CN1284863A - 用于递送nsai药物的外用组合物 - Google Patents
用于递送nsai药物的外用组合物 Download PDFInfo
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- CN1284863A CN1284863A CN98812940A CN98812940A CN1284863A CN 1284863 A CN1284863 A CN 1284863A CN 98812940 A CN98812940 A CN 98812940A CN 98812940 A CN98812940 A CN 98812940A CN 1284863 A CN1284863 A CN 1284863A
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- Prior art keywords
- compositions
- ketoprofen
- gum
- mixture
- penetration enhancer
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- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 23
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Abstract
本发明提供了适于外用非甾体消炎(NSAI)药物的、半固体稠度的水性药物组合物。所述组合物包含一种或多种NSAI药物、非碱性聚合物皮肤渗透促进剂、和亲脂性溶剂。聚合物皮肤渗透促进剂以足以增强NSAI药物穿透皮肤的量含于本发明组合物中。所述亲脂性溶剂是C2-C8脂肪醇与C8-C30脂族酯的混合物。
Description
技术领域
本发明涉及用于将非甾体消炎药物对患者透皮给药的水性药物组合物。
背景技术
近些年,非甾体消炎(下文中称为NSAI)药物已被广泛用于治疗慢性风湿病或关节炎,并被用于控制疼痛。据信,这些化合物可通过抑制前列腺素在受影响关节或其它组织区域的生物合成来缓解疾病。水杨酸、或阿司匹林、和布洛芬是众所周知的NSAI药物。
口服NSAI药物的患者,在消化性溃疡和导致贫血的胃肠道失血方面的危险性有所增加。这些不利副作用尤其会折磨长期服用NSAI药物的患者。解决这种胃肠道并发症问题的一种途径是通过外用而不是口服来透皮递送NSAI药物。透皮给药还具有其它优点,包括较少的给药次数、更好地控制药物释放、和更好地将药物靶向递送到特定组织位点。
包括NSAI药物在内的大多数药物不能独自足够好地透入皮肤,以提供比得上口服给药所获得的药物浓度水平。为了克服该问题,外部给药制剂通常包含渗透促进剂。皮肤渗透促进剂也可称为吸收促进剂、促进剂、辅助剂、助溶剂、吸收增强剂等。无论其名称是什么,这类物质的作用是改善药物透过皮肤的吸收。理想的渗透促进剂应当不仅能促进药物透过皮肤吸收,而且还不具有刺激性、过敏性、或不损害皮肤。此外,理想的渗透促进剂应当不影响剂型的可用性(例如霜剂或凝胶剂)、或外用组合物的气味。
已经对大量化合物在促进药物透过皮肤方面效力进行过评价。参见例如,“透皮促进剂”,Maibach,H.I.和Smith,H.E.(eds.),CRCPress,Inc.,Boca Raton,F.L.(1995),该文献概括描述了各种皮肤渗透促进剂的应用和测试。
为了能有效地透皮递送NSAI药物,人们开发了多种含有渗透促进剂的NSAI霜剂和凝胶剂。例如,Mody等人的US 5210099公开了一种水包油乳霜剂,其中结晶形式的布洛芬与多种渗透促进剂悬浮在油相中。Wisniewski等人的US 5093133公开了布洛芬S-对映体(旋光异构体)的水醇凝胶剂,其中醇组分的作用是促进药物吸收。Noda等人的US4393076公开了含有二醇和低级醇混合物的中和酮洛芬凝胶剂。
这些和其它常规组合物的一种或一系列缺点如下:复杂和高成本的制备步骤或组分,产生浪费的超载药物需求,和不足的药物渗透力。
因此,本领域仍需要用于透皮递送NSAI药物加以改善的、低成本组合物。
发明简述
适于外用的半固体稠度的水性药物组合物包含非甾体消炎(NSAI)药物、非碱性聚合皮肤渗透促进剂、和亲脂性溶剂。聚合皮肤渗透促进剂,以足以增强NSAI药物穿透皮肤的量含于本发明组合物中。优选可分散在水中的非碱性(酸性或中性)聚合物或多糖、或它们的混合物。所述亲脂性溶剂是C2-C8脂肪醇与C8-C30脂族酯的混合物。
本发明组合物还可含有增稠剂、乳化剂和/或能给组合物提供约pH值3至生理学pH值的缓冲pH值的缓冲系统。
在优选的组合物中,NSAI药物是异丁苯乙酸类药物,聚合皮肤渗透促进剂是半乳甘露聚糖胶。
附图的简要说明
在附图中,
附图1是市售酮洛芬组合物和依据本发明制备的四种酮洛芬组合物(A-D)透过脱落蛇皮的累积药物穿透量的曲线图。
附图2是另外3个实施例组合物(E-G)与相同市售酮洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图3是另外5个实施例组合物(H-L)与相同市售酮洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图4是另外4个实施例组合物(M-P)与相同市售酮洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图5是另外6个实施例组合物(Q-V)与相同市售酮洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图6是另外6个实施例组合物(W-BB)与相同市售酮洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图7是另外2个实施例组合物(CC-DD)与相同市售酮洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图8是选自本发明制备的酮洛芬组合物与两种已知酮洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图9是3种依据本发明制备的外用布洛芬组合物与市售布洛芬组合物透过脱落蛇皮的累积药物穿透量的曲线图。
附图10是市售酮洛芬组合物与依据本发明制备的酮洛芬组合物透过人皮肤的累积药物穿透量的曲线图。
发明详述
本发明药物组合物包含NSAI药物、非碱性(即酸性或中性)聚合皮肤渗透促进剂、和共作用亲脂性溶剂。制备后,本发明组合物形成适于外用的半固体。如果需要的话,可加入酸性缓冲系统和稳定剂。在作为外用制剂使用时,本发明组合物表现出相当高的NSAI药物穿透量和生物利用率,同时无需浪费性超载药物浓度。本发明组合物还表现出皮肤刺激、过敏和损害作用减小。
本发明组合物含有一种或多种NSAI药物。虽然大多数是有机酸,但是NSAI药物包含多种化学结构。NSAI药物的一种常用分类方法如下:
(1)水杨酸衍生物类,包括阿司匹林;
(2)丙酸类,包括布洛芬、酮洛芬、噁丙嗪、吡洛芬、吲哚布芬、苯噻丙酸;
(3)对氨基苯酚衍生物类,包括对乙酰氨基酚;
(4)吲哚和茚乙酸类,包括吲哚美辛、舒林酸、依托度酸、卡布洛芬;
(5)杂芳基乙酸类,包括双氯酚酸、托耳米丁、酮咯酸;
(6)邻氨基苯甲酸(或芬那酸)类,包括甲芬那酸、依托芬那酯;
(7)烯醇酸类,包括炎痛喜康、美洛昔康、替诺西康;和
(8)链烷酮类。
上述类别描述在Goodman和Gilman的《治疗药理基础》,9th Ed.,McGraw-Hill Inc.,New York,N.Y.(1995)第27章中。“Cutting氏药物手册”描述了异丁苯乙酸类的特征,这是一类以异丁苯乙酸结构为基础的NSAI药物:[Cutting氏药物手册,7th Ed.,Whitehouse Station,Appleton-Century-Crotts,C.T.(1984),pp.615-617]。异丁苯乙酸类尤其包括水杨酸衍生物和丙酸类。对于本发明,异丁苯乙酸类药物是优选的。合适的异丁苯乙酸类药物的实例包括克利洛芬、非诺洛芬、氟比洛芬、布洛芬、酮洛芬、芬布芬、阿氯芬酸、氨芬酸钠、芬氯酸、萘普生、甲基萘丙醇、和双氟尼酸。在异丁苯乙酸类药物中,最优选酮洛芬。
属于上述NSAI药物类别的具体化合物是本领域技术人员众所周知的,并且有很多文献记载了其化学结构、药理活性、副作用、和正常口服剂量范围。例如,参见,“医生常用参考”(Physician’s DeskReference),51st ed.(1997),The Merck Index,12th Ed.,Merck&Co.,N.J.(1996)和“马丁德尔超全药典”(Martindale The ExtraPharmacopoeia),28th Ed.,London,The Pharmaceutical Press(1982)。
代表性异丁苯乙酸类药物的结构式如下:
布洛芬:
非诺洛芬:
本说明书所提及的化合物包括该化合物的可药用衍生物,并包括其可药用盐,例如钠盐。
在烯醇酸类药物中,炎痛喜康是优选的:
NSAI药物在本发明药物组合物中的含量取决于所需剂量、该NSAI药物的溶解度、以及剂型(例如栓剂或外用凝胶剂)。按组合物总重量计,本发明组合物优选含有约0.1%-约10%重量的NSAI药物,最优选含有约0.5%-约10%重量的NSAI药物。
本发明组合物中的重要组分是聚合物皮肤渗透促进剂。本说明书所用术语“皮肤渗透促进剂”是指能促进药物穿过皮肤扩散的物质。聚合物皮肤渗透促进剂是非碱性的,即酸性或中性的,并且以足以促进所选NSAI药物或药物组合透过皮肤的量含于组合物中。其具体含量随促进剂类型、NSAI药物类型、和所需释放速度的不同而不同。
聚合物皮肤渗透促进剂优选是可分散在水中的酸性聚合物或多糖胶或二者的混合物。水溶性酸性聚合物的实例是聚丙烯酸聚合物。其中一种适用于实施本发明的聚丙烯酸聚合物制剂是通常称为“卡波姆”的材料,卡波姆是与聚链烯基聚醚轻度交联的聚丙烯酸聚合物。其可以以商品名“CARBOPOL”从B.F.Goodrich Company(Akron,Ohio)购得。特别优选的一种卡波姆是称为“CARBOPOL 940P”的卡波姆。
其它适于实施本发明的聚丙烯酸聚合物是商品名为“PemulenTM”(B.F.Goodrich Compan)和“POLYCARBOPHILTM”(A.H.Robbins,Richmond,VA)的市售产品。“PemulenTM”聚合物是与蔗糖烯丙基醚或季戊四醇烯丙基醚交联的、C10-C30烷基丙烯酸酯与一个或多个丙烯酸、异丁烯酸或它们的简单酯单体的共聚物。“POLYCARBOPHILTM”促进剂是与丁二烯二醇交联的聚丙烯酸。
当使用聚丙烯酸聚合物作为渗透促进剂时,按组合物总重量计,其在本发明组合物中的含量为约0.5%-5%,优选为约2%-约3%。聚丙烯酸聚合物优选保持酸性或中性pH。
本发明组合物也可以使用多糖胶作为渗透促进剂。合适的代表性树胶是属于黄原胶和半乳甘露聚糖胶类的树胶。树胶、尤其是半乳甘露聚糖胶是众所周知的材料。参见例如,《工业用树胶:多糖及其衍生物》(Industrial Gums:Polysaccharides & Thier Derivatives),WhistlerR.L.,BeMiller J.N.(eds.),3rd Ed.Academic Press(1992)和Davidson,R.L.,《水溶性树胶和树脂手册》(Handbook of Water-Soluble Gums&Resins),McGraw-Hill,Inc.,N.Y.(1980)。
半乳甘露聚糖胶是含有D-半乳糖和D-甘露糖单元的糖类聚合物,或这种聚合物的其它衍生物。存在大量半乳甘露聚糖,其组成随其起源的不同而不同。半乳甘露聚糖胶的的特征是,具有(1→4)连接的β-D-吡喃甘露糖基单元直链结构。与主链(1→6)连接的α-D-吡喃甘露糖基单一单元作为侧链。半乳甘露聚糖包括瓜尔胶,它是两种豆科植物(cyamposistetragonalobus和psoraloids)种子的粉碎胚乳,和刺槐豆胶,它是在角豆树(长角豆)种子的胚乳中发现的。角豆树胶也是半乳甘露聚糖。
其它合适的代表性树胶包括琼脂胶、藻酸盐、角叉菜胶、茄替胶、刺梧桐胶、卡塔亚胶(kadaya gum)、鼠李糖胶(rhamsan gum)、黄原胶和半乳甘露聚糖聚合物的衍生物。
黄原胶是通过用野油菜黄单胞杆菌微生物培养发酵制得的高分子量天然糖。黄原胶含有3种不同单糖:甘露糖、葡萄糖、和葡萄糖醛酸(钾盐、钠盐和钙盐的混合物)。每一重复聚合链段具有5个糖单元(两个葡萄糖、两个甘露糖、一个葡萄糖醛酸)。该聚合物的主链由通过1位和4位连接的β-D-葡萄糖单元构成;因此,其主链的化学结构与纤维素相同。
藻酸盐也是多糖,它是藻酸的盐。藻酸包含D-甘露糖醛酸和L-葡萄糖醛酸残基,并具有3种聚合段:一种是由D-甘露糖醛酸单元构成的聚合段,另一种是由L-葡萄糖醛酸单元构成的聚合段,第三种是由交替的D-甘露糖醛酸和L-葡萄糖醛酸残基构成的聚合段。通常称为藻酸丙二醇酯的由藻酸与丙二醇形成的酯是本发明优选的藻酸酯。
本发明组合物还可含有不同树胶(或它们的衍生物)的混合物、或树胶与酸性聚合物的混合物。
当使用多糖胶作为渗透促进剂时,按组合物总重量计,其在本发明组合物中的含量为约1%-约5%。举例说明的组合物在下文中的实施例中给出。
其它合适的聚合物皮肤渗透促进剂是纤维素衍生物,例如乙基纤维素、甲基纤维素、羟丙基纤维素。
此外,如果需要的话,还可加入已知的经皮渗透促进剂。其实例有二甲亚砜(DMSO)和二甲基乙酰胺(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-2-酮(Azone,NelsonResearch的注册商标)、N,N-二甲基甲酰胺、N-甲基-2-吡咯烷酮、巯基乙酸钙、和其它促进剂,例如二氧戊环、环酮、和它们的衍生物等。举例来说,一类是N,N-2-(二取代氨基)链烷酸烷基酯的生物可降解吸收促进剂,描述在Wong等人的US 4980378和US 5082866中。优选的补充促进剂是N,N-2-(二取代氨基)链烷酸烷基酯、(N,N-二取代氨基)链烷醇链烷酸酯、和它们的混合物。
本发明组合物的另一重要组分是亲脂性溶剂。本说明书所用术语“亲脂性溶剂”是指具有亲脂性和吸水性的NSAI药物溶剂。所述亲脂性溶剂是C2-C8脂肪醇与C8-C30脂族酯的混合物。合适的醇的实例有乙醇、正丙醇、异丙醇和甘油、丙二醇,合适的酯的实例有乙酸乙酯、乙酸丁酯、月桂酸乙酯、丙酸甲酯、肉豆蔻酸异丙酯、和棕榈酸异丙酯。优选乙醇、异丙醇或丙二醇与肉豆蔻酸异丙酯的混合物。
所需的亲脂性溶剂浓度取决于其它因素,例如NSAI药物的溶解性、所需半固体稠度、和所需皮肤渗透促进效果。优选的本发明药物组合物含有占组合物总重量约10%-约40%的亲脂性溶剂。当使用脂肪醇与脂族酯的混合物时,醇的含量优选为约10%-约35%,脂族酯的含量优选为约5%-约10%。
本发明组合物的任选(但是优选)组分是酸性缓冲系统。酸性缓冲系统的作用是使组合物pH维持或缓冲在所需范围内。
本发明药物组合物的最终pH值可在生理上可耐受范围内变化。最终pH必须不刺激人体皮肤。在不背离该限制的情况下,需要时可选择pH来改善NASI药物的溶解性,达到最佳皮肤渗透速度和调节稠度。可采用所有用于调节水溶液pH值的合适方法,例如通过缓冲系统、或有机碱,例如三乙醇胺、异丙基胺等、或无机碱例如氢氧化钠(NaOH)进行调节。在这些因素限制下,优选的pH值为约3-生理pH值范围。当使用的NSAI药物是酮洛芬时,优选的pH为约4.5-约5.5。
本说明书所用术语“缓冲系统”或“缓冲剂”是指这样的溶质或试剂,当它们在水溶液中时,能稳定该溶液,使得当向溶液中加入酸或碱时pH(氢离子浓度或活性)不发生大的变化。由此,防止pH从上述起始缓冲pH值范围变化的溶质或试剂是众所周知的。
本发明组合物的其余组分是水。按组合物总重量计,本发明组合物含有约60%-约90%的水。水的具体含量并不关键,然而其含量应当是可调节的以获得所需稠度和/或其它组分浓度。
本发明半固体药物组合物的剂型是霜剂、凝胶剂等,还包括(但不限于)适于用透皮贴片和类似器件给药的组合物。
可以以任意顺序和方式将上述组分混合,以制得溶解、和均匀分散在整个单相水性半固体中的NSAI药物组合物。其中一种制备这种组合物的方法包括制备聚合物皮肤渗透促进剂的水溶液,称为“A部分”。最好该溶液是蒸馏水中含有聚合物。为了形成A部分,称重出所需量的皮肤渗透促进剂,并分散在水中或适当缓冲水系统中。对于B部分,称重出所需量的NSAI药物,并用所需量的亲脂性溶剂溶解。为了使NSAI药物溶解完全,可采用加热和剧烈搅拌。将A部分和B部分混合后,视需要进行中和,以产生使组合物凝胶化的pH值。任选的缓冲系统是磷酸盐缓冲剂。
与现有技术中的NSAI外用组合物相比,所制得的均相凝胶表现出有利的上述特征,包括改善了NSAI药物的渗透和生物利用率,同时没有超载药物,皮肤损伤和有关炎症减轻了,并且提高了在设计剂型方面的灵活性。这些组合物可用于关节炎和其它通过NSAI药物治疗的病症的长期治疗,同时避免了出现与口服给药有关的胃肠道并发症。通过将NSAI药物在本发明外用组合物中涂敷在患者皮肤上,能将预定量NSAI药物持续地对患者给药,并防止了由于单次或多次给药大剂量所带来的不利作用。通过维持持久的给药速度,能更好地将患者血中的NSAI药物水平维持在最佳治疗范围内。
在下述实施例中证实了本发明的实践。这些实施例只是举例说明本发明,而不是对本发明范围的限制。在治疗组合物中进行的不会对NSAI药物带来副作用的改变,对于本领域技术人员来说是显而易见的,并且这些改型也在本发明范围内。例如,可将其它组分,如着色剂加到本发明组合物中,只要所得组合物保留其上述所期望的性质即可。除非另外指出而外,其中每一组合物都是通过将各自组分常规混合在一起制得的。另外,除非另外指出,否则每一组合物都是用能提供约3-生理pH范围的缓冲剂(缓冲系统)配制的。
实施例1:酮洛芬组合物A
如下所述制备组合物A。将两份聚合物皮肤渗透促进剂(聚丙烯酸聚合物,CARBOPOL 940)溶于60.5ml毫微级纯度水中,制得A部分。将30份乙醇、5份肉豆蔻酸异丙酯、和2.5份酮洛芬混合来制备B部分。然后将A部分和B部分充分混合。下述表1列出了各组分及含量。
用脱落蛇皮作为模型屏障来评价所得组合物的皮肤渗透效果。所用脱落蛇皮得自堪萨斯州大学的Animal Care Unit。将蛇皮头部和尾部去掉后,把蛇皮随机切成测试片,然后通过浸泡使之水合。
然后用Franz-型渗滤池(表面积为1.8cm2)评价样本。具体来说,将蛇皮片固定在垂直组装渗滤池的接受池顶上,其中插入一个小磁棒,并装有等渗缓冲剂。在蛇皮片的上面放置一个密封带,然后放置一个供给池。然后将这两个池夹在一起。把已知量的制剂涂在有盖小瓶(重量=约5克)的底部,其中该小瓶与供给池精确吻合以确保均匀分布。将供给池中的小瓶置于蛇皮上。为了组分较少蒸发,用防水粘合带把供给池和小瓶轻轻地系在一起。把各池置于搅拌水浴(32℃)中。周期性地从池中取出样本,分析NSAI药物的浓度,以浓度的变化表示渗透的量。
对于脱落蛇皮在药物渗透评价中的应用讨论,参见Higuchi的US4771004,将其引入本发明以作参考。
比较酮洛芬从组合物A和市售外用酮洛芬组合物(Profenid,Rhone-Poulenc Rorer)中的渗透量。通过用多个蛇皮样本进行测试,获得数据用于平均。
与该市售组合物相比,组合物A中的酮洛芬渗透的更快。该渗透实验的结果如下面表6和附图1所示。
实施例2:酮洛芬组合物B
用下面表1所示组分制备组合物B.所用聚合物皮肤渗透促进剂是聚丙烯酸聚合物(CARBOPOL940)。所用亲脂性溶剂是乙醇和月桂酸乙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图1所示。
与市售组合物相比,组合物B渗透的更快。
实施例3:酮洛芬组合物C
用下面表1所示组分制备组合物C。所用聚合物皮肤渗透促进剂是聚丙烯酸聚合物(CARBOPOL940)。所用亲脂性溶剂是乙醇、甘油、和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图1所示。
与市售组合物相比,组合物C渗透的更快。
实施例4:酮洛芬组合物D
用下面表1所示组分制备组合物D。所用聚合物皮肤渗透促进剂是聚丙烯酸聚合物(CARBOPOL940)。所用亲脂性溶剂是异丙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图1所示。
表1:酮洛芬聚丙烯酸组合物
组分(wt%) A B C DA部分:CARBOPOL 940 2 2 2 2
水 61 61 61 61B部分: 酮洛芬 2.5 2.5 2.5 2.5
乙醇 30 30 15 -
异丙醇 - - 30
甘油 - - 15 -
肉豆蔻 5 - 5 5
酸异丙酯
月桂酸乙酯 - 5 - -
实施例5:酮洛芬组合物E
用下面表2所示组分制备组合物E。所用聚合物皮肤渗透促进剂是半乳甘露聚糖胶、刺槐豆胶。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图2所示。
实施例6:酮洛芬组合物F
用下面表2所示组分制备组合物F。所用聚合物皮肤渗透促进剂是半乳甘露聚糖胶、刺槐豆胶。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透,所得结果如下面表6和附图2所示。
实施例7:酮洛芬组合物G
用下面表2所示组分制备组合物G。所用聚合物皮肤渗透促进剂是预水合刺槐豆胶。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图2所示。
表2:酮洛芬刺槐豆胶组合物
组分(wt%) E F GA部分: 刺槐豆胶 3 3 3
莲糖硬脂酸酯 0.5 - 0.5
水 74 75 74B部分: 酮洛芬 2.5 2.5 2.5
乙醇 15 15 15
肉豆蔻 5 5 5
酸异丙酯
实施例8:酮洛芬组合物H
用下面表3所示组分制备组合物H。所用聚合物皮肤渗透促进剂是半乳甘露聚糖胶、瓜尔胶。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图3所示。
实施例9:酮洛芬组合物I
用下面表3所示组分制备组合物I。所用聚合物皮肤渗透促进剂是合成瓜尔胶:瓜尔胶2-(羟基-3-三甲基铵)丙基醚氯化物脂族羧酸。以商品名“Jaguar C13S”从Rhone-Poulenc Rorer购得。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图3所示。
实施例10:酮洛芬组合物J
用下面表3所示组分制备组合物J。所用聚合物皮肤渗透促进剂是解聚阳离子瓜尔胶,以商品名“HI CARE 1000”从Rhone-Poulenc Rorer购得。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图3所示。
实施例11:酮洛芬组合物K
用下面表3所示组分制备组合物K。所用聚合物皮肤渗透促进剂是合成瓜尔胶(Jaguar C13S)。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图3所示。
实施例12:酮洛芬组合物L
用下面表3所示组分制备组合物L。所用聚合物皮肤渗透促进剂是瓜尔胶2-羟基丙基醚。以商品名“Jaguar HP120”从Rhone-Poulenc Rorer购得。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图3所示。
实施例13:酮洛芬组合物M
用下面表3所示组分制备组合物M。所用聚合物皮肤渗透促进剂是合成瓜尔胶(Jaguar C13S)。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图4所示。
实施例14:酮洛芬组合物N
用下面表3所示组分制备组合物N。所用聚合物皮肤渗透促进剂是瓜尔胶2-羟基丙基醚(Jaguar HP120)。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图3所示。
实施例15:酮洛芬组合物O
用下面表3所示组分制备组合物O。所用聚合物皮肤渗透促进剂是瓜尔胶2-羟基丙基醚(Jaguar HP120)。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图4所示。
实施例16:酮洛芬组合物P
用下面表3所示组分制备组合物P。所用聚合物皮肤渗透促进剂是瓜尔胶2-羟基丙基醚(Jaguar HP120)。所用亲脂性溶剂是乙醇和Miglyol840的混合物。Miglyol 840是丙二醇与癸酸和辛酸混合二酯的混合物,是从Huls America(Piscataway,NJ)购得的。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图4所示。
表3:酮洛芬瓜尔胶组合物
组分(wt%) H I J K L M N O PA部分: 瓜尔胶 3 - - - - - - 2 2
Jaguar C135 - 2 - - - 2 - - -
Jaguar HP120 - - - 2 2 2 - -
HI CARE 1000 - - 2 - - - - - -
水 74 76 76 76 76 61 61 76 61
蔗糖硬脂酸酯 0.5 - - - - - - - -B部分: 酮洛芬 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5
乙醇 15 15 15 15 15 30 30 15 30
Miglyol 840 - - - - - - - - 5
肉豆蔻酸异 5 5 5 5 5 5 5 5 -
丙酯
实施例17:酮洛芬组合物Q-U
用下面表4所示组分制备组合物Q-U。所用聚合物皮肤渗透促进剂是黄原胶,以商品名“KELTROL T”从Monsanto(San Giego,CA)购得。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6和附图5所示。
实施例18:酮洛芬组合物V和W
用下面表4所示组分制备组合物V和W。所用聚合物皮肤渗透促进剂是黄原胶(KELTROL T)。所用亲脂性溶剂是乙醇、丙二醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6以及附图5和6所示。
实施例19:酮洛芬组合物X-Z
用下面表4所示组分制备组合物X-Z。所用聚合物皮肤渗透促进剂是黄原胶(KELTROL T)。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6以及附图6所示。
实施例20:酮洛芬组合物AA
用下面表4所示组分制备组合物AA。所用聚合物皮肤渗透促进剂是黄原胶(KELTROL T)。所用亲脂性溶剂是丙二醇和Miglyol 810的混合物,Miglyol 810是从Huls America(Piscataway,NJ)购得的癸酸/辛酸甘油三酯溶液。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6以及附图6所示。
实施例21:酮洛芬组合物BB
用下面表4所示组分制备组合物BB。所用聚合物皮肤渗透促进剂是黄原胶(KELTROL T)。所用亲脂性溶剂是乙醇与辛酸及癸酸混合二酯(Miglyol 840)的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6以及附图6所示。
表4:酮洛芬黄原胶组合物
组分(wt%) Q R S T U VA部分: 黄原胶 2 2 2 2 2 2
水 61 61 61 61 61 61B部分: 酮洛芬 2.5 2.5 2.5 2.5 2.5 2.5
乙醇 30 30 30 30 30 10
异丙醇 - - - - - 10
丙二醇 - - - - - 10
肉豆蔻酸异 5 5 5 5 5 5
丙酯
表4(续):酮洛芬黄原胶组合物
组分(wt%) W X Y Z AA BBA部分: 黄原胶 2 2 2 2 2 2
水 61 76 76 76 61 61B部分: 酮洛芬 2.5 2.5 2.5 2.5 2.5 2.5
乙醇 10 15 15 15 30 30
异丙醇 10 - - - - -
丙二醇 10 - - - - -
Miglyol 810 - - - - 5 -
Miglyol 840 - - - - - 5
肉豆蔻酸异 5 5 5 5 - -
丙酯
实施例22:酮洛芬组合物CC
用下面表5所示组分制备组合物CC。所用聚合物皮肤渗透促进剂是以商品名“Methocal E4M Premium,NF”购自Dow Chemical Company(Midland,MI)的羟丙基甲基纤维素。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6以及附图7所示。
实施例23:酮洛芬组合物DD
用下面表5所示组分制备组合物DD。所用聚合物皮肤渗透促进剂是丙二醇藻酸酯。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定酮洛芬皮肤渗透。所得结果如下面表6以及附图7所示。
表5:酮洛芬组合物组分(wt%) Q RA部分:甲基纤维素 3 -
PG藻酸酯 - 3
水 60 76B部分: 酮洛芬 2.5 2.5
乙醇 30 15
肉豆蔻酸异 5 5
丙酯
实施例24:渗透特性比较
如实施例1所述测定酮洛芬的累积渗透量。结果如下面表6和附图1-7所示。
表6表示每一本发明实施例组合物和市售样本(Profenid)在第1、2、4、8、20和24小时后的酮洛芬累积渗透量。这些数据证实了与现有技术组合物相比,本发明组合物能更好地透皮递送NSAI药物。附图1-7是用表6所示数据制成的。正如附图所示,本发明组合物能非常有效地透皮递送酮洛芬,酮洛芬的经皮渗透速度比市售组合物要快很多。
表6:酮洛芬累积渗透量(μg/cm2)小时 市售组合物 A B C D E F G1 0 145 80 59 81 113 85 482 0 392 207 142 200 334 246 1414 0 650 417 312 487 520 402 3518 2.1 1432 698 631 1021 976 802 69618 - 2222 1735 1163 1785 - - -20 7.8 - - - - 1947 1755 132124 13.1 2410 2019 1405 1979 2229 2048 1515
表6(续):酮洛芬累积渗透量(μg/cm2)小时 H I J D L M N O P Q1 115 74 63 14 21 87 121 57 51 342 293 171 161 55 81 245 347 160 233 1124 487 370 352 153 223 535 745 347 450 3028 903 761 705 372 511 1257 1532 768 867 800*20 1781 1666 1465 976 1208 2458 2568 1531 2287 143424 2024 1865 1635 1167 1403 2677 2738 1738 2501 1764
*对于组合物Q,在第10小时测定。
表6(续):酮洛芬累积渗透量(μg/cm2)小时 R S T U V W X Y Z AA1 160 23 59 96 125 64 31 66 9 32 362 97 186 220 299 178 122 160 41 194 798 306 473 498 725 460 248 358 134 718 1463 785 1159 1130 1417 1020 556 718 343 19720 2386 1840 2362 2400 2552 2250 1290 1516 896 52224 2569 2103 2677 2660 2872 2595 1491 1749 1052 596表6(续):酮洛芬累积渗透量(μg/cm2)
小时 R Z AA
1 14 136 60
2 49 263 161
4 128 536 327
8 287 986 575
20 602 1674 1290
24 663 1793 1495
为了进一步评价本发明组合物的有效性,依据Wisniewski等人的US 5093133(对比组合物1)和Noda等人的US 4393076(对比组合物2)制备对比实施例组合物。具体来说,使用下述组分。
对比组合物1:
酮洛芬 2.5 wt%
乙醇 44.2 wt%
水 37.5 wt%
对羟基苯甲酸甲酯 0.1 wt%
对羟基苯甲酸甲酯 0.1 wt%
羟丙基纤维素 2.5 wt%
三乙醇胺 0.25 wt%
对比组合物2:
CARBOPOL 940
酮洛芬 2.5 wt%
乙醇 30 wt%
丙二醇 30 wt%
碳酸亚丙基酯 15 wt%
羟丙基纤维素 2 wt%
水 20 wt%
如实施例1所述,测定这些比较实施例组合物的酮洛芬皮肤渗透。所得结果如下表7所示。表7:对比实施例酮洛芬累积渗透量(μg/cm2)
小时 对比组合物1 对比组合物2
1 0 0
2 0 0
4 4 0.4
8 15 5.5
20 73 36
24 103 64
在附图8中,通过曲线图比较表7数据和所选组合物的数据。渗透数据表明,与用作对比的现有技术组合物相比,本发明组合物递送了更多的NSAI药物、递送速度更快。
实施例25:布洛芬组合物EE
用下面表8所示组分制备组合物EE。所用聚合物皮肤渗透促进剂是聚丙烯酸聚合物(CARBOPOL940)。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述,采用与酮洛芬所用技术相同的技术测定布洛芬皮肤渗透。
比较布洛芬从组合物EE和市售外用Ibuleve制剂(DiomedDevelopment Ltd.(Hitchin,United Kingdon))中的渗透情况。与该市售组合物相比,布洛芬从组合物EE中渗透的更快。所得结果如下表9和附图9所示。
实施例26:布洛芬组合物FF
用下面表8所示组分制备组合物FF。所用聚合物皮肤渗透促进剂是黄原胶(KELTROL T)。所用亲脂性溶剂是乙醇和肉豆蔻酸异丙酯的混合物。如实施例1所述测定布洛芬皮肤渗透。所得结果如下表9和附图9所示。
与市售组合物相比,布洛芬从组合物FF中渗透的更快。
实施例27:布洛芬组合物GG
用下面表8所示组分制备组合物GG。所用聚合物皮肤渗透促进剂是黄原胶(KELTROL T)。所用亲脂性溶剂是乙醇、异丙醇和肉豆蔻酸异丙酯的混合物。所得结果如下表9和附图9所示。
与市售组合物相比,布洛芬从组合物GG中渗透的更快。
表8:布洛芬组合物
组分(wt%) EE FF GGA部分: CARBOPOL 940 2 - -
黄原胶 - 2 2
水 63 63 63B部分: 布洛芬 5 5 5
乙醇 30 30 15
异丙醇 - - 15
肉豆蔻酸异 5 5 5
丙酯表9:布洛芬累积渗透量(μg/cm2)小时 市售组合物 EE FF GG
1 14 327 92 114
2 32 620 250 255
4 66 1039 536 532
8 135 1561 1039 994
20 334 2383 2105 2015
24 397 2657 2428 2352
实施例28:用人皮肤对比
为了进一步评价本发明组合物的有效性,用人皮肤测定市售酮洛芬外用组合物(Profenid)和组合物Q的酮洛芬渗透情况。
具体来说,使用热分离技术制备人胸部皮肤样本。将人皮肤样本在60℃的水中浸泡60秒。小心地将表皮膜从下面真皮上挑下来,并用水洗涤。在空气中干燥后,把样本在干燥器中放置24小时,然后在冰箱中贮存。测试前,把皮肤片从冰箱中取出,在室温放置4小时,并在缓冲溶液中水合30分钟。接下来把皮肤片固定在Franz-型渗滤池(表面积为1.8cm2)中,如实施例1所述进行评价。把所得结果制成表(表10),并在附图10中以曲线图表示。表10:人皮肤测试酮洛芬累积渗透量(μg/cm2)
小时 组合物Q 市售组合物
1 34 0
2 112 0
4 302 0
8 800 2
20 1434 8
24 1764 13
所得结果证实了蛇皮测试的结果,组合物Q递送酮洛芬的速度很快,并且与市售组合物相比要快很多。
上述实施例只是为了举例说明本发明,而不是限制本发明。在不背离本发明实质和范围的情况下,可对本发明进行许多改变和修饰。
Claims (18)
1.具有半固体稠度的、适于外用的水性药物组合物,其中包含:
非甾体消炎药物;
其含量足以增强所述非甾体消炎药物穿透皮肤的非碱性聚合物皮肤渗透促进剂,其中所述聚合物皮肤渗透促进剂选自可分散在水中的酸性聚合物、多糖胶、和它们的混合物;和
亲脂性溶剂,其中所述亲脂性溶剂是C2-C8脂肪醇与C8-C30脂族酯的混合物。
2.权利要求1的组合物,其中所述消炎药物是异丁苯乙酸类消炎药物。
3.权利要求1的组合物,其中所述消炎药物是芳基丙酸衍生物。
4.权利要求1的组合物,其中所述非甾体消炎药物选自克利洛芬、非诺洛芬、氟比洛芬、布洛芬、酮洛芬、芬布芬、阿氯芬酸、氨芬酸钠、芬氯酸、异丁苯乙酸、萘普生、甲基萘丙醇、和双氟尼酸。
5.权利要求1的组合物,其中所述消炎药物是酮洛芬。
6.权利要求1的组合物,其中所述消炎药物是布洛芬。
7.权利要求1的组合物,其中所述消炎药物是炎痛喜康。
8.权利要求1的组合物,其中所述聚合物皮肤渗透促进剂是聚丙烯酸。
9.权利要求1的组合物,其中所述聚合物皮肤渗透促进剂是卡波姆。
10.权利要求1的组合物,其中所述聚合物皮肤渗透促进剂是半乳甘露聚糖胶。
11.权利要求10的组合物,其中所述半乳甘露聚糖胶是瓜尔胶。
12.权利要求10的组合物,其中所述半乳甘露聚糖胶是刺槐豆胶。
13.权利要求1的组合物,其中所述聚合物皮肤渗透促进剂是选自琼脂胶、藻酸盐、角豆树胶、角叉菜胶、茄替胶、瓜尔胶、刺梧桐胶、卡塔亚胶(kadaya gum)、刺槐豆胶、鼠李糖胶(rhamsan gum)、黄原胶、和它们的混合物的多糖胶。
14.权利要求1的组合物,其中所述聚合物皮肤渗透促进剂是纤维素衍生物。
15.权利要求15的组合物,其中所述纤维素衍生物选自乙基纤维素、甲基纤维素、羟丙基纤维素、及它们的混合物。
16.权利要求1的组合物,其中所述C2-C8脂肪醇选自乙醇、正丙醇、异丙醇、丙二醇、甘油、和它们的混合物。
17.权利要求1的组合物,其中所述C2-C30脂族酯选自乙酸乙酯、乙酸丁酯、月桂酸乙酯、丙酸甲酯、丙酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、和它们的混合物。
18.权利要求1的组合物,其中所述组合物还含有能给所述组合物提供约3-约7.4的缓冲pH值的缓冲系统。
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US08/965,001 US6083996A (en) | 1997-11-05 | 1997-11-05 | Topical compositions for NSAI drug delivery |
US08/965,001 | 1997-11-05 |
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US (1) | US6083996A (zh) |
EP (1) | EP1028710A4 (zh) |
JP (1) | JP2001521887A (zh) |
KR (1) | KR100621817B1 (zh) |
CN (1) | CN1198586C (zh) |
BR (1) | BR9813947A (zh) |
CA (1) | CA2309178C (zh) |
HK (1) | HK1034898A1 (zh) |
IL (1) | IL135886A (zh) |
TR (1) | TR200002159T2 (zh) |
TW (1) | TW522021B (zh) |
WO (1) | WO1999022716A1 (zh) |
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- 1998-11-05 KR KR1020007004899A patent/KR100621817B1/ko not_active IP Right Cessation
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CN101052384B (zh) * | 2004-11-05 | 2011-07-27 | 立德化学株式会社 | 含有非甾体类抗炎镇痛药的非水系透皮吸收制剂 |
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TR200002159T2 (tr) | 2000-11-21 |
EP1028710A1 (en) | 2000-08-23 |
EP1028710A4 (en) | 2006-03-15 |
WO1999022716A1 (en) | 1999-05-14 |
IL135886A0 (en) | 2001-05-20 |
KR100621817B1 (ko) | 2006-09-13 |
BR9813947A (pt) | 2002-01-15 |
CN1198586C (zh) | 2005-04-27 |
CA2309178C (en) | 2008-04-29 |
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CA2309178A1 (en) | 1999-05-14 |
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