CN101636148A - 基于连接剂的卵磷脂微型乳剂输送载体 - Google Patents
基于连接剂的卵磷脂微型乳剂输送载体 Download PDFInfo
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- CN101636148A CN101636148A CN200780051074A CN200780051074A CN101636148A CN 101636148 A CN101636148 A CN 101636148A CN 200780051074 A CN200780051074 A CN 200780051074A CN 200780051074 A CN200780051074 A CN 200780051074A CN 101636148 A CN101636148 A CN 101636148A
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- microemulsion
- lecithin
- bridging agent
- acid
- oil
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Abstract
本发明涉及生物相容性微型乳剂系统,该系统设计用于控释药物输送,由磷脂,如卵磷脂(表面活性剂),烷基中包括9个或更多的C原子、亲水亲油平衡(HLB)值为5或更低的亲脂性添加剂(连接剂)和烷基尾中包含6-9个C原子的类表面活性剂亲水性添加剂(连接剂)配制而成。连接剂和磷脂的结合使得制剂具有以低的表面活性剂浓度,最小的细胞毒副作用将高浓度的难溶药物输送到表皮组织的能力。
Description
技术领域
本发明涉及一种微型乳剂系统,设计用于控释药物输送。
背景技术
微型乳剂具有众多优点,包括:(1)对水溶性和油溶性药物均具有高溶解能力;(2)热力学稳定的;(3)透明的;(4)不需要加入外部能量就能自发形成。1998年的一篇关于微型乳剂药物输送领域现状的综述文章指出,微型乳剂相对于其它系统的主要优势源于以下能力:提高(水中)难溶药物在载体中的溶解度,和增大用于传质(由于小的颗度)的界面面积致使药物通过上皮组织的渗透性增强(Malmstem,Handbook of Microemulsion Science and Technology.Kumar,P.Ed.Marcell Dekker,Inc.:New York,1999)。在该篇综述文章中还指出,虽然非离子型表面活性剂显著地降低与微型乳剂相关的毒性,但只有当使用天然表面活性剂(如卵磷脂)并避免使用短链和中链的醇配制微型乳剂时,完全无毒的和生物相容的微型乳剂才可能获得。
在更近的一篇综述文章(Prausnitz,M.R.;Mitragotri,S.and Langer,R.Nat RevDrug Discovery,2004,3(2):115-24)中比较了不同的药物输送方式,其中包括表面活性剂系统。作者指出,基于表面活性剂的载体典型性地通过溶解油脂和使角质层的角蛋白变性增加药物渗透性,导致如皮肤红斑和湿疹等毒副作用的增加。作者指出,仅通过对载体-药物-皮肤的相互作用的更好的理解,基于表面活性剂和其它化学增强剂的制剂的新突破将成为可能。
在Roentsch等的、专利号为5,654,337美国专利中,描述了一种用于通过皮肤输送药物活性剂的制剂,其由生物相容性的有机溶剂(豆蔻酸异丙酯),极性油脂(卵磷脂),表面活性剂,水和尿素组成。上述工作得到了一种“快速凝胶”产品,该产品和有机凝胶(基于微型乳剂的凝胶)相似,但不同于微型乳剂,原因为该快速凝胶为亚稳定的(由于高粘性),而微型乳剂是热力学稳定的并能被设计为低粘性,使得微型乳剂适用范围更广。
在Owen等的、专利号为5,688,761的美国专利中描述了一种水包油微型乳剂。该微型乳剂适用于水溶性蛋白药物给药。通过水溶液的加入,该水包油乳剂很容易地转变为油包水微型乳剂,并释放活性物质。然而,由于表面活性剂改性剂的需求使得表面活性剂的含量降低至权利要求中规定的量,其在实际的应用中是无效的。
在Ekwuribe等的、专利号为6,191,105的美国专利中,描述了一种亲水亲油平衡(HLB)值在3-7之间的油包水型微型乳剂,该微型乳剂被描述为用于与聚合体共价连接的胰岛素蛋白的口服或注射给药。在该特殊制剂中,对于形成微型乳剂系统,聚乙二醇或丙二醇(能增加该组合物的粘性,并不容易被代谢)的应用是必不可少的。
在von Corswant的、专利号为6,602,511的美国专利中描述了一种水包油或双连续型微型乳剂,其适于亲脂性药物的注射、口服和透皮给药。该系统由一种亲水性表面活性剂,一种疏水性表面活性剂(卵磷脂),一种表面活性剂薄膜改性剂,和一种或多种调节该微型乳剂极性的组分组成。该系统被认为是提供了一种药学上可接受的非毒性载体。然而,在该发明描述的制剂中包含3-13%的乙醇,多次给药后会产生组织刺激和过敏。和专利6,191,105相似,该专利也需要使用亲水性聚合物,如聚乙二醇。
最后,在Dennis等的、专利号为6,638,537的美国专利中,描述了一种用于油溶性药物的静脉输送的水包油微型乳剂。该微型乳剂由一种长聚合链表面活性剂和一种作为助表面活性剂的短链脂肪酸(C8-C12)表面活性剂组成。通过与市场上可买到的药物制剂相比较,简单地公开了药物从微型乳剂微胶粒中的释放率。该微型乳剂不包括任何醇类,但可产生满意效果。然而,该组合物的一个问题在于,其需要至少25%w/v的表面活性剂以形成微型乳剂系统,从而增加了粘度、成本和潜在的毒副作用。
已发现,由亲脂性连接剂,如油醇(两亲分子,其HLB为5或更低,烷基中C原子数超过9),亲水性连接剂,如乙基配糖物的(两亲分子,烷基中C原子数为6-9)和卵磷脂的混合物制备的微型乳剂具有范围广泛的油,且不需要短链或中链醇(Acosta,E.;Nguyen,T.;Witthayapanyanon,A.;Harwell,J.H.and Sabatini,D.A.Linker-based bio-compatible microemulsions,Enviro.Sci.Technol.2005,39:1275-1282)。
在药物输送系统中连接剂微型乳剂的使用和其细胞毒性的影响是未知的。因此,需要一种用于药物输送系统的、基于连接剂的卵磷脂制剂,能够通过增强上皮组织的药物吸收提高药物摄取、并伴随最低的细胞毒副作用。
发明内容
本发明涉及生物相容的微型乳剂制剂,作为控制释放输送载体用于难溶活性成分的局部、透皮、口服、经鼻和静脉内的输送。该制剂是由:(1)卵磷脂(提取自豆类或其它来源);(2)亲脂的两亲物,其尾部基团中具有9个或更多的C原子,亲水亲油平衡(HLB)值为5或更低;(3)亲水的两亲物,具有阴离子的,非离子的,阳离子的或两性离子的首部基团和包含6-9个C原子的尾部基团;(4)可能用于稀释活性成分的载体或溶剂油(脂肪酸烷基酯或萜烯),和(5)水形成的组合物。具备特定比率的该组合物产生热力学稳定的微型乳剂,能将疏水性药物(如利多卡因,或α-醋酸生育酚)的溶解度(在等渗溶液中)提高到20倍以上。溶解性的提高使得活性成分透过(人或动物的)上皮组织和树叶的蜡状表皮的吸收和渗透性提高,且没有显著的细胞毒副作用,这可在其它基于表面活性剂载体中典型地观测到。
大部分被报道的使用卵磷脂作为表面活性剂的制剂需要高浓度(5%w/w或更高)的C2-C6醇或聚乙二醇作为助溶剂。然而,在大部分例子中,上述助溶剂的高浓度引起过敏反应。本发明的制剂不需要使用这些助溶剂。
附图说明
在下文中,仅以举例的方式,参照附图给出了优选实施例的详细说明,在附图中:
图1显示的是通过MATTERTM人类皮肤输送利多卡因的各种载体的体外细胞毒性。
图2显示的是利多卡因的累积渗透量。
图3显示的是利多卡因释放曲线。
在附图中,以举例的方式示出了本发明的一个实施例。应当理解,说明书和附图仅是为了举例说明和便于理解,而无意于限制本发明的范围。
具体实施方式
本发明涉及由亲水性和亲脂性连接剂分子配制的基于卵磷脂的微型乳剂,作为(水中)难溶的活性成分的经局部的,透皮的,口服的,经鼻的和静脉内给药途径的输送载体。发现,脱脂的大豆提取的卵磷脂与一种亲脂性连接剂(两亲化合物,包含9个或以上C原子,且HLB为5或更低),如山梨糖醇酐单油酸酯,和一种亲水性连接剂(两亲化合物,包含6-9个C原子),如部分皂化的辛酸,的结合能制备水包油(I型),油包水(II型),和双连续(III型和IV型)的微型乳剂,该乳剂能溶解(在水中)难溶的活性成分并将其输送到和/或通过表皮组织,伴随最小的细胞毒副作用。上述微型乳剂在等渗环境下制造,该等渗环境包含氯化钠,没有短链(C1-C3)和/或中链(C4-C8)醇,或聚合添加剂,可以包含一种溶剂或制药上可接受的载体油,如脂肪酸酯或香精油。
(在水中)难溶活性成分与连接剂微型乳剂载体的经皮渗透/局部吸收的提高是由于:(1)活性成分溶解度的提高,(2)皮肤渗透性的提高,和(3)在皮肤上药物吸收的意外提高。而且发现,上述连接剂制剂能提高难溶药物在皮肤内的吸收,在很多实例中,相对于其它载体(水,豆蔻酸异丙酯,和含有中链醇的卵磷脂微型乳剂)提高了100%甚至更多,同时不产生显著的细胞毒副作用。而且还发现,与常规卵磷脂微型乳剂相反,与水包油(I型)和双连续(III型和IV型)的微型乳剂相比,油包水(II型)连接剂微型乳剂是(在水中)难溶药物的最好的载体,因为其具有较大的药物吸收和经皮渗透,以及较低的细胞毒性。上述水包油(II型)制剂的一个显著特性为,能使用低至2%w/w的卵磷脂制备,并与包含8%w/w的卵磷脂的制剂保持相同水平的皮肤吸收和透皮输送。
当II型卵磷脂连接剂微型乳剂被用在利多卡因(作为试验药物)局部施用时,其产生的缓释曲线超过了12小时的周期,与经皮贴片化合物获得的曲线相似。
卵磷脂连接剂微型乳剂制剂需要使用卵磷脂作为主要乳化剂,其浓度范围为0.1%-8%w/w。术语卵磷脂(包括溶血卵磷脂)通常指的是卵磷脂与其它油脂的化合物或混合物,其中,包含至少90%w/w的单烷基或双烷基卵磷脂,其来源于动物(如蛋),植物(如大豆)或通过化学合成获得。
亲脂性连接剂帮助将卵磷脂分子桥接到油相,以0.1-24%w/w的浓度使用。亲脂性连接剂通常为在烷基链上包含9个或更多的C原子,HLB为5或更低的两亲水脂分子。亲脂性连接剂的例子包括醇类如十二烷醇,油醇,胆固醇;脂肪酸如月桂酸,棕榈酸,油酸,ω6-脂肪酸,ω3-脂肪酸;多元醇(山梨糖醇,麦芽糖醇,木糖醇,异麦芽酮糖醇,乳糖醇,赤藻糖醇,季戊四醇,丙三醇)的脂肪酸酯如山梨糖醇酐单油酸酯,油酸甘油酯,及其它物质。
亲水性连接剂为烷基上包含6-9个C原子的两亲化合物,以0.1-24%w/w的浓度使用,如其名称所示,具有高亲水性。在上述连接剂中的亲水基团可以为阴离子的(硫酸盐,磺酸盐,磷酸盐,亚磷酸盐,羧酸盐,磺基丁二酸酯盐),如碘苯腈辛酸酯,磺酸辛酯,二丁基磺基丁二酸酯;非离子的(羧酸,α-羟基酸,多元醇的酯,或葡糖苷,二级乙氧基醇,吡咯烷酮),如辛酸,2-羟基辛酸,己基和辛基聚葡萄糖苷,辛基吡咯烷酮;阳离子的(胺类,季铵盐,氧化胺),如辛胺;或两性离子(烷基丙氨酸,甜菜碱,硫代甜菜碱,卵磷脂),如辛基硫代甜菜碱,联丁酰基卵磷脂,以及其它物质。
载体(溶剂)油可能需要以0-95%w/w的浓度范围配制上述微型乳剂。优选的溶剂(载体油)包括脂肪酸烷基酯,如豆蔻酸异丙酯,癸酸乙酯,油酸甲酯;萜烯,如柠檬烯,蒎烯;和甘油一酸、二酸和三酸酯的混合物。载体油用于溶解组合物中的难溶的活性成分。
其它必要的成分包括水(0-90%w/w),和电解液,例如氯化钠,和氯化钙与氯化钠的混合物,以配制等渗溶液。
适合于以上述制剂输送的(在水中)难溶的药物具有以下性质:室温条件下在等渗溶液中的溶解度小于1%,可溶于上述描述的有机(载体)溶液。合适的药物包括:二萘嵌苯,萘并萘,屈,3-甲(基)胆蒽,3,4-苯并芘,六氯苯,苯并蒽,依托咪酯,苯并菲,蒽,腈苯唑,嵌二萘,洛伐他汀,甲硫哒嗪,氯法齐明,达那唑,叶酸,苯酮酸,马烯雌(甾)酮,马萘雌酮,毒死蜱,咯菌腈,二羟蒽醌,菲,双氯芬酸,拌种咯,舒林酸,雌激素三醇,α-生育酚,α-醋酸生育酚,芴,雌二醇,吲哚洛芬,茚甲新,雄诺龙,苯醚威,特非那定,二氢马萘雌(甾)酮,炔诺酮,氟灭酸,G-BHC(林丹),萘嵌戊烷,三碘氨苯乙基丙酸,格拉非宁,17α-乙炔雌二醇,二氟苯水杨酸,5-乙基-5-壬基巴比妥酸盐,阿密曲替林,1,3,5--三氯(代)苯,氟哌丁苯,孕酮,异菌脲,二氢马烯雌酮,氯吡嗪,联苯,苯哌利多,异丙嗪,二苯乙内酰脲,5,5-二苯基巴比妥酸盐,螺旋内酯甾酮,甲氧萘丙酸,羟哌氯丙嗪,辛伐他汀,三唑仑,1,4-二溴代苯,睾丸激素,普拉雄酮,甲基睾〔丸〕酮,雌激素酮,去甲羟基安定,氨苯喋啶,5-乙基-5-辛基巴比妥酸盐,皮蝇硫磷,替诺昔康,二氯苯氧苯乙酸,喷他佐辛,茚磺苯酰胺,甲氯噻嗪,倍他米松,甲灭酸,1,2,3-三氯(代)苯,敌草隆,苯甲二氮,氟比洛芬,萨立多胺,氟羟氢化泼尼松,萘,劳拉西泮,地塞米松,鸟嘌呤,布美他尼,5-t-丁基-5-(3-甲基-2-烯)巴比妥酸盐,磺胺嘧啶,利谷隆,阿特拉津,(左旋)苯丙氨酸氮芥,呋喃妥英,异丙隆,伏草隆,氯噻酮,去氧皮质酮,硫唑嘌呤,布洛芬,尿酸,异鸟嘌呤,齐留通,萘啶酸,番木鳖碱,酰胺咪嗪,可的松,灰黄霉素,肾上腺酮,5-乙基-5-庚基巴比妥酸盐,脱氢皮质(甾)醇,胃复安,环己胺-螺巴比妥酸盐,苯酮苯丙酸,吗啡,氨苯丁酯,阿氯芬酸,羟苯丁酯,氢化可的松,氨苯砜,环戊烷-螺巴比妥酸盐,诺氟沙星,己巴比妥,氢氟甲噻,呋喃并色酮,庚巴比妥,戒酒硫,环庚烷-螺巴比妥酸盐,羟氨喹,布尔佐胺,氯四环素,安眠酮,酚酞,吡喹酮,硫苯酰胺,三甲氧苄二氨嘧啶,氯唑沙宗,2,4-滴丙酸,奎纳定,磺胺塞唑,海洛因,奎宁,泛影酸,双环辛巴比妥,5,5-Di-i-丙基巴比妥酸盐,肾上腺素,羟戊丁氨酯6-羟基喋啶,喋啶-7-硫醇,磺胺甲恶唑,二氢氯噻,二甲基吗啡,喋啶-4-硫醇,苯基丁氮酮,普里米酮,喋啶-2-硫醇,薯蓣皂苷配基,头孢唑啉,对氨基苯甲酸乙酯(苯佐卡因),5-甲基-5-(3-甲基-2-烯基)巴比妥酸盐,5-i-丙基-5-(3-甲基-2-烯基)巴比妥酸盐,丝裂霉素C,丙对苯,可可碱,洛美沙星,5,5-二丙基巴比妥酸盐,卡巴呋喃,乙酰唑胺,黄嘌呤,异戊巴比妥,前列腺素,异(恶)唑(酰)肼,戊烯比妥,别嘌呤醇,腺嘌呤,戊巴比妥,苯甲比妥,乙酰对氨苯乙醚,苯巴比妥,蝶啶-4-甲基-硫醇,环丁烷-螺巴比妥酸盐,5-烯丙基-5-苯基巴比妥酸盐,对羟基苯甲酸乙酯,6-氨基蝶啶,5-乙基-5-苯基巴比妥酸盐,苯乙哌啶酮,异丁比妥,司可巴比妥,碘达酸,4-氨基蝶啶,7-氨基蝶啶,2-氨基蝶啶,次黄嘌呤,环巴比妥,磺胺甲嘧啶,二甲磺酸丁酯,古柯碱,5-对氨基水杨酸,5-乙基-5-(3-甲基-2-烯基)巴比妥酸盐,丙基硫尿嘧啶,甲氨二氮,烯丙基丁基巴比妥,2-萘酚,甲砜氯霉素,异丙巴比妥,7-羟基喋啶,阿托品,布他比妥,氯霉素,四氧普林,莰酮,头孢他啶,残杀威,他布比妥,米诺地尔,p-对氨基水杨酸,2-羟基喋啶,天仙子胺,二苯环庚啶,环乙烷-螺巴比妥酸盐,水杨酰胺,L-二羟苯丙氨酸,氨甲丙二酯,7-丁基茶碱,水杨酸,二烯丙巴比妥,利多卡因,蝶啶-2-甲基-硫醇,7-丁基-8-甲基茶碱,5,5-二甲基巴比妥盐,乙酰水杨酸,腺苷,糖精,阿嗪米特,阿普比妥,甲基-p-羟苯酸盐,双异丙吡胺,托吡卡胺,巴氯芬,正丁巴比妥,环丙烷-螺巴比妥酸盐,氨曲南,1-丁基可可碱,5-乙基-5-烯丙基巴比妥酸盐,甲氰咪胍,7-异丁基-8-甲基茶碱,安息香酸,蝶啶-7-甲基-硫醇,过氧化苯甲酰,丁化羟基茴香醚(BHA),丁基羟基苯甲醚(BHT),维生素A,类葫萝卜素(西红柿红素,叶黄素,胡萝卜素,丁子香酚)。
由于微型乳剂为热力学平衡系统,制剂的自由度由相律调整。在一个给定的温度和压力下,上述制剂具有很多成分-二自由度。为获得期望的制剂,需要确定卵磷脂的浓度,其中一种连接剂(典型的亲脂性连接剂)的浓度,电解液浓度,油/水体积比(典型的为1∶1)和总体积。然后,剩余的连接剂(典型的亲水性连接剂)的浓度被系统性地(在不同的试管中)增加,以形成相位扫描。随着亲水性连接剂浓度的增加,系统经历从类型II(油包水)到类型III或IV(双连续)到类型I系统(水包油)的相转变。因此亲水性连接剂需要的浓度由适合于特定的释放应用的微型乳剂类型(I型,III-IV型,II型)确定。优选的亲水性连接剂为辛酸和辛酸钠的混合物。由于每一相摄取不同水平的油和水,最终制剂组分通过相分离后的(油或水的)物料平衡获得。
卵磷脂的浓度能依照输送系统的特定需要而变化,典型的选自0.1%-8%w/w。低于该范围的浓度难以溶解药物,而高于该范围的浓度趋向于形成不需要的液晶相。对于II型微型乳剂,适宜的卵磷脂水平大约为2%w/w,对于I型和IV型微型乳剂为6%w/w。亲脂性连接剂的浓度也能依照输送系统的特定需要而变化。为促进清晰的微型乳剂相的形成,亲脂性连接剂与卵磷脂的质量比控制为1∶1-3∶1,优选的比例为3∶1,优选的亲脂性连接剂为山梨糖醇酐单油酸酯,油酸甘油酯和油酸。
虽然所有类型的微型乳剂引起药物输送到表皮组织或通过表皮组织的水平提高,但是由于具有最小的细胞毒副作用及最大限度的药物吸收和表皮穿透量,接近转化为双连续型(III型,IV型)微型乳剂的油包水(II型)微型乳剂和双连续型(IV型)微型乳剂是优选的。作为选择性的应用,例如口服和静脉内输送,水包油(I型)微型乳剂系统是该制剂优选的形式。
公开的制剂能作为药物输送载体用于透皮和局部给药,以及口服、经鼻和静脉内给药。优选的应用领域是透皮给药和局部给药。这些制剂的低粘性(4-40cp),使其能在粘度调节剂,如黄胶原或羧甲基纤维素被加入后,被用作喷雾,滚抹的,泡沫和凝胶产品。上述制剂的集料粒度(油膨胀胶团或水膨胀反胶团)的范围为3-10nm,使得上述制剂光学透明,具有高界面面积,并能透过肠和肺泡的上皮细胞。
此外,公开的制剂能作为渗透增强剂和润湿剂,用于通过植物叶子的蜡状表皮输送农用化学品。
通常,微型乳剂制剂相对于如聚乙二醇的常规溶剂载体的优势在于因为油助溶剂的存在产生的油溶解性的显著增强,和作为渗透增强剂的表面活性分子的存在。多数表面活性剂和短、中链醇助表面活性剂通过溶解角质层的一些油脂组分增加皮肤渗透性。该油脂溶解过程允许各种组分,包括表面活性剂本身穿透皮肤。由于常规阴离子表面活性剂和醇触发细胞因子应答,传统的制剂趋于引起皮肤刺激和过敏。使用天然油脂,如卵磷脂,而不使用中链和短链的醇,和使用植物油来源的连接剂和溶剂油可以使制剂对于上皮细胞更温和。如实施例6和图1所示,I类,II类和IV类连接剂微型乳剂在暴露5.5小时后的存活率高于35%(超过欧洲关于温和皮肤腐蚀性标准)。考虑到在这些制剂中包含达到30%的总表面活性剂含量和8%利多卡因,上述结果很显著。将上述结果放到上下文中,需要阐明的是,图1中标记为“水”的柱含有包含0.4%的利多卡因的等渗溶液。换句话说,20倍以上的利多卡因(是细胞毒的)能被溶解在微型乳剂中,而不影响制剂的温和性。
上述卵磷脂连接剂微型乳剂的令人惊喜的药物吸收/释放机理被发现,连接剂卵磷脂组合物携带高浓度的活性成分在上皮组织被吸收(不需要“溶解”细胞组织)。事实上,相对于常规的基于表面活性剂的输送系统(10倍增加或更多),连接剂卵磷脂微型乳剂显示了相对低的皮肤渗透性提高(2倍增加),但相比于溶剂油,上述连接剂系统提高了3-4倍的皮肤分割。
吸收到皮肤的活性成分的增加和皮肤渗透性(低细胞毒性)的相对小的增加的结合产生了能被作为控制释放机制使用的总的“隐藏”输送效果。经证实,载有局部施用剂量的连接剂-卵磷脂微型乳剂制剂会在12小时时期内缓慢释放活性成分,这与经皮贴片的释放曲线相似。该隐藏的释放方法优于常规途径之处在于有制定剂量的能力(作用于皮肤区域),具有较低的成本,避免粘合剂使用,无形施药(卵磷脂连接剂组合物是透明的,还不产生油脂残渣),施药的适应性(该组合物几乎能在身体的所有部分使用)。
含有卵磷脂的连接剂和油溶剂可以不同的比例结合以提供全范围的具有不同的疏水性和极性的组合物。实质上,这暗示着微型乳剂释放载体的物理性质、我们描述为“可编程的”。溶剂油产生适当的环境以溶解高疏水性/亲脂性的非极性药物;亲脂性连接剂提供合适的环境以溶解极性亲脂性分子;磷脂表面活性剂汇集所有环境并促进表面活性药物的溶解。另外,磷脂表面活性剂充当生物粘附剂来提高在上皮组织上的吸收。最后,更多的亲水性药物在亲水性连接剂和水分子周围找到适合的增溶位置。这使得连接剂微型乳剂作为活性成分释放载体应用范围广泛。
关于上述连接剂微型乳剂的另一个令人惊喜的发现是II型微型乳剂被确定为是用于(水中)难溶药物,如利多卡因,的最好的系统。根据前述关于常规(无连接剂)的微型乳剂的报道,利多卡因最好使用I型(水包油)微型乳剂透皮输送。对于卵磷脂连接剂制剂来说,与I型微型乳剂相比,II型(油包水)微型乳剂显示了更好的药物溶解能力,更好的皮肤渗透性,更好的药物吸收和更低的神经毒性作用。
实施例1、利多卡因-豆蔻酸异丙酯制剂
在该制剂中,大豆提取的卵磷脂被用作主要的表面活性剂,其水溶液初始浓度为8%w/w。辛酸钠和辛酸被用作亲水性连接剂。辛酸水溶液的初始浓度为6%w/w。辛酸钠的初始浓度从1%增加到14%w/w,每一个试管中间隔1%w/w。山梨糖醇酐单油酸酯(Span 80)用作亲脂性连接剂,其水溶液的初始浓度为24%w/w。上述微型乳剂制剂通过在室温下使适当量的上述组分混合并适度搅拌而自然形成。所有的微型乳剂系统经彻底地搅动,在37℃稳定至少2周,维持相平衡。制备含有代替连接剂的作为助表面活性剂的戊醇的常规II型微型乳剂制剂(P),用于与含有基于连接剂的常规制剂进行比较。
通过混合5ml水溶液(前述组分)和5ml 10%w/w利多卡因的豆蔻酸异丙酯溶液进行相态特性研究。通过在恒定的温度,水电解液浓度(0.9%NaCl)和压力(1个大气压)下,改变辛酸钠浓度来实现辛酸钠扫描。通过测量每个试管中每个相的高度确定相体积。利多卡因(作为试验药物)以10%w/w的浓度预先溶解在豆蔻酸异丙酯(IPM)中。
在室温下使用CV-2200落球式粘度计(Gilmont Instruments,Barrington,Illinois,U.S.A)测定载药微型乳剂的粘度。
在25℃,采用BI-200SM动态激光光散射仪(Brookhaven Instruments Corporation,Holtsville,New York,U.S.A.)测定水包油(o/w)和油包水(w/o)微型乳剂的平均粒径。以90°的固定角度进行测量。
每一相中的利多卡因的浓度通过配有反向柱(Genesis,C18,4μm,150×4.6mm)的高效液相色谱(Shimadzu model HPLC,PerkinElmer LC235C Diode Array Detector,SIL-10AP auto-sampler with a 20μl loop,200LC pump,Class D-7500 integrationsoftware)定量测定。其流动相为乙腈-0.05M NaH2PO4(30∶70,v/v),在等度洗脱条件(1.0ml/min)下于230nm处进行测量。利多卡因在上述条件下的保留时间为2.0-3.0分钟。峰面积与药物浓度在100-1000μg/mL范围内线性相关。。
表1概括了微型乳剂聚集体的组分,微型乳剂类型,相体积,粘度和粒径(其中,(a)是卵磷脂;(b)是山梨糖醇酐单油酸酯;(c)是辛酸;(d)是辛酸钠;(e)是水;(f)是利多卡因;(g)是豆蔻酸异丙酯;(v)是微型乳剂体积。浓度以重量百分比(w/w)表示)。
表1、利多卡因-豆蔻酸异丙酯微型乳剂的组分和性质
系列# | %(a) | %(b) | %(c) | %(d) | %(e) | %(f) | %(g) | 类型 | 粘度cP | 大小nm | (v).ml |
LO-31 | 6.8 | 20.5 | 5.1 | 0.9 | 1.8 | 5.8 | 64.9 | II | 11+/-1 | 6+/-1 | 5.9 |
LO-32 | 6.5 | 19.5 | 4.9 | 1.6 | 5.6 | 5.9 | 61.9 | II | 14+/-1 | 7+/-1 | 6.1 |
LO-33 | 6.2 | 18.7 | 4.7 | 2.3 | 9.0 | 6.0 | 59.1 | II | 14+/-1 | 8+/-1 | 6.4 |
LO-34 | 6.0 | 17.9 | 4.5 | 3.0 | 12.1 | 6.0 | 56.6 | II | 17+/-1 | 8+/-1 | 6.7 |
LO-35 | 5.6 | 16.8 | 4.2 | 3.5 | 16.7 | 6.1 | 53.2 | II | 21+/-2 | 8+/-1 | 7.1 |
LO-36 | 5.0 | 15.0 | 3.8 | 3.8 | 25.0 | 5.7 | 47.5 | II | 27+/-3 | 9+/-1 | 8.0 |
LO-37 | 4.0 | 12.0 | 3.0 | 3.5 | 39.5 | 5.4 | 38.0 | II | 30+/-4 | 9+/-1 | 10.0 |
LO-38 | 4.0 | 12.0 | 3.0 | 4.0 | 27.0 | 5.0 | 50.0 | IV | 22+/-2 | 8+/-1 | 10.0 |
LO-39 | 4.4 | 13.1 | 3.3 | 4.9 | 29.0 | 5.0 | 45.3 | IV | 27+/-5 | 8+/-1 | 9.1 |
LO-310 | 5.2 | 15.6 | 3.9 | 6.5 | 33.7 | 4.8 | 35.2 | I | 31+/-3 | 10+/-1 | 7.7 |
LO-311 | 5.4 | 16.2 | 4.0 | 7.4 | 34.3 | 4.5 | 32.7 | I | 37+/-3 | 9+/-1 | 7.4 |
LO-312 | 5.6 | 16.8 | 4.2 | 8.4 | 35.0 | 4.3 | 30.0 | I | 36+/-4 | 8+/-1 | 7.1 |
LO-313 | 5.8 | 17.5 | 4.4 | 9.5 | 35.7 | 4.3 | 27.1 | I | 35+/-3 | 8+/-1 | 6.9 |
LO-314 | 6.1 | 18.3 | 4.6 | 10.7 | 36.5 | 4.1 | 23.9 | I | 33+/-2 | 8+/-1 | 6.6 |
实施例2、利多卡因-癸酸乙酯制剂
除载体油使用癸酸乙酯代替豆蔻酸异丙酯外,采用与实施例1相同的制备过程。表2概括了上述制剂的组分和性质(其中,(a)是卵磷脂;(b)是山梨糖醇酐单油酸酯;(c)是辛酸;(d)是辛酸钠;(e)是水;(f)是利多卡因;(g)是癸酸乙酯;(v)是微型乳剂体积。浓度以重量百分比(w/w)表示)。
表2、利多卡因-癸酸乙酯微型乳剂的组分和性质
系列# | %(a) | %(b) | %(c) | %(d) | %(e) | %(f) | %(g) | 类型 | 粘度cP | (v).ml |
LE-83 | 6.4 | 19.1 | 4.77 | 2.4 | 6.9 | 7.7 | 52.7 | II | 6.3 | |
LE-84 | 6.2 | 18.7 | 4.67 | 3.1 | 8.2 | 7.6 | 51.6 | II | 7+/-1 | 6.4 |
LE-85 | 5.8 | 17.5 | 4.38 | 3.6 | 13.2 | 7.1 | 48.3 | II | 6.9 | |
LE-86 | 5.7 | 17.1 | 4.29 | 4.3 | 14.3 | 7.0 | 47.3 | II | 7.0 | |
LE-87 | 5.3 | 15.8 | 3.96 | 4.6 | 20.1 | 6.5 | 43.7 | II | 16+/-2 | 7.6 |
LE-88 | 4.0 | 12.0 | 3.00 | 4.0 | 39.0 | 5.0 | 33.0 | IV | 10.0 | |
LE-89 | 4.0 | 12.0 | 3.00 | 4.5 | 38.5 | 5.0 | 33.0 | IV | 22+/-4 | 10.0 |
LE-810 | 4.0 | 12.0 | 3.00 | 5.0 | 38.0 | 5.0 | 33.0 | IV | 10.0 | |
LE-811 | 4.4 | 13.1 | 3.28 | 6.0 | 41.0 | 5.0 | 27.2 | I | 33+/-5 | 9.1 |
LE-812 | 4.7 | 14.0 | 3.50 | 7.0 | 43.2 | 5.0 | 22.7 | I | 8.6 | |
LE-813 | 4.8 | 14.5 | 3.62 | 7.8 | 44.1 | 4.9 | 20.3 | I | 8.3 | |
LE-814 | 5.4 | 16.2 | 4.04 | 9.4 | 48.5 | 4.8 | 11.7 | I | 38+/-4 | 7.4 |
实施例3、使用油酸甘油酯作为亲脂性连接剂的利多卡因-豆蔻酸异丙酯(IPM)
除亲脂性连接剂使用油酸甘油酯代替山梨糖醇酐单油酸酯(Span 80)外,采用与实施例1相同的制备过程(其中,(a)是卵磷脂;(b)是油酸甘油酯;(c)是辛酸;(d)是辛酸钠;(e)是水;(f)是利多卡因;(g)是豆蔻酸异丙酯;(v)是微型乳剂体积。浓度以重量百分比(w/w)表示)。
表3、利多卡因-IPM+油酸甘油酯组合物的组分和性质
系列# | %(a) | %(b) | %(c) | %(d) | %(e) | %(f) | %(g) | 类型 | (v).ml |
GM-1 | 5.8 | 17.4 | 4.35 | 0.7 | 16.7 | 7.1 | 48.0 | II | 6.9 |
GM-2 | 6.3 | 19.0 | 4.76 | 1.6 | 7.9 | 7.7 | 52.6 | II | 6.3 |
GM-3 | 5.9 | 17.6 | 4.41 | 2.2 | 14.0 | 7.2 | 48.7 | II | 6.8 |
GM-4 | 5.5 | 16.4 | 4.11 | 2.7 | 19.2 | 6.7 | 45.4 | II | 7.3 |
GM-5 | 5.1 | 15.2 | 3.80 | 3.2 | 24.7 | 6.2 | 41.9 | II | 7.9 |
GM-6 | 4.7 | 14.1 | 3.53 | 3.5 | 29.4 | 5.8 | 38.9 | II | 8.5 |
GM-7 | 4.0 | 12.0 | 3.00 | 3.5 | 39.5 | 5.0 | 33.0 | IV | 10.0 |
GM-8 | 4.0 | 12.0 | 3.00 | 4.0 | 39.0 | 5.0 | 33.0 | IV | 10.0 |
GM-9 | 4.7 | 14.0 | 3.49 | 5.2 | 44.8 | 5.0 | 22.9 | I | 8.6 |
GM-10 | 4.9 | 14.8 | 3.70 | 6.2 | 46.9 | 5.1 | 18.4 | I | 8.1 |
GM-11 | 5.2 | 15.6 | 3.90 | 7.1 | 48.7 | 5.0 | 14.5 | I | 7.7 |
GM-12 | 5.5 | 16.4 | 4.11 | 8.2 | 50.7 | 4.8 | 10.3 | I | 7.3 |
GM-13 | 5.7 | 17.1 | 4.29 | 9.3 | 52.1 | 4.6 | 6.8 | I | 7 |
GM-14 | 6.0 | 17.9 | 4.48 | 10.4 | 53.7 | 4.0 | 3.5 | I | 6.7 |
实施例4、α-醋酸生育酚(维生素E的一种构型)-豆蔻酸异丙酯(IPM)制剂
除活性组分(利多卡因)被高疏水性的α-醋酸生育酚代替外,采用与实施例1相同的制备过程(其中,(a)是卵磷脂;(b)是山梨糖醇酐单油酸酯;(c)是辛酸;(d)是辛酸钠;(e)是水;(f)是α-醋酸生育酚;(g)是豆蔻酸异丙酯;(v)是微型乳剂体积。浓度以重量百分比(w/w)表示)。
表4、醋酸生育酚-IPM组合物的组分和性质
系列# | %(a) | %(b) | %(c) | %(d) | %(e) | %(f) | %(g) | 类型 | (v).ml |
LO-56 | 5.7 | 17.2 | 4.31 | 4.3 | 13.8 | 7.2 | 47.4 | II | 7.0 |
LO-57 | 5.5 | 16.5 | 4.12 | 4.8 | 16.8 | 6.9 | 45.4 | II | 7.3 |
LO-58 | 5.2 | 15.5 | 3.87 | 5.2 | 21.3 | 6.5 | 42.6 | II | 7.8 |
LO-59 | 4.6 | 13.9 | 3.47 | 5.2 | 28.8 | 5.8 | 38.2 | II | 8.6 |
LO-510 | 4.0 | 12.0 | 3.00 | 5.0 | 38.0 | 5.0 | 33.0 | IV | 10.0 |
LO-511 | 4.0 | 12.0 | 3.00 | 5.5 | 37.5 | 5.0 | 33.0 | IV | 10.0 |
LO-512 | 5.5 | 16.5 | 4.14 | 8.3 | 51.0 | 3.1 | 11.4 | I | 7.3 |
LO-513 | 5.7 | 17.1 | 4.27 | 9.3 | 52.0 | 2.9 | 8.8 | I | 7.0 |
LO-514 | 5.9 | 17.6 | 4.39 | 10.2 | 52.7 | 2.7 | 6.6 | I | 6.8 |
实施例5、卵磷脂连接剂制剂的利多卡因体外渗透研究
通过重组人皮肤EpiDermTM EPI-200和猪耳背侧皮肤,采用实施例1-3中选定的制剂在体外测定利多卡因渗透性。该模型皮肤放置在商业MATTEKEM渗透装置(MPD)内。试验制剂(0.4ml)用在供体室内。受体室充满5mlPBS(0.01M磷酸盐,0.137M NaCl,pH7.4)。在预定时间,从受体室将受体溶液全部取出并立即使用新鲜的缓冲液替代。在所有时间内均维持渗透条件。在5.5h时,结束试验。所有的渗入试验在室温条件下重复进行3次。
除了在实施例1-3中选定的制剂外,还有3种其他制剂作为基准目的被评估,包括:
1)仅水:含有4000mg/L的利多卡因(饱和条件)的蒸馏水;
2)仅IPM:含10%w/w利多卡因的豆蔻酸异丙酯;
3)仅EC:含10%w/w利多卡因的癸酸乙酯。
4)戊醇微型乳剂:5.7%w/w卵磷脂,17.2%w/w山梨糖醇酐单油酸酯,11.5%w/w戊醇,10.9%w/w水(包含0.9%w/w的NaCl),7.2%w/w利多卡因,47%w/w异丙醇。
供体溶液中的利多卡因通过配有反向柱(Genesis,C18,4μm,150×4.6mm)的高效液相色谱(Shimadzu model HPLC,PerkinElmer LC235C Diode Array Detector,SIL-10AP auto-sampler with a 20μl loop,200LC pump,Class D-7500integrationsoftware)定量测定。流动相为乙腈-0.05M NaH2PO4(30∶70,v/v),在等度洗脱条件(1.0ml/min)下于230nm进行测量。利多卡因在上述条件下的保留时间为2.0-3.0分钟。峰面积与药物浓度在100-1000μg/mL范围内线性相关。
受体溶液中的利多卡因通过紫外分光光度计(ULTRASPEC PLUSTM,AmershamPharmacia Biotech,U.S.A.)测定。受体溶液使用甲醇稀释,并检测在230nm的吸光度。在230nm,浓度在0-100μg/ml范围内测得利多卡因的线性校准曲线,其线性度为0.999。
经皮肤渗透的利多卡因的累积量标绘为时间(h)的函数,平均稳态通量(J,μg/h/cm2)的计算如下:曲线的线性部分的斜率除以暴露的皮肤表面面积(0.256cm2)的。表5总结了不同制剂通过MATTERTM和猪耳皮肤的利多卡因通量。
为测量猪耳皮肤中的利多卡因的浓度,组织被从MATTERTM渗透装置移开,使用PBS溶液洗涤,然后使用不起毛的纸巾将剩余的液体吸除。将组织在2ml甲醇中浸泡24h。然后,使用上述描述的高效液相色谱方法检测利多卡因的浓度。提取出的利多卡因的质量除以组织的体积(组织厚度×截面面积),得到的浓度与皮肤中利多卡因浓相等。皮肤渗透性通过透皮通量除以利多卡因皮肤浓度计算获得。
表5、选定制剂中的利多卡因透皮通量、皮肤浓度和皮肤渗透性
制剂 | 微型乳剂类型 | 利多卡因含量,%w/w | MatTekTM通量μg/hr-cm2 | 猪耳皮肤通量,μg/hr-cm2 | 皮肤中的猪耳皮肤利多卡因,μg/ml | 猪耳皮肤渗透性,μm/hr |
水 | N.A. | 0.4 | 320+/-20 | 110+/-10 | 6800+/-400 | 160+/-20 |
戊醇 | II | 7.0 | 160+/-10 | 130+/-20 | 5800+/-200 | 220+/-20 |
IPM | N.A. | 10.0 | 310+/-20 | 140+/-10 | 8400+/-200 | 170/-20 |
LO-32 | II | 5.9 | 550+/-20 | 420+/-40 | 12300+/-200 | 340+/-30 |
LO-38 | IV | 5.0 | 460+/-20 | 340+/-20 | 13500+/-300 | 250+/-20 |
LO-314 | I | 4.1 | 310+/-30 | 150+/-20 | 9500+/-200 | 170+/-20 |
EC | N.A. | 5.0 | N.D. | 110+/-20 | 4000+/-200 | 270+/-20 |
LEC-83 | II | 7.7 | N.D. | 400+/-20 | 8300+/-200 | 480+/-30 |
LEC-88 | IV | 5.0 | N.D. | 260+/-20 | 7600+/-200 | 340+/-20 |
LEC-814 | I | 4.8 | N.D. | 150+/-20 | 5000+/-200 | 300+/-30 |
GM-2 | II | 7.7 | N.D. | 230+/-20 | N.D. | N.D. |
GM-8 | IV | 5.0 | N.D. | 150+/-20 | N.D. | N.D. |
GM-14 | I | 4.0 | N.D. | 100+/-30 | N.D. | N.D. |
实施例6、利多卡因制剂的细胞毒性
在重组人皮肤EPIDERMTM EPI-200上进行细胞存活率检测,其中,EPIDERMTMEPI-200在标准MATTEKTM的MTT-ET-50中被描述。该方法通常基于活细胞的活跃的线粒体脱氢酶还原微黄色的MTT为难溶于水的紫色的甲臜而被使用和确定。在渗透研究的暴露期(5.5h)的后期,EPIDERMTM皮肤模型被从MPD移除,并使用1mg/ml的MTT孵化3h以形成甲臜。然后提取难溶于水的甲臜并使用分光光度计分析。在该检测中,1%(w/v)TRITONTMX-100被用于阳性对照,PBS被用作阴性(无毒)对照。提取样品的光密度除以阴性对照的光密度,其值为相对存活率。图1显示了实施例5中评价的选定制剂的细胞存活率。
实施例7、连接剂微型乳剂中利多卡因释放的利多卡因剂量-响应曲线
使用低卵磷脂浓度重新配置制剂LO-32(II型卵磷脂连接剂微型乳剂)。选定制剂的透皮通量也通过猪耳背侧皮肤测定,其过程如上所述。表6概括了实验结果。(其中,(a)是卵磷脂;(b)是山梨糖醇酐单油酸酯;(c)是辛酸;(d)是辛酸钠;(e)是水;(f)是利多卡因;(g)是豆蔻酸异丙酯;(v)是微型乳剂体积。浓度以重量百分比(w/w)表示。)
表6、低卵磷脂含量的卵磷脂连接剂利多卡因II型微型乳剂:制剂和利多卡因通过切除的猪耳皮肤的透皮通量
系列# | %(a) | %(b) | %(c) | %(d) | %(e) | %(f) | %(g) | (v),ml | 通量μg/cm2 |
IPM | 10 | 90 | 130+/-10 | ||||||
LO-32-10 | 0.7 | 2.0 | 0.5 | 0.8 | 0.6 | 8.3 | 87.2 | 5.1 | 200+/-10 |
LO-32-30 | 2.0 | 5.9 | 1.5 | 0.9 | 1.7 | 7.9 | 80.2 | 5.3 | 330+/-10 |
LO-32-60 | 3.9 | 11.7 | 2.9 | 1.2 | 3.3 | 7.5 | 69.4 | 5.7 | 400+/-20 |
LO-32-70 | 4.6 | 13.7 | 3.4 | 1.3 | 3.9 | 7.3 | 65.8 | 5.8 | 400+/-10 |
LO-32-80 | 5.2 | 15.6 | 3.9 | 1.4 | 4.5 | 7.2 | 62.2 | 5.9 | 400+/-20 |
LO-32-100 | 6.5 | 19.5 | 4.9 | 1.6 | 5.6 | 6.8 | 55.1 | 6.2 | 420+/-40 |
相似的稀释和评价过程用于LO-314(I型连接剂微型乳剂)。表7概括了实验结果。(其中,(a)是卵磷脂;(b)是山梨糖醇酐单油酸酯;(c)是辛酸;(d)是辛酸钠;(e)是水;(f)是利多卡因;(g)是豆蔻酸异丙酯;(v)是微型乳剂体积。浓度以重量百分比(w/w)表示。)
表7、低卵磷脂含量的卵磷脂连接剂利多卡因I型微型乳剂:制剂和利多卡因通过切除的猪耳皮肤的透皮通量
系列# | %(a) | %(b) | %(c) | %(d) | %(e) | %(f) | %(g) | (v),ml | 通量μg/cm2 |
水 | 99.8 | 0.24 | 5.0 | 70+/-10 | |||||
LO-314-10 | 0.8 | 2.3 | 0.6 | 4.8 | 88.0 | 0.72 | 2.8 | 5.2 | 70+/-10 |
LO-314-30 | 2.2 | 6.6 | 1.6 | 8.3 | 71.9 | 1.51 | 7.9 | 5.5 | 80+/-10 |
LO-314-60 | 4.0 | 12.1 | 3.0 | 9.6 | 53.7 | 3.05 | 14.5 | 6.0 | 110+/-20 |
LO-314-70 | 4.6 | 13.7 | 3.4 | 10.0 | 48.4 | 3.40 | 16.5 | 6.1 | 120+/-30 |
LO-314-80 | 5.1 | 15.3 | 3.8 | 10.3 | 43.6 | 3.60 | 18.3 | 6.3 | 130+/-20 |
LO-314 | 6.1 | 18.2 | 4.5 | 10.7 | 34.6 | 4.10 | 21.8 | 6.6 | 150+/-20 |
实施例8、II型卵磷脂连接剂微型乳剂中的利多卡因的缓释
前述实施例中,0.4ml供体溶液置于皮肤表面以提供持续的药物释放。然而,如表5所示,当其配制到卵磷脂连接剂制剂中时,大量的利多卡因被吸收。为检测上述制剂提供的利多卡因的缓释能力,三片切除的猪耳皮肤(直径0.74cm)浸没在5ml制剂LO-32(II型微型乳剂,见表1)中30min。然后,使用不起毛的纸巾将剩余的液体从上述皮肤上吸除。将上述皮肤装配到MATTEKTM渗透装置上,以实施缓释研究。除无供体溶液加入以及受体溶液在1,2,3,6,12和24小时后更换新鲜溶液外,实验步骤与实施例5中的描述相似。图2比较了该缓释系统获得的利多卡因的累积渗透量以及含有相同LO-32制剂的供体溶液中和作为受体溶液的饱和利多卡因的水中的利多卡因累积渗透量。图3显示了从皮肤释放的利多卡因的释放率(LO-32缓释)。
本领域的技术人员能理解,只要其没有脱离本发明的范围,上述优选实施例的其他变化也是本发明所要求保护的。
Claims (27)
1、一种微型乳剂,作为载体用于输送活性成分,其特征在于,所述微型乳剂包括:
(a)一种卵磷脂化合物;
(b)一种亲脂性添加剂;和
(c)一种亲水性添加剂。
2、如权利要求1所述的微型乳剂,其特征在于,所述微型乳剂为生物相容性的,且所述输送为局部、透皮、口服、经鼻或静脉内输送。
3、如权利要求1所述的微型乳剂,其特征在于,所述微型乳剂为油包水(II型),且局部或透皮输送产生缓释曲线。
4、如权利要求1所述的微型乳剂,其特征在于,所述卵磷脂化合物为0.1%~8.0%w/w。
5、如权利要求4所述的微型乳剂,其特征在于,所述卵磷脂化合物包含至少90%w/w的单烷基或双烷基卵磷脂。
6、如权利要求4所述的微型乳剂,其特征在于,所述卵磷脂化合物来源于动物,植物或化学合成。
7、如权利要求1所述的微型乳剂,其特征在于,所述亲脂性添加剂为0.1%~24.0%w/w。
8、如权利要求7所述的微型乳剂,其特征在于,所述亲脂性添加剂由一种或多种选自以下组群的组分组成:长链醇,长链脂肪酸,甘油一酸酯和脱水山梨糖醇酯。
9、如权利要求7所述的微型乳剂,其特征在于,所述亲脂性添加剂由一种或多种选自以下组群的组分组成:十二烷醇,油醇,胆固醇,月桂酸,棕榈酸,十八烯酸,ω6-脂肪酸,ω3-脂肪酸,上述脂肪酸和山梨糖醇、麦芽糖醇、木糖醇、异麦芽、乳糖醇、赤藻糖醇、季戊四醇、丙三醇形成的酯,例如山梨糖醇酐单油酸酯,和油酸甘油酯。
10、如权利要求1所述的微型乳剂,其特征在于,所述亲水性添加剂为0.1%~24.0%w/w。
11、如权利要求10所述的微型乳剂,其特征在于,所述亲水性添加剂包括部分皂化的C6-C9脂肪酸。
12、如权利要求10所述的微型乳剂,其特征在于,所述亲水性添加剂由一种或多种选自以下组群的组分组成:C6-C9的烷基硫酸盐,磺酸盐,磷酸盐,亚磷酸盐,羧酸盐,磺基丁二酸酯;碘苯腈辛酸酯,磺酸辛酯,二丁基磺基丁二酸酯,C6-C9的羧酸,α-羟基酸,多元醇的酯,葡糖苷,二级乙氧基醇,吡咯烷酮,辛酸,2-羟基辛酸,己基和辛基聚葡萄糖苷,辛基吡咯烷酮,C6-C9胺类,季铵盐,氧化胺,辛胺;例如,C6-C9烷基丙氨酸,甜菜碱,硫代甜菜碱,卵磷脂,辛基硫代甜菜碱,和联丁酰基卵磷脂。
13、如权利要求10所述的微型乳剂,其特征在于,所述亲水性添加剂为辛酸和辛酸钠的混合物。
14、如权利要求1所述的微型乳剂,其特征在于,还包括一种载体油。
15、如权利要求14所述的微型乳剂,其特征在于,所述载体油为0~95%w/w。
16、如权利要求14所述的微型乳剂,其特征在于,所述载体油由脂肪酸的烷基酯,萜烯,或甘油一酸酯,甘油二酸酯或甘油三酸酯的混合物组成。
17、如权利要求1所述的微型乳剂,其特征在于,水达到90%w/w。
18、如权利要求17所述的微型乳剂,其特征在于,还包括电解液,以形成等渗溶液。
19、如权利要求1所述的微型乳剂,其特征在于,所述活性成分为一种药物,室温下其在等渗溶液中的溶解度低于1%w/w,且所述药物可溶于载体油。
20、如权利要求1所述的微型乳剂的应用,其特征在于,作为渗透增强剂和润湿剂用于通过植物叶子的蜡状表皮输送农用化学品。
21、一种控制活性成分的输送的方法,其特征在于,所述方法包括:
(a)通过合并以下成分形成一种微型乳剂:
(i)一种卵磷脂化合物;
(ii)一种亲脂性添加剂;和
(iii)一种亲水性添加剂;
(b)将所述活性成分溶解于一种载体油,以形成一种活性成分溶液;和
(c)将所述微型乳剂和所述活性成分溶液合并。
22、如权利要求21所述的方法,其特征在于,所述输送为局部、透皮、口服、经鼻或静脉内输送。
23、如权利要求21所述的方法,其特征在于,所述微型乳剂为油包水(II型),且局部或透皮输送产生缓释曲线。
24、如权利要求21所述的方法,其特征在于,所述亲脂性添加剂为山梨糖醇酐单油酸酯,油酸甘油酯或油酸,所述亲水性添加剂为辛酸和辛酸钠的混合物。
25、如权利要求21所述的方法,其特征在于,所述载体油为脂肪酸的烷基酯,萜烯,或甘油一酸酯,甘油二酸酯或甘油三酸酯的混合物。
26、如权利要求21所述的方法,其特征在于,所述微型乳剂为水包油(I型),所述输送为口服和静脉内输送。
27、如权利要求21所述的方法,其特征在于,所述微型乳剂为双连续的微型乳剂(III型或IV型),所述输送为局部、透皮、口服、经鼻或静脉内输送。
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