TW202245770A - Brexpiprazole oral film inclusion complex, preparation method and use thereof - Google Patents

Brexpiprazole oral film inclusion complex, preparation method and use thereof Download PDF

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TW202245770A
TW202245770A TW111114134A TW111114134A TW202245770A TW 202245770 A TW202245770 A TW 202245770A TW 111114134 A TW111114134 A TW 111114134A TW 111114134 A TW111114134 A TW 111114134A TW 202245770 A TW202245770 A TW 202245770A
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cyclodextrin
film
inclusion compound
buripiprazole
weight
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TWI835118B (en
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郭楨
王璇
王婷婷
應述歡
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大陸商上海博志研新藥物技術有限公司
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Abstract

The present disclosure discloses a Brexpiprazole oral film inclusion complex, preparation method and use thereof. The brexpipraxole oral film composition includes one or more of following components: an active pharmaceutical, a film-forming material, a plasticizer, a sweetener and an organic acid, the active pharmaceutical by the following formula I is selected from 7- [4- (4- benzos [B] thiophene -4- bases -1- (piperazine) butoxy)] -2(1H)- quinolone and/or its pharmaceutically acceptable salt, and the pH value of the brexpipraxole oral film composition is 2.5-4.5. The Brexpiprazole oral film composition of the present disclosure has a good dissolution rate, a uniform appearance, a good flexibility, a uniformity content meet the requirement, and will not settle during the preparation process of the film liquid, or cause any gritty feeling after dissolving in mouth.

Description

布瑞哌唑口溶膜包合物、其製備方法及用途Orally dissolving film inclusion compound of brepiprazole, its preparation method and use

本發明涉及一種布瑞哌唑口溶膜包合物、其製備方法及用途。The invention relates to an orally dissolving film inclusion compound of breiprazole, its preparation method and application.

布瑞哌唑片由日本大冢製藥株式會社和丹麥靈北製藥有限公司共同開發，並於2015年7月美國食品藥物管理局 (U.S. Food and Drug Administration, FDA)批准上市，劑型為片劑，規格為0.25mg、0.5mg、1mg、2mg、3mg和4mg。Bripiprazole Tablets was jointly developed by Otsuka Pharmaceutical Co., Ltd. of Japan and Lundbeck Pharmaceutical Co., Ltd. of Denmark, and was approved for marketing by the U.S. Food and Drug Administration (FDA) in July 2015. The dosage form is a tablet. The strengths are 0.25mg, 0.5mg, 1mg, 2mg, 3mg and 4mg.

布瑞哌唑片作為5-HT1A受體及多巴胺D2受體促效劑，5-HT2A受體拮抗劑，臨床上用於重度抑鬱症和精神分裂症（又稱思覺失調症）的治療。用於重度抑鬱症治療時，起始劑量為0.5mg/天或1mg/天，然後增至目標劑量2mg，每日一次，最大推薦劑量為3mg/天；用於精神分裂治療時，起始劑量為1mg/天，推薦目標劑量為2mg至4mg，每日一次，最大推薦劑量為4mg/天。布瑞哌唑在多個單胺系統具有廣泛的活性，對多巴胺D2受體的部分促效劑活性下降，且對特定5-HT受體(如5-HT1A、5-HT2A、5-HT7)的親和力提高，具有更好的療效和耐受性，可減少患者靜坐不能、不安或失眠等不良反應。As a 5-HT1A receptor and dopamine D2 receptor agonist and a 5-HT2A receptor antagonist, Bripiprazole Tablets are clinically used for the treatment of severe depression and schizophrenia (also known as schizophrenia). For the treatment of severe depression, the initial dose is 0.5mg/day or 1mg/day, and then increased to the target dose of 2mg, once a day, the maximum recommended dose is 3mg/day; for the treatment of schizophrenia, the initial dose 1mg/day, the recommended target dose is 2mg to 4mg, once a day, the maximum recommended dose is 4mg/day. Bripiprazole has a wide range of activities in multiple monoamine systems, and the activity of some agonists on dopamine D2 receptors is reduced, and it has specific 5-HT receptors (such as 5-HT1A, 5-HT2A, 5-HT7) The improved affinity of the drug has better curative effect and tolerance, and can reduce adverse reactions such as akathisia, restlessness or insomnia in patients.

布瑞哌唑為白色或類白色結晶粉末，在水中幾乎不溶，且自身具有苦麻刺激感，可在口腔黏膜引起顯著的刺激感覺。Bripiprazole is a white or off-white crystalline powder, almost insoluble in water, and has a bitter and tingling sensation, which can cause significant irritation in the oral mucosa.

布瑞哌唑普通片必須現在胃中崩解才能開始釋放藥物，起效慢，從而限制生物利用度。服用也不方便，作為精神類疾病的治療藥物，該適應症人群在配合治療方面較差，易發生拒絕治療、藏藥、吐藥等情况。The regular tablet of brepiprazole must now disintegrate in the stomach to start releasing the drug, and the onset of action is slow, thereby limiting bioavailability. It is also inconvenient to take. As a therapeutic drug for mental diseases, people with this indication are poor in cooperating with treatment, and are prone to refusal of treatment, Tibetan medicine, and vomiting.

專利CN105078910A公開一種布瑞哌唑口崩片製備方法，將含有布瑞哌唑採用凍乾技術製備成凍乾口崩片，使其崩解速度加快，提高溶出。但該技術相對繁瑣，生產需要專門設備，產品造價高，且製備的製劑較容易碎裂，不適於運輸，增加了包裝、運輸難度。且服用時不能沾水，提高對患者的要求，不利於精神分裂患者的順應性。Patent CN105078910A discloses a method for preparing orally disintegrating tablets containing buripiprazole, which is prepared into freeze-dried orally disintegrating tablets containing buripiprazole by using freeze-drying technology, so as to accelerate the disintegration speed and improve dissolution. However, this technology is relatively cumbersome, requires special equipment for production, and the product cost is high, and the prepared preparation is easily broken, which is not suitable for transportation, which increases the difficulty of packaging and transportation. And can not touch water when taking, improve the requirement to the patient, be unfavorable for the compliance of the schizophrenic patient.

專利CN105395528A公開一種布瑞哌唑口腔速溶膜，但由於布瑞哌唑在水中幾乎不溶，難以分散在親水性的膠液中，在刮塗烘乾過程中，藥物易發生團聚現象，從而影響主藥的含量均勻度。同時患者服用後也會有口感不適的現象，影響順應性。Patent CN105395528A discloses a bripiprazole oral instant film, but because bripiprazole is almost insoluble in water, it is difficult to disperse in the hydrophilic glue, and the drug is prone to agglomeration during the scraping and drying process, thus affecting the main body. drug content uniformity. At the same time, patients will also experience discomfort in the mouth after taking it, which will affect compliance.

因此，迫切需要開發服用方便、患者順應性好、生物利用度高、適合於工業化生產的布瑞哌唑的劑型。Therefore, there is an urgent need to develop a dosage form of brepiprazole that is convenient to take, has good patient compliance, high bioavailability, and is suitable for industrial production.

本發明所要解決的技術問題是為了克服現有技術中布瑞哌唑普通片必須先在胃中崩解才能開始釋放藥物、起效慢、從而限制生物利用度、服用不方便、患者順應性差等缺陷而提供了一種布瑞哌唑口溶膜包合物、其製備方法及用途。本發明的布瑞哌唑口溶膜包合物，具有厚度薄、口感良好、性質穩定、且無需飲水即可在口腔內即刻溶化、口服吸收速度快的優點，同時製程簡單、載藥量高、藥物含量均勻度好，解決了精神分裂症患者服藥順應性差及藏藥和吐藥現象，特別適宜有吞咽困難的患者。The technical problem to be solved by the present invention is to overcome the defects in the prior art that brepiprazole ordinary tablets must first disintegrate in the stomach to release the drug, slow onset of action, thereby limiting bioavailability, inconvenient taking, poor patient compliance, etc. Provided is an orally dissolving film inclusion compound of breiprazole, its preparation method and application. The mouth-dissolving film clathrate of buripiprazole of the present invention has the advantages of thin thickness, good taste, stable properties, instant dissolution in the oral cavity without drinking water, fast oral absorption speed, simple manufacturing process and high drug loading capacity 1. The uniformity of drug content is good, which solves the poor drug compliance of schizophrenia patients and the phenomenon of Tibetan medicine and vomiting medicine, especially suitable for patients with dysphagia.

本發明要求享有2021年4月13日向中國國家知識產權局提交的申請號為CN202110395944.3，名稱為“一種布瑞哌唑口溶膜包合物、其製備方法及應用”的發明專利申請的優先權。該申請的全文以引用的方式併入本文。The present invention claims to be entitled to the invention patent application with the application number CN202110395944.3 and the name "a kind of buripiprazole mouth-dissolving film inclusion compound, its preparation method and application" submitted to the State Intellectual Property Office of China on April 13, 2021. priority. This application is incorporated herein by reference in its entirety.

本發明提供了一種布瑞哌唑口溶膜包合物，其包含以下組分：活性藥物包合物、成膜材料、填充劑、增塑劑和甜味劑中的一種或多種，所述的活性藥物為如式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（即布瑞哌唑）和/或其藥學上可接受的鹽；所述的活性藥物包合物是由活性藥物和環糊精包合組成。如下式I：

Figure 02_image001
I                                           。 The invention provides a kind of orally dissolving film inclusion compound of buripiprazole, which comprises the following components: one or more of active drug inclusion compound, film-forming material, filler, plasticizer and sweetener, said The active drug is 7-[4-(4-benzo[B]thiophen-4-yl-1-piperazine) butoxy]-2(1H)-quinolinone (ie, cloth Repiprazole) and/or its pharmaceutically acceptable salt; the active drug inclusion compound is composed of the active drug and cyclodextrin. Formula I as follows:
Figure 02_image001
I.

本發明中，所述的活性藥物與環糊精的摩爾比優選2:1～1:4。In the present invention, the molar ratio of the active drug to cyclodextrin is preferably 2:1-1:4.

本發明中，所述的環糊精優選α-環糊精、β-環糊精、羥丙基-β-環糊精或璜丁基-β-環糊精。In the present invention, the cyclodextrin is preferably α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin or sulfonyl-β-cyclodextrin.

本發明中，所述的活性藥物的重量百分含量優選1%～30%，例如3.4%，所述的重量百分含量是指活性藥物的重量占布瑞哌唑口溶膜包合物總重量的百分比。In the present invention, the weight percentage of the active drug is preferably 1% to 30%, such as 3.4%. The weight percentage means that the weight of the active drug accounts for the total percent by weight.

本發明中，所述的成膜材料為藥物的載體選自明膠、蟲膠、阿拉伯膠、澱粉、糊精、瓊脂、海藻酸鈉、玉米朊、羥丙甲纖維素、羥丙基纖維素、聚乙烯醇、聚氧乙烯、丙烯酸共聚物、聚維酮、聚乳酸和矽橡膠中的一種或多種。In the present invention, 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 acid copolymer, povidone, polylactic acid and silicone rubber.

本發明中，所述的成膜材料的重量百分含量優選30%～70%，例如51.6%，所述的重量百分含量是指成膜材料的重量占布瑞哌唑口溶膜包合物總重量的百分比。In the present invention, the weight percentage of the film-forming material is preferably 30% to 70%, such as 51.6%. The weight percentage means that the weight of the film-forming material accounts for percentage of the total weight of the object.

本發明中，所述的增塑劑是指用於降低膜的玻璃轉化溫度，增加塑性、韌性、提高拉伸率的物質選自聚乙二醇、甘油、丙二醇、矽油、二甲矽油、聚丙二醇和己二醇中的一種或多種。In the present invention, the plasticizer refers to the material used to reduce the glass transition temperature of the film, increase plasticity, toughness, and increase elongation selected from polyethylene glycol, glycerin, propylene glycol, silicone oil, simethicone, poly One or more of propylene glycol and hexylene glycol.

本發明中，所述的增塑劑的重量百分含量優選5%～30%，例如8.6%、8.8%或17.4%，所述的重量百分含量是指增塑劑的重量占布瑞哌唑口溶膜包合物總重量的百分比。In the present invention, the weight percentage of the plasticizer is preferably 5% to 30%, such as 8.6%, 8.8% or 17.4%. The weight percentage means that the weight of the plasticizer accounts for The percentage of the total weight of azole orolytic film inclusion compound.

本發明中，所述的甜味劑是指在膜劑中起矯味作用的物質，選自阿斯巴甜、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、糖精和糖精鈉中的一種或多種。In the present invention, the sweetener refers to a substance that acts as a flavoring agent in the film, and is selected from aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, fragrance, saccharin and One or more of sodium saccharin.

本發明中，所述的甜味劑的重量百分含量優選0.05%～0.5%，例如0.2%，所述的重量百分含量是指甜味劑的重量占布瑞哌唑口溶膜包合物總重量的百分比。In the present invention, the weight percentage of the sweetener is preferably 0.05% to 0.5%, such as 0.2%. The weight percentage means that the weight of the sweetener accounts for percentage of the total weight of the object.

本發明中，所述的填充劑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體物質。選自甘露醇、蔗糖、葡萄糖、麥芽糖、乳糖、山梨醇、木糖醇、麥芽糖醇、半乳糖醇、赤蘚糖醇、糊精和海藻糖中的一種或多種。In the present invention, 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, increase the weight, and reduce the cost of the material. One or more selected from mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose.

本發明中，所述的填充劑的重量百分含量優選5%～30%，例如25.8%，所述的重量百分含量是指填充劑的重量占布瑞哌唑口溶膜包合物總重量的百分比。In the present invention, the weight percentage of the filler is preferably 5% to 30%, such as 25.8%, and the weight percentage means that the weight of the filler accounts for the total percent by weight.

本發明所述的布瑞哌唑口溶膜組合物，優選進一步包括崩解劑，或者崩解劑與唾液刺激劑和著色劑中的一種或多種的組合。The buripiprazole orally dissolving film composition of the present invention preferably further includes a disintegrating agent, or a combination of a disintegrating agent and one or more of a saliva stimulating agent and a coloring agent.

本發明中，所述的崩解劑是指促使藥物在胃腸道中迅速崩解成小粒子的輔料，選自低取代羥丙基纖維素、交聯聚維酮、交聯羧甲基纖維素鈉、交聯羧甲基澱粉鈉、澱粉、微晶纖維素、預糊化澱粉中的一種或多種。In the present invention, the disintegrant refers to an adjuvant that promotes the rapid disintegration of the drug into small particles in the gastrointestinal tract, and is selected from low-substituted hydroxypropyl cellulose, crospovidone, and croscarmellose sodium , one or more of croscarmellose sodium starch, starch, microcrystalline cellulose, and pregelatinized starch.

本發明中，所述的唾液刺激劑是指刺激唾液產生的物質，選自檸檬酸、酒石酸、蘋果酸和甘露醇中的一種或多種。In the present invention, the saliva stimulating agent refers to a substance that stimulates saliva production, and is selected from one or more of citric acid, tartaric acid, malic acid and mannitol.

本發明中，所述的著色劑是指能改善製劑的外觀顔色，可用來識別製劑的濃度、區分應用方法和減少病人對服藥的厭惡感的物質，選自二氧化鈦、色素和色澱中一種或多種。In the present invention, the coloring agent 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. It is selected from one or more of titanium dioxide, pigments and color lakes. Various.

本發明所述的布瑞哌唑口溶膜組合物，可以為以下任一配方：The brepiprazole orally dissolving film composition of the present invention can be any of the following formulations:

配方一：3.4%布瑞哌唑、10.3%β-環糊精、34.4%羥丙甲纖維素、17.2%聚乙烯醇、25.8%甘露醇、8.6%甘油、0.2%三氯蔗糖；Formula 1: 3.4% bripiprazole, 10.3% β-cyclodextrin, 34.4% hypromellose, 17.2% polyvinyl alcohol, 25.8% mannitol, 8.6% glycerin, 0.2% sucralose;

配方二：3.4%布瑞哌唑、10.3%α-環糊精、34.4%聚乙烯醇、17.2%明膠、25.8%甘露醇、8.6%甘油、0.2%二甲矽油、0.2%三氯蔗糖；Formula 2: 3.4% breiprazole, 10.3% α-cyclodextrin, 34.4% polyvinyl alcohol, 17.2% gelatin, 25.8% mannitol, 8.6% glycerin, 0.2% simethicone, 0.2% sucralose;

配方三：3.4%布瑞哌唑、10.3%羥丙基-β-環糊精、8.6%羥丙甲纖維素、42.9%明膠、17.2%甘露醇、17.2%甘油、0.2%二甲矽油、0.2%三氯蔗糖；Formula 3: 3.4% breiprazole, 10.3% hydroxypropyl-β-cyclodextrin, 8.6% hypromellose, 42.9% gelatin, 17.2% mannitol, 17.2% glycerin, 0.2% simethicone, 0.2 %Sucralose;

配方四：3.4%布瑞哌唑、10.3%璜丁基-β-環糊精、51.5%聚乙烯醇、17.2%甘露醇、17.2%甘油、0.2%二甲矽油、0.2%三氯蔗糖。Formula 4: 3.4% brepiprazole, 10.3% sulfonyl-β-cyclodextrin, 51.5% polyvinyl alcohol, 17.2% mannitol, 17.2% glycerin, 0.2% simethicone, 0.2% sucralose.

本發明還提供了所述的布瑞哌唑口溶膜包合物的製備方法，其包括以下步驟：The present invention also provides the preparation method of described buripiprazole orally dissolving film clathrate, which comprises the following steps:

1)   將活性藥物與環糊精製備成活性藥物環糊精包合物；1) Prepare active drug and cyclodextrin into active drug cyclodextrin inclusion compound;

2)   將填充劑、增塑劑、甜味劑，與純化水混合，攪拌，待完全溶解後加入步驟1）得到的活性藥物環糊精包合物，攪拌均勻，得溶液A；2) Mix the filler, plasticizer, and sweetener with purified water, stir, and add the active drug cyclodextrin inclusion compound obtained in step 1) after it is completely dissolved, and stir evenly to obtain solution A;

3)將成膜材料與蒸餾水，攪拌均勻，冷卻至完全溶解，得到膠液B；3) Stir the film-forming material and distilled water evenly, cool until completely dissolved, and obtain glue B;

4）將步驟3）得到的膠液B加入步驟2）得到的溶液A中，在真空條件下攪拌脫泡，得含藥膠液；4) Add the glue B obtained in step 3) into the solution A obtained in step 2), and stir and defoam under vacuum conditions to obtain the drug-containing glue;

5）將步驟4）得到的含藥膠液脫泡後用刮刀均勻塗布於聚酯帶上，加熱乾燥後切割成一定尺寸，得到布瑞哌唑口溶膜包合物。5) After defoaming the drug-containing glue solution obtained in step 4), spread it evenly on the polyester tape with a spatula, heat and dry it, and cut it into a certain size to obtain the buripiprazole mouth-dissolving film inclusion compound.

本發明還提供了一種布瑞哌唑口腔薄膜劑，其包含所述的布瑞哌唑口溶膜包合物。The present invention also provides a buripiprazole oral thin film, which comprises the buripiprazole orally dissolving film inclusion compound.

本發明還提供了所述的布瑞哌唑口溶膜包合物在製備治療中樞神經系統疾病的藥物中的用途。所述的治療中樞神經系統疾病可以為重度抑鬱症或精神分裂症。The present invention also provides the application of the orally dissolving film inclusion compound of buripiprazole in the preparation of medicaments for treating diseases of the central nervous system. The central nervous system disease for treatment may be severe depression or schizophrenia.

本發明還提供了一種治療中樞神經系統疾病的方法，其為需要的患者施用治療有效量的所述的布瑞哌唑口腔薄膜劑。The present invention also provides a method for treating diseases of the central nervous system, which comprises administering a therapeutically effective dose of the bripiprazole oral thin film to patients in need.

在不違背本領域常識的基礎上，上述各優選條件，可任意組合，即得本發明各較佳實例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

本發明所用試劑和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.

本發明的有益效果在於：本發明製得的布瑞哌唑口溶膜包合物，具有良好的溶出速率，在口腔中溶解後不會有沙礫感、且外觀均一、柔韌性好，同時在膜液配製過程中不會發生沉降，含量均一性符合要求。The beneficial effect of the present invention is that: the orally dissolving film clathrate of breiprazole prepared by the present invention has a good dissolution rate, does not have a gritty feeling after dissolving in the oral cavity, and has a uniform appearance and good flexibility. No sedimentation will occur during the preparation of the membrane solution, and the content uniformity meets the requirements.

下文將結合具體實施例對本發明的技術方案做更進一步的詳細說明。應當理解，下列實施例僅為示例性地說明和解釋本發明，而不應被解釋為對本發明保護範圍的限制。凡基於本發明上述內容所實現的技術均涵蓋在本發明旨在保護的範圍內。The technical solutions of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following examples are only for illustrating and explaining the present invention, and should not be construed as limiting the protection scope of the present invention. All technologies realized based on the above contents of the present invention are covered within the scope of protection intended by the present invention.

除非另有說明，以下實施例中使用的原料和試劑均為市售商品，或者可以通過已知方法製備。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

實施例1至5： 成分 占比（%，重量百分比） 實施例1 實施例2 實施例3 實施例4 實施例5 布瑞哌唑 2mg（3.4%） 2mg（3.4%） 2mg（3.4%） 2mg（3.4%） 2mg（10.5%） β-環糊精 6mg（10.3%） / / / / α-環糊精 / 6mg（10.3%） / / / 羥丙基-β-環糊精 / / 6mg（10.3%） / / 璜丁基-β-環糊精 / / / 6 mg（10.3%） / 羥丙甲纖維素 20mg（34.4%） / 5mg（8.6%） / 4.88mg（25.7%） 聚乙烯醇 10mg（17.2%） 20mg（34.4%） / 30mg（51.5%） 8mg（42.1%） 明膠 / 10mg（17.2%） 25mg（42.9%） / / 甘露醇 15mg（25.8%） 15mg（25.8%） 10mg（17.2%） 10mg（17.2%） / 甘油 5mg（8.6%） 5mg（8.6%） 10mg（17.2%） 10mg（17.2%） 4mg（21.1%） 二甲矽油 / 0.1mg（0.2%） 0.1mg（0.2%） 0.1mg（0.2%） 0.1mg（0.5%） 三氯蔗糖 0.1（0.2%） 0.1mg（0.2%） 0.1mg（0.2%） 0.1mg（0.2%） 0.02mg（0.1%） 純化水*  160 160 160 160 120 Examples 1 to 5: Element Proportion (%, weight percentage) Example 1 Example 2 Example 3 Example 4 Example 5 Bripiprazole 2 mg (3.4%) 2 mg (3.4%) 2 mg (3.4%) 2 mg (3.4%) 2 mg (10.5%) β-cyclodextrin 6mg (10.3%) / / / / α-cyclodextrin / 6mg (10.3%) / / / Hydroxypropyl-β-cyclodextrin / / 6mg (10.3%) / / Juanbutyl-β-cyclodextrin / / / 6 mg (10.3%) / hypromellose 20mg (34.4%) / 5 mg (8.6%) / 4.88mg (25.7%) polyvinyl alcohol 10mg (17.2%) 20mg (34.4%) / 30mg (51.5%) 8mg (42.1%) gelatin / 10mg (17.2%) 25mg (42.9%) / / Mannitol 15mg (25.8%) 15mg (25.8%) 10mg (17.2%) 10mg (17.2%) / glycerin 5 mg (8.6%) 5 mg (8.6%) 10mg (17.2%) 10mg (17.2%) 4mg (21.1%) Simethicone / 0.1mg (0.2%) 0.1mg (0.2%) 0.1mg (0.2%) 0.1mg (0.5%) Sucralose 0.1 (0.2%) 0.1mg (0.2%) 0.1mg (0.2%) 0.1mg (0.2%) 0.02mg (0.1%) purified water* 160 160 160 160 120

*在刮塗乾燥過程中除去。*Remove during drawdown drying.

製備製程：Preparation process:

1）對布瑞哌唑與環糊精進行預處理，得到活性藥物環糊精包合物；1) Pretreatment of breiprazole and cyclodextrin to obtain the active drug cyclodextrin inclusion compound;

2）稱取填充劑、增塑劑、甜味劑，與純化水混合，攪拌，待完全溶解後加入步驟1）得到的活性藥物環糊精包合物，攪拌均勻，得溶液A；2) Weigh the filler, plasticizer, and sweetener, mix them with purified water, stir, and add the active drug cyclodextrin inclusion compound obtained in step 1) after completely dissolving, and stir evenly to obtain solution A;

3）將成膜劑與蒸餾水，攪拌均勻，冷卻至完全溶解，得到膠液B；3) Stir the film-forming agent and distilled water evenly, cool until completely dissolved, and obtain glue B;

4）將步驟3）得到的膠液B加入步驟2）得到的溶液A中，在真空條件下攪拌脫泡，得含藥膠液；4) Add the glue B obtained in step 3) into the solution A obtained in step 2), and stir and defoam under vacuum conditions to obtain the drug-containing glue;

5）將步驟4）得到的含藥膠液脫泡後用刮刀均勻塗布於聚酯帶上，加熱乾燥後切割成一定尺寸，得到布瑞哌唑口溶膜包合物。5) After defoaming the drug-containing glue solution obtained in step 4), spread it evenly on the polyester tape with a spatula, heat and dry it, and cut it into a certain size to obtain the buripiprazole mouth-dissolving film inclusion compound.

檢測結果： 實施例 實施例1 實施例2 實施例3 實施例4 實施例5 溶液混懸狀態 混懸液均一，底部無可見聚集顆粒 混懸液均一，底部無可見聚集顆粒 混懸液均一，底部無可見聚集顆粒 混懸液均一，底部無可見聚集顆粒 混懸液均一，底部無可見聚集顆粒 含量均勻度 RSD%（N=10） 0.8 0.5 0.7 0.6 3.7 成膜性 成膜好 成膜好 成膜好 成膜好 能成膜 口感 無砂礫感 無砂礫感 無砂礫感 無砂礫感 有砂礫感 Test results: Example Example 1 Example 2 Example 3 Example 4 Example 5 solution suspension state Homogeneous suspension with no visible aggregated particles at the bottom Homogeneous suspension with no visible aggregated particles at the bottom Homogeneous suspension with no visible aggregated particles at the bottom Homogeneous suspension with no visible aggregated particles at the bottom Homogeneous suspension with no visible aggregated particles at the bottom Content uniformity RSD% (N=10) 0.8 0.5 0.7 0.6 3.7 Film forming Good film formation Good film formation Good film formation Good film formation Capable of forming a film Taste No grittiness No grittiness No grittiness No grittiness gritty

以上，對本發明的實施方式進行了說明。但是，本發明不限定於上述實施方式。凡在本發明的精神和原則之內，所做的任何修改、等同替換、改進等，均應包含在本發明的保護範圍之內。The embodiments of the present invention have been described above. However, the present invention is not limited to the above-mentioned embodiments. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

Figure 111114134-A0101-11-0002-3
Figure 111114134-A0101-11-0002-3

Claims (10)

一種布瑞哌唑口溶膜包合物，其包含以下組分：活性藥物包合物、成膜材料、填充劑、增塑劑和甜味劑中的一種或多種，該活性藥物為如式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/或其藥學上可接受的鹽，該活性藥物包合物是由活性藥物和環糊精包合組成；
Figure 03_image001
I                                              。 A kind of buripiprazole orally dissolving film clathrate, which comprises the following components: one or more of active drug clathrates, film-forming materials, fillers, plasticizers and sweeteners, the active drug is as follows: 7-[4-(4-benzo[B]thiophen-4-yl-1-piperazine)butoxy]-2(1H)-quinolinone shown in I and/or its pharmaceutically acceptable Salt, the active drug inclusion compound is composed of active drug and cyclodextrin inclusion compound;
Figure 03_image001
I. 如請求項1所述的布瑞哌唑口溶膜包合物，其中該活性藥物與該環糊精的摩爾比為2:1～1:4。The orally dissolving film inclusion compound of breiprazole according to claim 1, wherein the molar ratio of the active drug to the cyclodextrin is 2:1-1:4. 如請求項1或2所述的布瑞哌唑口溶膜包合物，該環糊精為α-環糊精、β-環糊精、羥丙基-β-環糊精或璜丁基-β-環糊精。The orally dissolving film inclusion compound of breiprazole as described in Claim 1 or 2, the cyclodextrin is α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin or sulfonyl - beta-cyclodextrin. 如請求項1至3中任一項所述的布瑞哌唑口溶膜包合物，其中該活性藥物的重量百分含量為1 %～30 %，該重量百分含量是指該活性藥物的重量占該布瑞哌唑口溶膜包合物總重量的百分比； 優選地，該成膜材料選自明膠、蟲膠、阿拉伯膠、澱粉、糊精、瓊脂、海藻酸鈉、玉米朊、羥丙甲纖維素、羥丙基纖維素、聚乙烯醇、聚氧乙烯、丙烯酸共聚物、聚維酮、聚乳酸和矽橡膠中的一種或多種； 和/或， 該成膜材料的重量百分含量為30%～70%，該重量百分含量是指該成膜材料的重量占該布瑞哌唑口溶膜包合物總重量的百分比； 優選地，該增塑劑選自聚乙二醇、甘油、丙二醇、矽油、二甲矽油、聚丙二醇和己二醇中的一種或多種； 和/或， 該增塑劑的重量百分含量為5%～30%，該重量百分含量是指該成膜材料的重量占該布瑞哌唑口溶膜包合物總重量的百分比； 優選地，該甜味劑選自阿斯巴甜、三氯蔗糖、果糖、蔗糖、甜菊苷、甘草甜素、香精、香料、糖精和糖精鈉中的一種或多種； 和/或， 該甜味劑的重量百分含量為0.05%～0.5%，該重量百分含量是指該甜味劑的重量占該布瑞哌唑口溶膜包合物總重量的百分比； 優選地，該填充劑選自甘露醇、蔗糖、葡萄糖、麥芽糖、乳糖、山梨醇、木糖醇、麥芽糖醇、半乳糖醇、赤蘚糖醇、糊精和海藻糖中的一種或多種； 和/或， 該填充劑的重量百分含量為5%～30%，該重量百分含量是指該填充劑的重量占該布瑞哌唑口溶膜包合物總重量的百分比； 優選地，該布瑞哌唑口溶膜包合物，進一步包括崩解劑，或者崩解劑與唾液刺激劑和著色劑中的一種或多種的組合。 The orally dissolving film inclusion compound of breiprazole as described in any one of claims 1 to 3, wherein the weight percentage of the active drug is 1% to 30%, and the weight percentage refers to the active drug The weight accounts for the percentage of total weight of this buripiprazole orally dissolving film clathrate; Preferably, the film-forming material is selected from gelatin, shellac, gum arabic, starch, dextrin, agar, sodium alginate, zein, hypromellose, hydroxypropyl cellulose, polyvinyl alcohol, polyoxyethylene , one or more of acrylic acid copolymer, povidone, polylactic acid and silicone rubber; and / or, The weight percentage of the film-forming material is 30% to 70%, and the weight percentage refers to the percentage of the weight of the film-forming material in the total weight of the buripiprazole orally dissolving film inclusion compound; Preferably, the plasticizer is selected from one or more of polyethylene glycol, glycerin, propylene glycol, silicone oil, simethicone, polypropylene glycol and hexylene glycol; and / or, The weight percentage of the plasticizer is 5% to 30%, and the weight percentage refers to the percentage of the weight of the film-forming material to the total weight of the buripiprazole orally dissolving film inclusion compound; Preferably, the sweetener is selected from one or more of aspartame, sucralose, fructose, sucrose, stevioside, glycyrrhizin, essence, fragrance, saccharin and sodium saccharin; and / or, The weight percentage of the sweetener is 0.05% to 0.5%, and the weight percentage refers to the percentage of the weight of the sweetener to the total weight of the buripiprazole orally dissolving film inclusion compound; Preferably, the filler is selected from one or more of mannitol, sucrose, glucose, maltose, lactose, sorbitol, xylitol, maltitol, galactitol, erythritol, dextrin and trehalose; and / or, The weight percentage of the filler is 5% to 30%, and the weight percentage refers to the percentage of the weight of the filler to the total weight of the buripiprazole orally dissolving film clathrate; Preferably, the orally soluble film inclusion compound of buripiprazole further includes a disintegrating agent, or a combination of a disintegrating agent and one or more of a saliva stimulating agent and a coloring agent. 如請求項4所述的布瑞哌唑口溶膜包合物，其中該崩解劑選自低取代羥丙基纖維素、交聯聚維酮、交聯羧甲基纖維素鈉、交聯羧甲基澱粉鈉、澱粉、微晶纖維素、預糊化澱粉中的一種或多種； 和/或， 該唾液刺激劑選自檸檬酸、酒石酸、蘋果酸和甘露醇中的一種或多種； 和/或， 該著色劑選自二氧化鈦、色素和色澱中的一種或多種。 The mouth-dissolving film inclusion compound of buripiprazole as described in claim 4, wherein the disintegrant is selected from low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, cross-linked One or more of sodium carboxymethyl starch, starch, microcrystalline cellulose, and pregelatinized starch; and / or, The saliva stimulating agent is selected from one or more of citric acid, tartaric acid, malic acid and mannitol; and / or, The colorant is selected from one or more of titanium dioxide, pigments and lakes. 如請求項1至5中任一項所述的布瑞哌唑口溶膜包合物，該布瑞哌唑口溶膜包合物，為以下任一配方： 配方一：3.4%布瑞哌唑、10.3%β-環糊精、34.4%羥丙甲纖維素、17.2%聚乙烯醇、25.8%甘露醇、8.6%甘油、0.2%三氯蔗糖； 配方二：3.4%布瑞哌唑、10.3%α-環糊精、34.4%聚乙烯醇、17.2%明膠、25.8%甘露醇、8.6%甘油、0.2%二甲矽油、0.2%三氯蔗糖； 配方三：3.4%布瑞哌唑、10.3%羥丙基-β-環糊精、8.6%羥丙甲纖維素、42.9%明膠、17.2%甘露醇、17.2%甘油、0.2%二甲矽油、0.2%三氯蔗糖； 配方四：3.4%布瑞哌唑、10.3%璜丁基-β-環糊精、51.5%聚乙烯醇、17.2%甘露醇、17.2%甘油、0.2%二甲矽油、0.2%三氯蔗糖。 The buripiprazole orally dissolving film inclusion compound as described in any one of claims 1 to 5, the buripiprazole orally dissolving film inclusion compound is any of the following formulations: Formula 1: 3.4% bripiprazole, 10.3% β-cyclodextrin, 34.4% hypromellose, 17.2% polyvinyl alcohol, 25.8% mannitol, 8.6% glycerin, 0.2% sucralose; Formula 2: 3.4% breiprazole, 10.3% α-cyclodextrin, 34.4% polyvinyl alcohol, 17.2% gelatin, 25.8% mannitol, 8.6% glycerin, 0.2% simethicone, 0.2% sucralose; Formula 3: 3.4% breiprazole, 10.3% hydroxypropyl-β-cyclodextrin, 8.6% hypromellose, 42.9% gelatin, 17.2% mannitol, 17.2% glycerin, 0.2% simethicone, 0.2 %Sucralose; Formula 4: 3.4% brepiprazole, 10.3% sulfonyl-β-cyclodextrin, 51.5% polyvinyl alcohol, 17.2% mannitol, 17.2% glycerin, 0.2% simethicone, 0.2% sucralose. 一種如請求項1至6中任一項所述的布瑞哌唑口溶膜包合物的製備方法，其包括以下步驟： 1) 將活性藥物與環糊精製備成活性藥物環糊精包合物； 2) 將填充劑、增塑劑、甜味劑與純化水混合，攪拌，待完全溶解後加入步驟1）得到的該活性藥物環糊精包合物，攪拌均勻，得溶液A； 3) 將成膜劑與蒸餾水，攪拌均勻，冷卻至完全溶解，得到膠液B； 4) 將步驟3）得到的該膠液B加入步驟2）得到的該溶液A中，在真空條件下攪拌脫泡，得含藥膠液； 5) 將步驟4）得到的該含藥膠液脫泡後用刮刀均勻塗布於聚酯帶上，加熱乾燥後切割成一定尺寸，得到該布瑞哌唑口溶膜包合物。 A preparation method of the buripiprazole orally dissolving film clathrate as described in any one of claim items 1 to 6, which comprises the following steps: 1) Prepare active drug and cyclodextrin into active drug cyclodextrin inclusion compound; 2) Mix the filler, plasticizer, sweetener and purified water, stir, and add the cyclodextrin inclusion complex of the active drug obtained in step 1) after completely dissolving, and stir evenly to obtain solution A; 3) Stir the film-forming agent and distilled water evenly, cool until completely dissolved, and obtain glue B; 4) Add the glue B obtained in step 3) into the solution A obtained in step 2), and stir and defoam under vacuum conditions to obtain a drug-containing glue; 5) After defoaming the drug-containing glue obtained in step 4), spread it evenly on the polyester tape with a spatula, heat and dry it, and cut it into a certain size to obtain the buripiprazole mouth-dissolving film inclusion compound. 一種布瑞哌唑口腔薄膜劑，其包含如請求項1至7之中任一項所述的布瑞哌唑口溶膜包合物。A buripiprazole oral thin film, which comprises the buripiprazole oral-soluble film inclusion compound as described in any one of claims 1 to 7. 一種如請求項1至7中任一項所述的布瑞哌唑口溶膜包合物在製備治療中樞神經系統疾病的藥物中的用途。A use of the orally dissolving film inclusion compound of breiprazole as described in any one of claims 1 to 7 in the preparation of medicines for treating central nervous system diseases. 如請求項9所述的用途，該中樞神經系統疾病為重度抑鬱症或精神分裂症。Use as described in claim item 9, the central nervous system disease is major depression or schizophrenia.
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