CN114939103B - 吲哚美辛凝胶剂及其制备方法和应用 - Google Patents
吲哚美辛凝胶剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于药物制剂技术领域,涉及一种吲哚美辛凝胶剂及其制备方法和应用。所述吲哚美辛凝胶剂包含吲哚美辛、基质材料、表面活性剂、保湿剂、促渗剂、pH调节剂、水,各成分占吲哚美辛凝胶剂的重量百分比为:吲哚美辛1‑2%,基质材料0.3%‑0.6%,表面活性剂0.5%‑1.2%,保湿剂5%‑12%,促渗剂0.03%‑0.09%。其制备如下:称取处方量卡波姆974于少量水中,室温静置得基质溶液;滴加表面活性剂吐温‑80,搅拌均匀;加入吲哚美辛,充分搅拌均匀后滴加处方量的保湿剂甘油;加入防腐剂羟苯乙酯搅拌均匀,随后滴加薄荷油于体系中,搅拌均匀后滴加三乙醇胺调节pH至6.8‑7.0,最后加水至足量即得。本发明能够实现药物在8小时至少80%以上的释放,且具有较好的吲哚美辛药物透皮渗透量。
Description
技术领域
本发明属于药物制剂技术领域,具体涉及一种吲哚美辛凝胶剂及其制备方法和应用。
背景技术
吲哚美辛,英文名Indomethacin,吲哚美辛化学名2-甲基-1-(4-氯苯甲酰基)-5-甲氧基-1H-吲哚-3-乙酸,属于BCS分类Ⅱ类药物,渗透性高,溶解度低,溶出度差,体内生物利用率低。吲哚美辛是非甾体抗炎药(NSAIDs),具有抗炎、解热及镇痛作用,其通过对环氧化酶的抑制减少前列腺素的合成来起到抗炎作用,而退热作用则与抑制下视丘的前列腺素合成有关。
凝胶制剂近年来发展迅速,由于便于携带、使用简单、不良反应少被越来越多的人所接受,凝胶制剂分为水性凝胶和油性凝胶,水性凝胶中尤其以卡波姆最为常见,卡波姆凝胶制备工艺相对简单,相对来说上市产品也比较多,但是市面上唯独吲哚美辛凝胶产品少之又少,经走访调查,目前仅有日本企业Kowa Company Ltd.Fuji Factory生产的万特力吲哚美辛凝胶,国产在这方面一片空白。
日产万特力吲哚美辛凝胶是一种治疗肌肉痛、肩部僵硬酸痛、腰痛、关节痛、腱鞘炎(手和腕部疼痛)、肘部疼痛(网球肘等)及跌打损伤、扭伤引起的疼痛的外用水性凝胶,效果优良,但其昂贵的价格让很多患者望而却步转而将目光投向其他可替代类型制剂,因此寻找一种成本低、价格低,工艺简单且疗效确切的新的吲哚美辛凝胶剂是目前药物研究领域的当务之急。
发明内容
为了克服现有技术的缺陷,本发明提供一种吲哚美辛凝胶剂,所述的吲哚美辛凝胶剂以卡波姆974为基质,辅以表面活性剂,保湿剂和促渗剂,不仅明显提高了吲哚美辛的体外累计释放量,而且能够明显提高吲哚美辛的药物渗透量。
本发明通过如下技术方案实现:
本发明提供一种吲哚美辛凝胶剂,包含吲哚美辛、基质材料、表面活性剂、保湿剂、促渗剂、pH调节剂、水,各成分占吲哚美辛凝胶剂的重量百分比为:吲哚美辛1-2%,基质材料0.3%-0.6%,表面活性剂0.5%-1.2%,保湿剂5%-12%,促渗剂0.03%-0.09%。
所述的基质材料为卡波姆974,表面活性剂为吐温-80,保湿剂为甘油,促渗剂为薄荷油,pH调节剂为三乙醇胺。
进一步地,本发明优选如下的吲哚美辛凝胶剂,各组分占凝胶剂的重量百分比为:吲哚美辛为1-2%,卡波姆974为0.34%-0.57%,吐温-80为0.57%-1.14%,甘油5.71%-11.43%,薄荷油0.03%-0.09%,三乙醇胺适量,水余量。
进一步地,所述的吲哚美辛凝胶剂还含有防腐剂,所述防腐剂为羟苯乙酯,用量为0.1%-0.14%。
进一步地,本发明优选如下的吲哚美辛凝胶剂,各组分占凝胶剂的重量百分比为:吲哚美辛为1-2%,卡波姆974为0.46%-0.57%,吐温-80为0.71%-0.86%,甘油8.63%-11.43%,薄荷油0.03%-0.06%,三乙醇胺1.71%,防腐剂0.1%-0.14%,水余量。
进一步地,本发明优选如下的吲哚美辛凝胶剂,各组分占凝胶剂的重量百分比为:吲哚美辛为1%,卡波姆974为0.46%-0.47%,吐温-80为0.85%-0.86%,甘油8.63%-9%,薄荷油0.06%,三乙醇胺1.71%,防腐剂0.1%-0.14%,水余量。
本发明还提供了所述的吲哚美辛凝胶剂的制备方法,包括如下步骤:
(1)称取处方量卡波姆974于少量水中,室温静置得基质溶液;
(2)向基质溶液中滴加表面活性剂吐温-80,搅拌均匀;
(3)向步骤(2)得到的溶液中加入吲哚美辛,充分搅拌均匀后滴加处方量的保湿剂甘油;
(4)加入防腐剂羟苯乙酯搅拌均匀,随后滴加薄荷油于体系中,搅拌均匀后滴加三乙醇胺调节pH至6.8-7.0,最后加水至足量即得吲哚美辛凝胶剂。
通过体外药物释放试验和透皮吸收试验评价了所制备的吲哚美辛凝胶剂的药学性质,试验结果表明,本发明制备的吲哚美辛凝胶剂能够在8小时实现至少80%以上的药物累计释放量。且透皮试验结果表明,吲哚美辛凝胶剂具有较好的吲哚美辛药物渗透量。
附图说明
图1为实施例1-5的体外累计释放曲线图。
图2为实施例3、实施例6-8的体外累计释放曲线图。
图3为实施例3、实施例9-10的体外累计释放曲线图。
图4为实施例3、实施例11-12的体外累计释放曲线图。
图5为实施例3和万特力的体外累计释放曲线图。
具体实施方式
以下通过实施例再对本发明的内容做进一步详细说明,但不应就此理解为本发明上述主题范围内仅限于以下实施例。在不脱离本发明上述技术前提下,根据本领域普通技术知识和惯用手段做出的相应替换或变更的修改,均包括在本发明的范围内。
以下所述吲哚美辛凝胶剂每支的规格为35g,其中每支中含有吲哚美辛0.35g。
实施例1:吲哚美辛凝胶剂的制备
处方:
水:30.46g 卡波姆974:0.20g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。相应的质量分数如下表:
卡波姆974 | 0.57% |
吐温-80 | 0.86% |
吲哚美辛 | 1% |
甘油 | 8.63% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.06% |
水 | 余量 |
总重 | 35g |
制备工艺为:
量取一部分处方量的水于100ml烧杯中,称取卡波姆974倒入烧杯中室温静置4h。向基质溶液中滴加吐温-80,搅拌均匀。加入吲哚美辛,充分搅拌均匀后滴加处方量的甘油。加入防腐剂羟苯乙酯搅拌均匀,随后滴加薄荷油于体系中,搅拌均匀后滴加三乙醇胺调节pH约至7,最后加水至35g即得吲哚美辛凝胶剂。
药物释放度试验:将称量好的凝胶剂置于预处理好的透析袋中(分子量为4000-6000),并在透析袋中加入1ml pH7.4磷酸盐缓冲液,再装入装有100ml pH7.4磷酸盐缓冲液的丝口瓶中。采用恒温水浴振荡器,搅拌速度为100r·min-1,水浴温度设置为(37±0.5)℃。在上述溶出条件下,进行实验,分别在0.08h,0.17h,0.25h,0.33h,0.5h,0.75h,1h,1.5h,2h,3h,4h,5h,6h,8h取5ml溶出介质(并补充相同温度相同体积的新鲜溶出介质),用0.45μm的水系微孔滤膜过滤。以pH7.4磷酸盐缓冲液为空白,在319nm下测定溶液吸光度,计算不同时间的释放度,绘制药物累计释放曲线图。
实施例2:
处方:
水:30.48g 卡波姆974:0.18g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.51% |
吐温-80 | 0.86% |
吲哚美辛 | 1% |
甘油 | 8.63% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.06% |
水 | 余量 |
总重量 | 35g |
制备工艺和药物释放度试验同实施例1。
实施例3:
处方:
水:30.5g 卡波姆974:0.16g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
制备工艺和药物释放度试验同实施例1。
实施例4:
处方:
水:30.52g 卡波姆974:0.14g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.40% |
吐温-80 | 0.86% |
吲哚美辛 | 1% |
甘油 | 8.63% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.06% |
水 | 余量 |
总重 | 35g |
制备工艺和药物释放度试验同实施例1。
实施例5:
处方:
水:30.54g 卡波姆974:0.12g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
制备工艺和药物释放度试验同实施例1。
实施例6:
处方:
水:30.4g 卡波姆974:0.16g 吐温-80:0.40g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.46% |
吐温-80 | 1.14% |
吲哚美辛 | 1% |
甘油 | 8.63% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.06% |
水 | 余量 |
总重 | 35g |
制备工艺和药物释放度试验同实施例1。
实施例7:
处方:
水:30.55g 卡波姆974:0.16g 吐温-80:0.25g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
制备工艺和药物释放度试验同实施例1。
实施例8:
处方:
水:30.6g 卡波姆974:0.16g 吐温-80:0.20g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.46% |
吐温-80 | 0.57% |
吲哚美辛 | 1% |
甘油 | 8.63% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.06% |
水 | 余量 |
总重 | 35g |
制备工艺和药物释放度试验同实施例1。
实施例9:
处方:
水:29.52g 卡波姆974:0.16g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:4.00g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.46% |
吐温-80 | 0.86% |
吲哚美辛 | 1% |
甘油 | 11.43% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.06% |
水 | 余量 |
总重 | 35g |
制备工艺和药物释放度试验同实施例1。
实施例10:
处方:
水:31.52g 卡波姆974:0.16g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:2.00g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.02g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.46% |
吐温-80 | 0.86% |
吲哚美辛 | 1% |
甘油 | 5.71% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.06% |
水 | 余量 |
总重 | 35g |
制备工艺和药物释放度试验同实施例1。
实施例11:
处方:
水:30.51g 卡波姆974:0.16g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.01g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.46% |
吐温-80 | 0.86% |
吲哚美辛 | 1% |
甘油 | 8.63% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.03% |
水 | 余量 |
总重 | 35g |
制备工艺和药物释放度试验同实施例1。
实施例12:
处方:
水:30.49g 卡波姆974:0.16g 吐温-80:0.30g
吲哚美辛:0.35g 甘油:3.02g 羟苯乙酯:0.05g
三乙醇胺:0.60g 薄荷油:0.03g
经检测pH值约等于7,符合人体要求。
卡波姆974 | 0.46% |
吐温-80 | 0.86% |
吲哚美辛 | 1% |
甘油 | 8.63% |
羟苯乙酯 | 0.14% |
三乙醇胺 | 1.71% |
薄荷油 | 0.09% |
水 | 余量 |
总重 | 35g |
制备工艺和药物释放度试验同实施例1。
通过对各实施例累计释放曲线进行比较,结果表明:卡波姆974对于药物的释放具有较大的影响,实施例1-3中,当卡波姆974用量为0.46-0.57%时,吲哚美辛的8小时累计释放量达85%以上,而当卡波姆974用量低于0.46%时,吲哚美辛的8小时累计释放量明显降低,低于75%。当卡波姆974的用量在0.5%-0.57%间时,吲哚美辛8小时的累计释放量有所下降,但下降不明显。当卡波姆974用量为0.46-0.5%时,其8小时累计释放量最大。实施例3、9和10表明,甘油在组方中的用量对于吲哚美辛的累计释放量影响不大,其用量在5.71-11.43%之间时,吲哚美辛的8小时累计释放量均可达90%以上。最佳地,当卡波姆974为0.46%-0.47%,吐温-80为0.85%-0.86%,甘油为8.63%-9%,薄荷油为0.06%时,吲哚美辛的累计释放量最大,最高可达95%以上。
实施例13:
大鼠透皮试验
本实验使用立式扩散池,将大鼠鼠皮固定于给药池和接收池之间,角质层面向供给室,真皮层面向接受室,有效扩散面积为1.54cm2。分别取含4mg药量的市售万特力凝胶、实施例1-12的吲哚美辛凝胶加入给药池,均匀涂抹在大鼠鼠皮上,另将4ml pH7.4磷酸盐缓冲液加入接受池中,排除气泡,使大鼠鼠皮与液面相接。在37℃及100(r/min)的条件下持续搅拌,在给药后0.5h、1.5h、2h、3h、4h、5h、6h、8h抽取接受液4ml并且补充相同体积相同温度的新鲜接受液,将抽取的接受液使用0.22μm滤膜过滤获得续滤液,测定紫外吸光度,计算累计渗透量Q。
ρn为第n个取样点的药物质量浓度(μg·mL-1),V为取样体积,A为渗透面积。结果如下:
结果表明:卡波姆974、吐温80、薄荷油的用量对吲哚美辛凝胶剂的透皮吸收都有不同程度的影响,甘油的含量在5.71-11.43%时对吲哚美辛的透皮吸收效果影响不大。本发明制备吲哚美辛凝胶剂的累积药物透皮量均在500μg·cm2以上。当甘油含量为5.71-11.43%时,卡波姆974、吐温80、薄荷油的用量分别为0.46-0.57%、0.86%和0.06%时,累积药物透皮量达720μg·cm2以上。其中,当甘油含量为8.63-11.43%,卡波姆974、吐温80、薄荷油的用量分别为0.46%、0.86%、0.06%时,累积药物透皮量达800μg·cm2尤其是实施例3,其累积药物透皮量达835.89μg·cm2,优于万特力的累积药物透皮吸收量。
Claims (5)
1.吲哚美辛凝胶剂,由吲哚美辛、基质材料、表面活性剂、保湿剂、促渗剂、pH调节剂、防腐剂、水组成,其特征在于,所述的基质材料为卡波姆974,表面活性剂为吐温-80,保湿剂为甘油,促渗剂为薄荷油,pH调节剂为三乙醇胺,防腐剂为羟苯乙酯,各成分占吲哚美辛凝胶剂的重量百分比为:吲哚美辛为1%,卡波姆974为0.46%-0.57%,吐温-80为0.86%,甘油5.71-11.43%,薄荷油0.06%,三乙醇胺1.71%,羟苯乙酯为0.1%-0.14%,水余量。
2.如权利要求1所述的吲哚美辛凝胶剂,其特征在于,吲哚美辛为1%,卡波姆974为0.46%-0.47%,吐温-80为0.86%,甘油8.63%-9%,薄荷油0.06%,三乙醇胺1.71%,羟苯乙酯0.1%-0.14%,水余量。
3.如权利要求1或2所述的吲哚美辛凝胶剂,其特征在于,吲哚美辛为1%,卡波姆974为0.46%,吐温-80为0.86%,甘油8.63%,薄荷油0.06%,羟苯乙酯0.1-0.14%,三乙醇胺1.71%,水余量。
4.如权利要求1所述的吲哚美辛凝胶剂的制备方法,其特征在于,包括如下步骤:
(1)称取卡波姆974于少量水中,室温静置得基质溶液;
(2)向基质溶液中滴加表面活性剂吐温-80,搅拌均匀;
(3)向步骤(2)得到的溶液中加入吲哚美辛,充分搅拌均匀后滴加保湿剂甘油;
(4)加入羟苯乙酯搅拌均匀,随后滴加薄荷油于体系中,搅拌均匀后滴加pH调节剂三乙醇胺调节pH至6.8-7.0,最后加水至足量即得吲哚美辛凝胶剂。
5.权利要求1-3任何一项所述的吲哚美辛凝胶剂在制备抗炎、解热或镇痛药物中的应用。
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