TWI820674B - 布瑞哌唑物口腔薄膜劑、其製備方法及用途 - Google Patents
布瑞哌唑物口腔薄膜劑、其製備方法及用途 Download PDFInfo
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- TWI820674B TWI820674B TW111114135A TW111114135A TWI820674B TW I820674 B TWI820674 B TW I820674B TW 111114135 A TW111114135 A TW 111114135A TW 111114135 A TW111114135 A TW 111114135A TW I820674 B TWI820674 B TW I820674B
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Abstract
本發明提供了一種布瑞哌唑物口腔薄膜劑、其製備方法及用途。本發明公開了一種布瑞哌唑 (brexpiprazole)口腔薄膜劑，其包含以下組分：活性藥物、成膜材料、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-苯並[B]噻吩-4-基-1-呱嗪)丁氧基]-2(1H)-喹啉酮 (7-{4-[4-(1-Benzothiophen4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) 和/或其藥學上可接受的鹽，活性藥物粒徑 D
90≤30 μm。本發明的布瑞哌唑口腔薄膜劑，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。
Description
本申請要求享有2021年4月13日向中國國家知識產權局提交的申請號為CN202110395930.1，名稱為「一種布瑞哌唑口腔薄膜劑、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。
本發明涉及一種布瑞哌唑 (brexpiprazole) 口腔薄膜劑、其製備方法及用途。
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月在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 0.25 mg、0.5 mg、1 mg、2 mg、3 mg和4 mg。
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 0.5 mg/天或 1 mg/天，然後增至目標劑量 2 mg，每日一次，最大推薦劑量為 3 mg/天；用於精神分裂治療時，起始劑量為 1 mg/天，推薦目標劑量為 2 mg 至 4 mg，每日一次，最大推薦劑量為 4 mg/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。
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。
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。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。
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。
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。
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、服用不方便、患者順應性差等缺陷而提供了布瑞哌唑口腔薄膜劑、其製備方法及用途，本發明的布瑞哌唑口腔薄膜劑具有厚度薄、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。
本發明提供了一種布瑞哌唑口腔薄膜劑，其特徵在於包含以下組分：活性藥物、成膜材料、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-苯並[B]噻吩-4-基-1-呱嗪)丁氧基]-2(1H)-喹啉酮(7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one) 和/或其藥學上可接受的鹽，活性藥物粒徑 D
90≤30 μm；
I 。
本發明中，所述的活性藥物粒徑 D
90優選小於 20.0μm，進一步優選小於 10.0 μm，例如 1.8 μm、9.7 μm、16.5 μm 或 27.8 μm。
本發明中，所述的活性藥物的重量百分含量較佳為1%～30%，例如 25%，所述的重量百分含量是指活性藥物的重量占布瑞哌唑口腔薄膜劑總重量的百分比。
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 (Zein maize)、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（也稱聚乙烯吡咯烷酮）、聚乳酸和矽橡膠中的一種或多種。
本發明中，所述的成膜材料的重量百分含量優選 30%～70%，例如 54.4%，所述的重量百分含量是指成膜材料的重量占布瑞哌唑口腔薄膜劑總重量的百分比。
本發明中，所述的增塑劑是指用於降低膜的玻璃轉化溫度，增加塑性和韌性、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。
本發明中，所述的增塑劑的重量百分含量優選 5%～30%，例如 20.5%，所述的重量百分含量是指增塑劑的重量占布瑞哌唑口腔薄膜劑總重量的百分比。
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 (Aspartame)、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。
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 0.1%，所述的重量百分含量是指甜味劑的重量占布瑞哌唑口腔薄膜劑總重量的百分比。
本發明所述的布瑞哌唑口腔薄膜劑，優選進一步包括崩解劑，或者崩解劑與（1）唾液刺激劑、（2）填充劑和（3）著色劑中的一種或多種的組合。
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 (crosslinking polyvinyl pyrrolidone)、交聯羧甲基纖維素鈉 (CCMC-Na)、交聯羧甲基澱粉鈉 (CCMS-Na)、澱粉、微晶纖維素、預糊化澱粉 (pregelatinized starch) 中的一種或多種。
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。
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（又稱赤藻糖醇）、糊精和海藻糖中的一種或多種。
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、色素和色澱中的一種或多種。
本發明所述的布瑞哌唑口腔薄膜劑，可以為以下配方：25.0% 布瑞哌唑、14.4% 羥丙甲纖維素、40.0% 聚乙烯醇、20.0% 甘油、0.5% 二甲矽油、0.1% 三氯蔗糖；所述的布瑞哌唑 D
90為 1.8 μm、9.7 μm、16.5 μm 或 27.8 μm。
本發明還提供了所述的布瑞哌唑口腔薄膜劑的製備方法，其包括以下步驟：
1) 將活性藥物研磨至 D
90≤30 μm，得到活性藥物顆粒；
2) 將步驟1)得到的活性藥物顆粒與成膜材料和水混合，得到混懸液；
3) 將步驟2)得到的混懸液消泡，得到消泡後的混懸液；
4) 將步驟3)得到的消泡後的混懸液塗布在基材上，乾燥，成膜，得到布瑞哌唑口腔薄膜劑。
步驟1)中所述的研磨可以採用本領域中常規研磨方法，可以為球磨法、氣流粉碎法或膠體磨法。
步驟2)中所述的混合優選均質混合。
本發明還提供了所述的布瑞哌唑口腔薄膜劑在製備治療中樞神經系統疾病的藥物中的應用。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。
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。
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。
本發明所用試劑和原料均市售可得。
本發明的積極進步效果在於：本發明的布瑞哌唑口腔薄膜劑，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。
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。
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，或者可以經由已知方法製備。
實施例1至5：處方如下所示（表中%為重量百分比）
| 實施例 | 實施例1 | 實施例2 | 實施例3 | 實施例4 | 實施例5 |
| 成分 | D 90=1.8 μm | D 90=9.7 μm | D 90=16.5 μm | D 90=27.8 μm | D 90=35.1 μm |
| 布瑞哌唑 | 5 mg（25.0%） | ||||
| 羥丙甲纖維素 | 2.88 mg（14.4%） | ||||
| 聚乙烯醇 | 8 mg（40.0%） | ||||
| 甘油 | 4 mg（20.0%） | ||||
| 二甲矽油 | 0.1 mg（0.5%） | ||||
| 三氯蔗糖 | 0.02 mg（0.1%） | ||||
| 純化水 | 160 mg（製程過程中去除） |
製備方法：
1) 將活性藥物研磨至D
90≤30 μm，得到活性藥物顆粒；
2) 將步驟1)得到的活性藥物顆粒與成膜材料和水混合，得到混懸液；
3) 將步驟2)得到的混懸液消泡，得到消泡後的混懸液；
4) 將步驟3)得到的消泡後的混懸液塗布在基材上，經刮塗刀塗布成厚度均一的藥膜後，於50~80 ℃下乾燥，溶劑在乾燥過程中揮發，成膜後，將膜取出，切割成適合的大小和形狀，並包裝，得到布瑞哌唑口腔薄膜劑。
| 實施例 | 實施例1 | 實施例2 | 實施例3 | 實施例4 | 實施例5 |
| 粒徑 | D 90=1.8 μm | D 90=9.7 μm | D 90=16.5 μm | D 90=27.8 μm | D 90=35.1 μm |
| 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，底部可見少量聚集顆粒 | 混懸液不均一，底部可見一層沉澱物 |
| 含量均勻度 RSD%（N=10） | 0.2 | 0.3 | 1.3 | 3.2 | 5.9 |
| 成膜性 | 成膜好 | 成膜好 | 能成膜 | 膜稍脆 | N/A |
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。
Claims (9)
- 一種布瑞哌唑口腔薄膜劑，其由以下組分所組成：一活性藥物、一成膜材料、一增塑劑和一甜味劑，所述的活性藥物為如式I所示的7-[4-(4-苯並[B]噻吩-4-基-1-呱嗪)丁氧基]-2(1H)-喹啉酮和/或其藥學上可接受的鹽，活性藥物粒徑D9030μm；
- 如請求項1所述的布瑞哌唑口腔薄膜劑，其中，所述的活性藥物粒徑D90小於20.0μm。
- 如請求項1所述的布瑞哌唑口腔薄膜劑，其中，所述的活性藥物粒徑D90小於10.0μm。
- 如請求項1所述的布瑞哌唑口腔薄膜劑，其中，所述的活性藥物的重量百分含量為1%~30%，所述的重量百分含量是指所述活性藥物的重量占所述布瑞哌唑口腔薄膜劑總重量的百分比；和/或，所述的成膜材料進一步具有明膠、蟲膠、阿拉伯膠、澱粉、糊精、瓊脂、海藻酸鈉、玉米朊、羥丙基纖維素、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， 所述的成膜材料的重量百分含量為30%~70%，所述的重量百分含量是指所述的成膜材料的重量占所述的布瑞哌唑口腔薄膜劑總重量的百分比；和/或，所述的增塑劑進一步具有聚乙二醇、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，所述的增塑劑的重量百分含量為5%~30%，所述的重量百分含量是指所述增塑劑的重量占所述布瑞哌唑口腔薄膜劑總重量的百分比；所述的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，所述的甜味劑的重量百分含量為0.05%~0.5%，所述的重量百分含量是指所述甜味劑的重量占所述布瑞哌唑口腔薄膜劑總重量的百分比。
- 一種布瑞哌唑口腔薄膜劑，其由以下組分所組成：一活性藥物、一成膜材料、一增塑劑、一甜味劑及一崩解劑，或者其由以下組分所組成：一活性藥物、一成膜材料、一增塑劑、一甜味劑、一崩解劑，與一唾液刺激劑、一填充劑和一著色劑中的一種或多種的組合；所述的活性藥物為如式I所示的7-[4-(4-苯並[B]噻吩-4-基-1-呱嗪)丁氧基]-2(1H)-喹啉酮和/或其藥學上可接受的鹽，活性藥物粒徑D9030μm；
- 如請求項5所述的布瑞哌唑口腔薄膜劑，其中：所述的崩解劑選自低取代羥丙基纖維素、交聯聚乙烯吡咯烷酮、交聯羧甲基纖維素鈉、交聯羧甲基澱粉鈉、澱粉、微晶纖維素和預糊化澱粉中的一種或多種；和/或，所述的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，所述的填充劑選自甘露醇、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，所述的著色劑選自二氧化鈦、色素和色澱中一種或多種。
- 如請求項1至4中任一項所述的布瑞哌唑口腔薄膜劑，其中：所述的布瑞哌唑口腔薄膜劑，為以下配方：25.0%布瑞哌唑、14.4%羥丙甲纖維素、40.0%聚乙烯醇、20.0%甘油、0.5%二甲矽油、0.1%三氯蔗糖；所述的布瑞哌唑D90為1.8μm、9.7μm、16.5μm、或27.8μm。
- 一種將如請求項1至7中任一項所述的布瑞哌唑口腔薄膜劑用於製備治療中樞神經系統疾病的藥物的用途。
- 如請求項8所述的用途，其中，所述的中樞神經系統疾病為重度抑鬱症或精神分裂症。
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