WO2019205030A1 - 盐酸金刚烷胺软胶囊及其制备方法 - Google Patents

盐酸金刚烷胺软胶囊及其制备方法 Download PDF

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WO2019205030A1
WO2019205030A1 PCT/CN2018/084491 CN2018084491W WO2019205030A1 WO 2019205030 A1 WO2019205030 A1 WO 2019205030A1 CN 2018084491 W CN2018084491 W CN 2018084491W WO 2019205030 A1 WO2019205030 A1 WO 2019205030A1
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soft capsule
amantadine hydrochloride
mass ratio
mixture
contents
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PCT/CN2018/084491
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English (en)
French (fr)
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叶翔
刘波
沈福星
丁超
常丹
李琳
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人福普克药业（武汉）有限公司
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Priority to PCT/CN2018/084491 priority Critical patent/WO2019205030A1/zh
Publication of WO2019205030A1 publication Critical patent/WO2019205030A1/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
    • A61K31/13—Amines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses

Definitions

  • the invention belongs to the field of medicine, and in particular, the invention relates to a amantadine hydrochloride soft capsule and a preparation method thereof.
  • Amantadine Hydrochloride chemical name: 1-adamantanamine hydrochloride, molecular formula: C 10 H 18 ClN; molecular weight: 187.711; chemical structural formula is as follows:
  • Amantadine hydrochloride is a white to off-white crystalline powder; melting point: 359-360 ° C, soluble in water, ethanol and methanol, soluble in chloroform, slightly soluble in dichloromethane, almost insoluble in ether. Amantadine hydrochloride does not have any chiral centers, is not optically active, and is stable in light, heat and air.
  • Amantadine hydrochloride can be used to treat respiratory palsy patients, drug-induced extrapyramidal reactions, carbon monoxide poisoning and Parkinson's syndrome, and respiratory infections caused by Asian influenza A-II viruses, which can inhibit viral penetration into host cells, treatment and prevention. Viral infection. According to the nature of amantadine hydrochloride, most of them are currently made into tablets and granules on the market, and capsules are produced in a small number.
  • amantadine hydrochloride hard capsule developed by Sandoz Pharmaceutical Co., Ltd. (referred to as the original research drug, the same below), was designated by the FDA as a reference standard with a specification of 100 mg.
  • the preparation process of the hard capsule and the soft capsule is completely different.
  • the hard capsule is filled with the solid medicine in the hard capsule shell, and the soft capsule is closed in the soft capsule shell by the liquid or the suspension, and the bioequivalence is consistent.
  • Amantadine hydrochloride soft capsules can increase the dosage form of amantadine hydrochloride.
  • the invention aims to solve the technical problems in the prior art to some extent, develop a liquid filling formula and a soft capsule shell formula, and propose a soft capsule of amantadine hydrochloride in which the amantadine hydrochloride is in the content mixture. Disperse evenly and have good stability.
  • the amantadine hydrochloride soft capsule comprises: a mixture of contents and a soft capsule shell, wherein the content mixture is a suspension comprising amantadine hydrochloride, soybean oil, lecithin, white beeswax Mixture and methyl silicone oil.
  • the mass ratio of soybean oil in the content of amantadine hydrochloride soft capsule is 51.60-52.60%
  • the mass ratio of lecithin is 1.00%-1.10%
  • the mass ratio of white beeswax mixture is 4.92%-5.32%.
  • the mass ratio of methyl silicone oil is 0.008-0.02%, and the rest is amantadine hydrochloride.
  • the white beeswax mixture comprises white peak wax, hydrogenated vegetable oil type I and hydrogenated vegetable oil type II, and the three mass ratios are 1:0.8-1.2:3.8-4.3, for example 1:1:4.
  • amantadine hydrochloride soft capsule of the present invention may further have the following additional technical features:
  • the soft capsule shell contains gelatin, glycerin, sorbitol and water.
  • the soft capsule shell has a glycerin mass ratio of 5% to 15%, a gelatin mass ratio of 35-50%, and a sorbitol mass ratio of 8-20%.
  • the gelatin is a type B pharmaceutical gelatin having a jelly strength of 150 brumm.
  • the invention also provides a preparation method of the above-mentioned amantadine hydrochloride soft capsule, the method comprising:
  • capsule shell mixing gelatin, glycerin, sorbitol and water in a gel melting tank to 65-75 degrees Celsius, completely dissolving the gel, vacuum degassing, maintaining a temperature of 50 when the viscosity is 8000-25000 Cps -65 degrees Celsius;
  • preparation method of the amantadine hydrochloride soft capsule of the present invention may further have the following additional technical features:
  • the first mixing of the contents in the step (2) is to heat the soybean oil to 65-75 degrees Celsius, heat, stir at 100-120 rpm, add a white beeswax mixture, and mix at 200-300 rpm. Uniformly, cool to 40-45 degrees Celsius, add lecithin and stir at 200-300 rpm for 25-35 min, continue to add methyl silicone oil to maintain stirring for 10-20 min, and finally add amantadine hydrochloride at 200-300 rpm at 200-300 rpm. The mixture was stirred at a speed of 30-60 min to obtain a mixture of contents.
  • the grinding in the step (2) is performed by a colloid mill.
  • the remixing of the contents in the step (2) means stirring at a rotation speed of 200 to 300 rpm for 40 to 80 minutes.
  • the remixing of the contents in the step (2) is carried out at 40 to 45 degrees Celsius.
  • the thickness of the gel strip pressed in the step (3) is from 0.70 to 0.90 mm.
  • the speed of the mold pressed in the step (3) is 2.0-4.0 rpm, and the cooling drum temperature is 14-18 degrees Celsius.
  • the amantadine hydrochloride soft capsule produced by the above formula uses white beeswax as a suspending agent, increases the viscosity of the formulation, maintains the uniformity of the drug in the formulation, and uses lecithin as an emulsifier to make the hydrochloric acid
  • the alkylamine is uniformly dispersed in the mixture of contents, and the stability is increased.
  • the developed soft capsule preparation has a degree of coincidence with the original preparation agent of more than 95%, and achieves the same clinical effect as the original preparation agent, and Preparation method
  • the production process is simple, and there is no problem of leakage or deformation of the capsule.
  • Fig. 1 is a graph showing the dissolution profile of the amantadine hydrochloride soft capsule of Example 5 and the original amantadine hydrochloride hard capsule.
  • compositions, step, method, article or device comprising the listed elements is not necessarily limited to those elements, but may include other elements not specifically listed or inherent to such compositions, steps, methods, articles or devices. Elements.
  • Approximating terms used in the specification and claims are used to modify the quantity, and the invention is not limited to the specific number, and includes a portion that is close to the quantity that is acceptable without causing a change in the relevant basic function.
  • a numerical value is modified by "about”, “about” or the like, meaning that the invention is not limited to the precise value. In some instances, the approximation may correspond to the accuracy of the instrument that measures the value.
  • the scope of the invention may be combined and/or interchanged, and if not stated otherwise, the scope includes all subranges.
  • the present invention provides a amantadine hydrochloride soft capsule.
  • the amantadine hydrochloride soft capsule comprises: a mixture of contents and a soft capsule shell, wherein the content mixture is a suspension Containing amantadine hydrochloride, soybean oil, lecithin, white beeswax, hydrogenated vegetable oil type I, hydrogenated vegetable oil type II and methyl silicone oil.
  • the sedimentation rate of the suspending agent and the emulsifier is a key factor.
  • white beeswax can increase the viscosity of the formulation to maintain the uniformity of the drug in the formulation.
  • Lecithin acts as an emulsifier to uniformly distribute the amantadine hydrochloride in the mixture of contents and increase the stability.
  • the mass ratio of soybean oil in the content of amantadine hydrochloride soft capsule is 51.60-52.60%
  • the mass ratio of lecithin is 1.00%-1.10%
  • the mass ratio of white beeswax mixture is 4.92-5.32. %.
  • the mass ratio of the white peak wax, the hydrogenated vegetable oil type I and the hydrogenated vegetable oil type II in the white peak wax mixture is 1:0.8-1.2:3.8-4.3, for example 1:1:4.
  • the amantadine hydrochloride is uniformly dispersed in the content mixture, and the stability is good.
  • the developed soft capsule preparation has a degree of coincidence with the original preparation agent of 95% or more, which is the same as the original preparation agent. Clinical effects.
  • the mixing of contents is a key step in the preparation process of the soft capsule. Since the formulation contains lecithin or the like, small particles are easily generated during mixing, and it is more difficult to mix the contents of the mixture. According to a specific embodiment of the present invention, a colloid mill is used. Increasing the degree of mixing allows the contents to be more thoroughly mixed. The invention is described below with reference to specific embodiments.
  • the white peak wax in the mixture of white peak wax hydrogenated vegetable oil type I: hydrogenation
  • the vegetable oil type II mass ratio may be 1:0.8-1.2:3.8-4.3.
  • the content mixture is in a state of uniform stirring under different parameters, and the content of the contents in the upper, middle, middle, and lower portions of the contents preparation tank is taken, and whether the mixture is uniformly stirred is examined. .
  • the improper thickness of the gel strip will cause the capsule to be trapped during the pressing process, and under the condition of the cooling drum temperature, the mold speed and the sealing temperature, the sample will be leaked when the thickness of the gel strip is different.
  • the thickness of the gel strip is shown in Table 8.
  • the composition of the contents is: soybean oil mass ratio is 51.60%, lecithin mass ratio is 1.10%, white beeswax mass ratio is 0.82%, hydrogenated vegetable oil type I mass ratio is 0.98%, hydrogenated vegetable oil type II mass ratio is 3.52%, The base silicone oil mass ratio was 0.02%, and the balance was amantadine hydrochloride.
  • the preparation method is as follows:
  • capsule shell glycerin, sorbitol and water are mixed in a gel melting tank and heated to 80 degrees Celsius, and B type gelatin with a freezing force of 150 is added to continue mixing until the temperature of the melting tank reaches 70 degrees Celsius and is maintained for 40-50 minutes.
  • the gel is completely dissolved, degassed under vacuum, and the viscosity is measured. When the viscosity is 8000-25000 Cps, the temperature is maintained at 60 ° C;
  • the soybean oil is heated to 70 degrees Celsius, kept warm, stirred at 100-120 rpm, added with white peak wax, hydrogenated vegetable oil type I and hydrogenated vegetable oil type II, and then uniformly mixed at 200-300 rpm, cooling Add lecithin to 40-45 degrees Celsius and stir at 200-300 rpm for 25-35 minutes. Continue to add methyl silicone oil to maintain stirring for 10-20 minutes. Finally, add amantadine hydrochloride and stir at 40-45 degrees Celsius at 200-300 rpm. -60min, the content mixture is obtained, and the content is repeatedly ground by a colloid mill for 3 times, then stirred at 40-45 degrees Celsius, 200-300 rpm for 40-80 minutes, vacuum degassed for 30 minutes, and the contents are again mixed;
  • the pressing parameters are: gel strip thickness 0.70-0.90 mm, mold speed 2.0-4.0 rpm, cooling drum temperature 14-18 degrees Celsius.
  • the amantadine hydrochloride obtained in the present example is uniformly dispersed in the content mixture, has good stability, and has no problem of leakage or deformation of the capsule during the pressing process, and the soft capsule developed according to the consistency evaluation bioequivalence test.
  • the degree of agreement between the preparation and the original preparation agent is over 95%, which achieves the same clinical effect as the original development agent.
  • the composition of the contents was: the mass ratio of soybean oil was 52.60%, the mass ratio of lecithin was 1.00%, the mass ratio of white beeswax mixture was 0.88%, the mass ratio of hydrogenated vegetable oil type I was 0.70%, and the mass ratio of hydrogenated vegetable oil type II was 3.34%.
  • the mass ratio of methyl silicone oil was 0.008%, and the rest was amantadine hydrochloride.
  • the preparation method is as follows:
  • capsule shell Preparation of capsule shell: mixing glycerin, sorbitol and water in a gel melting tank to 65 degrees Celsius, adding B-type gelatin with a freezing force of 150 and continuing mixing until the melting tank temperature reaches 70 degrees Celsius and maintaining for 40-50 minutes, The gel is completely dissolved, degassed under vacuum, and the viscosity is measured. When the viscosity is 8000-25000 Cps, the temperature is maintained at 55 ° C;
  • soybean oil is heated to 70 degrees Celsius, kept warm, stirred at 100-120 rpm, added with white peak wax, hydrogenated vegetable oil type I and hydrogenated vegetable oil type II, and then uniformly mixed at 200-300 rpm, cooling Add lecithin to 40-45 degrees Celsius and stir at 200-300 rpm for 25-35 minutes. Continue to add methyl silicone oil to maintain stirring for 10-20 minutes. Finally, add amantadine hydrochloride at 30-45 degrees Celsius at 200-300 rpm.
  • the content mixture was obtained, and the contents were repeatedly ground by a colloid mill for 3 times, and then stirred at 40-45 ° C, 200-300 rpm for 40-80 min, vacuum degassed for 30 min, and the contents were again mixed;
  • the pressing parameters are: gel strip thickness 0.70-0.90 mm, mold speed 2.0-4.0 rpm, cooling drum temperature 14-18 degrees Celsius.
  • the amantadine hydrochloride obtained in the present example is uniformly dispersed in the content mixture, has good stability, and has no problem of leakage or deformation of the capsule during the pressing process, and the soft capsule developed according to the consistency evaluation bioequivalence test.
  • the degree of agreement between the preparation and the original preparation agent is over 95%, which achieves the same clinical effect as the original preparation.

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Abstract

一种盐酸金刚烷胺软胶囊及其制备方法，所述盐酸金刚烷胺软胶囊包括：内容物混合液和软胶囊壳，其中，所述内容物混合液是混悬液，包含盐酸金刚烷胺，大豆油，卵磷脂，白蜂蜡混合物和甲基硅油，白蜂蜡混合物包含白峰蜡、氢化植物油I型和氢化植物油II型。由上述配方生产的盐酸金刚烷胺软胶囊使用白蜂蜡作为助悬剂，增加配方的粘度，使药物在配方中保持均匀性，使用卵磷脂作为乳化剂，使盐酸金刚烷胺在内容物混合液中分散均匀，增加稳定性，根据一致性评价生物等效性试验，开发的软胶囊制剂与原研制剂吻合度达到95％以上，达到跟原研制剂一样的临床效果，且制备方法生产过程简单，不会出现胶囊漏液或变形的问题。

Description

盐酸金刚烷胺软胶囊及其制备方法 技术领域
本发明属于医药领域，具体而言，本发明涉及盐酸金刚烷胺软胶囊及其制备方法。
背景技术
盐酸金刚烷胺(Amantadine Hydrochloride)，化学名：1-金刚烷胺盐酸盐，分子式：C 10H 18ClN；分子量：187.711；化学结构式如下：
Figure PCTCN2018084491-appb-000001
盐酸金刚烷胺为白色至类白色结晶性粉末；熔点：359-360℃，易溶于水，乙醇和甲醇，溶于氯仿，微溶于二氯甲烷，几乎不溶于乙醚。盐酸金刚烷胺没有任何手性中心，不具有光学活性，在光、热和空气中稳定。
盐酸金刚烷胺可用于治疗震颤麻痹患者、药物诱发的锥体外系反应、一氧化碳中毒和帕金森综合征及亚洲A－Ⅱ型流感病毒引起的呼吸道感染，可以抑制病毒穿入宿主细胞，治疗和预防病毒性感染。根据盐酸金刚烷胺性质，目前市场上大多将其制成片剂，颗粒剂，制成胶囊剂占少数。
Sandoz制药公司开发的盐酸金刚烷胺硬胶囊(简称原研药，下同)，被FDA指定为参考标准品，规格为100mg。硬胶囊与软胶囊的制备工艺完全不同，硬胶囊是将固体药物填充于硬胶囊壳中，而软胶囊是将液体或者混悬液封闭于软胶囊壳中，开发出达到生物等效性一致的盐酸金刚烷胺软胶囊能够增加盐酸金刚烷胺的剂型种类。
发明内容
本发明旨在一定程度上解决现有技术中的技术问题，开发液体填充配方和软胶囊壳配方，提出一种盐酸金刚烷胺软胶囊，该软胶囊中盐酸金刚烷胺在内容物混合液中分散均匀，稳定性良好。
本发明中，所述盐酸金刚烷胺软胶囊包括：内容物混合液和软胶囊壳，其中，所述内容物混合液是混悬液，包含盐酸金刚烷胺，大豆油，卵磷脂，白蜂蜡混合物和甲基硅油。
优选的，本发明中，所述盐酸金刚烷胺软胶囊内容物中大豆油质量比为51.60-52.60％，卵磷脂质量比为1.00％-1.10％，白蜂蜡混合物质量比为4.92％-5.32％，甲基硅油质量比为0.008-0.02％，其余为盐酸金刚烷胺。
白蜂蜡混合物包含白峰蜡、氢化植物油I型和氢化植物油II型，三者质量比为1：0.8-1.2：3.8-4.3，例如1:1:4。
另外，本发明的盐酸金刚烷胺软胶囊还可以具有如下附加技术特征：
本发明中，所述软胶囊壳中包含明胶、甘油、山梨醇和水。
本发明中，所述软胶囊壳中甘油质量比为5％-15％，明胶质量比为35-50％，山梨醇质量比为8-20％。
本发明中，所述明胶为胶冻强度150勃鲁姆克的B型药用明胶。
本发明还提供了一种上述盐酸金刚烷胺软胶囊的制备方法，该方法包括：
(1)制备胶囊壳：将明胶、甘油、山梨醇和水混合于凝胶熔化罐中加热至65-75摄氏度，使凝胶完全溶解，真空脱气，粘度为8000-25000Cps时，保持温度为50-65摄氏度；
(2)制备内容物，包括内容物的初次混合，研磨初次混合后的内容物，再次混合内容物；
(3)压制成盐酸金刚烷胺软胶囊。
另外，本发明盐酸金刚烷胺软胶囊的制备方法还可以具有如下附加技术特征：
本发明中，所述步骤(2)中内容物的初次混合是将大豆油加热到65-75摄氏度，保温，在100-120rpm转速下搅拌，加入白蜂蜡混合物，再在200-300rpm转速下混合均匀，冷却至40-45摄氏度加入卵磷脂以200-300rpm转速搅拌，维持25-35min，继续加入甲基硅油维持搅拌10-20min，最后加入盐酸金刚烷胺，在40-45摄氏度以200-300rpm转速搅拌30-60min，得到内容物混合液。
本发明中，所述步骤(2)中研磨是采用胶体磨研磨。
本发明中，所述步骤(2)中再次混合内容物是指在200-300rpm转速下搅拌40-80min。
本发明中，所述步骤(2)中再次混合内容物是在40-45摄氏度条件下进行的。
本发明中，所述步骤(3)中压制的凝胶条厚度为0.70-0.90mm。
本发明中，所述步骤(3)中压制的模具转速2.0-4.0rpm，冷却鼓温度14-18摄氏度。
与现有技术相比，由上述配方生产的盐酸金刚烷胺软胶囊使用白蜂蜡作为助悬剂，增加配方的粘度，使药物在配方中保持均匀性，使用卵磷脂作为乳化剂，使盐酸金刚烷胺在内容物混合液中分散均匀，增加稳定性，根据一致性评价生物等效性试验，开发的软胶囊制剂与原研制剂吻合度达到95％以上，达到跟原研制剂一样的临床效果，且制备方法生产过程简单，不会出现胶囊漏液或变形的问题。
附图说明
图1是实施例5的盐酸金刚烷胺软胶囊和原研的盐酸金刚烷胺硬胶囊的溶出曲线图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。应当理解，以下描述仅仅用以解释本发明，并不用于限定本发明。
本文中所用的术语“包含”、“包括”、“具有”、“含有”或其任何其它变形，意在覆盖非排它性的包括。例如，包含所列要素的组合物、步骤、方法、制品或装置不必仅限于那些要素，而是可以包括未明确列出的其它要素或此种组合物、步骤、方法、制品或装置所固有的要素。
连接词“由…组成”排除任何未指出的要素、步骤或组分。如果用于权利要求中，此短语将使权利要求为封闭式，使其不包含除那些描述的材料以外的材料，但与其相关的常规杂质除外。当短语“由…组成”出现在权利要求主体的子句中而不是紧接在主题之后时，其仅限定在该子句中描述的要素；其它要素并不被排除在作为整体的所述权利要求之外。
当量、浓度、或者其它值或参数以范围、优选范围、或一系列上限优选值和下限优选值限定的范围表示时，这应当被理解为具体公开了由任何范围上限或优选值与任何范围下限或优选值的任一配对所形成的所有范围，而不论该范围是否单独公开了。例如，当公开了范围“1至5”时，所描述的范围应被解释为包括范围“1至4”、“1至3”、“1至2”、“1至2和4至5”、“1至3和5”等。当数值范围在本文中被描述时，除非另外说明，否则该范围意图包括其端值和在该范围内的所有整数和分数。
单数形式包括复数讨论对象，除非上下文中另外清楚地指明。“任选的”或者“任意一种”是指其后描述的事项或事件可以发生或不发生，而且该描述包括事件发生的情形和事件不发生的情形。
说明书和权利要求书中的近似用语用来修饰数量，表示本发明并不限定于该具体数量，还包括与该数量接近的可接受的而不会导致相关基本功能的改变的修正的部分。相应的，用“大约”、“约”等修饰一个数值，意为本发明不限于该精确数值。在某些例子中，近似用语可能对应于测量数值的仪器的精度。在本申请说明书和权利要求书中，范围限定可以组合和/或互换，如果没有另外说明这些范围包括其间所含有的所有子范围。
本发明要素或组分前的不定冠词“一种”和“一个”对要素或组分的数量要求(即出现次数)无限制性。因此“一个”或“一种”应被解读为包括一个或至少一个，并且单数形式的要素或组分也包括复数形式，除非所述数量明显只指单数形式。
此外，下面所描述的术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不是必须针对相同的实施例或示例。而且，本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
本发明提供了一种盐酸金刚烷胺软胶囊，根据本发明的实施例，该盐酸金刚烷胺软胶囊包括：内容物混合液和软胶囊壳，其中，所述内容物混合液是混悬液，包含盐酸金刚烷胺，大豆油，卵磷脂，白蜂蜡，氢化植物油I型，氢化植物油II型和甲基硅油。
药物的分散，软胶囊内容物为混悬液时，助悬剂和乳化剂的沉降率考察是关键因素。白蜂蜡作为助悬剂，可以增加配方的粘度，使药物在配方中保持均匀性，卵磷脂作为乳化剂使盐酸金刚烷胺在内容物混合液中分散均匀，增加稳定性。
根据本发明的一个具体实施例，所述盐酸金刚烷胺软胶囊内容物中大豆油质量比为51.60-52.60％，卵磷脂质量比为1.00％-1.10％，白蜂蜡混合物 质量比为4.92-5.32％。
根据本发明的又一个实施例，白峰蜡混合物中白峰蜡、氢化植物油I型和氢化植物油II型的质量比为1：0.8-1.2：3.8-4.3，例如1:1:4。
如此，盐酸金刚烷胺在内容物混合液中分散均匀，稳定性良好，根据一致性评价生物等效性试验，开发的软胶囊制剂与原研制剂吻合度达到95％以上，达到跟原研制剂一样的临床效果。
内容物混合是软胶囊制备工艺的关键步骤，由于配方中含有卵磷脂等，混合时容易产生小颗粒，使内容物混合液混合均匀难度加大，根据本发明的一个具体实施例，采用胶体磨增加其混合度，可使内容物更加充分混合均匀。下面参考具体实施例，对本发明进行描述。
实施例1
含不同白蜂蜡混合物的样品的沉降速率研究：制备含不同比例白蜂蜡，氢化植物油I型，氢化植物油II型的内容物样品溶液，考察样品在0天，2天，4天的沉降速率(V n/V 0)，结果如表1所示。
表1 含不同白蜂蜡混合物的样品沉降速率试验
Figure PCTCN2018084491-appb-000002
制备含不同比例白蜂蜡，氢化植物油I型，氢化植物油II型的内容物样品溶液填充至原研硬胶囊壳中，溶出实验结果见表2。
表2 含不同白蜂蜡混合物的样品溶出试验
Figure PCTCN2018084491-appb-000003
当氢化植物油I型含量越高，沉降率相差不大，但药物粘度越大，分布不均匀。白峰蜡的含量越高，药物越稳定，但过高会导致药物释放迟缓，综合考虑沉降速率(V n/V 0)和药物释放速率结果，白峰蜡混合物中白峰蜡：氢化植物油I型：氢化植物油II型质量比可以为1：0.8-1.2：3.8-4.3。
实施例2
含不同比例白峰蜡混合物和卵磷脂的样品沉降速率研究：制备含不同比例白峰蜡混合物和卵磷脂的内容物样品溶液，考察样品在0天，2天，3天，4天，5天，10天的沉降速率(V n/V 0)，结果如表3所示。
表3 不同内容物样品沉降速率(V n/V 0)考察结果
Figure PCTCN2018084491-appb-000004
Figure PCTCN2018084491-appb-000005
制备含不同比例白峰蜡混合物和卵磷脂的内容物填充至原研硬胶囊壳中，考察药物释放速率，结果如表4所示。
表4 不同内容物样品溶出实验结果
Figure PCTCN2018084491-appb-000006
根据上述沉降速率(V n/V 0)考察结果和溶出实验结果可知，当卵磷脂的含量一定时，白峰蜡混合物的含量越高，药物越稳定，但过高会导致药物释放迟缓，卵磷脂可以加速填充物的分离，药物的释放，白蜂蜡能够防止填充物的沉降，综合考虑沉降速率(V n/V 0)和药物释放速率结果，最终选择卵磷脂质量比为1.00％-1.10％，白蜂蜡混合物质量比为4.92-5.32％。
实施例3
再次混合内容物时，考察内容物混合液在在不同参数下的搅拌均匀状态，取内容物准备罐上中，上边，中间，下中，下边部位样品测定内容物的含量，考察混合物是否搅拌均匀。
在250rpm转速下搅拌60min，考察搅拌温度不同时搅拌均匀状态，结果如表5所示。
表5 搅拌温度的考察
Figure PCTCN2018084491-appb-000007
在温度45摄氏度条件下搅拌60min，考察搅拌速度不同时搅拌均匀状态，结果如表6所示。
表6 搅拌速度的考察
Figure PCTCN2018084491-appb-000008
在温度45摄氏度，转速250rpm条件下搅拌，考察搅拌时间不同时搅拌均匀状态，结果如表7所示。
表7 搅拌时间的考察
Figure PCTCN2018084491-appb-000009
Figure PCTCN2018084491-appb-000010
根据表5-7的考察结果发现搅拌温度过低，内容物不能充分搅拌均匀，盐酸金刚烷胺不能完全溶解在辅料中，温度过高，对设备要求高，能耗大，还会导致活性成分含量偏低，产生杂质，搅拌速度低于200rpm，搅拌时间过短时，内容物混合不均匀，在温度40-45摄氏度，200-300rpm转速下搅拌40-80min时能够达到较好的混合均匀效果。
实施例4
凝胶条的厚薄度不合适会导致胶囊在压制过程中包封引起漏夜，在冷却鼓温度，模具速度，封边温度一致的条件下，考察凝胶条厚度不同时样品是否漏夜，可确定合适的凝胶条厚度，考察结果如表8所示。
表8 凝胶条厚度的考察
Figure PCTCN2018084491-appb-000011
Figure PCTCN2018084491-appb-000012
结果表明，凝胶条厚度在0.70-0.90mm下对胶囊压制没有影响，过薄或过厚都将影响胶囊漏液。
实施例5
内容物组成为：大豆油质量比为51.60％，卵磷脂质量比为1.10％，白蜂蜡质量比为0.82％，氢化植物油I型质量比为0.98％，氢化植物油II型质量比为3.52％，甲基硅油质量比为0.02％，其余为盐酸金刚烷胺。
制备方法如下：
(1)制备胶囊壳：将甘油、山梨醇和水混合于凝胶熔化罐中加热至80摄氏度，加入冻力150的B型明胶继续混合直至熔化罐温度达到70摄氏度并维持40-50分钟，使凝胶完全溶解，真空脱气，测定粘度，粘度为8000-25000Cps时，保持温度为60摄氏度；
(2)制备内容物：将大豆油加热到70摄氏度，保温，在100-120rpm转速下搅拌，加入白峰蜡，氢化植物油I型和氢化植物油II型，再在200-300rpm转速下混合均匀，冷却至40-45摄氏度加入卵磷脂以200-300rpm转速搅拌，维持25-35min，继续加入甲基硅油维持搅拌10-20min，最后加 入盐酸金刚烷胺，在40-45摄氏度以200-300rpm转速搅拌30-60min，得到内容物混合液，采用胶体磨重复研磨内容物3次，再在40-45摄氏度，200-300rpm转速下搅拌40-80min，真空脱气30min，再次混合内容物；
(3)压制成盐酸金刚烷胺软胶囊，压制参数为：凝胶条厚度0.70-0.90mm，模具转速2.0-4.0rpm，冷却鼓温度14-18摄氏度。
由本实施例所得的盐酸金刚烷胺在内容物混合液中分散均匀，稳定性良好，压制过程中未出现胶囊漏液或变形的问题，且根据一致性评价生物等效性试验，开发的软胶囊制剂与原研制剂吻合度达到95％以上，达到了跟原研制剂一样的临床效果。
将按照最终内容物配方重新制备盐酸金刚烷胺软胶囊与原研溶出比较，结果如表9所示。
表9 溶出结果比较
取样时间/min 样品 原研
5 1 61
10 12 92
20 68 97
30 94 98
45 104 99
60 105 100
实施例6
内容物组成为：大豆油质量比为52.60％，卵磷脂质量比为1.00％，白蜂蜡混合物质量比为0.88％，氢化植物油I型质量比为0.70％，氢化植物油II型质量比为3.34％，甲基硅油质量比为0.008％，其余为盐酸金刚烷胺。
制备方法如下：
(1)制备胶囊壳：将甘油、山梨醇和水混合于凝胶熔化罐中加热至65摄氏度，加入冻力150的B型明胶继续混合直至熔化罐温度达到70摄氏度 并维持40-50分钟，使凝胶完全溶解，真空脱气，测定粘度，粘度为8000-25000Cps时，保持温度55摄氏度；
(2)制备内容物：将大豆油加热到70摄氏度，保温，在100-120rpm转速下搅拌，加入白峰蜡，氢化植物油I型和氢化植物油II型，再在200-300rpm转速下混合均匀，冷却至40-45摄氏度加入卵磷脂以200-300rpm转速搅拌，维持25-35min，继续加入甲基硅油维持搅拌10-20min，最后加入盐酸金刚烷胺，在40-45摄氏度以200-300rpm转速30-60min，得到内容物混合液，采用胶体磨重复研磨内容物3次，再在40-45摄氏度，200-300rpm转速下搅拌40-80min，真空脱气30min，再次混合内容物；
(3)压制成盐酸金刚烷胺软胶囊，压制参数为：凝胶条厚度0.70-0.90mm，模具转速2.0-4.0rpm，冷却鼓温度14-18摄氏度。
由本实施例所得的盐酸金刚烷胺在内容物混合液中分散均匀，稳定性良好，压制过程中未出现胶囊漏液或变形的问题，且根据一致性评价生物等效性试验，开发的软胶囊制剂与原研制剂吻合度达到95％以上，达到跟原研制剂一样的临床效果。
本领域的技术人员容易理解，以上所述实施例仅仅是示例性的，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种盐酸金刚烷胺软胶囊，其特征在于，该盐酸金刚烷胺软胶囊包括：内容物混合液和软胶囊壳，其中，所述内容物混合液是混悬液，包含盐酸金刚烷胺，大豆油，卵磷脂，白蜂蜡混合物和甲基硅油。
  2. 根据权利要求1所述的盐酸金刚烷胺软胶囊，其特征在于，所述盐酸金刚烷胺软胶囊内容物中大豆油质量比为51.60-52.60％，卵磷脂质量比为1.00％-1.10％，白蜂蜡混合物质量比为4.92％-5.32％，甲基硅油质量比为0.008-0.02％，其余为盐酸金刚烷胺。
  3. 根据权利要求1所述的盐酸金刚烷胺软胶囊，其特征在于，所述白蜂蜡混合物包含白峰蜡、氢化植物油I型和氢化植物油II型，三者质量比为1：0.8-1.2：3.8-4.3，例如1:1:4。
  4. 根据权利要求1所述的盐酸金刚烷胺软胶囊，其特征在于，所述软胶囊壳中包含明胶、甘油、山梨醇和水。
  5. 根据权利要求4所述的盐酸金刚烷胺软胶囊，其特征在于，所述软胶囊壳中甘油质量比为5％-15％，明胶质量比为35-50％，山梨醇质量比为8-20％。
  6. 根据权利要求5所述的盐酸金刚烷胺软胶囊，其特征在于，所述明胶为胶冻强度150勃鲁姆克的B型药用明胶。
  7. 根据权利要求1-6任一项所述盐酸金刚烷胺软胶囊的制备方法，该方法包括以下步骤：
    (1)制备胶囊壳：将明胶、甘油、山梨醇和水混合于凝胶熔化罐中加热至65-75摄氏度，使凝胶完全溶解，真空脱气，粘度为8000-25000Cps时，保持温度为50-65摄氏度；
    (2)制备内容物，包括内容物的初次混合，研磨初次混合后的内容物，再次混合内容物，优选的，所述研磨是采用胶体磨研磨；
    (3)压制成盐酸金刚烷胺软胶囊。
  8. 根据权利要求7所述盐酸金刚烷胺软胶囊的制备方法，其特征在于，所述步骤(2)中内容物的初次混合是将大豆油加热到65-75摄氏度，保温，在100-120rpm转速下搅拌，加入白蜂蜡混合物，再在200-300rpm转速下混合均匀，冷却至40-45摄氏度加入卵磷脂以200-300rpm转速搅拌，维持25-35min，继续加入甲基硅油维持搅拌10-20min，最后加入盐酸金刚烷胺，在40-45摄氏度以200-300rpm转速搅拌30-60min，得到内容物混合液。
  9. 根据权利要求7所述的盐酸金刚烷胺软胶囊的制备方法，其特征在于，所述步骤(2)中再次混合内容物是指在200-300rpm转速下搅拌40-80min，优选的，再次混合内容物是在40-45摄氏度条件下进行的。
  10. 根据权利要求7所述的盐酸金刚烷胺软胶囊的制备方法，其特征在于，所述步骤(3)中压制的凝胶条厚度为0.70-0.90mm，优选的，压制的模具转速为2.0-4.0rpm，冷却鼓温度为14-18摄氏度。
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CN113559079A (zh) * 2020-04-28 2021-10-29 江苏恒瑞医药股份有限公司 一种软胶囊及其制备方法和用途

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