CN113056257A - 应用于组织修复的含有吡非尼酮的半固体的基于油的药物组合物 - Google Patents
应用于组织修复的含有吡非尼酮的半固体的基于油的药物组合物 Download PDFInfo
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- CN113056257A CN113056257A CN201980064402.9A CN201980064402A CN113056257A CN 113056257 A CN113056257 A CN 113056257A CN 201980064402 A CN201980064402 A CN 201980064402A CN 113056257 A CN113056257 A CN 113056257A
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- pirfenidone
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Abstract
本发明描述了含有吡非尼酮的半固体药物组合物,由于其渗透性和吸收特性,其相比于现有技术中已知的其它皮肤给药的药物形式提供了优势,其用于恢复已经遭受细胞外基质流失或降解(所述细胞外基质流失或降解导致了皱纹的形成或皮肤变薄)的组织的治疗中。
Description
发明领域
本发明涉及包含作为活性成分的吡非尼酮(Pirfenidone)的,呈药膏(unguent)、凝胶剂、乳膏剂或软膏剂形式的半固体制剂;在治疗和预防纤维化病变中,其相对于现有技术中已知的皮肤给药药物形式提供了优势。
发明背景
本发明涉及半固体药物组合物及其在修复纤维化病变组织和预防纤维化病变的治疗中的用途,涉及包含作为活性抗纤维化成分的5-甲基-1-苯基-2(1H)-吡啶酮的组合物。
吡非尼酮是分子量为185.23道尔顿的非肽类合成分子。它的化学元素如C12H11NO所表示的那样,并且它的结构是已知的。吡非尼酮的合成已经被解决了。吡非尼酮被制备为且被临床评价为广谱抗纤维化药物。吡非尼酮通过降低TNF-α表达、降低PDGF表达和降低胶原蛋白表达而具有抗纤维化性质。5-甲基-1-苯基-2(1H)-吡啶酮具有下面的结构式:
美国专利第3,974,281、4,042,699和4,052,509号进一步披露了化合物5-甲基-1-苯基-2-(1H)-吡啶酮“(吡非尼酮”)用于降低血清尿酸和葡萄糖水平、治疗炎性上呼吸道病症,以及治疗人类和其他哺乳动物的炎性皮肤病症的用途。
吡非尼酮在修复和预防纤维化病变中的用途披露于专利EP-A-0383591和EP-A-0702551中。
因此,本发明的主要目的是提供用于修复和预防纤维化病变组织的半固体组合物。
在本文中,术语“抗纤维(anti-fibro)”、“抗纤维化的(anti-fibrotic)”或“抗纤维化(anti-fibrosis)”是指修复和/或预防病理性胶原蛋白聚合、胶原蛋白病、皱纹等,以及修复和正常化现有病理性纤维化组织。
本发明的另一个目的是提供这种包含作为活性抗纤维化成分的5-甲基-1-苯基-2-(1H)-吡啶酮(“吡非尼酮”)的半固体组合物。
本发明的其他目的及其具体特征和优势将在下面的描述中进行解释,或者在下面的描述中将是明显的。
发明目的
本发明描述了含有吡非尼酮的半固体药物组合物,由于它的渗透性和吸收特性,其相比于现有技术中已知的其它皮肤(cutaneously)给药的药物形式提供了优势;其用于恢复已经遭受细胞外基质流失或降解的组织,所述细胞外基质流失或降解导致皱纹的形成或皮肤变薄。也就是说,为了展示含有吡非尼酮的半固体组合物的使用在恢复由胶原蛋白和其它细胞外基质蛋白(例如纤维粘连蛋白和弹性蛋白)流失造成的皮肤缺陷中是有效的。
本发明的另一个目的是提供用于皮肤给药的呈乳膏剂、软膏剂和药膏(unguent)形式的半固体组合物,其包含吡非尼酮(作为活性成分)、吸收基质、增溶剂、防腐剂、润肤剂(emollient agent)和纯净水。
发明描述
5-甲基-1-苯基-2(1H)-吡啶酮(吡非尼酮)是本发明的半固体组合物的主要组分,其诱导经历过细胞外基质蛋白(例如胶原蛋白、纤维粘连蛋白和弹性蛋白)降解的皮肤的“填补”。
目前已经使用了不同的资源(resources)和治疗,但它们中没有一种被证明是实际有效的。作为抗纤维化药物的吡非尼酮,已经在不同的病理学和器官中展现了其效能,这已经在先前的工作中被证明;在这些工作中,我们已经在实验模型和临床试验中均观察到它们对成纤维细胞和胶原蛋白产生的的影响。
最近获得的额外信息使我们能够得出结论:吡非尼酮诱导参与刺激胶原蛋白和非胶原蛋白降解的基因激活(ignition)的转录因子的表达。然而,视吡非尼酮浸渍的微环境而定,在缺乏过量细胞外基质的情况下(例如糖尿病足溃疡和静脉曲张溃疡,其中存在广泛(extensive)的组织缺损以及生产和合成细胞的细胞外基质的缺失,形成面部皱纹,以及皮肤变薄和失去弹性),它将精确诱导出与之前报道的关于其为了重塑疤痕而诱导胶原酶(降解胶原蛋白的酶)的能力相反的效果。
软膏剂和药膏(unguent)
药膏(unguent)被定义为含有掺入到合适基质里的药物和添加剂的软性粘稠性(consistency)制剂,所述基质为该药膏(unguent)提供了主体(body)和粘稠性。其粘附并施加至皮肤和粘膜。所述基质可以是脂溶性的或水溶性的,它通常是无水的或最多含有20%的水。当药膏(unguent)含有可洗的或水可去除的基质时,它还被称作亲水性药膏(unguent),也被称作软膏剂。
在1955年,USP引入了软膏剂的定义。该定义范围广,并且包括矿脂基质(即油包水(W/O)或水包油(O/W)乳液基质)和所谓的水溶性基质。
因为它们被设计用于特定用途并且为了促进它们的施用,所以将它们进行选择或设计以获得最佳的药物分散性,还将它们进行选择或设计以赋予润肤性质或其他医学特征。
基质不能有刺激性,其必须易于去除,其不能留下污迹,其必须稳定,其不能依赖于pH值,以及其必须与多种药物广泛相容。
使用乳膏剂或药膏(unguent)形式的制剂相对于凝胶剂制剂中的现有技术,其技术优势主要由下面的属于该制剂类型的性质组成:令人满意的抗氧化稳定性、良好的生理耐受性、吡非尼酮的充分释放、良好的敏感性;在皮肤上施用软膏剂所追求的目的是使药物深入皮肤,而不像以前的制剂,其治疗效果对伤口或皮肤损伤有效。
通过使用大多数的软膏剂,尝试局部治疗。
在药物可以渗透皮肤之前,它必须从软膏剂基质中释放出来。
软膏剂基质在治疗中的一个适用性标准是药物的传输速率。
通过摩擦或按摩,药物的渗透性提高到两倍或三倍(is doubled or tripled)。
·蜡剂:当软膏剂含有至少25%比例的蜡时。
·甘油剂(glicerolate):当它含有至少50%的甘油时。
·药膏(unguent):用于皮肤或粘膜外敷的半固体制剂,并且其使用油脂和/或树脂作为载体。
·糊剂:它们是含有高百分比固体的半固体药物形式,并且它们旨在用于局部施用。它们可以由水性凝胶剂或脂肪性(fatty)赋形剂制备得到,在这些情况下,脂肪性赋形剂具有通常在体温下不会软化的厚稠(thick)的药膏(unguent),因此在施用它们的区域起到保护层的作用。
·乳膏剂:它们是含有一种或多种活性成分以及水的乳化的半固体药物形式,所述水含量为20%至80%。这一术语传统上应用于下面的半固体物质:具有相对流动的配制稠度(relatively fluid formulated consistency);无论是作为油包水还是水包油的乳液。然而,最近这一术语已经仅限于由水包油乳液或脂肪酸的水性微晶分散系或易清洗的长链醇组成的产品,在美容(cosmetically)和美观上更易接受。
它们是由两种相(一种是亲脂相,另一种是水相)组成的药物形式。
由于它们的高含水量,它们具有软性粘稠性,以及牛顿流动或假塑性流动(Newtonian or pseudoplastic flow)。
乳膏剂和软膏剂的区别在于软膏剂几乎不流动,乳膏剂易于流动,而且软膏剂总是单相的。
·非渗透性或表皮的:它们旨在抵御某些物理或化学试剂、润滑剂、软化剂、收敛剂、润肤剂或角质软化剂、腐蚀剂、角质促成剂、清新剂。
·真皮的或内胚层的:发红剂、愈合剂、止痒剂。
·真皮下的或皮下的:局部麻醉剂、激素、维生素、抗风湿剂。
半固体组合物
含有2%至12%的吡非尼酮的半固体组合物是通过使用以下制备得到的:20%至60%的溶剂-保湿剂、5%至10%的一种乳化剂或乳化剂的组合、2%至8%的稠度(consistency)和软化(emollience)剂、0.5%至3%的一种或多种润肤剂、0.1%至2%的防腐剂、0.05%至0.2%的流变剂或粘度剂、0.05%至0.2%的中和剂、0.05%至0.2%的防腐剂、和0.0005%至0.003%的稳定剂,以及任选地,0.008%至0.8%的抗菌剂/防腐剂。
其中所述溶剂-保湿剂选自甘油、乙醇、Transcutol-P、N-甲基吡咯烷酮、2-吡咯烷酮、聚氧乙烯蓖麻油RH-40(Cremophor RH-40)、丙二醇;所述乳化剂选自鲸蜡醇、硬脂醇、十六十八醇(Cetostearyl alcohol)、司盘80(Span 80)、司盘60(Span 60)、单硬脂酸甘油酯,聚乙二醇硬脂酸酯、聚氧乙烯蓖麻油A-6、十六十八醇、鲸蜡醇、单硬脂酸甘油酯、鲸蜡(Spermaceti)、聚氧乙烯蓖麻油A-25;所述稠度和软化剂选自十六十八醇、聚乙二醇十六十八醇醚(Macrogol cetostearyl ether)、鲸蜡硬脂醇聚醚-25(Ceterareth-25)、鲸蜡醇、鲸蜡、蜂蜡、单硬脂酸甘油酯、固体石蜡、鲸蜡醇和硬脂醇;所述润肤剂选自二甲基硅油(Dimeticon)、矿物油、己二酸异丙酯、异十六烷、辛酸/癸酸甘油三酯、肉豆蔻基葡糖苷、山嵛醇、C12-15烷基苯甲酸酯、异硬脂酸异丙酯;所述防腐剂选自对羟基苯甲酸甲酯钠、对羟基苯甲酸丙酯钠、苯氧乙醇、重氮烷基脲(Diazolinidyl urea)、碘丙炔基丁基氨甲酸酯;所述粘度剂选自对羟基苯甲酸丙酯钠,所述中和剂可以是三乙醇胺或氢氧化钠;所述稳定剂可以选自柠檬酸或合成维生素C家族。
为了更好地理解本发明,制备含有吡非尼酮的半固体组合物的方法及其用途和施用(application)的说明性示例如下面所展示。
根据下面的方法制备半固体组合物:
1.制备乳膏剂形式的半固体吡非尼酮药物组合物的方法,其包括下面的步骤:
A)油相
将司盘60(Span 60)、鲸蜡醇、硬脂醇、聚氧乙烯蓖麻油A-6、聚氧乙烯蓖麻油A-25和二甲基硅油放入反应器中,搅拌并加热至(75℃-80℃),直至完全融化为止。
称为油相
B)混合物A
将全部纯净水的30%置于适当容量的不锈钢容器中,并且逐渐加入卡波姆,同时持续进行搅拌,直至完全湿润为止。
称为混合物A
C)溶液“A”
将丙二醇放入锅(pot)中并加热至(75℃-80℃),并且在131rpm±10%下进行搅拌。
逐渐加入吡非尼酮,同时持续进行搅拌,并保持加热至(75℃-80℃),直至完全溶解为止。保持30分钟。
(称为溶液“A”)
D)溶液“B”
将全部水的30%置于适当容量的不锈钢容器中;
将下面的物质逐渐加入所述不锈钢容器,同时持续搅拌直至完全溶解为止:对羟基苯甲酸甲酯钠、对羟基苯甲酸丙酯钠、无水柠檬酸、聚山梨酯60。
称为溶液“B”
E)水相
将混合物“A”和溶液“B”的内容物逐渐加入到称为“A”的溶液中,同时持续搅拌并保持加热至(75℃-80℃)。在131rpm±10%保持搅拌并加热至完全混合为止。
称为水相
F)相混合物
将所述水相加入到具有所述油相的反应器中,同时在75℃-80℃的恒定温度下持续搅拌。在71rpm±10%下保持持续搅拌20分钟,并将该混合物温度降低至40℃-45℃。
G)溶液“C”
将剩余的水分别置入不锈钢容器中,并且将三乙醇胺逐渐加入到所述容器中,同时持续搅拌直至完全溶解为止。
称为溶液“C”
H)最终混合物
将溶液C加入到所述反应器中,在71rpm±10%下搅拌60分钟或直至温度达到30℃-35℃为止。
2.制备软膏剂形式的半固体吡非尼酮药物组合物的方法,其包括以下步骤:
A)油相
将下面的物质置于反应器中,搅拌并加热至(75℃-80℃),直到完全融化为止:司盘60(Span 60)、鲸蜡醇、硬脂醇、聚氧乙烯蓖麻油A-6、聚氧乙烯蓖麻油A-25和白矿脂钠。
称为油相
B)溶液“A”
将丙二醇置于锅中,加热至75℃-80℃并在131rpm±10%下搅拌,以及搅拌。逐渐加入吡非尼酮,同时持续搅拌并且保持加热到(75℃-80℃),直到完全溶解为止。在搅拌和加热下保持20分钟,逐渐加入2%的M-DDO,搅拌10分钟;加入吐温60并搅拌10分钟。
C)相混合物
将所述水相的所有内容物加入到具有所述油相的反应器中,同时在71rpm下持续搅拌20分钟。将温度降低至30-35℃。
3.制备药膏(unguent)形式的半固体吡非尼酮药物组合物的方法,其包括以下步骤:
A)油相
将下面的物质加入到反应器中,搅拌并加热至(75℃-80℃),直到完全融化为止:司盘60(Span 60)、硬脂醇、和白矿脂钠。
称为油相
B)溶液“A”
将丙二醇置于锅中,加热至75℃-80℃并在131rpm±10%下搅拌,以及搅拌。逐渐加入吡非尼酮,同时持续搅拌并且保持加热到(75℃-80℃),直到完全溶解为止。在搅拌和加热下保持20分钟,逐渐加入M-DDO 2%,搅拌10分钟;加入吐温60并搅拌10分钟。
C)溶液“B”
将纯净水置于适当容量的不锈钢容器中,并逐渐加入柠檬酸和聚山梨酯60。
D)水相
将溶液“B”逐渐加入到称为“A”的溶液中,同时持续搅拌并保持加热至(75℃-80℃),保持30分钟。
E)水相
将所述水相加入到具有所述油相的反应器中,同时在恒定温度下持续搅拌20分钟。
实施例
乳膏型的半固体组合物的实施例如表1中所示:
软膏型的半固体组合物的实施例如表2中所示:
药膏(unguent)型的半固体组合物的实施例如表3中所示:
尽管本发明已经使用有限数量的实施方案进行了描述,但是一个实施方案的具体特征不应该归属于本发明的其它实施方案。单一实施方案不能代表本发明的所有方面。在一些实施方案中,所述组合物和方法可以包括本文未提及的若干化合物或步骤。在其它实施方案中,所述组合物或方法不包括,或基本没有本文未提及的化合物或步骤。存在基于描述的实施方案的变化和修饰。
Claims (16)
1.半固体吡非尼酮药物组合物,其特征在于它包含2%至12%的吡非尼酮、20%至60%的溶剂-保湿剂、5%至10%的一种乳化剂或乳化剂的组合、2%至8%的稠度和软化剂、0.5%至3%的一种或多种润肤剂、0.1%至2%的防腐剂、0.05%至0.2%的流变剂或粘度剂、0.05%至0.2%的中和剂、0.05%至0.2%的防腐剂、和0.0005%至0.003%的稳定剂,以及任选地,0.008%至0.8%的抗菌剂/防腐剂。
2.根据权利要求1所述的半固体吡非尼酮药物组合物,其特征在于所述溶剂-保湿剂选自甘油、乙醇、Transcutol-P、N-甲基吡咯烷酮、2-吡咯烷酮、聚氧乙烯蓖麻油RH-40、丙二醇;所述乳化剂选自鲸蜡醇、硬脂醇、十六十八醇、司盘80、司盘60、单硬脂酸甘油酯,聚乙二醇硬脂酸酯、聚氧乙烯蓖麻油A-6、十六十八醇、鲸蜡醇、单硬脂酸甘油酯、鲸蜡、聚氧乙烯蓖麻油A-25;所述稠度和软化剂选自十六十八醇、聚乙二醇十六十八醇醚、鲸蜡硬脂醇聚醚-25、鲸蜡醇、鲸蜡、蜂蜡、单硬脂酸甘油酯、固体石蜡、鲸蜡醇和硬脂醇;所述润肤剂选自二甲基硅油、矿物油、己二酸异丙酯、异十六烷、辛酸/癸酸甘油三酯、肉豆蔻基葡糖苷、山嵛醇、C12-15烷基苯甲酸酯、异硬脂酸异丙酯;所述防腐剂选自对羟基苯甲酸甲酯钠、对羟基苯甲酸丙酯钠、苯氧乙醇、重氮烷基脲、碘丙炔基丁基氨甲酸酯;所述粘度剂选自对羟基苯甲酸丙酯钠,所述中和剂可以是三乙醇胺或氢氧化钠;所述稳定剂可以选自柠檬酸或合成维生素C家族;
其中所述半固体药物组合物呈乳膏剂的形式。
3.根据权利要求2所述的呈乳膏剂的形式的半固体吡非尼酮药物组合物,其特征在于所述保湿基质是丙二醇,所述乳化剂是司盘60、聚氧乙烯蓖麻油A-6、聚氧乙烯蓖麻油A-25和吐温60;所述稠度和软化剂是鲸蜡醇和硬脂醇;所述润肤剂是二甲基硅油,所述防腐剂是对羟基苯甲酸甲酯钠和对羟基苯甲酸丙酯钠,所述流变剂或粘度剂是卡波姆;所述中和剂是三乙醇胺;以及所述稳定剂是无水柠檬酸。
4.根据权利要求3所述的呈乳膏剂的形式的半固体吡非尼酮药物组合物,其特征在于它包含2%至12%的吡非尼酮,以及它是通过使用50%的丙二醇、6.382%的司盘60、2%的鲸蜡醇、2%的硬脂醇、1%的聚氧乙烯蓖麻油A-6、1%的聚氧乙烯蓖麻油A-25、1%的二甲基硅油、0.617%的吐温60、0.147%的对羟基苯甲酸甲酯钠、0.1%的卡波姆、0.1%的三乙醇胺、0.066%的对羟基苯甲酸丙酯钠、0.001%的柠檬酸、和足量至100%的水进行制备。
5.制备根据权利要求2所述的呈乳膏剂的形式的半固体吡非尼酮药物组合物的方法,其特征在于它包括下面的步骤:
A)油相
将司盘60、鲸蜡醇、硬脂醇、聚氧乙烯蓖麻油A-6、聚氧乙烯蓖麻油A-25和二甲基硅油放入反应器中,搅拌并加热至(75℃-80℃),直至完全融化为止;
称为油相
B)混合物A
将全部纯净水的30%置于适当容量的不锈钢容器中,并且逐渐加入卡波姆,同时持续进行搅拌,直至完全湿润为止;
称为混合物A
C)溶液“A”
将丙二醇放入锅中并加热至(75℃-80℃),并且在131rpm±10%下进行搅拌;
逐渐加入吡非尼酮,同时持续进行搅拌,并保持加热至(75℃-80℃),直至完全溶解为止;保持30分钟;
(称为溶液“A”)
D)溶液“B”
将待使用的全部水的30%置于适当容量的不锈钢容器中;
将下面的物质逐渐加入所述容器,同时持续搅拌直至完全溶解为止:
对羟基苯甲酸甲酯钠、对羟基苯甲酸丙酯钠、无水柠檬酸、聚山梨酯60;
称为溶液“B”
E)水相
将混合物“A”和溶液“B”的内容物逐渐加入到称为“A”的溶液中,同时持续搅拌并保持加热至(75℃-80℃);在131rpm±10%保持搅拌并加热至完全混合为止;
称为水相
F)相混合物
将所述水相加入到具有所述油相的反应器中,同时在75℃-80℃的恒定温度下持续搅拌;在71rpm±10%下保持持续搅拌20分钟,并将该混合物温度降低至40℃-45℃;
G)溶液“C”
将剩余的水分别置入不锈钢容器中,并且将三乙醇胺逐渐加入到所述容器中,同时持续搅拌直至完全溶解为止;
称为溶液“C”
H)最终混合物
将溶液C加入到所述反应器中,在71rpm±10%下搅拌60分钟或直至温度达到30℃-35℃为止。
6.根据权利要求1所述的半固体吡非尼酮药物组合物在制备用于恢复由胶原蛋白和其它细胞外基质蛋白流失造成的皮肤缺陷的药物中的用途,所述其它细胞外基质蛋白例如纤维粘连蛋白和弹性蛋白。
7.根据权利要求2所述的呈乳膏剂的形式的半固体吡非尼酮药物组合物在制备用于恢复由胶原蛋白和其它细胞外基质蛋白流失造成的皮肤缺陷的药物中的用途,所述其它细胞外基质蛋白为例如纤维粘连蛋白和弹性蛋白。
8.根据权利要求1所述的半固体吡非尼酮药物组合物,其特征在于所述保湿基质是丙二醇,所述乳化剂是司盘60、聚氧乙烯蓖麻油A-6、聚氧乙烯蓖麻油A-25和吐温60;所述稠度和软化剂是鲸蜡醇和硬脂醇;所述抗菌剂/防腐剂是改性的二烯丙基二硫氧化物(M-DDO),以及所述稠度基质是固体白矿脂;
其中所述半固体药物组合物呈软膏剂的形式。
9.根据权利要求8所述的呈软膏剂的形式的半固体吡非尼酮药物组合物,其特征在于它包含10%的丙二醇、18.234%司盘60、1%的聚氧乙烯蓖麻油A-6、1%的聚氧乙烯蓖麻油A-25、2.122%的吐温60;1%的鲸蜡醇、1%的硬脂醇;0.016%M-DDO、以及足量至100%的固体白矿脂CBP。
10.制备根据权利要求8所述的呈软膏剂的形式的半固体吡非尼酮药物组合物的方法,其特征在于它包括下面的步骤:
A)油相
将下面的物质置于反应器中,搅拌并加热至(75℃-80℃),直到完全融化为止:司盘60、鲸蜡醇、硬脂醇、聚氧乙烯蓖麻油A-6、聚氧乙烯蓖麻油A-25和白矿脂钠;
称为油相
B)溶液“A”
将丙二醇置于锅中,加热至75℃-80℃并在131rpm±10%下搅拌,以及搅拌;逐渐加入吡非尼酮,同时持续搅拌并且保持加热到(75℃-80℃),直到完全溶解为止;在搅拌和加热下保持20分钟,逐渐加入2%的M-DDO,搅拌10分钟;加入吐温60并搅拌10分钟;
C)相混合物
将所述水相的所有内容物加入到具有所述油相的反应器中,同时在
71rpm下持续搅拌20分钟;将温度降低至30-35℃。
11.根据权利要求8所述的呈软膏剂的形式的半固体吡非尼酮药物组合物在制备用于恢复由胶原蛋白和其它细胞外基质蛋白流失造成的皮肤缺陷的药物中的用途,所述其它细胞外基质蛋白例如纤维粘连蛋白和弹性蛋白。
12.根据权利要求1所述的半固体吡非尼酮药物组合物,其特征在于所述保湿基质是丙二醇,所述乳化剂是司盘60,所述乳化剂是吐温60;所述稠度和软化剂是硬脂醇;所述防腐剂是M-DDO,所述稠度基质是白矿脂,以及含有足量的水,以赋予所述制剂稠度;
其中所述半固体药物组合物呈药膏的形式。
13.根据权利要求12所述的呈药膏的形式的半固体吡非尼酮药物组合物,其特征在于它的制剂含有2%至12%的吡非尼酮、45%的丙二醇、18.234%的司盘60、3%的硬脂醇、17%的固体白矿脂、1.764%的吐温60、0.001%的柠檬酸、0.016%的M-DDO。
14.制备根据权利要求12所述的呈药膏的形式的半固体吡非尼酮药物组合物的方法,其特征在于它包括下面的步骤:
A)油相
将下面的物质加入到反应器中,搅拌并加热至(75℃-80℃),直到完全融化为止:司盘60、硬脂醇、和白矿脂钠;
称为油相
B)溶液“A”
将丙二醇置于锅中,加热至75℃-80℃并在131rpm±10%下搅拌,以及搅拌;逐渐加入吡非尼酮,同时持续搅拌并且保持加热到(75℃-80℃),直到完全溶解为止;在搅拌和加热下保持20分钟,逐渐加入M-DDO2%,搅拌10分钟;加入吐温60并搅拌10分钟;
C)溶液“B”
将纯净水置于适当容量的不锈钢容器中,并逐渐加入柠檬酸和聚山梨酯60;
D)水相
将溶液“B”逐渐加入到称为“A”的溶液中,同时持续搅拌并保持加热至(75℃-80℃),保持30分钟;
E)水相
将所述水相加入到具有所述油相的反应器中,同时在恒定温度下持续搅拌20分钟。
15.根据权利要求12所述的呈药膏的形式的半固体吡非尼酮药物组合物在制备用于恢复由胶原蛋白和其它细胞外基质蛋白流失造成的皮肤缺陷的药物中的用途,所述其它细胞外基质蛋白为例如纤维粘连蛋白和弹性蛋白。
16.恢复由胶原蛋白和其它细胞外基质蛋白流失造成的皮肤缺陷的方法,所述其它细胞外基质蛋白例如纤维粘连蛋白和弹性蛋白,其特征在于它包括向需要所述治疗的个体的皮肤给药根据权利要求1-4、8-9和12-13任一项中所述的半固体吡非尼酮药物组合物。
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MX2007009796A (es) | 2007-08-14 | 2009-02-25 | Cell Therapy And Technology S | Gel conteniendo pirfenidona. |
MX346763B (es) | 2012-03-28 | 2017-03-31 | Cell Therapy And Tech S A De C V | Composición tópica semisólida conteniendo pirfenidona y dialil óxido de disulfuro modificado (odd-m) para eliminar o prevenir el acné. |
MX366086B (es) | 2017-08-15 | 2019-06-27 | Cell Therapy And Tech S A De C V | Composicion topica semisolida conteniendo un agente antimicrobiano y pirfenidona para el tratamiento de daños cronicos de la piel. |
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US20060039931A1 (en) * | 2002-09-13 | 2006-02-23 | Mepha Ag | Stable cream preparations of phenyl-pyridone compounds for topical application |
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CL2021000509A1 (es) | 2021-07-19 |
US20210401989A1 (en) | 2021-12-30 |
AR116033A1 (es) | 2021-03-25 |
UY38355A (es) | 2020-03-31 |
AU2019329007A1 (en) | 2021-04-01 |
CA3111314A1 (en) | 2020-03-05 |
JP2024029232A (ja) | 2024-03-05 |
IL281142A (en) | 2021-06-30 |
PE20212365A1 (es) | 2021-12-21 |
WO2020046102A2 (es) | 2020-03-05 |
JP2022508418A (ja) | 2022-01-19 |
ECSP21022187A (es) | 2021-06-30 |
EP3842030A2 (en) | 2021-06-30 |
JP7421558B2 (ja) | 2024-01-24 |
CO2021003927A2 (es) | 2021-07-30 |
MX368750B (es) | 2019-10-15 |
BR112021003877A2 (pt) | 2021-05-18 |
WO2020046102A3 (es) | 2020-09-10 |
CR20210161A (es) | 2021-08-19 |
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