CN101426475A - 使用用于经皮或经粘膜应用的制剂治疗热潮红的方法 - Google Patents
使用用于经皮或经粘膜应用的制剂治疗热潮红的方法 Download PDFInfo
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- CN101426475A CN101426475A CNA2007800144260A CN200780014426A CN101426475A CN 101426475 A CN101426475 A CN 101426475A CN A2007800144260 A CNA2007800144260 A CN A2007800144260A CN 200780014426 A CN200780014426 A CN 200780014426A CN 101426475 A CN101426475 A CN 101426475A
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Abstract
本发明涉及经皮的或经粘膜的制剂、用于制备治疗热潮红的药剂的方法和通过将这种制剂经皮或经粘膜的给药以提供雌激素来治疗热潮红的方法。服用令人吃惊的低日剂量的制剂是有效的，优选治疗热潮红的最低有效剂量的雌激素，即在包括C2－C4烷醇、多元醇、和二甘醇单烷基醚渗透促进剂的递送赋形剂中约0.45至约0.6mg雌激素/天。雌激素的给药量产生接受治疗的受试者的约10至约15毫克的评估额定的每日雌激素剂量及约25pg/ml至约50pg/ml的血清雌二醇水平。
Description
技术领域
本发明一般涉及通过给药用于雌激素经皮或经粘膜递送的制剂来治疗热潮红的方法。本发明的制剂在令人惊讶的低日剂量有效地治疗热潮红，优选有效治疗热潮红的最低有效剂量的雌激素。优选制剂包括雌激素、烷醇、多元醇、和渗透促进剂。优选，制剂基本不含引起恶臭和刺激的长链脂肪醇、长链脂肪酸、和长链脂肪酯，并且递送有效治疗水平的雌激素。
背景技术
活性试剂的经皮和/或经粘膜的递送提供了将活性试剂给药受试者的便捷、无痛、和非侵袭性的方法。另外，活性试剂例如药物通过皮肤或粘膜表面的给药避免了活性试剂经口给药遭遇的与“首过效应”有关的已证实的问题。如本领域所知，经口给药的药物被吸收并进入血液中，在血液中它们在进入身体的大循环前通过门静脉直接被输送到肝脏。如果药物须经高度肝脏清除，即它被肝脏迅速代谢，然后被吸收剂量的基本部分从血液中被提取并在它到达体循环前被代谢。此“首过效应”现象的结果是药物的生物利用度显著减少。在一些情况下，首过效应如此大以致药物的经口给药无效。此外，所有经口吸收的药物在门静脉中浓缩在门脉血液中产生比相应全身水平高出好多的浓度。甾族激素的情况下，包括雌激素，药物的较高门静脉浓度主要涉及剂量依赖的基因组对肝脏蛋白合成比经皮或经粘膜递送体系影响大。一段时间以来，按月的顺序，门静脉中这些非常高的激素水平迅速显著地刺激形成血栓凝固蛋白因子和游离脂肪酸的较高循环水平的产生。此现象未被发现同于经皮给药的程度，因为经皮吸收的激素在排除蛋白和脂肪酸产生中此快速增加的较低全身激素水平到达肝脏。
尽管活性试剂的经皮和/或经粘膜递送克服了一些与活性试剂经口给药相关的问题，例如以上所述，但它们有自身的缺陷。有疑问的，经皮药物递送体系典型地限于低分子量药物和含具有适当亲脂/亲水平衡的结构的那些。高分子量药物、或具有太高或太低亲水平衡的药物通常不能以克服通过角质层的不渗透性的足够高浓度混入常规经皮体系中。具体地说，极性药物趋于极缓慢地渗透皮肤，并且因为大部分药物是极性，所以此限制是显著的。
现有技术中已作努力以化学改性皮肤的屏障特性来允许某些试剂渗透(因为扩散通过角质层基本上被控制)，增强被递送试剂的效力，增强递送次数，减少递送剂量，减少来自各种递送方法的副作用，减少患者反应等等。
在这点上，渗透促进剂被用于增强皮肤表面对药物的渗透性，并且通常是质子接受溶剂例如二甲亚砜(DMSO)和二甲基乙酰胺。已被研究及报导的其它有效渗透促进剂包括2-吡咯烷、N，N-二乙基-m-甲苯酰胺(避蚊胺)、1-dodecal-azacycloheptane-2-酮N，N-二甲基甲酰胺、N-甲基-2-吡咯烷、巯基乙酸钙、己醇、脂肪酸和酯、吡咯烷酮衍生物、1，3-二氧(杂环乙烷)的衍生物和1，3-二氧(杂环乙烷)、1-N-十二烷基-2-吡咯烷酮-5-羧酸、2-戊烷基-2-氧代-吡咯烷乙酸、2-十二烷基-2-氧代-1-吡咯烷乙酸、1-苄基-2-酮-2-dodecylacetic acid、和氨基醇衍生物、包括1，3-二氧(杂环乙烷)的衍生物、除了别的以外。
所用及认为是经皮递送活性试剂必需的渗透促进剂例如类固醇激素，即如长链脂肪酸如油酸、长链脂肪醇如月桂醇和长链脂肪酯如豆蔻酸异丙酯的化合物，倾向于包括使制剂油质及恶臭的脂肪基。
例如，美国专利US5,891,462教导了月桂醇作为雌二醇和醋炔诺酮的渗透促进剂的用途。这种制剂不诉诸于使用者和与使用者密切近似的其他任何人。尽管此特殊专利公开了不含月桂醇组分的雌二醇或醋炔诺酮制剂的三个实施例，这种制剂是为了说明长链脂肪醇例如月桂醇是经皮递送结合雌二醇的醋炔诺酮给受试者所必需的长期持续形势的比较实施例。
另外，例如，已知的睾丸激素凝胶制剂FORTIGEL
和TOSTRELLE(Cellegy Pharma，South San Francisco，加拿大)，均包括作为乙醇、丙醇、丙二醇、卡波姆、三乙醇胺、纯化水、和作为渗透促进剂的油酸，后者引起这些制剂的刺激和恶臭特征。TESTIM(AuxiliumPharmaceuticals，Norristown，巴拿马)也是1％睾丸激素凝胶并且包括十五酸内酯、丙烯酸脂、甘油、聚乙二醇(PEG)、和作为渗透促进剂的十五酸内酯。它是非常有气味的化合物。TESTIM也是不需要的因为它含有非需量的甘油其不能很好地被皮肤耐受。
因而，需要充分递送活性试剂给患者的具有皮肤耐受性的经皮制剂，但不包括同于现有技术制剂的令人不快的气味。
发明概述
本发明通过给药需要这种治疗的受试者局部经皮或经粘膜的制剂来提供用于治疗热潮红的方法和组合物，制剂包括有效治疗热潮红的一定量的雌激素和经皮或经粘膜可接受地递送赋形剂。如本文所述，已发现制剂以令人吃惊的低日剂量有效治疗热潮红。根据本发明，制剂中雌激素的量是有效治疗有此需要的受试者所患热潮红的最低有效剂量。如本文所用，术语“最低有效剂量”是有效治疗热潮红的日剂量，在其之下没有更低的有效剂量。
例如，出乎意料地发现根据发明的提供约10至约15毫克的评估额定的每日雌激素剂量及约25至约50pg/ml雌二醇的最终血清水平的包含0.52mg雌激素的制剂的0.87g日剂量对接受治疗的受试者所患热潮红的治疗是有效的。
发明的制剂包括量为约0.45mg至约0.6mg的雌激素和递送赋形剂，在一个实施方案中，递送赋形剂可包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过哺乳动物皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂。
在一个实施方案中，制剂用于递送治疗患者所患热潮红的最低有效剂量的雌激素。制剂通常以每日约0.75g至约1g的量被给药，优选每日约0.85g至约0.9g，更优选以每日约0.87g的量。在另一个实施方案中，制剂包括约0.01％(重量)至约10％(重量)的雌激素。一个更优选的实施方案中，制剂包括约0.06％(重量)的雌激素，相当于约0.45mg雌激素在0.75g剂量的制剂中，约0.52mg雌激素在0.87g剂量的制剂中，约0.6mg雌激素在1g剂量的制剂中。
在一个实施方案中，制剂提供了约10至约15毫克的评估额定的每日雌激素剂量，优选约11至约14毫克，更优选约12至约13毫克，甚至更优选约12.5毫克的评估额定的每日雌激素剂量。
在另一个实施方案中，雌激素的给药量在接受该制剂的受试者身上有效地产生约25pg/ml至约50pg/ml，优选约30pg/ml至约40pg/ml的量，最优选约34.4pg/ml的量的最终血清雌二醇水平。
在一个普遍优选的实施方案中，制剂以每日约0.87g的量被给药，包括约0.06％(重量)的雌激素(相当于约0.52mg雌激素)，制剂提供的评估额定的每日雌激素剂量是约12.5mg，最终血清雌二醇水平是约34.3pg/ml。
有利地，制剂基本不含长链脂肪醇、长链脂肪酸和长链脂肪酯，因而避免制剂使用期间这种化合物引起的可能的不需要的气味和刺激作用。因而，有利地，本发明的制剂不包括引起不需要气味及引起刺激的渗透促进剂，其曾经被认为是这种经皮或经粘膜的制剂所必需的。
根据发明，多元醇可以有利地以占赋形剂约1％(重量)至30％(重量)的量存在。二甘醇单烷基醚可以以占赋形剂约0.2％(重量)至25％(重量)的量存在，烷醇可以以占赋形剂约5％(重量)至75％(重量)的量存在。通常烷醇可以存在于含水的水醇混合物中。
烷醇可以是乙醇、异丙醇、或正丙醇。优选烷醇是乙醇。多元醇可以是丙二醇、丁二醇、己二醇、和乙二醇。优选多元醇是丙二醇。二亚乙基单烷基醚渗透促进剂例如是二甘醇单乙基醚或二甘醇单甲基醚。优选渗透促进剂是二甘醇单乙基醚。
雌激素可以以任何现有技术中已知的形式存在，例如，17β-雌二醇、雌二醇、苯甲酸雌二醇、17β-环戊烷丙酸雌二醇、雌三醇、雌酮、乙炔雌二醇、炔雌醇甲醚、甲氧炔雌醇、双甲雌三烯二醇、磷酸聚雌二醇、雌二醇3环戊醚、和炔雌醚、或其任意组合。
制剂可以进一步包括胶凝剂、中和剂、缓冲剂、保湿剂、润湿剂、表面活性剂、抗氧化剂、润滑剂、或缓冲等等中的至少一种。制剂可以以凝胶、洗液、乳膏、喷雾、气溶胶、软膏剂、乳液、悬浮液、脂质体体系、漆、补片、绷带或闭合敷料等等的形式被应用。
发明也涉及制备用于递送最低有效剂量雌激素以治疗受试者的热潮红的局部经皮或经粘膜的制剂的方法，其包括：通过将C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂混合来形成递送赋形剂；和包括在递送赋形剂中量为提供约0.45mg至约0.6mg日剂量的雌激素。
发明也涉及通过给需要这种治疗的受试者长达至少5周每日给药局部经皮或经粘膜的制剂来治疗热潮红的方法，该制剂包括：日剂量为约0.45mg至约0.6mg/天的雌激素；和包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂的递送赋形剂。
发明的另一个实施方案是局部经皮或经粘膜制剂在制备用于治疗受试者热潮红的药剂中的用途，该治疗包括给需要这种治疗的受试者长达至少5周每日给药该制剂，其中制剂包括：日剂量为约0.45mg至约0.6mg/天的雌激素；和包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂的递送赋形剂。
在这种方法和用途中，本文公开的任一制剂可以为这些目的而制备。这些制剂可以给药患有热潮红的男性和女性受试者。在一个实施方案中，受试者是女性，举例来说，绝经女性。在另一个实施方案中，受试者是男性。在另一个实施方案中，受试者雌激素缺乏。
附图说明
从以下举例说明的实施方案的详细描述和附图来看发明的特征和效益将变得更清楚，其中：
图1是描述了Bio-E Gel 0.87g/天(◆)、1.7g/天(●)、2.6g/天(■)、和安慰剂(▲)给药后每日中等至严重热潮红比率自基线的平均变化的图。
图2是描述了Bio-E Gel 0.87g/天(◆)、1.7g/天(●)、2.6g/天(■)、和安慰剂(▲)给药后每日热潮红严重度自基线的平均变化的图。
图3是描述了Bio-E Gel 0.87g/天(◆)、1.7g/天(●)、2.6g/天(■)、和安慰剂(▲)给药后Bio-E Gel中位谷浓度随时间的图。
优选实施方案的详细描述
本发明提供了通过给药需要这种治疗的受试者局部经皮或经粘膜的制剂来提供用于治疗热潮红的方法和组合物，该制剂包括有效治疗热潮红的一定量的雌激素和经皮或经粘膜可接受的递送赋形剂。一个优选的递送赋形剂包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过哺乳动物皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂。
如本文所述，申请者已发现本发明的制剂以出乎意料的低剂量有效治疗热潮红。根据发明，雌激素的给药量是每日约0.45mg至约0.6mg，优选每天约0.52mg。在一个实施方案中，雌激素的量是有效治疗有此需要的受试者所患热潮红的最低有效剂量。
制剂可以包括约0.01％(重量)至约10％(重量)的雌激素。在一个实施方案中，制剂包括约0.01％(重量)至约5％(重量)的雌激素。在另一个实施方案中，制剂包括约0.01％(重量)至约1％(重量)的雌激素。在另一个实施方案中，制剂包括约0.01％(重量)至约0.5％(重量)的雌激素。在另一个实施方案中，制剂包括约0.01％(重量)至约0.1％(重量)的雌激素。在一个通常优选的实施方案中，制剂包括约0.06％(重量)的雌激素。
发明的制剂可以以任何测定安全并有效治疗热潮红的量被给药，并且优选含有治疗接受治疗的患者所患热潮红的最低有效剂量的雌激素。当然，雌激素剂量依据多种因素例如接受治疗的受试者的体重、年龄、性别、体脂肪和代谢率，并且可被本领域技术人员测定。在一个实施方案中，雌激素剂量是约0.45mg至约0.6mg，优选约0.5mg至约0.55mg，更优选约0.52mg。
典型的给药制剂(即雌激素和递送赋形剂)总量范围在每日约0.1g至约10g。在一个实施方案中，制剂以每日约0.25g至约5g的量被给药。在另一个实施方案中，制剂以每日约0.75g至约1g的量被给药。在另一个实施方案中，制剂以每日约0.85g至约0.9g的量被给药。在一个通常优选的实施方案中，制剂以每日约0.87g的量被给药。
在一个实施方案中，雌激素的给药量在接受该制剂的受试者身上有效地产生约25pg/ml至约50pg/ml或更少的最终血清雌二醇水平。在另一个实施方案中，雌激素的给药量有效地产生约30pg/ml至约40pg/ml或更少的最终血清雌二醇水平。在另一个实施方案中，雌激素的给药量有效地产生约34.3pg/ml或更少的最终血清雌二醇水平。如本文所述，已出乎意料地发现这些低日剂量水平有效地治疗热潮红。
在一个实施方案中，制剂提供给接受制剂的受试者约10至约15毫克的评估额定的每日雌激素剂量。在另一个实施方案中，制剂提供了约11至约14毫克的评估额定的每日雌激素剂量。在另一个实施方案中，制剂提供了约12至约13毫克的评估额定的每日雌激素剂量。在一个通常优选的实施方案中，制剂提供了约12.5毫克的评估额定的每日雌激素剂量。
在一个通常优选的实施方案中，制剂以每日约0.87g的量被给药，制剂提供的评估额定的每日雌激素剂量是约12.5mg，最终血清雌二醇水平是约34.3pg/ml。优选实施方案的制剂包括约0.06％(重量)的雌激素，相当于每0.87g制剂中约0.52mg雌激素。
如本文所用，术语“治疗”包括改善、预防、镇压、抑制或减少热潮红的发生率，或减轻热潮红的症状或严重度。
本发明的制剂可以是清澈的、可水洗的、冷却至可触(cool to thetouch)、快速干燥的、易涂开的和/或非多脂的制剂，例如凝胶。发明的其它方面，制剂可以是喷雾、软膏剂、气溶胶、补片、含服和舌下药片、栓剂、阴道剂型、或其它用于通过皮肤或粘膜表面吸收的被动或主动经皮的设备。本发明的制剂可以直接应用于皮肤例如通过，例如且不受限，凝胶、软膏剂、或乳膏或间接地通过补片、绷带、或其它闭合敷料施用。
有利地，长链脂肪醇、长链脂肪酸和长链脂肪酯的基本省略提供了不具有包含一种或多种这种化合物的现有技术制剂引起的令人不快气味、刺激、和/或多脂质地的制剂。因而，根据本发明的制剂将导致更大的患者顺应性。在一个实施方案中，制剂基本不含这种醇、脂肪酸和长链脂肪酯以致与这些化合物相关的气味不会从制剂中散出。在这点上，“基本不含”意味着在1米或更少的距离里不带给制剂可察觉的气味的量，优选不带给接受制剂的受试者可察觉的气味的量。这种制剂也被认为是基本无味，除乙醇的气味之外，其在应用后快速蒸发。为了实例和举例说明的目的，包含量少于制剂的约0.04％(重量)的脂肪醇、脂肪酸和/或脂肪酯的制剂是基本无味的。
本发明通常涉及用于提供活性试剂如雌激素给受试者的制剂。制剂以令人吃惊的低剂量雌二醇有效治疗接受制剂的受试者所患的热潮红。在一个优选的实施方案中，发明进一步涉及用于雌激素经皮或经粘膜给药的制剂，其基本没有长链脂肪醇、长链脂肪酸和长链脂肪酯引起的恶臭和刺激。令人吃惊的是，本发明的制剂可以在不含至今为止所用的长链脂肪醇、长链脂肪酸和长链脂肪酯的情况下实现充分吸收以导致有效剂量的活性试剂在血清中循环。
本发明的递送赋形剂优选包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过哺乳动物皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂。
根据发明，多元醇有利地以赋形剂的约1％(重量)至30％(重量)，优选3％(重量)至20％(重量)，更优选约4％(重量)至10％(重量)的量存在。二甘醇单烷基醚以约0.2％(重量)至25％(重量)，优选约1％(重量)至15％(重量)，更优选约2％(重量)至8％(重量)的量存在。烷醇以约5％(重量)至75％(重量)，优选约15％(重量)至65％(重量)，更优选约20％(重量)至55％(重量)的量存在。烷醇可以存在于含水的水醇混合物中。混合物以递送赋形剂的约40％(重量)至98％(重量)的量存在，同时醇以水醇混合物的约5％(重量)至80％(重量)的量存在，以及水以水醇混合物的约20％(重量)至95％(重量)的量存在。优选，烷醇以约40％(重量)至60％(重量)的量存在，优选约46％(重量)并且水的量占水醇混合物的40至50％(重量)，优选约41％(重量)。
例如，二甘醇单烷基醚是二甘醇单甲基醚或二甘醇单乙基醚或其混合物。也例如，多元醇是丙二醇、二丙(撑)二醇或其混合物。多元醇和渗透促进剂可以以约2:1至1:1的重量比存在。作为选择，多元醇和渗透促进剂可以以约1.25:1至1.2:1的重量比存在。
为了举例说明而非限制的目的，烷醇可以是C2-C4醇例如乙醇、异丙醇或正丙醇。烷醇优选是乙醇。如现有技术所知，制剂中醇组分的量可以被选择以最大化扩散活性试剂通过皮肤同时最小化任何对活性试剂本身或制剂的所需特性的负面影响。
本发明可利用的雌激素的例子包括例如17β-雌二醇、雌二醇、苯甲酸雌二醇、17β-环戊烷丙酸雌二醇、雌三醇、雌酮、乙炔雌二醇、炔雌醇甲醚、甲氧炔雌醇、双甲雌三烯二醇、磷酸聚雌二醇、雌二醇3环戊醚、炔雌醚、或其任意组合的雌激素。
制剂可以进一步包括充足量存在以改变制剂粘度的增稠剂或胶凝剂。胶凝剂可以选自包括：卡波姆、羧乙烯(carboxyethylene)或聚丙烯酸例如Carbopol 980或940 NF、981或941 NF、1382或1342NF、5984或934 NF、ETD 2020、2050、934P NF、971P NF、974P NF、Noveon AA-1 USP；纤维素衍生物例如乙基纤维素、羟丙基甲基纤维素(HPMC)、乙基羟乙基纤维素(EHEC)、羧甲基纤维素(CMC)、羟丙基纤维素(HPC)(Klucel不同级别)、羟乙基纤维素(HEC)(Natrosol级别)、HPMCP55、Methocel级别；天然橡胶例如阿拉伯胶、黄原胶、瓜尔豆胶、海藻酸盐；聚乙烯吡咯烷酮衍生物例如Kollidon级别；聚氧乙烯聚氧丙烯共聚物例如Lutrol F等级68、127的组。其它胶凝剂包括壳聚糖、聚乙烯醇、果胶、硅酸镁铝级别。叔胺例如三羟乙基胺或三乙醇胺可以被包含以增稠和中和体系。
丙烯酸的聚合物或共聚物例如卡波姆作为胶凝形式起作用并便于亲脂活性试剂和渗透促进剂的释放。优选，胶凝剂是Lutrol F级别和Carbopol级别。胶凝剂依据聚合物的类型以制剂的约0.2％(重量)至约30.0％(重量)存在。例如，对于聚丙烯酸胶凝剂优选以约0.5％(重量)至2％(重量)的量存在，对于纤维素约1％(重量)至5％(重量)。
制剂中胶凝剂的量和类型可被选来提供所需的产品稠度和/或粘度以便于应用于皮肤。
防腐剂。制剂可以进一步包括防腐剂例如，但不局限于，苯扎氯胺及衍生物、苯甲酸、苯甲醇及衍生物、溴硝丙二醇、对羟苯甲酸、centrimide、洗必太、甲酚及衍生物、咪唑烷脲、苯酚、苯氧乙醇、苯乙醇、苯汞基盐、硫柳汞、山梨酸及衍生物。防腐剂依据化合物的类型以约0.01至约10.0重量％存在。
抗氧化剂。制剂可以任选包括抗氧化剂例如但不局限于维生素E及衍生物、维生素c及衍生物、丁基化羟基茴香醚、丁基化羟氢甲苯、富马酸、苹果酸、没食子酸丙酯、焦亚硫酸钠(metabisulfates)及衍生物。抗氧化剂依据化合物的类型以制剂的约0.001至约5.0重量％存在。
缓冲剂。制剂可以进一步包括缓冲剂例如碳酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂、醋酸盐缓冲剂、盐酸、乳酸、酒石酸(tartricacid)、二乙胺、三乙胺、二异丙基胺、氨基甲基胺(aminomethylamine)。尽管其它现有技术已知的缓冲剂可被包含。缓冲剂可替代至制剂中水量的100％
润湿剂。制剂可以进一步包括润湿剂，例如但不局限于甘油、丙烯、乙二醇、山梨糖醇、三醋精。润湿剂依据化合物的类型以制剂的约1至10.0重量％存在。
螯合剂。制剂可以进一步包括螯合剂例如依地酸。螯合剂依据化合物的类型以制剂的约0.001至约5.0重量％存在。
表面活性剂。制剂可以进一步包括阴离子的、非离子的或阳离子的表面活性剂。表面活性剂依据化合物的类型以制剂的约0.1至约30.0重量％存在。
pH调整剂。任选地，制剂可以包括pH调整剂，通常，中和剂，其可以任选具有交联功能。为了举例并不受限，pH调整剂可以包括三级胺例如三羟乙基胺、缓血酸胺、四羟丙基乙二胺(tetrahydroxypropylethylendiamine)、NaOH溶液。pH调整剂在制剂中以约0.05至约2.0重量％存在。
保湿剂和润滑剂。任选地，制剂可以包括保湿剂和/或润滑剂以使皮肤变柔软和光滑以保持和保留水分。为了举例并不受限，保湿剂和润滑剂可以包括胆固醇、卵磷脂、轻质矿物油、矿脂、和尿素。
对于一个特殊的制剂，活性试剂和其它成分可以被选来实现所需药物递送图和所需渗透量。最佳pH也可被测定并可以依据，例如，激素的种类、基础、和所需流出程度来确定。
在某些本发明的优选实施方案，制剂可以具有以下处方。
表1
| 雌二醇 | 0.01％-2％ |
| 卡波姆 | 0.05％-4％ |
| 三羟乙基胺(调整至pH 5.9) | 0.05％-1％ |
| 醇 | 20％-65％ |
| 丙二醇 | 1％-15％ |
| 二甘醇单乙醚 | 1％-15％ |
| 离子交换纯化水q.ad. | 20％-65％ |
表2
| 雌二醇 | 0.01％-1％ |
| 卡波姆940 | 1.2％ |
| 三羟乙基胺(调整至pH 5.9) | 0.4％ |
| 醇 | 46.28％ |
| 丙二醇 | 6％ |
| 二甘醇单乙醚 | 5％ |
| 乙二胺四醋酸二钠 | 0.06％ |
| 离子交换纯化水q.ad. | 100％ |
表3
至少因为以下原因，本发明的制剂是有优点的。首先，制剂的令人吃惊的低剂量提高了有效治疗热潮红的雌二醇的血清水平。例如，已出乎意料地发现包含约0.52mg雌激素的约0.87g制剂提供约12.5mg的评估额定每日雌激素剂量和约34.3pg/ml的最终血清雌二醇水平。令人惊讶的是，此剂量被测定为治疗热潮红的最低有效剂量。有利地，制剂是安全的并与先前所用更高的剂量相比副作用和风险减少。
第二，在一个实施方案中，本发明的制剂基本不含长链脂肪醇、长链脂肪酸和长链脂肪酯。令人惊讶的是，制剂显示充分的皮肤渗透以递送有效剂量的所需活性试剂给使用者。此是本领域技术人员不易发现的出乎意料的优点，因为通常理解为长链脂肪醇、长链脂肪酸和长链脂肪酯被需要以增强皮肤渗透从而允许有效剂量的活性试剂渗透进皮肤。
第三，因为制剂优选不包括脂肪酸基团，例如脂肪酸，其通常被包含在局部凝胶或洗液中，它们不具有与如目前所用凝胶或洗液中该成分有关的气味和油质质地。
第四，长链脂肪醇、长链脂肪酸和长链脂肪酯的缺乏意味着刺激电位较低并且组分相互作用的机会更少，减少了制剂中抗氧化剂或防腐剂的需要。许多研究承认了不饱和脂肪酸如油酸引起刺激的电位。参见Tanojo H.Boelsma E、Junginger HE、Ponec M、Bodde HE，＂In vivohuman skin barrier modulation by topical application of fattyacids，＂Skin Pharmacol Appl.Skin Physiol.1998 3-4月；11(2)87-97。然而它被理解为如果需要这种防腐剂，发明包括包含抗氧化剂或防腐剂的制剂。成分数目的减少至少在减少制造成本、可能的皮肤刺激和转移到其它上是有利的。另外，成分数目的减少通过减少被递送前成分互相作用的机会来增加制剂的贮藏稳定性。然而，这不意味着为了特殊的审美和/或功能作用额外的成分不能被包含在制剂中。例如，制剂可以任选包括一种或多种为了水合皮肤的保湿剂或为了使皮肤柔软和光滑的润滑剂。甘油是这种适合的保湿添加剂的例子。
发明的制剂可以每天用一次，或依据患者的情况每天多次。发明的制剂可以被局部应用于任何身体部位，例如大腿、腹部、肩部、和上臂。
发明包括上述制剂的治疗受试者以提高患者体内活性试剂的循环水平的用途。
优选的剂量单位是能长达约24小时递送有效量活性试剂。“有效”或“治疗有效”量的活性试剂意味着无毒，但充足量的试剂提供需要的效果。最小或最低有效剂量的每种活性试剂当然是优选最小化与用所选活性试剂治疗有关的副作用。制剂优选根据有规律的定时基础应用以便活性试剂的给药基本连续。
实施例
以下实施例是举例说明而不应解释为作为限制。
实施例1用于治疗绝经女性血管舒缩症状和阴道萎缩症状的局部Bio-E Gel的安全性和功效的研究。
此研究的目的是评价0.87g、1.7g和2.6g Bio-E Gel(分别含有0.52mg、1.02mg、和1.56mg雌二醇)作为每日给药方案给药，与安慰剂凝胶相比在绝经女性血管舒缩症状和阴道萎缩症状治疗上的安全性和功效。合格的受试者是健康的绝经女性，具有≤2.0ng/dL的雌二醇血清浓度、>40mIU/mL的卵泡刺激素(FSH)血清浓度，其在筛选的头两周期间每周表现≥60的中等至严重的热潮红。
Bio-E Gel由含0.06％雌二醇的水醇凝胶制剂组成，在每次应用时通过计量剂量瓶递送0.87g(0.52mg雌激素)Bio-E Gel、1.7g(1.02mg雌激素)Bio-E Gel、或2.6g(1.56mg雌激素)Bio-E
。Bio-E 
的每日局部应用是通过受试者在上臂/肩部被给药。
评价的参数包括热潮红比率和严重度、阴道萎缩评价、副作用、安全性实验室试验、生命体征、信号、体重、身体的及包括子宫内膜活组织检查的妇产科医学的检查和乳腺检查、和皮肤刺激。
结果
血管舒缩症状(初级)
1 每日中等至严重热潮红比率随时间的自基线的平均变化
如图1和表4所示，在第4周主要终点，每个治疗组表现中等至严重热潮红比率自基线的减少，接受1.7g/天Bio-E 
和2.6g/天Bio-E 
的受试者的变化比安慰剂在统计学上显著地大(-8.2和-9.5，分别地，对比-5.4；p<0.0001关于两个比较)。另外，这些Bio-E 
组和安慰剂组在每天热潮红的人数上的差异>2.0，表明减少也有临床意义。对于接受0.87g/天Bio-E 
的受试者而言，每日中等至严重热潮红比率自基线的变化在第四周接近统计学显著差异(-6.6对比-5.4；p＝0.0965)。然而，在第5周开始观察到来自安慰剂的临床和统计学的显著差异，表明0.87g/天是关于中等至严重热潮红减少的Bio-E 
最低有效剂量。
在第12周主要的终点，接受0.87g/天Bio-E Gel、1.7g/天Bio-E
和2.6g/天Bio-E 
的受试者每日中等至严重热潮红比率自基线的变化比安慰剂在统计学上和临床上显著(-9.1、-10.7、和-11.3，分别地，对比-6.1；p<0.0001关于两个比较)(表4和图1)。
每日中等至严重热潮红比率自基线的平均变化(ITT-LOCF)
2)每日热潮红严重度随时间的自基线的平均变化
如表5所示，在第4周主要的终点，接受1.7g/天Bio-E 
和2.6g/天Bio-E 
的受试者的每日热潮红严重度自基线的减少比安慰剂在统计学上显著的大(-0.7和-1.0，分别地，对比-0.3；p<0.0001关于两个比较)。平均而言，Bio-E 
组中轻微至中等热潮红严重度类型的受试者发生减少，同时安慰剂组中那些仍处于中等至严重类型。在第4周接受0.87g/天Bio-E 
的受试者的变化与安慰剂相比接近统计学显著性(-0.5对比-0.3；p＝0.0714)。然而，在第5周开始，观察到此剂量组与安慰剂的临床上(轻微至中等对比中等至严重)和统计学上(-0.6对比-0.3；p＝0.0083)的显著差异。
在第12周主要的终点，接受0.87g/天Bio-E Gel、1.7g/天Bio-E和2.6g/天Bio-E 
的受试者每日热潮红严重度自基线的变化与安慰剂相比统计学上显著的大(-0.9、-1.4和-1.6，分别地，对比-0.4；p<0.001关于所有比较)(表5)。
如图2所示，接受Bio-E 
的受试者的每日热潮红严重度自基线的减少是依赖于剂量的，随着在每个研究的时间点Bio-E 
剂量的增加显示的效果逐渐增大。另外，热潮红严重度的减少量依赖于剂量和时间。相似地，严重度减少的开始时间依赖于剂量，接受0.87g/天Bio-E 
的受试者发生的比接受2.6g/天或1.7g/天的那些迟些。在第5周观察到接受0.87g/天Bio-E 
的受试者(-0.6对比-0.3；p＝0.0083)，在第3周观察到接受1.7g/天的受试者(-0.5对比-0.3；p＝0.0031)，以及在第2周观察到接受2.6g/天的受试者(-0.4对比-0.2；p＝0.0210)的热潮红严重度自基线的平均变化与安慰剂相比的显著差异(表5)。
每日热潮红严重度自基线的平均变化(ITT-LOCF)
阴道萎缩症状(初级)
1 最讨厌的中等至严重的症状自基线的平均变化(第12周/最后就 诊)
受试者最讨厌的中等至严重的阴道萎缩症状至第12周自基线的平均变化(或过早终止的受试者的最后就诊)见表6。每个治疗组中约一半的受试者确定了在基线最讨厌的症状其是属于此分析中中等至严重的。治疗组整体最讨厌的中等至严重的阴道萎缩症状的平均基线严重度范围在2.23至2.48。在第12周主要的终点，观察到接受使用Bio-EGel的活性治疗的受试者最讨厌的阴道萎缩症状的严重度自基线的临床意义的减少。具体而言，接受0.87g/天、1.7g/天、和2.6g/天Bio-E Gel的受试者自基线的平均减少(-1.74、-1.53、和-1.75，分别地)为无至轻微范围内的平均严重度，同时接受安慰剂的那些，减少(-1.31)为轻微至中等范围内的平均严重度。仅在0.87g/天Bio-E
组观察到与安慰剂的统计学显著差异(-1.74对比-1.31；p＝0.0183)，对于第12周数据而言其具有最大样本大小(N＝67)(表6)。更高剂量Bio-E 
治疗组中更小的样本大小可以解释这些组与安慰剂治疗相比显著性的缺乏，尽管2.6g/天组接近统计显著性(p＝0.0518)。
2 阴道pH自基线的平均变化(第12周/最后就诊)
阴道pH在基线>5.0的阴道pH的受试者中至第12周自基线的平均变化(或过早终止的受试者的最后就诊)见表6。治疗组整体在基线的平均阴道pH范围在6.07至6.31。相对于安慰剂，所有Bio-E 
治疗组在第12周显示更酸性的阴道pH，同时0.87g/天、1.7g/天、和2.6g/天Bio-E 
组中阴道pH自基线的平均变化是-1.21、-1.20、和-1.31。相对于安慰剂(-0.17)，所有减少是统计学上显著的更大(p<0.0001)。
阴道成熟指数(VMI)自基线的平均变化(第12周/最后就诊)
阴道壁样本中表面细胞≤5％的受试者在基线的VMI见表6。治疗组整体在基线的平均VMI相似，范围在40.6至42.3，并且所有接受Bio-EGel的受试者中在第12周明显增加(即副基底细胞减少以及表面细胞增加)。对于安慰剂在第12周VMI的变化评分是1.2，而接受0.87g/天Bio-EGel的受试者的VMI平均增加是约18，接受1.7g/天的受试者是26，接受2.6g/天的受试者是28(p<0.0001对于所有Bio-E Gel组)(表6)。
表6 最讨厌的中等至严重的阴道萎缩症状、阴道pH、和阴道成熟指数自基线a的平均变化(ITT-观察数据)
雌二醇剂量、浓度、和与反应的关系
雌二醇谷血清浓度在进入双盲治疗期时(第1天)和在双盲治疗期的第4周、第8周、和第12周的平均值、中值、和范围见表7；中位谷血清浓度见图3。
治疗组整体雌二醇的平均槽水平在第1天非常类似并且在后来的时间点仅在接受Bio-E Gel的受试者身上升高。在第4周和连续经至第12周，接受任何剂量Bio-E Gel的受试者的雌二醇平均槽水平比接受安慰剂的那些显著地高。此外，在依据剂量的形式血清雌二醇中位值随着Bio-E Gel剂量的增加而增加(图3)。1.7g/天和2.6g/天组中雌二醇平均血清水平在第4周、第8周、和第12周是相似的。1.7g/天剂量在第29天和第57天的重算是为了排除两个极端异常值。在第29天，1.7g/天剂量的中位雌二醇值未变(23pg/mL)，但平均值±SD血清雌二醇从41.7±73.4pg/mL变至36.9±48.7pg/mL，同时第57天血清雌二醇的分析从42.7±99.0pg/mL变至34.5±32.4pg/mL，中值未变(23.0pg/mL)。通过此重算，中位血清雌二醇依据剂量增加以及平均血清雌二醇浓度大约依据剂量增加。
表7
表7 随时间的雌二醇谷血清浓度(ITT-观察数据)
讨论
关于热潮红比率与热潮红严重度的初级功效结果，观察到相比安慰剂，所有剂量的Bio-E Gel的每日中等至严重热潮红比率统计学上显著减少。0.87g/天剂量在第5周开始(第4周p＝0.0965)，1.7g/天和2.6g/天剂量在第3周。在第5、4、和3周分别首次发现，相比安慰剂治疗组，接受0.87g/天Bio-E Gel、1.7g/天Bio-E Gel和2.6g/天Bio-E Gel的研究组的热潮红比率临床意义上的减少。热潮红严重度的减少与安慰剂治疗有统计学上显著差异，在0.87g/天剂量Bio-EGel为第5周，(第4周p＝0.0714)，1.7g/天为第3周，2.6g/天剂量为第2周。所有Bio-E Gel剂量组的每日中等至严重热潮红比率的减少具有临床意义与统计显著性以及热潮红严重度的减少具有统计显著性，从开始出现持续至第12周。
关于雌二醇浓度，用渐增剂量Bio-E Gel的治疗显示雌二醇中位槽浓度依据剂量增加以及雌二醇平均浓度大约依据剂量增加。Bio-EGel对血管舒缩症状的功效与剂量有关并与观察到的雌二醇中位血清浓度与剂量相关的增加一致。
此研究的功效结果支持0.87g/天作为治疗绝经女性血管舒缩症状及阴道萎缩症状的Bio-E 
的最低有效剂量。
安全性
此研究关于Bio-E 
安全性的一般发现是体验应用位置反应的少数受试者具有良好的局部耐受性。Bio-E 
不产生非已公知的关于用于治疗与绝经有关的血管舒缩及阴道症状的雌激素药品的任何副反应。
急救处理副反应的全面发生率随Bio-E 
剂量的增加(在这三个剂量中为59％至68％)而增加并且比安慰剂组的发生率(56％)略高。对于所有Bio-E 
剂量，12周治疗期间>5％的受试者发生的急救处理副反应是恶心、外周性水肿、乳房触痛、子宫出血、阴道排出物、乳头痛、子宫内膜增生、鼻咽炎、和上呼吸道感染。
研究结论
此研究的结果证明了Bio-E 
有效减少了与绝经有关的血管舒缩及阴道症状。相对于更高剂量(1.7g/天和2.6g/天)，考虑到伴随显著增加雌二醇水平的能力的Bio-E 
最低剂量(0.87g/天)的功效和比较安全性，0.87g/天Bio-E 
被认为是治疗绝经女性血管舒缩症状及阴道症状的最低有效剂量。
说明书描述了本发明特殊实施方案的同时，本领域技术人员可以在不背离发明概念的情况下设计本发明的变体。因而，本文描述及主张的发明的范围不被本文公开的特殊实施方案所限制，因为这些实施方案是被打算作为发明某些方面的举例说明。实际上，从上述内容来看，对于本领域技术人员而言除本文所示及所描述的那些之外发明的各种改进将是显而易见的。这种改进也被打算是落入所附权利要求范畴之内的。
Claims (32)
1用于递送最低有效剂量雌激素以治疗受试者的热潮红的局部经皮或经粘膜的制剂包括：
量为提供约0.45mg至约0.6mg日剂量的雌激素；和
包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂的递送赋形剂。
2权利要求1的制剂，其中每日给药的雌激素量是治疗受试者热潮红的最低有效剂量并且包括制剂中雌激素的量占制剂的约0.01重量％至10重量％以及制剂每日给药量是约0.75g至约1g。
3权利要求2的制剂，其中制剂包括雌激素的量占制剂的约0.06重量％以及制剂每日给药量是约0.85g至约0.9g。
4权利要求1的制剂，其中雌激素选自17β-雌二醇、雌二醇、苯甲酸雌二醇、17β-环戊烷丙酸雌二醇、雌三醇、雌酮、乙炔雌二醇、炔雌醇甲醚、甲氧炔雌醇、双甲雌三烯二醇、磷酸聚雌二醇、雌二醇3环戊醚、炔雌醚、及其任意组合。
5权利要求1的制剂，其中多元醇的量占赋形剂的约1重量％至30重量％，烷醇的量占赋形剂的5重量％至75重量％，以及渗透促进剂的量占赋形剂重量的约0.2重量％至25重量％。
6权利要求5的制剂，其中烷醇的量占制剂的约20％(重量)至65％(重量)，多元醇的量占制剂的约1％(重量)至15％(重量)，以及渗透促进剂的量占制剂的约1％(重量)至15％(重量)。
7权利要求6的制剂，其中烷醇选自乙醇、异丙醇、和正丙醇，并且其中多元醇是聚丙二醇。
8权利要求6的制剂，其中多元醇和渗透促进剂重量比为1.25:1至1.2:1并且制剂进一步包括量为制剂的0.05重量％至约4％(重量)的胶凝剂、量为制剂的约0.05重量％至1％(重量)的中和剂、量为制剂的约20重量％至65％(重量)的水以便制剂作为凝胶被提供。
9权利要求8的制剂，其中制剂基本不含长链脂肪醇、长链脂肪酸和长链脂肪酯以避免制剂使用期间这种化合物引起的不需要的气味和刺激作用。
10权利要求1的制剂，其中制剂进一步包括胶凝剂、中和剂、螯合剂、缓冲剂、保湿剂、润湿剂、表面活性剂、抗氧化剂、润滑剂、或缓冲中的至少一种。
11权利要求10的制剂，其中胶凝剂选自卡波姆、羧乙烯、聚丙烯酸、纤维素衍生物、乙基纤维素、羟丙基甲基纤维素、乙基羟乙基纤维素、羧甲基纤维素、羟丙基纤维素、、天然橡胶、阿拉伯胶、黄原胶、瓜耳豆胶、海藻酸盐、聚乙烯吡咯烷酮衍生物、聚氧乙烯聚氧化丙烯共聚物、壳聚糖、聚乙烯醇、果胶、和硅酸镁铝；缓冲剂选自碳酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂、醋酸盐缓冲剂、盐酸、乳酸、酒石酸、二乙胺、三乙胺、二异丙基胺、四羟丙基乙二胺、和氨基甲基胺基；或螯合剂是依地酸。
12权利要求1的制剂，其中制剂是凝胶、洗液、乳膏、喷雾、气溶胶、软膏剂、乳液、悬浮液、脂质体体系、漆、或非闭合敷料的形式。
13权利要求1的制剂，具有以下组分：
14权利要求1的制剂，具有以下组分：
15权利要求1的制剂，具有以下组分：
16制备用于递送最低有效剂量雌激素以治疗受试者的热潮红的局部经皮或经粘膜的制剂的方法，其包括：
通过将C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂混合来形成递送赋形剂；和
包括在递送赋形剂中量为提供约0.45mg至约0.6mg日剂量的雌激素。
17权利要求16的方法，其中制剂包括量占制剂的约0.01重量％至10％(重量)的雌激素以及制剂每日给药量是约0.75g至约1g。
18权利要求17的方法，其中制剂包括量占制剂的约0.06重量％的雌激素以及制剂每日给药量是约0.85g至约0.9g。
19权利要求17的方法，其中受试者是女性并且雌激素的每日给药量是有效的以在受试者身上产生约25pg/ml至约50pg/ml的血清雌二醇水平，其中制剂提供的评估额定的每日雌激素剂量是约10至约15毫克。
20权利要求16的方法，其中雌激素选自17β-雌二醇、雌二醇、苯甲酸雌二醇、17β-环戊烷丙酸雌二醇、雌三醇、雌酮、乙炔雌二醇、炔雌醇甲醚、甲氧炔雌醇、双甲雌三烯二醇、磷酸聚雌二醇、雌二醇3环戊醚、炔雌醚、及其任意组合。
21权利要求16的方法，其中多元醇的量占赋形剂的约1％(重量)至30％(重量)，烷醇的量占赋形剂的5％(重量)至75％(重量)，以及渗透促进剂的量占赋形剂的约0.2％(重量)至25％(重量)。
22权利要求21的方法，其中烷醇的量占制剂的约20％(重量)至65％(重量)，多元醇的量占制剂的约1％(重量)至15％(重量)，以及渗透促进剂的量占制剂的约1％(重量)至15％(重量)。
23权利要求22的方法，其中烷醇选自乙醇、异丙醇、和正丙醇，并且其中多元醇是聚丙二醇。
24权利要求23的方法，其中多元醇和渗透促进剂重量比为1.25:1至1.2:1并且制剂进一步包括量为制剂的0.05重量％至约4％(重量)的胶凝剂、量为制剂的约0.05重量％至1％(重量)的中和剂、量为制剂的约20重量％至65％(重量)的水以便制剂作为凝胶被提供。
25权利要求24的方法，其中制剂基本不含长链脂肪醇、长链脂肪酸和长链脂肪酯以避免制剂使用期间这种化合物引起的不理想的气味和刺激作用。
26权利要求16的方法，其中制剂进一步包括胶凝剂、中和剂、螯合剂、缓冲剂、保湿剂、润湿剂、表面活性剂、抗氧化剂、润滑剂、或缓冲中的至少一种。
27权利要求26的方法，其中胶凝剂选自卡波姆、羧乙烯、聚丙烯酸、纤维素衍生物、乙基纤维素、羟丙基甲基纤维素、乙基羟乙基纤维素、羧甲基纤维素、羟丙基纤维素、羟乙基纤维素、天然橡胶、阿拉伯胶、黄原胶、瓜耳豆胶、海藻酸盐、聚乙烯吡咯烷酮衍生物、聚氧乙烯聚氧化丙烯共聚物、壳聚糖、聚乙烯醇、果胶、和硅酸镁铝；缓冲剂选自碳酸盐缓冲剂、柠檬酸盐缓冲剂、磷酸盐缓冲剂、醋酸盐缓冲剂、盐酸、乳酸、酒石酸、二乙胺、三乙胺、二异丙基胺、四羟丙基乙二胺、和氨基甲基胺基；或螯合剂是依地酸。
28权利要求16的方法，其中制剂是凝胶、洗液、乳膏、喷雾、气溶胶、软膏剂、乳液、悬浮液、脂质体体系、漆、或非闭合敷料的形式。
29治疗热潮红的方法，其包括给需要这种治疗的受试者长达至少5周每日给药局部经皮或经粘膜的制剂，该制剂包括：
日剂量为约0.45mg至约0.6mg/天的雌激素；和
包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂的递送赋形剂。
30治疗热潮红的方法，其包括给需要这种治疗的受试者长达至少5周每日给药局部经皮或经粘膜的制剂，该制剂包括根据权利要求2-15所述制剂中的一种。
31局部经皮或经粘膜的制剂在制备用于治疗受试者热潮红的药剂中的用途，治疗包括给需要这种治疗的受试者长达至少5周每日给药该制剂，其中制剂包括：
日剂量为约0.45mg至约0.6mg/天的雌激素；和
包括C2-C4烷醇、多元醇、和足够量以增强活性试剂渗透通过皮肤或粘膜表面的二甘醇单烷基醚渗透促进剂的递送赋形剂。
32局部经皮或经粘膜的制剂在制备用于治疗受试者热潮红的药剂中的用途，治疗包括给需要这种治疗的受试者长达至少5周每日给药该制剂，其中制剂包括根据权利要求2-15所述制剂中的一种。
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- 2007-04-04 CN CNA2007800144260A patent/CN101426475A/zh active Pending
- 2007-04-04 CA CA2646667A patent/CA2646667C/en not_active Expired - Fee Related
- 2007-04-19 US US11/737,389 patent/US8268346B2/en active Active
-
2008
- 2008-09-15 ZA ZA200807895A patent/ZA200807895B/xx unknown
- 2008-10-02 IL IL194465A patent/IL194465A0/en unknown
-
2012
- 2012-08-13 US US13/584,302 patent/US8647665B2/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101940790A (zh) * | 2009-07-01 | 2011-01-12 | 润和生物医药科技(汕头)有限公司 | 一种新型促渗剂组合物及其在透皮给药系统中的应用 |
| CN101940790B (zh) * | 2009-07-01 | 2012-07-25 | 润和生物医药科技(汕头)有限公司 | 一种新型促渗剂组合物及其在透皮给药系统中的应用 |
| CN113662913A (zh) * | 2013-02-28 | 2021-11-19 | 诺万公司 | 局部组合物及其使用方法 |
| CN108653195A (zh) * | 2018-08-08 | 2018-10-16 | 江苏知原药业有限公司 | 透皮或透粘膜给药制剂 |
Also Published As
| Publication number | Publication date |
|---|---|
| US8268346B2 (en) | 2012-09-18 |
| WO2007124250A3 (en) | 2007-12-21 |
| IL194465A0 (en) | 2009-08-03 |
| NZ571460A (en) | 2010-10-29 |
| CA2646667C (en) | 2014-03-11 |
| US8647665B2 (en) | 2014-02-11 |
| ZA200807895B (en) | 2009-07-29 |
| US20080025920A1 (en) | 2008-01-31 |
| CA2646667A1 (en) | 2007-11-01 |
| US20120308648A1 (en) | 2012-12-06 |
| WO2007124250A2 (en) | 2007-11-01 |
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