CN113143889A - 孟鲁司特钠凝胶贴膏的制备及应用 - Google Patents
孟鲁司特钠凝胶贴膏的制备及应用 Download PDFInfo
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- CN113143889A CN113143889A CN202110205568.7A CN202110205568A CN113143889A CN 113143889 A CN113143889 A CN 113143889A CN 202110205568 A CN202110205568 A CN 202110205568A CN 113143889 A CN113143889 A CN 113143889A
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- Prior art keywords
- gel
- sodium
- montelukast sodium
- layer
- plaster
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- 229960001951 montelukast sodium Drugs 0.000 title claims abstract description 44
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- 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
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种孟鲁司特钠凝胶贴膏的制备及其应用于小儿哮喘病的治疗。该凝胶贴膏由背衬层、含药凝胶层和保护膜（防粘层）组成，其中含药凝胶层由活性药物孟鲁司特钠、凝胶基质材料、保湿剂、防腐剂、透皮促进剂及其它药学可接受的外用制剂辅料组成，所述凝胶贴膏的制备方法为：将上述含药凝胶均匀涂抹在背衬层上，再贴上保护膜，最后进行裁切、包装即得凝胶贴膏。本发明的优势在于，孟鲁司特钠凝胶贴膏用于小儿哮喘病的治疗具有安全性高、胃肠道副作用少、给药无痛等特点，可极大提高小儿的用药顺应性。
Description
技术领域
本发明涉及药物制剂领域，具体涉及一种孟鲁司特钠凝胶贴膏的制备及应用。
背景技术
孟鲁司特钠属于半胱氨酰白三烯受体拮抗剂，是一种具有平喘以及抗过敏作用的药物（参见Hon et al, Drug Design, Development and Therapy, 8, 839 (2014)）。半胱氨酰白三烯是一种强效的炎症介质，这种炎症介质是由肥大细胞，嗜酸性粒细胞等多种细胞释放。孟鲁司特钠可以阻断半胱氨酰白三烯与呼吸道，鼻黏膜上的受体结合，抑制由半胱氨酰白三烯引起的支气管收缩，黏液分泌，血管通透性增加等气道炎性反应。孟鲁司特钠还可以缓解过敏性皮炎的鼻塞症状，临床上孟鲁司特钠主要是用于成人哮喘的预防和长期治疗，也可以用于减轻过敏性鼻炎引起的症状。
孟鲁司特钠已上市剂型包括片剂、咀嚼片、颗粒。其中咀嚼片和颗粒剂是专门针对儿科哮喘和过敏性鼻炎患者开发的剂型。国内企业除了开发上述3种剂型的孟鲁司特钠仿制药之外，过去也有尝试开发胶囊剂、分散片、口腔速溶膜等口服制剂产品，但均无改剂型的产品获批上市。最近，赛缪森等人发明了一种包含孟鲁司特与贻贝粘附蛋白的组合的局部制剂用于局部给药，以治疗炎症、炎症性病症和/或特征在于炎症的病状，包括伤口、烧伤、牛皮癣、痤疮和特应性皮炎（CN201880002883.6）。而关于孟鲁司特钠凝胶贴膏的专利跟文献未见报道。
凝胶贴膏具有使用方便，贴敷舒适，对皮肤无刺激性，缓慢递送药物，可长期起效，无痛给药，患者可自行给药等特点，对于哮喘患者尤其是小儿患者具有更好的用药顺应性。
发明内容
有鉴于此，本发明的主要目的在于提供一种使用方便、副反应小、效果明显、可长时间起效的孟鲁司特钠凝胶贴膏，以用于小儿哮喘病的治疗。本发明的技术方案如下：
治疗小儿哮喘的凝胶贴膏，包括以下组分：背衬层、含药凝胶层和保护膜（防粘层），含药凝胶层由活性药物孟鲁司特钠、凝胶基质材料、保湿剂、防腐剂、抗氧剂、透皮促进剂及其它药学可接受的外用制剂辅料组成。
其中，孟鲁司特钠的含量为凝胶贴膏总重量的1.0%-10.0%。优选地，孟鲁司特钠的含量为凝胶贴膏总重量的2.0%-6.0%。
含药凝胶层的凝胶基质材料选自聚丙烯酸部分中和物、聚丙烯酸及其盐（聚丙烯酸、聚丙烯酸钠、聚丙烯酸钾、聚丙烯酸二乙醇胺等）、羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、明胶、阿拉伯胶、卡波姆中至少一种。
保湿剂选自甘油、山梨醇、尿囊素、聚乙二醇中至少一种。
防腐剂选自苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、丙酸及其钙或钠盐中至少一种。
抗氧剂选自丁基羟基茴香醚（BHA）、二丁基羟基甲苯（BHT）、没食子酸丙酯（PG）、特丁基对苯二酚（TBHQ）中至少一种。
透皮促进剂选自丙二醇、克罗米通、己二酸二异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、L-薄荷醇中至少一种。
所述其他药学可接受的外用制剂辅料包括但不限于填充剂、交联剂、pH调节剂、色素、香精中的一种或多种。
填充剂选自高岭土、二氧化钛、滑石粉、碳酸钙、氧化锌中至少一种。
交联剂选自氢氧化铝、二羟基氨基乙酸铝、三氯化铝、柠檬酸铝中至少一种。
pH调节剂选自L-酒石酸、枸橼酸、磷酸、盐酸、硫酸中至少一种。
所述背衬层包括但不限于无纺布、聚酯无纺布、聚乙烯膜、铝箔中的一种。
所述保护膜包括但不限于涂有石蜡或二甲基硅油的PET聚酯膜、聚丙烯膜、聚乙烯膜、纸-聚酯复合膜中的一种。
孟鲁司特钠凝胶贴膏含药凝胶层的处方组成包含但不限于：
孟鲁司特钠 2.0%-6.0%
凝胶基质材料 5.0%-40.0%
保湿剂 10.0%-40.0%
防腐剂 1.0%-5.0%
透皮促进剂 0%-5.0%
抗氧化剂 1%-5.0%
填充剂 0%-10.0%
pH调节剂 0%-1.0%
交联剂 0%-8.0%
纯化水 40.0%-70.0%
孟鲁司特钠凝胶贴膏含药凝胶层的处方组成包含但不限于：
孟鲁司特钠 35.0 mg/g
聚丙烯酸钠 20.0 mg/g
卡波姆 30.0 mg/g
山梨醇 150.0 mg/g
甘油 150.0mg/g
苯甲酸钠 3.0mg/g
L-薄荷醇 3.0 mg/g
二丁基羟基甲苯 0.5 mg/g
滑石粉 3.5 mg/g
酒石酸 2.0 mg/g
二羟基氨基乙酸铝 2.0 mg/g
纯化水 601.0 mg/g
孟鲁司特钠凝胶贴膏的制备工艺如下：
A. 向处方量的卡波和酒石酸中加入纯化水使充分溶胀作为A相；
B. 将处方量的聚丙烯酸钠、甘羟铝、滑石粉、苯甲酸钠、二丁基羟基甲苯、L-薄荷醇混匀，加入处方量的甘油和山梨醇中，搅拌均匀，放至室温作为B相。
C. 另取适量纯化水，加入处方量的孟鲁司特钠使其溶解，作为C相。将A相与C相混合均匀后缓慢加至B相中，继续搅拌直至得到均匀的含药凝胶基质。以无纺布作为背衬层，涂二甲基硅油的PET聚酯膜作为防粘层，将以上基质进行涂布、裁切、包装等工序，得孟鲁司特钠凝胶贴膏。
所述孟鲁司特钠凝胶贴膏可用于治疗小儿哮喘病。
本发明的优势在于：
基于以上，本发明所提供的孟鲁司特钠凝胶贴膏具有使用方便，贴敷舒适，对皮肤无刺激性，缓慢递送药物，可长期起效，无痛给药，患者可自行给药等特点，对于哮喘患者尤其是小儿患者具有更好的用药顺应性。
附图说明
图1 透皮促进剂对孟鲁司特钠体外渗透的影响。
具体实施方式
所举实施例是为了更好地对本发明的内容进行说明，但并不是本发明的内容仅限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
实施例1 ：
处方组成：
制备工艺：
A. 向处方量的卡波和酒石酸中加入纯化水使充分溶胀作为A相；
B. 将处方量的聚丙烯酸钠、甘羟铝、苯甲酸钠、滑石粉、二丁基羟基甲苯、L-薄荷醇混匀，加入处方量的甘油和山梨醇中，搅拌均匀，放至室温作为B相。
C. 另取适量纯化水，加入处方量的孟鲁司特钠使其溶解，作为C相。将A相与C相混合均匀后缓慢加至B相中，继续搅拌直至得到均匀的含药凝胶基质。以无纺布作为背衬层，涂二甲基硅油的PET聚酯膜作为防粘层，将以上基质进行涂布、裁切、包装等工序，得孟鲁司特钠凝胶贴膏。
实施例2：
处方组成：
制备工艺：
A. 向处方量的卡波和酒石酸中加入纯化水使充分溶胀作为A相；
B. 将处方量的聚丙烯酸钠、甘羟铝、滑石粉、二丁基羟基甲苯混匀，加入处方量的甘油和山梨醇中，搅拌均匀，放至室温作为B相。
C. 另取适量纯化水，加入处方量的孟鲁司特钠使其溶解，作为C相。将A相与C相混合均匀后缓慢加至B相中，继续搅拌直至得到均匀的含药凝胶基质。以无纺布作为背衬层，涂二甲基硅油的PET聚酯膜作为防粘层，将以上基质进行涂布、裁切、包装等工序，得孟鲁司特钠凝胶贴膏。
实施例3 ：
处方组成：
制备工艺：
A. 向处方量的卡波和酒石酸中加入纯化水使充分溶胀作为A相；
B. 将处方量的聚丙烯酸钠、甘羟铝、苯甲酸钠、滑石粉、二丁基羟基甲苯混匀，加入处方量的甘油和山梨醇中，搅拌均匀，放至室温作为B相。
C. 另取适量纯化水，加入处方量的孟鲁司特钠使其溶解，作为C相。将A相与C相混合均匀后缓慢加至B相中，继续搅拌直至得到均匀的含药凝胶基质。以无纺布作为背衬层，涂二甲基硅油的PET聚酯膜作为防粘层，将以上基质进行涂布、裁切、包装等工序，得孟鲁司特钠凝胶贴膏。
实施例4：孟鲁司特钠凝胶贴膏的性能试验
初黏力的检测方法为：取凝胶贴膏，揭去防黏层，固定于初黏力测试仪上，倾斜角调整为30°。将一定重量规格(10号)的钢球，自斜面顶端自由滚下，测定钢球被膏体黏住时所滚动的距离，记录读数，重复测量3次，取平均值。以实际测得的最小距离为100分，其余按(最小值/测得值)× 100计算初黏力得分；
持黏力的检测方法为：取凝胶贴膏(6cm× 4cm)，粘贴于试验板表面，垂直放置，沿凝胶贴膏的下端悬挂一200g的砝码，记录5min内下滑距离，重复测量3次，取平均值。以实际测得的最小距离为100分，其余按(最小值/测得值)× 100计算持黏力得分；
剥离强度的检测方法为：取凝胶贴膏(6cm× 4cm)，粘贴于试验板表面，垂直放置，沿凝胶贴膏的上端悬挂一200g的砝码，记录膏体脱落所需时间，重复测量3次，取平均值。以实际测得时间的最小值为100分，其余按(最小值/测得值)× 100计算得分。
从以上实验结果可知，未添加填充剂的凝胶贴膏成型性较差且凝胶贴膏黏附力较大，可能会影响患者的使用感受，样品中应当添加一定量的填充剂。
实施例5：体外透皮试验
将实施例1和实施例3的孟鲁司特钠凝胶贴膏紧密贴于巴马香猪腹部皮肤的角质层面，剪去边缘，固定于Franz垂直扩散池上。接受液为pH7.4的磷酸缓冲液，温度为(32±0.5)℃，恒速搅拌，于0、2、4、6、8、12、24h从接收池中取样，检测接受液中孟鲁司特钠的浓度，并计算累积渗透速率及单位面积的累积渗透量。结果如附图1所示，实施例1的凝胶贴膏累计渗透速率为27.3±2.5 μg/(cm2·h)；实施例3的凝胶贴膏累积渗透速率为11.3±1.6μg/(cm2·h)。以上结果表明，添加了透皮促进剂的凝胶贴膏（实施例1）单位面积累积渗透速率更快，累积渗透量更大。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.治疗小儿哮喘的孟鲁司特钠凝胶贴膏，其特征在于，包括背衬层、含药凝胶层和保护膜（防粘层），含药凝胶层由活性药物孟鲁司特钠、凝胶基质材料、保湿剂、防腐剂、抗氧剂、透皮促进剂及其它药学可接受的外用制剂辅料组成；其中，孟鲁司特钠的含量为凝胶贴膏总重量的1.0%-10.0%，优选地，孟鲁司特钠的含量为凝胶贴膏总重量的2.0%-6.0%。
2.根据权利要求1所述的凝胶贴膏，其特征在于，所述含药凝胶层的凝胶基质材料选自聚丙烯酸部分中和物、聚丙烯酸及其盐（聚丙烯酸、聚丙烯酸钠、聚丙烯酸钾、聚丙烯酸二乙醇胺等）、羧甲基纤维素钠、聚乙烯醇、聚乙烯吡咯烷酮、明胶、阿拉伯胶、卡波姆中至少一种。
3.根据权利要求1-2所述的凝胶贴膏，其特征在于，所述保湿剂选自甘油、山梨醇、尿囊素、聚乙二醇中至少一种。
4.根据权利要求1-3所述的凝胶贴膏，其特征在于，所述防腐剂选自苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、丙酸及其钙或钠盐中至少一种。
5.根据权利要求1-4所述的凝胶贴膏，其特征在于，所述抗氧剂选自丁基羟基茴香醚（BHA）、二丁基羟基甲苯（BHT）、没食子酸丙酯（PG）、特丁基对苯二酚（TBHQ）中至少一种。
6.根据权利要求1-5所述的凝胶贴膏，其特征在于，所述透皮促进剂选自丙二醇、克罗米通、己二酸二异丙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、L-薄荷醇中至少一种。
7.根据权利要求1-6所述的凝胶贴膏，其特征在于，所述其他药学可接受的外用制剂辅料包括但不限于填充剂、交联剂、pH调节剂、色素、香精中至少一种。
8.根据权利要求1-7所述的凝胶贴膏，其特征在于，所述凝胶贴膏含药凝胶层的处方组成包含但不限于：
孟鲁司特钠 2.0%-6.0%
凝胶基质材料 5.0%-40.0%
保湿剂 10.0%-40.0%
防腐剂 1.0%-5.0%
透皮促进剂 0%-5.0%
抗氧化剂 1%-5.0%
填充剂 0%-10.0%
pH调节剂 0%-1.0%
交联剂 0%-8.0%
纯化水 40.0%-70.0%。
9.根据权利要求1-8所述的凝胶贴膏，其特征在于，所述凝胶贴膏含药凝胶层的处方组成包含但不限于：
孟鲁司特钠 35.0 mg/g
聚丙烯酸钠 20.0 mg/g
卡波姆 30.0 mg/g
山梨醇 150.0 mg/g
甘油 150.0mg/g
苯甲酸钠 3.0 mg/g
L-薄荷醇 3.0 mg/g
二丁基羟基甲苯 0.5 mg/g
滑石粉 3.5 mg/g
酒石酸 2.0 mg/g
二羟基氨基乙酸铝 2.0 mg/g
纯化水 601.0 mg/g。
10.根据权利要求9所述的凝胶贴膏，其特征在于，所述凝胶贴膏的制备工艺包括以下步骤：
A. 向处方量的卡波和酒石酸中加入纯化水使充分溶胀作为A相；
B. 将处方量的聚丙烯酸钠、甘羟铝、苯甲酸钠、滑石粉、二丁基羟基甲苯、L-薄荷醇混匀，加入处方量的甘油和山梨醇中，搅拌均匀，放至室温作为B相；
C. 另取适量纯化水，加入处方量的孟鲁司特钠使其溶解，作为C相；
将A相与C相混合均匀后缓慢加至B相中，继续搅拌直至得到均匀的含药凝胶基质；
以无纺布作为背衬层，涂二甲基硅油的PET聚酯膜作为防粘层，将以上基质进行涂布、裁切、包装等工序，得孟鲁司特钠凝胶贴膏。
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