CN1191060C - 输送前列腺素e1的表皮给药组合物 - Google Patents
输送前列腺素e1的表皮给药组合物 Download PDFInfo
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- CN1191060C CN1191060C CNB988129159A CN98812915A CN1191060C CN 1191060 C CN1191060 C CN 1191060C CN B988129159 A CNB988129159 A CN B988129159A CN 98812915 A CN98812915 A CN 98812915A CN 1191060 C CN1191060 C CN 1191060C
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- prostaglandin
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Abstract
提供了一种适于透皮给药的前列腺素E1半固体均匀性表皮给药组合物，该组合物包括前列腺素E1，渗透增强剂，多糖树胶，亲脂化合物和酸性缓冲体系。渗透增强剂是烷基-2-(N，N-二取代氨基)链烷酸酯，(N，N-二取代氨基)链烷醇链烷酸酯及其混合物，亲脂化合物可以是脂肪族C1-C8醇，脂肪族C8-C30酯及其混合物，该组合物包括能够给所述组合物提供约3-7.4范围缓冲pH值的缓冲体系。
Description
发明的技术领域
本发明涉及用前列腺素药物对患者实施透皮给药的药物组合物。
发明的背景
前列腺素E1是前列腺烷酸，20个碳原子的类脂酸的衍生物，以下式表示：
它可以从市场上买到，例如从Chinoin药物和化学加工有限公司(Budapest，Hungary)以商品名“Alprostadil USP”及从Upjohn公司(Kalamazoo，Michigan)以商品名“Prostin VR”买到。
前列腺素E1是用于维持扩张血管的血管扩张剂，因之尤其是用来治疗外周血管疾病。虽然由透皮输送前列腺素E1的潜在优点早以被承认，但是开发输送前列腺素的表皮给药组合物的重大努力目前还未完全成功。
特别是目前市场上买不到一种没有支撑体的(例如补片，胶带等)，用于表皮给药的半固体制剂。例如USP5,380,760(Wendel等人)描述了一种表皮给药的前列腺素制剂，该制剂包括聚异丁烯的压敏黏接片。
专门研究了包括前列腺素在内的大多数药物，它们均不能有效地穿透皮肤，以提供可以和其它药物输送途径相当的药物浓度水平。为了解决这一问题，表皮给药的药物制剂一般包括表皮渗透增强剂。表皮渗透增强剂也可以称为吸收增强剂，加速剂，辅剂，增溶剂，吸附促进剂等。无论什么名称，这种试剂都是用来改进药物透过皮肤吸收的。理想的渗透增强剂不仅增加药物透过皮肤的流动，而且应该没有刺激作用，致敏作用或不伤害皮肤。而且理想的渗透增强剂应该不影响剂量形式(例如乳膏或凝胶)的可利用性，或不影响表皮给药组合物的美容质量。
已经评价了许多化合物对增加药物穿透皮肤速度的有效性，例如参见“经皮渗透促进剂”(
Percutaneous Penetration Enhancers，Maibach H.I.和Smith H.E.eds.；CRC Press，Inc.，Boca Raton，F.L.1995)，该书综述了各种皮肤渗透增强剂的用途和试验；也参见Büyüktimkin等人的“透皮和表皮药物输送体系中透皮药物渗透增强的化学手段”(
Chemical Means of Transdermal Drug Permeation Enhancement in transdermal and Topical Drug Delivery Systems Gosh T.K.，PfisterW.R.，Yum S.I.，Eds.；Interpharm Press Inc.，Buffalo Grove，I.L.1997)。
前列腺素E1的完全成功的制剂目前还没有被认定，而且不幸的是前列腺素E1很容易通过重排和其它反应被转化，这种相对的不稳定性导致了配制透皮输送组合物时需要付出更艰苦的努力。
本发明致力于解决这些问题，以便提供相对迅速持久地输送前列腺素E1的半固体，抗分离的组合物。
发明概述
适于表皮给药的药物组合物包括前列腺素E1，渗透增强剂，多糖树胶，亲脂化合物和酸性缓冲体系。渗透增强剂是烷基-2-(N，N-二取代氨基)-链烷酸酯，(N，N-二取代氨基)-链烷醇链烷酸酯或它们的混合物。亲脂化合物可以是脂肪族C1-C8醇，脂肪族C8-C30的酯或它们的混合物。该组合物包括缓冲体系，该缓冲体系能够对于所述组合物提供约3-7.4范围的缓冲pH值。如果需要还可以包括稳定剂和乳化剂。
本发明的组合物可取表皮给药的半固体形式，在作为表皮给药药剂使用时，这种组合物表现出相对高的前列腺素渗透能力和生物利用率，不需要过量耗费前列腺素浓度，该组合物还表现出减低皮肤刺激作用，致敏作用和损害性。
根据本发明说明书和随后的权利要求书，本发明其它的和进一步的宗旨，目的，特点，优点，实施方案等对于本领域的技术人员是显而易见。
附图的简要说明
附图中，图1表示按照本发明制备的7种前列腺素E1组合物，当穿透蜕落的蛇皮时前列腺素E1的渗透累积情况；
图2是比较本发明制备的2种前列腺素E1组合物和2种对比组合物，当穿透蜕落的蛇皮时前列腺素E1的渗透累积情况。
本发明的详细说明
本发明的药物组合物包括前列腺素E1，烷基(N，N-二取代氨基)酯，多糖树胶，亲脂化合物和酸性缓冲体系。
前列腺素E1对于本领域的技术人员是公知的，其药理活性，副作用和通常的剂量范围可以参考各种参考文献，例如参见“医生常用参考”(
Physician′s Desk Reference，51st Ed.(1997))和
“莫克索引”，12th Ed.，(Merck & Co.，N.J.1996)；“马丁德尔附加药典”(
Martindale The Extra Pharmacopoeia，28th Ed.，(London，The Pharmaceutical Press1982)。前列腺素E1和本文有关的其它化合物均包括其药学上可接受的衍生物，其生理学上相容的盐和酯类衍生物。
本发明药物组合物中的前列腺素E1的量是治疗有效量，必须根据所需的剂量，剂型(例如栓剂或表皮给药剂型)和使用的前列腺素E1的特殊形式而改变。组合物一般含有以组合物总重量计0.1％-1％的前列腺素E1，优选0.3％-0.5％。
本发明中的一个重要成分是渗透增强剂，渗透增强剂是烷基-2-(N，N-二取代氨基)-链烷酸酯，(N，N-二取代氨基)-链烷醇链烷酸酯或它们的混合物。为了方便，将烷基-2-(N，N-二取代氨基)-链烷酸酯和(N，N-二取代氨基)-链烷醇链烷酸酯分类在一起，都称为烷基-2-(N，N-二取代氨基)酯。
适于本发明的烷基-2-(N，N-二取代氨基)-链烷酸酯表示如下：
其中n是约4-18范围的整数，R是由H，C1-C7烷基，苄基和苯基组成的一类中的成员，R1和R2是H，C1-C7烷基组成的一类中的成员，R3和R4是H，甲基，乙基组成的一类中的成员。
优选的烷基(N，N-二取代的氨基)-链烷酸酯是C4-C18烷基(N，N-二取代的氨基)-乙酸酯和C4-C18烷基(N，N-二取代的氨基)丙酸酯；烷基-2-(N，N-二取代的氨基)-链烷酸酯的具体实例包括2-(N，N-二取代的氨基)丙酸十二烷基酯(DDAIP)：
和2-(N，N-二取代的氨基)乙酸十二烷基酯(DDAA)：
烷基-2-(N，N-二取代的氨基)-链烷酸酯是公知的，例如2-(N，N-二取代的氨基)丙酸十二烷基酯(DDAIP)，可以从Steroids，Ltd.(Chicago，IK)买到。另外烷基(N，N-二取代的氨基)-链烷酸酯可以从更容易买到的化合物，如从USP4,980,378(Wong等人)记载的化合物来合成，该专利作为本文的参考取其与本发明没有不相容的内容。如本文所述，烷基(N，N-二取代的氨基)-链烷酸酯可以通过两步合成很容易地制备，第一步中，长链烷基氯代乙酸酯通过相应的长链烷醇和氯甲基甲酰氯等，在合适的碱，例如三乙胺存在下进行反应来制备，通常反应在溶剂，如氯仿中进行。该反应描述如下：
其中R，R3，R4和n定义如上，反应温度选择约10℃-200℃或回馏温度，优选室温，是否使用溶剂视需要决定，如果使用溶剂，可以选择各种有机溶剂，碱的选择同样没有限制，优选的碱包括叔胺，如三乙胺，吡啶等，反应时间一般约1小时到3天。
第二步骤中，长链烷基氯代乙酸酯和适当的胺按照以下反应式缩合：
其中n，R，R1，R2，R3和R4定义如上。过量的试剂胺通常作为碱使用，反应通常在合适的溶剂，如乙醚中进行。虽然温度可以改变，但是第二步反应优选在室温下进行，反应时间通常在约1小时到7天之间变化。采用常规的提纯技术，很容易得到用于药物化合物的酯。
合适的(N，N-二取代氨基)链烷醇链烷酸酯以下式表示：
其中n是约5-18范围的整数，Y是0-约5范围的整数，R1，R2，R3，R4，R5，R6和R7是由H，1-C8烷基和C1-C8芳基组成的一类中的成员，R8是由H，羟基，C1-C8烷基和C1-C8芳基组成的一类中的成员。
优选的(N，N-二取代氨基)链烷醇链烷酸酯是C5-C18羧酸酯，(N，N-二取代氨基)链烷醇链烷酸酯的具体实例包括1-(N，N-二甲基氨基)-2-丙醇月桂酸酯(DAIPD)：
1-(N，N-二甲基氨基)-2-丙醇肉豆蔻酸酯(DAIPM)：
1-(N，N-二甲基氨基)-2-丙醇油酸酯(DAIPO)：
(N，N-二取代氨基)链烷醇链烷酸酯，通过相应的氨基链烷醇和月桂酰氯在三乙胺存在下反应，很容易制备，视需要使用氯仿之类的溶剂，但是优选使用。例如1-(N，N-二甲基氨基)-2-丙醇可与月桂酰氯，在氯仿中于三乙胺存在下反应，形成1-(N，N-二甲基氨基)-2-丙醇月桂酸酯(DAIPD)。
对于本发明来说，合适的渗透增强剂中通常优选DDAIP。
渗透增强剂存在的量应该足够增加前列腺素E1的渗透性，具体量必须根据所需的输送速度和使用的前列腺素E1的特定形式而改变。一般来说该量为以组合物总重量计约0.5％-10％，优选渗透增强剂占组合物的约5％重量。
多糖树胶对于本发明的组合物也是很重要的成分，合适的代表性的树胶是半乳甘露聚糖树胶类树胶。半乳甘露聚糖树胶是含有D-半乳糖和D-甘露糖单元的碳水化合物的聚合物，或者是这种聚合物的其它衍生物。该组合物中存在相对大量的半乳甘露聚糖，而其在组合物中含量根据其来源而不同。半乳甘露聚糖树胶的特征是(1-4)连接的β-D-甘露吡喃单元直链结构。和主链(1-6)连接的单一成员α-D-甘露吡喃单元作为侧链存在。半乳甘露聚糖树胶包括瓜耳胶，它是两种豆科植物(cyamposis tetragonalobus和psoraloids)任何一种种子内粉末状的内胚乳，还包括刺槐豆胶，它是在角豆树(ceratonia siligua)种子的内胚乳中发现的。对于本发明刺槐豆树胶是优选的。
其它合适的代表性树胶包括琼脂树胶，角叉胶，茄替胶，刺梧桐树胶，鼠李聚糖树胶和苍耳烷树胶。本发明的组合物可以含有各种树胶的混合物或者树胶和酸性聚合物的混合物。
树胶，特别是半乳甘露聚糖树胶是公知的物质，例如参见“工业树胶：多糖及其衍生物”(
Industrial Gums：Polysaccharides & Their Derivetives，Whistler R.L.& BeMiller J.N.(eds.)3rd.，Ed.AcademicPress(1992))和“水溶性树胶和树脂手册”(
Handbook of Water-Soluble Gums & Resins，Davidson R.L.，McGraw-Hill，Inc.，N.Y.(1980))。大部分树胶能够以各种形式从市场上买到，通常是粉末，对于食品和表皮给药组合物很容易使用，例如粉末状的刺槐豆胶可以从Tic GumsInc.(Belcam，MD)买到。
多糖树胶存在的范围是以组合物总重量计约0.5％-5％，优选范围是约0.5％-2％，以下实施例给出了详细说明的组合物。
多糖树胶的任选替换物是聚丙烯酸聚合物，普通的各种聚丙烯酸聚合物一般称为卡波姆(carbomer)。卡波姆是用聚烯基聚醚轻度交联的聚丙烯酸聚合物，可以从B.F.Goodrich Company(Akron，Ohio)以商品名“CARBOPOLIM”买到，特别优选的卡波姆的商品名为“CARBOPOL940”。
适于本发明使用的其它聚丙烯酸聚合物是市场上可以买到的“PemulenTM”(B.F.Goodrich Company)和“POLYCARBOPHILTM”(A.H.Robbins，Richmond，VA)。“PemulenTM”聚合物是C10-C30的烷基丙烯酸酯和一个或多个丙烯酸，甲基丙烯酸或一个它们的简单酯的单体的共聚物，用蔗糖的烯丙基醚或季戊四醇的烯丙基醚交联；“POLYCARBOPHILTM”增强剂是用二乙烯基二醇交联的聚丙烯酸。
当聚丙烯酸聚合物存在时，其量为组合物总重量的约0.5-5％。
本发明的其它重要的成分是亲脂化合物，本文使用的术语亲脂化合物是指又亲脂又亲水的试剂。C1-C8的脂肪醇，C2-C30的脂肪酸酯及其混合物可以作为亲脂化合物。有代表性的合适的脂肪醇是乙醇，正丙醇和异丙醇，合适的酯是乙酸乙酯，乙酸丁酯，月桂酸乙酯，丙酸甲酯和肉豆蔻酸异丙酯。在本文中使用的“脂肪醇”包括多元醇，如甘油，丙二醇和聚乙二醇。优选醇和酯的混合物，特别是乙醇和月桂酸乙酯，肉豆蔻酸乙酯的混合物最优选。
必须根据其它因素来改变所需的亲脂化合物的浓度，例如根据所需的半固体稳定性和皮肤渗透促进效果，优选的透皮组合物含有以组合物总重量计约7％-40％的亲脂化合物，当使用脂肪醇和脂肪酸酯的混合物时，优选的脂肪醇量是约5％-15％范围，优选的脂肪酸酯的数量是约2％-15％范围(仍然以组合的总重量计)。
本发明视需要使用，但是优选的成分是乳化剂，虽然不是关键因素，合适的乳化剂通常有大于10的亲水-亲脂平衡数。蔗糖酯，特别是硬脂酸蔗糖酯可作为本发明表皮给药组合物的乳化剂。硬脂酸蔗糖酯是多种商业来源的公知乳化剂，当使用乳化剂时，优选蔗糖硬脂酸酯以组合物总重量计至多约2％。优选的蔗糖硬脂酸酯乳化剂的量也可以用乳化剂对多糖树胶的重量比表示，对于产生所需的半固体组合物的均匀性和抗分离性来说，1∶4的比例是优选的。
本发明包括酸性缓冲体系，酸性缓冲体系用于维持或缓冲所需的pH值范围。本文使用的术语“缓冲体系”或“缓冲剂”是指一种溶质或一种试剂，当它们溶在水溶液中时，能够稳定该溶液，使其当加入酸或碱时pH值(或氢离子浓度，或活度)不发生大的变化。上述溶质或试剂是公知，用于阻止pH离开开始时缓冲所达pH值，使其在上述指定的范围内变化。虽然有许多合适的缓冲剂，但是磷酸钾单水合物被证明对于本发明的组合物是有效的。
本发明药物组合物的最终pH值可以在生理可接受的范围内变化，最终的pH值必须不刺激人的皮肤。在不违反上述限制的条件下，通过选择pH值可以改进前列腺素E1的稳定性和需要时调节其均匀性。考虑这些因素，优选的pH值是约3.0-7.4，最优选的pH范围是约3.5-约6.0。
组合物的其余成分是水，水必须是纯水。组合物含有以组合物总重量计约50％-90％范围的水，水的具体量没有限制，但是可以调节，以便得到所需的均匀性和/或使其它成分的浓度达到所需水平。
另外，如果需要也可以使用公知的透皮渗透增强剂，实际例子是二甲亚砜(DMSO)，二甲基乙酰胺(DMA)，2-吡咯烷酮，N，N-二乙基间甲苯甲酰胺(DEET)，1-十二烷基氮杂环庚烷-2-酮(Azone，Nelson Research注册的商标)，N，N-二甲基甲酰胺，N-甲基-2-吡咯烷酮，硫代甘醇酸钙，噁唑烷酮，二氧戊环衍生物，月桂氮酮衍生物和大环增强剂，如大环酮。
可以加入前列腺素E1稳定剂，着色剂，流变剂和防腐剂，加入的量不能过度地限制前列腺素E1的皮肤渗透作用或防碍所需的半固体的均匀性。
本发明半固体的药物组合物的预期剂型是乳膏或凝胶等，也包括(但不限于)用于透皮补片等器械的合适的组合物。
上述成分可以以任何顺序和方式结合，只要能够得到含有前列腺素E1均匀分散在半固体制剂中的稳定的组合物即可。制备这种组合物的一种适当的方法包括均匀地将多糖树胶(或聚丙烯酸)分散在预先混合的水/缓冲溶液中，然后充分地匀化(即混合)所得的混合物，将其贴上“A份”标签。需要时，在分散多糖树胶之前将乳化剂加入到水/缓冲溶液中。可以使用任何合适的方法将A份的pH值调节到所需的水平，例如通过加入浓磷酸或氢氧化钠。
另外，将前列腺素E1于搅拌下溶解于亲脂化合物中，后者本身可以是醇类，酯类或醇和酯的混合物，然后加入渗透增强剂。当亲脂化合物包括醇和酯两者时，先加入渗透增强剂，随后加入酯，再将前列腺素E1溶解在醇中。在两种情况下均将所得混合物贴上“B份”标签。最后一步包括在不断搅拌下将B份慢慢加入(例如滴加)到A份中。
当进行比较时，所得的表皮给药组合物表现出上述优异的性质，包括改进前列腺素E1的渗透性和生物利用率，不需要过量药物，降低皮肤危害和相关的炎症，以及在设计剂量形式时的灵活性。这种组合物能够对外周血管疾病，阳萎和其它用前列腺素E1治疗的疾病延长治疗时间，同时能够避免低生物利用率及与其它输送方法相关的迅速化学分解作用。将本发明的表皮给药组合物中的前列腺素E1用于患者的皮肤，使得预定药量的前列腺素E1能不断地对患者给药，避免了通过注射一次或多次大剂量给药时的不理想的效果。通过维持持续的剂量速度，患者目标组织中的前列腺素E1的水平能够被较好地维持在最佳的治疗范围。
以下实施例说明本发明的实践，这些实施例用于举例说明本发明，并不限制本发明的范围，对于本领域的技术人员来说，在不损害前列腺素E1的有效性的情况下，很明显涉及组合物的各种变化，这些变化应属于本发明的范围。例如另外加入的成分，如着色剂，抗微生物的防腐剂，乳化剂，香料，前列腺素E1的稳定剂等可以包含在组合物中，只要得到的组合物保持了如上所述的所需性质。除了另有说明，每种组合物均通过常规方法，将指出的成分分别混合在一起来制备。
实施例1：表皮给药前列腺素E1的组合物A
组合物A按照以下方法制备，将0.4份前列腺素E1(Alprostadil USP)溶解于5份乙醇中形成A份，再将5份2-(N，N-二甲基氨基)丙酸十二烷基酯混入醇-前列腺素E1的溶液中，随后加入5份月桂酸乙酯。
从pH5.5的水/缓冲溶液开始制备B份：通过往纯水中加入足量的单水合磷酸钾得到0.1M的溶液，用强碱溶液(1N氢氧化钠)和强酸溶液(1N磷酸)将水/缓冲溶液的pH调节到5.5。缓冲溶液占组合物总量大约80份。
往缓冲溶液中加入0.5份月桂酸乙酯，再将刺槐豆胶(粉末)分散到缓冲溶液中，用匀化器匀化，下表1列出了各成分。
所得组合物是可以敷开的半固体，适合用于皮肤，不需要支撑体如贴片和黏接带，该组合物在表观和防止分离两方面都是均匀的。
用蜕落的蛇皮作为模型阻挡层评价前列腺素E1的皮肤渗透性能，蜕落的蛇皮从堪萨斯大学的动物保护单位得到，将头和尾部分除去，将皮随机切成试验片，然后用水浸泡。
样品用Frane型扩散池(表面1.8cm2)评价。具体来说，将蛇皮放在垂直扩散池中的接受池顶部，扩散池中插入一磁棒，并且加入等渗缓冲液。在蛇皮片的上方放一垫圈，再放上给样池，将两池钳在一起。将已知量的制剂放在有盖的小瓶(重量＝5g)的底部，小瓶正好与给样池吻合，以保证均匀地分布。小瓶放在给样池中的蛇皮上。为了减少各成分的蒸发，给样池和小瓶用防水胶带轻轻地黏贴在一起。将整个单元放在搅拌水浴中(32℃)。样品每小时从给样池抽出，共4小时，分析前列腺素E1的浓度，浓度的变化说明渗透量。将用多个蛇皮试样进行试验，将得到的结果平均。
为了讨论评价药物渗透中蜕落蛇皮的应用，参见USP4,771,004(Higuchi)，将该专利非不相容内容引入本文作为参考。
在4小时中，前列腺素E1以相对恒定的速度迅速地渗透，渗透研究的结果记载于下表2及图1。
实施例2：表皮给药前列腺素E1组合物B
使用表1所列成分制备组合物B。组合物B比组合物A含有更多的前列腺素E1，尽管增加了药物用量，组合物B表现出类似的半固体均匀性和均匀的外观。按照实施例1所述的方法测定前列腺素E1渗透性。组合物B提供了前列腺素E1的相对迅速恒定的输送，其结果列于表2和图1中。
实施例3： 表皮给药前列腺素E1组合物C
使用下表1所列成分制备组合物C。组合物C比组合物A或B含有更多的前列腺素E1，增加了药物用量对于均匀性和表观较少有(或者没有)影响，实际上和组合物A或B相当。仍然按照实施例1所述的方法测定前列腺素E1渗透性。根据本试验，组合物C也提供了前列腺素E1的相对迅速恒定的输送，结果列于下表2和图1中。
实施例4： 表皮给药前列腺素E1组合物D
使用下表1所列成分制备组合物D。再增加前列腺素E1的含量，实际上对于良好的均匀性和抗分离性并没有影响。仍然按照实施例1所述的方法测定前列腺素E1渗透性。结果列于下表2和图1中。
实施例5：表皮给药前列腺素E1组合物E
使用下表1所列成分制备组合物E。为了评价本发明组合物的重现性，组合物E再采用组合物D的配方。组合物E的良好的半固体均匀性和抗分离性实际上证实了其重现性。仍然按照实施例1所述的方法测定前列腺素E1渗透性。组合物E的前列腺素E1输送仍然相当迅速和恒定，结果列于以下的表2和图1中。
实施例6：表皮给药前列腺素E1组合物F
组合物F中的前列腺素E1的水平又增加，具体成分列于表1，良好的均匀性和分离稳定性没有降低，渗透分析结果列于以下表2和图1。
实施例7：表皮给药前列腺素E1组合物G
使用以下表1所列成分制备组合物G。对于组合物G，除了酯成分(月桂酸酯)被省略和相应增加乙醇用量以外，重复组合物F的配方，所得到的组合物也是能敷开的半固体，具有均匀的外观和抗分离性，渗透分析结果列于下表2和图1。结果仍然很好，该结果反映了由于使用包括酯类组份和醇类组份的亲脂化合物，本发明组合物具有相应的优点。
表1：表皮给药前列腺素E1组合物
成分(Wt％) A B C D E F G
A份 预水合的刺槐豆树胶 3 3 3 3 3 3 3
水/缓冲液(pH5.5) 81 81 81 81 81 81 81
蔗糖硬脂酸酯 0.5 0.5 0.5 0.5 0.5 0.5 0.5
B份 前列腺素E1 0.1 0.2 0.3 0.4 0.4 0.5 0.4
DDAIP 5 5 5 5 5 5 5
乙醇 5 5 5 5 5 5 10
月桂酸乙酯 5 5 5 5 5 5 -
实施例8：渗透图的比较
表2表示本发明各实施例的组合物于4小时期间每小时前列腺素E1渗透的累积量。这些数据说明本发明组合物透皮输送前列腺素E1药物的能力。
图1是从表1表示的数据得到的图形。鲜明而恰当地以图形的方式显示出本发明的组合物能够以相对迅速和恒定的速度有效地渗透皮肤。正如所预期的，累积渗透随着组合物中的前列腺素E1用量的增加而增加。
表2：前列腺素E1的累积渗透量(μg/cm2)
时间 A B C D E F G
(小时)
1 1.96 3.37 5.47 7.20 7.09 10.38 3.03
2 5.49 9.72 18.06 21.26 16.6 25.03 8.17
3 11.25 18.18 30.34 35.53 28.24 42.18 12.93
4 13.98 23.48 38.49 47.98 41.1 52.13 18.71
为了进一步评价本发明组合物的有效性，制备了比较实施例组合物。除了省略使用DDAIP渗透增强剂以外，第一个比较实施例(比较例1)以和组合物D及E相同的配方制备。比较实施例2(比较例2)也省略DDAIP，但是乙醇的用量增加了相应量，使用的具体成分列于以下表3。
表3：比较实施例
成分(Wt％) 比较例组合物1 比较例组合物2
A份 预水合的刺槐豆树胶 3 3
水/缓冲液(pH5.5) 86 81
蔗糖硬脂酸酯 0.5 0.5
B份 前列腺素E1 0.4 0.4
乙醇 5 10
月桂酸乙酯 5 5
按照实施例1所述的方法评价前列腺素E1的渗透性能，结果列于以下表4。
表4：比较实施例
前列腺素E1的累积渗透量(μg/cm2)
时间 比较例1的组合物 比较例2的组合物
(小时)
1 2.64 1.55
2 4.46 3.69
3 6.59 6.63
4 9.67 11.05
表4的数据以图形的方式和含量相同的前列腺素E1实施例组合物D和E进行比较，渗透数据说明本发明的组合物的优点主要是由于存在DDAIP渗透增强剂的结果。
上述说明书仅仅用于说明本发明，不是对本发明的限制，在本发明的精神和范围内的其它变化是可能的，并且对于本领域的技术人员来说是显而易见的。
Claims (4)
1.一种半固体表皮给药组合物，包含以组合物总重量计：
0.1-1重量％的前列腺素E1；
0.5-10重量％的皮肤渗透增强剂，该增强剂是2-(N，N-二甲基氨基)丙酸十二烷基酯；
0.5-5重量％的刺槐豆胶；
7-40重量％的亲脂化合物，该亲脂化合物选自乙醇、月桂酸乙酯及其混合物；
能为所述组合物提供3-7.4缓冲pH值的酸性缓冲体系。
2.按照权利要求1的表皮给药组合物，其中所述的亲脂化合物是月桂酸乙酯。
3.按照权利要求1的表皮给药组合物，其中所述的亲脂化合物是5-15重量％的乙醇和2-15重量％的月桂酸乙酯的混合物。
4.按照权利要求1的表皮给药组合物，其中还含有作为乳化剂的蔗糖硬脂酸酯。
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| HU (1) | HU230300B1 (zh) |
| IL (3) | IL135914A0 (zh) |
| MX (1) | MXPA01011560A (zh) |
| PT (1) | PT1178833E (zh) |
| TR (2) | TR200002158T2 (zh) |
| TW (1) | TW443933B (zh) |
| WO (2) | WO1999022714A1 (zh) |
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| GR1003199B (el) * | 1998-08-14 | 1999-09-01 | Χρηση της μισοπροστολης ή και της μισοπροστολης οξυ για την παρασκευη φαρμακευτικου προιοντος για τη θεραπευτικη αντιμετωπιση της σεξουαλικης δυσλειτουργιας στις γυναικες | |
| EA008720B1 (ru) * | 1998-12-10 | 2007-06-29 | Нексмед (Холдингс), Инк. | Применение композиции на основе простагландина для лечения расстройства сексуального возбуждения у женщин |
| US20070191320A1 (en) * | 1998-12-10 | 2007-08-16 | Nexmed Holdings, Inc. | Methods of treatment for female sexual arousal disorder |
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| US7105571B2 (en) * | 2000-01-10 | 2006-09-12 | Nexmed Holdings, Inc. | Prostaglandin compositions and methods of treatment for male erectile dysfunction |
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| US6693135B2 (en) * | 2000-01-10 | 2004-02-17 | Nexmed (Holdings) Incorporated | Prostaglandin compositions and methods of treatment for male erectile dysfunction |
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| CN1774237A (zh) * | 2003-03-21 | 2006-05-17 | 尼克美制药控股有限公司 | 前列腺素组合物及其促进血管生成的方法 |
| RU2358718C2 (ru) * | 2003-03-21 | 2009-06-20 | Нексмед Холдингс, Инк. | Противогрибковое покрытие для ногтей и способ его применения |
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| EP2417979A1 (en) * | 2004-04-19 | 2012-02-15 | Strategic Science & Technologies, LLC | Beneficial effects of increasing local blood flow |
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| US9226909B2 (en) | 2004-04-19 | 2016-01-05 | Strategic Science & Technologies, Llc | Beneficial effects of increasing local blood flow |
| AU2012201048B2 (en) * | 2004-04-19 | 2013-06-06 | Strategic Science & Technologies, Llc | Transdermal delivery of beneficial substances effected by a hostile biophysical environment |
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| US7560489B2 (en) * | 2006-10-11 | 2009-07-14 | Nexmed Holdings, Inc. | Stabilized prostaglandin E composition |
| GB0620685D0 (en) | 2006-10-18 | 2006-11-29 | Controlled Therapeutics Sct | Bioresorbable polymers |
| NZ592300A (en) * | 2008-10-03 | 2013-01-25 | Nexmed Holdings Inc | Stabilized composition for treating psoriasis |
| US8604081B2 (en) | 2009-06-24 | 2013-12-10 | Strategic Science & Technologies, Llc | Topical composition containing ibuprofen |
| US11684624B2 (en) | 2009-06-24 | 2023-06-27 | Strategic Science & Technologies, Llc | Treatment of erectile dysfunction and other indications |
| US9072659B2 (en) | 2009-06-24 | 2015-07-07 | Strategic Science & Technologies, Llc | Topical composition containing naproxen |
| MX2012012824A (es) * | 2010-05-04 | 2013-07-03 | Nexmed Holdings Inc | Composiciones de productos terapeuticos de moleculas pequeñas. |
| CN103237785A (zh) * | 2010-09-24 | 2013-08-07 | 尼克美控股公司 | 增强的经颊药物递送系统和组合物 |
| EP2658551B1 (en) | 2010-12-29 | 2020-07-01 | Strategic Science & Technologies, LLC | Treatment of erectile dysfunction and other indications |
| JP2014501283A (ja) | 2010-12-29 | 2014-01-20 | ストラテジック サイエンス アンド テクノロジーズ， エルエルシー | アレルギーおよび他の適応症の処置のためのシステムおよび方法 |
| US8940794B2 (en) | 2011-04-07 | 2015-01-27 | Nexmed Holdings, Inc. | Methods and compositions for treating Raynaud's disease |
| ITRM20120036A1 (it) * | 2012-02-02 | 2013-08-03 | Robert Davis Steigerwalt Jr | Applicazione transdermica di prostaglandina e1 per il trattamento dell¿ischemia oculare. |
| US20150320764A1 (en) * | 2014-05-09 | 2015-11-12 | Nexmed Holdings, Inc. | Treating female sexual arousal disorder and related symptoms |
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-
1997
- 1997-11-05 US US08/964,509 patent/US6046244A/en not_active Expired - Lifetime
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1998
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- 1998-11-05 TR TR2000/02158T patent/TR200002158T2/xx unknown
- 1998-11-05 WO PCT/US1998/023576 patent/WO1999022714A1/en active IP Right Grant
- 1998-11-05 JP JP2000518648A patent/JP4491560B2/ja not_active Expired - Lifetime
- 1998-11-05 IL IL13591498A patent/IL135914A0/xx not_active IP Right Cessation
- 1998-11-05 AT AT98957603T patent/ATE455535T1/de active
- 1998-11-05 BR BR9813945-2A patent/BR9813945A/pt not_active Application Discontinuation
- 1998-11-05 KR KR1020007004907A patent/KR100576986B1/ko not_active IP Right Cessation
- 1998-11-05 CN CNB988129159A patent/CN1191060C/zh not_active Expired - Lifetime
- 1998-11-05 DK DK98957603.8T patent/DK1028708T3/da active
- 1998-11-05 CA CA002309165A patent/CA2309165A1/en not_active Abandoned
- 1998-11-05 ES ES98957603T patent/ES2338389T3/es not_active Expired - Lifetime
- 1998-11-05 EP EP98957603A patent/EP1028708B1/en not_active Expired - Lifetime
- 1998-12-07 TW TW087118421A patent/TW443933B/zh not_active IP Right Cessation
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1999
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- 1999-05-13 EP EP99923024A patent/EP1178833B1/en not_active Expired - Lifetime
- 1999-05-13 AU AU39891/99A patent/AU757086B2/en not_active Expired
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- 1999-05-13 JP JP2000617929A patent/JP2002544240A/ja active Pending
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- 1999-05-13 DE DE69919594T patent/DE69919594T2/de not_active Expired - Lifetime
- 1999-05-13 DK DK99923024T patent/DK1178833T3/da active
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- 1999-05-13 KR KR10-2001-7014474A patent/KR100462442B1/ko not_active IP Right Cessation
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Effective date of registration: 20170714 Address after: The Swiss Lei Patentee after: Ferring International Center (Switzerland) S. A. Address before: new jersey Patentee before: Nexmed Inc. |
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