CN101410098A - 包括含亲脂性药物的纳米胶囊的微球 - Google Patents
包括含亲脂性药物的纳米胶囊的微球 Download PDFInfo
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- CN101410098A CN101410098A CNA2007800101975A CN200780010197A CN101410098A CN 101410098 A CN101410098 A CN 101410098A CN A2007800101975 A CNA2007800101975 A CN A2007800101975A CN 200780010197 A CN200780010197 A CN 200780010197A CN 101410098 A CN101410098 A CN 101410098A
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- 230000002936 tranquilizing effect Effects 0.000 description 1
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- PHLBKPHSAVXXEF-UHFFFAOYSA-N trazodone Chemical compound ClC1=CC=CC(N2CCN(CCCN3C(N4C=CC=CC4=N3)=O)CC2)=C1 PHLBKPHSAVXXEF-UHFFFAOYSA-N 0.000 description 1
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- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
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- 229960002835 trimipramine maleate Drugs 0.000 description 1
- YDGHCKHAXOUQOS-BTJKTKAUSA-N trimipramine maleate Chemical compound [O-]C(=O)\C=C/C([O-])=O.C1CC2=CC=CC=C2[NH+](CC(C[NH+](C)C)C)C2=CC=CC=C21 YDGHCKHAXOUQOS-BTJKTKAUSA-N 0.000 description 1
- PHYFQTYBJUILEZ-IUPFWZBJSA-N triolein Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC PHYFQTYBJUILEZ-IUPFWZBJSA-N 0.000 description 1
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Abstract
本发明提供微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述多个纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳。本发明还提供制备本发明微球的方法、包括该微球的药物组合物及微球的使用方法,尤其是在治疗、化妆品和诊断中的应用。
Description
技术领域
本发明涉及活性剂的传输系统,其优选地用于口服摄入。
现有技术
以下是现有技术的列表,其被认为适用于描述在本发明领域中的技术状态。通过在括号指明它们在列表中的号码,下文将不时地引述这些文献。
1.Holm R,Porter CJH,Edwards Ga,Mullertz A,Kristensen HG和Charman WN.Examination of oral absorption and lymphatic transport ofhalofantrine in a triple-cannulated canine model after administration inself-microemulsifying drug delivery system(SMEDDS)containing structuredtriglycerides(在含有结构化三甘油酯的自微乳化药物传输系统(SMEDDS)中施用后,卤泛群在三管犬模型(triple-cannulated canine model)中的口服吸收和淋巴运输(lymphatic transport)的检查).Eur.J.Pharm.Sci.20:91-97(2003)。
2.O′Driscoll CM.Lipid-based formulations for intestinal lymphaticdelivery(用于肠内淋巴传输的基于脂质的制剂).Eur J Pharm Sci.15:405-15.(2002)。
3.Tamura S,Ohike A,Ibuki R,Amidon GL,Yamashita S.Tacrolimus is aclass II low-solubility high-permeability drug:the effect of P-glycoproteinefflux on regional permeability of tacrolimus in rats(他克莫司是II类低溶解性高通透性药物:在大鼠中,P-糖蛋白外排对他克莫司区域通透性的作用).J Pharm Sci.91:719-29.(2002)。
4.Hauss DJ,Fogal SE,Ficorilli JV,Price CA,Roy T,Jayaraj AA,KeirnsJJ.Lipid-based delivery systems for improving the bioavailability andlymphatic transport of a poorly water-soluble LTB4 inhibitor(用于改善难溶于水的LTB4抑制剂的生物利用度和淋巴运输的基于脂质的传输系统).J.Pharm.Sci.87:164-9(1998)。
5.EP 480,729,Haibung L,Soonhong Y.Microencapsulation forcontrolled oral drug delivery system(用于控制型口服药物传输系统的微胶囊化作用)。
6.U.S.5,965,160,Benita S,等人.Self-emulsifiable formulationproducing an oil-in-water emulsion(可产生水包油乳液的可自乳化的制剂)。
7.Cook RO,Pannu RK,Kellaway IW.Novel sustained releasemicrospheres for pulmonary drug delivery(用于肺部药物传输的新型持续释放微球).J Control Release.104:79-90.(2005)。
8.Khoo SM,Humberstone.AJ,Porter CJH,Edwards GA,和CharmanWN.Formulation design and bioavailability assessment of lipidicself-emulsifying formulations of halofantrine(卤泛群的脂质的自乳化制剂的制剂设计和生物利用度评价).Int.J.Pharm.167:155-164(1998)。
9.Christensen,K.L,等人.Preparation of redisperible dry emulsions byspray drying(可再分散的经喷雾干燥的干燥乳液的制备).Intl.J.Pharm.212:187-194(2001)。
10.Honbo T,Kobayashi M,Hane K,Hata T,Ueda Y.The oral dosageform of FK-506(FK-506的口服剂型).Transplant.Proc.19(Suppl 6):17-22(1987)。
11.Shimada T,Terada A,Yokogawa K,Kaneko H,Nomura M,Kaji K,Kaneko S,Kobayashi K,Miyamoto K.Lowered blood concentration oftacrolimus and its recovery with changes in expression of CYP3A andP-glycoprotein after high-dose steroid therapy(在高剂量类固醇疗法后,伴随CYP3A和P-糖蛋白表达的变化,降低的血液浓度的他克莫司及其恢复).Transplantation.74:1419-24(2002)。
12.Uno T,Kazui T,Suzuki Y,Hashimoto H,Suzuki K,Muhammad BA.Pharmacokinetic advantages of a newly developed tacrolimus oil-in-water-typeemulsion via the enteral route(新近开发的他克莫司水包油型乳液经肠内途径的药代动力学优势).Lipids.34:249-54(1999)。
13.U.S.6,884,433,Yamashita K.,等人.Sustained release formulationcontaining tacrolimus(含有他克莫司的持续释放制剂)。
14.Manjunath等人,Pharmacokinetics,tissue distribution andbioavailability of clozapine solid lipid nanoparticles after intravenous andintraduodenal administration(静脉内及十二指肠施用后,氯氮平固体脂质纳米颗粒的药代动力学、组织分布和生物利用度),Journal of ControlledRelease 107(2005)215-228。
15.Swartz M.A.The physiology of the lymphatic system(淋巴系统生理学),Adv.Drug Deliv.Rev.50(2001)3-20。
16.Jani,PU.,等人,Uptake and translocation of latex nanospheres andmicrospheres after oral administration to rats(对鼠口服施用后,乳胶纳米球和微球的吸收和易位),J.Pharm.Pharmacol.41(1989)809-812。
17.Florence D.Evaluation of nano-and microparticles uptake by thegastrointestinal tract(纳米颗粒和微粒经胃肠道吸收的评估),Adv.DrugDeliv.Rev.34(1998)221-233。
18.Nishioka Y.,等人,Lymphatic targeting with nanoparticulate system(靶向淋巴的纳米颗粒系统),Adv.Drug Deliv.Rev.47(2001)55-64。
19.US 2003/0147965,Bassett M,Jacob J.和Enscore D.Methods andproducts useful in the formation and isolation of microparticles(用于微粒形成和分离的方法及产品)。
背景技术
在药物设计和传输中的新近进展(advance)已引起数目逐渐增长的可作为肠内淋巴运输的基质(substrate)的高度亲脂性药物分子的开发。然而,这些药物展现了低口服生物利用度,由于低溶解度、P-糖蛋白外排或先于胃肠道吸收的CYP3A4代谢,因此限制了它们的利用度。
这种药物的适当药物制剂仍是一项挑战,其尚未被完全解决。众所周知,脂质能够加强疏水性药物的淋巴运输,因此可减少由于肝的首关代谢所引起的药物清除。这改善了药物吸收、生物利用度特性、活性和较低的毒性。商业上成功的自乳化药物传输系统(SEDDS)制剂如(环孢霉素A)、(利托那韦)和(沙奎那韦)已引起在此类有前途的在基于乳液的传输系统中改善亲脂性药物口服生物利用度的兴趣(1)。相信作为精细油滴分布的SEDDS在GI道中可通过促进亲脂性药物的淋巴运输而提高生物利用度。的确,最近证实,经胸导管的淋巴运输的程度为针对以结构化三甘油酯SMEDDS给药的动物的卤范群剂量的27.4%(1)。另外,最近报导在某些情况下,淋巴管可以提供药物吸收的主要途径且导致在淋巴中,药物浓度比在系统血浆中的浓度高5-10,000倍(2)。在药物设计和传输中的新近进展,也已引起数目逐渐增长的可作为肠内淋巴运输基质的高度亲脂性药物分子的开发。存在对淋巴管在确定药物吸收和生物利用度特性、活性和毒性方面的作用的逐渐增长的兴趣。例如,逐渐增长的大量证据已指出某些脂质能够凭借肠壁抑制系统前药物代谢和p-糖蛋白介导(Pgp介导)的药物外排两者(3)。
EP 480,729(4)公开了用于口服施用的分散在小油滴(oil droplet)中的药物的微胶囊化作用的方法。使用多糖将所述小油滴胶囊化,所述多糖具有金属-鳌合能力且为可溶于水的聚合物。胶囊化作用保护了药物不在胃中释放,同时提供在小肠中的快速释放。既然在小油滴中的药物优先被淋巴吸收所吸收,那么其被保护而不被肝的首关代谢所降解。
U.S.5,965,160(5)公开了含有疏水性药物的自乳化油状制剂(SEOF),其包括油类成分和表面活性剂。SEOF的特征为油类成分包括油状载体和阳离子脂质和,任选地,亲脂性油状脂肪醇。SEOF和水溶液混合而形成的水包油乳液含有带正电的小油滴。
Cook,R.O.,等人(6)描述了针对肺部药物传输的产生持续释放颗粒的工艺。根据此工艺,亲水性、离子化的药物硫酸特布他林的纳米颗粒使用喷雾干燥方法被包载(entrapped)在疏水性微球中。
Khoo,SM,等人(7)公开了分散的用于口服传输亲脂性药物如卤范群的基于脂质的制剂。描述了脂质的自乳化药物传输系统(SEDDS)和自微乳化药物传输系统(SMEDDS)两者。系统包括甘油三酯、甘油单酯/甘油二酯、非离子表面活性剂、亲水相和药物物质。优化的制剂为中链甘油三酯(MCT)SEEDS和SMEDDS,及长链甘油三酯(LCT)SMEDDS。
Holm,R,等人(1)描述了含有具有不同中链脂肪酸和长链脂肪酸组合的甘油三酯的SMEDDS,其中在甘油骨架上的不同脂肪酸表现出不同的代谢结果(fate)。
Christensen,K.L.,等人(9)描述了能够通过在水中重配(reconstitution)而重新组成初始o/w乳液的稳定的干燥乳液的制备。干燥乳液含有可溶于水的聚合物如羟丙基甲基纤维素(HPMC)、甲基纤维素或聚维酮作为固体载体,和分馏的椰子油。液体o/w乳液在实验室喷雾干燥器中被喷雾干燥。重配的乳液的液滴尺寸近似为1μm。他克莫司是大环内酯类免疫抑制剂(MW为804),其衍生于真菌筑波山土壤链霉菌(streptomycestsukubaensis),且已被指出在移植(graft)排斥预防和在急性移植排斥和类固醇或环孢霉素抵抗的移植排斥的处理中有效。他克莫司被考虑为环孢霉素免疫抑制的替代物且被指出比环孢霉素多10-100倍效力。1994年4月,他克莫司被FDA证实可预防肝移植排斥。
类似于环孢霉素,他克莫司的药代动力学参数显示高度的个体内和个体间差异性且两种药物皆有窄治疗指数,要求疗法进行全血药物监测以优化治疗。他克莫司的吸收和口服生物利用度(10%到25%)低,在食物存在下吸收的速度和程度减少。他克莫司在胃肠道中被快速吸收,虽然并不完全。在口服施用后近似于1到2小时达到他克莫司在全血中峰浓度(Cmax)。由于低水溶性,他克莫司在口服或肠胃外疗法之后的组织分布是广泛的(10)。他克莫司主要结合白蛋白和α1酸糖蛋白。红细胞结合75%到80%药物,导致全血浓度比血浆浓度高10到30倍(10)。他克莫司在消除之前几乎被完全代谢。代谢通过在肝中的细胞色素P450(CYP)3A4同工酶完成,且在较小程度上,通过肠黏膜中的CYP3A4同工酶和P-糖蛋白完成。他克莫司在肝移植患者中的消除半衰期为约12小时。小于1%的剂量未经改变地在尿中被排泄。他克莫司从肠细胞中回到肠内腔中的P-糖蛋白外排使在吸收之前被CYP3A4代谢,这样限制了他克莫司的利用度(11)。当他克莫司与CYP3A4和P-糖蛋白两者的抑制剂(即地尔硫、红霉素或酮康唑)一起被施用时,观察到口服生物利用度加强。存在通过药物传输加强他克莫司口服生物利用度的需要。
Uno,T等人(12)描述了基于油酸的药物他克莫司的水包油(o/w)乳液。o/w乳液液滴的平均直径为0.47μm。公开的制剂展现了乳液作为他克莫司肠途径载体,与标准的市场化制剂相比的生物利用度、药代动力学优势和潜在有效性。
US 6,884,433(13)描述了含有他克莫司及其它大环内酯类化合物的持续释放制剂。其中公开的持续释放制剂包括他克莫司或其水合物在包含可溶于水的聚合物(如羟丙基甲基纤维素)和不溶于水的聚合物(如乙基纤维素)及赋形剂(如乳糖)的混合物中的固体分散体。在此分散体中,颗粒尺寸等于或小于250μm。
为了克服首关代谢及因此的低口服生物利用度,因此可采用(exploite)药物的肠内淋巴运输。如先前所提到的,高度亲脂性化合物经过淋巴达到系统循环。发现具有14及以上链长度的大多数(majority)脂肪酸在胸淋巴中被重新获得(14)。
另外,尺寸为淋巴吸收的多个重要决定因素中的一种。发现淋巴吸收的优化尺寸在10nm和100nm之间(15)。然而,伴随颗粒尺寸增加,吸收更有选择性并更慢。较大颗粒可在派伊尔淋巴集结中保留较长时期,而较小颗粒被运输至胸导管(16)。口服施用的聚合物纳米颗粒和微粒通过肠的派伊尔淋巴集结的M细胞被淋巴系统吸收是明显的且在文献中被证实(17)。用疏水性聚合物包衣的纳米颗粒倾向于易于在体内被淋巴细胞捕获(18)。
用于将药物胶囊化作用为微粒的另一种方法被Bassett等人描述(19)。此方法涉及相转化,其通过将药物和第一聚合物溶解在溶剂中且向如此形成的混合物中添加溶解在“非溶剂”中的第二聚合物,其导致聚合物包衣的微粒或纳米颗粒的自发形成。
发明内容
本发明一个目的为提供用于传输多种活性剂的系统,所述活性剂的特征为在活体中为非亲水性。
因此,在本发明一方面,提供了微球,所述微球包括容纳(accommodate)在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳。
本发明还提供了微球的制备方法,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳,所述方法包括:
(a)提供有机相,其包括油、与水混溶的有机溶剂、溶解在该溶剂中的非亲水性活性剂和用于包衣所述油核心的聚合物或聚合物组合;
(b)向所述有机相中缓缓加入水以获得乳液;
(c)向乳液中继续加入水以引发所述乳液的相转化,从而获得水包油(o/w)乳液;
(d)将所述o/w乳液与凝胶形成聚合物或凝胶形成聚合物的组合混合;
(e)除去所述有机溶剂和水以获得所述微球。
本发明还提供药物组合物,其包括作为活性成分的微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳。
本发明进一步提供提高活性剂在人类受治疗者体内的生物利用度的方法,所述方法包括向所述受治疗者施用微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳。
本发明更进一步提供针对病理疾患治疗需要有效血液量的活性剂的所述治疗的受治疗者的方法,所述方法包括向所述受治疗者施用微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳。
附图说明
为理解本发明且为了解其如何在实践中被执行,现在将通过仅为非限制性例子的方式描述优选的实施方式,参考附图,其中:
图1A-1B是29号纳米胶囊制剂在添加羟丙基甲基纤维素溶液之前的TEM显微照片。丙酮溶液与水溶液的体积比为100∶75。条表示100nm尺寸。图1B是图1A的放大。
图2A-2B是29号纳米胶囊制剂添加羟丙基甲基纤维素溶液后的TEM显微照片。丙酮溶液与水溶液的体积比为100∶275。条在(图2A)中表示1000nm及在(图2B)中表示100nm。
图3A-3B是30号纳米胶囊制剂不添加羟丙基甲基纤维素溶液的TEM显微照片。丙酮溶液与水溶液的体积比为100∶75。条表示1000nm,其中图3B是图3A的放大。
图4指出在29号制剂喷雾干燥之前的颗粒尺寸分布。
图5A-5B是29号纳米胶囊制剂在添加羟丙基甲基纤维素溶液之前的SEM显微照片(条表示10.0μm图5A;2.0μm图5B)。
图6A-6B是29号纳米胶囊制剂喷雾干燥之后添加羟丙基甲基纤维素溶液的SEM显微照片(条表示20.0μm图6A;10.0μm图6B)。
图7A-7B是29号纳米胶囊制剂在添加羟丙基甲基纤维素溶液后且溶解3小时之后的SEM显微照片(条表示20.0μm图7A;10.0μm图7B)。
图8A-8D是30号纳米胶囊制剂在添加羟丙基甲基纤维素溶液之后且喷雾干燥之后的SEM显微照片(条表示50.0μm图8A;20.0μm图8B;10.0μm图8C;5.0μm图8D)。
图9A-9B是30号纳米胶囊制剂在添加羟丙基甲基纤维素溶液之后且喷雾干燥之后且溶解3小时之后SEM显微照片(条表示10.0μm图9A;5.0μm图9B)。
图10是显示DXPL从甲基纤维素微球中的释放性质(profile)的图表,所述微球包括具有不同Eudragit混合物包衣的纳米胶囊。
图11是显示DXPL从微胶囊化的装载DXPL的Eudragit纳米胶囊和微胶囊化的装载DXPL的水包油乳液中的释放性质的图表。
图12是显示在对大鼠P.O.施用不同制剂之后的他克莫司系统血液浓度的图表(平均值±SD,n=6)。
图13是显示对大鼠P.O.施用不同制剂之后的他克莫司系统血液浓度的图表(平均值±SD,n=6)。
图14是显示在口服吸收多种制剂中的0.7mg/kg他克莫司剂量后的他克莫司血液水平的图表(他克莫司被配制为胶囊商业产品悬浮剂(Comm.Prod.)、乳液(Emuls.)、包埋在不含Eudragit但含有羟丙基甲基纤维素的微球中的乳液(Dry Emuls.)、包埋在不含羟丙基甲基纤维素但含有Eudragit的纳米胶囊及作为喷雾干燥剂的乳糖的微球中的乳液(NoMethocel))。
图15是显示对大鼠P.O.施用两批相同制剂29后,他克莫司系统血液浓度的图表(对于第I批平均值±SD,n=6,及对于第II批平均值±SD,n=3),评估批次重现性。
图17是显示大鼠在口服吸收不同制剂中的0.7mg/kg他克莫司剂量之后的他克莫司血液水平的图表(平均值±SD,n=3-6,p>0.05)。
图18是在口灌29号制剂30分钟后,大鼠十二指肠组织切片的荧光显微照片,所述29号制剂装载有香豆素-6作为标记物(marker)。
图19A-19D是干燥的(图19A)或浸渍的(图19B-19D)以Eudragit L∶RS(75∶25)纳米胶囊包衣和羟丙基甲基纤维素基质包衣制备的空纳米胶囊的显微照片。
图20是显示对小型猪口服施用在商业制剂(Prograf)中或在29号制剂中的1mg他克莫司剂量后,他克莫司血液水平的图表(平均值±SD,n=4)。
发明详述
本发明基于发现微球的形成可显著地提高溶解在油核心中的亲脂性药物的血液水平,所述微球包括多个以聚合物混合物包衣的微小的小油滴,多个以聚合物包衣的小油滴进一步被容纳在凝胶形成聚合物中。这些“双重包衣的油滴”已导致认识到容纳多个纳米胶囊的微球可作为多种本质上为非亲水性的活性剂的传输载体。
这样,根据一个实施方式,提供了微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳。
可与术语“微粒”交换地使用的术语“微球”广泛地定义了通常地主要由固体或半固体材料组成的且能够携带并释放封闭(enclose)在其中的拥有药物或任何其它活性剂的纳米胶囊的微米级或亚微米级颗粒。根据本发明的微球或多或少是包括加入(如包埋、胶囊化、包载)了活性剂的纳米胶囊聚集体的球形结构。通常地,被理解为经激光衍射测定的重均直径的本发明微球的平均直径,其范围从近似于10μm到近似于500μm。更优选地,平均微球直径在约10μm到约20μm之间。
如本文使用的术语“纳米胶囊”指包括以聚合物包衣形成包衣的小油滴(精细油滴)的钠米级或亚钠米级结构。聚合物包衣形成包装油核心的硬外壳。纳米胶囊有在约100nm到约1000nm之间的平均直径,优选地在约100nm到900nm之间及更优选地在约100-300nm到约300-500nm之间。此外,微球中纳米胶囊的尺寸必须与具有1微米以下直径的约99%的小油滴一致。如本文使用的术语“纳米胶囊”应被理解为任何聚合物包衣的小油滴或具有聚合物包衣的小油滴的同义词。
如本文使用的术语“多个纳米胶囊”指两个或更多个此类容纳在凝胶形成聚合物中的纳米胶囊。
活性剂被包装在纳米胶囊中。作为结果,在活性剂与形成微球的凝胶形成聚合物之间不存在直接接触。事实上,当变湿且溶胀时,微球在GI道中释放纳米胶囊本身但不释放“裸”活性剂,其是指,活性剂(如药)自身的颗粒形式或在其分子水平上的剂(agent)。
如本文使用的术语“非亲水性活性剂”指至少在某些程度上被认作为是阻水的任何化合物。换句话说,任何展现低度、中度或高度疏水性或亲脂性的剂可被认作为非亲水性剂。非亲水性剂可被表征该剂(作为溶质)在两相之间的分配/分布系数的参数所定义,所述两相例如有机溶剂和水(最常使用的系统为辛醇-水)。通常地,分配系数(logP)描述中性化合物的疏水性,而分布系数(logD,为pKa和logP的组合)是剂的pH依赖的疏水性的量度标准。根据本发明的非亲水性活性剂是具有logP>1.5的任何化合物。
纳米胶囊的油核心可包括单一油类型或油类的组合且可选自广泛范围的从极性油类到非极性油类的通常可用的油类,只要它们不与水相混合且总体是液体即可。根据一个实施方式,小油滴包括选自长链植物油类、酯油类、较高级液体醇类、较高级液体脂肪酸类、天然脂肪类和油类及硅油类的油。根据优选的实施方式,油核心包括天然油如玉米油、花生油、椰子油、蓖麻油、芝麻油、豆油、紫苏油、葵花油、摩洛哥坚果油和胡桃油。
小油滴各自包装在聚合物包衣中以形成包括油核心和包裹油核心的聚合物外壳的纳米胶囊。聚合物包衣提供包裹油核心的外壳结构。在本发明上下文中的术语“外壳”指任何包装小油滴的固体或半固体聚合物结构。外壳可包括单一聚合物或两种或更多种聚合物的组合或混合,其将在下文中被进一步讨论。当聚合物包衣包括聚合物混合物时,优选至少一种聚合物在pH大于5.0时可溶,或至少一种聚合物可溶于水(非pH依赖型)。
根据一个实施方式,至少两种聚合物的组合包括聚合物混合物,该混合物包括可溶于水(非pH依赖型)或在pH大于5.0时可溶的第一聚合物(聚合物组)及为不溶于水的聚合物的第二聚合物(第二聚合物组)。
术语“可溶于水的聚合物”指任何聚合物,其在25℃下被引入到水相中时,在质量浓度等于1%时,可能获得宏观上均匀且透明的溶液,即有最小透光系数值的溶液,所述值在波长为500nm时,透过0.1cm厚的样品测得,为至少80%且优选为至少90%。
术语“在pH大于5.0时可溶的聚合物”指任何在5.0以下的pH时且在25℃下,通过溶解在介质中,不失去多于10%的其干重,而在同样温度下,在pH大于5.0的水介质中,其形成水凝胶或溶解以形成宏观均匀且透明的溶液的聚合物。不时以术语“肠内聚合物”提及此类聚合物。
许多可溶于水的聚合物在本领域内已知。在本发明上下文中适合的聚合物包括,但不限于多元醇和多糖。示例性可溶于水的聚合物包括羟化的纤维素,如,例如,羟丙基甲基纤维素和羟甲基纤维素。其它适合的可溶于水的聚合物包括聚乙二醇。两种或更多种可溶于水的聚合物的组合也被涵盖。
同样,许多只在pH大于5.0时可溶的聚合物在本领域内已知。对于本发明适用的肠内聚合物的非限制性例子包括,从:邻苯二甲酸羟丙基甲基纤维素酯(HP55)、乙酸邻苯二甲酸纤维素酯、邻苯二甲酸羧甲基纤维素酯及其它任何邻苯二甲酸纤维素酯衍生物、虫胶、Eudragit L100-55、玉米蛋白。
优选的肠内聚合物是Eudragit L 100-55。
术语“不溶于水的聚合物”指任何通过溶解在水介质中不失去多于10%其干重的聚合物,与介质的pH无关。不溶于水的聚合物的非限制性例子包括纤维素酯类,如二酰化物和三酰化物,其包括混合的酯类如,例如,乙酸纤维素酯、二乙酸纤维素酯、三乙酸纤维素酯、丙酸纤维素酯、乙酸丁酸纤维素酯、乙酸丙酸纤维素酯、三丙酸纤维素酯;纤维素醚类如乙基纤维素;尼龙;聚碳酸酯;聚(二烷基硅氧烷类);聚(甲基丙烯酸)酯类;聚(丙烯酸)酯类;聚苯醚;聚(乙烯醇);芳香族含氮聚合物;聚环氧化物;再生纤维素;在反渗透或透析应用中适用的成膜材料;琼脂乙酸酯(agaracetate);三乙酸直链淀粉酯;乙酸β-葡聚糖酯;乙醛二甲基乙酸酯(acetaldehyde dimethyl acetate);乙酸甲基氨基甲酸纤维素酯;乙酸琥珀酸纤维素酯;乙酸二甲氨基乙酸纤维素酯;乙酸乙基碳酸纤维素酯;乙酸氯乙酸纤维素酯;乙酸乙基草酸纤维素酯;乙酸丙酸纤维素酯;聚(乙烯基甲基醚)共聚物;乙酸丁基磺酸纤维素酯;乙酸辛酸纤维素酯;乙酸十二酸纤维素酯;乙酸对甲苯磺酸纤维素酯;刺槐豆胶(locust gum bean)的三乙酸酯;羟基化乙烯-醋酸乙烯酯;乙酸丁酸纤维素酯;蜡或类似蜡的物质;脂肪醇类;氢化植物油类;聚酯类;均聚物和共聚物,如聚乳酸或PLAGA及类似物;及其组合。
优选的根据本发明的不溶于水的聚合物是Eudrgit RS或Eudragit RL或其组合。
当纳米胶囊包括至少两种聚合物时,第一聚合物是不溶于水的聚合物和第二聚合物在pH大于约5.0时可溶。
根据优选的实施方式,第一聚合物(即不溶于水的聚合物或聚合物组)与第二组聚合物(即在pH大于约5.0时可溶的聚合物或此类聚合物组)之间的重量/重量比率,优选的范围在5∶95和50∶50之间。
不被理论所束缚,相信在不溶于水的聚合物和在pH大于约5.0时可溶的聚合物(“非不溶”聚合物)之间的比例对于活性剂从纳米胶囊中控制释放是重要的。在纳米胶囊暴露于水或具有pH大于5.0的水介质之后,具有不溶于水的第一聚合物和在水中可溶或在pH大于5.0时在水中可溶的第二聚合物使聚合物缓慢溶解,同时基本上保持不溶聚合物的一般排列。换句话说,“非不溶”聚合物的缓慢溶解导致在从不溶于水的聚合物形成的聚合物“骨架”中形成类似于渠道的通道,活性剂可通过该通道脱离纳米胶囊。为了促进活性剂从纳米胶囊的控制释放,已设想在第一聚合物,即不溶于水的聚合物与所谓的在pH大于约5.0时利于聚合物可溶的“非不溶”聚合物之间的优选比率(如利于非不可溶于水的聚合物的重量∶重量比率为75∶25)。
根据一个实施方式,聚合物的组合包括选自Eudragit RL或Eudragit RS或其组合的第一聚合物或聚合物组(不可溶聚合物)与选自Eudragit L100-55和邻苯二甲酸羟丙基甲基纤维素酯(HPMPC)或其组合的第二聚合物或聚合物组(可溶于水的或在pH大于5.0时可溶的聚合物)的混合物。根据本发明的聚合物组合的特殊选择包括以重量/重量比率为从约25∶75到约50∶50的Eudragit RS和Eudragit L100-55。
多个纳米胶囊被容纳在凝胶形成聚合物中。
如本文使用的术语“凝胶形成聚合物”指任何亲水性聚合物,其在被湿化时,形成溶胀的聚合物网状物或凝胶。凝胶形成聚合物有时也被称为水凝胶形成聚合物。凝胶形成聚合物可为天然蛋白质或合成的聚合物。根据本发明一个优选的实施方式,凝胶形成聚合物是当湿化时,变“粘”的聚合物,即能够增强湿化的微球和包含在其中的纳米胶囊对肠上皮细胞的粘合力。
如本文使用的术语“容纳”指用凝胶形成聚合物包装、包衣、包埋、包裹(surrounding)、封闭、包载或任何其他方式地整合纳米胶囊以致于提供包装排列的具有第二层保护的含有活性剂的多个纳米胶囊。
天然凝胶形成聚合物的非限制性例子包括蛋白质如明胶或胶原质和多糖如琼脂、角叉胶、葡甘露聚糖、硬葡聚糖、裂褶多糖、结冷胶(gellangum)、褐藻酸、凝胶多糖、果胶、透明质酸或瓜尔胶。
合成的凝胶形成聚合物的非限制性例子包括聚丙烯酸、改性的纤维素、甲基纤维素、甲基丙基纤维素、羧甲基纤维素、阳离子化的纤维素、羟丙基甲基纤维素、羟乙基纤维素、羧乙烯基聚合物、聚乙烯吡咯烷酮、聚乙烯基乙缩醛二乙氨基乙酸酯、聚乙烯醇、羧甲基纤维素钠、2-甲基-5-乙烯基吡啶、卡波姆(carbomer)及类似聚合物。
本发明一个方面涉及微球作为活性剂经由GI道的传输系统的用途,即用于口服施用。根据本发明此方面的一个优选的实施方式涉及为P-gp外排泵基质的活性剂的传输。
替代地,微球可被设计为经注射施用。
如本文使用的,可与术语“P-gp基质”交换使用的术语“P-gp外排泵基质”指任何活性物质(用于治疗、化妆品或诊断目的),其经历活性运输、经P-gp膜连接转运子“外排”到细胞外。P-gp沿着肠的全长被表达且也在肝、肾、血脑屏障和胎盘中被表达。在此背景下,本发明涉及医学物质,其经历通过定位在上皮细胞的顶端细胞膜上的肠p-gp的活性运输。利用ATP水解所产生的能量,P-gp驱使各种基质逆着浓度梯度外排且因此减少它们的细胞内浓度且在活性物质的情况下,减少它们的口服生物利用度。
因此,根据本发明一个优选的实施方式,活性剂是任何医用的、化妆品的或诊断的物质,其在口服施用之后,作为P-gp外排机制的结果,它的血液生物利用度被减低或抑制了。P-gp基质可根据它们的溶解性及代谢水平被归类。根据此分类的P-gp基质的非限制性列表包括:
低溶解性及强代谢:阿伐他汀、阿奇霉素、卡马西平、环孢素、格列本脲、氟哌啶醇、伊曲康唑、他克莫司、西罗莫司、利托那韦、沙奎那韦、洛伐他汀。
高溶解性及弱代谢:氨氯吡咪(amiloide)、阿莫西林、氯喹、环丙沙星、双氯西林、红霉素、非索芬那定、左旋多巴、咪达唑仑、吗啡、硝苯地平、伯氨喹、丙嗪、异丙嗪、奎尼丁、奎宁;及
低溶解性及弱代谢-环丙沙星和他林洛尔。
在本发明上下文中,非亲水性活性剂是亲脂性或两亲化合物或包含此类化合物的复合物或混合物。非亲水性活性剂也包括已经被改性的亲水性化合物,如通过连接亲脂性部分以提高剂的亲脂性。在本文,不时用术语“前药”提及这些改性的化合物。
活性剂可为游离酸形式、游离碱形式或盐形式且可使用活性剂混合物。
根据一个实施方式,活性剂是亲脂性剂。本文使用术语“亲脂性剂”指具有大于2.0-3.0的logP(辛醇/水)及具有超过10mg/mL的甘油三酯(TG)溶解度的任何化合物,所述溶解度如,例如,通过在豆油或类似油类中的溶解度所测量。此定义包括中度亲脂性药物即具有在3.0到6之间的logP及高度亲脂性药物,其具有大于6的logP。
根据本发明适于包载在纳米胶囊中的中度亲脂性治疗活性剂的例子包括以下:
止痛剂和抗炎剂:阿洛普令、金诺芬、阿扎丙宗、扑炎痛、二氟尼柳、依托度酸、芬布芬、非诺洛芬钙(fenoprofen calcim)、氟吡洛芬、布洛芬、吲哚美辛、酮洛芬、甲氯芬那酸、甲灭酸、萘丁美酮、萘普生、坦特利尔、苯基保泰松、吡罗昔康、舒林酸。
驱虫剂:阿苯达、羟萘苄芬宁、坎苯达唑、双氯酚、伊维菌素、甲苯达唑、奥沙尼喹、奥芬达唑、奥克太尔、吡喹酮、双羟萘酸噻嘧啶、噻苯哒唑。
抗心律失常剂:胺碘酮、丙吡胺、乙酸氟卡尼、硫酸奎尼丁。
抗菌剂:苯明青霉素、西诺沙星、环丙沙星、克拉霉素、氯法齐明、氯唑西林、地美环素、多西环素、红霉素、硫异烟胺、亚胺培南、萘啶酸、呋喃妥因、利福平、螺旋霉素、苯酰磺胺(sulphabenzamide)、磺胺多辛、磺胺二甲基嘧啶(sulphamerazine)、磺胺乙酰、磺胺嘧啶、磺胺异噁唑、磺胺甲噁唑、磺胺吡啶、四环素、甲氧苄啶。
抗凝剂:双香豆素、双嘧达莫、醋硝香豆素、苯茚二酮。
抗抑郁药:阿莫沙平、马普替林、米安色林、去甲替林、曲唑酮、马来酸曲米帕明。
抗糖尿病药:醋磺己脲、氯磺丙脲、格列本脲、格列齐特、格列吡嗪、妥拉磺脲、甲苯磺丁脲。
抗癫痫药:贝克拉胺、卡马西平、氯硝西泮、乙苯妥英、甲妥英、甲琥胺、甲基苯巴比妥、奥卡西平、甲乙双酮、苯乙酰脲、苯巴比妥、苯妥英、苯琥胺、扑米酮、硫噻嗪、丙戊酸。
抗真菌剂:两性霉素、硝酸布康唑、克霉唑、硝酸益康唑、氟康唑、氟胞嘧啶、灰黄霉素、伊曲康唑、酮康唑、咪康唑、纳他霉素、制霉菌素、硝酸硫康唑、特比萘芬、特康唑、噻康唑、十一烯酸。
抗痛风剂:别嘌醇、丙磺舒、苯磺唑酮。
抗疟药:阿莫地喹、氯喹、氯丙胍、卤泛群、甲氟喹、氯胍、乙胺嘧啶、硫酸奎宁。
抗偏头痛剂:甲磺酸双氢麦角胺、酒石酸麦角胺、马来酸美西麦角、马来酸苯噻啶、琥珀酸舒马曲坦。
抗毒蕈碱剂:阿托品、苯海索、比哌立登、普罗吩胺、莨菪碱、溴美喷酯、羟苯利明(oxyphencylcimine)、托吡卡胺。
抗肿瘤剂和免疫抑制剂:氨鲁米特、安吖啶、硫唑嘌呤、白消安、苯丁酸氮芥、环孢菌素、达卡巴嗪、雌莫司汀、依托泊甙、洛莫司汀、美法仑、巯基嘌呤、甲氨蝶呤、丝裂霉素、米托坦、米托蒽醌、甲基苄肼、柠檬酸他莫昔芬、睾内酯、他克莫司、西罗莫司。
抗原生动物剂:倍他唑、氯碘羟喹、地考喹酯、二碘羟喹啉、糠酸二氯尼特、二硝托胺、呋喃唑酮、甲硝唑、硝吗乙唑、呋喃西林、奥硝唑、替硝唑。
抗甲状腺剂:甲亢平、丙基硫尿嘧啶。
抗焦虑药(Alixiolytic)、镇静剂、安眠药和抗精神病药:阿普唑仑、异戊巴比妥、巴比妥、苯他西泮、溴西泮、溴哌利多、溴替唑仑、丁巴比妥、卡溴脲、氯氮卓、氯美噻唑、氯丙嗪、氯巴占、氯噻西泮、氯氮平、安定、氟哌利多、炔己蚁胺、氟阿尼酮(flunanisone)、氟硝西泮、三氟丙嗪、三氟噻吨癸酸酯、氟奋乃静癸酸酯、氟西泮、氟哌啶醇(baloperidol)、劳拉西泮、氯甲西泮、美达西泮、甲丙氨酯、甲喹酮、咪达唑仑、硝西泮、奥沙西泮、戊巴比妥、奋乃静、匹莫齐特、丙氯拉嗪、舒必利、替马西泮、硫利达嗪、三唑仑、佐匹克隆。
β-阻滞剂:醋丁洛尔、阿普洛尔、阿替洛尔、拉贝洛尔、美托洛尔、纳多洛尔、氧烯洛尔、吲哚洛尔、普萘洛尔。
心脏变力剂(Cardiac Inotropic agent):氨力农、洋地黄毒苷、地高辛、依诺昔酮、毛花苷C、甲地高辛。
糖皮质激素:倍氯米松、倍他米松、布地奈德、乙酸可的松、去氧米松、地塞米松、乙酸氟氢可的松、氟尼缩松、氟可龙、丙酸氟替卡松、氢化可的松、甲基泼尼松龙、泼尼松龙、泼尼松、曲安西龙。
利尿剂:乙酰唑胺、氨氯吡咪、苄氟噻嗪、布美他尼、氯噻嗪、氯噻酮、依他尼酸、呋塞米、美托拉宗、螺内酯、三氨蝶呤。
抗震颤麻痹剂:甲磺酸溴隐亭、马来酸麦角乙脲(lysuride maleate)。
胃肠剂:比沙可啶、西咪替丁、西沙必利、地芬诺酯、多潘立酮、法莫替丁、洛哌丁胺、美沙拉嗪、尼扎替丁、奥美拉唑、奥丹西隆、雷尼替丁、柳氮磺吡啶。
组胺H,-受体拮抗剂:阿伐斯汀、阿司咪唑、桂利嗪、赛克力嗪、赛庚啶、茶苯海明、氟桂利嗪、氯雷他定、美可洛嗪、奥沙米特、特非那丁。
血脂调节剂:苯扎贝特、氯贝特、非诺贝特、吉非罗齐、普罗布考。
硝酸盐和其它抗心绞痛剂:硝酸戊酯、三硝酸甘油酯、二硝酸异山梨酯、单硝酸异山梨酯、季戊四醇四硝酸酯。
营养剂:β胡萝卜素、维生素A、维生素B2、维生素D、维生素E、维生素K。
HIV蛋白酶抑制剂:奈非那韦,
阿片止痛剂:可待因、丙氧匹林(dextropropyoxyphene)、海洛因、双氢可待因、美普他酚、美沙酮、吗啡、纳布啡、喷他佐辛。
性激素:柠檬酸克罗米酚、达那唑、炔雌醇、乙酸甲羟孕酮、美雌醇、甲基睾酮、炔诺酮、炔诺孕酮、雌二醇、轭合雌激素、孕酮、羟甲烯龙、己烯雌酚、睾酮、替勃龙。
刺激剂:苯丙胺、右苯丙胺、右芬氟拉明、芬氟拉明、马吲哚。
另外,不被限制地,根据本发明的优选药物包括:他克莫司、西罗莫司、卤泛群、利托那韦、洛匹那韦(loprinavir)、安普那韦、沙奎那韦、骨化三醇(calcitrol)、屈大麻酚、异维A酸、维A酸、利培酮碱、丙戊酸,同时优选的前药包括地塞米松棕榈酸酯、紫杉醇棕榈酸酯、多西紫杉醇棕榈酸酯。
一些可被加入到本发明传输系统中的亲脂性药物及它们的医学应用的非限制性例子被Robert G.Strickley[Strickley R.G.PharmaceuticalResearch,21(2):201-230;(2004)]和Kopparam Manjunath等人[Manjunath K.等人,Journal of Controlled Release 107:215-228;(2005)]所描述。
根据另一个实施方式,活性剂是两亲剂。本文使用的术语“两亲剂”是指具有在1.5-2.5之间的log P值的任何化合物且具有甘油三酯(TG)溶解性,如所测定的,通过在豆油或类似物中的溶解性,超过10mg/mL。
可被本发明系统传输的两亲活性剂的例子包括,但不限于水杨酸毒扁豆素(pysostigmine salicylate)、氯丙嗪、氟奋乃静、三氟拉嗪和利多卡因、布比卡因、两性霉素B、依托泊甙、替尼泊甙和抗真菌剂棘白菌素类和唑类,如克霉唑和伊曲康唑(itaconazole)。
另一个适于包载在根据本发明的纳米胶囊中的治疗的非亲水性活性剂的例子包括,但不限于氯氮平。氯氮平是应用在难治性精神分裂症中的有效的非典型的抗精神病药。氯氮平可被快速地口服吸收,其生物利用度为27%。氯氮平是被肝微粒体酶(CYP1A2和CYP3A4)强代谢的且形成N-去甲基和N-氧化物代谢物。因此,氯氮平是被本发明系统传输的良好候选剂。
本发明还提供容纳多个根据本发明的纳米胶囊的微球的制备方法,所述方法包括:
(a)提供有机相,其包括油、与水混溶的有机溶剂、溶解在溶剂中的非亲水性活性剂和用于包衣所述油核心的聚合物或聚合物组合;
(b)向所述有机相中缓缓加入水以获得油包水乳液;
(c)向油包水乳液中继续加入,优选逐滴地加入水以引发所述乳液的相转化,从而获得水包油(o/w)乳液;
(d)将所述o/w乳液与凝胶形成聚合物或凝胶形成聚合物的组合混合;
(e)除去所述有机溶剂和水以获得所述容纳多个纳米胶囊的微球。有必要注意纳米胶囊包括油核心,活性剂溶解或分散在其中并注意此油核心被聚合物外壳所包装。多个外壳包衣的油核心容纳在凝胶形成聚合物中,以致于剂与凝胶形成聚合物之间不存在直接接触。
在本发明方法中使用的有机溶剂可为任何与水混溶的有机溶剂,其具有接近或低于水沸点的沸点。此类有机溶剂的非限制性列表包括乙醇、甲醇、丙酮、乙酸乙酯、异丙醇(沸点108℃,尽管如此在本发明背景中被认为是挥发性的)。
油和有机溶剂的组合的使用使各种剂能够在纳米胶囊中被胶囊化,所述剂必须本质上为非亲水性。油核心也可包括一种或多种非亲水性赋形剂(如亲脂性赋形剂)。出于此原因,本发明方法也可包括在有机相中添加一种或多种赋形剂。赋形剂优选任何在油相中具有至少1%溶解度的赋形剂。根据一个实施例,赋形剂是亲脂性表面活性剂如labrafil M 1944 CS、聚山梨醇酯80、聚山梨醇酯20。
向含有油的有机相中,缓缓地加入水,必要地,为逐滴地。在开始时,形成水包油乳液,即水滴分散在有机相中。然而,向介质中继续缓慢滴加水最终产生相反的现象,其中连续和不连续是“转换的”以致于用聚合物包衣来包衣的小油滴分散在水中。
本文使用的术语“乳液”指具有至少两种液相的系统,其中一种液相分散在另一种液相中。分散的相也被称为内相、不连续相、不连贯相(分散的滴)而外相也被称为连贯相或连续相。乳液可包括多于两种的相。例如,它们可包括三种液相(即三重乳液),或两种液相及一种固相。所有乳液的共同之处为它们的外相是液体状态。如果存在第三相,如液相或固相,其通常分散在分散相中,所述分散相分散在外相中。乳化剂可以存在或也可以不存在。
不同类型的乳液可被定义,通过参考形成外相的液体类型对形成分散相的液体类型。就此而论,当油相分散在水相中时,乳液采用术语“水包油乳液”或“正相乳液”。然而,也可能形成“反相或油包水(w/o)乳液”。在反相乳液中,水滴被分散在油的连续相中。
当形成纳米胶囊时,最初,形成油包水乳液且此w/o乳液通过向油/有机相中添加水被转化为o/w乳液。不被理论所束缚,认为作为结果,系统中的聚合物在油水分界面沉积,其包载所有内部小油滴且将它们与连续的水相隔离。产生的包括以包衣聚合物包衣的小油滴的乳液随后与凝胶形成聚合物的溶液混合。一旦形成水包油乳液并添加凝胶形成聚合物,有必要除去溶剂(或溶剂混合物)和水。
存在若干可用于从乳液中除去溶剂(或溶剂组合)的技术,如本领域技术人员已知的技术,其包括加热和溶剂蒸发、挥发溶剂蒸发随后冻干等。根据本发明,优选地用喷雾干燥法除去溶剂,所提供的活性剂不是热敏的。在活性剂是热敏的情况下,可使用从乳液中除去溶剂的其它方法,如本领域技术人员已知和认可的方法。
喷雾干燥是在20世纪30年代发展的机械的微胶囊化方法。因此,乳液可通过将浆从旋转盘中泵到喷雾干燥器的热室中被自动化为液滴喷雾。在热室中,乳液中的溶剂和水被蒸发以获得干燥微球。
可根据任何预期应用将所产生的干燥微球进行配制。此类微胶囊化的材料存在几乎无限的应用。除其他因素之外,取决于所用活性剂,微球可应用于农业、药物、食品、化妆品和香水、纺织品、纸、颜料、涂料(coating)和粘合剂、印刷应用及许多其它行业中。
根据优选的实施方式,微球可用于医药、化妆品或诊断中。
更优选地,干燥微球被配制为药物组合物,优选地用于口服施用。出于此原因,干燥微球可被包括在肠内媒介中,如肠内胶囊。肠内胶囊的非限制性例子包括本领域已知的肠溶包衣的软胶囊或硬胶囊。
应注意到,当通过使用此类肠内媒介可保护干燥微球免受胃液侵蚀时,小油滴(在纳米胶囊中)不需要以在pH大于5.0时可溶的聚合物包衣。换句话说,可溶于水的聚合物和不溶于水的聚合物的组合是可应用的。
另一方面,使用包括只在pH大于5.0时可溶的聚合物的聚合物混合物,微球的其它传输形式是可能的,如以小药囊(sachet)形式。
因此,应理解取决于具体的制剂类型,药剂师或任何其它配方师可确定根据本发明使用的具体的聚合物组合。
针对口服传输,可使用片剂、丸剂、粉剂、锭剂、小药囊、扁胶剂、酏剂、悬浮剂、气溶胶(作为固体或在液体介质中)及灭菌包装粉剂及其他传输形式。
本发明微球被指出与商业产品或乳液制剂(在结果部分命名的油)相比,可提供示例性活性剂升高的血液水平。
根据一个实施方式,本发明微胶囊提供活性剂的控制释放。如本文使用的,“控制释放”意指不立即释放的任何类型的释放。例如,控制释放可被设计为改性的、广泛的、持续的、延迟的、延长的或恒量的(即0级)释放。理论上,最有效的释放特性中的一种为在预定的时间期间内的恒量释放。认为剂的控制释放可通过应用到液滴的包衣来获得及活性剂的释放特性可被在形成外壳的聚合物的组分中的变量所规定。如本领域已知,也可通过在核滴上应用多种聚合物混合物的包衣制成控制速度的聚合物包衣。
应注意到,使用本发明方法,构造了微球,以致于在活性剂和凝胶形成聚合物(其可为凝胶形成聚合物的混合物)之间不存在直接接触。此外,应注意到本发明方法使任何过量的形成外壳的聚合物与凝胶形成聚合物混合,即形成包衣纳米胶囊的微球的部分。这样,在终产品与水环境接触时,凝胶形成聚合物凝胶化且溶胀同时过量的与凝胶形成聚合物混合的可溶于水的聚合物或在pH大于5.0时可溶的聚合物被溶解。不被理论所束缚,相信通过这种在微球结构中的凝胶形成聚合物和过量的其它聚合物(用于构造纳米胶囊壁)的组合,包括活性剂的完整的纳米胶囊从微球中被释放(假定通过在微球中形成的间隙,所述间隙是可溶聚合物溶解所产生的)及以其游离的形式的药物不被释放。不被理论所束缚,还相信纳米胶囊从凝胶中被释放及以其游离的形式的药物不被释放,这允许剂从P-gp外排中脱离且因此它们被淋巴管吸收。
本发明还提供提高活性剂在人类受治疗者体内生物利用度的方法,所述方法包括向所述受治疗者提供本发明微球。本发明得出的结果显示通过使用根据本发明的微球,测试活性剂在血液中的生物利用度将增加,至少增加1.3倍,优选地2倍,更优选地3倍,这与所使用的对照药物有关(见例如图12)。
本发明还提供针对病理疾患以在需要所述治疗的受治疗者的血液系统中的有效量活性剂治疗受治疗者的方法,所述方法包括向所述受治疗者提供本发明微球。
本文使用的术语“病理疾患”指为了改善受治疗者健康状态要求传输药物或前药或诊断剂的活性剂(如上文列举的那些)的任何疾患。当活性剂是非亲水性实体时,例如但不限于亲脂性剂或两亲剂,或活性剂的任何亲脂性/两亲衍生物,根据本发明的活性剂的传输优选地,通过淋巴运输。疾患的非限制性列表包括,除其它事物以外,炎症和自身免疫紊乱、寄生(如疟疾)、细菌、病毒或真菌感染、心脏病(如心率不齐)、凝血功能紊乱、抑郁、糖尿病、癫痫症、偏头痛、癌症、免疫疾病、荷尔蒙失调、精神疾患、胃肠道疾病、营养疾患及许多其它疾病,如本领域已知的。
活性剂在其药物组合物中和其剂型单元中的有效量可被广泛地改变或调整,取决于特殊的应用、引入方式、特殊活性剂的潜力、剂向纳米胶囊的装载和预期浓度。有效量通常在适当设计的临床试验(剂量范围研究)中被确定且为了确定此有效量本领域技术人员将知道如何精确的操作此类试验。如通常已知的,有效量取决于多种因素、各种药理学参数如在体内的半衰期、预期的副作用、因素如年龄和性别(如果有的话)等,所述多种因素包括活性剂的疏水性(hydrophibiclity)和当相关时,亲脂性/两亲性、形成纳米胶囊的聚合物的选择(小油滴的包衣)和/或外部的凝胶形成的封装、活性剂在从纳米胶囊中被释放后在体内的分布特性。
术语“单元剂型”指物理上不连续的单元,其适于作为针对人类受治疗者和其它哺乳动物的单一剂量与适合的药物赋形剂联合,每个单元含有预定量的活性剂,其被计算产生预期的治疗作用。治疗的活性剂的浓度可变化。
本发明组合物可作为单一剂量且在若干天之内,在延长的时间期间内以单一的每日剂量或每天若干剂量等被施用。治疗周期一般将具有与疾病过程的时间长度及具体的微球的效力(如通过淋巴系统的有效传输、剂的效力等)及被治疗的患者物种成比例的时间长度。
如所意识到的,虽然在下文详述的说明书中伴随着提及微球及它们的制备方法描述了本发明,但是应理解在本发明中还包括包含它们的药物组合物及使用此药物的治疗方法,及微球的任何其它用途。
如在说明书和权利要求书中所使用的,词形“一种(a)”、“一种(an)”和“the”包括单数及复数含义除非上下文明确地另有所指。例如,术语“一种聚合物”包括一种或多种聚合物及术语“油”包括一种或多种油类。
此外,如本文使用的术语“包括”是用来指含有列举的成分的微球,但不排除其它成分。术语“基本上由......组成的”被用于定义含有列举的成分但不排除其它成分的微球,所述其它成分对于亲脂性剂在受治疗者体内的生物利用度具有实质意义。例如,基本上由以可溶于水的聚合物(非pH依赖型)包衣的小油滴组成的微球将不包括pH依赖型聚合物或只包括可忽略量的(对非亲水性剂从微球释放具有可忽略的作用的量)pH依赖型聚合物,所述聚合物关于它们的溶解度是pH依赖型,如肠内聚合物。“由......组成”将因此指排除多于痕量成分的其它成分。被这些过渡术语中的每一个所定义的实施方式在本发明范围内。
此外,所有数值,如当涉及组成微球的成分的量或范围时,为近似值,围绕规定值上下浮动达20%,有时达10%。即使不总是明确规定,应理解在所有的数字名称之前加上了术语“约”。
具体实施方式
实施例1:容纳在微球中的纳米胶囊
材料和方法
材料
聚(丙烯酸乙酯、甲基丙烯酸甲酯、甲基丙烯酸三甲基乙基氯化氨)1∶2∶0.2(Eudragit RL)、聚(丙烯酸乙酯、甲基丙烯酸甲酯、甲基丙烯酸三甲基乙基氯化氨)1∶2∶0.1(Eudragit RS PO)和聚(甲基丙烯酸、丙烯酸乙酯)1∶1(Eudragit L 100-55)从Rohm(Dramstadt,GmbH,德国)购得,邻苯二甲酸羟丙基甲基纤维素酯(HPMCP 55 NF)从Eastman(Rochester,USA)获得。羟丙基甲基纤维素(Methocel E4M Premium)从Dow Chemical Company(Midland,MI,USA)获得,甲基纤维素(Metolose 90SH 100,000)从Shin-Etsu(Tokyo,Japan)获得,摩洛哥坚果油(Argan Oil)从Alban-Muller(Vincenny,France)购得,聚氧乙烯基油酸甘油酯(Labrafil M 1944 CS)是Gattefosse(St.Priest,France)友情捐赠的,地塞米松棕榈酸酯(DXPL)按照2.1中所描述合成,他克莫司(为一水化物)从Concord Biotech Limited(Ahmedabad,India)购得,两性霉素B可从Alpharma(Lot N:A1960561)购得。其它化学品和溶剂是分析纯试剂并且在研究中使用双蒸水。
方法
纳米胶囊的制备
各种初步制剂按照表1和表2所描述被制备。
在本研究中针对纳米胶囊制备使用两种不同的溶剂添加方法。第一种方法基于已为大家接受的Fessi等人的方法[Fessi H等人.Nanocapsuleformation by interfacial polymer deposition following solvent displacement(在替代溶剂之后通过分界面聚合物沉积制得的纳米胶囊).Int J Pharm 1989 55:R1-R4(1989).],其在从油/有机相中替代与水混溶的半极化共溶剂系统(丙酮∶乙醇;19∶1)之后,使用包衣聚合物的分界面沉积。包括丙酮溶液的油相、亲脂性表面活性剂、包衣聚合物(形成纳米胶囊封装的聚合物)及各自的药物被倒入最终含有乳液稳定剂的水溶液中。作为纳米胶囊形成的结果,水相立即变为乳状,具有带蓝色的乳白光(表1)。相反,在表2中所提出的纳米胶囊制剂中,水相被缓缓加到丙酮∶乙醇/有机相中,首先导致w/o微乳液的形成,其在替代双极性溶剂之后继续加水时产生相反的o/w乳液,导致纳米胶囊的形成。
应强调,他克莫司是非常昂贵和有毒的药物,其需要被小心地加工。因此,决定用地塞米松棕榈酸酯(DXPL)实行初步实验,所述DXPL为亲脂性药物,其作为模型药物特别地用于评价体外释放动力学实验。
地塞米松棕榈酸酯的合成
地塞米松(1当量)被溶解在新干燥的吡啶中(对每1克地塞米松使用2.5ml吡啶)。所产生的溶液用二氯甲烷稀释1到5并在冰浴中被冷却到4℃(溶液A)。棕榈酰氟(1.2当量,Aldrich)被溶解在二氯甲烷中(对每1克棕榈酰氯使用15ml二氯甲烷)并且也冷却到0℃(溶液B)。溶液B被转移到均压漏斗中并逐滴添加到剧烈搅拌并冷却的溶液A中。添加完成之后(5g地塞米松30分钟),反应混合物用氮气吹扫、封顶并在冰浴中搅拌过夜。第二天早上取样品使用薄层色谱评价反应进程,用乙酸乙酯∶己烷(按体积3∶1)洗提。通常获得三个主峰:第一个代表地塞米松,第二个是棕榈酰氯且第三个代表产物地塞米松棕榈酸酯。在反应未完成的情况下,混合物被留下搅拌另外12小时。在此时期结束时,在减压下(加热不超过60℃)除去有机溶剂。向残余物中加100ml 2∶1的乙酸乙酯∶己烷混合物。所得到的悬浮液被剧烈搅拌且通过Buckner漏斗过滤。用乙酸乙酯洗涤半固体且分离所得过滤物。用100ml 5%的冷氢氧化钠溶液洗涤有机层两次,用水洗涤两次且用氯化钠饱和溶液洗涤一次。有机层在无水硫酸钠上过滤且蒸发以干燥。残余物被溶解在最小量的氯仿中且被应用到硅柱(40cm长)用于快速色谱。以氯仿∶己烷(1∶1)洗提柱且合并富含地塞米松棕榈酸酯的组分,蒸发至干燥并用HPLC检测产物纯度。实际产率为60%。
他克莫司纳米胶囊制备
Eudragit RS、Eudragit L100 55、Labrafil 1944 CS、摩洛哥坚果油和他克莫司以表3中所描述的浓度被溶解在100ml丙酮∶乙醇(90∶10)溶液(油相)中。向油相中加入75ml水(在2分钟之内)以形成分散体。向分散体溶液中,在喷雾干燥步骤之前加入200ml 0.5%的甲基纤维素溶液。仅在纳米胶囊形成之后加入甲基纤维素和最后的水部分。除非另外说明,甲基纤维素指Methocel E4M。
本文示例了三种制剂:29号制剂和30号制剂,其中它们的成分在表3、4中描述。这些制剂在它们的聚合物比例上不同:分别地,Eudragit RS∶Eudragit L100-55为25∶75或75∶25。进一步的制剂为32号制剂,其具有与29号制剂相似的成分,但是没有Eudragit RS和Eudragit L100-55。
表3:29号纳米胶囊制剂组成
*制剂32与制剂29的成分相同,但不含Eudragit RS和Eudragit l100-55。
表4:30号纳米胶囊制剂组成
两性霉素B纳米胶囊制备
Eudragit RS、Eudragit L100 55、Labrafil 1944 CS、摩洛哥坚果油和(以乙酸溶解的两性霉素)以表3所描述的浓度被溶解在100ml丙酮∶乙醇(90∶10)溶液(“有机相”)中。向有机相添加75ml水(在2分钟内)导致分散体的形成。在喷雾干燥步骤之前,向分散的溶液中加入200ml 0.5%的羟丙基甲基纤维素溶液。羟丙基甲基纤维素与最后一批水只在纳米胶囊形成之后被添加,羟丙基甲基纤维素指Methocel E4M。纳米胶囊制剂在表5中表示。
表5:两性霉素A纳米胶囊制剂组成
编号 | 材料名称 | 量 |
1 | 丙酮 | 90ml |
2 | Eudragit RS | 0.25g |
3 | Eudragit L 100-55 | 0.75g |
4 | 乙醇 | 10ml |
5 | 摩洛哥坚果油 | 1ml |
6 | Labrafil M 1944 CS | 0.2ml |
7 | 两性霉素 | 60mg |
8 | DD水 | 75ml |
9 | Methocel E4M | 1g |
10 | DD水 | 200ml |
他克莫司或两性霉素B纳米胶囊被喷雾干燥法微胶囊化
用Buchi小型喷雾干燥仪B-190仪器(Flawil,Switzerland)在以下条件下将悬浮液喷雾干燥:入口温度为180℃;出口温度为113℃;通风(aspiration)50%;悬浮液的进料速度为2.5ml/分。在旋风分离器中收集粉末且计算出口产率。
他克莫司纳米胶囊和随后的微胶囊的物理化学性质
药物含量
他克莫司在粉末中的总量通过将样品溶解在5ml PBS中被分析。在聚合物被溶解之后,加入1ml乙腈(ACN)且搅拌(100rpm)混合物1小时。随后,加入3ml乙酸乙酯并剧烈搅拌混合物并在4000rpm下离心分离5分钟。
用乙酸乙酯反复萃取他克莫司3次以确保药物从混合物中全部除去。不同的乙酸乙酯层(上层)被转移到干净的管中并在空气中蒸发至干燥。合并的残余物被溶解在1ml ACN中,并在以下条件下向HPLC中注射50μl:流动相-乙腈100%,流速-0.5ml/分,波长-213nm,柱100RP-18(5μm),4/120mm。以范围在5μg/ml到250μg/ml之间的他克莫司浓度建立的标准曲线产生线性相关性。发现他克莫司检测限值为3.9μg/ml。
用以下公式计算他克莫司加入产率:
两性霉素B在粉末中的总量通过将样品溶解在5ml二甲亚砜(DMSO)中被分析。在聚合物被溶解之后,搅拌(100rpm)混合物1小时。之后,在波长407nm处用分光光度计测定两性霉素B的浓度。从两性霉素B浓度从0.781μg/ml到100μg/ml的范围建立的标准曲线产生线性相关性(具有R2=0.999)。发现喷雾干燥的粉末的两性霉素B的含量为0.85%w/w。
DXPL含量
药物在粉末中的总量通过将样品溶解在5ml PBS中被分析。在聚合物被溶解之后,加入5ml甲醇且搅拌(100rpm)混合物1小时。之后,加入3ml二氯甲烷并剧烈地搅拌混合物,并在4000rpm下离心分离5分钟。用二氯甲烷重复萃取DXPL三次以确保药物从混合物中全部除去。不同的二氯甲烷层(下层)被转移到干净的管中并在空气中蒸发至干燥。合并的残余物被溶解在200μl甲醇中,并在以下条件下将50μl注射到HPLC中:流动相-甲醇100%,流速-0.7ml/分,波长-242nm,柱100 RP-18(5μm),4/120mm。
从DXPL浓度在0.01μg/ml和5μg/ml之间的范围建立的标准曲线产生线性相关性。
发现DXPL的检测限为9.8ng/ml。
用以下公式计算DXPL的加入产率:
DXPL从微粒体外释放动力学的评价
由于当漏槽条件占优势时他克莫司的检测限值受限制,体外动力学实验以DXPL进行,使用无任何压力的超滤技术[Magenhiem B,等人A newin vitro technique for the evaluation of drug release profile from colloidalcarriers-ultrafiltration technique at low pressure(一种用于评估药物从胶质载体中的释放特性的新的体外技术-在低压下的超滤技术).Int J Pharm94:115-123(1993).]。
使用超滤细胞装置Amicon(Amicon Corp,Danvers,Mass,USA)。所使用的过滤器为ISOPORETM 8.0μm TEPT(Millipore,Bedford,MA,USA)。在此研究中,匹配漏槽条件释放。将微粒样品(5mg)置于100ml释放介质中(10%乙腈的pH 7.4的磷酸盐缓冲液,其不改变纳米胶囊的物理稳定性)。在给定的时间间隔内,释放介质的0.5ml样品通过8.0μm过滤器被收集,其使纳米胶囊通过此过滤器扩散。随后,加入0.5ml甲醇并涡旋以使纳米胶囊溶解。之后,加入3ml二氯甲烷并剧烈地涡旋混合物,随后在4000rpm下离心分离超过5分钟。在离心分离之后,将二氯甲烷层(下层)转移到干净的管中并在空气下蒸发至干燥。残余物被溶解在200μl甲醇中,并在先前描述的条件下将50μl注射到HPLC中。
确定最初纳米胶囊及第二微球颗粒尺寸
使用ALV非侵入性背散射高效粒度仪(Non-Invasive Back ScatteringHigh Performance Particle Sizer)(ALV-NIBS HPPS;Langen,Germany)在25℃下并以水做溶剂执行纳米胶囊尺寸测定。使用在632nm波长的激光束。灵敏度范围为0.5nm-5μm。喷雾干燥的微粒被扫描电子显微镜定性地评估。
扫描电子显微镜(SEM)
使用扫描电子显微镜(型号:Quanta 200,FEI,Germany)执行纳米胶囊和喷雾干燥的微球的形态学评估。使用双面胶带将样品固定在SEM-stub上并随后在真空下按照金溅射(gold spattering)(pilaron E5100)试验方案进行标准包衣使之导电。
透射电子显微镜(TEM)
使用TEM分析完成纳米胶囊的形态学评估。样品被放在火棉胶-包衣的、碳-稳定化的铜网中1分钟,用1%磷钨酸(PTA)染色。样品被干燥且用TEM(Phillips CM-12;Philips,Eindhoven,The Netherlands)检查。
在大鼠中的吸收研究
本研究由本地实验动物管理伦理委员会根据与实验动物的管理和使用相关的准则和方针MD 104.01-3所批准。在此研究中,使用重为300-325g的Sprague Dawley大鼠。使动物住在SPF条件下并在实验前禁食24小时。第二天早上,动物在禁食的状态下,用0.2mg/鼠的他克莫司经口灌给药,所述他克莫司被配制为胶囊成分(批次-5C5129B exp.-06/2007,Fujisawa Ltd.UK)(CAPS)的悬浮液、水包油乳液(OIL)或新型DDS(29号制剂和30号制剂)或32号制剂。
从剂量施用后在0分钟、30分钟和1、2、3、4、6和24小时从大鼠尾部取血液样品(100-150μL)。血液样品用含有肝素的管收集。样品被立即冷冻在-20℃并遵循公司所表示的方法使用PRO-TracTM II ELISA试剂盒(DiaSorin,USA)检验他克莫司水平。此ELISA方法在临床实践中被广为接受且可准确地检测从0.3ng/ml到30ng/ml的他克莫司血液水平。
生物利用度计算
使用初始浓缩物注射安瓿(5mg/ml)(批次:5A3098H exp:11/06,Fujisawa Ltd.UK)通过I.V推注以160μg/kg他克莫司对每只大鼠给药。在5分钟、30分钟和1、2、3、4、6和24小时从动物尾部取血液样品(100-150μL)。样品被处理并如上文所描述被分析。使用WinNonlin软件(版本4.0.1),使用计算AUC的梯形法则计算不同制剂的药物动力学参数。
口服的不同制剂的绝对生物利用度通过使用以下公式被计算:
与标准的市场化制剂(CAPS)相比,任何口服制剂的相对生物利用度使用以下公式计算:
在不同实验条件下的油核心的稳定性评价
在5mg他克莫司溶解在300μl摩洛哥坚果油∶Labrafil 5∶1溶液(ALSOL.)中后,他克莫司在摩洛哥坚果油/labrafil中在不同的实验条件下经过长期储存在37℃下的化学稳定性被评估。各种抗氧化剂赋形剂也被溶解在表6中所描述的油制剂中。被储存在完好封闭的玻璃小瓶中的制剂中的一些以氮气吹扫以确保惰性的气体条件。
表6:含1.66%他克莫司的油制剂组成
在小型猪中吸收研究
在此研究中,使用重18kg到21kg的小型猪。给每只动物口服施用1mg他克莫司,执行吸收研究,所述他克莫司被配制为明胶胶囊商业产品(Comm.Prod.),和使用不同Eudragit混合物的新型DDS明胶胶囊(新型DDS=制剂29)。
手术步骤:Hebrew University的动物管理和使用委员会(MD 117.04-3)检查并批准了所有手术和实验步骤。针对所有研究使用重为18-21kg的小猪。动物被禁食过夜;在研究中允许自由得到饮用水。第二天早上,使用isofloran(面具)将动物麻醉短时期(10分钟)。在此期间动物被:
(2)将导管插入颈静脉中用于取血液样品并将其固定在猪背上。在0、15min、30min和1、1.5、2、3、4、8、12和24小时时取血液样品(1ml)并收集在含有肝素的管中(在实验中动物是有知觉的)。
样品立即被冷冻在-20℃下并使用PRO-TracTM II ELISA试剂盒(DiaSorin,USA)检验他克莫司水平。
结果与讨论
形态学分析
出人意料地,当水相被缓慢加到有机相时(表2);首先,水在油相中分散,随后,在约为15ml水的水量加到100ml丙酮溶液中后,形成了o/w乳液,证据为在分散介质中乳白光的快速形成。在此阶段,内部丙酮/乙醇相向外部水相的快速扩散发生,导致疏水聚合物在o/w界面的沉积及由油核心组成的纳米胶囊的形成,所述油核心被如在图1中描述的Eudragit聚合物混合物包衣,其中丙酮溶液比水的最终比例为100∶75 v/v。应强调在相同的Eudragit混合物浓度下但在不含有油时,Eudragit相分离现象和反映聚合物从丙酮溶液中分离的乳白光,在45和35ml水分别地加到29号制剂和30号制剂中后发生。此不同可能由于在制剂29和制剂30之间,Eudragit RS和Eudragit L100-55在混合物中的不同比例。明显地,当水缓慢地加到含有labrafil表面活性剂的展示为4的低HLB值的丙酮∶乙醇/油相中时,形成透明的w/o微乳液且注意到没有相分离。当水进行性和继续添加时,在某种亲水性∶亲脂性体积比,相反的o/w乳液自发形成,随后立即地丙酮和乙醇向外部的水相取代(扩散),导致疏水Eudragit聚合物混合物在小油滴的o/w分界面上沉积,导致在摩洛哥坚果油核心周围的纳米胶囊封装的形成,其中药物和表面活性剂溶解在油核心中。在此阶段仅加入了75ml水,在纳米胶囊周围的Eudragit混合物膜仍然为部分水合的且薄,如在图1A和1B中所注意到的。当进一步添加200ml 0.5%甲基纤维素溶液时,发生了丙酮和乙醇从纳米胶囊中完全提取出来且更加刚性的和Eudragit膜形成,如可从在图2A和2B中的数据推导出来的。由于甲基纤维素的存在和在分散体中纳米胶囊的高浓度,形成大的纳米胶囊聚集体。在小油滴周围的刚性聚合物膜是不同的且与在图1A和1B中显现的纳米胶囊中的薄膜相比可被轻易地识别。
当30号制剂用75ml不含甲基纤维素溶液(即100∶75,v/v)的水稀释时,这进一步被证实。更加显著的Eudragit混合物的分界面沉积发生且形成厚度定性地估计为30nm的刚性Eudragit膜,如在图3A和3B中所示。确实,此特殊混合物的溶解性比在制剂29中的当加入至少45ml水时稍后分离的Eudragit混合物的溶解性小,而对于制剂30,替代的35ml。非油相或小油滴使用此方法检测,如在表2中所描述的。所选纳米胶囊分散体29号制剂的颗粒尺寸分布展现窄的范围,具有平均直径为479nm(图4)。
SEM分析证实先前的TEM结果并显示在向制剂29中加入75ml水后形成单独的纳米胶囊(图5A和5B)。然而,在加入甲基纤维素溶液和喷雾干燥之后,球状微球(定性地尺寸范围为从2μm到5μm)形成的小聚集体(定性地尺寸范围为从10μm到30μm)可被检测到(图6A和6B)。此外,在喷雾干燥的聚集体在释放介质pH 7.4中浸渍超过3小时后,不可能区别出任何规则的结构形态学(图7A和7B)。实际上,在29号制剂中的Eudragit形成膜混合物包括Eudragit L100-55∶Eudragit RS 75∶25。Eudragit L100-55在大于pH 5.5时是易于溶解的而Eudragit RS无论何种pH都是不可溶的。这样,最初甲基纤维素包衣和第二纳米胶囊Eudragit混合物包衣被快速的溶解且没有确定的结构可被鉴别。然而,可从SEM分析(图8A-8D)观察到在干燥喷雾之后,30号制剂展现较少的聚集体和更多的球状结构,作为真空的结果,其是坍陷的。此外,在图9A和9B中,在释放介质中浸渍超过3小时后,在微球的空核心中可检测到许多纳米胶囊,证明了包括EudragitRS∶Eudragit L100-55为75∶25的Eudragit混合物纳米胶囊包衣更能够抵抗水释放介质和能够控制胶囊化的药物随时间释放的发现。
体外释放动力学评估
体外释放数据可暗示剂从微球中的释放可被在小油滴周围应用的聚合物包衣的变化所控制。如从图10中可被注意到的,DXPL的释放特性为在具有Eudragit L∶RS,75∶25时比具有RS∶L,75∶25时要快,说明Eudragit L可更容易地渗透且比Eudragit RS得到快的释放速度。
图11显示没有Eudragit包衣的DXPL亚微米乳液在与29号制剂相同的实验条件下被喷雾干燥的结果。两种类型的微球得到相似的释放特性。不同于溶解的DXPL和装载有DXPL的纳米胶囊的释放,溶解的DXPL和装载有DXPL的小油滴被释放,反映出对于两个实验的DXPL总释放量相同。这些发现暗示释放动力学实验不能区别溶解的DXPL和掺入小油滴或纳米胶囊中的DXPL。
在不同实验条件下被溶解于纳米胶囊油核心中的他克莫司的稳定性评价
可从表7中所描述的数据中推出,他克莫司当溶解在油制剂中在37℃下储存一个月后,即使在氮气氛下及在各种抗氧化剂存在时也是不稳定的,除非用BHT和五倍子酸丙酯配制且与氮气氛相结合。
储存在室温下的微胶囊化他克莫司纳米胶囊的稳定性评估
在室温下,微胶囊化的他克莫司纳米胶囊的最终干燥制剂被储存在完好封闭的塑料容器中。在3和4个月后,检验29号制剂且发现用HPLC测定的他克莫司含量分别为各自含量的初始的99%和95%。在室温下,最终产物的稳定性在继续的监视中。最终选择的最终制剂在不久的将来将进行加速稳定性实验。
表7:当储存在37℃时,作为制剂参数的函数的在油核心中的他克莫司含量的评估
制剂 | 抗氧化剂 | 1周为初始含量的% | 1月为初始含量的% |
AL SOL.1 | 维生素E+N2 | 92.2 | 84.4 |
AL SOL.2 | BHT、五倍子酸丙酯+N2 | 117.6 | 115.5 |
AL SOL.3 | BHT、五倍子酸丙酯 | 99.7 | 82.0 |
AL SOL.4 | N2 | 84.9 | 59.8 |
AL SOL.5 | 无 | 113.1 | 85.2 |
在大鼠中的吸收研究
如先前提到的,在口服施用之后,他克莫司与显著可变的生物利用度和药代动力学相关联。这表示着他克莫司本质的空肠通透性相当高。也检查了他克莫司的区域依赖的通透性,且研究揭露与在空肠中相比在回肠和结肠中他克莫司通透性显著地降低。在那种情况下,很多他克莫司的可变性似乎由其他因素导致,如P-糖蛋白(P-gp)外排机制或CYP3A代谢作用,其可造成观察到的区域依赖性(5)。确实,经报导CYP3A和P-gp在肠吸收和口服生物利用度上的合并作用是他克莫司口服药物传输的主要障碍[Kagayama A,等人,Oral absorbtion of FK506 in rats(在大鼠中FK506的口服吸收).Pharm Res.10:1446-50(1993)]。已尝试通过o/w油酸乳液将药物选择性地运输到淋巴系统中以改进他克莫司吸收(15)。作者将他克莫司乳液以2mg/kg和1mg/kg的剂量口服地施用给大鼠且将它与商业产品比较。观察到将剂量从2mg/kg减少到1mg/kg显著地降低了在大鼠血液中的Cmax,对于商业和乳液剂型分别地为从36.3±18.3到8.5±4.8和从32.1±9.6到6.0±2.2ng/ml。当以剂量1、3.2和10mg/kg将分散体剂型的他克莫司口服施用给喂养的大鼠时,相似的结果被报导,其产生的Cmax值为8.8±4.9、11.6±5.3和40.2±19.4ng/ml。
现在的结果显示以剂量0.7mg/kg口服施用商业产品(CAPS)展现了1.1±0.8ng/ml的Cmax,极大地小于报导值,清楚地显示了施用剂量对Cmax值的显著影响。此外,乳液展现了2.2±0.46ng/ml的Cmax值而29号制剂展现了11.1±2.7ng/ml的Cmax值,如在表8中所描述的。
另外,制剂29展现的吸收特性显著的好于乳液和商业产品产生的特性(图12)。然而,与制剂29相比,制剂30不展现加强的释放特性(图13)。
另外,在口服吸收对大鼠给药的各种制剂中0.7mg/kg(平均值±SD,n=3-6,p>0.05)的他克莫司之后,检测他克莫司血液水平(图14)。使用口灌法,以0.7mg/kg(0.2mg/鼠)他克莫司执行大鼠吸收研究,所述他克莫司被配制为胶囊商业产品(Comm.Prod.)的悬浮液、乳液(Emuls.)、包埋在不含Eudragit但含有甲基纤维素的微球中的乳液(干燥Emuls.)、包埋在不含甲基纤维素但含有Eudragit纳米胶囊和作为喷雾干燥剂的乳糖的微球中的乳液(不含Methocel)。
从制剂30的较差的表现来看,决定评估以制剂29获得的装载有微胶囊化的他克莫司的纳米胶囊的生产工艺的重现性。可从在图15中提出的数据推导出与制剂29相同的制剂31展现的吸收特性与制剂29产生的特性接近。
考虑他克莫司吸收的高可变性,这些发现暗示工艺参数为良好控制的和重现的。
此外,从图16中提出的数据可推导出,明显地29号制剂可对他克莫司的肝旁路有贡献且促进他克莫司的一些淋巴吸收,导致与商业产品相比,更加加强的生物利用度。
为了计算口服制剂的绝对生物利用度,执行静脉内药代动力学研究且数据在图17中提出。口服制剂的绝对生物利用度小于12%,证实了已经在他克莫司生物利用度上报导的数据(表8)。然而,用29号制剂达到的结果显示生物利用度比表8中所显示的商业胶囊制剂提高了490%,在表8中对于所有制剂AUC0-24值和Cmax值被描述。也应指出,与商业产品相比乳液制剂将相对生物利用度提高了210%但仅展现了制剂29的生物利用度的42.8%,如从在表8中的各自的AUC0-24值所反映出来的。他克莫司被实际的微胶囊化的纳米胶囊(本发明微球)改良的口服吸收可被肠淋巴吸收所介导。微粒和纳米颗粒被胃肠上皮的吸收现在是被广泛接受的现象且已促进研究者注意于此传输途径,对于易分解的分子使用微粒载体(29)。
表8:药代动力学参数及生物利用度计算值
在表8中提出的结果显示纳米胶囊的形成对于传输系统的性能是重要的。简单乳液不能在油核心中保持他克莫司,导致显著的他克莫司系统代谢前降解,如被制剂32展现的结果清楚地反映,所述制剂32在成分上与制剂29相同但不含形成纳米胶囊包衣壁的Eudragit混合物。
另外,在口灌29号制剂30分钟之后,从大鼠十二指肠取组织病理学薄片。用荧光显微镜检查薄片且在组织的各种区域轻易地检测到纳米胶囊。这些发现暗示颗粒也可经历向正常肠上皮细胞的内吞作用。
另一方面,在派伊尔淋巴集结区域发现明显的纳米颗粒的聚集体(图18)。显著的大量纳米胶囊在派伊尔淋巴集结中的存在因此被暗示为潜在的从P-gp外排脱离和它们被淋巴管吸收的指示,这使得胶囊内含物在系统血液循环中通过肝首关效应被释放。
另外,取以下不同的显微照片(photomicrograph)(图19A-19D):
-干燥的微胶囊化的以Eudragit L∶RS(75∶25)纳米胶囊包衣和甲基纤维素基质(matrix)包衣制备的空纳米胶囊(图19A);
-在以磷酸盐缓冲液(pH 7.4)培养3分钟后,以Eudragit L∶RS(75∶25)纳米胶囊包衣和甲基纤维素基质包衣制备的浸渍的微胶囊化的空纳米胶囊(图19B);
-在以磷酸盐缓冲液(pH 4.8)培养5分钟后,以Eudragit L∶RS(75∶25)纳米胶囊包衣和甲基纤维素基质包衣制备的浸渍的微胶囊化的空纳米胶囊(图19C和19D,图19D是图19C部分的放大)。
显微照片描述的结果引起暗示,微球基质不仅包括甲基纤维素也包括过量的Eudragit RS和L,其不参与纳米胶囊包衣的形成。这样,在pH小于5时,观察不到基质的快速凝胶化和溶胀,而在pH7.4时,Eudragit L快速溶解且对基质的快速凝胶化和溶胀及纳米胶囊从微球中的释放有贡献。
不被理论所束缚,因此假设微胶囊化的纳米胶囊的活性剂改良的口服吸收被肠内淋巴颗粒吸收所介导。
这也是从获得的结果得到的证据,当在成分上与29号制剂相同,但不含Eudragit聚合物微胶囊包衣时的制剂不展现增加的生物利用度,如在图17(Emul.和干燥的Emuls.)和上文表8中所注意到的。
此外不被理论所束缚,暗示根据本发明的传输系统不仅可以促进淋巴吸收,也可以摆脱代谢前降解和P-gp外排。普通的乳液,虽然与商业产品相比有改良的生物利用度,但程度与制剂29不同,可能因为他克莫司在GI(胃肠)液中的分配在其被肠上皮细胞摄取之前。
这样,本发明传输系统可优选地应用于传输各种活性剂,其作为或被认为是P-gp外排基质。
此外,上文提出的发现显示类似于29号制剂但不含Eudragit聚合物纳米胶囊包衣的干燥乳液不能在GI液中将他克莫司保持在油核心中,导致比商业产品更低的生物利用度。
更进一步,不含Methocel的Eudragit纳米胶囊未得到显著的血液水平,说明现行的纳米胶囊包衣不能够在现在的实验条件下保持他克莫司,且不能致力于阻止他克莫司外排。
这些发现已被4个小型猪交叉动物实验所证实。在图19和在下文的表9中提出的结果显示本发明传输系统,如通过制剂29所示例的,得出被肝旁路他克莫司贡献的高出2.4倍的药物水平,导致与商业产品相比加强的生物利用度。
表9:在小型猪中,药代动力学参数和生物利用度计算值(平均值±SD,n=4)
从在小型猪中的吸收研究中得出的结果中明显可知通过本发明药物传输系统达到的相对生物利用度比测试制剂的大2.4倍。
在本发明中,从新型药物传输系统如何显著地增加药物的口服吸收的可能机理解释所提出的整体结果来看,可因此涉及,不被理论所束缚:(a)内吞吸收-通过内吞作用被肠上皮细胞吸收的颗粒(颗粒尺寸<500nm);(b)淋巴吸收-被派伊尔淋巴集结的M细胞吸收的颗粒(颗粒尺寸<5μm)及(c)适当的生物粘合的羟丙基甲基纤维素包衣引起了微球和纳米胶囊向肠上皮加强的粘合,全面导致显著的向肠细胞吸收的改良,由于从耐多药的泵蛋白脱离的能力。
Claims (48)
1.一种微球,其包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述多个纳米胶囊包括携带非亲水性活性剂的油核心及聚合物包衣外壳。
2.根据权利要求1所述的微球,其中所述聚合物包衣包括至少一种聚合物或聚合物的组合,所述聚合物不溶于水或在pH大于约5.0时可溶。
3.根据权利要求2所述的微球,其中所述聚合物包衣包括至少两种聚合物的组合。
4.根据权利要求3所述的微球,其中所述至少两种聚合物的组合包括至少一种在pH大于约5.0时可溶的聚合物及至少一种不溶于水的聚合物。
5.根据权利要求2到4中任一项所述的微球,其中所述在pH大于约5.0时可溶的聚合物选自邻苯二甲酸羟丙基甲基纤维素酯(HPMPC)、乙酸邻苯二甲酸纤维素酯、邻苯二甲酸羧甲基纤维素酯、虫胶、EudragitL100-55、玉米蛋白。
6.根据权利要求2到5中任一项所述的微球,其中所述不溶于水的聚合物选自乙基纤维素、Eudragit RS、Eudragit RL、聚乳酸(PLA)、聚乙醇酸(PGA)及PLA和PGA的共聚物(PLAGA)、乙基纤维素。
7.根据权利要求3到6中任一项所述的微球,其中所述聚合物的组合包括至少两种聚合物,不溶于水的第一聚合物和在pH大于约5.0时可溶的第二聚合物,所述不溶于水的聚合物与在pH大于约5.0时可溶的聚合物之间的比率为在5∶95和70∶30之间的范围内。
8.根据权利要求3到7中任一项所述的微球,其中所述至少两种聚合物的组合包括选自Eudragit RL或Eudragit RS的第一聚合物与选自EudragitL100-55和邻苯二甲酸羟丙基甲基纤维素酯(HPMPC)的第二聚合物的混合物。
9.根据权利要求1到8中任一项所述的微球,其中所述纳米胶囊具有在约100nm和900nm之间的平均直径。
10.根据权利要求1到9中任一项所述的微球,其中所述凝胶形成聚合物的特征在于其为以下中的至少一种:可溶于水的聚合物;或在水存在下溶胀的聚合物。
11.根据权利要求1到10中任一项所述的微球,其中所述凝胶形成聚合物是改性的纤维素。
12.根据权利要求11所述的微球,其中所述改性的纤维素选自羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、邻苯二甲酸羟丙基甲基纤维素酯或乙酸琥珀酸羟丙基甲基纤维素酯、乙酸邻苯二甲酸纤维素酯、邻苯二甲酸甲基纤维素酯及微晶纤维素。
13.根据权利要求10所述的微球,其中所述可溶于水的聚合物选自羟丙基甲基纤维素、低分子量的甲基纤维素、分子量在5000以上的聚乙二醇。
14.根据权利要求1到13中任一项所述的微球,其中所述微球具有在约5μm到约500μm之间的平均直径。
15.根据权利要求1到14中任一项所述的微球,其中所述活性剂是P-gp外排泵的基质。
16.根据权利要求1到15中任一项所述的微球,其中所述活性剂是亲脂性活性剂或两亲活性剂。
17.根据权利要求16所述的微球,其中所述亲脂性活性剂是药物,其选自他克莫司、西罗莫司、卤泛群、利托那韦、洛匹那韦、安普那韦、沙奎那韦、骨化三醇、屈大麻酚、异维A酸、维A酸、利培酮碱、丙戊酸。
18.根据权利要求17所述的微球,其中所述亲脂性活性剂是前药,其选自地塞米松棕榈酸酯、紫杉醇棕榈酸酯、多西紫杉醇棕榈酸酯。
19.一种制备微球的方法,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述多个纳米胶囊包括携带非亲水性活性剂的油核心和聚合物包衣外壳,所述方法包括:
(a)提供有机相,其包括油、与水混溶的有机溶剂、溶解在所述溶剂中的非亲水性活性剂和用于包衣所述油核心的聚合物或聚合物组合;
(b)向所述有机相中缓缓加入水以获得油包水(w/o)乳液;
(c)向所述w/o乳液中继续加入水以引发所述乳液的相转化,从而获得水包油(o/w)乳液;
(d)将所述o/w乳液与凝胶形成聚合物或凝胶形成聚合物的组合混合;
(e)除去所述有机溶剂和水以获得所述微球。
20.根据权利要求19所述的方法,其中所述有机溶剂选自乙醇、甲醇、丙酮、乙酸乙酯、异丙醇。
21.根据权利要求19或20所述的方法,其中所述聚合物包衣包括至少一种聚合物或聚合物的组合,所述聚合物不溶于水或在pH大于约5.0时可溶。
22.根据权利要求21所述的方法,其中所述聚合物包衣包括至少两种聚合物的组合。
23.根据权利要求22所述的方法,其中所述至少两种聚合物的组合包括至少一种在pH大于约5.0时可溶的聚合物与至少一种不溶于水的聚合物。
24.根据权利要求21到23中任一项所述的方法,其中所述在pH大于约5.0时可溶的聚合物选自:邻苯二甲酸羟丙基甲基纤维素酯(HP55)、乙酸邻苯二甲酸纤维素酯、邻苯二甲酸羧甲基纤维素酯、虫胶、EudragitL100-55、玉米蛋白。
25.根据权利要求21到24中任一项所述的方法,其中所述不溶于水的聚合物选自乙基纤维素、Eudragit RS、Eudragit RL、聚乳酸(PLA)、聚乙醇酸(PGA)及PLA和PGA的共聚物(PLAGA)、乙基纤维素。
26.根据权利要求19到25中任一项所述的方法,其中所述聚合物的组合包括两种聚合物,不溶于水的第一聚合物和在pH大于约5.0时可溶的第二聚合物,所述不溶于水的聚合物与在pH大于约5.0时可溶的聚合物之间的比率在5∶95和70∶30之间的范围内。
27.根据权利要求26所述的方法,其中所述聚合物的组合包括选自Eudragit RL或Eudragit RS的第一聚合物与选自Eudragit L 100-55和邻苯二甲酸羟丙基甲基纤维素酯(HPMPC)的第二聚合物的混合物。
28.根据权利要求27所述的方法,其中所述聚合物的组合包括比率为约25∶75的Eudragit RS和Eudragit L100-55。
29.根据权利要求19到28中任一项所述的方法,其中所述有机相包括亲脂性赋形剂。
30.根据权利要求19到29中任一项所述的方法,其中所述有机相包括亲脂性表面活性剂。
31.根据权利要求19到31中任一项所述的微球,其中所述凝胶形成聚合物的特征在于其为以下中的至少一种:可溶于水的聚合物;或在水存在下溶胀的聚合物。
32.根据权利要求19到25中任一项所述的方法,其中所述凝胶形成聚合物是改性的纤维素。
33.根据权利要求26所述的方法,其中所述改性的纤维素选自羟乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和微晶纤维素。
34.根据权利要求19到27中任一项所述的方法,其中所述活性剂是P-gp外排泵的基质。
35.根据权利要求19到28中任一项所述的方法,其中所述活性剂是亲脂性活性剂或两亲活性剂。
36.根据权利要求29所述的方法,其中所述亲脂性活性剂是药物,其选自他克莫司、西罗莫司、卤泛群、普罗布可、利托那韦、洛匹那韦、安普那韦、沙奎那韦、骨化三醇、屈大麻酚、异维A酸、维A酸、利培酮碱、丙戊酸。
37.根据权利要求29所述的方法,其中所述亲脂性活性剂是前药,其选自地塞米松棕榈酸酯、紫杉醇棕榈酸酯、多西紫杉醇棕榈酸酯。
38.根据权利要求19到31中任一项所述的方法,其中除去所述有机溶剂和水是可通过喷雾干燥获得的。
39.一种药物组合物,其包括根据权利要求1到18中任一项所述的微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊且包括携带非亲水性活性剂的油核心和聚合物包衣外壳。
40.一种药物组合物,其包括可通过权利要求19到34中任一项所述的方法获得的微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊且包括携带非亲水性活性剂的油核心和聚合物包衣外壳。
41.根据权利要求41所述的药物组合物,其是口服施用的剂型。
42.根据权利要求34或35所述的药物组合物,其为干燥的药物组合物。
43.根据权利要求34到36中任一项所述的药物组合物,其中所述微球包括可溶于水的凝胶形成聚合物及所述微球被包装在肠包衣的载体中。
44.根据权利要求37所述的药物组合物,其中所述肠包衣的载体是肠包衣的胶囊。
45.根据权利要求34到38中任一项所述的药物组合物,其用于所述活性剂从所述微球中控制释放。
46.一种提高亲脂性剂在人类受治疗者体内的生物利用度的方法,所述方法包括向所述受治疗者施用微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带亲脂性剂的油核心和聚合物包衣外壳。
47.一种针对病理疾患治疗需要有效血液水平的活性剂的所述治疗的受治疗者的方法,所述方法包括向所述受治疗者施用微球,所述微球包括容纳在凝胶形成聚合物中的多个纳米胶囊,所述纳米胶囊包括携带亲脂性剂的油核心和聚合物包衣外壳。
48.根据权利要求40或41所述的方法,所述方法包括向所述受治疗者口服提供所述微球,其中所述微球如在根据权利要求1到18中任一项所定义或所述微球可通过权利要求20到32中任一项所述的方法获得。
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WO2007083316A2 (en) | 2007-07-26 |
ATE446087T1 (de) | 2009-11-15 |
AU2007206582A1 (en) | 2007-07-26 |
BRPI0706949A2 (pt) | 2011-04-12 |
CN101410098B (zh) | 2012-01-18 |
EP2026771A2 (en) | 2009-02-25 |
CA2639921C (en) | 2014-01-21 |
KR101411100B1 (ko) | 2014-07-08 |
JP5403585B2 (ja) | 2014-01-29 |
US20090011009A1 (en) | 2009-01-08 |
CA2639921A1 (en) | 2007-07-26 |
JP2009523843A (ja) | 2009-06-25 |
EP2026771B1 (en) | 2009-10-21 |
WO2007083316A3 (en) | 2007-11-22 |
KR20080108426A (ko) | 2008-12-15 |
AU2007206582B2 (en) | 2011-09-29 |
US9023386B2 (en) | 2015-05-05 |
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