WO2022218358A1 - 一种布瑞哌唑物口腔薄膜剂、其制备方法及应用 - Google Patents
一种布瑞哌唑物口腔薄膜剂、其制备方法及应用 Download PDFInfo
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- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002288 dopamine 2 receptor stimulating agent Substances 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
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- 230000004048 modification Effects 0.000 description 1
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- 239000002994 raw material Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
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- 238000004062 sedimentation Methods 0.000 description 1
- 239000002400 serotonin 2A antagonist Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
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Classifications
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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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
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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
- A61K31/495—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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/24—Antidepressants
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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
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7007—Drug-containing films, membranes or sheets
Definitions
- the invention relates to a bripiprazole oral film, a preparation method and application thereof.
- Bripiprazole tablets were jointly developed by Japan's Otsuka Pharmaceutical Co., Ltd. and Denmark's Lundbeck Pharmaceutical Co., Ltd. and were approved by the FDA in July 2015.
- the dosage form is tablet, and the specifications are 0.25mg, 0.5mg, 1mg, 2mg, 3mg and 4mg.
- bripiprazole tablets are clinically used for the treatment of major depression and schizophrenia.
- the initial dose is 0.5 mg/day or 1 mg/day, and then increased to the target dose of 2 mg once a day, with a maximum recommended dose of 3 mg/day; for the treatment of schizophrenia, the initial dose It is 1 mg/day, the recommended target dose is 2 mg to 4 mg once daily, and the maximum recommended dose is 4 mg/day.
- Bripiprazole has broad activity at multiple monoamine systems, decreased partial agonist activity at dopamine D2 receptors, and reduced activity at specific 5-HT receptors (eg, 5-HT1A, 5-HT2A, 5-HT7).
- the improved affinity has better efficacy and tolerance, and can reduce adverse reactions such as akathisia, restlessness or insomnia.
- Bripiprazole is a white or off-white crystalline powder, almost insoluble in water, and has a bitter and numb irritating feeling, which can cause a significant irritating feeling in the oral mucosa.
- Patent CN105078910A discloses a preparation method of bripiprazole orally disintegrating tablets, which is prepared into freeze-dried orally disintegrating tablets containing bripiprazole by freeze-drying technology, so that the disintegration speed is accelerated and the dissolution is improved.
- Patent CN105395528A discloses an oral instant film of bripiprazole, but because bripiprazole is almost insoluble in water, it is difficult to disperse in the hydrophilic glue, and the drug is prone to agglomeration in the process of scraping and drying. Thereby affecting the content uniformity of the main drug. At the same time, patients will also experience discomfort after taking it, which affects compliance.
- the technical problem to be solved by the present invention is to overcome the defects of the prior art, such as bripiprazole ordinary tablets must be disintegrated in the stomach before the drug can be released, the onset is slow, the bioavailability is limited, the taking is inconvenient, and the patient's compliance is poor.
- the bripiprazole oral film, its preparation method and application are provided.
- the bripiprazole oral film of the present invention has the advantages of thin thickness, good taste, stable properties, and can be instantly melted in the oral cavity without drinking water, and can be absorbed orally
- the advantages of high speed, simple process, high drug loading, and good drug content uniformity solve the problems of poor medication compliance and Vietnamese medicine and vomiting of schizophrenia patients, especially suitable for patients with dysphagia.
- the invention provides a bripiprazole oral film, which is characterized by comprising the following components: one or more of an active drug, a film-forming material, a plasticizer and a sweetener, and the active drug is 7-[4-(4-Benzo[B]thiophen-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone as shown in formula I and/or pharmaceutically acceptable Accepted salt, active drug particle size D90 ⁇ 30 ⁇ m;
- the particle size D90 of the active drug is preferably less than 20.0 ⁇ m, more preferably less than 10.0 ⁇ m, such as 1.8 ⁇ m, 9.7 ⁇ m, 16.5 ⁇ m or 27.8 ⁇ m.
- the mass percentage of the active drug is preferably 1% to 30%, such as 25%, and the mass percentage refers to the percentage of the active drug to the total mass of the bripiprazole oral film. .
- the film-forming material is a drug carrier, selected from gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hypromellose, hydroxypropyl cellulose , one or more of polyvinyl alcohol, polyoxyethylene, acrylic copolymer, povidone, polylactic acid and silicone rubber.
- the mass percentage of the film-forming material is preferably 30% to 70%, for example, 54.4%, and the mass percentage means that the mass of the film-forming material accounts for the total mass of the bripiprazole oral film. percentage.
- the plasticizer refers to a substance used to reduce the glass transition temperature of the film, increase the plasticity and toughness, and improve the elongation rate, and is selected from polyethylene glycol, glycerin, propylene glycol, silicone oil, dimethicone, One or more of polypropylene glycol and hexylene glycol.
- the mass percentage of the plasticizer is preferably 5% to 30%, for example, 20.5%, and the mass percentage refers to the total mass of the plasticizer in the total mass of the bripiprazole oral film. percentage.
- the sweetener refers to a substance that plays a role in correcting taste in the film, and is selected from aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, spice, saccharin and one or more of sodium saccharin.
- the mass percentage of the sweetener is preferably 0.05% to 0.5%, such as 0.1%, and the mass percentage refers to the total mass of the sweetener in the bripiprazole oral film. percentage.
- the bripiprazole oral film preparation of the present invention preferably further comprises a disintegrating agent, or a combination of a disintegrating agent and one or more of a saliva stimulating agent, a filler and a coloring agent.
- the disintegrant refers to an auxiliary material that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and is selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose One or more of sodium, croscarmellose sodium, starch, microcrystalline cellulose, and pregelatinized starch.
- the saliva stimulating agent refers to a substance that stimulates the production of saliva, and is selected from one or more of citric acid, tartaric acid, malic acid and mannitol.
- the filler refers to a solid substance added to the material that can improve the performance of the material or can increase the volume, increase the weight, and reduce the cost of the material, and is selected from mannitol, sucrose, glucose, maltose, lactose, sorbitol, One or more of xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.
- the colorant refers to a substance that can improve the appearance color of the preparation, can be used to identify the concentration of the preparation, distinguish the application method and reduce the patient's aversion to taking the medicine, and is selected from one of titanium dioxide, pigment and lake. or more.
- the bripiprazole oral film of the present invention can be the following formula: 25.0% bripiprazole, 14.4% hypromellose, 40.0% polyvinyl alcohol, 20.0% glycerin, 0.5% dimethicone, 0.1 % sucralose; the bripiprazole D 90 is 1.8 ⁇ m, 9.7 ⁇ m, 16.5 ⁇ m or 27.8 ⁇ m.
- the present invention also provides the preparation method of the described bripiprazole oral film, which comprises the following steps:
- step 2) mixing the active drug particles obtained in step 1) with a film-forming material and water to obtain a suspension;
- step 2) defoaming the suspension obtained in step 2) to obtain a defoamed suspension
- step 4) Coating the defoamed suspension obtained in step 3) on a substrate, drying, and forming a film to obtain a bripiprazole oral film.
- the grinding described in step 1) can adopt conventional grinding methods in the art, which can be ball milling process, jet pulverization process or colloid milling process.
- the mixing described in step 2) is preferably homogeneous mixing.
- the present invention also provides the application of the bripiprazole oral film preparation in the preparation of a medicine for treating diseases of the central nervous system.
- Said treatment of central nervous system disease can be major depression or schizophrenia.
- the present invention also provides a method for treating diseases of the central nervous system, which comprises administering a therapeutically effective amount of the bripiprazole oral film to a patient in need.
- the reagents and raw materials used in the present invention are all commercially available.
- the positive improvement effect of the present invention is: the bripiprazole oral film preparation of the present invention has a good dissolution rate, does not have a gritty feeling after dissolving in the oral cavity, has a uniform appearance, and has good flexibility. Sedimentation does not occur in the medium, and the content uniformity meets the requirements.
- Embodiment 1-5 prescription is as follows (in the table % is weight percentage)
- step 2) mixing the active drug particles obtained in step 1) with a film-forming material and water to obtain a suspension;
- step 2) defoaming the suspension obtained in step 2) to obtain a defoamed suspension
- step 4) Coat the defoamed suspension obtained in step 3) on the substrate, coat it into a uniform thickness drug film by a doctor blade, and then dry it at 50-80° C. The solvent volatilizes during the drying process , after the film is formed, the film is taken out, cut into a suitable size and shape, and packaged to obtain a bripiprazole oral film.
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Abstract
一种布瑞哌唑口腔薄膜剂、其制备方法及应用，其包含以下组分：活性药物、成膜材料、增塑剂和甜味剂中的一种或多种，所述的活性药物为如式(I)所示的7-[4-(4-苯并[B]噻吩-4-基-1-哌嗪)丁氧基]-2(1H)-喹啉酮和/或其药学上可接受的盐，活性药物粒径D90≤30μm。该布瑞哌唑口腔薄膜剂，具有良好的溶出速率，在口腔中溶解后不会有沙砾感、且外观均一、柔韧性好、同时在膜液配制过程中不会发生沉降，含量均一性符合要求。
Description
本申请要求享有2021年4月13日向中国国家知识产权局提交的申请号为CN202110395930.1，名称为“一种布瑞哌唑口腔薄膜剂、其制备方法及应用”的发明专利申请的优先权。该申请的全文以引用的方式并入本文。
本发明涉及一种布瑞哌唑口腔薄膜剂、其制备方法及应用。
布瑞哌唑片由日本大冢制药株式会社和丹麦灵北制药有限公司共同开发，并于2015年7月在FDA批准上市，剂型为片剂，规格为0.25mg、0.5mg、1mg、2mg、3mg和4mg。
布瑞哌唑片作为5-HT1A受体及多巴胺D2受体激动剂，5-HT2A受体拮抗剂，临床上用于重度抑郁症和精神分裂症的治疗。用于重度抑郁症治疗时，起始剂量为0.5mg/天或1mg/天，然后增至目标剂量2mg，每日一次，最大推荐剂量为3mg/天；用于精神分裂治疗时，起始剂量为1mg/天，推荐目标剂量为2mg至4mg，每日一次，最大推荐剂量为4mg/天。布瑞哌唑在多个单胺系统具有广泛的活性，对多巴胺D2受体的部分激动剂活性下降，且对特定5-HT受体(如5-HT1A、5-HT2A、5-HT7)的亲和力提高，具有更好的疗效和耐受性，可减少患者静坐不能、不安或失眠等不良反应。
布瑞哌唑为白色或类白色结晶粉末，在水中几乎不溶，且自身具有苦麻刺激感，可在口腔粘膜引起显著的刺激感觉。
布瑞哌唑普通片必须现在胃中崩解才能开始释放药物，起效慢，从而限制 生物利用度。服用也不方便，作为精神类疾病的治疗药物，该适应症人群在配合治疗方面较差，易发生拒绝治疗、藏药、吐药等情况。专利CN105078910A公开了一种布瑞哌唑口崩片制备方法，将含有布瑞哌唑采用冻干技术制备成冻干口崩片，使其崩解速度加快，提高溶出。但该技术相对繁琐，生产需要专门设备，产品造价高，且制备的制剂较容易碎裂，不适于运输，增加了包装、运输难度。且服用时不能沾水，提高对患者的要求，不利于精神分裂患者的顺应性。
专利CN105395528A公开了一种布瑞哌唑口腔速溶膜，但由于布瑞哌唑在水中几乎不溶，难以分散在亲水性的胶液中，在刮涂烘干过程中，药物易发生团聚现象，从而影响主药的含量均匀度。同时患者服用后也会有口感不适的现象，影响顺应性。
因此，迫切需要开发服用方便、患者顺应性好、生物利用度高、适合于工业化生产的布瑞哌唑的剂型。
发明内容
本发明所要解决的技术问题是为了克服现有技术中布瑞哌唑普通片必须现在胃中崩解才能开始释放药物、起效慢、从而限制生物利用度、服用不方便、患者顺应性差等缺陷而提供了布瑞哌唑口腔薄膜剂、其制备方法及应用，本发明的布瑞哌唑口腔薄膜剂具有厚度薄、口感良好、性质稳定、且无需饮水即可在口腔内即刻溶化、口服吸收速度快的优点，同时工艺简单、载药量高、药物含量均匀度好，解决了精神分裂症患者服药顺应性差及藏药和吐药现象，特别适宜有吞咽困难的患者。
本发明提供了一种布瑞哌唑口腔薄膜剂，其特征在于包含以下组分：活性药物、成膜材料、增塑剂和甜味剂中的一种或多种，所述的活性药物为如式I所示的7-[4-(4-苯并[B]噻吩-4-基-1-哌嗪)丁氧基]-2(1H)-喹啉酮和/或其药学上可接受的盐，活性药物粒径D90≤30μm；
本发明中，所述的活性药物粒径D90优选小于20.0μm，进一步优选小于10.0μm，例如1.8μm、9.7μm、16.5μm或27.8μm。
本发明中，所述的活性药物的质量百分含量优选1％～30％，例如25％，所述的质量百分含量是指活性药物的质量占布瑞哌唑口腔薄膜剂总质量的百分比。
本发明中，所述的成膜材料为药物的载体，选自明胶、虫胶、阿拉伯胶、淀粉、糊精、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟丙基纤维素、聚乙烯醇、聚氧乙烯、丙烯酸共聚物、聚维酮、聚乳酸和硅橡胶中的一种或多种。
本发明中，所述的成膜材料的质量百分含量优选30％～70％，例如54.4％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口腔薄膜剂总质量的百分比。
本发明中，所述的增塑剂是指用于降低膜的玻璃转化温度，增加塑性和韧性、提高拉伸率的物质，选自聚乙二醇、甘油、丙二醇、硅油、二甲硅油、聚丙二醇和己二醇中的一种或多种。
本发明中，所述的增塑剂的质量百分含量优选5％～30％，例如20.5％，所述的质量百分含量是指增塑剂的质量占布瑞哌唑口腔薄膜剂总质量的百分比。
本发明中，所述的甜味剂是指在膜剂中起矫味作用的物质，选自阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、糖精和糖精钠中的一种或多种。
本发明中，所述的甜味剂的质量百分含量优选0.05％～0.5％，例如0.1％，所述的质量百分含量是指甜味剂的质量占布瑞哌唑口腔薄膜剂总质量的百分比。
本发明所述的布瑞哌唑口腔薄膜剂，优选进一步包括崩解剂，或着崩解剂 与唾液刺激剂、填充剂和着色剂中的一种或多种的组合。
本发明中，所述的崩解剂是指促使药物在胃肠道中迅速崩解成小粒子的辅料，选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、淀粉、微晶纤维素、预胶化淀粉中的一种或多种。
本发明中，所述的唾液刺激剂是指刺激唾液产生的物质，选自柠檬酸、酒石酸、苹果酸和甘露醇一种或多种。
本发明中，所述的填充剂是指加入物料中可以改善物料性能或能增容、增重、降低物料的成本的固体物质，选自甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种。
本发明中，所述的着色剂是指能改善制剂的外观颜色，可用来识别制剂的浓度、区分应用方法和减少病人对服药的厌恶感的物质，选自二氧化钛、色素和色淀中一种或多种。
本发明所述的布瑞哌唑口腔薄膜剂，可以为以下配方：25.0％布瑞哌唑、14.4％羟丙甲纤维素、40.0％聚乙烯醇、20.0％甘油、0.5％二甲硅油、0.1％三氯蔗糖；所述的布瑞哌唑D
90为1.8μm、9.7μm、16.5μm或27.8μm。
本发明还提供了所述的布瑞哌唑口腔薄膜剂的制备方法，其包括以下步骤：
1)将活性药物研磨至D90≤30μm，得到活性药物颗粒；
2)将步骤1)得到的活性药物颗粒与成膜材料和水混合，得到混悬液；
3)将步骤2)得到的混悬液消泡，得到消泡后的混悬液；
4)将步骤3)得到的消泡后的混悬液涂布在基材上，干燥，成膜，得到布瑞哌唑口腔薄膜剂。
步骤1)中所述的研磨可以采用本领域中常规研磨方法，可以为球磨工艺、气流粉碎工艺或胶体磨工艺。
步骤2)中所述的混合优选均质混合。
本发明还提供了所述的布瑞哌唑口腔薄膜剂在制备治疗中枢神经系统疾病 的药物中的应用。所述的治疗中枢神经系统疾病可以为重度抑郁症或精神分裂症。
本发明还提供了一种治疗中枢神经系统疾病的方法，其为需要的患者施用治疗有效量的所述的布瑞哌唑口腔薄膜剂。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的布瑞哌唑口腔薄膜剂，具有良好的溶出速率，在口腔中溶解后不会有沙砾感、且外观均一、柔韧性好、同时在膜液配制过程中不会发生沉降，含量均一性符合要求。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1-5：处方如下所示(表中％为重量百分比)
制备方法：
1)将活性药物研磨至D90≤30μm，得到活性药物颗粒；
2)将步骤1)得到的活性药物颗粒与成膜材料和水混合，得到混悬液；
3)将步骤2)得到的混悬液消泡，得到消泡后的混悬液；
4)将步骤3)得到的消泡后的混悬液涂布在基材上，经刮涂刀涂布成厚度均一的药膜后，于50-80℃下干燥，溶剂在干燥过程中挥发，成膜后，将膜取出，切割成适合的大小和形状，并包装，得到布瑞哌唑口腔薄膜剂。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
- 一种布瑞哌唑口腔薄膜剂，其特征在于包含以下组分：活性药物、成膜材料、增塑剂和甜味剂中的一种或多种，所述的活性药物为如式I所示的7-[4-(4-苯并[B]噻吩-4-基-1-哌嗪)丁氧基]-2(1H)-喹啉酮和/或其药学上可接受的盐，活性药物粒径D90≤30μm；
- 如权利要求1所述的布瑞哌唑口腔薄膜剂，其特征在于：所述的活性药物粒径D90小于20.0μm。
- 如权利要求1或2所述的布瑞哌唑口腔薄膜剂，其特征在于：所述的活性药物粒径D90小于10.0μm。
- 如权利要求1-3任一项所述的布瑞哌唑口腔薄膜剂，其特征在于：所述的活性药物的质量百分含量为1％～30％，所述的质量百分含量是指活性药物的质量占布瑞哌唑口腔薄膜剂总质量的百分比。优选地，所述的成膜材料选自明胶、虫胶、阿拉伯胶、淀粉、糊精、琼脂、海藻酸钠、玉米朊、羟丙甲纤维素、羟丙基纤维素、聚乙烯醇、聚氧乙烯、丙烯酸共聚物、聚维酮、聚乳酸和硅橡胶中的一种或多种；和/或，所述的成膜材料的质量百分含量为30％～70％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口腔薄膜剂总质量的百分比。优选地，所述的增塑剂选自聚乙二醇、甘油、丙二醇、硅油、二甲硅油、聚丙二醇和己二醇中的一种或多种；和/或，所述的增塑剂的质量百分含量为5％～30％，所述的质量百分含量是指增塑剂的质量占布瑞哌唑口腔薄膜剂总质量的百分比。优选地，所述的甜味剂选自阿司帕坦、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、糖精和糖精钠中的一种或多种；和/或，所述的甜味剂的质量百分含量为0.05％～0.5％，所述的质量百分含量是指甜味剂的质量占布瑞哌唑口腔薄膜剂总质量的百分比。
- 如权利要求1-4任一项所述的布瑞哌唑口腔薄膜剂，其特征在于：布瑞哌唑口腔薄膜剂，进一步包括崩解剂，或着崩解剂与唾液刺激剂、填充剂和着色剂中的一种或多种的组合。
- 如权利要求5所述的布瑞哌唑口腔薄膜剂，其特征在于：所述的崩解剂选自低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、交联羧甲基淀粉钠、淀粉、微晶纤维素、预胶化淀粉中的一种或多种；和/或，所述的唾液刺激剂选自柠檬酸、酒石酸、苹果酸和甘露醇一种或多种；和/或，所述的填充剂选自甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种；和/或，所述的着色剂选自二氧化钛、色素和色淀中一种或多种。
- 如权利要求1-6任一项所述的布瑞哌唑口腔薄膜剂，其特征在于：所述的布瑞哌唑口腔薄膜剂，为以下配方：25.0％布瑞哌唑、14.4％羟丙甲纤维素、40.0％聚乙烯醇、20.0％甘油、0.5％二甲硅油、0.1％三氯蔗糖；所述的布瑞哌唑D 90为1.8μm、9.7μm、16.5μm、27.8μm。
- 如权利要求1～7任一项所述的布瑞哌唑口腔薄膜剂的制备方法，其特征在于包括以下步骤：1)将活性药物研磨至D90≤30μm，得到活性药物颗粒；2)将步骤1)得到的活性药物颗粒与成膜材料和水混合，得到混悬液；3)将步骤2)得到的混悬液消泡，得到消泡后的混悬液；4)将步骤3)得到的消泡后的混悬液涂布在基材上，干燥，成膜，得到布瑞哌唑口腔薄膜剂。
- 如权利要求1～7任一项所述的布瑞哌唑口腔薄膜剂在制备治疗中枢神经系统疾病的药物中的应用。
- 如权利要求9所述的应用，其特征在于：所述的治疗中枢神经系统疾病为重度抑郁症或精神分裂症。
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| AR071621A1 (es) * | 2008-05-01 | 2010-06-30 | Wyeth Corp | Formulaciones para barnizado de formas farmaceuticas solidas |
| CN107397730A (zh) * | 2011-10-14 | 2017-11-28 | 大塚制药株式会社 | 含有7‑[4‑(4‑苯并[b]噻吩‑4‑基‑哌嗪‑1‑基)丁氧基]‑1H‑喹啉‑2‑酮或其盐的片剂 |
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