 double emulsification-solvent evaporation method.
  • naltrexone sustained-release microspheres are prepared by an O/W emulsification-solvent evaporation method.
  • preparation method of described risperidone sustained-release microspheres comprises the following steps:
  • the additive is selected from at least one of sodium chloride, mannitol, disodium hydrogen phosphate and sodium dihydrogen phosphate.
  • the fat-soluble polymer is selected from polylactic acid (PLA), polylactic acid-glycolic acid block copolymer (PLGA), polycaprolactone (PCL), polycarbonate, polyglycolic acid (PGA), poly At least one of nitrile acrylate and polyetherester.
  • water-soluble polymer is selected from polyvinyl alcohol.
  • the ratio of polylactic acid and glycolic acid in the polylactic acid-glycolic acid block copolymer (PLGA) is 1-9:1.
  • the weight average molecular weight (M w ) of the water-soluble polymer or fat-soluble polymer is 6,000-220,000 Da, preferably 50,000-100,000 Da.
  • the organic solvent is selected from at least one of dichloromethane and ethyl acetate.
  • the dosage ratio of the additive and the purified water is 50-300 mg/mL, preferably 75-150 mg/mL.
  • the concentration of risperidone is 100-300 mg/mL, preferably 100-150 mg/mL; the concentration of the fat-soluble polymer is 100-300 mg/mL, preferably 100-150 mg/mL.
  • the dosage ratio of the colostrum and the aqueous solution of the water-soluble polymer compound is 1-3:80, preferably 2-3:80.
  • the content of the water-soluble polymer is 0.1wt%-2wt%.
  • the content of the water-soluble polymer is 0.5wt%-0.6wt%.
  • the aqueous solution contains 0-5wt% sodium chloride or 0-10wt% sucrose.
  • the stirring speed is 500-5000 rpm, preferably 700-1,000 rpm, the volatilization is at 30-40°C, and the stirring speed is 200-3,000 rpm, preferably 500-1,000 rpm /min, stirring and volatilizing for 24 hours.
  • preparation method of described naltrexone sustained-release microspheres comprises the following steps:
  • the fat-soluble polymer is selected from polylactic acid (PLA), polylactic acid-glycolic acid block copolymer (PLGA), polycaprolactone (PCL), polycarbonate, polyglycolic acid (PGA), poly At least one of nitrile acrylate and polyetherester.
  • water-soluble polymer is selected from polyvinyl alcohol.
  • the organic solvent is selected from at least one of dichloromethane and ethyl acetate.
  • the ratio of lactic acid and glycolic acid in the polylactic acid-glycolic acid block copolymer (PLGA) is 1-9:1.
  • the weight average molecular weight (M w ) of the water-soluble polymer or fat-soluble polymer is 6,000-220,000 Da, preferably 50,000-100,000 Da.
  • the concentration of naltrexone is 50-300 mg/mL, preferably 100-150 mg/mL; the concentration of the fat-soluble polymer is 100-300 mg/mL, preferably 100-150 mg/mL.
  • the dosage ratio of the oil phase and the aqueous solution of the water-soluble polymer compound is 1-3:80, preferably 2-3:80.
  • the content of the water-soluble polymer is 0.1wt%-2wt%, preferably 0.5wt%-1wt%.
  • the aqueous solution contains 0-10wt% sodium chloride or 0-20wt% sucrose, preferably 8-10wt% sucrose.
  • the stirring speed is 500-5000 rpm, preferably 700-1,000 rpm, the volatilization is at 30-40°C, and the stirring speed is 200-3,000 rpm, preferably 5,00- 1000 rpm, stirring and volatilizing for 24 hours.
  • Another object of the present invention is to provide a formulation comprising the composition, which is prepared by uniformly mixing, tableting and coating the composition and a lubricant.
  • the lubricant is selected from at least one of sodium stearate fumarate, magnesium stearate and stearic acid.
  • the amount of the lubricant is 0.05-0.1% by weight of the composition.
  • One object of the present invention is to provide a kind of application of described composition and described preparation, and described application is the application in the product of treating or relieving amphetamines, ketamines, cocaines, marijuana drug addiction.
  • opioid or drug-addicted patients are often accompanied by mental illness symptoms. Therefore, when treating opioid or drug-addicted patients, it is equally important to perform auxiliary intervention for their mental stability at the same time.
  • the combination of troxone and risperidone is used at the same time to further enhance the therapeutic effect of opioid or drug-addicted patients.
  • the sustained-release preparation in the present invention is composed of risperidone microspheres, naltrexone, biodegradable pharmaceutical polymer materials and additives.
  • the preparation method of the present invention improves the stability of naltrexone and risperidone in the preparation process and release process, the method is simple, easy to operate, and has good reproducibility.
  • the sustained-release microspheres prepared by the present invention can be sustained-released in vitro for more than 12 weeks, the release conforms to an approximate zero-order mode, and the release rate is stable.
  • the present invention adopts a suitable preparation method and parameter control, so that the release rates of naltrexone sustained-release microspheres and risperidone sustained-release microspheres can be synchronized, which is more convenient to control the dosing cycle and prevent the occurrence of inconsistent release of the two drugs. Synchronization results in undetermined dosing cycles.
  • the preparation provided by the invention can better help the patient to avoid the relapse in the empty window period due to frequent medication due to its own long-acting drug release characteristics.
  • Fig. 1 the scanning electron microscope picture of the naltrexone sustained-release microsphere prepared by the embodiment of the present invention 3;
  • Fig. 2 the scanning electron microscope picture of the risperidone sustained-release microsphere prepared by the embodiment of the present invention 3;
  • Figure 3 In vitro cumulative release curve of naltrexone and risperidone compound sustained-release preparation prepared in Example 1 of the present invention, ordinate: cumulative release percentage (%), abscissa: time (day);
  • Figure 4 In vitro cumulative release curve of naltrexone and risperidone compound sustained-release preparation prepared in Example 2 of the present invention, ordinate: cumulative release percentage (%), abscissa: time (day);
  • Figure 5 In vitro cumulative release curve of naltrexone and risperidone compound sustained-release preparation prepared in Example 3 of the present invention, ordinate: cumulative release percentage (%), abscissa: time (day);
  • Figure 6 In vitro cumulative release curve of naltrexone and risperidone compound sustained-release preparation prepared in Comparative Example 1 of the present invention, ordinate: cumulative release percentage (%), abscissa: time (day);
  • Figure 7 In vitro cumulative release curve of naltrexone and risperidone compound sustained-release preparation prepared in Comparative Example 2 of the present invention, ordinate: cumulative release percentage (%), abscissa: time (day);
  • Figure 8 In vivo drug-time curve of the compound sustained-release preparation of naltrexone and risperidone prepared in Example 1 of the present invention, ordinate: blood concentration percentage (%), abscissa: time (day);
  • Figure 9 is the comparison of the sensitization data of the animal model of the embodiment of the present invention, the ordinate: distance (cm), and the abscissa: time (day).
  • naltrexone microspheres 1 part risperidone microspheres were mixed with 0.05% magnesium stearate and then compressed.
  • the in vitro cumulative release curve of this example is shown in Figure 3, it can be seen that the in vitro cumulative release exceeds 90 days, and naltrexone and risperidone are released simultaneously.
  • naltrexone microspheres 5 parts were mixed with 0.1% sodium stearyl fumarate and then compressed.
  • the in vitro cumulative release curve of this example is shown in Figure 4. It can be seen that the in vitro cumulative release exceeds 90 days, and naltrexone and risperidone are released simultaneously.
  • naltrexone microspheres The indicated 5 parts naltrexone microspheres and 2 parts risperidone microspheres were mixed with 0.025% sodium stearyl fumarate, 0.025% magnesium stearate and then compressed.
  • the in vitro cumulative release curve of this example is shown in Figure 5. It can be seen that the in vitro cumulative release exceeds 90 days, and naltrexone and risperidone are released simultaneously.
  • naltrexone microspheres 1 part risperidone microspheres were mixed with 0.05% magnesium stearate and then compressed.
  • naltrexone microspheres and 1 part risperidone microspheres were mixed with 0.05% magnesium stearate and then compressed. 4. Spray coating to obtain the compound sustained-release preparation of naltrexone and risperidone.
  • Example 1 and Comparative Example 1 when the preparation methods of risperidone are different and the preparation methods of naltrexone are the same, the release behavior of risperidone is similar, but the release behavior of naltrexone is quite different; From Example 1 and Comparative Example 2, when the preparation methods of risperidone are the same and the preparation methods of naltrexone are different, the release behavior of naltrexone is similar, but the release behavior of risperidone is quite different. .
  • naltrexone microspheres 1 part risperidone microspheres were mixed with 0.05% magnesium stearate and then compressed.
  • naltrexone reference substance solution Take an appropriate amount of naltrexone reference substance, accurately weigh it, add release medium to dissolve and quantitatively dilute to make a solution of about 50 ⁇ g per 1ml, as naltrexone reference substance solution.
  • risperidone reference substance solution Take an appropriate amount of risperidone reference substance, accurately weigh it, add release medium to dissolve and quantitatively dilute to make a solution of about 50 ⁇ g per 1ml, as risperidone reference substance solution.
  • Animals SD rats, half male and half male, the naltrexone compound preparation sample was from Example 1, the compound sustained-release preparation was implanted on the back, and blood was collected at a set time point to analyze drug data.
  • Blood collection method After isoflurane anesthesia, about 1 mL of blood was collected from the retro-orbital venous plexus. The collected whole blood was immediately placed in an EP tube containing heparin, shaken three times, placed in crushed ice, and centrifuged within 1 h (4°C). , 4000rpm centrifugation for about 5min), the plasma samples after centrifugation are stored below -20 °C. LC-MS/MS method was used to detect naltrexone and its metabolite 6 ⁇ -naltrexol, risperidone and risperidone metabolite 9-hydroxyrisperidone in blood samples. According to the time points of 0h, 4h, D1, D3, D7, D10, D16, D39, D45, D60, D75, D90, blood was collected once a week for analysis.
  • mice were raised under the same conditions, and the model group was surgically implanted with the product of the present invention before the experiment; the positive control group had the same experimental conditions as the model group except that the product of the present invention was not implanted; the negative control group was fed normally without Do experimental treatment. The behavioral differences among the model group, positive control group and negative control group were observed during the experiment.
  • mice Take 36 SD mice, weighing 120-150 g, half male and half male. Randomly divided into 3 groups, namely positive control group, negative control group and model group. In the model group, compound sustained-release preparations (samples from Example 1) were implanted on the back before administration, and challenge experiments were performed on the second day after operation.
  • the positive control group and model group were injected with methamphetamine (2 mg/kg) intraperitoneally every day, and the negative control group was intraperitoneally injected with the same amount of normal saline for 7 days; in the transformation period, the drug was stopped for 7 days without any treatment; the expression period lasted for 12 weeks, and the period All animals were challenged by intraperitoneal injection of methamphetamine (2 mg/kg) every 7 days, and the spontaneous activity of mice was observed 30 min later.
  • mice in the model group did not gradually increase on the 14th day, the 42nd day, the 49th day, the 56th day, the 77th day and the 84th day, like the positive control group. It shows that the compound sustained-release preparation of naltrexone and risperidone can antagonize methamphetamine in mice after pre-implantation, and protect the body.

Abstract

本发明涉及制剂的制备方法，具体涉及一种纳曲酮和利培酮复方缓释组合物及其制备方法和应用。本发明提供的纳曲酮和利培酮复方缓释组合物及其制剂，可在体外缓释达12周以上，释放符合近似零级模式，释放速率稳定；本发明采用合适的制备方法以及参数控制，使纳曲酮缓释微球和利培酮缓释微球在体内的释放率达到同步，更便于把控给药周期；进一步地，本发明提供的产品在甲基苯丙胺成瘾性试验中取得了较好的效果，可以用于制备治疗甲基苯丙胺成瘾的产品中。

Description

一种纳曲酮和利培酮复方缓释组合物 技术领域
本发明涉及制剂的制备方法，具体涉及一种纳曲酮和利培酮复方缓释组合物及其制备方法和应用。
背景技术
纳曲酮(Naltrxone)是阿片受体纯拮抗剂，对μ-，δ-，κ-阿片受体均有阻断作用。能阻断再吸毒品时的效应，从而减弱正性强化作用和负性强化作用，在防复吸中起到良好的辅助作用。其化学结构如下：
Figure PCTCN2020135369-appb-000001
利培酮(Risperidone)是对阳性及阴性症状及其伴发的情感症状(如焦虑、抑郁等)有较好的疗效。也可减轻与精神分裂症有关的情感症状。对于急性期治疗有效的患者，在维持期治疗中，本品可继续发挥其临床疗效。其化学结构如下：
Figure PCTCN2020135369-appb-000002
溶液剂、混悬剂和乳剂等传统的注射剂型在肌肉或皮下注射后快速从体内去除，因此治疗慢性疾病时需要频繁注射给药。为了解决上述问题而提出了长效微粒(Sustained release microparticle)，具体是指将药物封包裹到由高分子化合物内构成的微囊(Microcapsules)剂型或药物分散或被吸附在高分子化合物中而形成的微球((Microcsphere))分散体系。微球通常具有μm单位的大小，所以能注射给药到人体或动物的肌肉或皮下。微球剂型可以制作成各种不同的药物释放速度， 进而控制药物传递时间。因此，只要一次给药就能长时间维持药物有效治疗浓度，最大限度降低治疗所需的药物的总给药量，提高患者对药物治疗的顺应度。
上市药物
Figure PCTCN2020135369-appb-000003
有效成分为纳曲酮，该制剂己被证实在改善阿片类复吸控制及戒酒精成瘾方面具有良好效果，但是在新型毒品成瘾治疗中无法取得较好的效果，特别是甲基苯丙胺类毒品成瘾治疗直接中效果不理想。
目前并未见纳曲酮和利培酮复方组合物在成瘾治疗中的相关报道。
发明内容
本发明要解决的技术问题是提供一种能有效延长纳曲酮和利培酮复方在体内作用时间的纳曲酮缓释微球制剂，降低纳曲酮和利培酮的给药频率。
本发明的一个目的在于提供一种纳曲酮和利培酮复方缓释组合物，按重量份数计，包括以下成分：
纳曲酮缓释微球5-10份、
利培酮缓释微球1-2份、
进一步地，所述利培酮缓释微球通过W 1/O/W 2复乳化-溶剂挥发法制备。
进一步地，所述纳曲酮缓释微球通过O/W乳化-溶剂挥发法制备。
进一步地，所述利培酮缓释微球的制备方法包括以下步骤：
使用W 1/O/W 2复乳化-溶剂挥发法制备
S1：将添加剂溶于纯化水中，组成内水相；
S2：将利培酮和脂溶性高分子化合物溶解在有机溶剂中，组成油相；
S3：将内水相加入至油相，超声乳化形成初乳；
S4：将初乳滴加至水溶性高分子化合物的水溶液中，搅拌匀化，将有机溶剂挥发，洗涤，收集，干燥，即得所述利培酮缓释微球。
进一步地，所述添加剂选自氯化钠、甘露醇、磷酸氢二钠和磷酸二氢钠中的至少一种。
进一步地，所述脂溶性高分子选自聚乳酸(PLA)、聚乳酸-羟基乙酸嵌段共聚物(PLGA)、聚己内酯(PCL)、聚碳酸酯、聚乙醇酸(PGA)、聚腈基丙烯酸醋和聚醚酯中的至少一种。
进一步地，所述水溶性高分子选自聚乙烯醇。
进一步地，所述聚乳酸-羟基乙酸嵌段共聚物(PLGA)中聚乳酸和羟基乙酸 的比例为1-9:1。
进一步地，所述的水溶性高分子或脂溶性高分子的重均分子量(M w)为6,000-220,000Da，优选为50000-100000Da。
进一步地，所述有机溶剂选自二氯甲烷和乙酸乙酯中的至少一种。
进一步地，所述S1中，所述添加剂和纯化水的用量比例为50-300mg/mL，优选为75-150mg/mL。
进一步地，所述S2中，利培酮浓度为100-300mg/mL，优选为100-150mg/mL；所述脂溶性高分子浓度为100-300mg/mL，优选为100-150mg/mL。
进一步地，所述S4中，所述初乳和水溶性高分子化合物的水溶液的用量比例为1-3:80，优选为2-3:80。
进一步地，所述S4中，所述水溶性高分子水溶液中，水溶性高分子的含量为0.1wt％-2wt％。
进一步地，所述S4中，所述水溶性高分子的含量为0.5wt％-0.6wt％。
进一步地，所述水溶液为含有0-5wt％氯化钠或者0-10wt％蔗糖。
进一步地，所述搅拌速度为500-5000转/分，优选为700-1,000转/分，所述挥发是在30-40℃，搅拌速度为200-3,000转/分，优选为500-1,000转/分，搅拌挥发24小时。
进一步地，所述纳曲酮缓释微球的制备方法包括以下步骤：
使用O/W复乳化-溶剂挥发法制备
S1’：将纳曲酮和脂溶性高分子化合物溶解在有机溶剂中，组成油相；
S2’：将油相滴加至水溶性高分子化合物的水溶液中，搅拌匀化，将有机溶剂挥发，洗涤，收集，干燥，即得所述纳曲酮缓释微球。
进一步地，所述脂溶性高分子选自聚乳酸(PLA)、聚乳酸-羟基乙酸嵌段共聚物(PLGA)、聚己内酯(PCL)、聚碳酸酯、聚乙醇酸(PGA)、聚腈基丙烯酸醋和聚醚酯中的至少一种。
进一步地，所述水溶性高分子选自聚乙烯醇。
进一步地，所述有机溶剂选自二氯甲烷和乙酸乙酯中的至少一种。
进一步地，所述聚乳酸-羟基乙酸嵌段共聚物(PLGA)中乳酸和羟基乙酸的比例为1-9:1。
进一步地，所述的水溶性高分子或脂溶性高分子的重均分子量(M w)为6,000-220,000Da，优选为50000-100000Da。
进一步地，所述S1’中，纳曲酮浓度为50-300mg/mL，优选为100-150mg/mL；所述脂溶性高分子浓度为100-300mg/mL，优选为100-150mg/mL。
进一步地，所述S2’中，所述油相和水溶性高分子化合物的水溶液的用量比例为1-3:80，优选为2-3:80。
进一步地，所述S2’中，所述水溶性高分子水溶液中，水溶性高分子的含量为0.1wt％-2wt％，优选为0.5wt％-1wt％。
进一步地，所述水溶液为含有0-10wt％氯化钠或者0-20wt％蔗糖，优选为8-10wt％蔗糖。
进一步地，所述搅拌速度为500-5000转/分，优选为700-1,000转/分，所述挥发是在30-40℃，搅拌速度为200-3,000转/分，优选为5,00-1000转/分，搅拌挥发24小时。
本发明的另一目的在于提供一种包含所述组合物的制剂，所述制剂由所述组合物和润滑剂经均匀混合、压片、包衣制得。
进一步地，所述润滑剂选自硬脂富马酸钠，硬脂酸镁和硬脂酸中的至少一种。
进一步地，所述润滑剂的用量为所述组合物重量的0.05-0.1％。
本发明的在一个目的在于提供一种所述组合物和所述制剂的应用，所述应用为在治疗或缓解苯丙胺类、氯胺酮类、可卡因类、大麻类毒品成瘾的产品中的应用。
本发明的优势在于
阿片类药物或毒品成瘾患者除成瘾症状外，常伴随精神类疾病症状，因此在治疗阿片类药物或毒品成瘾患者时，同时对其精神的稳定进行辅助干预同样重要，本发明将纳曲酮和利培酮组成复方同时使用，进一步加强阿片类药物或毒品成瘾患者的治疗效果。
1.本发明中的缓释制剂由利培酮微球由纳曲酮、生物可降解的药用高分子材料和添加剂组成。
2.本发明的制备方法提高了纳曲酮和利培酮在制备工艺和释放过程中的稳定性，方法简便，易于操作，重现性好。
3.本发明所制备的缓释微球可在体外缓释达12周以上，释放符合近似零级模式，释放速率稳定。
4.本发明采用合适的制备方法以及参数控制，使纳曲酮缓释微球和利培酮缓释微球的释放率达到同步，更便于把控给药周期，防止出现两种药物释放不同步导致的给药周期无法确定的情况。
5.针对目前市场，没有防苯丙胺类毒品的复吸产品，本发明提供的制剂由于其自身的长效释药特点，能够更好的帮助病人避免由于频繁用药出现的空窗期复吸。
附图说明
图1：本发明实施例3制备的纳曲酮缓释微球的扫描电镜图片；
图2：本发明实施例3制备的利培酮缓释微球的扫描电镜图片；
图3：本发明实施例1所制备的纳曲酮和利培酮复方缓释制剂的体外累积释放曲线，纵坐标：累积释放释放百分率(％)，横坐标：时间(天)；
图4：本发明实施例2所制备的纳曲酮和利培酮复方缓释制剂的体外累积释放曲线，纵坐标：累积释放释放百分率(％)，横坐标：时间(天)；
图5：本发明实施例3所制备的纳曲酮和利培酮复方缓释制剂的体外累积释放曲线，纵坐标：累积释放释放百分率(％)，横坐标：时间(天)；
图6：本发明对比实施例1所制备的纳曲酮和利培酮复方缓释制剂的体外累积释放曲线，纵坐标：累积释放释放百分率(％)，横坐标：时间(天)；
图7：本发明对比实施例2所制备的纳曲酮和利培酮复方缓释制剂的体外累积释放曲线，纵坐标：累积释放释放百分率(％)，横坐标：时间(天)；
图8：本发明实施例1所制备的纳曲酮和利培酮复方缓释制剂的体内药时曲线，纵坐标：血药浓度百分率(％)，横坐标：时间(天)；
图9：是本发明实施例动物模型的敏化数据对比，纵坐标：路程(cm)，横坐标：时间(天)。
具体实施方式
以下结合附图对本发明的内容作进一步说明。
实施例1
1、利培酮微球制备：
使用W 1/O/W 2复乳化-溶剂挥发法制备
(1)将0.6g氯化钠溶解于3ml的纯化水中，组成内水相。
(2)取3.5g利培酮与3.5gPLA(M w8,0000Da)溶于二氯甲烷中，利培酮浓度为150mg/mL，PLA浓度为150mg/mL，组成油相；
(3)将内水相加入至油相，超声乳化形成初乳；
(4)将初乳滴按1:40滴加到水溶液(含0.5％聚乙烯醇和5％氯化钠)中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，洗涤，收集，干燥即得。
2、纳曲酮微球制备：
使用O/W复乳化-溶剂挥发法制备
(1)将3.5g纳曲酮和3.5gPLA(M w8,0000Da)溶于二氯甲烷中，纳曲酮浓度为150mg/ml，PLA浓度为150mg/ml，组成油相；
(2)将油相滴按1:40滴加到水溶液(含0.5％聚乙烯醇和10％蔗糖)中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，收集，干燥即得。
3、混合压片：
将所指的10份纳曲酮微球和1份利培酮微球与0.05％的硬脂酸镁混合，然后压片。
4、喷雾包衣，即得纳曲酮和利培酮复方缓释制剂。
本实施例体外累积释放曲线见图3，可以看出，体外累积释放超过90天，且纳曲酮和利培酮同步释放。
实施例2
1、利培酮微球制备：
使用W 1/O/W 2复乳化-溶剂挥发法制备
(1)将0.3g磷酸二氢钠溶解于2mL的水中，组成内水相。
(2)取4.0g利培酮与6.0gPLGA(乳酸：羟基乙酸＝90:10,M w50,000Da)溶于二氯甲烷中，利培酮浓度为100mg/mL，PLGA浓度为150mg/mL，组成油相；
(3)将内水相加入至油相，超声乳化形成初乳；
(4)将初乳按3:80滴加到水溶液(含0.6％聚乙烯醇和5％氯化钠)中，搅拌充分匀化，搅拌速度为700转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为1,000转/分，即得缓释微球，洗涤，收集，干燥即得。
2、纳曲酮微球制备：
使用O/W复乳化-溶剂挥发法制备
(1)将4.5g纳曲酮和6gPLGA(乳酸：羟基乙酸＝90:10,M w50,000Da)溶于二氯甲烷中，纳曲酮浓度为150mg/ml，PLGA浓度为200mg/ml，组成油相；
(2)将油相按3:80滴加到水溶液(含1.0％聚乙烯醇和8％蔗糖)中，搅拌充分匀化，搅拌速度为700转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为1000转/分，即得缓释微球，收集，干燥即得。
3、混合压片：
将所指的5份纳曲酮微球和1份利培酮微球与0.1％的硬脂富马酸钠混合，然后压片。
4、喷雾包衣，即得纳曲酮和利培酮复方缓释制剂。
本实施例体外累积释放曲线见图4，可以看出，体外累积释放超过90天，且纳曲酮和利培酮同步释放。
实施例3
1、利培酮微球制备：
使用W 1/O/W 2复乳化-溶剂挥发法制备
(1)将0.5g磷酸氢二钠溶解于5mL的水中，组成内水相。
(2)取5.0g利培酮与6.0gPLGA(乳酸：羟基乙酸＝50:50,M w100,000Da)溶于乙酸乙酯中，利培酮浓度为100mg/mL，PLGA浓度为120mg/mL，组成油相；
(3)将内水相加入至油相，超声乳化形成初乳；
(4)将初乳按1:40滴加到水溶液(含0.5％聚乙烯醇和15％蔗糖)中，搅拌充分匀化，搅拌速度为800转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为700转/分，即得缓释微球，洗涤，收集，干燥即得。
2、纳曲酮微球制备：
使用O/W复乳化-溶剂挥发法制备
(1)将5g纳曲酮和5gPLGA(50:50,M w100,000Da)溶于二氯甲烷中，纳曲 酮浓度为100mg/ml，PLGA浓度为100mg/ml，组成油相；
(2)将油相按1:40滴加到水溶液(含0.7％聚乙烯醇和10％蔗糖)中，搅拌充分匀化，搅拌速度为900转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为700转/分，即得缓释微球，收集，干燥即得。
3、混合压片：
将所指的5份纳曲酮微球和2份利培酮微球与0.025％的硬脂富马酸钠、0.025％的硬质酸镁混合，然后压片。
4、喷雾包衣，即得纳曲酮和利培酮复方缓释制剂。
本实施例体外累积释放曲线见图5，可以看出，体外累积释放超过90天，且纳曲酮和利培酮同步释放。
对比实施例1-和实施例1相比，利培酮采用O/W复乳化-溶剂挥发法制备
1、利培酮微球制备：
使用O/W复乳化-溶剂挥发法制备
(1)取3g利培酮与3g PLA(M w8,0000Da)溶于二氯甲烷中，利培酮浓度为150mg/mL，PLA浓度为150mg/mL，组成油相；
(2)将油相按1:40滴加到水溶液(含0.5％聚乙烯醇和10％蔗糖)中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，洗涤，收集，干燥即得。
2、纳曲酮微球制备：
使用O/W复乳化-溶剂挥发法制备
(1)将3g纳曲酮和3gPLA(M w8,0000Da)溶于二氯甲烷中，纳曲酮浓度为150mg/ml，PLA浓度为150mg/ml，组成油相；
(2)将油相按1:40滴加到水溶液(含0.5％聚乙烯醇和10％蔗糖)中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，收集，干燥即得。
3、混合压片：
将所指的10份纳曲酮微球和1份利培酮微球与0.05％的硬脂酸镁混合，然后压片。
4、喷雾包衣，即得纳曲酮和利培酮复方缓释制剂。
本实施例体外累积释放曲线见图6，可以看出，纳曲酮释放时间仅70天，且纳曲酮和利培酮无法同步释放。
对比实施例2-和实施例1相比，纳曲酮采用W 1/O/W 2复乳化-溶剂挥发法制备1、利培酮微球制备：
使用W 1/O/W 2复乳化-溶剂挥发法制备
(1)将0.6g氯化钠溶解于3ml的纯化水中，组成内水相。
(2)取3.5g利培酮与PLA(M w80000Da)溶于二氯甲烷中，利培酮浓度为150mg/mL，PLA浓度为150mg/mL，组成油相；
(3)将内水相加入至油相，超声乳化形成初乳；
(4)将初乳按1:40滴加到水溶液(含0.5％聚乙烯醇和5％氯化钠)溶液中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，收集，干燥即得。
2、纳曲酮微球制备：
使用W 1/O/W 2复乳化-溶剂挥发法制备
(1)将0.6g氯化钠溶解于4ml的纯化水中，组成内水相。
(2)将3.5g纳曲酮和3.5gPLA(M w80000Da)溶于二氯甲烷中，纳曲酮浓度为150mg/ml，PLA浓度为150mg/ml，组成油相；
(3)将内水相加入至油相，超声乳化形成初乳；
(4)将初乳滴按1:40滴加到水溶液(含0.5％聚乙烯醇和10％蔗糖)溶液中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌2小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，收集，干燥即得。
3、混合压片：
将所指的10份纳曲酮微球和1份利培酮微球与0.05％的硬脂酸镁混合，然后压片。4、喷雾包衣，即得纳曲酮和利培酮复方缓释制剂。
本实施例体外累积释放曲线见图7，可以看出，纳曲酮和利培酮释放时间均在80天以下，且纳曲酮和利培酮无法同步释放。
从实施例1和对比实施例1来看，在两者利培酮的制备方法不同而纳曲酮制备方法相同的情况下，利培酮的释放行为相似而纳曲酮释放行为差距较大；而从实施例1和对比实施例2来看，在两者利培酮的制备方法相同而纳曲酮制备方法 不同的情况下，纳曲酮的释放行为相似而利培酮释放行为差距较大。这说明了本发明两种缓释微球混合时释放行为的复杂性，为了达到本发明使两者同步释放的效果，应当将各参数限定在本发明所要求的范围内。
对比实施例3-和实施例1相比，脂溶性高分子分子量不同
1、利培酮微球制备：
使用W 1/O/W 2复乳化-溶剂挥发法制备
(1)将0.6g氯化钠溶解于3ml的纯化水中，组成内水相。
(2)取3.5g利培酮与PLA(M w5,000Da)溶于二氯甲烷中，利培酮浓度为150mg/mL，PLA浓度为150mg/mL，组成油相；
(3)将内水相加入至油相，超声乳化形成初乳；
(4)将初乳按1:40滴加到水溶液(含0.5％聚乙烯醇和5％氯化钠)溶液中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，收集，干燥即得。
2、纳曲酮微球制备：
使用O/W复乳化-溶剂挥发法制备
(1)将3.5g纳曲酮和3.5gPLA(M w5,000Da)溶于二氯甲烷中，纳曲酮浓度为150mg/ml，PLA浓度为150mg/ml，组成油相；
(2)将油相按1:40滴加到水溶液(含0.5％聚乙烯醇和10％蔗糖)中，搅拌充分匀化，搅拌速度为1,000转/分，35℃条件下继续低速搅拌24小时挥发有机溶剂，搅拌速度为800转/分，即得缓释微球，收集，干燥即得。
3、混合压片：
将所指的10份纳曲酮微球和1份利培酮微球与0.05％的硬脂酸镁混合，然后压片。
4、喷雾包衣，即得纳曲酮和利培酮复方缓释制剂。
此时利培酮和纳曲酮无法达到同步释放的效果。
实施例 体外释放度考察
取纳曲酮对照品适量，精密称定，加释放介质溶解并定量稀释制成每1ml中约50μg的溶液，作为纳曲酮对照品溶液。
取利培酮对照品适量，精密称定，加释放介质溶解并定量稀释制成每1ml中约50μg的溶液，作为利培酮对照品溶液。
取本品，分别置6个100ml具塞锥形瓶中，以0.1M无水磷酸氢二钾(精密吸取1M氢氧化钠溶液25ml置1000ml量瓶中，加0.1M无水磷酸氢二钾溶液稀释，调pH值为11.2±0.05的溶液)溶液80ml为溶剂，密塞，置37℃±0.5℃水浴振荡器中，振荡频率为每分钟100次。分别在1、3、6、9、12、15...120天更换介质，溶液滤过，取续滤液作为供试品溶液，并及时在操作容器中补充释放介质。按照高效液相色谱法(中国药典2020版四部0512高效液相色谱法)，在280nm波长检测定。
体外累计释放结果见附图3-7，可以看出本发明提供的产品释放周期在12周以上，并且实现的纳曲酮和利培酮药物释放的同步，而对比实施例无法取得两种药物同步释放的效果，释放终点相差两周以上。
实施例 动物体内药代动力学
动物：SD大鼠，雌雄各半，纳曲酮复方制剂样品来源于实施例1，在背部植入复方缓释制剂，在设定时间点进行取血分析药时数据。
取血方法：异氟烷麻醉后，眼眶后静脉丛取血约1mL，采集后的全血立即放入含肝素的EP管中，倒摇三次，放入碎冰中，1h内离心(4℃，4000rpm离心约5min)，离心后血浆样品-20℃以下保存。采用LC-MS/MS方法检测血样中纳曲酮及纳曲酮代谢物6β-纳曲醇，利培酮及利培酮代谢物9-羟利培酮。按照时间点0h、4h、D1、D3、D7、D10、D16、D39、D45、D60、D75、D90每周一次进行取血分析。
药时分析结果见图8，可以看出，本发明提供的产品在实验动物体内可以有效释放利培酮和纳曲酮进入血液，在90天内保持稳定的血药浓度。
实施例 动物药效学评价
所有小鼠在相同条件下饲养，模型组在实验前手术植入本发明的产品；阳性对照组除了不植入本发明的产品外，其他实验条件和模型组相同；阴性对照组正常饲养，不做实验处理。实验期间观察模型组、阳性对照组和阴性对照组之间的行为区别。
取SD鼠36只，体重120-150g，雌雄各半。随机分成3组，即对阳性照组、阴性对照组、模型组。模型组在给药前在背部植入复方缓释制剂(样品来源于实施例1)，术后第二天进行挑战实验。
形成期阳性对照组、模型组每天腹腔注射甲基苯丙胺(2mg/kg)，阴性对照 组腹腔注射等量生理盐水，连续7d；转化期停药7d无任何处理；表达期位持续12周，期间每7天所有动物腹腔注射甲基苯丙胺(2mg/kg)激发，30min后观察小鼠的自发活动。
结果如图9所示，可以看出，阳性对照组在第7天起小鼠活动性显著升高(P<0.05)，表明甲基苯丙胺慢性给药小鼠的自发活动性明显，表明甲基苯丙胺能诱导行为敏化。与阳性对照组相比，模型组在第7天、第14天、第42天、第49天、第56天、第77天和第84天，小鼠自发活动性显著下降(P<0.01)，基本上与阴性对照组相当。与第7天模型组相比，模型组的第14天、第42天、第49天、第56天、第77天和第84天小鼠活动性并没有像阳性对照组一样逐渐升高，表明纳曲酮和利培酮复方缓释制剂预埋植后使小鼠对甲基苯丙胺具有拮抗作用，起到机体得到保护。
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. 一种纳曲酮和利培酮复方缓释组合物，按重量份数计，包括以下成分：
    纳曲酮缓释微球 5-10份、
    利培酮缓释微球 1-2份；
    所述纳曲酮缓释微球通过W 1/O/W 2复乳化-溶剂挥发法制备；所述利培酮缓释微球通过O/W乳化-溶剂挥发法制备。
  2. 根据权利要求1所述的组合物，其特征在于，所述利培酮缓释微球中，制备原料包括利培酮、添加剂、脂溶性高分子和水溶性高分子；优选地，所述添加剂选自氯化钠、甘露醇、磷酸氢二钠和磷酸二氢钠中的至少一种；所述脂溶性高分子选自聚乳酸、聚乳酸-羟基乙酸嵌段共聚物、聚己内酯、聚碳酸酯、聚乙醇酸、聚腈基丙烯酸醋和聚醚酯中的至少一种；所述水溶性高分子选自聚乙烯醇；所述聚乳酸-羟基乙酸嵌段共聚物中乳酸和羟基乙酸的比例为1-9:1；所述的水溶性高分子或脂溶性高分子的重均分子量为6,000-220,000Da，优选为50000-100000Da。
  3. 根据权利要求1所述的组合物，其特征在于，所述利培酮缓释微球的制备方法包括以下步骤：
    使用W 1/O/W 2复乳化-溶剂挥发法制备，具体步骤如下，
    S1：将添加剂溶于纯化水中，组成内水相；
    S2：将利培酮和脂溶性高分子化合物溶解在有机溶剂中，组成油相；
    S3：将内水相加入至油相，超声乳化形成初乳；
    S4：将初乳滴加至水溶性高分子化合物的水溶液中，搅拌匀化，固化，将有机溶剂挥发，收集，干燥，即得所述利培酮缓释微球。
  4. 根据权利要求3所述的组合物，其特征在于，所述S1中，所述添加剂和纯化水的用量比例为50-300mg/mL；所述S2中，利培酮浓度为100-300mg/mL，所述有机溶剂选自二氯甲烷和乙酸乙酯中的至少一种；所述脂溶性高分子浓度为100-300mg/mL；所述S4中，所述初乳和水溶性高分子化合物的水溶液的用量比例为1-3:80；所述S4中，所述水溶性高分子水溶液中，水溶性高分子的含量为0.1wt％-2wt％，优选为0.5wt％-0.6wt％。
  5. 根据权利要求4所述的组合物，其特征在于，所述S4中，所述水溶液含有 ≤5wt％氯化钠或者≤15wt％蔗糖；所述搅拌速度为500-5,000转/分，优选为700-1,000转/分，所述挥发是在30-40℃，搅拌速度为200-3,000转/分，优选为500-1,000转/分，搅拌挥发24小时。
  6. 根据权利要求1所述的组合物，其特征在于，所述纳曲酮缓释微球中，制备原料包括纳曲酮、脂溶性高分子和水溶性高分子；优选地，所述脂溶性高分子选自聚乳酸、聚乳酸-羟基乙酸嵌段共聚物、聚己内酯、聚碳酸酯、聚乙醇酸、聚腈基丙烯酸醋和聚醚酯中的至少一种；所述水溶性高分子选自聚乙烯醇；所述聚乳酸-羟基乙酸嵌段共聚物中乳酸和羟基乙酸的比例为1-9:1；所述的水溶性高分子或脂溶性高分子的重均分子量为6,000-220,000Da，优选为50000-100000Da。
  7. 根据权利要求1所述的组合物，其特征在于，所述纳曲酮缓释微球的制备方法包括以下步骤：
    使用O/W复乳化-溶剂挥发法制备，具体步骤如下，
    S1’：将纳曲酮和脂溶性高分子化合物溶解在有机溶剂中，组成油相；
    S2’：将油相滴加至水溶性高分子化合物的水溶液中，搅拌匀化，固化，将有机溶剂挥发，收集，干燥，即得所述利培酮缓释微球。
  8. 根据权利要求7所述的组合物，其特征在于，所述S1’中，纳曲酮浓度为50-300mg/mL，所述脂溶性高分子浓度为100-300mg/mL；所述有机溶剂选自二氯甲烷和乙酸乙酯中的至少一种；所述S2’中，所述油相和水溶性高分子化合物的水溶液的用量比例为1-3:80；所述S2’中，所述水溶性高分子水溶液中，水溶性高分子的含量为0.1wt％-2wt％，优选为0.5wt％-1wt％；所述水溶液含有0-10wt％氯化钠或者0-20wt％蔗糖，优选为8-10wt％蔗糖；所述搅拌速度为1,000-5,000转/分，优选为700-1,000转/分，所述挥发是在30-40℃，搅拌速度为200-3,000转/分，优选为500-1,000转/分，搅拌挥发24小时以上。
  9. 一种包含权利要求1-8任一项所述的组合物的制剂，所述制剂由所述组合物和润滑剂经均匀混合、压片、包衣制得；优选地，所述润滑剂选自硬脂富马酸钠，硬脂酸镁和硬脂酸中的至少一种，用量为所述组合物重量的0.05-1％。
  10. 一种如权利要求1-8任一项所述组合物或权利要求9所述制剂的应用，所述应用为治疗或缓解苯丙胺类、氯胺酮类、可卡因类、大麻类毒品成瘾的产品中的应用。
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CN115518048A (zh) * 2022-09-28 2022-12-27 深圳善康医药科技股份有限公司 纳曲酮和利培酮的复方缓释植入剂及其制备方法和应用
CN115518048B (zh) * 2022-09-28 2023-11-07 深圳善康医药科技股份有限公司 纳曲酮和利培酮的复方缓释植入剂及其制备方法和应用
WO2024067745A1 (zh) * 2022-09-28 2024-04-04 深圳善康医药科技股份有限公司 纳曲酮和利培酮的复方缓释植入剂及其制备方法和应用
CN115737568A (zh) * 2022-11-24 2023-03-07 东南大学 一种利培酮鼻用粉雾剂及其制备方法
CN116473927A (zh) * 2023-06-07 2023-07-25 深圳聚生生物科技有限公司 一种可注射pla微球制备方法及其应用
CN116473927B (zh) * 2023-06-07 2023-11-17 深圳聚生生物科技有限公司 一种可注射pla微球制备方法及其应用

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