CN117338719A - 一种治疗脱发的泡沫剂、制备方法及其应用 - Google Patents
一种治疗脱发的泡沫剂、制备方法及其应用 Download PDFInfo
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Abstract
本发明涉及一种治疗脱发的泡沫剂、制备方法及其应用，含有治疗脱发的活性成分和几种药学上可以接受的适用于泡沫剂的辅料，活性成分的含量为0.5％～5％，该制剂适用于局部用药，该泡沫剂为无助推剂、容易生产和易于涂抹。具有润肤、保湿的功能，对皮肤无刺激，无瘙痒、灼烧感和刺痛感等副作用，停药后无相关皮肤病症状。本发明泡沫剂可用于治疗脂溢性脱发、斑秃、原发性三角形脱发、男性型脱发等。
Description
技术领域
本发明属于药物制剂领域，涉及一种治疗脱发的泡沫剂、制备方法及其应用。
背景技术
米诺地尔，商品名为长压定、敏乐定。化学名为6-(1-哌啶基)-2，4－嘧啶二胺-3-氧化物，为白色或类白色结晶性粉末，分子式：C9H15N50，分子量：209.2，主要作用于血管壁，扩张小动脉，降低血压，用于治疗顽固性高血压、原发性高血压或肾型高血压。
近年发现米诺地尔对于脂溢性脱发的有效率可以达到90％，对斑秃、原发性三角形脱发等多种类型的脱发都有较好的临床治疗效果。临床表明它可以直接剌激毛囊的增殖和分化，促使血管生成，增加局部血液供应，开放饵通道，使毛囊由休止期向生长期转化，并延长生长期。
度他雄胺为一种白色和类白色结晶性粉末，临床上主要用于前列腺肿大、男性型脱发、脂溢性脱发、遗传性脱发的治疗。
非那雄胺是一种四氮杂甾体化合物，具有竞争性和选择性抑制5-α还原酶活性，从而抑制睾酮转化成双氢睾酮(DHT)而使前列腺消肿。本品临床用于治疗男性型脱发，良性前列腺增生，使增大的前列腺缩小，改善尿流以及改善良性前列腺增生带来的症状。泡沫剂使用方便，密度小，较其他外用制剂更容易分布于表皮。目前国外己上市的泡沫释药系统主要药物品种有皮质激素类药、消毒药、抗真菌药、消炎药、局部麻醉药、皮肤洗涤剂和防护剂等。泡沫剂中含有疏水性溶剂，可起到润滑皮肤作用：还可含水溶性、油溶性和混悬的活性成分：泡沫剂易扩散，可治疗大面积患处，如臂、腿和乳房等。由于泡沫可有效地分布于皱果和皱纹内，因而泡沫剂不需额外地涂擦活性成分即可均匀地分布和被吸收。
CN105434352A公开了一种米诺地尔泡沫剂及其制备方法，该泡沫剂采用的辅料包括有机溶剂、泡沫载体、表面活性剂、缓冲剂、推进剂、保湿剂以及余量的水，其中有机溶剂为乙醇。该泡沫剂较其它外用制剂(酊剂、溶液、凝胶、喷雾剂)更容易分布于表皮，更利于涂沫后药物散布均匀；但是该泡沫剂使用了有机溶剂乙醇，会使一定的患者产生局部的过敏和刺激，对生产车间要求高。同时还含有助推剂，对设备要求也很高。基于此，亟需开发一种安全性更高，适合工业化生产的治疗脱发的泡沫剂。
发明内容
本发明的目的在于克服目前已经上市的外用溶液或泡沫剂的处方均存在大量乙醇，大量的乙醇会使一定患者产生局部过敏和刺激，且生产上需要防爆车间。泡沫剂还需要助推剂(需要超低温设备进行溶液的配制)等不足问题，本发明提供一种治疗脱发的水性泡沫剂、制备方法及其应用。
本发明的目的是通过以下技术方案来实现的：
本发明涉及一种治疗脱发的泡沫剂、制备方法及其应用，所述泡沫剂由含有治疗脱发的活性成分和辅料组成，所述辅料包括水相表面活性剂(发泡型)、保湿剂或溶剂、抗氧剂和防腐剂。
其中，所述治疗脱发的活性成分为米诺地尔、度他雄胺、非那雄胺的任意一种，按质量百分比计，所述治疗脱发的活性成分的质量占比0.5％-5％，所述水相表面活性剂的质量占比为10-30％，保湿剂或溶剂的质量占比为4-35％，抗氧化剂的质量占比为0.01-1％，pH值调节剂的质量占比为0.5％-5％，防腐剂的质量占比为0.5-3％。
其中，水相表面活性剂选自辛酸癸酸聚乙二醇甘油酯、鲸蜡硬脂醇聚氧乙烯醚-20、月桂醇聚氧乙烯醚中的任意一种或者多种，优选辛酸癸酸聚乙二醇甘油酯或鲸蜡硬脂醇聚氧乙烯醚-20一种或者两种。
其中，保湿剂或溶剂选自丙二醇、甘油、聚乙二醇-200等中的任一种或者多种，优选丙二醇和聚乙二醇-200中的一种或者两种。
其中，防腐剂为苯氧乙醇、苯甲醇、对羟基苯甲酸丙酯、对羟基苯甲酸甲酯、对羟基苯甲酸乙酯等中的任一种或者多种，优选苯甲醇。
其中，抗氧剂为焦亚硫酸钠、硫代硫酸钠，优选硫代硫酸钠。
作为一个实施方案，本发明涉及米诺地尔泡沫剂，优选2％-5％的米诺地尔活性成分，米诺地尔泡沫剂为溶液型制剂，含水相表面活性剂10-30％，优选15-25％，含抗氧剂0.01-1％，优选0.05-0.5％，含保湿剂或溶剂4-35％，优选10-30％，含防腐剂0.5-3％，优选1.5-2.5％。
作为一个实施方案，本发明涉及的治疗脱发的泡沫剂，其原辅料以及处方占比(以占米诺地尔泡沫剂总重的质量百分比计)如下：
本发明还涉及一种治疗脱发的泡沫剂的制备方法，所述方法包含如下步骤：
(1)在30-80℃下，将处方量的活性成分溶解于保湿剂、溶剂、防腐剂、抗氧剂的水中并调节溶液pH值，降温至室温，加入在水相表面活性剂搅拌均匀，即得泡沫剂。
本发明还涉及一种治疗脱发的泡沫剂在作为治疗脂溢性脱发、斑秃、原发性三角形脱发、男性型脱发等外用药中的应用。
与现有技术相比，本发明具有如下有益效果：
含治疗脱发的泡沫剂的组合物，无助推剂，当水相表面活性剂、保湿剂或溶剂、抗氧剂、防腐剂以适当的浓度混合在一起时，光学各向同性的和热力学稳定的。该泡沫剂可提高药物溶解度、降低皮肤刺激性、保持药物的内相外相浓度差而促进药物持续透过角质层。该泡沫剂将通过特定的给药装置，无需助推剂即可喷出泡沫，具有良好的铺展性，易于涂抹，患者的顺应性良好，特别是针对含有毛发的皮肤的使用，更方便和具有较高的皮肤滞留和渗透。
附图说明
通过阅读参照以下附图对非限制性实施例所作的详细描述，本发明的其它特征、目的和优点将会变得更明显：
图1实施例1泡沫剂的发泡情况；
图2实施例2泡沫剂的发泡情况；
图3实施例3泡沫剂的发泡情况；
图4实施例4泡沫剂的发泡情况；
图5实施例5泡沫剂的发泡情况；
图6对照例2泡沫剂的发泡情况。
具体实施方式
下面结合实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干调整和改进。这些都属于本发明的保护范围。
本发明的治疗脱发的泡沫剂的制备方法包括如下步骤：
在30-50℃下，将处方量的活性成分溶解于保湿剂、溶剂、防腐剂、抗氧剂的水中并调节溶液pH值，降温至室温，加入在水相表面活性剂搅拌均匀，即得泡沫剂。
具体应用示例如下：
实施例1 -4
本实施例1-4涉及一种米诺地尔泡沫剂的制备，其原辅料以及占比如下表1：
表1
实施例5度他雄胺
| 实施例5 | ||
| 名称 | 比例(％) | 辅料作用 |
| 度他雄胺 | 2 | API |
| 辛酸癸酸聚乙二醇甘油酯 | 20 | 水相表面活性剂 |
| 丙二醇 | 18 | 保湿剂、溶剂 |
| 苯甲醇 | 2 | 防腐剂 |
| 硫代硫酸钠 | 0.1 | 抗氧剂 |
| 枸橼酸 | 调节pH值至5.0 | pH调节剂 |
| 水 | 57.9 | 溶剂 |
| Qs | 100 |
对比例1对照制剂
已上市的米诺地尔外用溶液(JOHNSON AND JOHNSON GROUP CONSUMERCOMPANIES)，作为对照制剂。
对比例2
本对比例涉及一种米诺地尔泡沫剂的制备，其原辅料以及占比如下表2，制备方法同实施例1，但是所采用的表面活性剂不同。
表2
| 名称 | 比例(％) | 辅料作用 |
| 米诺地尔 | 2 | API |
| 吐温80 | 18 | 表面活性剂 |
| 丙二醇 | 20 | 保湿剂、溶剂 |
| 硫代硫酸钠 | 0.1 | 抗氧剂 |
| 苯甲醇 | 2 | 防腐剂 |
| 枸橼酸 | 调节pH值至5.0 | pH调节剂 |
| 水 | 57.9 | 溶剂 |
| Qs | 100 |
实施例6质量对比研究
对实施例1-5以及对比例1-2进行了性状、pH、含量、有关物质检测，结果如下表3。
表3
结论：实施例1-5和对比例2制备得到的泡沫剂发泡情况见附图1-6。按照实施例1至5制备得泡沫剂具有良好的发泡能力，对比例2的发泡能力较差，临床使用中容易未涂抹均匀即变成溶液而导致泡沫剂从皮肤表面流淌或者滴落。
实施例7长期稳定性对比研究结果
将实施例1-5以及对比例1和2的样品，放置于温度为30±2℃、湿度为RH60％±5％的条件下，分别于1月、3月取样检测性状、pH值、含量、有关物质，具体检测结果见下表4。
表4
从实施例7长期稳定性对比数据可知，实施例1-5制备的泡沫剂，具有良好的稳定性，在长期三个月期间，性状、pH值、含量、有关物质指标均无显著性变化。说明按照实施例1-5制备的泡沫剂基本可以满足使用期间的稳定性要求。
实施例8体外透皮试验对比研究：
1)方法：Franz扩散池法；
2)仪器：禄亘药物透皮扩散试验仪,LOGAN 918-12系统
3)皮肤：实验用猪皮，厚度0.8-1mm，接触直径2cm；
4)接收液：生理盐水；
5)接收液温度：32±0.5℃；
6)转速：600rpm；
7)样本：分别将不同处方的制剂均匀涂布在实验用猪皮上，每个制剂的样本量分别为200mg左右，同时将未涂抹乳膏的猪皮作为空白猪皮。
8)扩散池容积：12ml；
9)采样方式：全部取样；
10)采样时间点：2h、4h、6h、10h、21h、24h；
11)样本分析：LC/MS测定，检测结果见表5。
表5
从实施例8体外透皮试验可以看到，实施例1-4制备得到的米诺地尔泡沫剂具有比软外用溶液剂更大的皮肤渗透和皮肤滞留量，体外渗透实验表明其具有比对比例1更好的临床效果。该泡沫剂是水性泡沫剂，在使用后可为患者提供不油腻的感觉，并且不会弄脏衣服。临床使用简洁方便。
以上对本发明的具体实施例进行了描述。需要理解的是，本发明并不局限于上述特定实施方式，本领域技术人员可以在权利要求的范围内做出各种变形或修改，这并不影响本发明的实质内容。
Claims (10)
1.一种治疗脱发的泡沫剂，其特征在于含有治疗脱发的活性成分和辅料组成，所述辅料包括水相表面活性剂、保湿剂或溶剂、抗氧化剂、pH值调节剂和防腐剂。
2.根据权利要求1所述的治疗脱发的泡沫剂，其特征在于所述治疗脱发的活性成分为米诺地尔、度他雄胺、非那雄胺的任意一种。
3.根据权利要求1所述的治疗脱发的泡沫剂，其特征在于，按质量百分比计，所述治疗脱发的活性成分的质量占比0.5％-5％，所述水相表面活性剂的质量占比为10-30％，优先15-25％，保湿剂或溶剂的质量占比为4-35％，优先10-30％，抗氧化剂的质量占比为0.01-1％，优先0.05-0.5％，pH值调节剂的质量占比为0.5％-5％，优先为0.5-2％，防腐剂的质量占比为0.5-3％，优先1.5-2.5％。
4.根据权利要求1或3任意一项所述的治疗脱发的泡沫剂，其特征在于，所述水相表面活性剂为辛酸癸酸聚乙二醇甘油酯、鲸蜡硬脂醇聚氧乙烯醚-20、月桂醇聚氧乙烯醚的任意一种或者两种。
5.根据权利要求1或3任意一项所述的治疗脱发的泡沫剂，其特征在于，所述保湿剂或溶剂选自丙二醇、甘油、聚乙二醇-200中的任意一种或者两种。
6.根据权利要求1或3任意一项所述的治疗脱发的泡沫剂，其特征在于，所述抗氧剂选自焦亚硫酸钠、硫代硫酸钠中的任意一种或者两种。
7.根据权利要求1或3任意一项所述的治疗脱发的泡沫剂，其特征在于，所述pH值调节剂选自乳酸、醋酸、枸橼酸、酒石酸中的任意一种。
8.根据权利要求3所述的治疗脱发的泡沫剂，其特征在于，所述活性成分和辅料以泡沫剂总重的质量百分比计，占比如下：所述治疗脱发的活性成分2-5％，水相表面活性剂为辛酸癸酸聚乙二醇甘油酯占比15-25％，保湿剂为丙二醇占比10-30％，抗氧化剂为硫代硫酸钠占比0.05％-0.5％，防腐剂为苯甲醇占比1.5-2.5％，pH值调节剂为枸橼酸钠适量，水定重至100，其中，所述治疗脱发的活性成分为米洛地尔。
9.根据权利要求1所述的治疗脱发的泡沫剂，其特征在于，所述pH值范围5.0～5.5。
10.权利要求1所述的治疗脱发的泡沫剂在治疗脂溢性脱发、斑秃、原发性三角形脱发、男性型脱发中的应用。
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