WO2022218356A1 - 一种布瑞哌唑口溶膜组合物、其制备方法及应用 - Google Patents
一种布瑞哌唑口溶膜组合物、其制备方法及应用 Download PDFInfo
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- WO2022218356A1 WO2022218356A1 PCT/CN2022/086678 CN2022086678W WO2022218356A1 WO 2022218356 A1 WO2022218356 A1 WO 2022218356A1 CN 2022086678 W CN2022086678 W CN 2022086678W WO 2022218356 A1 WO2022218356 A1 WO 2022218356A1
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- bripiprazole
- film composition
- mouth
- dissolving film
- acid
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Classifications
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
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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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
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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
- 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
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the invention relates to a bripiprazole mouth-dissolving film composition, 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.
- Bripiprazole regular tablets must now disintegrate in the stomach to begin releasing the drug, which is slow to act, limiting bioavailability. It is also inconvenient to take.
- the indication population is poor in cooperating with treatment, and is prone to refusal of treatment, Vietnamese medicine, and vomiting.
- 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.
- this technology is relatively cumbersome, requires special equipment for production, and has high product cost, and the prepared preparation is relatively easy to break, which is not suitable for transportation, and increases the difficulty of packaging and transportation.
- it should not be soaked in water when taking it, which increases the requirements for patients and is not conducive to the compliance of patients with schizophrenia.
- 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. And provide a bripiprazole mouth dissolving film composition, its preparation method and application.
- the bripiprazole mouth-dissolving film composition of the present invention has the advantages of thin thickness, good taste, stable properties, instant dissolving in the oral cavity without drinking water, fast oral absorption speed, simple process, high drug loading,
- the uniformity of the drug content is good, which solves the problem of poor medication compliance, Vietnamese medicine and vomiting of schizophrenia patients, and is especially suitable for patients with dysphagia.
- the present invention provides a bripiprazole oral dissolving film composition, which is characterized by comprising one or more of active drugs, film-forming materials, plasticizers, sweeteners and organic acids, and the active drugs are: 7-[4-(4-Benzo[B]thiophen-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone as shown in formula I and/or pharmaceutically acceptable
- active drugs are: 7-[4-(4-Benzo[B]thiophen-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone as shown in formula I and/or pharmaceutically acceptable
- the accepted salt, the pH value of the bripiprazole mouth-dissolving film composition is 2.5-4.5;
- the pH value of the bripiprazole oral dissolving film composition may be 3.1, 3.5, 2.8, or 4.4.
- the organic acid is selected from one or more of lactic acid, phosphoric acid, glycolic acid, malic acid, tartaric acid, citric acid, succinic acid and acetic acid.
- the mass percentage of the active drug is preferably 1% to 30%, such as 11.8%, and the mass percentage means that the mass of the active drug accounts for the total mass of the bripiprazole oral dissolving film composition. percentage.
- the film-forming material is a drug carrier, selected from gelatin, shellac, gum arabic, starch, dextrin, cyclodextrin, sugar, cholesterol, agar, sodium alginate, zein, hypromelline
- a drug carrier selected from gelatin, shellac, gum arabic, starch, dextrin, cyclodextrin, sugar, cholesterol, agar, sodium alginate, zein, hypromelline
- cellulose hydroxypropyl cellulose, 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, 64.1%, and the mass percentage refers to the mass percentage of the film-forming material in the bripiprazole mouth-dissolving film composition. percentage of total mass.
- the plasticizer is 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, poly One or more of propylene glycol and hexylene glycol.
- the mass percentage content of the plasticizer is preferably 5% to 30%, for example, 24.1%, and the mass percentage content means that the mass of the film-forming material accounts for the bripiprazole mouth-dissolving film composition. percentage of total mass.
- 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 mass percentage of the sweetener in the bripiprazole mouth-dissolving film composition. percentage of total mass.
- the bripiprazole mouth-dissolving film composition 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 that can be added to the material to improve the performance of the material, or to increase the volume and weight, and reduce the cost of the material.
- 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 mouth-dissolving film composition of the present invention can be the following formula: 11.8% bripiprazole, 17.0% hypromellose, 47.1% polyvinyl alcohol, 23.5% glycerin, 0.59% dimethicone , 0.1% sucralose and organic acid; the pH of the bripiprazole mouth dissolving film composition is 3.1, 3.5, 2.8 or 4.4.
- the present invention also provides the preparation method of the described bripiprazole mouth-dissolving film composition, which comprises the following steps:
- step 2) adding an organic acid to the mixture obtained in step 1), and adjusting the pH to 2.5-4.5 to obtain an acidic solution;
- step 3 adding active drug to the acid solution obtained in step 2), stirring and dissolving to obtain a solution;
- step 5 placing the solution obtained in step 3) in the blank glue solution obtained in step 4), stirring until the dispersion is uniform, and stirring and defoaming under vacuum conditions to obtain a drug-containing glue;
- step 5 After defoaming, the drug-containing glue solution obtained in step 5) is evenly coated on a polyester tape with a doctor blade, heated, dried and cut to obtain a bripiprazole mouth-dissolving film composition.
- the present invention also provides the application of the bripiprazole oral dissolving film composition in preparing a medicine for treating central nervous system diseases.
- 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 dissolving composition to a patient in need.
- the reagents and raw materials used in the present invention are all commercially available.
- the bripiprazole oral dissolving film composition obtained by the invention has a good dissolution rate, does not have a gritty feeling after dissolving in the oral cavity, has a uniform appearance, has good flexibility, and does not settle during the preparation process of the film liquid. Content uniformity meets the requirements.
- the prescription is as follows
- Embodiment 1 ⁇ 4 preparation method
- step 2 Add active drug to the acid solution obtained in step 2), stir and dissolve to obtain a solution;
- step 3 The solution obtained in step 3) is placed in the blank glue solution obtained in step 4), stirred until the dispersion is uniform, and stirred and defoamed under vacuum conditions to obtain a drug-containing glue;
- the drug-containing glue solution obtained in step 5) after defoaming is evenly coated on a polyester tape with a doctor blade, and then cut into a certain size after heating and drying to obtain a bripiprazole mouth-dissolving film composition.
- Embodiment 5 preparation method is a first step:
- step 1) Adding bripiprazole to the blank glue solution obtained in step 1), stirring until dispersed uniformly, stirring and defoaming under vacuum conditions, to obtain a drug-containing glue solution;
- the drug-containing glue solution obtained in step 2) is evenly coated on a polyester tape with a scraper after defoaming, and then cut into a certain size after heating and drying to obtain a bripiprazole mouth-dissolving film composition.
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- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pain & Pain Management (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Nutrition Science (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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- Cosmetics (AREA)
Abstract
提供了一种布瑞哌唑口溶膜组合物、其制备方法及应用。所述口溶膜组合物包含活性药物、成膜材料、增塑剂、甜味剂和有机酸中的一种或多种，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，所述口溶膜组合物的pH值为2.5-4.5。所述口溶膜组合物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CN202110395940.5，名称为“一种布瑞哌唑口溶膜组合物、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溶膜组合物、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溶膜组合物、其制备方法及应用。本发明的布瑞哌唑口溶膜组合物，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。
本发明提供一种布瑞哌唑口溶膜组合物，其特征在于包含活性药物、成膜材料、增塑剂、甜味剂和有机酸中的一种或多种，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，所述的布瑞哌唑口溶膜组合物的pH值为2.5-4.5；
本发明中，所述的布瑞哌唑口溶膜组合物的pH值可以为3.1、3.5、2.8、或4.4。所述的有机酸选自乳酸、磷酸、羟乙酸、苹果酸、酒石酸、柠檬酸、丁二酸和乙酸中的一种或多种。
本发明中，所述的活性药物的质量百分含量优选1％～30％，例如11.8％，所述的质量百分含量是指活性药物的质量占布瑞哌唑口溶膜组合物总质量的百分比。
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、环糊精、糖、胆固醇、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64.1％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口溶膜组合物总质量的百分比。
本发明中，所述的增塑剂是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24.1％，所述的质量百分含量是指成膜材料的质量占布瑞哌唑口溶膜组合物总质量的百分比。
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溶膜组合物总质量的百分比。
本发明所述的布瑞哌唑口溶膜组合物，优选进一步包括崩解剂，或者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溶膜组合物，可以为以下配方：11.8％布瑞哌唑、17.0％羟丙甲纤维素、47.1％聚乙烯醇、23.5％甘油、0.59％二甲硅油、0.1％三氯蔗糖和有机酸；所述的布瑞哌唑口溶膜组合物的pH为3.1、3.5、2.8或4.4。
本发明还提供了所述的布瑞哌唑口溶膜组合物的制备方法，其包括以下步骤：
1)将除活性药物、成膜材料和有机酸外的各组分溶于水中，形成混合物；
2)向步骤1)得到的混合物中加入有机酸，调节pH值至2.5-4.5，得到酸性溶液；
3)向步骤2)得到的酸性溶液中加入活性药物，搅拌溶解，得到溶液；
4)将增塑剂溶于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；
5)将步骤3)得到的溶液置于步骤4)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；
6)将步骤5)得到的含药胶液脱泡后用刮刀均匀涂布于聚酯带上，加热、干燥、切割，得布瑞哌唑口溶膜组合物。
本发明还提供了所述的布瑞哌唑口溶膜组合物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溶膜组合物。
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。
本发明的有益效果：
本发明得到的布瑞哌唑口溶膜组合物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
实施例1～4制备方法：
将除活性药物、成膜材料和有机酸外的各组分在搅拌下溶于水中，形成混合物；
向步骤1)得到的混合物中加入有机酸，调节其pH值至2.5-4.5，得到酸性溶液；
向步骤2)得到的酸性溶液中加入活性药物，搅拌溶解，得到溶液；
将增塑剂溶于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；
将步骤3)得到溶液置于步骤4)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；
将脱泡后的步骤5)得到的含药胶液用刮刀均匀涂布于聚酯带上，加热干燥后切割成一定尺寸，得布瑞哌唑口溶膜组合物。
实施例5制备方法：
将除布瑞哌唑和成膜材料外的各组分在搅拌下溶化或分散于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；
向步骤1)得到的空白胶液中加入布瑞哌唑，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶液；
将步骤2)得到的含药胶液脱泡后用刮刀均匀涂布于聚酯带上，加热干燥后切割成一定尺寸，得布瑞哌唑口溶膜组合物。
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)
- 一种布瑞哌唑口溶膜组合物，其特征在于包含活性药物、成膜材料、增塑剂、甜味剂和有机酸中的一种或多种，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，所述的布瑞哌唑口溶膜组合物的pH值为2.5-4.5；
- 如权利要求1所述的布瑞哌唑口溶膜组合物，其特征在于：所述的布瑞哌唑口溶膜组合物的pH值为3.1、3.5、2.8、或4.4。
- 如权利要求1或2所述的布瑞哌唑口溶膜组合物，其特征在于：所述的有机酸选自乳酸、磷酸、羟乙酸、苹果酸、酒石酸、柠檬酸、丁二酸和乙酸中的一种或多种。
- 如权利要求1-3任一项所述的布瑞哌唑口溶膜组合物，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溶膜组合物总质量的百分比。
- 如权利要求1-4任一项所述的布瑞哌唑口溶膜组合物，其特征在于：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溶膜组合物总质量的百分比。
- 如权利要求1-5任一项所述的布瑞哌唑口溶膜组合物，其特征在于：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成膜材料的质量占布瑞哌唑口溶膜组合物总质量的百分比；和/或，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溶膜组合物总质量的百分比。优选地，所述的布瑞哌唑口溶膜组合物，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1-6任一项所述的布瑞哌唑口溶膜组合物，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1-7任一项所述的布瑞哌唑口溶膜组合物，其特征在于：所述的布瑞哌唑口溶膜组合物，为以下配方：11.8％布瑞哌唑、17.0％羟丙甲纤维素、47.1％聚乙烯醇、23.5％甘油、0.59％二甲硅油、0.1％三氯蔗糖和有机酸；所 述的布瑞哌唑口溶膜组合物的pH为3.1、3.5、2.8或4.4。
- 如权利要求1～8任一项所述的布瑞哌唑口溶膜组合物的制备方法，其特征在于包括以下步骤：1)将除活性药物、成膜材料和有机酸外的各组分溶于水中，形成混合物；2)向步骤1)得到的混合物中加入有机酸，调节pH值至2.5-4.5，得到酸性溶液；3)向步骤2)得到的酸性溶液中加入活性药物，搅拌溶解，得到溶液；4)将增塑剂溶于水中，搅拌均匀后加入成膜材料，60℃～70℃加热搅拌，溶化后得空白胶液；5)将步骤3)得到的溶液置于步骤4)得到的空白胶液中，搅拌至分散均匀，在真空条件下搅拌脱泡，得含药胶；6)将步骤5)得到的含药胶液脱泡后用刮刀均匀涂布于聚酯带上，加热、干燥、切割，得布瑞哌唑口溶膜组合物。
- 如权利要求1～8任一项所述的布瑞哌唑口溶膜组合物在制备治疗中枢神经系统疾病的药物中的应用；优选地，所述的中枢神经系统疾病为重度抑郁症或精神分裂症。
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| CN105395528A (zh) * | 2015-12-25 | 2016-03-16 | 北京康立生医药技术开发有限公司 | 依匹哌唑口腔速溶膜 |
| CN109890365A (zh) * | 2016-09-23 | 2019-06-14 | 戴尔普尔有限公司 | 小分子治疗剂化合物的组合物 |
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| CN105395528A (zh) * | 2015-12-25 | 2016-03-16 | 北京康立生医药技术开发有限公司 | 依匹哌唑口腔速溶膜 |
| CN109890365A (zh) * | 2016-09-23 | 2019-06-14 | 戴尔普尔有限公司 | 小分子治疗剂化合物的组合物 |
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