CN102056481A - 包含低浓度的在水和水混溶性有机溶剂中的悬浮液形式的过氧苯甲酰的局部药物制剂 - Google Patents
包含低浓度的在水和水混溶性有机溶剂中的悬浮液形式的过氧苯甲酰的局部药物制剂 Download PDFInfo
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- CN102056481A CN102056481A CN2009801207389A CN200980120738A CN102056481A CN 102056481 A CN102056481 A CN 102056481A CN 2009801207389 A CN2009801207389 A CN 2009801207389A CN 200980120738 A CN200980120738 A CN 200980120738A CN 102056481 A CN102056481 A CN 102056481A
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- benzoyl peroxide
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Abstract
本发明涉及用于局部施用于皮肤的含水制剂，所述含水制剂包含水、水混溶性有机溶剂和过氧苯甲酰，其中所述有机溶剂的浓度足以在所述制剂中不含表面活性剂的情况下提供过氧苯甲酰在所述含水制剂中的稳定悬浮液，其中所述制剂中的水和有机溶剂的浓度比足以在施用于皮肤后使所述过氧苯甲酰以饱和溶解度保持在所述制剂中，并且其中所述制剂中的过氧苯甲酰的浓度为小于5.0％且至少1.0％w/w。所述制剂还可以包含除过氧苯甲酰之外的有效治疗痤疮的化合物。本发明的含水制剂可用于治疗痤疮和红斑痤疮。
Description
技术领域
本发明涉及用于治疗皮肤病症的局部施用药物制剂领域。具体地，本发明涉及包含过氧苯甲酰和任选的抗痤疮化合物如抗生素的制剂。
背景技术
过氧苯甲酰常用于治疗皮肤病症如通常称作痤疮的寻常痤疮的局部药物制剂中。局部施用的抗生素也已被用于治疗皮肤病症如痤疮的局部制剂中。已被局部使用以治疗痤疮的抗生素的实例包括大环内酯抗生素如红霉素和林可霉素族抗生素如克林霉素和林可霉素。
包含过氧苯甲酰和抗生素的联合产品已被使用，并提供与仅包含过氧苯甲酰或抗生素的制剂相比增加的抗痤疮功效。Klein的美国专利4,497,794公开了用于治疗痤疮的包含过氧苯甲酰和红霉素的联合制剂。通常如Klein‘794所述制备的组合物以商品名Benzamycin
(Dermik Laboratories，Berwyn，PA)销售。Klein的美国专利5,767,098、Baroody的美国专利5,733,886和Stiefel的美国专利5,466,446公开了过氧苯甲酰和林可霉素族抗生素如克林霉素的联合。通常如Klein‘098所述制备的组合物以商品名Benzaclin
(Dermik Laboratories)销售，通常如Stiefel所述制备的组合物以商品名Duac(Stiefel Laboratories，Inc.，Coral Gables，FL)销售。
与使用仅包含过氧苯甲酰的组合物、或包含过氧苯甲酰和抗生素的联合的组合物的局部治疗有关的问题之一施用部位的局部刺激。已经表明，过氧苯甲酰具有浓度依赖性的刺激可能性。参见Mills等人，International Journal of Dermatology，25(10)：664-667(1986)和Lassus，Current Medical Research and Opinion，7(6)：370-373(1981)。以上每一种产品均包含浓度为5％w/w的过氧苯甲酰，该浓度与刺激有关。
过氧苯甲酰实际上不溶于水。已经确定由于施用包含过氧苯甲酰的组合物所致的刺激是由悬浮的过氧苯甲酰部分导致的，而溶解的过氧苯甲酰导致很少或不导致皮肤刺激。参见Schwarz的美国专利7,153,888；和De Villez的美国专利4,923,900。Schwarz公开了包含过氧苯甲酰的组合物，其中所述组合物的全部过氧苯甲酰是在有机溶剂中的溶液的形式。因为过氧苯甲酰的溶解促进了过氧苯甲酰的降解，Schwarz公开在所述组合物中包含抗氧化剂以改善所述溶液的稳定性。
Schwarz的一个缺点是：为了溶解过氧苯甲酰，必需高浓度的有机溶剂。高浓度的有机溶剂具有刺激皮肤的趋势，主要因为由皮肤脂质的增溶作用导致的干燥效应。在表1-3中，Schwarz公开了包含各种有机溶剂和过氧苯甲酰的组合物的多个实例。在每个实例中，在所述组合物中，有机溶剂的浓度是过氧苯甲酰的浓度的10倍，并且一般是15倍。
De Villez公开了包含过氧苯甲酰、水和挥发性小于水且过氧苯甲酰在其中可溶的水混溶性有机溶剂的组合物。在施用在皮肤上之前，所述过氧苯甲酰悬浮于所述组合物中。然而，当施用于皮肤时，与所述有机溶剂相比，水较为迅速地从所述组合物中蒸发。然后，所述组合物的过氧苯甲酰原位溶解在所述有机溶剂中，在全部水蒸发后形成过氧苯甲酰的溶液。
为了使De Villez组合物从悬浮液转变为溶液，所述组合物必须保持驻留在皮肤表面足够的时间，以便所述组合物中的水蒸发。在该时间内，所述过氧苯甲酰悬浮于所述组合物中，并且悬浮的颗粒能够与皮肤接触以致产生刺激。而且，类似Schwarz，De Villez要求比较高浓度的有机溶剂，该有机溶剂可能是这些组合物的刺激可能性的原因。
发明内容
已经令人惊讶地发现，通过提供包含低浓度过氧苯甲酰在水和水混溶性有机溶剂的饱和溶液中的悬浮液的含水局部制剂，获得了基本上与通过使用包含5.0％过氧苯甲酰的含水局部制剂所获得的临床抗痤疮功效相似的临床抗痤疮功效。在本说明书中，所有的％浓度均指％w/w。相对于施用类似的5.0％过氧苯甲酰制剂，本发明的制剂减小施用该制剂导致的皮肤刺激，而不损害临床功效。
在一个实施方案中，本发明是用于局部施用的药物制剂，所述制剂包含水、水混溶性有机溶剂和过氧苯甲酰，其中所述水和所述有机溶剂的浓度比高，并且其中过氧苯甲酰在所述制剂中的浓度低。本文中使用的术语“低浓度”，在指过氧苯甲酰在制剂中的浓度时，指小于5.0％w/w。优选地，所述药物制剂是水凝胶制剂。优选地，所述药物制剂不含表面活性剂。
所述过氧苯甲酰在所述制剂中分布为均匀的悬浮液。优选地，悬浮的过氧苯甲酰具有小于100微米的平均粒径，更优选地具有1-50微米的平均粒径，且最优选地具有2.5-30微米的平均粒径。必然地，部分所述过氧苯甲酰还会被溶解在所述有机溶剂中，而且小部分所述过氧苯甲酰会被溶解在所述水中。因此，所述制剂是过氧苯甲酰的饱和溶液，其所具有的过氧苯甲酰溶解浓度高于在没有所述有机溶剂的情况下溶解在水中时的浓度。
在优选的实施方案中(但不是一定的)，本发明的制剂包含至少一种有效治疗痤疮的其他化合物。所述抗痤疮化合物可以悬浮或溶解在所述制剂中。优选地，所述抗痤疮化合物可溶于水并因此溶解在所述制剂中。一个这样的优选的抗痤疮化合物是抗生素。优选的抗生素包括大环内酯族抗生素中的那些，如红霉素、阿奇霉素、克拉霉素、替米考星和泰乐菌素，以及林可霉素族抗生素中的那些，如克林霉素和林可霉素。与过氧苯甲酰联合用于本发明的制剂的特别优选的抗生素是克林霉素，如盐酸克林霉素或克林霉素磷酸酯。可包含于含有或不含有抗生素的本发明制剂中的其他局部抗痤疮活性成分包括水杨酸、壬二酸、烟酰胺、尿素和类视黄醇如维甲酸、阿达帕林和他佐罗汀。
所述其他抗痤疮化合物，如果存在于本发明的制剂中，则优选地以在不存在过氧苯甲酰的情况下显示抗痤疮效力的浓度存在。例如，如果林可霉素存在于本发明的制剂中，则所述林可霉素的浓度优选至少为0.5％，优选1％的浓度。在所述制剂中可以使用更高的林可霉素浓度，如2.5％、5.0％或更高。
本发明制剂的有机溶剂具有以下特点：
(1)可混溶于水中，
(2)在0℃-40℃的温度下不与过氧苯甲酰化学反应，
(3)在0℃-40℃的温度下是液体，
(4)在环境温度下能够溶解的过氧苯甲酰的浓度至少为0.1％，
(5)在不存在表面活性剂的情况下能够将过氧苯甲酰分散在水凝胶中。
用于本发明制剂的优选的有机溶剂的实例是多元醇(polyol)，也称作多元醇(polyhydric alcohol)。多元醇的代表性实例包括二醇和糖醇。用于本发明制剂的优选的多元醇包括聚醚二醇如乙氧基二甘醇(ethoxydiglycol)，以及丙二醇。优选的水混溶性有机溶剂是丙二醇。本发明人已通过HPLC分析测得，在室温下，过氧苯甲酰可以0.2％-0.3％w/w的水平溶于100％丙二醇中。另一种优选的有机溶剂是乙氧基二甘醇，如以商品名Transcutol
(Gattefosse，Saint-Priest，France)销售的乙氧基二甘醇。已通过HPLC分析测得，在室温下，过氧苯甲酰可以约4.9％的水平溶于乙氧基二甘醇中。另一种优选的有机溶剂是聚乙二醇，如PEG400。
所述制剂中有机溶剂的浓度应该足够高以在不存在表面活性剂的情况下提供过氧苯甲酰在含水液体中的稳定悬浮液。所述有机溶剂的浓度应该小于会在从所述制剂中除去全部的水之后使全部所述过氧苯甲酰溶解在所述制剂中的浓度。一般地，在所述制剂中，所述有机溶剂的浓度应该是所述过氧苯甲酰的浓度的1-4倍。
而且，所述制剂中水与有机溶剂的浓度比应该高，以使所述过氧苯甲酰以饱和溶解度或接近饱和溶解度保持在施用所述制剂且随后水从所述制剂中蒸发之后保留在皮肤上的剩余制剂中，从而使所述剩余制剂中的过氧苯甲酰对皮肤的热力学活性最大化。因此，优选的是，在本发明的制剂中，水与所述有机溶剂的相对浓度应该是至少7∶1，例如至少9∶1或10∶1，优选至少12∶1，且最优选至少20∶1，如达到98∶1。
所述制剂中过氧苯甲酰的浓度是小于5.0％且有效治疗痤疮的体征和/或症状的量。在过氧苯甲酰在本发明制剂中的该浓度下，与含有5.0％过氧苯甲酰的制剂相比，皮肤刺激减小。因此，1.0％-4.5％的过氧苯甲酰浓度适于本发明。优选的过氧苯甲酰浓度范围为2.0％-3.5％。最优选的过氧苯甲酰浓度为介于2.3％和2.7％之间的约2.5％。
所述制剂可以是包含水作为主要成分的许多局部剂型(包括溶液剂、凝胶剂、乳膏、喷雾剂和泡沫剂)之一。优选的(但不一定)是，所述制剂是水凝胶的形式。因此，本发明的制剂可以包含胶凝剂或增稠剂。水分散性的、适于用在上皮组织如皮肤上并形成粘稠度(consistency)基本均匀的水凝胶的任何胶凝剂都适用于本发明的组合物。一种优选的胶凝剂是羟丙基纤维素，如以商品名KLUCEL
(Hercules Incorporated，Wilmington，DE，USA)销售的羟丙基纤维素。另一种优选的胶凝剂是羟乙基纤维素，如以商品名NATROSOL
(Hercules Incorporated)销售的羟乙基纤维素。其他的合适胶凝剂包括聚羧乙烯，也称作卡波姆，如以商品名CARBOPOL
934、940、941、980和981(B.F.Goodrich Co.，Akron，OH，USA)、ETD2020TM和ULTREZ
(Noveon，Inc.，Cleveland，OH，USA)销售的那些。其他的合适胶凝剂是聚乙烯醇、聚环氧乙烷、丙二醇藻酸酯、甲基纤维素、羟丙基甲基纤维素和天然聚合物树胶如黄原胶和角叉菜胶。所述组合物中胶凝剂的浓度可以根据几种因素加以改变，包括所述BPO悬浮液期望的稳定程度和所述凝胶组合物期望的粘度。
如果需要，本发明的制剂可以进一步包含一般用于制剂中且为本领域技术人员所知的其他药学可接受的赋形剂。这样的赋形剂包括例如保湿剂(humectant)、润肤剂(emollient)、pH稳定剂、防腐剂、螯合剂和抗氧化剂。
本发明的制剂可用于通过将所述制剂施用于皮肤的受累部位如面部、颈部、背部和胸部上来治疗痤疮。优选每日施用所述制剂一次或更多次，持续足以改善痤疮的体征的时间。已经令人惊讶地发现，包含2.5％过氧苯甲酰的本发明制剂在痤疮的治疗中具有的功效与用包含5.0％过氧苯甲酰的制剂取得的功效相当(两种制剂都包含抗生素林可霉素1％)。还令人惊讶的是，当仅每天一次地施用本发明的制剂并每天两次地施用包含5.0％过氧苯甲酰的制剂时，也观察到这种相当的功效。
本发明的制剂还可用于治疗红斑痤疮。在治疗红斑痤疮时，将本发明的制剂施用于受累部位，优选每日施用一次或更多次，持续足以改善红斑痤疮的体征和症状的时间。
本发明的制剂可以通过将本发明的组分组合以提供药物制剂的任何方法来制备。例如，可以通过组合水、水混溶性有机溶剂和过氧苯甲酰制备过氧苯甲酰的悬浮液。优选地，例如通过搅拌、超声处理、研磨和/或振摇来混合所述组合，以制备过氧苯甲酰颗粒在水和有机溶剂中的均匀悬浮液。其他成分如胶凝剂和其他赋形剂可以在获得所述均匀悬浮液之前或之后加入。
如果在所述制剂中包含另外的抗痤疮药物，可以在形成过氧苯甲酰的悬浮液之前或之后将该抗痤疮药物与其他组分组合。备选方案是提供所述抗痤疮药物如克林霉素的单独的水溶液，并将该溶液与所述过氧苯甲酰悬浮液组合，以获得最终制剂。
在以下实施例中进一步说明本发明，所述实施例是示例性的而不是限制性的。
实施例1-本发明的示例性制剂
制备了包含如表1所示的以下组分的本发明药物制剂。
表1
实施例2-本发明的示例性制剂
制备了包含如表2所示的以下组分的本发明药物制剂，所述药物制剂还包含除过氧苯甲酰外的抗痤疮药物。
*相当于1.0％克林霉素
表2
实施例3-比较功效
在治疗399名患者的大型临床研究中，试验了实施例2的包含2.5％过氧苯甲酰、5％丙二醇、89％水和1％克林霉素的水凝胶制剂在治疗痤疮损伤中的功效。该本发明的制剂是制剂A。制备了包含5.0％过氧苯甲酰、10％丙二醇、82.5％水和1.0％克林霉素的类似水凝胶制剂，并在设计非常相似的第二临床研究中试验了该制剂在治疗痤疮损伤中的功效。该制剂(不是本发明的制剂)是制剂B。将这些结果与关于水凝胶商品(BenzaClinTopical Gel，Dermik Laboratories，Bridgewater，NJ)的功效的处方信息中提供的数据进行比较，所述水凝胶商品包含5.0％过氧苯甲酰、1.0％克林霉素、二辛基磺基琥珀酸钠(表面活性剂)和水。该现有技术制剂是制剂C。制剂A和B不含表面活性剂。在12周的治疗期间内，制剂A仅每天一次地施用，而各自包含5.0％过氧苯甲酰的制剂B和C均每天两次地施用。施用12周后试验制剂A。制剂B和C的数据是在施用10周后。
指示试验个体将制剂施用于面部，制剂B和C每天施用两次，制剂A每天施用一次。制剂B和C施用10周后，制剂A施用12周后，测定炎性损害和非炎性痤疮损害的平均百分比减少。通过从基线总炎性损害计数中减去研究结束时(10或12周)的总炎性损害计数，然后乘以100，除以基线总炎性损害计数，来计算炎性损害(脓疱和丘疹)的百分比减少。非炎性损害包括开放性粉刺和封闭性粉刺，而且以同样的方法计算非炎性损害的百分比减少。该痤疮研究的结果示于表3。
| 制剂A | 制剂B | 制剂C | |
| 个体数量 | 399 | 481 | 215 |
| 炎性痤疮损害的平均％减少 | 48.8 | 59.2 | 53.5 |
| 非炎性痤疮损害的平均％减少 | 42.6 | 51.0 | 36.1 |
表3
表3的数据显示，含有仅2.5％过氧苯甲酰的制剂A的功效与制剂B和C相似。这些结果特别令人惊讶，因为制剂A每天仅施用一次，然而制剂B和C每天施用两次。
实施例4-刺激可能性
试验了各自包含过氧苯甲酰和1.0％克林霉素的实施例3的制剂A和B，以测定这两种制剂的刺激可能性对比。本发明的制剂A包含2.5％过氧苯甲酰、浓度为过氧苯甲酰的两倍的丙二醇、和浓度为丙二醇的17.8倍的水。制剂B包含5.0％过氧苯甲酰、浓度为过氧苯甲酰的两倍的丙二醇、和浓度为丙二醇的8.25倍的水。
将在单独的闭合贴片下的凝胶制剂A和B施用于33个健康个体的背部，每周3次，持续3周。每次施用之后，评估者针对刺激或炎症的体征对每次施用观察48小时，并使用刺激的标准分级系统根据严重程度指定由0(无刺激体征)至4(具有水肿的红斑和发疱)的分数。得自该研究的数据显示，与使用制剂B相比，使用本发明的制剂A导致总体累计刺激评分减少33％。
本领域技术人员会明白本文所述的发明的其他改变、用途和应用。这样的改变也包括在以上的说明书和以下的权利要求中。
Claims (54)
1.用于局部施用于皮肤的含水制剂，所述含水制剂包含水、水混溶性有机溶剂和过氧苯甲酰，其中所述有机溶剂的浓度足以在所述制剂中不含表面活性剂的情况下提供过氧苯甲酰在所述含水制剂中的稳定悬浮液，其中所述制剂中的水和有机溶剂的浓度比足以在施用于皮肤后使所述过氧苯甲酰以饱和溶解度保持在所述制剂中，并且其中所述制剂中的过氧苯甲酰的浓度为小于5.0％且至少1.0％w/w。
2.权利要求1的含水制剂，其中所述过氧苯甲酰的浓度为2.0％-3.5％w/w。
3.权利要求2的含水制剂，其中所述过氧苯甲酰的浓度为约2.5％w/w。
4.权利要求1的含水制剂，其中所述有机溶剂为多元醇。
5.权利要求4的含水制剂，其中所述多元醇为丙二醇。
6.权利要求1的含水制剂，其中所述有机溶剂的浓度小于会在从所述制剂中除去全部的水之后使全部所述过氧苯甲酰溶解在所述制剂中的浓度。
7.权利要求1的含水制剂，其中在所述制剂中，所述有机溶剂的浓度是所述过氧苯甲酰的浓度的1-4倍。
8.权利要求1的含水制剂，其中所述制剂中水与有机溶剂的比例w/w为至少7∶1。
9.权利要求8的含水制剂，其中所述比例为至少10∶1。
10.权利要求9的含水制剂，其中所述比例为至少20∶1。
11.权利要求1的含水制剂，其不含表面活性剂。
12.权利要求1的含水制剂，其包含表面活性剂。
13.权利要求1的含水制剂，其还包含水分散性胶凝剂。
14.权利要求1的含水制剂，其还包含除过氧苯甲酰之外的有效治疗痤疮的化合物。
15.权利要求14的含水制剂，其中所述化合物可溶于水。
16.权利要求14的含水制剂，其中所述化合物为抗生素。
17.权利要求16的含水制剂，其中所述抗生素是大环内酯族或林可霉素族抗生素的成员。
18.权利要求17的含水制剂，其中所述抗生素为克林霉素。
19.制备用于局部施用于皮肤的含水制剂的方法，所述方法包括组合水、水混溶性有机溶剂和过氧苯甲酰，其中被组合的有机溶剂的浓度足以在所述制剂中不含表面活性剂的情况下提供过氧苯甲酰在所述含水制剂中的稳定悬浮液，其中被组合在所述制剂中的水和有机溶剂的浓度比足以在施用于皮肤后使所述过氧苯甲酰以饱和溶解度保持在所述制剂中，并且其中被组合在所述制剂中的过氧苯甲酰的浓度为小于5.0％且至少1.0％w/w。
20.权利要求19的方法，其中所述过氧苯甲酰的浓度为2.0％-3.5％w/w。
21.权利要求20的方法，其中所述过氧苯甲酰的浓度为约2.5％w/w。
22.权利要求19的方法，其中所述有机溶剂为多元醇。
23.权利要求22的方法，其中所述多元醇为丙二醇。
24.权利要求19的方法，其中被组合的有机溶剂的浓度小于会在从所述制剂中除去全部的水之后使全部所述过氧苯甲酰溶解在所述制剂中的浓度。
25.权利要求19的方法，其中在所述制剂中，被组合的有机溶剂的浓度是被组合的过氧苯甲酰的浓度的1-4倍。
26.权利要求19的方法，其中被组合在所述制剂中的水与有机溶剂的比例w/w为至少7∶1。
27.权利要求26的方法，其中所述比例为至少10∶1。
28.权利要求27的方法，其中所述比例为至少20∶1。
29.权利要求19的方法，其中不将表面活性剂组合在所述制剂中。
30.权利要求19的方法，其中将表面活性剂组合在所述制剂中。
31.权利要求19的方法，其还包括将水分散性胶凝剂组合在所述制剂中。
32.权利要求19的方法，其还包括组合除过氧苯甲酰之外的有效治疗痤疮的化合物。
33.权利要求32的方法，其中所述化合物可溶于水。
34.权利要求32的方法，其中所述化合物为抗生素。
35.权利要求34的方法，其中所述抗生素是大环内酯族或林可霉素族抗生素的成员。
36.权利要求35的方法，其中所述抗生素为克林霉素。
37.用于治疗痤疮的方法，所述方法包括向皮肤的受累部位施用用于局部施用于皮肤的含水制剂，持续足以改善痤疮的体征和/或症状的时间，所述含水制剂包含水、水混溶性有机溶剂和过氧苯甲酰，其中所述有机溶剂的浓度足以在所述制剂中不含表面活性剂的情况下提供过氧苯甲酰在所述含水制剂中的稳定悬浮液，其中所述制剂中的水和有机溶剂的浓度比足以在施用于皮肤后使所述过氧苯甲酰以饱和溶解度保持在所述制剂中，并且其中所述制剂中的过氧苯甲酰的浓度为小于5.0％且至少1.0％w/w。
38.权利要求37的方法，其中所述含水制剂中的过氧苯甲酰的浓度为2.0％-3.5％w/w。
39.权利要求38的方法，其中所述过氧苯甲酰的浓度为约2.5％w/w。
40.权利要求37的方法，其中所述有机溶剂为多元醇。
41.权利要求40的方法，其中所述多元醇为丙二醇。
42.权利要求37的方法，其中所述有机溶剂的浓度小于会在从所述制剂中除去全部的水之后使全部所述过氧苯甲酰溶解在所述制剂中的浓度。
43.权利要求37的方法，其中在所述制剂中，所述有机溶剂的浓度是所述过氧苯甲酰的浓度的1-4倍。
44.权利要求37的方法，其中所述制剂中水与有机溶剂的比例w/w为至少7∶1。
45.权利要求44的方法，其中所述比例为至少10∶1。
46.权利要求45的方法，其中所述比例为至少20∶1。
47.权利要求37的方法，其中所述含水制剂不含表面活性剂。
48.权利要求37的方法，其中所述含水制剂包含表面活性剂。
49.权利要求37的方法，其中所述制剂还包含水分散性胶凝剂。
50.权利要求37的方法，其中所述制剂还包含除过氧苯甲酰之外的有效治疗痤疮的化合物。
51.权利要求50的方法，其中所述化合物可溶于水。
52.权利要求50的方法，其中所述化合物为抗生素。
53.权利要求52的方法，其中所述抗生素是大环内酯族或林可霉素族抗生素的成员。
54.权利要求53的方法，其中所述抗生素为克林霉素。
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| FR2910321B1 (fr) * | 2006-12-21 | 2009-07-10 | Galderma Res & Dev S N C Snc | Gel creme comprenant au moins un retinoide et du peroxyde de benzole |
| EP1967180A1 (de) | 2007-03-06 | 2008-09-10 | Almirall Hermal GmbH | Topische Zusammensetzung enthaltend einen Retinoid-Rezeptor-Agonist |
| US8288434B2 (en) | 2008-06-05 | 2012-10-16 | Dow Pharmaceutical Sciences, Inc. | Topical pharmaceutical formulations containing a low concentration of benzoyl peroxide in suspension in water and a water-miscible organic solvent |
| US9526689B2 (en) * | 2011-12-09 | 2016-12-27 | Mary Kay Inc. | Skin care formulation |
| EP3941454A1 (en) * | 2019-03-18 | 2022-01-26 | Bausch Health Ireland Limited | Topical compositions and methods for treating acne vulgaris |
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| CN108159425A (zh) * | 2012-11-27 | 2018-06-15 | 索尔-格尔科技有限公司 | 用于治疗红斑痤疮的组合物 |
| CN107304177A (zh) * | 2016-04-20 | 2017-10-31 | 武汉诺安药业有限公司 | 一种过氧苯甲酰微粉化的化学制备方法 |
| CN107375209A (zh) * | 2017-08-30 | 2017-11-24 | 江苏嘉逸医药有限公司 | 一种过氧苯甲酰的局部药物制剂 |
| CN107737135A (zh) * | 2017-11-28 | 2018-02-27 | 江苏万川医疗健康产业集团有限公司 | 一种药物制剂及其制备方法与应用 |
| CN114126582A (zh) * | 2019-08-01 | 2022-03-01 | 博世健康爱尔兰有限公司 | 局部用组合物 |
| CN113577022A (zh) * | 2021-05-18 | 2021-11-02 | 南京欣通瑞亿医药科技有限公司 | 一种氨苯砜类化合物混悬液及其制备方法和应用 |
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