TWI820673B - 布瑞哌唑口溶膜組合物、其製備方法及用途 - Google Patents
布瑞哌唑口溶膜組合物、其製備方法及用途 Download PDFInfo
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- TWI820673B TWI820673B TW111114133A TW111114133A TWI820673B TW I820673 B TWI820673 B TW I820673B TW 111114133 A TW111114133 A TW 111114133A TW 111114133 A TW111114133 A TW 111114133A TW I820673 B TWI820673 B TW I820673B
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Abstract
本發明提供了一種布瑞哌唑口溶膜組合物、其製備方法及用途。布瑞哌唑口溶膜組合物，其包含活性藥物、成膜材料、增塑劑、甜味劑和有機酸中的一種或多種，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，布瑞哌唑口溶膜組合物的pH值為2.5~4.5。本發明得到的布瑞哌唑口溶膜組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。
Description
本發明涉及一種布瑞哌唑口溶膜組合物、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0.25mg、0.5mg、1mg、2mg、3mg和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。
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CN202110395940.5，名稱為“一種布瑞哌唑口溶膜組合物、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。
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布瑞哌唑口溶膜組合物、其製備方法及用途。本發明的布瑞哌唑口溶膜組合物，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。
本發明提供一種布瑞哌唑口溶膜組合物，其包含活性藥物、成膜材料、增塑劑、甜味劑和有機酸中的一種或多種，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)-喹啉酮和/或其藥學上可接受的鹽，所述的布瑞哌唑口溶膜組合物的pH值為2.5~4.5。如下式I：
I 。
本發明中，所述的布瑞哌唑口溶膜組合物的pH值可以為3.1、3.5、2.8、或4.4。所述的有機酸選自乳酸、磷酸、羥乙酸、蘋果酸、酒石酸、檸檬酸、丁二酸和乙酸中的一種或多種。
本發明中，所述的活性藥物的重量百分含量優選1%～30%，例如11.8%，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組合物總重量的百分比。
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、環糊精、糖、膽固醇、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。
本發明中，所述的成膜材料的重量百分含量優選30%～70%，例如64.1%，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組合物總重量的百分比。
本發明中，所述的增塑劑是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24.1%，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組合物總重量的百分比。
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、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溶膜組合物總重量的百分比。
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、填充劑和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、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。
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、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溶膜組合物，可以為以下配方：11.8%布瑞哌唑、17.0%羥丙甲纖維素、47.1%聚乙烯醇、23.5%甘油、0.59%二甲矽油、0.1%三氯蔗糖和有機酸；所述的布瑞哌唑口溶膜組合物的pH為3.1、3.5、2.8或4.4。
本發明還提供了所述的布瑞哌唑口溶膜組合物的製備方法，其包括以下步驟：
1) 將除活性藥物、成膜材料和有機酸外的各組分溶於水中，形成混合物；
2) 向步驟1）得到的混合物中加入有機酸，調節pH值至2.5~4.5，得到酸性溶液；
3) 向步驟2）得到的酸性溶液中加入活性藥物，攪拌溶解，得到溶液；
4) 將增塑劑溶於水中，攪拌均勻後加入成膜材料，60℃至70℃加熱攪拌，溶化後得空白膠液；
5) 將步驟3）得到的溶液置於步驟4）得到的空白膠液中，攪拌至分散均勻，在真空條件下攪拌脫泡，得含藥膠；
6) 將步驟5）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、切割，得布瑞哌唑口溶膜組合物。
本發明還提供了所述的布瑞哌唑口溶膜組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。
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溶膜組合物。
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。
本發明的有益效果：
本發明得到的布瑞哌唑口溶膜組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。
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
| 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 | 2g（11.8%） | 2g（11.8%） | 2g（11.8%） | 2g（11.8%） | 2g（11.8%） |
| 有機酸 | pH值調至2.8 | pH值調至3.1 | pH值調至3.5 | pH值調至4.4 | / |
| 羥丙甲纖維素 | 2.88g（17.0%） | ||||
| 聚乙烯醇 | 8（47.1%） | ||||
| 甘油 | 4（23.5%） | ||||
| 二甲矽油 | 0.1（0.59%） | ||||
| 三氯蔗糖 | 0.02（0.1%） | ||||
| 純化水 | 100（製程過程中去除） |
實施例1至4製備方法：
1）將除活性藥物、成膜材料和有機酸外的各組分在攪拌下溶於水中，形成混合物；
2）向步驟1）得到的混合物中加入有機酸，調節其pH值至2.5~4.5，得到酸性溶液；
3）向步驟2）得到的酸性溶液中加入活性藥物，攪拌溶解，得到溶液；
4）將增塑劑溶於水中，攪拌均勻後加入成膜材料，60℃～70℃加熱攪拌，溶化後得空白膠液；
5）將步驟3）得到溶液置於步驟4）得到的空白膠液中，攪拌至分散均勻，在真空條件下攪拌脫泡，得含藥膠；
6）將脫泡後的步驟5）得到的含藥膠液用刮刀均勻塗布於聚酯帶上，加熱乾燥後切割成一定尺寸，得布瑞哌唑口溶膜組合物。
實施例5製備方法：
1）將除布瑞哌唑和成膜材料外的各組分在攪拌下溶化或分散於水中，攪拌均勻後加入成膜材料，60℃～70℃加熱攪拌，溶化後得空白膠液；
2）向步驟1）得到的空白膠液中加入布瑞哌唑，攪拌至分散均勻，在真空條件下攪拌脫泡，得含藥膠液；
3）將步驟2）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，得布瑞哌唑口溶膜組合物。
| 實施例 | 實施例1 | 實施例2 | 實施例3 | 實施例4 | 實施例5 |
| pH值 | 2.8 | 3.1 | 3.5 | 4.4 | 7.5 |
| 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，底部可見少量聚集顆粒 |
| 含量均勻度 RSD%（N=10） | 0.8 | 0.3 | 1.3 | 1.9 | 3.8 |
| 成膜性 | 能成膜 | 成膜好 | 成膜好 | 能成膜 | 膜稍脆 |
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 (12)
- 一種布瑞哌唑口溶膜組合物，其由活性藥物、成膜材料、增塑劑、甜味劑和有機酸中的一種或多種組成，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，該布瑞哌唑口溶膜組合物的pH值為2.5~4.5；該有機酸選自乳酸、磷酸、羥乙酸、蘋果酸、酒石酸、檸檬酸、丁二酸和乙酸中的一種或多種；
- 如請求項1所述的布瑞哌唑口溶膜組合物，該布瑞哌唑口溶膜組合物的pH值為3.1、3.5、2.8、或4.4。
- 如請求項1所述的布瑞哌唑口溶膜組合物，該布瑞哌唑口溶膜組合物的pH值為3.1~3.5。
- 如請求項1所述的布瑞哌唑口溶膜組合物，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組合物總重量的百分比。
- 如請求項1所述的布瑞哌唑口溶膜組合物，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組合物總重量的百分比。
- 如請求項1至5中任一項所述的布瑞哌唑口溶膜組合物，其中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%至30%，該重量百分含量是指成該膜材料的重量占該布瑞哌唑口溶膜組合物總重量的百分比；和/或，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組合物總重量的百分比。
- 一種如請求項1至5中任一項所述的布瑞哌唑口溶膜組合物，其中，該布瑞哌唑口溶膜組合物，進一步包括崩解劑，或者崩解劑與唾液刺激劑、填充劑和著色劑中的一種或多種的組合。
- 如請求項7所述的布瑞哌唑口溶膜組合物，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所述的布瑞哌唑口溶膜組合物，其中：該布瑞哌唑口溶膜組合物，為以下配方：11.8%布瑞哌唑、17.0%羥丙甲纖維素、47.1%聚乙烯醇、23.5%甘油、0.59%二甲矽油、0.1%三氯蔗糖和有機酸；所述的布瑞哌唑口溶膜組合物的pH為3.1、3.5、2.8或4.4。
- 一種如請求項1至9中任一項所述的布瑞哌唑口溶膜組合物的製備方法，其包括以下步驟：1)將除活性藥物、成膜材料和有機酸外的各組分溶於水中，形成混合物；2)向步驟1)得到的混合物中加入有機酸，調節pH值至如請求項1至9中的pH值，得到酸性溶液；3)向步驟2)得到的酸性溶液中加入該活性藥物，攪拌溶解，得到溶液；4)將增塑劑溶於水中，攪拌均勻後加入該成膜材料，60℃至70℃加熱攪拌，溶化後得空白膠液；5)將步驟3)得到的該溶液置於步驟4)得到的該空白膠液中，攪拌至分散均勻，在真空條件下攪拌脫泡，得含藥膠； 6)將步驟5)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、切割，得該布瑞哌唑口溶膜組合物。
- 一種如請求項1至9中任一項所述的布瑞哌唑口溶膜組合物在製備治療中樞神經系統疾病的藥物中的用途。
- 如請求項11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。
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