CN1989955A - 联苯乙酸巴布剂 - Google Patents
联苯乙酸巴布剂 Download PDFInfo
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- CN1989955A CN1989955A CN 200510135284 CN200510135284A CN1989955A CN 1989955 A CN1989955 A CN 1989955A CN 200510135284 CN200510135284 CN 200510135284 CN 200510135284 A CN200510135284 A CN 200510135284A CN 1989955 A CN1989955 A CN 1989955A
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Abstract
本发明公开了一种联苯乙酸巴布剂及制备方法，基质含有水溶性高分子化合物骨架、填充剂、交联剂、交联调节剂、保湿剂、透皮促进剂。该巴布剂中的药物经透皮吸收良好，可持续性地释放药物，作用时间可达12小时，透气性好，无刺激性，该巴布剂基质的pH值为3－7，含有平均粒径5～70μm的联苯乙酸结晶。
Description
发明领域
本发明涉及一种能通过皮肤缓慢吸收、避免NSAIDs胃肠道反应的镇痛消炎外用联苯乙酸(Felbinac)巴布剂。
背景技术
联苯乙酸是芬布芬进入体内后代谢的活性成份，是一种非甾体类抗炎药，可通过有效抑制体内前列腺素的合成，起到抗炎、镇痛的作用。
由于口服联苯乙酸会产生NSAIDs反应，现临床上多使用联苯乙酸凝胶剂，但凝胶剂易粘污衣物，所以我们根据药物的特点制备了外用制剂巴布剂。巴布剂不同于一般贴剂，除具有无首过效应、血药浓度平稳、起效快、作用时间长、生物利用度高等特点外，还具有透气性好、载药量大、药物可缓慢释放、对皮肤无刺激性，且适用于工业化生产等优势。
联苯乙酸是一种难溶性的药物，为制备联苯乙酸的巴布剂，发现一种适宜的巴布剂基质并制备成具有理想的透皮率，并没有明显的皮肤刺激性的联苯乙酸巴布剂是急需解决的。
发明内容
本发明提供了一种联苯乙酸巴布剂，含有由联苯乙酸、水溶性聚合物、溶剂或助溶剂、交联剂、交联调节剂、保湿剂组成的基质，还可以含有皮肤促渗剂和赋形剂，在给药后能无迟滞地顺利释放并可达到长效的目的。
在本发明中基质含有水溶性高分子聚合物，可以选自聚丙烯酸钠、聚丙烯酸钠-聚丙烯酸、聚丙烯酸中的一种或多种，优选聚丙烯酸钠-聚丙烯酸(50∶50)。
本发明中基质还含有作为溶剂或助溶剂的二乙醇胺，三乙醇胺、二异丙醇胺和吐温中的一种或多种，优选吐温80；
在本发明中基质还含有选自氢氧化铝、氧化铝、水合三氯化铝、醋酸铝、硫酸铝、甘氨酸铝和甘羟铝的一种或多种的交联剂，优选甘羟铝
在本发明中基质还含有选自酒石酸、柠檬酸、乳酸、磷酸、马来酸、苹果酸、EDTA的交联调节剂，优选酒石酸；
在本发明中基质还含有选自甘油、丙二醇、山梨醇、木糖醇等多元醇做为保湿剂，优选甘油；
在本发明中的基质还含有为了调节基质的硬度使用了赋型剂交联聚维酮PVPK-90。
在本发明中基质还含有渗透增强剂，选自N-甲基-吡咯烷酮、丙二醇、聚乙二醇、乙醇、油醇中的一种或多种。
在本发明中还提供一种的巴布剂，其基质的pH为3～8，优选4～6。
在本发明中还提供一种的巴布剂，其基质中含有平均粒径为5～70μm，优选5～30μm，最优选5μm的联苯乙酸结晶颗粒。
本发明还提供了一种联苯乙酸巴布剂的制备方法：将水溶性高分子化合物与交联剂分散于甘油中得到A相，将联苯乙酸、交联调节剂溶解在含有有机弱酸或有机弱碱的水溶液中得到B相，然后将B相置于A相中搅拌交联成含有联苯乙酸的巴布剂基质，将该巴布剂基质涂在无粘性的无纺布表面即可。
本发明还提供一种联苯乙酸巴布剂：含有联苯乙酸0.4～0.5％，水溶性高分子化合物4～6％、填充剂2％，交联剂0.1～0.4％，交联调节剂0.2％，保湿剂30～50％，透皮促进剂3～5％，药物溶剂3～7％，水20～40％。该巴布剂基质的pH值为4.0～7.0，并且含有平均粒径为5～70μm，优选5～30μm的联苯乙酸结晶颗粒，涂铺厚度为800μm。
具体实施方式
本发明通过以下实施例作进一步阐述，但并不限制本发明的范围。
实施例1
处方
| 序号 | 名称 | Percent(％) | 重量(g) |
| A相123B相1234567 | 聚丙烯酸钠-聚丙烯酸(50∶50)甘羟铝甘油酒石酸EDTA蒸馏水PVPK-90N-甲基-吡咯烷酮三乙醇胺联苯乙酸 | 50.228.570.30.0757.142.863.571.790.5 | 0.70.034.00.040.018.00.40.50.250.07 |
| 总量 | 14 | ||
制备工艺：
将聚丙烯酸钠-聚丙烯酸与甘羟铝分散于甘油中得到A相，将联苯乙酸、三乙醇胺、酒石酸与EDTA、N-甲基-吡咯烷酮、PVPK-90溶解在水中得到B相，然后将B相快速倒入A相后迅速搅拌均匀，放置5h后，将交联好的混合物涂在无黏性的薄膜表面，置聚乙烯袋内密封即可。在得到的巴布剂中，联苯乙酸以20μm的结晶形态存在于基质中。
实施例2
处方
| 序号 | 名称 | Percent(％) | 重量(g) |
| A相123B相1234567 | 聚丙烯酸钠-聚丙烯酸(50∶50)甘羟铝甘油酒石酸EDTA蒸馏水PVPK-90N-甲基-吡咯烷酮吐温-80联苯乙酸 | 50.228.570.30.0757.572.863.571.790.5 | 0.70.034.00.040.018.060.40.50.250.07 |
| 总量 | 14 | ||
制备工艺：
将聚丙烯酸钠-聚丙烯酸与甘羟铝分散于甘油中得到A相，将联苯乙酸、吐温-80、酒石酸与EDTA、N-甲基-吡咯烷酮、PVPK-90溶解在水中得到B相，然后将B相快速倒入A相后迅速搅拌均匀，放置5h后，将交联好的混合物涂在无黏性的薄膜表面，置聚乙烯袋内密封即可。在得到的巴布剂中，联苯乙酸以5μm的结晶形态存在于基质中。
实施例3
处方
| 序号 | 名称 | Percent(％) | 重量(g) |
| A相123B相1234567 | 聚丙烯酸钠-聚丙烯酸(50∶50)甘羟铝甘油酒石酸EDTA蒸馏水PVPK-90N-甲基-吡咯烷酮三乙醇胺联苯乙酸 | 50.228.570.70.0757.142.863.571.790.5 | 0.70.034.00.10.018.00.40.50.250.07 |
| 总量 | 14 | ||
制备工艺：
将聚丙烯酸钠-聚丙烯酸与甘羟铝分散于甘油中得到A相，将联苯乙酸、三乙醇胺、酒石酸与EDTA、N-甲基-吡咯烷酮、PVPK-90溶解在水中得到B相，然后将B相快速倒入A相后迅速搅拌均匀，放置5h后，将交联好的混合物涂在无黏性的薄膜表面，置聚乙烯袋内密封即可。在得到的巴布剂中，联苯乙酸以大约30μm的结晶形态存在于基质中。
实施例4
处方
| 序号 | 名称 | Percent(％) | 重量(g) |
| A相123B相1234567 | 聚丙烯酸钠-聚丙烯酸(50∶50)甘羟铝甘油柠檬酸EDTA蒸馏水PVPK-90N-甲基-吡咯烷酮三乙醇胺联苯乙酸 | 50.228.570.30.0757.142.863.571.790.5 | 0.70.034.00.040.018.00.40.50.250.07 |
| 总量 | 14 | ||
制备工艺：
将聚丙烯酸钠-聚丙烯酸与甘羟铝分散于甘油中得到A相，将联苯乙酸、三乙醇胺、柠檬酸与EDTA、N-甲基-吡咯烷酮、PVPK～90溶解在水中得到B相，然后将B相快速倒入A相后迅速搅拌均匀，放置5h后，将交联好的混合物涂在无黏性的薄膜表面，置聚乙烯袋内密封即可。在得到的巴布剂中，联苯乙酸以大约10μm的结晶形态存在于基质中。
对比实施例1
处方
| 序号 | 名称 | Percent(％) | 重量(g) |
| A相123B相1234567 | 聚丙烯酸钠-聚丙烯酸(50∶50)甘羟铝甘油酒石酸EDTA蒸馏水PVPK-90N-甲基-吡咯烷酮三乙醇胺药物 | 50.226.780.30.0757.142.863.573.570.5 | 0.70.033.750.040.018.00.40.50.50.07 |
| 总量 | 14 | ||
制备工艺：
将处方量的聚丙烯酸钠-聚丙烯酸与甘羟铝分散于甘油中得到A相，将联苯乙酸、三乙醇胺、酒石酸与EDTA、N-甲基-吡咯烷酮、PVPK-90溶解在水中得到B相，然后将B相快速倒入A相后迅速搅拌均匀，放置5h后，最后将混合物涂在无黏性的薄膜表面，置聚乙烯袋内密封即可。在得到的巴布中，联苯乙酸以溶解状态存在基质中。
各实施例大鼠皮肤透过实验。
为了比较制剂中联苯乙酸的经皮肤吸收性，利用大鼠进行皮肤透过实验，采用体重约200g的Wistar大鼠的背部皮肤，考察实施例1、2、3、4中药物的透过量。实验装置中使用改进的Franz型扩散池，用pH 7.4磷酸盐缓冲液作为接受池溶液，在32.0±0.5℃条件下进行实验。把大鼠皮肤置于Franz型扩散池上部，将巴布剂冲裁成3.8cm2(φ＝2.2cm)的圆片置于皮肤上。然后分别于1、2、4、8、12、18h吸取受体溶液2ml，并立即补充同量的接受液，采用HPLC法测定含量，测定条件为C8色谱柱，水∶甲醇＝30∶70为流动相，检测波长为254nm，测定透过了大鼠皮肤的药物累积透过量。测定结果(各3例的平均值，单位μg/cm2)见表1中。
表1：联苯乙酸巴布剂中药物经皮累积透过量
| 时间(h) | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 比较例1 |
| 12481218 | 0.901.342.659.3720.4336.66 | 0.431.464.8410.4017.5135.13 | 0.270.783.8314.7829.0352.44 | 0.670.981.735.5011.2823.01 | 0.360.962.636.2610.6110.93 |
本发明从上述结果可以看出，药物以结晶形式存在基质时，经皮累积透过量在18h内大于以溶解状态；而且发现药物呈不同的粒径大小而有不同的皮肤透过率，其中以颗粒为5～30μm时为佳，以5μm时最佳，从上表可见，不同的溶剂对药物的透过量也有不同的影响，其中以吐温80时较好，可能此非离子表面活性剂同时具有透皮促进剂的作用。
Claims (10)
1.一种联苯乙酸巴布剂，其特征在于含有由联苯乙酸、水溶性聚合物、溶剂或助溶剂、交联剂、交联调节剂、保湿剂组成的基质，还可含有皮肤促渗剂和赋形剂。
2.权利要求1所述的巴布剂，其特征在于含有天然的或人工合成的水溶性聚合物，可选自聚丙烯酸钠、聚丙烯酸钠-聚丙烯酸和聚丙烯酸中的一种或多种，优选聚丙烯酸钠-聚丙烯酸(50∶50)。
3.权利要求1所述的巴布剂，其特征在于溶剂或助溶剂为选自二乙醇胺、三乙醇胺，二异丙醇胺和吐温的一种或几种，优选吐温-80。
4.权利要求1所述的巴布剂，其特征在交联剂为选自氢氧化铝、氧化铝、水合三氯化铝、醋酸铝、硫酸铝、甘氨酸铝和甘羟铝的一种或多种，优选甘羟铝。
5.权利要求1所述的巴布剂，其特征在于交联调节剂为选自酒石酸、柠檬酸、乳酸、磷酸、马来酸、苹果酸和EDTA的一种或多种，优选酒石酸。
6.权利要求1中的巴布剂，其特征在于保湿剂为选自甘油、丙二醇、山梨醇和木糖醇的一种或几种，优选甘油。
7.权力要求1～7任一项所述的巴布剂，其特征在于基质的pH为3～8，优选4～6。
8.权力要求1～8任一项所述的巴布剂，其特征在于基质中含有平均粒径为5～70μm，优选5～30μm，最优选5μm的联苯乙酸结晶颗粒。
9.权利要求1所述的巴布剂的制备方法，将水溶性高分子化合物与交联剂分散于甘油中得到A相，将联苯乙酸、交联调节剂溶解在含有有机弱酸或有机弱碱的水溶液中得到B相，然后将B相置于A相中搅拌交联成含有联苯乙酸的巴布剂基质，将该巴布剂基质涂在无粘性的无纺布表面即可。
10.用于镇痛消炎的如权力要求1～9任一项所述的外用联苯乙酸巴布剂。
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| CN101416955B (zh) * | 2008-11-26 | 2013-03-27 | 重庆医药工业研究院有限责任公司 | 一种改良的巴布剂的基质及其运用 |
| CN103356508A (zh) * | 2012-03-27 | 2013-10-23 | 上海卫生材料厂有限公司 | 积雪草总苷巴布剂及其制备方法 |
| WO2022188861A1 (zh) * | 2021-03-12 | 2022-09-15 | 上海创始医疗科技(集团)股份有限公司 | 一种具有缓释功能的高分子水凝胶及其制备方法和应用 |
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| JP4648518B2 (ja) * | 2000-06-01 | 2011-03-09 | 帝國製薬株式会社 | ４−ビフェニル酢酸含有貼付剤 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101416955B (zh) * | 2008-11-26 | 2013-03-27 | 重庆医药工业研究院有限责任公司 | 一种改良的巴布剂的基质及其运用 |
| CN103356508A (zh) * | 2012-03-27 | 2013-10-23 | 上海卫生材料厂有限公司 | 积雪草总苷巴布剂及其制备方法 |
| WO2022188861A1 (zh) * | 2021-03-12 | 2022-09-15 | 上海创始医疗科技(集团)股份有限公司 | 一种具有缓释功能的高分子水凝胶及其制备方法和应用 |
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