CN102018671B - 一种***透皮喷雾剂及其制备方法 - Google Patents
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Abstract
本发明公开了一种***透皮喷雾剂由以下重量百分比原料组成:0.1%~10%***;0.5%~10%聚合物;0~20%促渗剂;0~10%增塑剂;余量为溶剂。本发明的***透皮喷雾剂以喷雾的形式给药于皮肤,溶剂挥发后形成均一的聚合物薄膜,药物以分子的形式分散在薄膜中,不但提高药物经皮渗透的效果,具有持续稳定的血药浓度,而且患者顺应性好。***透皮喷雾剂装于喷雾装置内可直接使用,使用方便、简单,并可根据需要,自由的调整用药量。本发明还公开了***透皮喷雾剂的制备方法,可操作性强,工艺条件要求不高,简单易行,易于工业化生产。
Description
技术背景
本发明涉及药物制剂领域,具体涉及一种***透皮喷雾剂及其制备方法。
背景技术
***是内源性***,主要的临床应用有:改善更年期症状(治疗更年期综合症)、降低缺血性心血管疾病的危险性和病死率、预防早老性痴呆即阿尔兹海默病、防治骨质疏松症等。
目前,***最常用的给药方法是口服、***给药和经皮给药。口服的给药方法,由于存在肝首过效应,***的口服生物利用度很低,半衰期为1.7h;且***会影响肝内蛋白质的代谢,可能导致胆囊炎等疾病,存在较大的副作用。***给药方式会对患者产生子宫放大反应的副作用,且患者适应性差。
理想的经皮给药方式候选药物的分子量应在500以下,熔点小于200℃,在水和油中均有一定的溶解度,饱和水溶液的pH在5~9之间。由于皮肤对外界物质的屏障作用,候选药物的日给药剂量一般小于50mg/天。另外,生物半衰期短(<5h)、首过效应大、分布容积小的药物,制成经皮给药制剂可以避免首过效应,延长药物作用时间,减少血药浓度波动。***的理化性质符合经皮给药候选药物的要求。
***经皮给药不但可以达到与口服给药一样好的效果,而且能避免肝脏首过效应和血药浓度的波动,同时,胃肠道的副反应也更少。***的经皮给药已广泛用于绝经后潮红、盗汗等症状的治疗,同时,也用于心血管疾病、骨质疏松和卵巢功能退化的预防。
目前,***的经皮给药制剂有贴剂、乳膏和凝胶等。***的经皮给药贴剂含有活性物质***和一些促透剂或其他活性物质,并具有对活性物质和湿气不渗透的背层、含活性物质的基质层以及保护层的层状结构。市场上在售的***贴剂有伊尔、得美素(Dermestril)、松奇(Fem 7)、欧适可(Oesclim)、康美华(Climara),国外市场还有Esclim、EstradermMENOSTAR、Vivelle-Dot等。申请号为CN95194678.1、CN99808853.6、CN95197296.0的中国专利申请以及中国专利ZL95194677.3、ZL95111587.1、ZL99808852.8、ZL94192007.0和ZL01819090.1中公开了不同的***贴剂,这些***贴剂都具有基本层状结构,但它们又各自具有不同的特点。市场上在售的凝胶商品有***凝胶、爱斯妥(EstroGel),国外市场还有Elestrin、。贴剂给药存在着皮肤刺激性和粘贴性能的问题,乳膏和凝胶等半固体制剂不能准确地决定给药剂量,容易因摩擦而去除,不仅影响透皮效果,而且污染衣物,患者顺应性差,存在着技术缺陷。
美国食品和药物管理局(FDA)批准维瓦士(VIVUS)公司的***定量透皮喷雾剂伊伐米特(EvaMist)上市,用于治疗绝经后妇女中度至严重的血管舒缩症状。此透皮喷雾剂由***、挥发性溶媒乙醇和水杨酸乙基己酯组成,但存在着药效持久性相对较差的技术问题。
发明内容
本发明提供了一种具有持续稳定的血药浓度的***透皮喷雾剂,该药剂以喷雾的形式给药于皮肤,溶剂挥发后形成均一的聚合物薄膜,药物以分子的形式分散在薄膜中,不但提高了药物经皮渗透的效果,而且患者顺应性好。
本发明还提供了一种***透皮喷雾剂的制备方法,该制备方法简单,可操作性强,工艺条件要求不高,简单易行,易于工业化生产。
一种***透皮喷雾剂,由以下重量百分比的原料组成:
*** 0.1%~10%;
聚合物 0.5%~10%;
促渗剂 0~20%;
增塑剂 0~10%;
溶剂 余量。
为了达到更好的发明效果,优选所述的***透皮喷雾剂,由以下重量百分比的原料组成:
*** 0.2%~6%;
聚合物 2%~8%;
促渗剂 0~5%;
增塑剂 0~1%;
溶剂 余量。
为了达到***透皮喷雾剂持续稳定给药的目的,需要加入能形成薄膜的聚合物,所述的聚合物优选为甲基丙烯酸酯共聚物、乙烯吡咯烷酮共聚物、纤维素衍生物中的一种或多种,具体使用时可根据这些聚合物理化性质通过溶剂调节其在***透皮喷雾剂中的浓度,以使***透皮喷雾剂在使用时的成膜速度和成膜性状良好。
所述的甲基丙烯酸酯共聚物优选为丙烯酸丁酯/甲基丙烯酸二甲氨基乙酯/甲基丙烯酸甲酯聚合物(如尤特奇E100(Eudragit E100))、丙烯酸乙酯/甲基丙烯酸甲酯/甲基丙烯酸氯化三甲胺基乙酯聚合物(如尤特奇RSPO(Eudragit RS PO)、尤特奇RL PO(Eudragit RL PO))、甲基丙烯酸/甲基丙烯酸甲酯聚合物(如尤特奇S100(Eudragit S100))、肠溶型I号树脂、肠溶型II号树脂、肠溶型III号树脂中的一种或多种。
所述的乙烯吡咯烷酮共聚物优选为乙烯吡咯烷酮和醋酸乙烯酯共聚物(如Plasdone S630)、乙烯吡咯烷酮醋酸乙烯共聚物(如Agrimer VA64)、聚乙烯基吡咯烷酮K30(PVP K30)中的一种或多种。
所述的纤维素衍生物优选为羟丙基纤维素,所述的羟丙基纤维素可选用低取代羟丙基纤维素(L-HPC)、Klucel EF、Klucel MF、Klucel GF等中的一种或多种(Klucel为羟丙基纤维素的商品名)。
所述的聚合物在喷雾剂给药于皮肤后,溶剂挥发后形成均一的聚合物薄膜,使药物分子均匀分散在薄膜中,使得药剂具有持久稳定的血药浓度。
为了进一步改善***透皮喷雾剂的性能,可以在***透皮喷雾剂中加入促渗剂,以增加***透皮速率,所述的促渗剂优选为饱和脂肪酸、不饱和脂肪酸、饱和脂肪酸酯、不饱和脂肪酸酯、月桂氮酮(即氮酮)、醇、萜烯中的一种或多种。更优选地,促渗剂为月桂氮酮、吐温20、油酸、薄荷醇(又名薄荷脑)、肉豆蔻酰异丙酯中的一种或多种。
所述的增塑剂优选为柠檬酸三乙酯、柠檬酸丁酯、聚山梨酯80、醋酸三甘酯中的一种或多种。它们可以使聚合物形成的薄膜有一定的柔软性,有利于粘附于皮肤上。
所述的溶剂选用药用级溶剂,优选为乙醇、丙二醇、异丙醇中的一种或多种,它们可以溶解喷雾剂中的各种组分,形成均一的液体,其中乙醇具有较低的沸点容易挥发,丙二醇和异丙醇既可起到溶剂的作用也可起到增塑剂的作用。
所述的***透皮喷雾剂的制备方法,包括以下步骤:
以重量百分比计,取0.1%~10%***、0.5%~10%聚合物、0~20%促渗剂、0~10%增塑剂和余量的溶剂混合均匀后形成溶液,装于喷雾装置中,得到***透皮喷雾剂。
本发明的有益效果是:
相对于现有的药贴剂、乳膏等其他的经皮给药方式,本发明***透皮喷雾剂,以喷雾的形式给药于皮肤,溶剂挥发后形成均一的聚合物薄膜,药物以分子的形式分散在薄膜中,***通过喷雾经皮渗透途径给药,能够延长药物作用时间,维持稳定的血药浓度,减少药物的副作用。
本发明***透皮喷雾剂,其选择的原料组成和配比合理,刺激性小,副作用少,患者顺应性好。
本发明***透皮喷雾剂装于喷雾装置内可直接使用,使用方便、简单,并可根据需要,自由的调整用药量。
附图说明
图1是本发明实施例20制备的***透皮喷雾剂、市场上在售***贴剂和***凝胶剂的经皮渗透曲线;其中,■代表***透皮喷雾剂;◇代表***贴剂;△代表***凝胶。
具体实施方式
本发明通过以下的实施例做进一步阐述。除非另有说明,所述的百分比均为重量百分比。
实施例1~13
按下表称取***、聚合物、增塑剂和促渗剂,加乙醇溶解至10g,装于定量喷雾装置内,制得***透皮喷雾剂。
将制得的***透皮喷雾剂喷雾于玻璃板上,观察是否能够形成喷雾、成膜速度和所成膜的性状。
表1喷雾剂的处方组成及成膜性能
实施例14
称取***0.1g、尤特奇RL PO 0.5g,加乙醇溶解至10g,装于定量喷雾装置内,制得***透皮喷雾剂。
将制得的***透皮喷雾剂进行体外经皮渗透实验:
采用TK-12型透皮扩散试验仪,以乳猪皮肤为皮肤模型,考察***喷雾剂的经皮渗透速率。取去除皮下组织的乳猪皮肤置于生理盐水中洗净。将其角质层朝上固定在扩散池的供给池与接受池之间,排尽气泡,循环水保持(37±0.5)℃。接受池内加入预先脱气的接受介质,加搅拌子以300r·min-1的速度搅拌。将***喷雾剂喷于皮肤上,分别于2,4,8,18,20,22,24h取样1ml,并补充等量同温的接收液。取得的接受液以12000r·min-1离心10min后,高效液相色谱(HPLC)-荧光法测定药物含量。
***的稳态渗透速率为0.12μg·cm-2·h-1,24h累积渗透量为2.67±0.039μg·cm-2。
实施例15
称取***0.1g、羟丙基纤维素Klucel EF 0.5g,加乙醇溶解至10g,装于定量喷雾装置内,制得***透皮喷雾剂。
将制得的***透皮喷雾剂进行体外经皮渗透实验,试验方法如实施例14。
***的稳态渗透速率为0.053μg·cm-2·h-1,24h累积渗透量为1.43μg·cm-2。
实施例16
称取***0.1g、尤特奇RL PO 0.5g、薄荷脑0.5g,加乙醇溶解至10g,装于定量喷雾装置内,制得***透皮喷雾剂。
将制得的***透皮喷雾剂进行体外经皮渗透实验,试验方法如实施例14。
***的稳态渗透速率为0.11μg·cm-2·h-1,24h累积渗透量为3.11μg·cm-2。
实施例17
称取***0.1g、尤特奇RL PO 0.5g、柠檬酸三乙酯0.1g,加乙醇溶解至10g,装于定量喷雾装置内,制得***透皮喷雾剂。
将制得的***透皮喷雾剂进行体外经皮渗透实验,试验方法如实施例14。
***的稳态渗透速率为0.087μg·cm-2·h-1,24h累积渗透量为1.88μg·cm-2。
实施例18
称取***0.1g、尤特奇RL PO 0.5g、油酸0.5g,加乙醇溶解至10g,装于定量喷雾装置内,制得***透皮喷雾剂。
将制得的***透皮喷雾剂进行体外经皮渗透实验,试验方法如实施例14。
***的稳态渗透速率为0.091μg·cm-2·h-1,24h累积渗透量为2.16μg·cm-2。
实施例19
称取***0.1g、尤特奇RL PO0.5g、肉豆蔻酸异丙酯0.5g,加乙醇溶解至10g,装于定量喷雾装置内,制得***透皮喷雾剂。
将制得的***透皮喷雾剂进行体外经皮渗透实验,试验方法如实施例14。
***的稳态渗透速率为0.093μg·cm-2·h-1,24h累积渗透量为2.44μg·cm-2。
实施例20
表2喷雾剂与贴剂和凝胶剂的稳态渗透速率和累积渗透量
稳态渗透速率(μg·cm-2·h-1) | 24h累积渗透量/μg·cm-2 | |
***贴剂 | 0.21±0.023 | 3.28±0.72 |
***透皮喷雾剂 | 0.32±0.035 | 5.53±0.56 |
***凝胶 | 0.086±0.013 | 2.59±0.27 |
根据表2和图1所示,与市场上在售的***贴剂和凝胶做比较,本发明***透皮喷雾剂的稳态渗透速率和24h累积透过量均高于市场上在售的贴剂和凝胶,同时,本发明***透皮喷雾剂还具有制备工艺简单,使用方便,给药量可以很好的控制等其他优点。
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CN1997357A (zh) * | 2003-03-11 | 2007-07-11 | 安塔雷斯制药Ipl股份公司 | 透皮或透粘膜应用活性剂的用途和制剂 |
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CN1997357A (zh) * | 2003-03-11 | 2007-07-11 | 安塔雷斯制药Ipl股份公司 | 透皮或透粘膜应用活性剂的用途和制剂 |
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