CN1246057A - 口服环孢菌素制剂 - Google Patents
口服环孢菌素制剂 Download PDFInfo
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- CN1246057A CN1246057A CN98801568A CN98801568A CN1246057A CN 1246057 A CN1246057 A CN 1246057A CN 98801568 A CN98801568 A CN 98801568A CN 98801568 A CN98801568 A CN 98801568A CN 1246057 A CN1246057 A CN 1246057A
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- cyclosporin
- polyethylene glycol
- oral
- based surfactants
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Abstract
本发明提供改进的环孢菌素口服制剂,其生物利用度高,能以液体和硬胶囊的形式给药。在所述制剂中,环孢菌素在包括至少一种2—3个碳原子的链烷醇溶剂和至少一种非离子型表面活性剂的口服可接受的载体中给药。所述制剂可进一步包含至少一种助溶剂,其中涉及的助溶剂包括脂肪酸和二元醇。所述制剂用于免疫抑制治疗。
Description
相关申请的交互参考
本申请是1996年3月21日提交的No.08/620,021申请的部分继续申请,后者是1995年8月25日提交的No.08/519,689申请的部分继续申请,这些申请在此引为参考。
引言
发明的领域
本发明的领域是口服环孢菌素制剂。
背景
尽管进行了通过宿主-供体组织类型适配以避免移植物排斥的各种努力,但在供体器官引入宿主的大多数移植过程中,免疫抑制治疗对于供体器官在宿主体内维持存活是关键性的。移植过程中已采用了各种免疫抑制剂,包括硫唑嘌呤、甲氨喋呤、环磷酰胺、FK-506、rapamycin和皮质激素类。因其对T细胞所介导的反应的优选效应而在免疫抑制治疗中使用日见增加的药物是环孢菌素类。
环孢菌素类是真菌Tolypocladium inflatum Gams产生的代谢产物,由11个氨基酸组成的环多肽。已观察到环孢菌素类可逆性地抑制细胞周期G0或G1相的免疫活性淋巴细胞,特别是T-淋巴细胞。还观察到环孢菌素类可逆性地抑制淋巴因子的产生和释放。虽然多数环孢菌素是已知的,但环孢菌素A是使用最广泛的。
据报告,环孢菌素A的使用延长了同种异体移植物(包括皮肤、心脏、肾脏、胰脏、骨髓、小肠和肺)的存活。在同种异体移植中,环孢菌素A显示出对体液免疫的抑制,并在更大程度上显示出对细胞介导的免疫反应的抑制,包括:同种异体移植物排斥反应、延迟型过敏反应、实验性变态反应性脑脊髓炎、弗氏佐剂型关节炎和移植物抗宿主反应疾病。虽然用环孢菌素A达到了成功,但该药物在移植后必须持续给药,环孢菌素治疗的益处是可逆的,一旦停止环孢菌素A的给药就会再出现移植物排斥反应。
环孢菌素口服和静脉给药制剂均已开发,但因其给药方便和易为患者接受而以环孢菌素的口服给药更为可取。而且,环孢菌素静脉给药可能导致过敏反应,这是口服制剂所没有的副作用。已经开发和最近上市的口服环孢菌素制剂包括软胶囊和溶液剂,它们均以SANDIMMUNE和NEORALTM的商标出售。
在免疫抑制治疗中使用口服环孢菌素制剂时,医护人员和制造商均需了解很多问题。采用口服环孢菌素制剂时,由于环孢菌素不溶于水及在水性环境中有沉淀的倾向,因此环孢菌素的生物利用度可能受到限制。此外,由于环孢菌素的疏水性,口服制剂中环孢菌素的浓度可能受到限制。最后,包装和储存稳定性是口服制剂的一个问题。例如,环孢菌素明胶软胶囊必须采用气密包装,因其体积大和高成本而不便利。况且,环孢菌素在低温下也可能是不稳定的,因为可产生环孢菌素结晶。
满意的口服环孢菌素制剂将是至少能对付上述问题中的几个问题的制剂。理想的是,口服制剂会促进高生物利用度,包含高浓度的环孢菌素,经得起液体或硬胶囊剂型的制备过程。
相关的文献
Physician′s Desk Reference(1994)pp 2071-2074描述了最近以SANDIMMUNE商标出售的口服环孢菌素制剂。
在NEORALTM包装插页(1995)(Sandoz Pharmaceuticals Corporation,EastHanover,New Jersey,07936)上也描述了口服环孢菌素制剂。
描述环孢菌素及其衍生物的有关美国专利包括:4,220,641;4,639,434;4,289,851;及4,384,996。美国专利No.5,047,396描述环孢菌素静脉给药制剂。美国专利No.4,388,307;4,970,076和4,990,337描述口服环孢菌素制剂的制备。
美国专利No.4,822,618、4,576,284、5,120,710和4,894,235描述了药物制剂供口服给药用硬胶囊的制备。
发明的概述
提供了口服环孢菌素制剂及其在免疫抑制治疗上的使用方法。在本发明的制剂中,环孢菌素存在于包含至少一种2-3个碳原子的链烷醇以及至少一种非离子型表面活性剂的口服可接受的赋形剂中。本制剂可进一步包含一种或多种助溶剂,涉及的助溶剂是脂肪酸酯和二醇类,优选聚乙二醇类。环孢菌素制剂可包装成硬胶囊。制剂基本上是无水的,这减少了环孢菌素在制剂中的沉淀并提高了生物利用度。
附图的简单说明
图1提供本发明的几种口服制剂在大鼠体内达到的环孢菌素峰浓度(Cmax),其中Cmax表示为与SANDIMMUNE口服制剂(SO)达到的Cmax相比的相对值。
图2提供图1所示每种制剂出现Cmax的时间(Tmax),其中Tmax表示为与SANDIMMUNE口服制剂(SO)的Tmax相比的相对值。
图3提供图1所示每种制剂的血浓度-时间曲线下面积(AUC),其中AUC表示为与SANDIMMUNE口服制剂(SO)的AUC相比的相对值。
图4提供本发明的几种口服制剂以及SANDIMMUNE口服制剂(图中为“Sand”)在人体内达到的环孢菌素峰浓度(Cmax)。
图5提供图4所示每种制剂出现Cmax的时间(Tmax)。
图6提供图4所示每种制剂的血浓度-时间曲线下面积(AUC)。
具体实施方案的描述
提供口服环孢菌素制剂,这些制剂增进生物利用度,可制成胶囊,特别是硬胶囊。在本发明的制剂中,环孢菌素存在于包含至少一种2-3个碳原子的链烷醇以及至少一种非离子型表面活性剂的口服可接受的赋形剂中。本发明的制剂可进一步包含至少一种助溶剂,涉及的助溶剂是脂肪酸酯和二醇类,优选一种或几种聚乙二醇。本发明制剂的每种成分都是药学上可接受的。除了提供高生物利用度外,本发明的制剂还提供从一批特定制剂到下一批制剂可重现的环孢菌素吸收。本发明制剂在免疫抑制治疗中找到了用途。
现有技术中已知有很多环孢菌素显示免疫抑制活性,可在本发明的口服制剂中给药。在本发明的制剂中给药的环孢菌素包括环孢菌素A、环孢菌素B、环孢菌素C、环孢菌素D和环孢菌素G及其合成类似物。见Merk Index(1989)2759。本发明的口服制剂特别适合于环孢菌素A的给药。在本发明的制剂中给药时,环孢菌素A浓度在50-150mg/ml范围内,通常是100-150mg/ml,根据制剂赋形剂成分的体积而定。
本发明制剂的赋形剂成分包括链烷醇溶剂成分,其中链烷醇溶剂成分包括至少一种链烷醇,通常不多于3种不同的链烷醇,更通常不多于2种不同的链烷醇,其中链烷醇通常有2-3个碳原子和1-2个羟基,这样以使每1.5个碳原子有不多于1个羟基。合适的链烷醇包括乙醇和丙二醇,优选无水乙醇。制剂中链烷醇溶剂的总量至少约为制剂的1%(v/v),通常至少约为3%(v/v),可以高达95%(v/v),但一般为约5-75%(v/v),常为约5-60%(v/v),更常为约10-60%(v/v)。制剂中存在乙醇作为链烷醇溶剂时,乙醇的量可为制剂的约5-25%(v/v),常为约5-20%(v/v),更常为约10-25%(v/v),而制剂中存在丙二醇作为链烷醇溶剂时,丙二醇的量可为制剂的约5-90%(v/v),常为约5-85%(v/v),更常为约10-50%(v/v)。
在口服可接受的赋形剂中存在的还有至少一种非离子型聚亚氧烷基表面活性剂,通常为不到2种非离子型聚亚氧烷基表面活性剂。聚亚氧烷基表面活性剂的亲水性亲油性平衡比率(HLB)约为5-20,通常约为8-16。本发明制剂中所用的非离子型聚亚氧烷基表面活性剂以聚氧乙烯化合物为佳。所涉及的聚氧乙烯化合物包括:乙氧基化醇,即聚氧乙烯醇,或乙氧基化脂肪醇,其中醇基团一般为10-18个碳原子,通常为10-14个碳原子,及其醚和酯取代基;以及脂肪酸偏酯的聚氧乙烯衍生物,通常是4-6个碳原子(常为6个碳原子)的多元醇的单酯,其中多元醇可以是多元醇酐,如脱水山梨醇。本表面活性剂的脂肪酸基团典型地为10-18个碳原子。氧化乙烯基团的数目一般为2-30,常为2-25。优选的表面活性剂为聚氧乙烯(4)月桂基醚(BRIJ 30)和聚氧乙烯(20)单脱水山梨醇单油酸酯(TWEEN80)。本发明制剂中非离子型表面活性剂的总量为制剂的5-80%,通常为5-70%,更常为5-65%,优选5-60%(v/v),更优选20-75%(v/v),常为50-80%。TWEEN80存在于制剂中时,其常用量为制剂的5-80%,更常用5-70%,优选5-60%,更优选约10-50%(w/v)。BRIJ存在于制剂中时,其常用量为制剂的10-45%,更常用15-40%(v/v)。
本发明的制剂可进一步包括一种或几种助溶剂,通常为不多于3种不同的助溶剂,更常为不多于2种不同的助溶剂,其中合适的助溶剂包括脂肪酸酯和二元醇,其中助溶剂可以是100%脂肪酸酯、100%二元醇或其组合。在含100%脂肪酸酯或100%二元醇助溶剂的制剂中,可组合采用不同的脂肪酸酯或二元醇。制剂中存在的助溶剂的总量可为约20-80%(v/v),常为约25-75%(v/v)。当制剂中存在助溶剂时,本制剂中助溶剂与溶剂之比约为1∶1至15∶1,通常约为1∶1至13∶1。
可在本发明制剂中充当助溶剂的脂肪酸酯是这样的脂肪酸酯,其中脂肪酸的烃链长度为12-18个碳原子,通常为14-18个碳原子,其中脂肪酸酯是低级链烷醇的单酯。合适的脂肪酸酯通常包含偶数(even)数目的脂肪酸链,其中烃链可以是饱和或不饱和的,通常具有不多于2个不饱和部位。涉及的脂肪酸通常来源于植物或哺乳动物,包括棕榈酸酯、硬脂酸酯、棕榈油酸酯、亚油酸、亚麻酸等,特别是肉豆蔻酸酯和油酸酯。脂肪酸单酯的醇为2-4个碳原子长度的低级链烷醇,通常为2-3个碳原子长度,有或无支链。特别涉及的脂肪酸酯是肉豆蔻酸异丙酯和油酸乙酯。存在肉豆蔻酸异丙酯时,其量约为总制剂的15-75%(v/v),存在油酸乙酯时,其量约为总制剂的15-75%(v/v)。通常,脂肪酸酯的存在量至少约相等于(v/v)至8倍于制剂中表面活性剂的量,常不多于制剂中表面活性剂量的5倍(v/v)。脂肪酸酯以无水的为宜。
本发明制剂中也可存在二元醇,其中二元醇可与脂肪酸酯助溶剂同时存在或代替脂肪酸酯存在。二元醇以无水的为宜。涉及作为助溶剂的二元醇在生理温度下一般是液体,包括8-28个碳原子的二元醇,通常为16-20个碳原子,其中二元醇可以是聚亚氧烷基二醇,其中亚烷基有2-3个碳原子,但是,也见使用具有显著较多的碳原子的二元醇。用作助溶剂的合适的二元醇可为约200-10,000道尔顿,常为约300-10,000道尔顿,更常为约400-10,000道尔顿,优选800-10,000道尔顿。特别涉及的二元醇包括聚乙二醇,特别是聚乙二醇200(PEG200)、聚乙二醇300(PEG300)、聚乙二醇400(PEG400)、聚乙二醇600(PEG600)、聚乙二醇1000(PEG1000)、聚乙二醇3400(PEG3400)、聚乙二醇8000(PEG8000),等。作为助溶剂存在于本制剂中时,二元醇常为制剂的约5-60%,更常为5-55%(w/v)。二元醇,特别是较高分子量的聚乙二醇(即如分子量为1000或更高的聚乙二醇),可起到吸附可能存在于制剂中的水分子的作用,从而显著降低因游离水分子使环孢菌素从制剂中沉淀出来的可能性。
在本发明的制剂中,助溶剂本身可赋予制剂满意的物理性质,如粘度、稳定性等。需要时,制剂还可包含赋予制剂满意的物理性质的其它物质,如增稠剂、悬浮剂、固化剂等,这些物质包括金合欢、羧甲基纤维素、羟丙基纤维素、卵磷脂、甲基纤维素、高分子量聚乙二醇,如分子量约为1000-10,000、常为1000-8000、更常为1000-6000道尔顿的聚乙二醇,以及聚烯吡酮、藻酸钠、黄蓍胶等。本发明制剂中还可存在提供各种功能的一些微量成分,如酶抑制剂、防腐剂、抗氧化剂、抗微生物剂、稳定剂、调味剂等。制剂中存在这些增稠剂和其它添加剂时,其总量通常不大于制剂的55重量%,常为45重量%,更常为25重量%。如现有技术中已知的,本发明制剂中还可存在一些赋形剂。这些外加的物质以无水的为佳。
制剂基本上无水,指它们的含水量低于1.0%(v/v),更佳为低于0.1%(v/v)。
本发明的制剂在宽的温度范围内是稳定的,稳定是指不损害制剂的物理完整性,例如不出现环孢菌素活性剂的结晶。本发明的制剂保持稳定的温度范围包括较低的温度,如冷藏时所用的温度,这样低的温度典型地约为0-15℃,更典型地约为2-8℃。
本发明的制剂适合于以液体和胶囊剂型(如硬胶囊和软胶囊)给药。制备包含液体制剂的硬胶囊的方法是本领域已知的,在美国专利No.4,822,618和4,576,284中有描述,它们公开的内容在此引为参考。一般来说,在本发明制剂中有用的硬胶囊包括两部分:壳部分和帽部分。壳部分和帽部分配装在一起形成有限定体积的腔密封在硬胶囊中。壳和帽部分可由亲水性聚合物制成,如淀粉或明胶。制备硬胶囊时,将液体制剂倾入壳部分,在壳部分上装上帽部分将胶囊密封。用EP116744描述的密封剂可使两部分的密封牢固,从而防止封入的制剂从胶囊中泄漏,该专利公开的内容在此引为参考。为了避免在胃中崩解,包含本发明的制剂的胶囊可包上肠溶包衣,该肠溶包衣抑制胶囊在胃的酸性环境中崩解。各种肠溶包衣是本领域已知的,例如见美国专利No.5,206,219,其公开内容在此引为参考。
对需要治疗的受治疗者,可将本发明的制剂与一种或几种免疫抑制剂联合给药。其中可与本发明的环孢菌素制剂共同给药的其它免疫抑制剂包括例如rapamycin、FK-506、麦考酚酸、其类似物及衍生物,硫唑嘌呤、甲氨喋呤、环磷酰胺、皮质激素类和其它免疫抑制化合物或分子或其类似物。
本发明的制剂在免疫抑制治疗中有用。在大量疾病中需要免疫抑制治疗,包括自发性肾病综合征、I型胰岛素依赖性糖尿病、Behcet′s综合征、活动性克罗恩氏疾病、再生障碍性贫血、严重的皮质激素依赖性哮喘、牛皮癣、类风湿性关节炎,及免疫系统可能起致病作用的其它疾病。特别的兴趣是在移植情况下使用本发明的制剂,包括同种和异种器官、组织或细胞移植,这种场合需要免疫抑制以确保维持被移植的器官或组织或细胞在移植后的成活力,即防止移植物排斥或防止移植物抗宿主反应疾病,如骨髓移植后。
在用本发明的制剂对宿主提供免疫抑制治疗时,根据所治疗的特定病情口服给予有效量的环孢菌素以达到该宿主所需要的免疫抑制水平。对于移植来说,通常在手术前或手术后给予首剂环孢菌素。供体器官移植到宿主上后,一般重复给予环孢菌素,即长期给宿主以维持免疫抑制作用。首剂在移植前4-12小时给予,可为5-18mg/kg宿主,通常为5-15mg/kg宿主。手术后,通常继续给予开始剂量,每天一次,1-3周,通常是1-2周。然后可将剂量逐渐减少到维持剂量3-10mg/kg/天,通常为3-6mg/kg/天。剂量渐渐减少到维持剂量的速度可以是每周3-8%,常为约每周5%。典型地根据血浓度谷水平调节剂量,维持浓度在100-350ng/ml,浓度用HPLC、RIA、ELISA或TDx测得。本发明的制剂可与另外的药物一起给药,辅助治疗受到推荐,并且是本领域已知的。例如,本发明的制剂可与肾上腺皮质激素、硫唑嘌呤等联合给药。
给宿主移植供体器官伴随使用本发明的制剂会抑制宿主对供体器官存在的免疫反应,其结果导致供体器官在宿主体内存活期延长。“存活期的延长”是指供体器官在宿主体内保持存活的时间长于不伴随移植采用免疫抑制治疗的存活时间。因此,存活期的延长包括使存活维持不确定的一段时间。供体器官只要在宿主环境中能维持其功能,即认为是存活的。
本发明制剂还可制成生物利用度好的环孢菌素微颗粒的水性胶态分散体。在这种情况下,微颗粒基本上是球形的,环孢菌素以无定形的形式存在,平均大小一般小于约1000nm,大于约50nm,一般在约200-800nm的范围内,常在约200-600nm的范围内。一般来说,环孢菌素总量的至少约50重量%是以所指出的大小范围的颗粒存在。当平均直径通常小于约50μm(更常小于约25μm)时,可能存在较大的颗粒,特别是微颗粒的聚集物,该聚集物通常不超过环孢菌素总量的40重量%。
组合物中环孢菌素无定形颗粒的量对于治疗效应来说是足够的。因为制剂可在给药前引入水性介质进行配制或直接引入胃液,因而不能说明特定的浓度,因其在胃中的稀释是不确定的。对于口服给药前在水性介质中制备来说,环孢菌素一般可以约0.01-2.5重量%存在,更常为约0.01-0.5重量%。混合的温度可在约10-50℃范围内,通常在约20-40℃范围内。混合通常会涉及搅拌足够的时间以提供环孢菌素溶液。
超微颗粒的无定形胶态悬浮液的稳定性足以使其在给药前能放置一段时间,通常长达约6小时,更常长达约3小时。
关于本发明的超微环孢菌素制剂的制备和使用详情可见PCT/US97/04627。
下面的实施例是以阐述性的方式而非限制性的方式提供的。
实施例
制备了一些按本发明所述的口服环孢菌素制剂。然后在大鼠和人身上观察所制备的多数制剂中环孢菌素的生物利用度。
1.口服环孢菌素制剂
制备了如下口服环孢菌素A制剂。在每种情况下,将标明的环孢菌素A、表面活性剂和乙醇或乙二醇的量加到1.0ml量瓶中,加入适当体积的脂肪酸酯和/或二元醇,任意地达到最终体积为1.0ml。
PG=丙二醇;EtOH=乙醇;Brij30=聚氧乙烯(4)月桂基醚;Tween 80=聚氧乙烯(20)单山梨糖醇单油酸酯;IM=肉豆蔻酸异丙酯;EO=油酸乙酯
制剂 | 组 成 |
19 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Tween 80 300mg (0.278ml)IM 适量至1.0ml (0.622ml)(531mg) |
20 | CsA 100mg (10%w/v)EtOH 0.05ml (5%)Brij 30 350mg (0.368ml)IM 适量至1.0ml (0.582ml)(496mg) |
21 | CsA 100mg (10%w/v)EtOH 0.05ml (5%)Brij 30 350mg (0.368ml)IM 适量至1.0ml (0.582ml)(496mg) |
22 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Tween 80 300mg (0.278ml)EO 适量至1.0ml (0.622ml)(541mg) |
23 | CsA 100mg (10%w/v)EtOH 0.05ml (5%)Brij 30 350mg (0.368ml)EO 适量至1.0ml (0.582ml)(506mg) |
24 | CsA 100mg (10%w/v)PG 0.05ml (5%)Brij 30 350mg (0.368ml)EO 适量至1.0ml (0.582ml)(506mg) |
33 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Brij 30 150mg (0.158ml)IM 适量至1.0ml (0.742ml)(633mg) |
34 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Brij 30 150mg (0.158ml)EO 适量至1.0ml (0.742ml)(646mg) |
35 | CsA 100mg (10%w/v)EtOH 0.105ml (10.5%)Tween 80 500mg (0.463ml)PG 适量至1.0ml (0.437ml)(453mg) |
36 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Tween 80 300mg (0.278ml)PG 100mg (0.097ml)EO 适量至1.0ml (0.525ml)(465mg) |
37 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Tween 80 300mg (0.278ml)PEG 400 100mg (0.088ml)EO 适量至1.0ml (0.534ml)(464mg) |
38 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Brij 30 300mg (0.316ml)PG 100mg (0.097ml)EO 适量至1.0ml (0.487ml)(424mg) |
39 | CsA 100mg (10%w/v)EtOH 0.1ml (10%)Brij 30 300mg (0.316ml)PG 200mg (0.193ml)EO 适量至1.0ml (0.391ml)(340mg) |
40 | CsA 100mg (10%w/v)PG 300mg (290ml)Brij 30 300mg (0.316ml)EO 适量至1.0ml (0.394ml)(343mg) |
41 | CsA 100mg (10%w/v)EtOH 0.06ml (5%)Brij 30 150mg (0.158ml)Tween 80 100mg (0.093ml)EO 适量至1.0ml(0.649ml)(565mg) |
42 | CsA 100mg (10%w/v)PG 0.05ml (5%)Brij 30 150mg (0.158ml)Tween 80 100mg (0.093ml)EO 适量至1.0ml(0.649ml)(565mg) |
43 | CsA 100mg (10%w/v)EtOH 0.10ml (10%)Tween 80 400mg (0.371ml)PG 适量至1.0ml(0.529ml) |
44-液体 | CsA 100mg (10%w/v)EtOH 0.125ml (12.5%)Tween 80 400mg (0.371ml)PEG400 适量至1.0ml(0.529ml)(601mg) |
44-硬胶囊 | CsA 100mg (10%w/v)EtOH 0.125ml (12.5%)Tween 80 400mg (0.371ml)PEG400 0.25mlPEG1000 0.25ml |
45 | CsA 100mg (10%w/v)EtOH 0.10ml (10%)Tween 80 300mg (0.278ml)PG 约250mg (0.243ml)PEG400 约250mg (0.220ml) |
46 | CsA 100mg (10%w/v)EtOH 0.10ml (10%)Tween 80 100mg (0.093ml)PG 适量至1.0ml (0.807ml) |
48 | CsA 100mg (10%w/v)EtOH 0.10ml (10%)Tween 80 200mg (0.186ml)PG 约250mg (0.243ml)PEG400 约250mg (0.220ml) |
49 | CsA 100mg (10%w/v)EtOH 0.10ml (10%)Tween 80 600mg (0.558ml)PG 适量至1.0ml (0.342ml) |
50 | CsA 100mg (10%w/v)EtOH 0.10ml (10%)Tween 80 300mg (0.278ml)PG 适量至1.0ml (0.622ml) |
51 | CsA 100mg (10%w/v)EtOH 0.10ml (10%)Tween 80 200mg (0.186ml)PG 适量至1.0ml (0.714ml) |
52 | CsA 100mg (10%w/v)EtOH 0.05ml (5%)Tween 80 400mg (0.371ml)PG 适量至1.0ml (0.579ml) |
100 | CsA 125mg (12.5%w/v)EtOH 0.125ml (12.5%)Tween 80 200mg (0.186ml)PEG300 约0.44mgPEG8000 约0.11mg |
101 | CsA 125mg (12.5%w/v)EtOH 0.125ml (12.5%)Tween 80 100mg (0.093ml)PEG300 约0.52mgPEG8000 约0.13mg |
102 | CsA 125mg (12.5%w/v)EtOH 0.125ml (12.5%)Tween 80 100mg (0.093ml)PEG300 约0.585mgPEG3400 约0.065mg |
103 | CsA 125mg (12.5%w/v)EtOH 0.125ml (12.5%)Tween 80 400mg (0.372ml)PEG300 约0.28mgPEG3400 约0.07mg |
104 | CsA 125mg (12.5%w/v)EtOH 0.15ml (15%)Tween 80 100mg (0.093ml)PEG300 约0.496mgPEG8000 约0.124mg |
105 | CsA 125mg (12.5%w/v)EtOH 0.15ml (15%)Tween 80 400mg (0.372ml)PEG300 约0.256mgPEG3400 约0.064mg |
106 | CsA 125mg (12.5%w/v)EtOH 0.125ml (12.5%)Tween 80 400mg (0.372ml)PEG300 约0.329mgPEG8000 约0.021mg |
107 | CsA 112mg (11.2%w/v)EtOH 0.158ml (15.8%)Tween 80 800mg (0.744ml) |
108 | CsA 112mg (11.2%w/v)EtOH 0.158ml (15.8%)Tween 80 700mg (0.651ml)PEG300 约0.105mgPEG8000 约0.045mg |
109 | CsA 112mg (11.2%w/v)EtOH 0.158ml (15.8%)Tween 80 700mg (0.651ml)PEG300 约0.075mgPEG8000 约0.075mg |
110 | CsA 112mg (11.2%w/v)EtOH 0.158ml (15.8%)Tween 80 600mg (0.558ml)PEG300 约0.20mgPEG8000 约0.05mg |
111 | CsA 112mg (11.2%w/v)EtOH 0.158ml (15.8%)Tween 80 600mg (0.558ml)PEG300 约0.15mgPEG8000 约0.10mg |
112 | CsA 112mg (11.2%w/v)EtOH 0.158ml (15.8%)Tween 80 500mg (0.465ml)PEG300 约0.3 15mgPEG8000 约0.035mg |
113 | CsA 112mg (11.2%w/v)EtOH 0.158ml (15.8%)Tween80 500mg (0.465ml)PEG300 约0.245mgPEG8000 约0.105mg |
114 | CsA 125mg (12.5%w/v)EtOH 0.158ml (15.8%)Tween 80 300mg (0.279ml)PEG300 约0.3 85mgPEG8000 约0.165mg |
115 | CsA 125mg (12.5%w/v)EtOH 0.158ml (15.8%)Tween 80 300mg (0.279ml)PEG300 约0.33mgPEG8000 约0.22mg |
116 | CsA 125mg (12.5%w/v)EtOH 0.158ml (15.8%)Tween 80 400mg (0.372ml)PEG300 约0.225mgPEG8000 约0.225mg |
II.制剂19-24和33-42的生物利用度研究
对制剂19-24和33-42中环孢菌素的生物利用度研究如下。测定下面的药物动力学参数作为生物利用度的度量:(a)环孢菌素血浓度峰值(Cmax);(b)达到Cmax所需要的时间(Tmax);和(c)血浓度-时间曲线下面积(AUC)。除了制剂19-24和33-42外,作为比较,观察了同样条件下SANDIMMUNE口服液(SO)中环孢菌素的生物利用度。对于上述每一种制剂,均采用首次试验CsA的Sprague Dawley大鼠,体重250-350克,喂饲颗粒化标准食物(Agway 3000,Granville Mill,Greensboro,NC),任意饮水。实验前一天,在乙醚轻麻下,将硅橡胶导管插入右颈静脉和右股静脉。禁食一夜后,通过胃管给予CsA。
给药后,从颈静脉收集200μl血样到含有0.3mg冻干EDTA-Na的0.5ml微量离心管中,立即涡旋10秒钟。接受口服制剂的动物的取样时间为给药后0、0.5、1、2、4、8、12、24、36、48和72小时。
用荧光偏振免疫试验(FPI)(Tdx,Abbot Lab)测定全血中的CsA(包括某些代谢产物)。简言之,将150μl全血样本定量转移到1.5ml微量离心管中。用含表面活性剂的增溶试剂50μl将细胞裂解和溶解。然后用300μl乙腈沉淀蛋白质。离心后,遵照Abbott Diagnostics推荐的步骤,将上清液在TDx自动分析仪中进行FPI试验。因为TDx试验原来是用于人血的,所以将某些推荐的步骤修改如下。将已知量的CsA加到用EDTA处理过的大鼠血液中,制成已知CsA浓度的一系列标准溶液。当样本中CsA浓度预计高于1.0μg/ml时,将血样用pH7.0的0.1M磷酸盐缓冲液稀释10倍。对于稀释的样本,用一系列含已知量CsA的标准溶液(其体积的10%为大鼠血样,90%为磷酸盐缓冲液)制成另一条校正曲线。
从非房室(non-compartmental)分析得到描述性的药物动力学参数。审察每只大鼠的原始浓度-时间曲线图,估测峰浓度(Cmax)和出现峰浓度的时间(Tmax)。按照线性梯形法(linear trapezoidal procedure)计算从时间0到最后的数据点的浓度-时间曲线下面积(AUC)(AUC0→t)。血浓度-时间曲线的尾部下的剩余面积(AUCt→∞)估测为最后观察到的浓度(C*)与浓度-时间曲线图的末端消除相有关的一级速率常数(λz)之比。通过浓度-时间曲线图的表观末端对数线性相中浓度-时间数据(即所分析的图的最后3-5个数据点)的对数线性回归测定速率常数λz。总的AUC(AUCt→∞)作为AUC0→t和AUCt→∞之和。
将每一制剂的结果与关于SO所得的结果相比较,见图1-3。结果证明,对于大多数制剂来说,与SANDIMMUNE口服液(SO)相比,所述制剂得到较大的环孢菌素生物利用度,表示为所述制剂的AUC值较大。
III.制剂35、43-46和48-52的人体生物利用度
48名年龄在19-55之间、与理想体重偏差不超过20%的健康男子被用作受试者。进行单剂量、禁食、随机、双盲、三路交叉(three-way crossover)研究。48名受试者随机分成6组,每组8名。每组在3个不同的试验周期从上述制剂或SANDIMMUNE口服液(SO)接受单剂量300mg环孢菌素,每个试验周期隔开7天的清洗期。
要求受试者在给药前10小时和给药后4小时禁食。除了在给药前1小时到给药后2小时之间,研究中可随意饮水。给药前,取15ml血样。为了给药,将制剂的3ml等分量(300mg)与200ml稀释剂合并,口服摄取。在t=0、0.5、1、1.5、2、3、4、6、8、10、12、16、20和24小时取10ml血样。后研究再取15血样。按照制造商的说明书,用TDx(Abbott Diabnostics,N.Chicago,IL)测试全部血样中的环孢菌素A浓度。
用标准方法得到非房室药物动力学。从浓度-时间数据收集最大全血浓度(Cmax)及其出现的时间(Tmax)。用线性梯形规则计算血浓度-时间曲线下面积(AUC)至灵敏度限度(25ng/ml)之上的最后血浓度,并外推到无穷大。
将观察到的每个制剂的Cmax、Tmax和AUC值进行平均。每个制剂的平均值见图4-6。结果证明,每个受试制剂至少出现两次Cmax,与SANDIMMUNE口服液(SO)在同样的条件下出现得一样快。而且,受试制剂观察到的AUC比在同样条件下观察到的SANDIMMUNE口服液(SO)的AUC大至少2000ng·hr/ml。根据这些结果,制剂35、43-46和48-52提供的生物利用度大于SANDIMMUNE口服液(SO)。
IV.液体制剂35和44的低温特征
将环孢菌素A液体制剂35、44和NEORAL口服液储存于各种低温下,测定其物理性质。具体地说,将环孢菌素A液体制剂35、44和NEORAL口服液在-10℃或2-8℃储存过夜。在-10℃时,制剂44和NEORAL口服液均固化,而制剂35则否,尽管变得很粘稠。有趣的是,冷制剂35溶液不出现环孢菌素A结晶沉淀。取出每种制剂放进室温中,固化的制剂44比固化的NEORAL口服液融化得快。
储存于2~8℃时,NEORAL口服液固化成膏状物,而制剂35和44均保持为液体粘稠液。制剂35或44的冷溶液均未出现环孢菌素A沉淀。
从上述结果和讨论,显然本发明提供了生物利用度高的新环孢菌素制剂。所述制剂能包含高浓度环孢菌素,并在宽的温度范围(包括通常用于冷藏的低温)稳定储存。所述制剂可改成以胶囊形式给药,包括硬胶囊,使易于储存和处置。
本说明书中引用的所有出版物和专利申请均在此引为参考,好象每一出版物或专利申请具体地、个别地引为参考。
通过阐述和实施例详细描述了上面的发明,目的在于清晰的理解,但是,本领域普通技术人员借助本发明的教导将会容易地明白,可对其作某些变动和修改而不背离所附权利要求的精神或范围。
Claims (23)
1.口服环孢菌素制剂,主要包括:
环孢菌素;
至少一种2-3个碳原子的链烷醇溶剂;
至少一种非离子型聚亚氧烷基表面活性剂,其中所述表面活性剂选自聚氧乙烯醇和4-6个碳原子的乙氧基化多元醇的脂肪酸单酯;和
至少一种聚乙二醇,其中所述的至少一种聚乙二醇分子量范围为800-10,000道尔顿。
2.如权利要求1所述的制剂,其中所述的聚乙二醇包括聚乙二醇。
3.如权利要求2所述的制剂,其中所述的链烷醇溶剂为所述制剂的约5-75%(v/v)。
4.如权利要求2所述的制剂,其中所述的链烷醇溶剂为所述制剂的约10-25%(v/v)。
5.如权利要求4所述的制剂,其中所述的链烷醇溶剂为无水乙醇。
6.如权利要求2所述的制剂,其中所述的至少一种非离子型聚亚氧烷基表面活性剂为所述制剂的约5-80%(w/v)。
7.如权利要求2所述的制剂,其中所述的至少一种非离子型聚亚氧烷基表面活性剂为所述制剂的约10-50%(w/v)。
8.如权利要求2所述的制剂,其中所述的至少一种非离子型聚亚氧烷基表面活性剂为所述制剂的约20-75%(v/v)。
9.如权利要求2所述的制剂,其中所述的至少一种非离子型聚亚氧烷基表面活性剂选自聚氧乙烯(20)单山梨糖醇单油酸酯和聚氧乙烯(4)月桂基醚。
10.如权利要求2所述的制剂,其中所述的至少一种聚乙二醇包括分子量在约1000-8000道尔顿范围内的聚乙二醇。
11.如权利要求2所述的制剂,其中所述的至少一种聚乙二醇包括具有不同分子量的两种不同聚乙二醇的混合物。
12.如权利要求2所述的制剂,其中所述的至少一种聚乙二醇为所述制剂的约20-80%(w/v)。
13.如权利要求1所述的制剂,其中环孢菌素浓度为100mg/ml,无水乙醇浓度为12.5%,聚氧乙烯(20)单山梨糖醇单油酸酯浓度为400mg/ml。
14.如权利要求1所述的制剂,所述制剂以硬胶囊的形式存在。
15.口服环孢菌素制剂,主要包括:
环孢菌素;
至少一种2-3个碳原子的链烷醇溶剂;和
至少一种非离子型聚亚氧烷基表面活性剂,其中所述表面活性剂选自聚氧乙烯醇和4-6个碳原子的乙氧基化多元醇的脂肪酸单酯。
16.如权利要求14所述的制剂,其中所述的链烷醇溶剂为所述制剂的约5-75%(v/v)。
17.如权利要求14所述的制剂,其中所述的链烷醇溶剂为所述制剂的约10-25%(v/v)。
18.如权利要求16所述的制剂,其中所述的链烷醇溶剂为无水乙醇。
19.如权利要求14所述的制剂,其中所述的至少一种非离子型聚亚氧烷基表面活性剂为所述制剂的约5-80%(w/v)。
20.如权利要求14所述的制剂,其中所述的至少一种非离子型聚亚氧烷基表面活性剂为所述制剂的约65-80%(w/v)。
21.如权利要求14所述的制剂,所述制剂以硬胶囊的形式存在。
22.包含环孢菌素和生理学上可接受的载体的口服环孢菌素制剂,其中所述制剂基本上是无水的。
23.在宿主身上达到免疫抑制作用的方法,所述方法包括:
对所述宿主投用按权利要求1-22任何一项所述的口服环孢菌素制剂,从而在所述宿主身上达到免疫抑制作用。
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-
1997
- 1997-10-23 US US08/956,841 patent/US5962019A/en not_active Expired - Fee Related
-
1998
- 1998-10-21 NZ NZ336253A patent/NZ336253A/en unknown
- 1998-10-21 HU HU0004733A patent/HUP0004733A3/hu unknown
- 1998-10-21 EP EP98952393A patent/EP0956035A1/en not_active Withdrawn
- 1998-10-21 KR KR1019997005738A patent/KR20000069688A/ko active IP Right Grant
- 1998-10-21 CA CA002275773A patent/CA2275773A1/en not_active Abandoned
- 1998-10-21 SK SK97199A patent/SK97199A3/sk unknown
- 1998-10-21 WO PCT/US1998/022330 patent/WO1999020296A1/en not_active Application Discontinuation
- 1998-10-21 BR BR9806271-9A patent/BR9806271A/pt not_active IP Right Cessation
- 1998-10-21 CN CN98801568A patent/CN1246057A/zh active Pending
- 1998-10-21 TW TW087117445A patent/TW592707B/zh active
- 1998-10-21 IL IL13063198A patent/IL130631A0/xx unknown
- 1998-10-21 PL PL98334100A patent/PL334100A1/xx unknown
- 1998-10-21 RU RU99113343/14A patent/RU2174405C2/ru active
- 1998-10-21 TR TR1999/01448T patent/TR199901448T1/xx unknown
- 1998-10-21 JP JP11524568A patent/JP2000516267A/ja active Pending
- 1998-10-21 AU AU98106/98A patent/AU9810698A/en not_active Abandoned
- 1998-10-22 AR ARP980105274A patent/AR013710A1/es not_active Application Discontinuation
- 1998-10-23 ZA ZA989684A patent/ZA989684B/xx unknown
-
1999
- 1999-06-22 NO NO993096A patent/NO993096L/no not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101032620B (zh) * | 2007-03-08 | 2010-05-19 | 上海凯昭医药科技有限公司 | 一种环孢素自乳化制剂及其制备方法 |
Also Published As
Publication number | Publication date |
---|---|
CA2275773A1 (en) | 1999-04-29 |
PL334100A1 (en) | 2000-01-31 |
TR199901448T1 (xx) | 1999-12-21 |
NO993096L (no) | 1999-08-17 |
NZ336253A (en) | 2001-06-29 |
HUP0004733A2 (hu) | 2001-05-28 |
JP2000516267A (ja) | 2000-12-05 |
AR013710A1 (es) | 2001-01-10 |
AU9810698A (en) | 1999-05-10 |
ZA989684B (en) | 1999-04-25 |
BR9806271A (pt) | 2000-04-04 |
HUP0004733A3 (en) | 2001-12-28 |
WO1999020296A1 (en) | 1999-04-29 |
IL130631A0 (en) | 2000-06-01 |
RU2174405C2 (ru) | 2001-10-10 |
KR20000069688A (ko) | 2000-11-25 |
EP0956035A1 (en) | 1999-11-17 |
TW592707B (en) | 2004-06-21 |
US5962019A (en) | 1999-10-05 |
NO993096D0 (no) | 1999-06-22 |
SK97199A3 (en) | 2004-10-05 |
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