CN116077419B - 一种犬用盐酸司来吉兰透皮吸收剂及其制备方法 - Google Patents
一种犬用盐酸司来吉兰透皮吸收剂及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种犬用盐酸司来吉兰透皮吸收剂及其制备方法,所述透皮吸收剂的组成为:盐酸司来吉兰为2~3%,二乙二醇单乙醚为8~12%,二甲基甲酰胺为12~18%,二丁羟基甲苯为0.01~0.03%,改性木薯淀粉为0.7~1.3%,软膏基质为65~78%。本发明提供的透皮吸收剂可以通过耳部或皮肤涂抹,透皮吸收进入血液,从而发挥治疗效果作用,适用于长期给药,并且制备工艺简单,效果稳定,使用顺从性好,而且采用合理的透皮剂,有助于主要成分缓慢透皮吸收,较长时间内维持一定浓度,1天用药1次,减少用药次数。
Description
技术领域
本发明涉及一种宠物用药,特别涉及一种犬用盐酸司来吉兰透皮吸收剂及其制备方法。
背景技术
犬的认知障碍综合征(Cognitive dysfunction symptom,CDS)是指犬随着年龄增大,在一段时间内,发生记忆、学习、感觉和意识等认知能力下降,主要表现为迷失方向、与主人互动减少和睡眠规律改变等,这会对犬和其主人的生活造成不利影响。在美国的相关调查发现,11~12岁犬有28%比例至少有一项认知障碍的症状,68%的15~16岁的犬至少有一项认知障碍的症状。也有机构针对7岁以上的犬调查,发现75%的7岁以上的犬至少有一种认知障碍症状。
对于犬CDS的药物治疗,北美仅批准了司来吉兰片,它是一种单胺氧化酶B抑制剂,能提高脑中2-苯乙胺的浓度,增加多巴胺和儿茶酰胺的功能,可能还有抗氧化的作用,80%以上的犬在服用一个月后症状好转。国内还没有用于治疗犬CDS的药品和司来吉兰相关制剂。盐酸司来吉兰作用强,分子量适宜(223.75),熔点较低(141.0-145.0℃),而且具有较大的油水分配系数,具备经皮给药系统类药物的特点,适于经皮给药系统。但是因为其分子量较小,熔点较低,活性成分也易于挥发,透皮吸收率较差。
CN1907271A公开了司来吉兰和/或盐酸司来吉兰贴剂基质及其贴剂,司来吉兰和/或盐酸司来吉兰占贴剂基质质量的0.5%~40%,胶粘剂占贴剂基质质量的10%~90%,余量为有机溶剂;其中有机溶剂为乙酸乙脂、乙醇、丙酮、丙二醇中的一种或几种组成。透皮吸收促进剂为油酸、N-甲基吡咯烷酮、聚乙二醇、丙二醇、月桂氮卓酮、三乙酸甘油酯、薄荷油、桉叶油中的一种或几种组成。
CN102144991A公开了含司来吉兰的组合物及含该组合物的透皮贴剂,组合物含有:50~90%的丙烯酸酯粘合剂、1%~15%的聚乙烯吡咯烷酮、1~30%的司来吉兰碱、2~5%的促渗剂。促渗剂选自氮酮、油酸、肉豆蔻酸异戊酯、N-甲基吡咯烷酮、月桂醇硫酸钠、乙酸乙酯、乙二醇、丙三醇、水杨酸等。优选氮酮。
王刚,杜洪光,张恩宏,等。促渗剂对司来吉兰贴片透皮性能的影响[J]。中国药房,2008,19(7):3。采用Franz扩散池进行体外经皮渗透试验,利用高效液相色谱法为浓度测定方法,以不含促渗剂的司来吉兰贴片为对照计算氮酮、油酸和肉豆蔻酸异丙酯的增渗比及表观扩散系数比较促渗剂渗透效果。结果:与对照组比较,质量分数为3%的3种促渗剂增渗倍数分别为1.53、1.37和1.26,表观扩散系数分别增至2.37、1.65、1.13倍。结论:3种促渗剂均可提高司来吉兰贴片的透皮性能,其中以3%氮酮的促渗效果较好。
由于犬的毛发较密长,皮肤比人的皮肤薄,人常用的贴剂并不合适犬用。同时,考虑到治疗犬CDS需要长期给药,宠物口服给药具有一定的不便利性,选择一种易涂抹、易清除,且能保留一定时间的外用剂型,能够克服给药难的问题。因此,针对以上问题,需要开发一种新型的药物治疗犬的认知障碍综合征。
发明内容
本发明的目的在于克服现有技术的至少一个不足,提供一种宠物用盐酸司来吉兰组合物及其制备方法。
本发明所采取的技术方案是:
第一个方面,本发明提供一种犬用盐酸司来吉兰透皮吸收剂,由盐酸司来吉兰、二乙二醇单乙醚、二甲基甲酰胺及药用辅料构成。
在一些实例中,所述盐酸司来吉兰的质量含量为2~3%。
在一些实例中,所述二乙二醇单乙醚的质量含量为8~12%。
在一些实例中,所述药用辅料包括抗氧化剂、肤感剂、软膏基质。
在一些实例中,所述抗氧化剂为二丁羟基甲苯,所述肤感剂为改性木薯淀粉,所述软膏基质由聚乙二醇400和聚乙二醇4000组成。
在一些实例中,所述软膏基质中聚乙二醇400和聚乙二醇4000的质量比为(2~3):1。
在一些实例中,所述透皮吸收剂各组分质量含量为:盐酸司来吉兰为2~3%,二乙二醇单乙醚为8~12%,二甲基甲酰胺为12~18%,二丁羟基甲苯为0.01~0.03%,改性木薯淀粉为0.7~1.3%,软膏基质为65~78%。
在一些实例中,所述犬用盐酸司来吉兰组合物为喷剂、贴膏剂、软膏剂或湿敷剂。
第二个方面,本发明提供的犬用盐酸司来吉兰透皮吸收剂在制备治疗犬的认知障碍综合征药物中的应用。
第三个方面,本发明提供一种犬用盐酸司来吉兰透皮吸收剂的制备方法,包括以下步骤:
1)取盐酸司来吉兰,依次加入二甲基甲酰胺、二乙二醇单乙醚、二丁羟基甲苯、改性木薯淀粉,搅拌至完全溶解,得到混合液体;
2)加热并搅拌软膏基质,待其全部溶解后,再加入步骤1的混合液体,匀质分装即可得到所述宠物用盐酸司来吉兰组合物。
本发明的有益效果是:本发明结合透皮制剂的技术,提供了一种外用的司来吉兰透皮吸收剂,可以通过耳部或皮肤涂抹,透皮吸收进入血液,从而发挥治疗效果作用,克服口服给药的不便利性,适用于长期给药。
本发明提供的盐酸司来吉兰透皮吸收剂工艺简单,效果稳定,使用顺从性好。采用合理的透皮剂,有助于主要成分缓慢透皮吸收,较长时间内维持一定浓度,1天用药1次,减少用药次数。
附图说明
图1为不同样品司来吉兰软膏累计渗透量。
图2为单位时间内不同样品司来吉兰软膏累计渗透量。
具体实施方式
本发明通过透皮剂和溶剂的组合筛选出一种具有24小时缓慢释放的盐酸司来吉兰软膏,长时间维持较为恒定的药物浓度,可以减少用药次数和药物的不良反应。采用水性基质具备易展涂和易清除的特点,合适毛发密长的动物给药。
下文的公开提供了许多不同的实施方式或例子用来实现本发明的不同方案。各种物质的作用列于表1。按照以下方法进行制备实施例1~4以及对比例1~2,不同之处在于,实施例采用的透皮剂为二乙二醇单乙醚,对比例采用的常规透皮剂油醇:
1)把聚乙二醇400和聚乙二醇4000按2.5:1的质量比混合,在65~70℃的温度下边加热边搅拌。待其全部溶解后,45±2℃保温,得软膏基质,备用;
2)取盐酸司来吉兰、加入溶剂和助溶剂,搅拌至完全溶解,再加入抗氧剂,搅拌至全部溶解,最后加入淀粉,置于磁力搅拌器搅拌10-15分钟;
3)将步骤1的软膏基质置于匀质机下,1500-2000转速匀质分散5分钟后,再加入步骤2的液体,匀质15-20分钟,即可。放置于室温后,分装。
表1
表2
名称 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 对比例1 | 对比例2 |
盐酸司来吉兰 | 2.50% | 2.50% | 2.50% | 1.00% | 2.50% | 2.50% |
二甲基甲酰胺 | 15.00% | 15.00% | 18.00% | 12.00% | 0.00% | 15.00% |
二乙二醇单乙醚 | 10.00% | 8.00% | 10.00% | 10.00% | 15.00% | 2.50% |
油醇 | 0.00% | 0.00% | 0.00% | 0.00% | 5.00% | 5.00% |
二丁基羟甲苯 | 0.01% | 0.01% | 0.01% | 0.01% | 0.01% | 0.01% |
改性木薯淀粉 | 1.00% | 1.00% | 1.00% | 1.00% | 1.00% | 1.00% |
软膏基质 | 71.50% | 73.50% | 68.50% | 76.00% | 77.00% | 74.00% |
然后对实施例1~4以及对比例1~2进行外观性状、展涂性、稳定性和体外透皮效果评价,具体评价标准见表3。
表3盐酸司来吉兰透皮软膏的评分标准
(一)外观性状评价
取适量样品,目检外观是否色泽均匀、质地细腻、稠度适宜对各组进行考察并评分,结果见表4。
表4软膏外观性状评价结果
样品 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 对比例1 | 对比例2 |
评价结果 | 10 | 10 | 10 | 9 | 9 | 10 |
(二)展涂性评价
取适量样品,在滤纸上小心涂抹,观察其均匀涂布的难易程度,记录结果并评分,结果见表5。
表5软膏展涂性评价结果
样品 | 实施例1 | 实施例2 | 实施例3 | 实施例4 | 对比例1 | 对比例2 |
评价结果 | 10 | 10 | 9 | 8 | 8 | 9 |
(三)稳定性评价
取软膏剂样品10g,置于离心管中,分别于-20℃和60℃条件下静置24h,恢复室温后,观察上述试验样品是否发生分层、变色等油水分离现象,记录结果并评分,结果见表6。
表6软膏外观性状评价结果
(四)透皮效果评价
采用生物透皮膜作为渗透屏障,使用Franz扩散池法收集渗透液,采用高效液相色谱法测定渗透液中盐酸司来吉兰含量,结果见表7~8以及图1~2。
表7盐酸司来吉兰软膏累计渗透量(ug/ml)
样品 | 1h | 2h | 4h | 6h | 12h | 24h |
实施例1 | 0.54 | 1.16 | 5.96 | 11.87 | 15.05 | 25.62 |
实施例2 | 0.46 | 1.36 | 5.61 | 8.53 | 12.39 | 19.39 |
实施例3 | 0.48 | 1.09 | 4.29 | 8.31 | 13.31 | 23.02 |
实施例4 | 0.56 | 1.20 | 5.73 | 9.79 | 14.11 | 27.54 |
对比例1 | 8.18 | 24.20 | 33.73 | 36.49 | 37.11 | 37.12 |
对比例2 | 3.54 | 10.77 | 13.24 | 13.89 | 15.46 | 15.48 |
表8盐酸司来吉兰软膏单位时间内渗透量(ug/ml)
样品 | 1h | 2h | 4h | 6h | 12h | 24h |
实施例1 | 0.54 | 0.62 | 4.8 | 5.91 | 3.18 | 10.57 |
实施例2 | 0.46 | 0.9 | 4.25 | 2.92 | 3.86 | 7.00 |
实施例3 | 0.48 | 0.61 | 3.2 | 4.02 | 5.00 | 9.71 |
实施例4 | 0.56 | 0.64 | 4.53 | 4.06 | 4.32 | 13.43 |
对比例1 | 8.18 | 16.02 | 9.53 | 2.76 | 0.62 | 0.01 |
对比例2 | 3.54 | 7.23 | 2.47 | 0.65 | 1.57 | 0.02 |
从表7~8中可以看出,由于实施例1~4采用二乙二醇单乙醚以及二甲基甲酰胺,能帮助制成的盐酸司来吉兰软膏在单位时间内渗透量相对平稳,相比于对比例1和对比例2而言,能够在较长时间内维持一定浓度,从而有助于盐酸司来吉兰缓慢透皮吸收,减少用药次数。
以上是对本发明所作的进一步详细说明,不可视为对本发明的具体实施的局限。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的简单推演或替换,都在本发明的保护范围之内。
Claims (5)
1.一种犬用盐酸司来吉兰透皮吸收剂,其特征在于,包括以下质量组成:2~3%盐酸司来吉兰,8~12%二乙二醇单乙醚,12~18%二甲基甲酰胺,65~78%软膏基质,所述软膏基质由聚乙二醇400和聚乙二醇4000组成,所述软膏基质中聚乙二醇400和聚乙二醇4000的质量比为(2~3):1,其余为药用辅料。
2.根据权利要求1所述犬用盐酸司来吉兰透皮吸收剂,其特征在于,所述药用辅料包括抗氧化剂、肤感剂。
3.根据权利要求2所述犬用盐酸司来吉兰透皮吸收剂,其特征在于,所述抗氧化剂为二丁羟基甲苯,所述肤感剂为改性木薯淀粉。
4.根据权利要求3所述犬用盐酸司来吉兰透皮吸收剂,其特征在于,所述透皮吸收剂各组分质量含量为:盐酸司来吉兰为2~3%,二乙二醇单乙醚为8~12%,二甲基甲酰胺为12~18%,二丁羟基甲苯为0.01~0.03%,改性木薯淀粉为0.7~1.3%,软膏基质为65~78%,所述软膏基质由聚乙二醇400和聚乙二醇4000组成,所述软膏基质中聚乙二醇400和聚乙二醇4000的质量比为(2~3):1。
5.一种如权利要求1~4任一项所述犬用盐酸司来吉兰透皮吸收剂在制备治疗犬的认知障碍综合征药物中的应用。
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