CN101829057B - 水杨酸脂质体和其系列外用制剂的制备方法及在痤疮治疗中应用 - Google Patents
水杨酸脂质体和其系列外用制剂的制备方法及在痤疮治疗中应用 Download PDFInfo
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Abstract
本发明涉及水杨酸脂质体的和其系列外用制剂的制备及在痤疮治疗中的应用，本发明以水杨酸为主药，制成水杨酸脂质体；再赋予凝胶剂、乳剂、霜剂、膜剂等外用剂型，制成稳定、均一的水杨酸脂质体系列外用制剂。初步疗效评价显示：其刺激性小、疗效确切、在治疗痤疮的同时，尚可改善肤质，具有一定的市场潜力。
Description
技术领域
本发明涉及药物制剂和功能性化妆品制备领域。具体涉及水杨酸脂质体和系列外用制剂的制备方法及在痤疮治疗中的应用。
背景技术
痤疮是一种常见于青春期的皮肤疾病，90％的青少年在不同程度上患有此病。可以不经治疗而自动痊愈，但严重的痤疮患者在青春后期会留下凹陷疤痕、瘢痕疙瘩，影响美观。目前，治疗痤疮的药物有口服和外用两大类；其中霜剂、膜剂、乳剂、凝胶剂等外用制剂应用较为广泛，国家食品药品监督管理局(SFDA)批准的痤疮外用制剂有20个，而口服药物才3个。因此，痤疮外用制剂所占销售份额远远大于口服药物。这些外用制剂添加的有效成分主要是大环内酯类抗生素、氯霉素、糖皮质激素、水杨酸等抗菌、消炎的药物。与其他药物相比水杨酸(salicylic acid)表现出很多优点：它是一种重要的精细化工原料，来源广泛，价格低廉，适合于工业化生产；在皮肤美容行业亦有广泛应用，具有治疗痤疮、美白、收缩毛孔、去角质、除皱等功效；在治疗痤疮的同时，还可以保养肤质。
但水杨酸酸性较强、脂溶性不高，限制了其在痤疮治疗方面的应用：浓度过高会对皮肤产生刺激性，过低则起不到治疗作用。
60年代初期，Bangham在电镜下发现磷脂在水中形成脂质体(liposome)。1971年，Rymen等人开始将脂质体用作药物载体，由于其组成和结构的特点，脂质体用作药物的载体使药剂学的研究领域进入靶向给药的新天地，同时也更新了给药途径和护肤观念。
脂质体是将药物包封于类脂双分子层形成的薄膜中间所制成的超微型球状载体制剂。脂质体类似细胞结构，有生物膜的特性和功能，它可以包裹水溶性和脂溶性两种类型的药物，是一种具有多功能的定向药物载体，能够降低药物毒副作用、提高生物利用度、并具有长效缓释作用。
近年来脂质体在透皮给药系统中的应用日益受到重视，若能将水杨酸制备成脂质体就会在表皮和真皮内形成药物贮库，形成一个缓、控释模型，药物可持久地对病变细胞起到局部治疗作用，减少进入血流量，提高治疗指数，避免全身毒副作用。
发明内容
本发明所要解决的技术问题是以脂质体为载药系统，将水杨酸包合，然后赋予系列外用剂型，考察其理化性质及稳定性。具体涉及水杨酸脂质体的制备，水杨酸脂质体乳剂、凝胶剂、霜剂、膜剂的制备。
本发明采用如下过程制备水杨酸脂质体系列外用制剂：
(1)制备水杨酸脂质体；
(2)以水杨酸脂质体为主药，制备其乳剂、凝胶剂、霜剂、膜剂；
下面我们将就该技术的具体操作进行详细的描述：
1.水杨酸脂质体的制备
可以采用注入法、薄膜分散法、逆向蒸发法、超声波分散法等方法制备水杨酸脂质体，最好采用注入法，更优选乙醇注入法。用于形成脂质体的脂类物质包括本领域技术人员已知的任何可以构成脂质体的脂类物质，包括(但不仅限于)下列物质中的一种或多种：磷脂、胆固醇、经过各种修饰磷脂等。其中磷脂采用天然磷脂或者采用半合成或全合成的磷脂，或者采用天然磷脂与半合成或全合成磷脂的混合物。磷脂与胆固醇的质量比为：1∶1～100∶1，优选10∶1～30∶1。水杨酸与脂类物质的质量比为：1∶2～1∶100。溶剂可以选择C1～C6脂肪醇、二氯甲烷、氯仿、丙酮、乙酸乙酯、四氢呋喃等，最好选用乙醇和二氯甲烷，更优选乙醇。可选用磷酸二氢钠、磷酸二氢钾、磷酸氢二钠、磷酸氢二钾等磷酸盐配制缓冲液，pH值范围控制在：5.5～9.8，最好在6.8～8.2，更优选7.4。相变温度为：0℃～67℃之间，最好在26℃～60℃之间，更优选55℃。可以采用分子排阻色谱法、微柱离心法、透析法、离心法、超速离心法、离子交换色谱法等方法测定包封率，最好采用透析法、离心法，更优选透析法。
2.水杨酸脂质体系列外用制剂的制备
采用不同的基质、辅料，分别制备水杨酸脂质体凝胶剂、乳剂、霜剂膜剂等。具体见实施方案。
3.水杨酸脂质体系列外用制剂的初步临床评价
中度痤疮患者志愿者，患痤疮多年，犹以背部较严重，局部涂抹水杨酸脂质体凝胶剂三月后(每日一次)，可明显观察到症状减轻，肤质也较三月前得到改善。具体见说明书附图。
本发明的有益效果：水杨酸“物美价廉”，以它为主药开发痤疮治疗产品，不仅可以降低成本，还可以达到治疗痤疮同时保养肤质的效果；用脂质体包合水杨酸，可以减少其对皮肤的刺激性，延长作用时间；本发明制备的水杨酸脂质体包封率高达80％以上，为今后的工业化生产奠定了基础；初步临床评价显示：水杨酸脂质体外用制剂对皮肤无刺激性，疗效显著，尚可改善肤质。
具体实施方式
通过下述实施例将有助于理解本发明，但不能局限本发明的内容。
实施例1
水杨酸脂质体的制备
制备工艺：称取水杨酸1g、大豆卵磷脂5g、胆固醇2g，置于烧杯中，加入适量无水乙醇使之溶解，用注射器均匀、慢速注入到pH值为7.4的磷酸盐缓冲液中，55℃搅拌并减压蒸发，除去乙醇，得到乳白色混悬液挤压过0.45μm聚碳酸酯膜，即得水杨酸脂质体，平均粒径＜120nm，包封率＞80％。
实施例2
水杨酸脂质体的制备
制备工艺：精密称取卵磷脂400mg和胆固醇50mg于100mL圆底烧瓶中，加入9mL氯仿，振摇使其溶解均匀，水浴旋转蒸发成透明的薄膜，再加入6mL乙醚，将膜重新溶解，将适量溶于20mL无水乙醇的水杨酸加入3mL磷酸缓冲盐溶液，加入烧瓶，超声几分钟后室温旋转蒸发除去有机溶剂至胶态，加入少量的磷酸盐缓冲溶液，进一步旋转，使其充分水化，依次过0.8μm、0.45μm滤膜，即得水杨酸脂质体，平均粒径＜120nm，包封率＞80％。
实施例3
水杨酸脂质体凝胶剂的制备
精密称取大豆卵磷脂2.5mg，胆固醇1mg，置于烧瓶中，加入二氯甲烷200mL使之溶解，旋转蒸发挥干成膜，将含有50mg水杨酸磷酸盐缓冲液(pH＝7.2)40mL加入其中，同时加入2mL吐温-80，旋转蒸发5min后，间断超声5min至乳化完全。以旋转薄膜蒸发方法回收溶剂，形成凝胶状物I；另取卡波姆-940lg溶于适量蒸馏水中，用三乙醇胺调pH至6～7II，将I加入II中搅匀即得水杨酸脂质体凝胶。
实施例4
水杨酸脂质体乳剂的制备
水杨酸脂质体1g加到10g凡士林中加热融化，然后加入硬脂酸10g，液体石蜡8g(此为油相)；同时将5％羟苯乙酯溶液2mL，甘油5g，三乙醇胺1g，香精适量加入100mL蒸馏水中溶解(此为水相)；将油相、水相加热至85℃，在不断搅拌下将油相缓慢加至水相中，并保持该温度15min，之后搅拌至室温即得。
实施例5
水杨酸脂质体霜剂的制备
取水杨酸脂质体1g加到5mL蓖麻油中(60℃)溶解，与硬脂酸3g、单硬酯酸甘油酯1g，凡士林2g混合为油相，另取三乙醇胺1mL，十二醇硫酸钠1g，硼砂0.1g，甘油3mL，尼泊金乙酯0.1g，蒸馏水为水相，分别在水浴上加热为70℃，然后将水相加入油相，并向一个方向不断搅拌霜剂形成即得。
实施例6
水杨酸脂质体膜剂的制备
壳聚糖5g，明胶10g，及50mL乙醇于100mL烧杯内混合，将烧杯置于40℃的电热水浴箱中，将混合物均匀搅拌至壳聚糖及明胶溶解，形成淡黄色凝胶。取一10cmx14cm的玻璃板，用75％的乙醇均匀涂抹表面，待酒精未干，铺一层聚乙烯薄膜，将10mL凝胶置于薄膜上用流涎法制膜，置于37℃温箱干燥12h后成膜并起膜，用紫外线消毒30min后，将药膜剪成1cmx1cm大小。
Claims (3)
1.一种水杨酸脂质体的制备方法，其特征在于：
称取水杨酸1g、大豆卵磷脂5g、胆固醇2g，置于烧杯中，加入200mL无水乙醇使之溶解；用注射器均匀、慢速注入到100mL pH 7.4的磷酸盐缓冲液中，55℃搅拌并减压蒸发，除去乙醇，得到乳白色混悬液挤压过0.45μm聚碳酸酯膜，即得。
2.一种水杨酸脂质体凝胶剂的制备方法，其特征在于：
称取大豆卵磷脂2.5mg，胆固醇1mg，置于烧瓶中，加入二氯甲烷200mL使之溶解，旋转蒸发挥干成膜；
将含有50mg水杨酸的pH7.2的磷酸盐缓冲液40mL加入其中，同时加入2mL吐温-80，旋转蒸发5min后，间断超声5min至乳化完全；
旋转薄膜蒸发方法回收溶剂，形成凝胶状物I；
另取卡波姆-940 lg溶于适量蒸馏水中，用三乙醇胺调pH至6～7得溶液II，将I加入II中搅匀即得水杨酸脂质体凝胶剂。
3.权利要求1和2所述的脂质体或脂质体凝胶在制备治疗痤疮的药物中的应用。
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