CN105250237A - 用于制备药物传递的纳/微米气泡的医药组成物 - Google Patents
用于制备药物传递的纳/微米气泡的医药组成物 Download PDFInfo
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- CN105250237A CN105250237A CN201410598857.8A CN201410598857A CN105250237A CN 105250237 A CN105250237 A CN 105250237A CN 201410598857 A CN201410598857 A CN 201410598857A CN 105250237 A CN105250237 A CN 105250237A
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Abstract
一种用于制备药物传递的纳/微米气泡的医药组成物。本发明提供一种医药组成物,用以形成药物传递的多个气泡。医药组成物包括一药物层,其包含一活性成分、一表面活性剂、一酸性成分以及一起泡剂。活性成分包含核酸、多肽或蛋白质。药物层的起泡剂与酸性成分在溶于水后反应产生二氧化碳进而形成气泡。气泡以表面活性剂包围二氧化碳气体核心并形成一双层结构,其中双层结构具有一内层及一外层,活性成分是包埋于双层结构的内层及外层之间所形成的一间隙中。
Description
技术领域
本发明是有关于一种医药组成物,尤其是一种用于制备药物传递的纳/微米气泡的医药组成物。
背景技术
有别于借由合成所获得的小分子药,生物制剂(例如蛋白质药物、多糖类药物等巨分子药物)是以细菌或哺乳类动物的细胞当作平台,经由生物体内作用生成,虽然制备门坎相对较高,然其具有较高的人体兼容性、高标靶性以及较低的毒性,因此已是近十年来逐渐崭露头角的热门药物,在全球占有极大的市场需求。
然而,亲水性巨分子药物如蛋白质、多肽、多糖体、核酸类药物因其结构特性以及在胃酸中的不稳定性,常必须被制备为针剂,而近年来为改善侵入性治疗所带来的不便,开发适合的药物载体而用于制备口服剂型已为目前的趋势。
常见口服剂型药物载体包含微脂体、以几丁聚糖(Chitosan)与聚谷氨酸(γ-PGA)所构成的纳/微米微粒载体等。以后者为例,几丁聚糖(Chitosan)与聚谷氨酸(γ-PGA)载体系统具有良好的胃酸耐受性,并可在小肠中溶解释放包覆于其中的有效成分,然而其过程十分繁复,须先将前驱药物以特殊过程进行混合干燥后,再包覆于明胶胶囊中,此恐造成实务面上量产的困难;再者,胶囊在小肠中的溶解情况常不完全并难以控制,易影响药效。因此,为提供长期施打该些药物的病患更好的药物剂型。
综合上述,开发合适的口服巨分子药物是目前相关产业努力的目标。
发明内容
有鉴于上述熟知现有技术的问题,本发明的其中一目的就是在提供一种用于制备药物传递的纳/微米气泡的医药组成物,其可有效地应用药物在人体中的传递、释放、及吸收。
根据本发明的目的,本发明的一实施例提供一种医药组成物,用以形成药物传递的多个气泡。医药组成物包括一药物层,其包含一活性成分、一表面活性剂、一酸性成分以及一起泡剂。活性成分包含核酸、多肽或蛋白质。药物层的起泡剂与酸性成分溶于水后反应产生二氧化碳进而形成气泡。气泡以表面活性剂包围二氧化碳气体核心并形成一双层结构,其中双层结构具有一内层及一外层,活性成分是包埋于双层结构的内层及外层的间所形成的一间隙中。
以下借由具体实施例配合所附的图式详加说明,当更容易了解本发明的目的、技术内容、特点及其所达成的功效。
附图说明
图1为根据本发明实施例的纳/微米气泡结构示意图。
图2至图5为本发明一实施例的实验数据。
图6a为根据本发明实施例的纳/微米气泡结构示意图。
图6b为图6a的局部放大图。
附图符号简单说明
1纳/微米气泡
11气体核心
12表面活性剂
121疏水端
122亲水端
13活性成分
具体实施方式
本发明将借由下述的较佳实施例及其配合的图式,做进一步的详细说明。需注意的是,以下各实施例所揭示的实验数据,是为便于解释本案技术特征,并非用以限制其可实施的方式。
请参阅图1,其是为根据本发明实施例的纳/微米气泡1结构示意图,其中多个表面活性剂12,包围气体核心11并形成一双层结构,其中每一表面活性剂12具有一亲水端122及一疏水端121,其中双层结构具有一内层及一外层,其中内层的表面活性剂12是以其疏水端121面向气体核心11以及外层的表面活性剂12是以其疏水端121朝向纳/微米气泡1的外侧,以及内层的表面活性剂12及双层结构的外层的表面活性剂12以其亲水端122彼此相对排列而形成双层结构。活性成分13是包埋于双层结构的内层及外层的间所形成的一间隙中。其中,表面活性剂12可包覆二氧化碳、空气或其它气体。
本发明的纳/微米气泡的粒径主要要取决于气体核心的大小,因此粒径范围相当大。在一实施例中,纳/微米气泡的粒径的主要范围可为50nm~100μm。
应注明的是,本发明的纳/微米气泡1中具有气体核心11,而熟知的微脂体或细胞膜的中心则为液态,因此本发明的纳/微米气泡1可与熟知的微脂体或细胞膜区隔。
再者,应注明的是在一较佳实施例中,本发明的纳/微米气泡1中表面活性剂12所形成的双层结构与熟知的微脂体或细胞膜所具有的脂双层(lipidbilayer)结构可为相反。详言之,表面活性剂12是以疏水端121面向气体核心11及朝向纳/微米气泡1的外侧,且以亲水端122彼此相对排列而形成双层结构。而熟知的脂双层结构则以亲水端面向核心及朝向外侧,且以疏水端彼此相对排列而形成双层结构以维持气体核心11的稳定。
一般而言,表面活性剂12可分类为阴离子表面活性剂、阳离子表面活性剂、两性表面活性剂或非离子表面活性剂。阴离子表面活性剂可包含但不限于烷基硫酸盐、正十二苯磺酸钠等;阳离子表面活性剂包含但不限于或聚氧乙烯十二甲胺盐等;非离子表面活性剂包含但不限于月桂硫酸钠、单油酸聚氧乙烯山梨糖醇酐等。
如图1所示,活性成分可包埋于表面活性剂的亲水端彼此相对排列所形成的间隙中,因此活性成分13的大小并未特别受限。活性成分13可为小分子药物或是生物巨分子。在一较佳实施例中,活性成分13可包含核酸、多肽或蛋白质。其中核酸包含脱氧核醣核酸(DNA)、核醣核酸(RNA);蛋白质可包含抗体或药物蛋白质。药物蛋白质例如胰岛素、红血球生成素(EPO)或干扰素等。
在一较佳实施例中,活性成分13可为亲水性,以增加活性成分与表面活性剂的亲水端的作用力。亲水性的活性成分13例如但不限于胰岛素及DNA等。
在一较佳实施例中,表面活性剂可视活性成分13所带的电性决定以增加活性成分与表面活性剂的结合能力。举例而言,在活性成分为DNA的情形中,因为DNA是带负电,因此可以选择具有正电的阳离子表面活性剂以增强活性成分与表面活性剂的结合能力。
请进一步参照本发明的图6a及图6b,其为分子仿真示意图显示本发明的纳/微米气泡,其中图6b为图6a的局部放大图。如图所示的实例中,双层结构的内层及外层的间所形成的间隙可为4.5nm,而双层结构的宽度可为7.5nm。其中活性成分13可为胰岛素六聚体而包埋于所形成的间隙中。
本发明的用于药物传递的纳/微米气泡可使用下列锭剂或胶囊医药组成物所制备,医药组成物包含表面活性剂、起泡剂以及活性成分。起泡剂较佳者为可遇酸的后产生二氧化碳的物质。起泡剂包含碳酸盐或碳酸氢盐,包含但不限于碳酸氢钠、碳酸钠或碳酸氢铵等。借由将本发明的配方在含酸的酸性环境中,起泡剂遇酸的后产生二氧化碳,由于二氧化碳为爆裂(burst)产生,因此使配方中表面活性剂包覆二氧化碳而形成本发明的双层结构并使活性成分位于间隙中,进而得到本发明的纳/微米气泡。
在一较佳实施例中,本发明的配方进一步包含酸性成分,酸性成分可在水中解离或水解为酸,进而使起泡剂产生二氧化碳。在这样的实施例中,本发明的配方可在中性或碱性环境中产生局部为酸性的环境进行,并进行如上述的反应,进而得到本发明的纳/微米气泡。酸性成分包括有机酸或无机酸。举例而言,酸性成分选自酒石酸、苹果酸、马来酸、富马酸、琥珀酸、乳酸、抗坏血酸、氨基酸、羟基乙酸、己二酸、硼酸、酒石酸氢钾以及它们的酸酐。有机酸可包含酸酐,包含但不限于柠檬酸酐、琥珀酸酐、枸橼酸酐、其它适宜的有机酸酐。
本发明技术人士可知形成气泡所需的酸性成分、起泡剂和表面活性剂比例。举例而言,酸性成分、起泡剂和表面活性剂的摩尔比为5:21∶6,在有水存在时酸性成分和起泡剂反应产生二氧化碳,并与表面活性剂形成气泡。
在一较佳实施例中,本发明的配方更包含一肠衣层,肠衣层包覆药物层。肠衣层的成份包含但不限于(甲基)丙烯酸共聚物、羟丙基纤维素酞酸酯、羟丙基纤维素乙酸酯、羟丙基纤维素琥珀酸酯、羧甲基乙基纤维素或纤维素酮酞酸酯。
举例而言,在一实例中,可将药物层进一步装填于明胶胶囊内部,再利用涂布的技术在胶囊外侧涂布以躲过胃酸的破坏,一直到小肠才将药品成分释放出来,并使酸性成分为可在水中解离为酸,而使起泡剂产生二氧化碳。在这样的实施例中,本发明的配方可在碱性环境(例如小肠)中产生局部为酸性的环境进行,并进行如上述的反应,进而得到本发明的纳/微米气泡。
在可接收的赋型剂方面,该药学组成物可任择地包括添加物,其诸如药学可接受的载剂或稀释液、香料、增甜剂、防腐剂、抗氧化剂、润湿剂、缓冲剂、释放控制成分、染料、黏着剂、悬浮剂、分散剂、着色剂、崩散剂、赋形剂、成膜剂、润滑剂、塑化剂、食用油或上述的二或多种的任何组合。
适合的药学上可接受的载剂或稀释液包括,但不限于乙醇、水、甘油、丙二醇或甘油、二乙二醇单乙基醚、维生素A与E油、矿物油、PPG2十四酰丙酸盐、磷酸钾或二氧化硅。适合的润滑剂是油酸钠、硬脂酸钠、月桂基反丁烯二酸钠、硬脂酸镁、苯甲酸钠、醋酸钠与氯化钠。适合的悬浮剂是皂土、乙基化的异硬脂基醇、聚氧乙烯山梨糖醇与脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝(aluminummetahydroxide)、琼脂与西黄蓍胶,或此等物质中的二或多种的混合物。适合的分散剂与悬浮剂是合成胶与天然胶,诸如植物胶、西黄蓍胶、金合欢胶、褐藻酸盐、葡萄聚糖、羧甲基纤维素钠盐、甲基纤维素、聚乙烯-吡咯烷酮与明胶。适合的成膜剂是羟丙基甲基纤维素、乙基纤维素与聚甲基丙烯酸酯。适合的塑化剂包括具不同分子量(如200-8000Da)的聚乙二醇、聚丙二醇与柠檬酸三乙酯。适合的着色剂是氧化铁、二氧化钛以及天然与合成色素。额外的添加剂的例子为山梨糖醇、滑石、硬三脂酸。
如上所述,在本发明的一实施例中,本发明的纳/微米气泡是产生于肠道。在纳/微米气泡产生后会与肠表皮上皮细胞相接触,此使表面活性剂可促进胞旁通道(Paracellularpathway)及跨细胞通道(transcellularpathway),并使本发明的活性成份可以送达更深层的体循环。
以下通过具体实施例配合附图详加说明,可更容易了解本发明的目的、技术内容、特点及所达成的功效,并据以实施,但不能以此限定本发明的保护范围。
纳/微米气泡配方的制备
表面活性剂为SDS,酸性成分为二乙烯三胺五乙酸二酐(diethylenetriaminepentaaceticdianhydride,DTPAdianhydride),起泡剂为小苏打(SBC),活性成分为胰岛素,肠衣层的成分为L100-55,制备方式如下:
1.SDS(7mg),DTPAdianhydride(14mg),SBC(7mg),胰岛素(5IU/Kg)均匀混合后填充于明胶胶囊(gelatincapsule)内。
2.将上述制备的明胶胶囊外层涂布L100-55(10%)后风干。纳/微米气泡的验证
请参照图2,分别以FITC标示胰岛素,以及荧光亲脂性阳离子吲哚羰花青染料DII(1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanineperchlorate)对SDS的疏水端染色,所得到荧光影像,证明胰岛素确实存在于本发明纳/微米气泡的中,且位于表面活性剂所构成的双层结构的间隙之中,显示本发明的纳/微米气泡是具有良好的活性成分包埋效果。
纳/微米气泡与细胞结合的细胞影像
请参照图3,其显示各成份与细胞共同培养后显微镜下的影像,其中分别对细胞的紧密型连结(tightjunction)Cld4、黏着型连结(adherinjunction)E-cadherin以及细胞核(DAPI)染色。结果显示DTPAdianhydride可促使FITC-insulin经由胞旁通道传输;而SDS则可促使FITC-insulin同时经由胞旁信道及跨细胞信道两种路径传输。
纳/微米气泡于活体内的细胞影像
请参照图4,其显示纳/微米气泡于肠道内作用的过程,其中在未加入起泡剂的组别,胰岛素仅限于局部区域,而使用起泡剂的本发明组别,则可明显看到经由起泡剂的作用,使纳/微米气泡破裂而释出胰岛素,藉此将胰岛素释放至小肠中段及末段,相较于未加起泡剂的组别是具有较佳的释放能力。
纳/微米气泡的药物动力试验
动物实验程序将依据农委会颁布的实验室动物管理与使用指南来执行(采用约300~350克的公鼠(maleWistarrats))。本研究的动物实验为探讨载体系统包覆药物Insulin以口服方式投药后,在大鼠体内治疗糖尿病的情形。实验中将老鼠保定后,以喂食针以口服投药(oraldrugdelivery,30IU/Kg)及皮下注射(Subcutaneous,5IU/Kg)的方式给药,于不同时间下,将动物置于抽血保定架内,使其尾巴露出,再以碘酒消毒尾巴以防止细菌感染。接着以手术刀将其尾巴划一切口,取其血液以观察血糖随时间的变化,同时以酶免疫分析法测量药物动力学。
在本实施例中,将本发明的纳/微米气泡(含30IU/kg的胰岛素)与口服胰岛素(30IU/kg)及皮下注射胰岛素(5IU/kg)的组别作比较,分别纪录受试者服用或注射药物0~10小时的血浆胰岛素浓度及血糖变化率,其结果如图5所示。而在血糖变化率的部分,皮下注射组别的血糖变化率快速下降又回升,显示其无法长效稳定地控制血糖浓度,而服用纳/微米气泡的组别则可使血糖缓降并稳定维持。上述实验结果显示本发明的纳/微米气泡确实可达到缓释且长效的效果,其具备良好的生物可利用性。
综上所述,本发明的用于药物传递的纳/微米气泡提供一种具有与传统脂双层载体排列相反的双层结构,此纳/微米气泡藉由遇酸产生气体膨胀及与小肠表皮细胞作用使此纳/微米气泡破裂,进而释放活性成分于小肠中并被小肠表皮细胞吸收。本发明的纳/微米气泡易于制备、具有优良的药物包埋效率以及相较于传统针剂具有更好的生物可利用性,因此可有效地应用于巨分子药物剂型开发。
以上所述的实施例仅是为说明本创作的技术思想及特点,其目的在使本领域技术人员能够了解本创作的内容并据以实施,当不能以之限定本创作的专利范围,即大凡依本创作所揭示的精神所作的均等变化或修饰,仍应涵盖在本创作的专利范围内。
Claims (13)
1.一种医药组成物,用以形成药物传递的多个气泡,其特征在于,该医药组成物包括:
一药物层,其包含:
一活性成分,其包含核酸、多肽或蛋白质;
一表面活性剂;
一酸性成分;以及
一起泡剂,从而使得该药物层的该起泡剂与该酸性成分在溶于水后反应产生二氧化碳,进而形成该些气泡,该些气泡以该表面活性剂包围二氧化碳为气体核心并形成一双层结构,其中该双层结构具有一内层及一外层,该活性成分是包埋于该双层结构的该内层及该外层之间所形成的一间隙中。
2.如权利要求1所述的医药组成物,其特征在于,该医药组成物为一锭剂或一胶囊。
3.如权利要求1所述的医药组成物,其特征在于,该表面活性剂包含阴离子表面活性剂、阳离子表面活性剂、两性表面活性剂或非离子表面活性剂。
4.如权利要求1所述的医药组成物,其特征在于,该表面活性剂包含月桂硫酸钠、单油酸聚氧乙烯山梨糖醇酐、烷基硫酸盐或正十二苯磺酸钠。
5.如权利要求1所述的医药组成物,其特征在于,该起泡剂包含碳酸盐或碳酸氢盐。
6.如权利要求1所述的医药组成物,其特征在于,该酸性成分包含有机酸或无机酸。
7.如权利要求1所述的医药组成物,其特征在于,该酸性成分包含二亚乙基三胺五乙酸二酐。
8.如权利要求1所述的医药组成物,其特征在于,该蛋白质包含抗体或胰岛素。
9.如权利要求1所述的医药组成物,其特征在于,更包含一明胶层,该明胶层包覆该药物层。
10.如权利要求1所述的医药组成物,其特征在于,更包含一肠衣层,该肠衣层包覆该药物层。
11.如权利要求10所述的医药组成物,其特征在于,该肠衣层的成份包含(甲基)丙烯酸共聚物、羟丙基纤维素酞酸酯、羟丙基纤维素乙酸酯、羟丙基纤维素琥珀酸酯或羧甲基乙基纤维素。
12.如权利要求1所述的医药组成物,其特征在于,该药物层更包含一释放控制成分。
13.如权利要求1所述的医药组成物,其特征在于,该医药组成物为用于口服。
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