CN1308548A - 粘合剂微球药物输递组合物 - Google Patents
粘合剂微球药物输递组合物 Download PDFInfo
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- CN1308548A CN1308548A CN99808170A CN99808170A CN1308548A CN 1308548 A CN1308548 A CN 1308548A CN 99808170 A CN99808170 A CN 99808170A CN 99808170 A CN99808170 A CN 99808170A CN 1308548 A CN1308548 A CN 1308548A
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- Prior art keywords
- acrylate
- compositions according
- microsphere
- acid
- medicine
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Abstract
本发明揭示了透皮药物输递组合物,它包括压敏粘合剂微球,所述的微球含有软化剂和/或药物。典型的是,微球含有至少10重量%软化剂。药物和/或软化剂可在它们形成时或形成后掺入微球。
Description
发明领域
本发明涉及含有压敏粘合微球的透皮药物输递组合物,所述的微球含有软化剂和/或治疗剂。本发明另外涉及在原处制备含有软化剂和/或治疗剂的压敏粘合微球的方法。
发明背景
本技术领域已知本身具有粘性的压敏粘合剂微球能用于可再放置的压敏粘合使用中,有许多文献讨论了本身具有粘性、弹性的聚合微球的制备和/或应用。压敏粘合剂微球可为固体或空心的,在一定程度上交联,结果粘合剂的特定性质能在加工和使用过程中得以保持。典型的是这样制备压敏粘合剂:在表面活性剂和/或悬浮液稳定剂存在下,使一种或多种游离基可聚合的单体悬浮聚合。选择表面活性剂和/或悬浮液稳定剂以及它们与特定单体的特定组合可决定悬浮稳定性、所需的颗粒形状、性能特性等。
将各种可共聚合的单体组份加入游离基可聚合单体、悬浮稳定剂和/或表面活性剂以改变这些悬浮聚合微球的粘合性质。例如,将含氮极性单体加入无酸的丙烯酸酯悬浮聚合混合物中,以形成含有多个内部空隙的粘合微球。没有可解离质子或可解离质子水平很低的极性共聚单体当与特定的表面活性剂和聚合稳定剂组合使用时,可加入悬浮可聚合配方中,得到粘合性质增强、同时保持了它们对各种表面的再放置性和自身清洁质量的粘合微球。
可共聚的或者以其它方法掺入的低聚的和聚合的添加剂已用于悬浮聚合的粘合微球里,以改变微球的粘合性质和其它的性能特性。悬浮可聚合粘合微球配方中已经包括亲水低聚物和聚合物以提供改进的微球稳定性,在一些制剂中改进其水可分散性。水不溶的聚合组份也已经通过(甲基)丙烯酸烷酯和其它共聚单体在这类聚合组份存在下的悬浮聚合而掺入粘合微球。该掺入方法能使水不溶聚合物组份包含于粘合微球里,而它在标准的游离基悬浮聚合条件下通常不能混入所述的粘合微球。该水不溶聚合物混入的另一个优点是修饰微球的物理和粘合性质。最后,在悬浮聚合期间也可加入结晶聚合物或可结晶的单体,以给出具有热控成形记忆的粘合微球。
药物和其它治疗活性剂可用各种方法和设备进行透皮或经皮给药。一个已知的方法是将药物或药物与一种或多种增加药物跨越皮肤输递的赋形剂的组合物混入连续的粘合剂基质。这类系统的例子可参见,如Nelson等,美国专利5,223,261和Peterson,美国专利5,494,680。
现有技术中也试图开发出用压敏粘合剂颗粒代替连续粘合剂基质的透皮药物输递系统。例如,JP 58-12255揭示了一种由丙烯酸聚合物颗粒构成的粘合带或片,它含有诸如类固醇的药物。EP 793,972揭示了含有细粉化丙烯酸酯粘合剂颗粒与药物组合的透皮药物输递装置。
发明概述
本发明透皮药物输递组合物包括压敏粘合剂微球,包括(a)至少10wt%混入微球的软化剂,任选地还包括(b)治疗有效量的药物。
使用本文揭示的聚合微球使配制的透皮药物输递组合物具有高度的挠性。特别是,本发明的透皮药物输递组合物可以耐受相对大量的软化剂而不损失粘着强度。对软化剂或赋形剂的耐受性使药物能通过皮肤优良地输递药物而不损伤粘合性质。
本发明也提供了透皮药物输递装置,包括由压敏粘合剂微球构成的透皮药物输递组合物,它包含(a)混入微球的至少10wt%软化剂,并任选地包含(b)放置在背衬上的治疗有效量的药物。
本发明的另一方面提供一种制备透皮药物输递组合物的方法,包括下列步骤:
a)形成油相,所述的油相包括一种或多种丙烯酸酯、甲基丙烯酸酯或乙烯酯单体,单独或其任何组合;非反应性、油溶的软化剂和/或药物;和一种在包括至少一种悬浮稳定剂或表面活性剂的水性介质的水相里的油溶游离基引发剂,和
b)引发水相里的油相的聚合,从而形成粘合剂微球透皮药物输递组合物。
除非特别指出,所有的重量百分数基于透皮药物输递组合物的总重量。
发明详述
本发明的透皮输递组合物可通过“加入后”方法形成,其中聚合的微球组份与软化剂和/或药物在使该软化剂和/或药物掺入微球的条件下混合。本发明制备透皮药物输递组合物的加入后方法包括下列步骤:
(a)提供聚合的微球组份;
(b)使聚合的微球组份与软化剂和/或药物,和任选的能溶解软化剂和/或药物和/或溶胀聚合微球组份的溶剂混合;和
(c)除去溶剂。
本发明组合物的聚合微球组份可通过悬浮、分散、直接乳液和改良乳液技术进行制备。优选的是,聚合微球组份根据如美国专利3,691,140;4,166,152;4,495,318;4,786,696;4,988,467;5,045,569;5,508,313;和5,571,617和PCT专利申请WO 96/01280;WO 97/46633;和WO 97/46634揭示的悬浮聚合方法来制备,所有文献并入本文供参考。优选的聚合微球组份由丙烯酸酯或乙烯酯微球构成。
在优选的悬浮聚合方法中,丙烯酸酯或乙烯酯微球可典型地通过形成包含(甲基)丙烯酸酯和/或乙烯酯单体的油相来制备,它任选地也含有可游离基聚合的极性共聚单体,和在包含有至少一种悬浮稳定剂或表面活性剂的水介质的水相里的油溶性游离基引发剂。根据单体、共聚单体、交联剂、低聚物或聚合添加剂、稳定剂、表面活性剂、反应条件和其它成份的类型和用量,和所用的其它方法,这些微球可能是空心的(即具有至少一个内孔隙或空腔的)或实心的(即没有内空隙或腔);水或溶剂可分散的;轻度或高度交联;并具有一定范围的直径(从约0.5-300微米)和聚合的形态。
用于丙烯酸酯微球的(甲基)丙烯酸酯单体是非叔烷醇的单官能团的不饱和(甲基)丙烯酸酯。这些醇类的烷基优选地含4-14个(更优选地含4-10个)碳原子。有用的单体例子包括丙烯酸仲丁酯、丙烯酸正丁酯、丙烯酸异戊酯、丙烯酸2-甲基丁酯、丙烯酸4-甲基-2-戊基酯、丙烯酸2-乙基己酯、丙烯酸异辛酯、丙烯酸异壬酯、甲基丙烯酸异癸酯、丙烯酸异癸酯、丙烯酸十二烷酯、丙烯酸十四烷酯和它们的混合物。特别优选的是丙烯酸正丁酯、丙烯酸仲丁酯、丙烯酸异戊酯、丙烯酸2-乙基己酯、丙烯酸异辛酯、丙烯酸异壬酯、丙烯酸异癸酯和它们的混合物。当然,最好的是丙烯酸异辛酯和丙烯酸2-乙基己酯。
用于提供乙烯酯微球的乙烯酯单体是衍生自直链或支链的、有1-14个,优选的是7-12个碳原子(羧基的碳原子不计算在内)的羧酸的不饱和的乙烯酯。合适的乙烯酯单体包括丙酸乙烯酯、壬酸乙烯酯、己酸乙烯酯、癸酸乙烯酯(vinyl caprate)、2-乙基己酸乙烯酯、辛酸乙烯酯、癸酸乙烯酯(vinyldecanoate)、月桂酸乙烯酯和它们的混合物。特别优选的是癸酸乙烯酯、2-乙基己酸乙烯酯、月桂酸乙烯酯和它们的混合物。
(甲基)丙烯酸酯或其它乙烯基单体,如丙烯酸乙酯、丙烯酸叔丁酯、丙烯酸异龙脑酯、甲基丙烯酸丁酯、乙酸乙烯酯、丙烯腈,它们的混合等,作为均聚物时,其玻璃转化温度高于-20℃到0℃,它们可用于与一种或多种(甲基)丙烯酸酯和乙烯酯单体配合使用,条件是所得微球的玻璃转化温度低于约0℃。
用于本发明的丙烯酸酯或乙烯酯微球可进一步包含与(甲基)丙烯酸酯或乙烯酯单体可共聚的可游离基聚合的极性共聚单体。可加入可游离基聚合极性共聚物以改进或修饰微球的粘着强度、贮存稳定性和玻璃转化温度。优选的是该极性单体的存在量按单体总重量来计,不多于约1-20重量份数。
除了与甲基(丙烯酸)酯或乙烯酯单体能共聚外,可游离基聚合的极性共聚单体是溶于油和水的单体,包括下列极性取代基之一:酰胺基团、腈基团、羟基和羧酸基团(包括酸式盐)。合适的极性单体类型包括单烯单羧酸、单烯二羧酸、它们的盐、丙烯酰胺、N-取代的丙烯酰胺、N-乙烯基内酰胺和前述物质的混合物。有用的极性单体的代表性例子包括丙烯酸、甲基丙烯酸、衣康酸、巴豆酸、马来酸、富马酸、甲基丙烯酸磺基乙酯、N-乙烯基吡咯烷酮、N-乙烯基己内酰胺、丙烯酰胺、叔丁基丙烯酰胺、二甲氨基乙基丙烯酰胺、N-辛基丙烯酰胺、丙烯酸羟基乙酯和甲基丙烯酸羟基乙酯。诸如甲基丙烯酸钠、丙烯酸铵、丙烯酸钠、三甲基胺对-乙烯基苯甲酰亚胺(benzimide)、N,N-二甲基-N-(β-甲氧基-乙基)丙酸铵甜菜碱、三甲胺甲基丙烯酰胺、1,1-二甲基-1-(2,3-二羟基丙基)胺甲基丙烯酸酰胺和它们的混合物的离子单体也可被使用。特别优选的极性共聚单体是丙烯酸、丙烯酸钠、N-乙烯基吡咯烷酮和它们的混合物。
用于本发明的聚合微球也可含有多官能团游离基可聚合的交联剂。这类交联剂通过使它们内在交联而增强单个微球的粘结强度和溶剂不溶性。“多官能团”指具有两个或多个游离基可聚合的烯不饱和基团的交联剂。有用的多官能团交联剂包括二醇(如丁二醇)、三醇(如甘油)和四醇(如季戊四醇)的(甲基)丙烯酸酯;聚合多官能团的(甲基)丙烯酸酯(如聚(环氧乙烷)二丙烯酸酯和聚(环氧乙烷)二甲基丙烯酸酯);多乙烯基化合物(如,取代和未取代的二乙烯基苯);二官能团聚氨酯丙烯酸酯;和它们的混合物。
使用交联剂时,典型的用量是最多达0.15当量重量百分数。在0.15当量重量%水平以上时,微球有失去它们压敏粘合性质的倾向,并最终在室温下对接触没有粘性。非粘性和粘性的微球均用于本发明。但交联水平影响颗粒的可溶胀性;交联程度越高,颗粒溶胀性越低。为了保证高的颗粒溶胀性并得到所需的流变性质,需要低水平的交联剂。
给定化合物的“当量重量百分数”被定义为在总的可聚合组合物里的该化合物的当量数除以游离基可聚合单体的当量总数。当量是克数除以当量重量。当量重量被定义为分子量除以单体中可聚合的基团数。若这些单体只有一个可聚合基团,当量重量等于分子量。
微球的交联也通过使用链转移剂进行控制。有用的链转移剂是一般适合于丙烯酸酯类游离基聚合反应的那些链转移剂。用于实施本发明的链转移剂包括,但不限于,四溴化碳、正十二烷基硫醇、异辛基硫代甘醇酸酯和它们的混合物。使用时,链转移剂的存在量占总可聚合组合物的约0.01-1%重量。
有用的油溶性游离基引发剂是适合用于丙烯酸酯或乙烯酯单体的游离基聚合的那些,它们是油溶性的,在水中的溶解度极低,典型的是20℃下低于1克/100克水。这类引发剂的例子是偶氮化合物、氢过氧化物、过氧化物等,光引发剂如苯酰苯、苯偶姻乙醚、2,2-二甲氧基-2-苯基乙酰苯。引发剂的用量通常占总的可聚合组合物的约0.01-10%重量,优选的是最高为5%。
使用基本上水溶性的聚合引发剂,如在乳化聚合中通常使用的聚合引发剂会形成有相当量的胶乳。在悬浮聚合期间,大量形成胶乳是不利的,因为其颗粒极小。
在反应混合物中一般存在表面活性剂,其存在量,按每100重量份可聚合单体计,优选地不大于约10重量份,更好是不大于约5重量份,最好是0.5-3重量份。
有用的表面活性剂(也称为乳化剂)包括阴离子、阳离子或非例子性表面活性剂,包括,但不限于,阴离子表面活性剂如烷基芳基醚硫酸盐和磺酸盐(诸如烷基芳基醚硫酸钠,如TritonTM X200,购自Rohm and Haas);烷基芳基聚醚硫酸盐和磺酸盐(诸如烷基芳基聚(环氧乙烷)硫酸盐和磺酸盐),优选的是有最多达四个环氧乙烷重复单元的烷基芳基聚(环氧乙烷)硫酸盐和磺酸盐;和烷基硫酸盐和磺酸盐(诸如月桂基硫酸钠、月桂基硫酸铵、月桂基硫酸三乙醇胺和十六烷基硫酸钠);烷基醚硫酸盐和磺酸盐(诸如月桂醚硫酸铵和烷基聚醚);和烷基聚醚硫酸盐和磺酸盐(诸如烷基聚(环氧乙烷)硫酸盐和磺酸盐),优选的是有最多达约4个环氧乙烷单元的烷基聚(环氧乙烷)硫酸盐和磺酸盐。优选的是硫酸烷酯、烷基醚硫酸盐和烷基芳基醚硫酸盐。其它阴离子表面活性剂包括,如烷基芳基硫酸盐和磺酸盐,如十二烷基苯硫酸钠和十二烷基苯磺酸钠,烷基硫酸钠盐和铵盐,如月桂基硫酸钠和月桂基硫酸铵;非离子表面活性剂,如乙氧基化的油醇和聚环氧乙烷辛基苯基醚;和阳离子表面活性剂,如烷基二甲基苄基氯化铵(其中烷基有10-18个碳原子)的混合物。两性表面活性剂也可用于本发明,包括,磺基甜菜碱、N-烷基氨基丙酸和N-烷基甜菜碱。
任选的是,可使用聚合稳定剂,若使用时,其存在量按每100重量份微球来计,为约0.05-3重量份,优选的是约0.1-1.5重量份。有利的是,稳定剂的存在可以使用相对少量的表面活性剂而仍然得到微球。
本发明中可使用能给最终聚合小滴提供足够的稳定并防止在悬浮聚合中聚集的任何聚合稳定剂。
聚合稳定剂的例子包括重均分子量大于5000的聚丙烯酸盐(例如铵盐、钠盐、锂盐和钾盐)、聚乙烯基醇、羧基改性的聚丙烯酰胺(例如购自美国氰胺公司的CyanamerTM A-370),丙烯酸和二甲氨基乙基甲基丙烯酸酯的共聚物等,聚合季胺类(如General Analine和Film’s GafquatTM 755,一种四级化的聚乙烯基-吡咯烷酮共聚物,或Union Carbide的″JR-400″,一种季铵取代的纤维素),纤维素类,和羧基改性的纤维素类(例如,Hercules’NatrosolTMCMC型7L,羧甲基纤维素钠)。
微球成珠子或珍珠状,但它们更可能是球体。典型的是,溶胀前它们的体积平均直径为约0.5-300微米(更典型的是,约1-100微米)。微球可为实心、空心或它们的混合,优选的是弹性体。本文使用的“弹性体”表示可拉伸并在施加的力释放后可迅速缩回它们基本上的初始尺度的无定形或非结晶材料。空心微球含有一个或多个空隙;即一个或多个完全在聚合微球壁里的空间。典型的是,空心部分的平均直径低于100微米。
在一些应用中,包含空心微球的微球组份是优选的,因为可将软化剂和/或药物负载在微球和交联的微球基质里的空腔中。若需要空心微球,可通过,如美国专利4,968,562揭示的“两步方法”或美国专利5,053,436揭示的“一步方法”得到,这些专利在此并入本文供参考。
实心微球可通过使用足以产生所需的颗粒的量(通常在临界胶束浓度附近)的离子或非离子的乳化剂的悬浮聚合技术进行制备。
直到油相(甲基)丙烯酸酯或乙烯基单体已经被引发前,通过停止加入所有或部分游离基可聚合的极性共聚体或其它反应性组份可修饰每个悬浮聚合方法(是否产生空心或实心微球)。但是,在此情况下,在(甲基)丙烯酸或乙烯酯单体100%转化前,必须将这些组份加入聚合混合物。同样,多官能可自由基聚合的交联剂(如果使用的话)可在微球组合物的单体100%转化为为聚合物之前的任何时间加入优选的是在引发前加入交联剂。
聚合后,在室温下得到稳定的微球水悬浮液。悬浮液可有约10-60%重量的非挥发性固体含量。在延长的放置中,悬浮液典型地分成两相,一相为水性的,基本上没有聚合物,另一相是聚合微球的水悬浮液,即富微球相。分离富微球相得到有非挥发固体内含物的水悬浮液。或者,若需要,在与软化剂和/或药物混合前,可在有机溶剂里分离微球,形成溶剂分散液。
一旦制得,或作为水悬浮液的纯净物,或作为溶剂分散液的微球组份与软化剂和/或药物混合。
本文使用的术语“治疗有效量”表示能有效地让组合物向对象输递足量的药物以得到治疗疾病下所需的治疗结果。该量根据所用药物的类型、被治疗的疾病、组合物与对象皮肤接触允许的时间和其它本技术领域公知的因素而改变。但是,本发明透皮药物输递组合物中药物存在量,按组合物的总重量计,一般为约0.01-40重量%,优选的是约0.5-10重量%。
适合用于透皮输递的任何药物可用于本发明的透皮药物输递组合物。有用的药物例子包括,但不限于,抗炎药物,甾族抗炎药物(如氢可的松、强的松龙、己酸丙炎松)和非甾族抗炎药物(如甲氧萘丙酸、吡氧噻嗪);抑菌剂(如洗必太、己雷锁辛);抗菌剂(如诸如青霉素V的青霉素、诸如头孢氨苄的头孢菌素、红霉素、四环素、庆大霉素、磺胺噻唑、硝基呋喃妥因,和诸如诺氟沙星、氟甲喹和ibafloxacin的喹诺酮);抗原生动物剂(如,甲硝哒唑);抗真菌剂(如,制霉菌素);冠状动脉扩张剂(如硝酸甘油);钙通道阻断剂(如硝苯吡啶、硫氮酮);支气管扩张剂(如,茶碱、吡丁醇、沙美特罗、异丙肾上腺素);诸如胶原酶抑制剂、蛋白酶抑制剂、弹性蛋白酶抑制剂、脂肪氧合酶抑制剂的酶抑制剂(如zileuton)和血管紧张素转化酶抑制剂(如卡托普利、赖诺普利);其它的抗高血压药(如,心得安);白三烯拮抗剂;诸如H2拮抗剂的抗溃疡药;甾族激素(如孕酮、睾丸酮、雌二醇);抗病毒剂和/或免疫调节剂(如,1-异丁基-1H-咪唑并[4,5-c]喹啉基-4-胺、1-(2-羟基-2-甲丙基)-iH-咪唑并[4,5-c]喹啉基-4-胺和美国专利4,689,338揭示的其它化合物,在此并入供参考,无环鸟苷);局部麻醉药(如苯并卡因、propofol);强心剂(如洋地黄、地高辛);止咳药(如可待因、右甲吗喃);抗组胺药(如苯海拉明、扑尔敏、丁苯哌丁醇);镇静止痛剂(如吗啡、芬太尼);肽激素(如人体或动物体生长激素,LHRH);性激素(如雌激素、睾丸激素、孕激素,如左旋18-甲基炔诺酮、炔诺酮、甲地妊娠素);诸如心房肽的心脏活性产物;蛋白质类产品(如胰岛素);酶(如抗斑酶、溶菌酶、葡聚糖酶);抗呕吐药(如东莨菪碱);抗惊厥药(如乙胺嗪);免疫抑制剂(如环孢素);精神治疗药(如,安定);镇静剂(如,苯巴比妥);抗凝血剂(如肝素);止痛剂(如扑热息痛);抗偏头痛药(如麦角胺、褪黑激素、舒马坦);抗无节律药(如哌氟酰胺);抗呕吐药(如metaclopromide、奥丹亚龙);抗癌药(如甲氨蝶呤);诸如抗焦虑药物的精神学上的营养药;止血药;抗肥胖药等以及它们药学上可接受的盐和酯。优选的药物包括睾丸酮、左旋18-甲基炔诺酮、雌二醇和甲地妊娠素。
合适的软化剂包括已用作透皮药物输递系统里的皮肤渗透增强剂或稳定剂的特定的药学上可接受的物质。例举性的物质包括C8-C36脂肪酸,如异硬脂酸、辛酸和油酸;C8-C36脂肪醇,如油醇和月桂醇;C8-C36脂肪酸的低级烷酯,如油酸乙酯、肉豆蔻酸异丙酯、硬脂酸丁酯和月桂酸甲酯;C6-C8二酸的二(低级)烷酯,如己二酸二异丙酯;C8-C36脂肪酸的单甘油酯,如单月桂酸甘油酯;四氢呋喃醇聚乙二醇醚;C6-C36烷基吡咯烷酮羧酸酯;聚乙二醇;丙二醇;2-(2-乙氧基乙氧基)乙醇;二乙二醇单甲醚;N,N-二甲基十二烷基胺-N-氧化物和前述物质的组合。聚环氧乙烷的烷基芳基醚、聚环氧乙烷单甲醚和聚环氧乙烷二甲醚也适合作为诸如甘油和N-甲基吡咯烷酮的增溶剂。萜是另一类软化剂,包括蒎烯、d-1,8-萜二烯、蒈烯、萜品醇、萜品烯-4-醇、香芹醇、香芹酮、长叶薄荷酮、薄荷酮、酮、醇、新醇、百里酚、樟脑、冰片、柠檬醛、紫罗酮和桉树脑,单独使用或组合使用。在萜中,优选的是萜品醇,特别是α-萜品醇。
特定的药物物质具有软化剂的功能,因而使之不再需要分开的药物和软化剂组份。这类软化的药物包括烟碱、硝酸甘油、扑尔敏、烟酸苄酯、邻甲苯海拉明、东莨菪碱和丙戊酸。若软化药物是唯一存在的软化剂,则其存在量,按透皮药物输递组合物总量来计,至少为10重量%。若除了软化药物外还存在其它软化剂,则软化剂的总量为至少10重量%。人们可以明白,可以使用软化剂和/或软化药物的任何组合。
优选的软化剂包括单月桂酸甘油酯、萜品醇、月桂醇、己二酸二异丙酯、丙二醇、肉豆蔻酸异丙酯、油酸乙酯、月桂酸甲酯、2-(2-乙氧基乙氧基)乙醇和油醇。
虽然许多上述软化剂会影响皮肤的渗透速率,但特定的软化剂会影响除了皮肤渗透速率外的性能。例如,它们在软化和增加柔量值和/或降低否则为不柔顺的(和因此是非压敏粘合的)聚合物的玻璃转化温度,使它们适合用作压敏皮肤粘合剂。虽然这类软化剂已知对透皮基质的性能有不利的影响,如使它们软化至内聚破坏点(此时在从皮肤上除去含聚合物的装置后在皮肤上留下大量的聚合物残留物),或从组合物的连续相里分离出来,但使用本发明的微球能包含相当大量的软化剂而没有这些不利影响。
透皮药物输递组合物所需的性质是本技术领域公知的。例如,组合物需要与皮肤密切接触,以便以稳定的速率输递药物。组合物需要具有极小的冷流动即在贮存时不发生流动,还优选的是它粘附于皮肤并从皮肤上清洁地脱去。为了达到皮肤接触、清洁脱去、优选的粘合水平和对冷流动的耐受力,可选择聚合微球中单体的用量和结构和软化剂的用量和结构以使组合物的柔量值(按照下述试验方法进行测定)的范围约3×10-6-1×10-3厘米2/达因,优选的是约1×10-5-5×10-4厘米2/达因,最好是约1×10-5-5×10-5厘米2/达因。从适合用作压敏粘合剂透皮输递组合物的组合物中有时得到了超出上述较宽范围的柔量值。但是,这些具有明显很较柔量值的组合物一般相对僵硬,与皮肤的接触和粘合较差。柔量值很高的组合物的冷流动性较不理想,从皮肤上取出时会留下明显的残留物。
为了增加药物的输递并保持可接受的粘合性能,软化剂的存在量,按透皮药物输递组合物总重量来计,为至少10重量%。软化剂优选的用量为约15-50重量%,更优选的是约25-50重量%。
软化剂和任选的药物一般在溶剂里混合,并按上述方法掺入组合物的微球组份。但是,也可这样制备合适的组合物:分别将药物和软化剂掺入微球,然后混合药物/微球和软化剂/微球混合物,以得到最终组合物。或者,含软化剂的微球与药物和常规的(即非微球的)粘合剂混合,得到最终的组合物。
在本发明的另一方面中,通过向游离基可聚合悬浮混合物里加入所有或其中部分的软化剂和/或药物的前述悬浮聚合方法的改良法来制备透皮药物输递组合物。用于该方法中的软化剂和药物(若有的话)应当足以溶于油以便在悬浮聚合混合物的油相里是相溶混的,且在游离基聚合和其它反应条件下是非反应性的。“非反应性的”表示软化剂或药物不含烯不饱和键或其它能共同反应的官能团,或干扰游离基反应性悬浮混合物的聚合的官能团,和/或在反应条件下不明显地破坏软化剂或药物的性能。
本发明在原处制备透皮药物输递组合物的方法包括下列步骤:
(a)形成包含(甲基)丙烯酸酯和/或乙烯基酯单体和非反应性的、油溶性的软化剂和/或药物的油相,和在水相里的油溶的游离基引发剂,所述的水相包含有至少一种悬浮稳定剂或表面活性剂的水介质;
(b)引发油相在水相里聚合;
(c)向原处聚合的粘合微球透皮药物输递组合物里任选地加入另外的非反应性、油溶的软化剂和/或药物。
用作涂覆了本发明透皮药物输递组合物的透皮药物输递装置的背衬可为常规地用作带背衬的材料或可为基本上对透皮药物输递组合物组份是惰性的其它弹性材料。这类背衬包括,但不限于,由选自聚(丙烯)、聚(乙烯)、聚(氯乙烯)、聚酯(如聚(对苯二甲酸亚乙酯),如″Scotch″膜8050,购自3M))、诸如购自DuPont Co.(美国DE,Wilmington)的商品名为“KAPTON”的聚酰胺膜、乙酸纤维素和乙基纤维素制成的材料。背衬也可为由合成或天然材料,诸如棉花、尼龙、人造纤维、玻璃陶瓷材料的线形成的纺织织物,或可为诸如天然或合成纤维的空气铺垫的无纺织物,或这些的混合物。另外,背衬可由选自金属、金属化聚合薄膜和陶瓷片材料的材料形成。
优选的材料包括,但不限于,塑料,如聚乙烯、聚丙烯、聚酯、乙酸纤维素、聚(氯乙烯)和聚(1,1-二氟乙烯),以及用这类塑料涂覆和成层的纸张或其它基片。这些涂覆的纸张或热塑性薄膜常常被硅氧烷化,或被其它方法处理以赋予改进的释脱特性。背衬或衬里的一面或两面具有这类释脱的特性。
本发明的装置具有各种结构型态。组合物可以单层存在,其中组合物由含有软化剂和/或药物的微球组成;由含软化剂的微球和含药物的微球的混合物组成;或由与药物和常规粘合剂混合的含软化剂的微球组成。也可以在多层里使用本发明的组合物。例如,含软化剂微球层可与在常规的粘合剂中的药物层成层或与含药物的微球层成层。这些层的厚度可以是均匀的,或它们可按一个或多个梯度排列。另外的层可为诸如稀松的平纹棉织物、膜等物质。所有对含软化剂的微球的论速也包括含有软化剂和药物的微球。
用于制备本发明粘合制品的典型的涂覆方法包括溶剂涂覆和水基涂层和本技术领域公知的常规技术。
本发明的目的和优点可由下列实施例作进一步的阐述。实施例中应用的特定材料和用量以及其它调节和细节并非用来限定本发明。除非进行陈述或表述,所有的材料是市售可得的。除非特别指出,用于本文的所有份数和百分数以重量为基。
柔量试验方法
用美国专利4,737,559揭示的蠕变柔量方法的修改版可得到下列实施例的柔量值。脱模衬里从被试验材料样品上除去。暴露的表面纵向地向回折叠,得到“三明治”结构,即背衬/粘合剂/背衬。该“三明治”样品通过层压机,然后用矩形模头切下两个等面积的试验样品。把试验样品放在剪切-蠕变流变仪固定平板的中心,试验样品的长轴放在平板短轴的中心。剪切-蠕变流变仪的非固定小平板被放在在固定平板上的第一样品中心上,使钩向上,对着流变仪前面。第二试验样品放在非固定大平板上表面的中心,与第一试验样品轴向相配。非固定大平板放在第二试验样品上方,整个组件被夹紧定位。与钩子末端相反的非固定小平板末端与图表记录仪连接。弹簧与非固定小平板的钩子连接,并延伸到流变仪的前滑轮上。在弹簧的游离端连接重物(如500克)。图表记录仪开始记录,同时迅速释放重力使其自由悬挂物。在整3分钟后除去重力。从图表记录仪里读取移动值。然后用下列等式计算柔量值: 其中A是试验样品一面的面积,h是粘合剂物料的厚度(即试验样品上粘合层厚度的两倍),X是移动值,f是与弹簧连接的质量施加的力。其中A表达为厘米2,h为厘米,X为厘米,f为达因,柔量值的单位为厘米2/达因。
体外皮肤渗透试验方法
用下列试验方法得到下面实施例里给出的皮肤渗透数据。使用带有无毛小鼠皮肤的扩散池。
评价透皮输递装置时,从2.0厘米2的贴片上除去脱模衬里,然后将该贴片贴到皮肤上,加压使之与皮肤均匀接触。将所得的贴片/皮肤叠层按贴片面朝上放,使它跨越扩散池下部小孔。组装扩散室,其下部充满10毫升温热的(32℃)接受液体,使接受液体与皮肤接触。用磁搅拌器搅拌接受液体。除了使用外覆盖取样口。
该扩散池然后放在恒温(32℃±2℃)和恒湿(50±10%相对湿度)室里。接受液体在整个实验中用磁搅拌器搅拌,以保证样品均匀并降低皮肤真皮面的扩散屏障。以特定的间隔取出接受液体的整个体积并马上用新鲜液体替代。取出的液体通过0.45μM过滤器过滤,然后用高效液相色谱分析药物含量。计算药物渗透过皮肤的累积量和通透率。
药物释放试验
用下列试验方法得到实施例里给出的药物释放数据。
将带有药物的微球涂覆在2密耳(51微米)聚酯背衬上,然后在185°F(85℃)的烘箱上干燥20分钟,在210°F(99℃)的烘箱上干燥20分钟。从干燥的织物切下一片贴片(5厘米2)。用双面粘合带将贴片紧固在不锈钢板上,使药物微球粘合层暴露于释放介质。不锈钢板浸在30%乙醇水性释放介质里。在整个实验过程中,使介质保持在32℃,通过磁搅拌器以中速(75rpm)搅拌。在特定的时间点,取出2毫升释放介质,马上用2毫升新鲜介质替代。取出的介质经0.22微米滤器过滤,除去任何颗粒,然后用高效液相色谱分析药物含量。计算释放药物的累积量。
粘着试验方法
用数字化Polyken探头粘着试验器,型号80-02-01(Testing Machines,Inc.,美国纽约)得到下列实施例里报告的粘着值。机器设置如下:速度:0.5cm/秒,逗留时间:2秒;模式:峰值。采用不锈钢探头。试验的结果是打破探头和试验样品表面间的粘结所需的力。该力以“粘着克”进行测定。
实施例1
向装有机械搅拌器、冷凝器和供真空和氩气入口-出口的管道的1升隔板式反应烧瓶里加入450克去离子水和6.0克月桂基硫酸铵(StandpolTMA,购自Henkel AG)。使反应器脱气,然后用氩气再填充。在400rpm下搅拌,使反应器加热到68℃。在反应罐里制备含141克丙烯酸异辛酯、9克丙烯酸和0.71克过氧化苯甲酰(Lucidol-70,购自Elf Atochem)的混合物。引发剂溶解后混合物倒入68℃下的反应器里。然后使反应器温度设置到65℃持续22小时。聚合期间保持氩气冲洗。22小时后,将悬浮液冷却到室温。然后倒空反应器,用十六烷基三甲基氯化铵凝结悬浮液,然后收集。所得的微球(94∶6丙烯酸异辛酯:丙烯酸)具有空心形态,粒径为45.5微米。微球用异丙醇洗涤,使用前再分散于异丙醇。
这些微球用于制备含左旋18-甲基炔诺酮和肉豆蔻酸异丙酯的粘合微球输递系统。通过将0.0252克左旋18-甲基炔诺酮溶于1.0克甲醇来制备左旋18-甲基炔诺酮的甲醇溶液。合并肉豆蔻酸异丙酯(0.5549克)、5.0克微球(14.75克在异丙醇里的分散液,有33.9%固体)和35.0克乙酸乙酯,在混合台上混合至少16小时。使25.15克所得混合物部分与左旋18-甲基炔诺酮溶液混合,在混合台上混合至少16小时。所得的制剂用27密耳(686微米)模口隙距的刀涂在硅氧烷脱模衬里上,在110°F(43℃)下烘20分钟。所得的粘合剂涂层含有1%左旋18-甲基炔诺酮、10%肉豆蔻酸异丙酯和89%粘合剂。涂层是均匀的,显微镜检查显示它基本上没有药物晶体。涂覆的衬里被层压到聚酯背衬上。
实施例2-5
用实施例1的一般方法和相同的微球粘合剂,制备一系列输递系统,其中肉豆蔻酸异丙酯的用量发生改变。在所有的情况下,粘合剂涂层含有1重量%左旋18-甲基炔诺酮,粘合剂是94∶6的IOA∶AA空心微球。肉豆蔻酸异丙酯的重量百分数列于表1和2。
用上述试验方法测定实施例1-5输递系统的粘着和柔量。结果如下表1所示,其中每个粘着值为5个独立测定的平均值,每个柔量值是3个独立测定值的平均值。
表1
实施例序号 | 肉豆蔻酸异丙酯(重量百分数) | 粘着(克) | 柔量(cm2/达因) |
1 | 10 | 294 | 0.92×10-5 |
2 | 20 | 235 | 1.23×10-5 |
3 | 30 | 227 | 3.42×10-5 |
4 | 40 | 141 | 3.97×10-5 |
5 | 50 | 112 | 6.36×10-5 |
用上述试验方法测定来自实施例1-5输递系统的左旋18-甲基炔诺酮通过无毛小鼠皮肤的渗透。接受溶液是30%重量m-pyrol的水溶液。在含量分析前使样品冷藏,贮存时间不超过两天。结果显示于下表2,其中每个流量值是3个独立测定值的平均值。0-24小时值是整个24小时期间的平均值。
表2
实施例序号 | 肉豆蔻酸异丙酯(wt%) | 流量(微克左旋18-甲基炔诺酮/cm2/小时)0-8小时 8-24小时 0-24小时 | ||
1 | 10 | 0.27 | 0.30 | 0.29 |
2 | 20 | 0.32 | 0.37 | 0.36 |
3 | 30 | 0.22 | 0.32 | 0.28 |
4 | 40 | 0.31 | 0.40 | 0.37 |
5 | 50 | 0.42 | 0.43 | 0.43 |
实施例6
向装有机械搅拌器、冷凝器和供真空和氩气入口-出口的管道的1升隔板式反应烧瓶里加入450克去离子水和6.0克月桂基硫酸铵(StandpolTMA)。使反应器脱气,然后用氩气再填充。在400rpm下搅拌,使反应器加热到68℃。在反应罐里制备含141克丙烯酸异辛酯、9克丙烯酸和0.71克过氧化苯甲酰(Lucidol-70)的混合物。引发剂溶解后混合物倒入68℃下的反应器里。然后使反应器温度设置到65℃持续22小时。聚合期间保持氩气冲洗。22小时后,将悬浮液冷却到室温。然后倒空反应器,用十六烷基三甲基氯化铵凝结悬浮液,然后收集。所得的微球(94∶6丙烯酸异辛酯∶丙烯酸)具有多孔隙空心形态,粒径为64.4微米。微球用异丙醇洗涤,使用前再分散于异丙醇。
这些微球用于制备含睾丸酮的粘合微球输递系统。通过将0.977克睾丸酮与23.445克微球(85.63克在异丙醇里的分散液,有27.38%固体)混合,然后在混合台上混合至少16小时来制备4%w/w睾丸酮在微球粘合剂里的混合物。使(7.38克)所得混合物部分与15.0克乙酸乙酯混合。所得的制剂用27密耳(686微米)模口隙距的刀涂在硅氧烷脱模衬里上,在110°F(43℃)下烘20分钟。所得的粘合涂层含有4%睾丸酮和96%粘合剂。涂层是均匀的,显微镜检查显示它基本上没有药物晶体。涂覆的衬里被层压到聚酯背衬上。
实施例7
如下制备含睾丸酮和萜品醇的粘合微球输递系统。通过将8.0261克睾丸酮溶于44.9667克萜品醇来制备15.2%w/w睾丸酮的萜品醇备用溶液。该溶液的部分(0.598克)与7.497克 4%w/w实施例6制备的睾丸酮微球粘合剂混合物和21.6克乙酸乙酯混合,然后在混合台上至少混合16小时。所得的制剂用27密耳(686微米)模口隙距的刀涂在硅氧烷释放衬里上,在110°F(43℃)下烘20分钟。所得的粘合涂层含有6.45重量%睾丸酮、20重量%萜品醇和73.55重量%粘合剂。涂层是均匀的,显微镜检查显示它基本上没有药物晶体。涂覆的衬里被层压到聚酯背衬上。
实施例8-10
用实施例7的一般方法,制备一系列输递系统,其中睾丸酮的用量和萜品醇的用量发生改变。在所有的情况下使用实施例6制备的微球粘合剂。睾丸酮和萜品醇的重量百分数列于下表3。
用上述试验方法测定来自实施例6-10输递系统的睾丸酮通过无毛小鼠皮肤的渗透。接受溶液是30%重量m-pyrol的水溶液。在含量分析前使样品冷藏,贮存时间不超过两天。结果显示于下表3,其中每个流量值是3个独立测定值的平均值。0-24小时值是整个24小时期间的平均值。
表3
实施例序号 | 睾丸酮(wt%) | 萜品醇(wt%) | 流量(μg睾丸酮/cm2/小时) | |||
0-4小时 | 4-8小时 | 8-24小时 | 0-24小时 | |||
6 | 4 | 0 | 0.8 | 2.0 | 2.1 | 1.9 |
7 | 6.45 | 20 | 2.0 | 4.2 | 3.5 | 3.3 |
8 | 7.68 | 30 | 1.5 | 2.2 | 1.9 | 1.9 |
9 | 8.76 | 40 | 1.6 | 2.8 | 2.6 | 2.4 |
10 | 9.93 | 50 | 2.4 | 9.1 | 5.8 | 5.8 |
实施例11
如下制备含萜品醇的粘合微球输递系统。使萜品醇(2.50克)、10.0克94∶6的IOA∶AA微球(36.52克在异丙醇中的分散液,有27.38%固体,实施例6)和26.52克乙酸乙酯混合,然后在混合台上混合至少16小时。所得的制剂用20密耳(508微米)模口隙距的刀涂在硅氧烷脱模衬里上,在110°F(43℃)下烘20分钟。所得的粘合涂层含有20重量%萜品醇和80重量%粘合剂。涂层是均匀的。涂覆的衬里被层压到聚酯背衬上。
实施例12-14
用实施例11的一般方法,制备一系列输递系统,其中萜品醇的用量发生改变。在所有的情况下使用实施例6制备的微球粘合剂。萜品醇的重量百分数列于下表4。
用上述试验方法测定实施例11-14输递系统的粘着和柔量。结果列于下表4,其中每个粘着值是5次独立测定值的平均值,每个柔量值是3次独立测定值的平均值。
表4
实施例号 | 萜品醇(wt%) | 粘着(克) | 柔量值(cm2/达因) |
11 | 20 | 399 | 0.82×10-5 |
12 | 30 | 354 | 1.94×10-5 |
13 | 40 | 274 | 3.44×10-5 |
14 | 50 | 171 | 5.56×10-5 |
实施例15
向装有机械搅拌器、冷凝器和供真空和氩气入口-出口的管道的1升隔板式反应烧瓶里加入390克去离子水和8.4克月桂基硫酸铵(StandpolTMA)。使反应器脱气,然后用氩气再填充。在425rpm下搅拌,使反应器加热到68℃。在反应罐里制备含210克丙烯酸异辛酯和0.69克2,2’-偶氮双(2-甲基丁腈)的混合物。引发剂溶解后混合物倒入68℃下的反应器里。然后使反应器温度设置到60℃持续22小时。聚合期间保持氩气冲洗。22小时后,将悬浮液冷却到室温。然后倒空反应器,用异丙醇凝结悬浮液,然后收集。所得的微球具有空心形态,粒径为50微米。微球使用前再分散于11/89异丙醇/乙酸乙酯。
这些微球用于制备含睾丸酮的粘合微球输递系统。通过将0.8358克睾丸酮与20.0克微球(181.88克在异丙醇/乙酸乙酯11/89w/w里的分散液,有11%固体)混合,然后在混合台上混合至少16小时来制备4%w/w睾丸酮在微球粘合剂里的混合物。所得的制剂部分用26密耳(660微米)模口隙距的刀涂在氟聚合物脱模衬里上,在110°F(43℃)下烘20分钟。所得的粘合涂层含有4%睾丸酮和96%粘合剂。涂层是均匀的,显微镜检查显示它起初没有药物晶体。涂覆的衬里被层压到聚酯背衬上。样品贮存在密封的、箔衬里的聚酯袋子里。贮存一周后,显微镜检查显示已形成了许多晶体。
实施例16
如下制备含睾丸酮和萜品醇的粘合微球输递系统。通过将7.347克睾丸酮与41.64克萜品醇混合,在混合台上混合3天,然后过滤除去不溶的睾丸酮来制备14%w/w睾丸酮在萜品醇里的备用溶液。用该方法制备的溶液经1:100稀释在甲醇中,进行高效液相层析分析,显示出含有14.0重量%睾丸酮。该溶液部分(0.35克)与实施例15制备的制剂部分(29.05克)混合,然后在平台混合器里混合至少16小时。所得的制剂用26密耳(660微米)模口隙距的刀涂在氟聚合物脱模衬里上,在110°F(43℃)下烘20分钟。所得的粘合涂层含有4.8%睾丸酮,8.2重量%萜品醇和87.0重量%粘合剂。涂层是均匀的,显微镜检查显示它起初没有药物晶体。涂覆的衬里被层压到聚酯背衬上。样品贮存在密封的、箔衬里的聚酯袋子里。贮存一周后,显微镜检查显示已形成了许多晶体。
实施例17-19
用实施例16的一般方法,制备一系列输递系统,其中睾丸酮的用量和萜品醇的用量发生改变。在所有的情况下粘合剂是IOA空心微球微球。睾丸酮和萜品醇的重量百分数列于下表5。在所有三个实施例中,涂层是均匀的,显微镜检查显示开始没有药物晶体;但贮存一周后,显微镜检查显示所有三个实施例都已形成了许多晶体。
实施例20
用实施例16的一般方法,制备含有8.8%睾丸酮、42.3%萜品醇和48.9%IOA微球粘合剂的输递系统。涂层是均匀的,显微镜检查显示开始和贮藏5周后基本上都没有药物晶体。
用上述试验方法测定来自实施例16-20输递系统的睾丸酮通过无毛小鼠皮肤的渗透。渗透试验在开始的样品上进行。接受溶液是30%重量m-pyrol的水溶液。在含量分析前使样品冷藏,贮存时间不超过两天。结果显示于下表5,其中每个流量值是3个独立测定值的平均值。0-24小时值是整个24小时期间的平均值。
表5
实施例序号 | 睾丸酮(wt%) | 萜品醇(wt%) | 流量(μg睾丸酮/cm2/小时) | |||
0-4小时 | 4-8小时 | 8-24小时 | 0-24小时 | |||
15 | 4 | 0 | 1.9 | 3.1 | 2.1 | 1.7 |
16 | 4.8 | 8.2 | 2.9 | 4.1 | 3.6 | 3.5 |
17 | 5.8 | 16.6 | 3.8 | 4.9 | 3.9 | 3.8 |
18 | 6.8 | 25.1 | 2.9 | 6.2 | 4.3 | 3.5 |
19 | 7.8 | 33.8 | 3.3 | 7.4 | 5.6 | 4.0 |
20 | 8.8 | 42.3 | 9.3 | 31.4 | 18.5 | 10.4 |
实施例21
向装有机械搅拌器、冷凝器和供真空和氩气入口-出口的管道的半升隔板式反应烧瓶里加入112.5克去离子水和1.5克月桂基硫酸铵(StandpolTMA)。使反应器脱气,然后用氩气再填充。在300rpm下搅拌,使反应器加热到68℃。在反应罐里混合丙烯酸异辛酯(36.75克)和0.75克β-雌二醇-3-苯甲酸酯,然后加热(约50℃)直至药物完全溶于单体为止。向罐里加入过氧化苯甲酰(0.18克Lucidol-70)。引发剂溶解后,使混合物在68℃下加入反应烧瓶。反应烧瓶的温度然后再设置到65℃持续22小时。聚合期间保持氩气冲洗。22小时后,将悬浮液冷却到室温。微球在水相里是稳定的。然后倒空反应器,悬浮液经干酪包布过滤以除去聚集物。在光学显微镜下,所得的微球是数种形态:空心、实心、多个不连续的空腔和多个链状空腔的混合物。用颗粒成象分析测定粒径,发现是24.90微米,样品涂覆在2密耳(51微米)的聚酯背衬上,然后先在185°F(85℃)后在210°F(99℃)下各烘20分钟。用上述试验方法测定柔量值,发现是0.1×10-5厘米2/达因。
实施例22
向装有机械搅拌器、冷凝器和供真空和氩气入口-出口的管道的半升隔板式反应烧瓶里加入112.5克去离子水和1.5克月桂基硫酸铵(StandpolTMA)。使反应器脱气,然后用氩气再填充。在300rpm下搅拌,使反应器加热到68℃。在罐里混合丙烯酸异辛酯(34.9克)、1.85克N-乙烯基吡咯烷酮、0.094克1,6-己二醇二丙烯酸酯和0.75克β-雌二醇-3-苯甲酸酯,然后加热(约50℃)直至药物完全溶于单体混合物为止。向罐里加入过氧化苯甲酰(0.36克Lucidol-70)。引发剂溶解后,使混合物在68℃下加入反应烧瓶。反应烧瓶的温度然后再设置到65℃持续22小时。聚合期间保持氩气冲洗。22小时后,将悬浮液冷却到室温。微球在水相里是稳定的。然后倒空反应器,悬浮液经干酪包布过滤以除去聚集物。在光学显微镜下,所得的微球是空心和实心微球的混合物。用颗粒成象分析测定粒径,发现是29.1微米,样品涂覆在2密耳(51微米)的聚酯背衬上,然后在185°F(85℃)下烘20分钟,在210°F(99℃)下烘20分钟。用上述试验方法测定柔量值,发现>6.0×10-5厘米2/达因。
实施例23
通过用氢氧化铵中和0.75克丙烯酸在56.25克去离子水里的混合物,达到约pH7来制备水相。向装有机械搅拌器、冷凝器和供真空和氩气入口-出口的管道的一升隔板式反应烧瓶里加入40克水相部分和0.25克月桂基硫酸铵(StandpolTMA)。使混合物在350rpm下搅拌,同时用氩气冲洗,加热到68℃。这样制备油相:使0.12克过氧化苯甲酰(Lucidol-70)和0.56克β-雌二醇-3-苯甲酸酯溶于18克丙烯酸异辛酯。水相剩余部分与0.38克单油酸脱水山梨醇酯(sorbitan monooleate)混合,HLB=4.3(Arlacel 80,购自ICISpecialties);所得的混合物均质化,形成泡沫。混合下向泡沫物里加入油相,形成水包油乳剂。然后将乳剂加入反应器,形成水包油再包水的乳剂供聚合。使反应器脱气,温度维持在65℃下达22小时。聚合期间保持氩气冲洗。22小时后,让反应器冷却到室温。微球在水相里是稳定的。然后倒空反应器,悬浮液经干酪包布过滤以除去聚集物。在光学显微镜下,所得的微球有多个空腔。用颗粒成象分析测定粒径,发现是55微米,样品涂覆在2密耳(51微米)的聚酯背衬上,然后在185°F(85℃)下烘20分钟,在210°F(99℃)下烘20分钟。用上述试验方法测定柔量值,发现是0.3×10-5厘米2/达因。
实施例24
用β-雌二醇二乙酸酯代替β-雌二醇-3-苯甲酸酯来重复实施例23的过程。发现微球有多空腔形态,粒径为70微米。柔量值>6.0×10-5厘米2/达因。
用上述试验方法测定实施例21-24组合物释放药物的能力。表6给出的值中每个值是三个独立测定的平均值,括号里的数值是平均值的标准差。
表6
实施例序号 | 释放的雌二醇的累积量(微克) | |||
0分钟 | 10分钟 | 45分钟 | 180分钟 | |
21 | 0 | 28.1(0.4) | 50.3(9.1) | 145.8(13.3) |
22 | 0 | 5.1(0.1) | 24.2(1.2) | 46/9(1.5) |
23 | 0 | 20.7(1.1) | 82.0(8.7) | 236.3(17.4) |
24 | 0 | 46.7(13.7) | 314.2(58.1) | 581.7(36.3) |
实施例25
向装有机械搅拌器、冷凝器和供真空和氩气入口-出口的管道的半升隔板式反应烧瓶里加入180克去离子水和4.8克月桂基硫酸铵(StandpolTMA)。使反应器脱气,然后用氩气再填充。在550rpm下搅拌,使反应器加热到68℃。在罐里混合丙烯酸异辛酯(117.6克)、2.4克聚(环氧乙烷)丙烯酸酯(AM-90G,购自Shin-Nakamura)、2.4克肉豆蔻酸异丙酯、0.03克1,6-己二醇二丙烯酸酯和0.57克过氧化苯甲酰(Lucidol-70)。在引发剂溶解后,混合物加到68℃下的反应器里。反应器温度再设置到65℃持续22小时。聚合期间保持氩气冲洗。22小时后,将悬浮液冷却到室温。倒空反应器,悬浮液经干酪包布过滤以除去聚集物。所得的微球有多个细小的空腔形态,平均体积大小为28.4微米。样品用丙烯酸乳胶(lpph的UCARpolyphobe-104,购自Union Carbide)增厚,涂覆在化学处理过的聚酯衬里上,然后烘干,得到厚度为4.4密耳(112微米)的干燥涂层。柔量值为7.87×10-5厘米2/达因。
实施例26
除在450rpm下搅拌外,其它重复实施例25的方法。所得的微球具有多个细小的空腔,平均体积粒径为45.4微米。样品用丙烯酸乳胶(1pph的UCARpolyphobe-104,购自Union Carbide)增厚,涂覆在化学处理过的聚酯衬里上,然后烘干,得到厚度为3.8密耳(96.5微米)的干燥涂层。柔量值为1.21×10-5厘米2/达因。
本发明已参照数个实施方案作了阐述。上述详细的叙述和实施例供澄清和理解本发明用,并非用来限定。很显然,本技术领域的人员可对揭示的实施方案作出许多改变而不背离本发明的精神和范围。因此,本发明的范围不为组合物和结构的细节所限定,而由权利要求书进行限定。
Claims (22)
1.一种透皮药物输递组合物,包含压敏粘合剂微球,所述的压敏粘合剂微球含有(a)掺入微球的至少10重量%软化剂和任选的(b)治疗有效量的药物。
2.根据权利要求1所述的组合物,其中所述微球是空心的。
3.根据权利要求1所述的组合物,其中微球是实心的。
4.根据权利要求1所述的组合物,其中所述组合物的柔量值约为3×10- 6cm2/达因到1×10-3cm2/达因。
5.根据权利要求1所述的组合物,其中所述微球由于丙烯酸酯聚合物构成。
6.根据权利要求5所述的组合物,其中所述丙烯酸酯聚合物包括至少一种丙烯酸酯或甲基丙烯酸酯和至少一种游离基可聚合的共聚单体的共聚物。
7.根据权利要求6所述的组合物,其中所述至少一种丙烯酸酯或甲基丙烯酸酯包括非叔烷基醇的单官能团不饱和丙烯酸酯或甲基丙烯酸酯,其中所述醇的烷基含有4-10个碳原子。
8.根据权利要求6所述的组合物,其中所述至少一种丙烯酸酯或甲基丙烯酸酯包括丙烯酸仲丁酯、丙烯酸正丁酯、丙烯酸叔丁酯、甲基丙烯酸丁酯、丙烯酸异戊酯、丙烯酸2-甲丁酯、丙烯酸4-甲基-2-戊酯、丙烯酸2-乙基己酯、丙烯酸异辛酯、丙烯酸异壬酯、甲基丙烯酸异癸酯、丙烯酸异癸酯、丙烯酸十二烷酯、丙烯酸十四烷酯、丙烯酸乙酯、丙烯酸异龙脑酯或它们的混合物。
9.根据权利要求6所述的组合物,其中所述至少一种丙烯酸酯或甲基丙烯酸酯包括丙烯酸异辛酯或丙烯酸2-乙基己酯。
10.根据权利要求6所述的组合物,其中所述游离基可聚合极性共聚单体包括单烯单羧酸或它的盐;单烯二羧酸或它的盐;丙烯酰胺;N-取代的丙烯酰胺;N-乙烯基内酰胺或它们的混合物。
11.根据权利要求6所述的组合物,其中所述游离基可聚合极性共聚单体包括丙烯酸、甲基丙烯酸、衣康酸、巴豆酸、马来酸、富马酸、乙酸乙烯酯、甲基丙烯酸磺基乙酯、N-乙烯基吡咯烷酮、N-乙烯基己内酰胺、丙烯酰胺、叔丁基丙烯酰胺、二甲氨基乙基丙烯酰胺、N-辛基丙烯酰胺、丙烯酸羟基乙酯和甲基丙烯酸羟乙酯、甲基丙烯酸钠、丙烯酸铵、丙烯酸钠、三甲基胺对-乙烯基苯甲酰亚胺、N,N-二甲基-N-(β-甲氧基-乙基)丙酸铵甜菜碱、三甲胺甲基丙烯酰胺、1,1-二甲基-1-(2,3-二羟基丙基)胺甲基丙烯酸酰胺或它们的混合物。
12.根据权利要求6所述的组合物,其中所述游离基可聚合极性共聚单体包括丙烯酸。
13.根据权利要求5所述的组合物,其中所述丙烯酸酯聚合物包括丙烯酸异辛酯和丙烯酸的共聚物。
14.根据权利要求1所述的组合物,其中所述软化剂包括萜、含8-36个碳原子的醇;有8-36个碳原子的脂肪酸、脂肪酸酯或脂肪酸酰胺;有8-36个碳原子的脂肪酸的甘油酯;烷基吡咯烷酮羧酸酯,其中烷基含6-36个碳原子或它们的混合物。
15.根据权利要求1所述的组合物,其中所述软化剂包括萜品醇、肉豆蔻酸异丙酯或它们的混合物。
16.根据权利要求1所述的组合物,其中所述药物掺入微球中。
17.根据权利要求1所述的组合物,其中所述药物包括类固醇。
18.根据权利要求17所述的组合物,其中所述药物包括类固醇类的组合。
19.根据权利要求18所述的组合物,其中所述药物包括雌激素和孕激素的组合。
20.根据权利要求1所述的组合物,其中药物包括睾丸酮或左旋18-甲基炔诺酮。
21.一种透皮药物输递装置,包括涂布在背衬上的如权利要求1所述的透皮药物输递组合物。
22.一种制备透皮药物输递组合物的方法,包括下列步骤:
a)形成油相,所述的油相包括一种或多种丙烯酸酯、甲基丙烯酸酯或乙烯酯单体,单独或其任何组合;非反应性、油溶的软化剂和/或药物;和一种在包括至少一种悬浮稳定剂或表面活性剂的水性介质的水相里的油溶的游离基引发剂,和
b)引发水相里油相的聚合,从而形成粘合剂微球透皮药物输递组合物。
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US09/071,667 | 1998-05-01 | ||
US09/071,667 US6312715B1 (en) | 1998-05-01 | 1998-05-01 | Adhesive microsphere drug delivery composition |
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CN1308548A true CN1308548A (zh) | 2001-08-15 |
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CN99808170A Pending CN1308548A (zh) | 1998-05-01 | 1999-03-25 | 粘合剂微球药物输递组合物 |
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US (1) | US6312715B1 (zh) |
EP (1) | EP1077727B1 (zh) |
JP (1) | JP2002513774A (zh) |
KR (1) | KR20010043191A (zh) |
CN (1) | CN1308548A (zh) |
AT (1) | ATE245450T1 (zh) |
AU (1) | AU749311B2 (zh) |
CA (1) | CA2330863A1 (zh) |
DE (1) | DE69909777T2 (zh) |
DK (1) | DK1077727T3 (zh) |
ES (1) | ES2200513T3 (zh) |
HU (1) | HUP0101512A3 (zh) |
IL (1) | IL139135A0 (zh) |
NO (1) | NO20005394D0 (zh) |
NZ (1) | NZ507631A (zh) |
PL (1) | PL343829A1 (zh) |
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-
1999
- 1999-03-25 KR KR1020007012115A patent/KR20010043191A/ko not_active Application Discontinuation
- 1999-03-25 EP EP99912893A patent/EP1077727B1/en not_active Expired - Lifetime
- 1999-03-25 PL PL99343829A patent/PL343829A1/xx unknown
- 1999-03-25 WO PCT/US1999/006577 patent/WO1999056782A1/en not_active Application Discontinuation
- 1999-03-25 CN CN99808170A patent/CN1308548A/zh active Pending
- 1999-03-25 JP JP2000546806A patent/JP2002513774A/ja active Pending
- 1999-03-25 DK DK99912893T patent/DK1077727T3/da active
- 1999-03-25 CA CA002330863A patent/CA2330863A1/en not_active Abandoned
- 1999-03-25 ES ES99912893T patent/ES2200513T3/es not_active Expired - Lifetime
- 1999-03-25 AT AT99912893T patent/ATE245450T1/de not_active IP Right Cessation
- 1999-03-25 DE DE69909777T patent/DE69909777T2/de not_active Expired - Lifetime
- 1999-03-25 HU HU0101512A patent/HUP0101512A3/hu unknown
- 1999-03-25 IL IL13913599A patent/IL139135A0/xx unknown
- 1999-03-25 NZ NZ507631A patent/NZ507631A/xx unknown
- 1999-03-25 AU AU31156/99A patent/AU749311B2/en not_active Ceased
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2004019920A1 (en) * | 2002-08-27 | 2004-03-11 | Carol Choi Fung Yuen | Transdermal delivery system |
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Publication number | Publication date |
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US6312715B1 (en) | 2001-11-06 |
EP1077727A1 (en) | 2001-02-28 |
ATE245450T1 (de) | 2003-08-15 |
HUP0101512A2 (hu) | 2002-03-28 |
EP1077727B1 (en) | 2003-07-23 |
HUP0101512A3 (en) | 2002-10-28 |
NO20005394L (no) | 2000-10-26 |
CA2330863A1 (en) | 1999-11-11 |
KR20010043191A (ko) | 2001-05-25 |
ES2200513T3 (es) | 2004-03-01 |
JP2002513774A (ja) | 2002-05-14 |
DE69909777T2 (de) | 2004-04-15 |
DK1077727T3 (da) | 2003-11-10 |
IL139135A0 (en) | 2001-11-25 |
PL343829A1 (en) | 2001-09-10 |
WO1999056782A1 (en) | 1999-11-11 |
NO20005394D0 (no) | 2000-10-26 |
AU3115699A (en) | 1999-11-23 |
AU749311B2 (en) | 2002-06-20 |
DE69909777D1 (de) | 2003-08-28 |
NZ507631A (en) | 2003-03-28 |
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