CN113712940A - 一种阿伐那非口腔速溶膜的制备方法 - Google Patents
一种阿伐那非口腔速溶膜的制备方法 Download PDFInfo
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Abstract
本发明提供一种治疗勃起功能障碍药物的速溶膜剂及制备方法,所述的治疗勃起功能障碍药物为他达拉非、阿伐那非、伐地那非、枸橼酸醇西地那非、优克那非;所述的速溶膜剂为口腔速溶膜剂,该膜剂组成为(以重量百分比表示):主药10‑25%;聚乙烯醇35‑60%;高取代羟丙基纤维素5%~15%;增塑剂5‑10%;填充剂10‑30%;水1‑8%。制备方法为通过溶剂浇铸法制备膜剂,然后进行压制。本发明重点是1、服药方便、快速给药,迅速起效,提高生物利用度,无首过效应。2、创造性地采用了高取代羟丙基纤维素作为成膜材料,使制剂具有成型好,不粘连不影响药物的稳定性。3、对膜剂进行压制,有利于提高药物的稳定性。
Description
技术领域
本发明涉及一种医药制剂,具体涉及一种口腔速溶膜剂及制备方法尤其是治疗勃起功能障的碍口腔速溶膜剂。
背景技术
口服固体速释制剂泛指口服给药后能快速崩解或溶解,通过口腔或胃肠黏膜迅速释放并吸收的固体制剂。其结合了口服固体和液体制剂的特点,避免普通固体制剂服用后溶散时间长,溶出度低及口服液体制剂携带不便等缺陷。其具有生物利用度高,服用方便,吸收快,不良反应小等优点。
口腔速溶膜(RDF)是把一定剂量的化学药品或中药提取物的有效成分固定在由成膜片材料中制成的制剂。其能在在唾液中崩解的速度约为一分钟,大部分在舌下及黏膜吸收。RDF无需水服,不会堵塞喉咙,释药快,口味好等特点与口腔崩解片相比无需采用特殊的冻干设备,制备工艺简单;无需加入大量的崩解剂,因此携带方便。RDF制剂深受老人及儿童患者喜爱,提高了患者的顺应性。然而速溶膜剂有一些缺陷,其载药量有限只能选择那些高活性的药物,掩盖主药的苦味剂也是要解决的一个问题。
口腔速溶膜剂(Oral Fast Dissolving Films,OFDF),又称为口溶膜、口腔分散膜剂、口腔速溶薄膜剂、口腔速解溶膜、舌下膜、舌膜剂,是一种新的药物传递系统,载药多聚体膜剂,即将一定剂量的化学药品或中药提取物的有效成分固定在变性淀粉及胶体做成的薄膜片上,其大小、形状、厚度类似于邮票,将其置于舌上,无需喝水即可在唾液中快速溶解、释放药物。
口腔速溶膜的优点主要体现在以下几方面:
1.对于局部作用的药物来说,可以直接作用于病灶,提高了生物利用度;
2.对于全身作用的药物来说,活性物质可以经口腔黏膜直接吸收,避免首过效应;
3.不需要用水送服,没有堵塞喉咙的危险,适合儿童和老年患者服用,提高了患者的适应性;
4.本品为固体制剂,形如邮票,都可以放在钱夹里,随身携带很方便;
5.与口腔崩解片和冻干片(Lyophilized Wafer)相比,生产工艺简单,包装成本较低,适合工业化生产。
口腔速溶膜也有特定的缺点,比如载药量有限,只能选择那些高活性的药物。如何掩盖主药的苦味、异味也是需要解决的问题
本发明的发明目的是提供一种口腔速溶膜剂及制备方法,以实现快速崩解,快速释药,携带方便。
为达到上述发明目的,本发明采用的技术方案是:一种口腔速溶膜剂,各组分以重量百分计为:
药物活性成分10-25%
水溶性成膜材料聚乙烯醇35-60%;高取代羟丙基纤维素5%~15%;
增塑剂5-10%
填充剂10-30%
水1-8%
所述药物活性成分为阿伐那非、优克那非。
上述技术方案中,所述水溶性成膜材料选自聚乙烯醇、高取代羟丙基纤维素中的一种或两种以上的混合物。
优选地,所述水溶性成膜材料是聚乙烯醇,所述聚乙烯醇的聚合度 500~1700,醇解度78~99。
更优选的所述聚乙烯醇的聚合度为1700,醇解度为88,即聚乙烯醇1788
所述增塑剂选自甘油、丙二醇的一种。
上述的口腔速溶膜的制备方法,包括下列步骤
1)将水溶性成膜材料在搅拌状态下加入水中,缓缓升温,于60~80℃水浴条件下充分搅拌,溶解,得到聚合物凝胶。
2)在上述聚合物凝胶中加入增塑剂、崩解剂并搅拌均匀。
)加入药物活性成分搅拌均匀得到含药溶液。
实施例3
加热干燥,加热干燥温度40~60℃,切割,得到所述膜剂
优选技术方案,步骤1中,水浴温度为80℃
由于上面方案运用,本发明与现有技术相比有以下优点
本发明重点是1)服药方便、快速给药,迅速起效,提高生物利用度,无首过效应。
2)创造性地采用了高取代羟丙基纤维素作为成膜材料,使制剂具有成型好,不粘连不影响药物的稳定性。对膜剂进行压制,有利于提高药物的稳定性。
按照申报临床研究用质量标准与中国药典2010年版二部附录“药物稳定性试验指导原则”胶囊剂的稳定性试验所列的考察项目,我们对本品进行了稳定性考察。
具体实施方式
下面结合实施例具体说明
实施例1
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入聚乙二醇4000,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能差,韧性差,易碎。
实施例2
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能差。
实施例3
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘油,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热 2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,柔韧,表面较黏。
实施例4
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入丙二醇,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,柔韧。
实施例5
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入聚乙二醇4000,甘油,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板, 40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,柔韧。
实施例6
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘油,山梨醇,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,柔韧。
实施例7
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,甘油,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,柔韧。
实施例8
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,微晶纤维素,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热 2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,表面有颗粒,不光滑。
实施例8
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,羟甲基纤维素钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好。
实施例9
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,羟甲基纤维素钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,表面有颗粒,不光滑。
实施例10
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,琼脂,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,表面有颗粒,不光滑。
实施例11
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将溶液均匀涂布于0.15×0.15㎡的不锈钢板,40~60℃鼓风装置加热 2小时。脱膜,切割,再得到膜剂,透明,脱膜性能好,柔韧。
实施例12
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将处方量的阿伐那非加入上述溶液,搅拌,使阿伐那非均匀分散于溶液中。将溶液均匀涂布于0.03×0.10㎡的不锈钢板,40~60℃鼓风装置加热2 小时。脱膜,按0.02×0.03㎡即得含药量为20mg/片的薄膜,该膜呈白色,脱膜性能好,柔韧。
实施例13
先将上述量的高取代羟丙基纤维素在搅拌状态下加入到纯化水中,水浴溶解,得到凝胶液,再加入甘露醇,透明质酸钠,搅拌溶解,将配置好的溶液静置或超声除去气泡,将处方量的阿伐那非加入上述溶液,搅拌,使阿伐那非均匀分散于溶液中。将溶液均匀涂布于0.03×0.10㎡的不锈钢板,40~60℃鼓风装置加热2小时。脱膜,按0.02×0.03㎡即得含药量为20mg/片的薄膜,该膜呈白色,脱膜性能好,柔韧。
实施例15
口腔溶膜崩解时间测定法
将100ml蒸馏水加入100ml置于磁力搅拌器上,37℃恒温水浴,转速100r/min, 将测试膜夹在夹子上,放在水浴中开始计时,记录溶解时间,每块膜剂将随机剪裁3块尺寸为0.01×0.01㎡的小膜测定,三块测量结果的平均时间为小膜崩解的时间。
采用本法对实施例获得的膜的崩解时间进行测定,可以看出改变空白膜中的增塑剂,崩解剂的组成及用量,均对崩解时间产生影响。
实施例16
按照申报临床研究用质量标准与中国药典2010年版二部附录“药物稳定性试验指导原则”稳定性试验所列的考察项目,我们对本品进行了稳定性考察。
影响因素试验
温度影响因素试验试验方法:取样品1批,除去外包装,分别置于温度室温、 40℃、60℃的条件下放置10天,于第5天、第10天分别取样检测,以外观、溶出度、阿伐那非含量有关物质为主要考察指标,与0天数据对比考察制剂对温度的稳定性。结果见表1。
表1 温度影响因素试验
*:代表透明薄膜
光照影响因素试验试验方法:取样品1批,除去外包装,分别置于室内、4500lx ±500lx光照的条件下放置10天,于第5天、第10天分别取样检测,以外观、溶出度、阿伐那非含量、有关物质为主要考察指标,与0天数据对比考察制剂对温度的稳定性。
表2 光照影响因素试验
*:代表透明薄膜
结果显示:本品对40℃高温、60℃高温、4500lx强光照、均表现稳定,性状、阿伐那非含量和0天比较均无明显差异。
加速试验试验方法:取样品3批,按上市包装,置温度为40℃±2℃、相对湿度为75%±5%的药物稳定性试验箱中,放置6个月,于第1、2、3、6月末取样检测,以外观、溶出度、阿伐那非含量、有关物质为主要考察指标,与0 月数据对比考察制剂加速稳定性。结果见表3。
表3 加速稳定性试验
*:代表透明薄膜
结果显示:本品40℃加速6个月,性状、溶出度、有关物质、阿伐那非含量均符合规定,且与0月比较无明显差异。
长期试验试验方法:取样品3批,按上市包装,在温度25℃±2℃、相对湿度60%±10%条件下放置36个月,分别于第3、6、9月末取样检测,以性状、溶出度、有关物质、阿伐那非含量为主要考察指标,与0月数据对比考察制剂长期稳定性。结果如表5所示。
长期稳定性试验
*:代表透明薄膜
结果显示:本品25℃长期9个月,性状、溶出度、有关物质、阿伐那非含量均符合规定,且与0月比较无明显差异。
Claims (7)
1.本发明提供一种快速起效的速溶膜剂及制备方法,所述的药物为阿伐那非、优克那非;所述的速溶膜剂为口腔速溶膜剂,该膜剂组成为(以重量百分比表示):主药10-25%;聚乙烯醇35-60%;高取代羟丙基纤维素5%~15%;增塑剂5-10%;填充剂10-30%;水1-8%。
2.制备方法为通过溶剂浇铸法制备膜剂,然后进行压制。
3.根据权利要求1所述的治疗勃起功能障碍的药物为阿伐那非、优克那非及其各个药物所对应的盐;
根据权利要求1所述的口腔速溶膜的制备方法中,其主要特征在于高取代羟丙基纤维素用量为5%~15%之间,更进一步优化的用量为8%~12%之间。
4.根据权利要求1所述的口腔速溶膜的制备方法中,增塑剂主要为甘油、丙二醇、聚乙烯醇、玻璃酸钠等。
5.根据权利要求4中,增塑剂其用量为5%~10%之间,更进一步优化的用量为8%~9%之间。
6.根据权利要求1所述的口腔速溶膜的制备方法中,填充剂主要为甘露醇、山梨醇等。
7.根据权利要求6中,填充剂其用量为10%~30%之间,更进一步优化的用量为20%~25%之间。
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