WO2021217388A1 - 一种盐酸美金刚缓释胶囊及其制备方法 - Google Patents

一种盐酸美金刚缓释胶囊及其制备方法 Download PDF

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WO2021217388A1
WO2021217388A1 PCT/CN2020/087372 CN2020087372W WO2021217388A1 WO 2021217388 A1 WO2021217388 A1 WO 2021217388A1 CN 2020087372 W CN2020087372 W CN 2020087372W WO 2021217388 A1 WO2021217388 A1 WO 2021217388A1
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release
sustained
memantine hydrochloride
parts
capsule
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PCT/CN2020/087372
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English (en)
French (fr)
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丁爱忠
成芳
赵锦花
孔凯丽
戴杰
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江苏天士力帝益药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • 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
    • A61K31/13—Amines
    • 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
    • A61K47/06—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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—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
    • A61K9/48—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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention belongs to the technical field of pharmacy, relates to the technical field of pharmaceutical preparations, and particularly relates to a memantine hydrochloride sustained-release capsule and a preparation method thereof.
  • Alzheimer’s Disease is a degenerative disease of the central nervous system and the most common type of senile dementia.
  • People with Alzheimer's disease have problems with memory, judgment, and thinking, making it difficult to work or participate in daily life. It is associated with senile dementia, which is the degeneration of intelligence (loss of intelligence) associated with aging.
  • Alzheimer's disease is defined as two main types: Alzheimer's type caused by generalized atrophy and those caused by vascular problems, mainly strokes. Among people over 80, 20% suffer from Alzheimer's disease.
  • AD patients Although there are medications that can improve symptoms, Alzheimer's disease cannot currently be cured. According to data released by the WHO in April 2012, there are nearly 35.6 million AD patients in the world, and the number is expected to double (65.7 million) by 2030 and triple the current number by 2050. There are about 6 million AD patients in my country, and it is estimated that there will be 10 million AD patients in my country by 2025.
  • Memantine hydrochloride is a low-to-medium affinity, non-competitive, strong voltage-dependent N-methyl-D-aspartate receptor antagonist, which can block over-opened receptors and effectively regulate excitatory transmitters It slows down the process of neurodegeneration and has a therapeutic effect on Alzheimer’s disease. It does not have the side effects on the central nervous system that other N-methyl-D-aspartate receptors usually have. It is the first approved by the FDA The medicine for the treatment of moderate to severe Alzheimer's disease has good application prospects.
  • Patent CN201410830047 discloses a sustained-release preparation for the treatment of Alzheimer’s disease and a preparation method thereof.
  • the sustained-release preparation is composed of a sustained-release tablet core and an immediate-release outer layer, and the immediate-release outer layer encapsulates the sustained-release tablet. Core; the sustained-release preparation prepared by the invention has fast onset, long-lasting action, and stable effects, and improves patient compliance.
  • this patented dosage form is a sustained-release tablet, which is different from the original dosage form, so it cannot be compared in terms of consistency.
  • Patent CN201410073178 discloses a memantine hydrochloride sustained-release preparation, including memantine hydrochloride sustained-release mini-tablets.
  • the patented dosage form is a sustained-release tablet, which is different from the originally developed dosage form and therefore cannot be compared in terms of consistency.
  • Patent CN201410254808 discloses a sustained-release pill of memantine hydrochloride.
  • the inner filling of the capsule is memantine hydrochloride sustained-release pellets.
  • the memantine hydrochloride sustained-release pellets include a blank pill core, a main drug layer containing memantine hydrochloride, an isolation coating layer, and a sustained-release coating layer from the inside to the outside. .
  • the invention has good stability and no sudden release phenomenon, ensures that the medicine is released continuously, uniformly and slowly, and improves the curative effect of the product.
  • this product adds an isolation coating layer, and the process is cumbersome.
  • Patent CN201110446337 discloses a preparation method of memantine hydrochloride sustained-release preparation.
  • the drug-containing pellets containing memantine hydrochloride are subjected to sustained-release coating to obtain sustained-release pellets.
  • the drug-containing pellets obtained by extrusion spheronization or solution application or suspension application the pellets are close to circular in shape, and the drug-containing pellets with controllable shape and particle size are subjected to sustained-release coating, so that the coating is formed
  • the thickness of the film is also controllable.
  • the product is released within 24 hours, and the 12-hour release degree is low in consistency with the reference preparation (original drug preparation), and the release degree of the reference preparation reaches more than 85% in 12 small trials.
  • the purpose of the present invention is to provide a memantine hydrochloride sustained-release capsule.
  • the present invention can maintain the memantine hydrochloride sustained-release capsule in terms of efficacy with the original memantine hydrochloride sustained-release capsule under different formulations and processes.
  • a high degree of consistency, compared with the original drug formulation, the dissolution curve F2 under a variety of dissolution media are all greater than 50.
  • this product is a capsule composed of multiple small pellets, and the release value of each capsule has little difference.
  • Another object of the present invention is to provide a method for preparing the memantine hydrochloride sustained-release capsule.
  • a sustained-release memantine hydrochloride capsule is prepared by filling sustained-release pellets in the capsule, and the sustained-release pellets are sequentially coated with an isolation layer and a sustained release
  • the drug-loaded pellets are composed of a sucrose pellet core, memantine hydrochloride, a binder and an anti-adhesive agent;
  • the isolation layer is composed of a film-forming material and an anti-adhesive agent;
  • the sustained-release layer is composed of It is composed of slow-release materials, plasticizers and anti-sticking agents.
  • the further improvement scheme of the present invention is:
  • the core particle size of the sucrose pellets is 0.6-0.71 mm.
  • sustained-release pellets need to be mixed with an antistatic agent before being filled, and then filled in a capsule; the added amount of the antistatic agent is 0.3% of the weight of the sustained-release pellets;
  • the antistatic agent is talc.
  • sustained-release pellets are composed of the following parts by mass of raw materials: 28 parts of memantine hydrochloride, 100 to 120 parts of sucrose pellet core, 10 to 30 parts of binder, 10 to 30 parts of anti-sticking agent, and film forming 6-12 parts of materials, 10-20 parts of slow-release materials, 1-2 parts of plasticizers.
  • the binder is polyvinylpyrrolidone, hydroxypropyl cellulose or povidone;
  • the anti-sticking agent is talc, colloidal silicon dioxide, magnesium stearate or magnesium silicate;
  • the film material is hypromellose, hydroxypropyl cellulose or polyvinylpyrrolidone;
  • the sustained-release material is ethyl cellulose, acrylic resin or cellulose acetate;
  • the plasticizer is polyethylene glycol 6000, lemon Triethyl phthalate or butyl benzyl phthalate.
  • the binder is povidone K30; the anti-sticking agent is talc; the film-forming material is hypromellose; the sustained-release material is ethyl cellulose; the plasticizer
  • the agent is polyethylene glycol 6000.
  • the further improvement scheme of the present invention is:
  • the method for preparing memantine hydrochloride sustained-release capsules as described above includes the following steps:
  • the bottom spray of fluidized bed is used to apply the drug, and the drug-loading layer, isolation layer, and sustained-release layer are sequentially coated to produce sustained-release pellets.
  • the antistatic agent is added to the pellets, mixed, and then filled into capsules to obtain memantine hydrochloride sustained-release capsules.
  • the further improvement scheme of the present invention is:
  • the memantine hydrochloride crude drug, the adhesive, and 1/3 of the anti-sticking agent are dissolved in the ethanol aqueous solution in order to prepare the drug-carrying layer bottom spray solution.
  • the mass concentration is 30%-50%.
  • the inlet air temperature of the fluidized bed is 33-43°C
  • the steady-state material temperature is 24-36°C
  • the rotation speed of the peristaltic pump It is 10 ⁇ 17g/min
  • the atomization pressure is 0.8 ⁇ 1.5bar
  • the air volume is 80 ⁇ 120m 3 /h.
  • the film-forming material and 1/3 of the anti-sticking agent are dissolved in purified water in sequence to prepare the spray liquid at the bottom of the isolation layer.
  • the fluidized bed inlet air temperature is 55 ⁇ 65°C
  • the steady state material temperature is 35 ⁇ 50°C
  • the peristaltic pump speed is 11 ⁇ 14g/min
  • the atomization pressure is 2.0bar
  • the air volume is 80 ⁇ 120m 3 /h
  • the weight gain of the isolation layer is 3% to 7%.
  • the sustained-release material, the plasticizer, and the remaining anti-sticking agent are dissolved in the ethanol aqueous solution in sequence to prepare a spray liquid at the bottom of the sustained-release layer, and the mass concentration of the ethanol aqueous solution is 70% ⁇ 90%, when spraying the drug coating slow-release layer at the bottom of the fluidized bed, the inlet air temperature of the fluidized bed is 35-40°C, the steady-state material temperature is 28-30°C, and the speed of the peristaltic pump is 12-22g/ min, the atomization pressure is 1 to 2.0 bar, and the air volume is 80 to 120 m 3 /h; the weight gain of the slow-release layer is 7% to 8%.
  • the solubility of memantine hydrochloride in water is 0.05g/ml, and its solubility in ethanol is significantly higher than that in water.
  • the application of the alcohol aqueous solution can significantly shorten the drug loading process time. Take 50% ethanol water as an example, 1000 tablets batch For prescriptions, the loading time is only 40% of the original time.
  • the film-forming material of the isolation layer needs to be spread evenly on the surface of the drug-loaded pellets to form a continuous and dense coating film to isolate and protect the drug-loaded pellets; because the solubility of memantine hydrochloride in ethanol is much greater than that of water, the slow-release layer Alcohol solution is used for coating. During the coating process, the drug may migrate into the coating layer, thereby affecting the final release of the drug. Therefore, it is necessary to wrap an isolation layer outside the drug-loading layer; the present invention uses hypromellose HPMC is used as the film-forming material of the isolation layer, and the anti-sticking agent talcum powder is added, and the prescription composition is simple.
  • the sustained-release layer of the present invention is coated with ethyl cellulose 70% to 90% alcohol aqueous solution.
  • ethyl cellulose 70% to 90% alcohol aqueous solution As the solvent evaporates during the coating process, the polymer concentration increases, and the polymer molecular chains originally stretched in the solution curl and Intertwining each other, as the residual solvent further evaporates to form a continuous coating film.
  • This prescription process does not require a heat treatment process after the coating is completed.
  • the present invention can maintain a high degree of consistency with the original drug formulation memantine hydrochloride sustained-release capsule in terms of efficacy.
  • the dissolution curve F2 under multiple dissolution media is greater than 50.
  • this product is a capsule composed of multiple small pellets, and the release value of each capsule has little difference.
  • Figure 1 is the dissolution profile of the memantine hydrochloride sustained-release capsule prepared in Example 1 in pH 1.2 hydrochloric acid, pH 4.5 acetate buffer and pH 6.8 phosphate buffer;
  • Figure 2 shows the dissolution curves of memantine hydrochloride sustained-release capsules prepared in Examples 1 to 3 and the original drug in a medium of pH 1.2 hydrochloric acid solution (with sodium chloride).
  • the bottom spray of fluidized bed is used to apply the drug, and the drug-loading layer, isolation layer, and sustained-release layer are sequentially coated to produce sustained-release pellets.
  • the antistatic agent is added to the pellets, mixed, and then filled into capsules to obtain memantine hydrochloride sustained-release capsules.
  • the coating process of the drug-carrying layer sequentially dissolve memantine hydrochloride raw material, povidone (K30) and talc in an ethanol aqueous solution to prepare a spray liquid at the bottom of the drug-carrying layer, and the mass concentration of the ethanol aqueous solution is 30% ⁇ 50%, when spraying at the bottom of the fluidized bed to coat the drug-loading layer, the inlet air temperature of the fluidized bed is 33 ⁇ 43°C, the steady-state material temperature is 24 ⁇ 36°C, and the rotation speed of the peristaltic pump is 10 ⁇ 17g/ min, the atomization pressure is 0.8-1.5bar, and the air volume is 80-120m 3 /h.
  • the coating process of the isolation layer Dissolve hypromellose (E5) and talc in purified water in sequence to prepare a spray liquid at the bottom of the isolation layer.
  • E5 Dissolve hypromellose
  • talc talc in purified water in sequence to prepare a spray liquid at the bottom of the isolation layer.
  • the bed inlet temperature is 55 ⁇ 65°C
  • the steady state material temperature is 35 ⁇ 50°C
  • the rotation speed of the peristaltic pump is 11 ⁇ 14g/min
  • the atomization pressure is 2.0bar
  • the air volume is 80 ⁇ 120m 3 /h
  • the isolation layer Weight gain is 3% to 7%.
  • the coating process of the sustained-release layer sequentially dissolve ethyl cellulose (10cps), polyethylene glycol (6000) and talc in an ethanol aqueous solution to prepare a spray solution at the bottom of the sustained-release layer.
  • the mass concentration of the ethanol aqueous solution is 70% ⁇ 90%, when spraying the drug coating slow-release layer at the bottom of the fluidized bed, the inlet air temperature of the fluidized bed is 35-40°C, the steady-state material temperature is 28-30°C, and the speed of the peristaltic pump is 12 ⁇ 22 g/min, atomization pressure is 1 to 2.0 bar, air volume is 80 to 120 m 3 /h; the weight gain of the slow-release layer is 7% to 8%.

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Abstract

一种盐酸美金刚缓释胶囊及其制备方法，所述的盐酸美金刚缓释胶囊由缓释微丸灌装于胶囊而制得，所述缓释微丸由载药微丸依次包覆隔离层、缓释层制备而成；所述载药微丸由蔗糖微丸丸芯、盐酸美金刚、粘合剂以及抗粘剂组成；所述隔离层由成膜材料与抗粘剂组成；所述缓释层由缓释材料、增塑剂以及抗粘剂组成。在配方以及工艺不同的情况下，其与原研药制剂盐酸美金刚缓释胶囊在药效上能够保持高度的一致性，与原研药制剂对比在多种溶出介质下的溶出曲线F2均大于50。另外，本品为由多个小微丸组成的胶囊剂，每粒胶囊的释放度值差异不大。

Description

一种盐酸美金刚缓释胶囊及其制备方法 技术领域
本发明属于制药技术领域，涉及药物制剂技术领域，尤其涉及一种盐酸美金刚缓释胶囊及其制备方法。
背景技术
阿尔兹海默症(Alzheimer’s Disease，AD)是一种中枢神经系统退行性疾病，是老年期痴呆最常见的一种类型。一种脑细胞(神经元)恶化的不可逆进行性紊乱，其导致认知功能、主要记忆、判断和推理、运动协调性和图形识别的丧失。在该疾病的晚期，所有的记忆和智力功能都可能丧失。患有阿尔茨海默症的人在记忆、判断和思考方面存在问题，从而使其难以工作或参与日常生活。它和老年性痴呆，即与老龄有关的智力退化(智能丧失)有关联。老年性痴呆被定义为两种主要类型：由广义的萎缩症引起的阿尔茨海默型和由血管问题引起的，主要是中风等。在80岁以上的人中，20％患有阿尔茨海默症。尽管有能改善症状的药物，但阿尔茨海默症目前不能被治愈。据WHO在2012年4月公布数据显示，全世界有近3560万AD患者，预计人数到2030年翻一番(6570万)，到2050年将达到现在的三倍。我国AD患者有600万左右，预计到2025年我国将有1000万AD患者。
盐酸美金刚是一种低中亲和力、非竞争性、强电压依赖性的N-甲基-D-天门冬氨酸受体拮抗剂，可以阻断过度开放的受体，有效调控兴奋性递质，减缓神经退化过程，对阿尔茨海默症起到治疗作用,而没有其他N-甲基-D-天门冬氨酸受体通常会有的对中枢神经的副作用，是FDA批准的第一个用于治疗中、重度老年痴呆症的药物，具有很好应用前景。
由于阿尔茨海默症需要长期服药，因此将盐酸美金刚制成缓释制剂可减少服用次数，方便患者应用，提高依从性。2010年6月，美国FDA批准森林公司的美金刚缓释胶囊(Namenda XR 7，14，21，28mg)用于治疗中、重度AD。低剂量用于起始剂量和肾功能严重损害者，维持剂量为28mg。
专利CN201410830047公开了一种用于治疗阿尔茨海默症的缓释制剂及其制备方法，所述缓释制剂由缓释片芯和速释外层组成，所述速释外层包裹缓释片芯；该发明所制得的缓释制剂起效快、作用时间持久、稳定的效果，提高病人的依从性。但是此专利剂型为缓释片剂，与原研制剂剂型不同，因此在一致性上无法比较。
专利CN201410073178公开了一种盐酸美金刚缓释制剂，包括盐酸美金刚缓释迷你片，同样地，该专利剂型为缓释片剂，与原研制剂剂型不同，因此在一致性上无法比较。
专利CN201410254808公开了一种盐酸美金刚缓释药丸。该胶囊内填充物为盐酸美金刚缓释小丸，所述盐酸美金刚缓释小丸从里至外依次包括空白丸芯、含盐酸美金刚的主药层、隔 离包衣层和缓释包衣层。该发明稳定性好、无突释现象，确保药物持续、均匀缓慢地释放药物，提高了产品的疗效。但是此产品为了解决盐酸美金刚缓释胶囊的突释问题，加入了隔离包衣层，工艺较繁琐。
专利CN201110446337公开了一种盐酸美金刚缓释制剂的制备方法。是将含盐酸美金刚的含药小丸进行缓释包衣得到缓释微丸。通过挤出滚圆或者是溶液上药或是混悬液上药得到的含药小丸，该小丸在形状上接近圆形，对形状粒度可控的含药小丸进行缓释包衣，使得包衣形成的膜的厚薄也可控。但是该产品在24小时内的范围内释放，且12小时的释放程度与参比制剂(原研药制剂)一致性低，参比制剂在12小试内释放程度达到85％以上。
由上可知，现有专利的美金刚制剂与Forest Lab和Merz公司联合开发的盐酸美金刚缓释胶囊NamendaXR在药效一致性上相去甚远，目前市场上还未有符合要求的盐酸美金刚缓释胶囊NamendaXR仿制药制剂。因此，有必要研发出一款以盐酸美金刚缓释胶囊NamendaXR为原研药制剂且具有高度一致性的仿制药制剂。
发明内容
针对现有技术的不足，本发明的目的在于提供一种盐酸美金刚缓释胶囊，本发明在配方以及工艺不同的情况下，其与原研药制剂盐酸美金刚缓释胶囊在药效上能够保持高度的一致性，与原研药制剂对比在多种溶出介质下的溶出曲线F2均大于50。另外，本品为由多个小微丸组成的胶囊剂，每粒胶囊的释放度值差异不大。本发明的另一目的在于提供该盐酸美金刚缓释胶囊的制备方法。
本发明是通过以下技术方案实现的：
一种盐酸美金刚缓释胶囊，所述的盐酸美金刚缓释胶囊由缓释微丸灌装于胶囊而制得，所述缓释微丸由载药微丸依次包覆隔离层、缓释层制备而成；所述载药微丸由蔗糖微丸丸芯、盐酸美金刚、粘合剂以及抗粘剂组成；所述隔离层由成膜材料与抗粘剂组成；所述缓释层由缓释材料、增塑剂以及抗粘剂组成。
本发明的进一步改进方案为：
所述蔗糖微丸丸芯粒径为0.6-0.71mm。
进一步的，所述缓释微丸在进行灌装之前需加入消静电剂混合后，再灌装于胶囊；所述消静电剂的加入量为所述缓释微丸重量的0.3％；所述消静电剂为滑石粉。
进一步的，所述缓释微丸由以下质量份的原料组成：盐酸美金刚28份、蔗糖微丸丸芯100～120份、粘合剂10～30份、抗粘剂10～30份、成膜材料6～12份、缓释材料10～20份、增塑剂1～2份。
进一步的，所述粘合剂为聚乙烯吡咯烷酮、羟丙基纤维素或聚维酮；所述抗粘剂为滑石 粉、胶态二氧化硅、硬脂酸镁或硅酸镁；所述成膜材料为羟丙甲纤维素、羟丙基纤维素或聚乙烯吡咯烷酮；所述缓释材料为乙基纤维素、丙烯酸树脂或醋酸纤维素；所述增塑剂为聚乙二醇6000、柠檬酸三乙酯或邻苯二甲酸丁苄酯。
进一步的，所述粘合剂为聚维酮K30；所述抗粘剂为滑石粉；所述成膜材料为羟丙甲纤维素；所述缓释材料为乙基纤维素；所述增塑剂为聚乙二醇6000。
本发明的更进一步改进方案为：
如上述的一种盐酸美金刚缓释胶囊的制备方法，包括以下步骤：
按以下重量份配比，称取各原料备用：盐酸美金刚28份、蔗糖微丸丸芯100～120份、粘合剂10～30份、抗粘剂10～30份、成膜材料6～12份、缓释材料10～20份、增塑剂1～2份；
以蔗糖微丸丸芯为空白丸芯，采用流化床底喷进行上药，依次进行载药层包覆、隔离层包覆以及缓释层包覆，来生产缓释微丸，再向缓释微丸中加入消静电剂，进行混合，而后灌装胶囊，得到盐酸美金刚缓释胶囊。
本发明的再进一步改进方案为：
所述载药层的包覆过程中，依次将盐酸美金刚原料药、粘合剂以及1/3的抗粘剂溶解于乙醇水溶液中，配制载药层底喷药液，所述乙醇水溶液的质量浓度为30％～50％，在流化床底喷进行上药包覆载药层时，流化床进风温度为33～43℃，稳态物料温度为24～36℃，蠕动泵转速为10～17g/min，雾化压力为0.8～1.5bar，风量为80～120m 3/h。
所述隔离层包覆过程中，依次将成膜材料与1/3的抗粘剂溶于纯化水中，配制隔离层底喷药液，在流化床底喷进行上药包覆隔离层时，流化床进风温度为55～65℃，稳态物料温度为35～50℃，蠕动泵转速为11～14g/min，雾化压力为2.0bar，风量为80～120m 3/h；所述隔离层增重3％～7％。
所述缓释层包覆过程中，依次将缓释材料、增塑剂以及剩下的抗粘剂溶于乙醇水溶液中，配制缓释层底喷药液，所述乙醇水溶液质量浓度为70％～90％，在流化床底喷进行上药包覆缓释层时，流化床进风温度为35～40℃，稳态物料温度为28～30℃，蠕动泵转速为12～22g/min，雾化压力为1～2.0bar，风量为80～120m 3/h；所述缓释层增重7％～8％。
本发明的有益效果为：
盐酸美金刚在水中的溶解度为0.05g/ml，其在乙醇中溶解度要明显高于水中溶解度，采用醇水溶液上药能显著缩短载药工艺时间，以50％乙醇水为例，1000粒批次处方，载药时间只需原来的40％。
隔离层成膜材料需要在载药微丸表面均匀铺展，形成连续致密的衣膜，从而起到隔离、保护载药丸的作用；由于盐酸美金刚在乙醇中的溶解度远大于水，而缓释层采用的是乙醇溶 液包衣，在包衣过程中，药物可能迁移至包衣层中，从而影响药物最终的释放，因此需要在载药层外面包一层隔离层；本发明采用羟丙甲纤维素(HPMC)作为隔离层成膜材料，并加入抗粘剂滑石粉，处方构成简单。
本发明的缓释层采用乙基纤维素70％～90％醇水溶液包衣，在包衣过程中随着溶剂的蒸发，聚合物浓度增大，原来在溶液中伸展的聚合物分子链卷曲并相互缠绕，随着残留溶剂的进一步蒸发，形成连续的包衣薄膜，该处方工艺不需要进行包衣结束后的热处理过程。
本发明在配方以及工艺不同的情况下，其与原研药制剂盐酸美金刚缓释胶囊在药效上能够保持高度的一致性，与原研药制剂对比在多种溶出介质下的溶出曲线F2均大于50。另外，本品为由多个小微丸组成的胶囊剂，每粒胶囊的释放度值差异不大。
附图说明
图1为实施例1制得的盐酸美金刚缓释胶囊在pH1.2盐酸、pH4.5醋酸盐缓冲液以及pH6.8磷酸盐缓冲液中的溶出曲线；
图2为实施例1～3制得的盐酸美金刚缓释胶囊与原研药在pH1.2盐酸溶液(加氯化钠)介质中的溶出曲线。
具体实施方式
实施例1-3
按下表配制各原辅料：
表1盐酸美金刚缓释胶囊处方(10万粒)
Figure PCTCN2020087372-appb-000001
按以下步骤制备盐酸美金刚缓释胶囊：
以蔗糖微丸丸芯为空白丸芯，采用流化床底喷进行上药，依次进行载药层包覆、隔离层包覆以及缓释层包覆，来生产缓释微丸，再向缓释微丸中加入消静电剂，进行混合，而后灌装胶囊，得到盐酸美金刚缓释胶囊。
载药层的包覆过程：依次将盐酸美金刚原料药、聚维酮(K30)以及滑石粉溶解于乙醇水溶液中，配制载药层底喷药液，所述乙醇水溶液的质量浓度为30％～50％，在流化床底喷进行上药包覆载药层时，流化床进风温度为33～43℃，稳态物料温度为24～36℃，蠕动泵转速为10～17g/min，雾化压力为0.8～1.5bar，风量为80～120m 3/h。
隔离层的包覆过程：依次将羟丙甲纤维素(E5)与滑石粉溶于纯化水中，配制隔离层底喷药液，在流化床底喷进行上药包覆隔离层时，流化床进风温度为55～65℃，稳态物料温度为35～50℃，蠕动泵转速为11～14g/min，雾化压力为2.0bar，风量为80～120m 3/h；所述隔离层增重3％～7％。
缓释层的包覆过程：依次将乙基纤维素(10cps)、聚乙二醇(6000)以及滑石粉溶于乙醇水溶液中，配制缓释层底喷药液，所述乙醇水溶液质量浓度为70％～90％，在流化床底喷进行上药包覆缓释层时，流化床进风温度为35～40℃，稳态物料温度为28～30℃，蠕动泵转速为12～22g/min，雾化压力为1～2.0bar，风量为80～120m 3/h；所述缓释层增重7％～8％。
试验例1
将实施例1～3制得的盐酸美金刚缓释胶囊与原研比较，结果见表2：
表2检验结果
Figure PCTCN2020087372-appb-000002
由上表可知，三批的关键质量指标与原研比较，均无明显差异。
试验例2
取实施例1制得的盐酸美金刚缓释胶囊，考察其在pH1.2盐酸、pH4.5醋酸盐缓冲液以及pH6.8磷酸盐缓冲液中释放速率，结果见图1和表3。
表3不同pH值介质中释放度比较
Figure PCTCN2020087372-appb-000003
试验例3
在区分能力较好的pH1.2盐酸溶液(加氯化钠)介质中，比较实施例1～3制得的盐酸美金刚缓释胶囊与原研药(BE研究用)的溶出曲线，试验结果采用FDA推荐的8个点计算的f2值以及质量标准对应的1h，4h，8h，12h四个点计算的f2值基本一致，均大于50。另外，本品为由多个小微丸组成的胶囊剂，每粒胶囊的释放度值差异不大，因此12粒胶囊的释放度RSD都很小，测定结果见图2及表4。
表4 pH1.2盐酸溶液+NaCl介质中的溶出曲线(n＝12)
Figure PCTCN2020087372-appb-000004

Claims (10)

  1. 一种盐酸美金刚缓释胶囊，其特征在于，所述的盐酸美金刚缓释胶囊由缓释微丸灌装于胶囊而制得，所述缓释微丸由载药微丸依次包覆隔离层、缓释层制备而成；所述载药微丸由蔗糖微丸丸芯、盐酸美金刚、粘合剂以及抗粘剂组成；所述隔离层由成膜材料与抗粘剂组成；所述缓释层由缓释材料、增塑剂以及抗粘剂组成。
  2. 根据权利要求1所述的一种盐酸美金刚缓释胶囊，其特征在于：所述蔗糖微丸丸芯粒径为0.6-0.71mm。
  3. 根据权利要求1所述的一种盐酸美金刚缓释胶囊，其特征在于：所述缓释微丸在进行灌装之前需加入消静电剂混合后，再灌装于胶囊；所述消静电剂的加入量为所述缓释微丸重量的0.3％；所述消静电剂为滑石粉。
  4. 根据权利要求1所述的一种盐酸美金刚缓释胶囊，其特征在于：所述缓释微丸由以下质量份的原料组成：盐酸美金刚28份、蔗糖微丸丸芯100～120份、粘合剂10～30份、抗粘剂10～30份、成膜材料6～12份、缓释材料10～20份、增塑剂1～2份。
  5. 根据权利要求1或2任意一项所述的一种盐酸美金刚缓释胶囊，其特征在于：所述粘合剂为聚乙烯吡咯烷酮、羟丙基纤维素或聚维酮；所述抗粘剂为滑石粉、胶态二氧化硅、硬脂酸镁或硅酸镁；所述成膜材料为羟丙甲纤维素、羟丙基纤维素或聚乙烯吡咯烷酮；所述缓释材料为乙基纤维素、丙烯酸树脂或醋酸纤维素；所述增塑剂为聚乙二醇6000、柠檬酸三乙酯或邻苯二甲酸丁苄酯。
  6. 根据权利要求5所述的一种盐酸美金刚缓释胶囊，其特征在于：所述粘合剂为聚维酮K30；所述抗粘剂为滑石粉；所述成膜材料为羟丙甲纤维素；所述缓释材料为乙基纤维素；所述增塑剂为聚乙二醇6000。
  7. 如权利要求1所述的一种盐酸美金刚缓释胶囊的制备方法，其特征在于，包括以下步骤：
    按以下重量份配比，称取各原料备用：盐酸美金刚28份、蔗糖微丸丸芯100～120份、粘合剂10～30份、抗粘剂10～30份、成膜材料6～12份、缓释材料10～20份、增塑剂1～2份；
    以蔗糖微丸丸芯为空白丸芯，采用流化床底喷进行上药，依次进行载药层包覆、隔离层包覆以及缓释层包覆，来生产缓释微丸，再向缓释微丸中加入消静电剂，进行混合，而后灌装胶囊，得到盐酸美金刚缓释胶囊。
  8. 根据权利要求7所述的一种盐酸美金刚缓释胶囊的制备方法，其特征在于：所述载药层的包覆过程中，依次将盐酸美金刚原料药、粘合剂以及1/3的抗粘剂溶解于乙醇水溶液中，配制载药层底喷药液，所述乙醇水溶液的质量浓度为30％～50％，在流化床底喷进行上药包覆载药层时，流化床进风温度为33～43℃，稳态物料温度为24～36℃，蠕动泵转速为10～ 17g/min，雾化压力为0.8～1.5bar，风量为80～120m 3/h。
  9. 根据权利要求7所述的一种盐酸美金刚缓释胶囊的制备方法，其特征在于：所述隔离层包覆过程中，依次将成膜材料与1/3的抗粘剂溶于纯化水中，配制隔离层底喷药液，在流化床底喷进行上药包覆隔离层时，流化床进风温度为55～65℃，稳态物料温度为35～50℃，蠕动泵转速为11～14g/min，雾化压力为2.0bar，风量为80～120m 3/h；所述隔离层增重3％～7％。
  10. 根据权利要求7所述的一种盐酸美金刚缓释胶囊的制备方法，其特征在于：所述缓释层包覆过程中，依次将缓释材料、增塑剂以及剩下的抗粘剂溶于乙醇水溶液中，配制缓释层底喷药液，所述乙醇水溶液质量浓度为70％～90％，在流化床底喷进行上药包覆缓释层时，流化床进风温度为35～40℃，稳态物料温度为28～30℃，蠕动泵转速为12～22g/min，雾化压力为1～2.0bar，风量为80～120m 3/h；所述缓释层增重3％～7％。
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