CN112891325A - 一种酮咯酸贴剂的制备及应用 - Google Patents
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Abstract
本发明公开了一种酮咯酸贴剂的制备及应用。贴剂的组成成分包括活性成分、基质材料及其他药学上可接受的外用制剂辅料，基质材料包括热熔型基质材料及溶剂型基质材料。其中，酮咯酸的含量为贴剂总重量的0.1%‑10.0%。酮咯酸贴剂可用于治疗或缓解各种肌肉、软组织及关节的中至重度疼痛。本发明的优势在于，酮咯酸贴剂使用方便、副反应小、安全性高、长时间起效，可提高患者的用药顺应性。
Description
技术领域
本发明涉及药物制剂领域，具体涉及一种酮咯酸贴剂的制备及应用。
背景技术
酮咯酸是一种非甾体类解热镇痛药物，通过抑制前列腺素的合成发挥镇痛、抗炎的作用，可用于缓解多种中至重度急性疼痛及术后疼痛。主要作用于外周的环氧合酶受体，对中枢神经无影响，不会产生成瘾性。
目前已上市的含有酮咯酸的剂型包括口服制剂、注射剂及滴眼液等。但由于酮咯酸的体内代谢较快，口服制剂及注射剂需连续使用，从而导致较严重的胃肠道副作用，使患者顺应性较低。此外，滴眼液本身无法严格控制每次给药剂量，疗效及安全性不可控。
近年来，为克服现有制剂的缺点，已有较多酮咯酸经皮吸收制剂的研究。相较于上述给药剂型，贴剂的优势在于：可避免胃肠道副作用及肝脏首过效应；给药剂量准确，药物血药浓度波动小，安全性高；给药方便，患者顺应性高等。目前已有较多专利公开了含酮咯酸的储库型贴剂，如WO9410986A1公开了一种含有（-）酮咯酸的储库型透皮贴剂。但储库型贴剂制备较为困难，存在剂量倾泻风险。以上制剂都在一定程度上影响了该药在临床上的使用及推广。
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、安全性高、可长时间起效的含酮咯酸的基质型贴剂，以用于治疗或缓解中至重度疼痛。
本发明的技术方案如下：
本发明提供了一种含酮咯酸的皮肤外用贴剂，包括活性成分、基质材料及其他药学上可接受的外用制剂辅料，其特征在于，基质材料包括热熔型基质材料及溶剂型基质材料。其中，酮咯酸的含量为贴剂总重量的0.1%-10.0%。
所述贴剂的活性成分为酮咯酸及其药学上可接受的盐、酯等；优选地，活性成分为酮咯酸。
所述热熔型基质材料选自苯乙烯-异戊二烯-苯乙烯嵌段共聚物（SIS）、聚异丁烯、异戊二烯橡胶、苯乙烯-丁二烯-苯乙烯嵌段共聚物（SBS）中的一种或多种。
所述溶剂型基质材料选自丙烯酸类及其衍生物（丙烯酸聚合物、丙烯酸酯、聚丙烯酸酯、丙烯酸嵌段共聚物等）、聚氨酯类及其衍生物等中的一种或多种。
所述其他药学可接受的外用制剂辅料包括但不限于增粘剂、增塑剂、透皮促进剂、抗氧化剂、防腐剂、pH调节剂等。
增粘剂包括但不限于萜烯树脂、氢化松香甘油酯、松香树脂中的一种或多种。
增塑剂包括但不限于矿物油、聚乙二醇、丙二醇、丙三醇中的一种或多种。
透皮促进剂包括但不限于丙二醇、肉豆蔻酸异丙酯、己二酸二异丙酯、l-薄荷醇中的一种或多种。
抗氧化剂包括但不限于二丁基羟基甲苯、生育酚、抗坏血酸及其盐中的一种或多种。
防腐剂包括但不限于对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、对羟基苯甲酸丙酯、苯甲醇中的一种或多种。
所述溶剂型贴剂的处方组成包含但不限于：
酮咯酸 0.1%-10.0%
溶剂型基质 5.0%-40.0%
增粘剂 5.0%-30.0%
增塑剂 10%-40%
透皮促进剂 0.1%-10.0%
防腐剂 0%-5.0%
pH调节剂 0%-1.0%
抗氧化剂 0%-5.0%
所述热熔型贴剂的处方组成包含但不限于：
酮咯酸 0.1%-10.0%
热熔型基质 5.0%-40.0%
增粘剂 5.0%-30.0%
增塑剂 10%-40%
透皮促进剂 0.1%-10.0%
防腐剂 0%-5.0%
pH调节剂 0%-1.0%
抗氧化剂 0%-5.0%
所述溶剂型贴剂的制备工艺如下：
将处方量的酮咯酸、有机溶剂及溶剂型基质、增塑剂、增粘剂、透皮促进剂等其他辅料混合均匀，涂布于背衬层上，干燥，压合保护层，即得到酮咯酸溶剂型贴剂。
所述热熔型贴剂的制备工艺如下：
将热熔型基质、增塑剂、增粘剂等其他辅料加热熔融并混合均匀；将处方量的酮咯酸、透皮促进剂、防腐剂等其他辅料混合均匀或加至有机溶剂中混合均匀。将上述混合物置于混合容器中，充分混匀，涂布于背衬层上，干燥，压合保护层；或将混合物涂布于背衬层后，直接压合保护层，即得到酮咯酸热熔型贴剂。
所述酮咯酸贴剂可用于治疗或缓解中至重度疼痛。优选地，酮咯酸贴剂可用于治疗或缓解各种肌肉、软组织及关节的中至重度疼痛。
本发明的优势在于：
基于以上，本发明所提供的酮咯酸贴剂使用方便，除去包装及保护膜后将贴剂粘贴于皮肤表面即可。此外，酮咯酸贴剂的安全性高、胃肠道副作用少、给药无痛、长时间起效，可提高患者的用药顺应性。
具体实施方式
在下面的描述中阐述了很多具体细节以便于充分理解本发明。但是本发明能够以很多不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似改进，因此本发明不受下面公开的具体实施的限制。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
实施例1 ：溶剂型贴剂
处方组成：
| 组分 | 处方占比（mg/g） | 作用 |
| 酮咯酸 | 25 | 活性成分 |
| 丙烯酸酯压敏胶（DURO-TAK 129A） | 875 | 溶剂型基质 |
| 丙二醇 | 50 | 透皮促进剂 |
| 肉豆蔻酸异丙酯 | 30 | 透皮促进剂 |
| 二丁基羟基甲苯 | 20 | 防腐剂 |
制备工艺：将酮咯酸、二丁基羟基甲苯溶于丙二醇和肉豆蔻酸异丙酯中，混合均匀。随后将其加入丙烯酸酯压敏胶溶液（DURO-TAK 129A）中，混合均匀。将以上混合物涂布在背衬层上，干燥，接着贴合保护层，切割成需要的大小，即得到酮咯酸溶剂型贴剂。
实施例2 ：溶剂型贴剂
处方组成：
| 组分 | 处方占比（mg/g） | 作用 |
| 酮咯酸 | 50 | 活性成分 |
| 丙烯酸酯压敏胶（DURO-TAK 129A） | 850 | 溶剂型基质 |
| 丙二醇 | 50 | 透皮促进剂 |
| 肉豆蔻酸异丙酯 | 30 | 透皮促进剂 |
| 二丁基羟基甲苯 | 20 | 防腐剂 |
制备工艺：将酮咯酸、二丁基羟基甲苯溶于丙二醇和肉豆蔻酸异丙酯中，混合均匀。随后将其加入丙烯酸酯压敏胶溶液（DURO-TAK 129A）中，混合均匀。将以上混合物涂布在背衬层上，干燥，接着贴合保护层，切割成需要的大小，即得到酮咯酸溶剂型贴剂。
实施例3 ：热熔型贴剂
处方组成：
| 组分 | 处方占比（mg/g） | 作用 |
| 酮咯酸 | 25 | 活性成分 |
| SIS | 200 | 热熔型基质 |
| 聚异丁烯 | 100 | 热熔型基质 |
| 萜烯树脂 | 300 | 增粘剂 |
| 液体石蜡 | 300 | 增塑剂 |
| 肉豆蔻酸异丙酯 | 30 | 透皮促进剂 |
| 己二酸二异丙酯 | 20 | 透皮促进剂 |
| 二丁基羟基甲苯 | 25 | 防腐剂 |
制备工艺：将酮咯酸溶于乙醇，在120～160℃的温度下将所有成分进行熔融炼合，涂布在背衬层上，接着贴合保护层，切割成需要的大小，即得到酮咯酸热熔型贴剂。
实施例4 ：热熔型贴剂
处方组成：
| 组分 | 处方占比（mg/g） | 作用 |
| 酮咯酸 | 50 | 活性成分 |
| SIS | 200 | 热熔型基质 |
| 聚异丁烯 | 100 | 热熔型基质 |
| 萜烯树脂 | 300 | 增粘剂 |
| 液体石蜡 | 275 | 增塑剂 |
| 肉豆蔻酸异丙酯 | 30 | 透皮促进剂 |
| 己二酸二异丙酯 | 20 | 透皮促进剂 |
| 二丁基羟基甲苯 | 25 | 防腐剂 |
制备工艺：将酮咯酸溶于乙醇，在120～160℃的温度下将所有成分进行熔融炼合，涂布在背衬层上，接着贴合保护层，切割成需要的大小，即得到酮咯酸热熔型贴剂。
实施例5：酮咯酸贴剂的黏附力试验
取实施例1-4的酮咯酸贴剂各3片，按照《中国药典（2020年版）》规定，依据通则0952第一法进行贴剂的黏附力检查。结果显示，实施例1-4均可黏住19号钢球，表明以上贴剂均具有良好的初黏力。
实施例6：药效学试验
（1）实验分组
①空白对照组（不进行处理）；②溶剂型酮咯酸贴剂组（实施例1）；③溶剂型酮咯酸贴剂组（实施例2）；④热熔型酮咯酸贴剂组（实施例3）；⑤热熔型酮咯酸贴剂组（实施例4）。
（2）给药方案及评价
取雄性昆明种大鼠50只，雌雄各半，随机分成5组，每组10只，在实验前24 h用电动剃须刀剃除腹部相同部位的鼠毛，约4 cm2，使皮肤裸露。受试组分别于脱毛区贴附酮咯酸贴剂，贴药面积为1 cm x 1 cm，每天给药1次，每次给药6 h，连续给药3天。末次给药后，去除贴剂，每只大鼠腹腔注射新配的0.6%醋酸溶液0.2 ml/10g，计数20 min内大鼠扭体次数并计算疼痛抑制率（抑制率=（空白对照组扭体次数平均值-实验组扭体次数平均值）/空白对照组扭体次数平均值*100%）。
实验结果如下表所示，与空白对照组比较，酮咯酸贴剂各给药组均可显著减少由醋酸所致的扭体次数，且高剂量组（实施例2与实施例4）的镇痛效果略优于低剂量组（实施例1与实施例3）。
| 组别 | 扭体次数 | 抑制率（%） |
| ① 空白对照组 | 16.0±9.3 | N/A |
| ② 溶剂型酮咯酸贴剂组 | 7.8±8.3 | 51.25 |
| ③ 溶剂型酮咯酸贴剂组 | 4.6±8.4 | 71.25 |
| ④ 热熔型酮咯酸贴剂组 | 7.7±8.6 | 51.88 |
| ⑤ 热熔型酮咯酸贴剂组 | 4.5±8.3 | 71.88 |
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)
1.一种酮咯酸贴剂，包括活性成分、基质材料及其他药学上可接受的外用制剂辅料，其特征在于，基质材料包括热熔型基质材料及溶剂型基质材料。
2.根据权利要求1所述的贴剂，其特征在于，活性成分为酮咯酸及其药学上可接受的盐、酯等；优选地，活性成分为酮咯酸。
3.根据权利要求1-2所述的贴剂，其特征在于，酮咯酸的含量为贴剂总重量的0.1%-10.0%。
4.根据权利要求1-3所述的贴剂，其特征在于，所述热熔型基质材料选自苯乙烯-异戊二烯-苯乙烯嵌段共聚物（SIS）、聚异丁烯、异戊二烯橡胶、苯乙烯-丁二烯-苯乙烯嵌段共聚物（SBS）中的一种或多种。
5.根据权利要求1-4所述的贴剂，其特征在于，所述溶剂型基质材料选自丙烯酸类及其衍生物（丙烯酸聚合物、丙烯酸酯、聚丙烯酸酯、丙烯酸嵌段共聚物等）、聚氨酯类及其衍生物等中的一种或多种。
6.根据权利要求1-5所述的贴剂，所述其他药学可接受的外用制剂辅料包括但不限于增粘剂、增塑剂、透皮促进剂、抗氧化剂、防腐剂、pH调节剂等。
7.根据权利要求1-6所述的贴剂，其特征在于，所述溶剂型贴剂的处方组成包含但不限于：
酮咯酸 0.1%-10.0%
溶剂型基质 5.0%-40.0%
增粘剂 5.0%-30.0%
增塑剂 10%-40%
透皮促进剂 0.1%-10.0%
防腐剂 0%-5.0%
pH调节剂 0%-1.0%
抗氧化剂 0%-5.0% 。
8.根据权利要求1-6所述的贴剂，其特征在于，所述热熔型贴剂含药凝胶层的处方组成包含但不限于：
酮咯酸 0.1%-10.0%
热熔型基质 5.0%-40.0%
增粘剂 5.0%-30.0%
增塑剂 10%-40%
透皮促进剂 0.1%-10.0%
防腐剂 0%-5.0%
pH调节剂 0%-1.0%
抗氧化剂 0%-5.0% 。
9.根据权利要求1-8所述的贴剂，其特征在于，所述贴剂可用于治疗或缓解中至重度疼痛。
10.根据权利要求9所述的贴剂，其特征在于，所述贴剂可用于治疗或缓解各种肌肉、软组织及关节的中至重度疼痛。
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