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CN1170539C - 含有伊曲康唑的抗真菌口服组合物及其制备方法 - Google Patents

含有伊曲康唑的抗真菌口服组合物及其制备方法 Download PDF

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CN1170539C
CN1170539C CNB008089485A CN00808948A CN1170539C CN 1170539 C CN1170539 C CN 1170539C CN B008089485 A CNB008089485 A CN B008089485A CN 00808948 A CN00808948 A CN 00808948A CN 1170539 C CN1170539 C CN 1170539C
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itraconazole
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phosphoric acid
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禹钟守
李鸿基
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Hanmi Pharmaceutical Industries Co Ltd
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Abstract

含有伊曲康唑和磷酸的熔凝混合物的抗真菌口服组合物可以达到很高的伊曲康唑体内生物利用度。

Description

含有伊曲康唑的抗真菌口服组合物及其制备方法
发明领域
本发明涉及具有改善的伊曲康唑(itraconazole)生物利用度的伊曲康唑的口服组合物及其制备方法。
发明背景
伊曲康唑是一种三唑化合物，已知它具有优良的抗真菌活性。但是，口服给药伊曲康唑的生物利用度非常低，因为它在水中的溶解度很低，不到1μg/ml，并且由于它的pKa值为3.7，因此在胃液中仍保持未电离的状态。此外，已知口服给药伊曲康唑的生物利用度在个体之间有很大差异，并且还取决于摄入的食物等其它因素。
PCT国际申请公开号WO 85/02767和美国专利4,764,604教导了一种通过使用伊曲康唑的环糊精包合物来增加伊曲康唑溶解度的方法。但是，该方法的问题是伊曲康唑溶解度的增加并不明显，并且还需要各种复杂的制备方法。
最近，PCT国际申请公开号WO 94/05263公开了一种包衣珠制剂，其中，将由药物惰性或中性的蔗糖、糊精、淀粉等制成的核芯用伊曲康唑和亲水性聚合物的混合物包衣，然后，将形成的珠再次用聚合物例如聚乙二醇包衣。该包衣珠制剂可以从Janssen Pharmaceutica(Beerse，Belgium)以Sporanox胶囊的商标名购买到。但是，上述制剂的生产方法非常复杂，因为平均直径仅有600至700μm的小珠在生产过程中会趋向于形成大块。
PCT国际申请公开号WO 97/44014公开了一种伊曲康唑在水溶性聚合物中的固体分散体，该分散体通过将伊曲康唑和水溶性聚合物的混合物在245℃至265℃的温度范围内进行熔融挤出过程制得。据称该固体分散体具有改善的伊曲康唑的生物利用度，其生物利用度不受摄入的食物的影响，并且可以从Janssen Pharmaceutica(Beerse，Belgium)以Sporanox片剂的商标名购买到。但是，固体分散体的生产方法受到在控制各种方法可变参数时的许多困难的限制，并且上述分散体所能达到的伊曲康唑的体内生物利用度仍然很低。
因此，仍需要开发一种具有改善的伊曲康唑体内生物利用度的口服组合物。
发明概述
因此，本发明的目的是提供一种含有伊曲康唑的改进了的口服组合物。
本发明的另一个目的是提供制备所述口服组合物的方法。
根据本发明的一个方面，本发明提供了用于口服给药的抗真菌组合物，该组合物含有伊曲康唑和磷酸、可药用载体和表面活性剂的熔凝混合物(fused mixture)。
附图概述
通过以下对本发明的描述并结合附图，可以清楚地看出本发明的上述和其它目的及特点，其中：
图1显示了本发明的伊曲康唑制剂和市售的伊曲康唑制剂的生物利用度。
发明详述
在整个说明书中，通过将伊曲康唑和磷酸熔融形成熔化物然后将该熔化物冷却所得到的固体均称为伊曲康唑和磷酸的熔凝混合物。该混合物的熔点远远低于伊曲康唑，并且与固体伊曲康唑相比，伊曲康唑从所述混合物到水溶液中的溶出有了很大的提高，从而增加了伊曲康唑的体内生物利用度。
在本发明的熔凝混合物中，伊曲康唑和磷酸的重量比为1∶0.1至1∶10，优选1∶0.5至1∶5。
含有伊曲康唑和磷酸的熔凝混合物的本发明组合物可以含有可药用载体，例如乳糖、糊精、淀粉、微晶纤维素、羟丙甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素、甲基纤维素、聚乙二醇、二氧化硅、水滑石、硅酸镁铝(aluminum magnesium silicate)、氢氧化铝、硅酸铝、硅酸镁铝(magnesium aluminum metasilicate)、膨润土及其混合物。
本发明的抗真菌口服组合物还可以含有表面活性剂，它可以促进伊曲康唑和磷酸的熔凝混合物在含水溶媒中的润湿。表面活性剂的代表性例子包括：
(1)聚氧乙烯二醇化(polyoxyethylene glycolated)的天然或氢化植物油例如聚氧乙烯乙二醇化的天然或氢化蓖麻油(Cremophor，BASF)，
(2)聚氧乙烯-脱水山梨醇-脂肪酸酯，其中的脂肪酸是单-或三-月桂酸、棕榈酸、硬脂酸、油酸(Tween，ICI)，
(3)聚氧乙烯脂肪酸酯，例如聚氧乙烯硬脂酸酯(Myrj，ICI)，
(4)聚氧乙烯-聚氧丙烯嵌段共聚物(Poloxamer，BASF)，
(5)二辛基磺基琥珀酸钠或十二烷基硫酸钠，
(6)磷脂，
(7)丙二醇单-或二-脂肪酸酯，例如丙二醇二辛酸酯、丙二醇二月桂酸酯、丙二醇异硬脂酸酯、丙二醇月桂酸酯、丙二醇蓖麻油酸酯、丙二醇辛酸-癸酸二酯(Miglyol840，Huls)，
(8)天然植物油甘油三酯和聚亚烷基多元醇的反式酯化的产物(LabrafilM，Gattefosse)，
(9)单-、二-或单/二-甘油酯，例如辛酸/癸酸单-和二-甘油酯(Imwitor，Huls)，和
(10)脱水山梨醇脂肪酸酯，例如脱水山梨醇单月桂酸酯、脱水山梨醇单棕榈酸酯和脱水山梨醇单硬脂酸酯(Span，ICI)。
在上述表面活性剂中，本发明优选使用聚氧乙烯乙二醇化的天然或氢化植物油、聚氧乙烯-脱水山梨醇-脂肪酸酯和聚氧乙烯-聚氧丙烯嵌段共聚物。
此外，根据本发明的另一方面，本发明提供了制备本发明组合物的方法，该方法包括，(a)将伊曲康唑和磷酸混合，(b)将混合物加热至100至170℃得到均匀的熔融(melt)混合物，(c)向其中加入可药用载体和表面活性剂，(d)将形成的混合物冷却得到固体，和(e)将固体粉碎。
或者，本发明的组合物可以用有机溶剂例如乙醇、二氯甲烷和氯仿来制备。具体地讲，将伊曲康唑与磷酸混合然后向形成的混合物中加入少量有机溶剂得到溶液。随后，向其中加入可药用载体和表面活性剂，将形成的溶液加热蒸除溶剂然后冷却得到固体，然后将固体粉碎。
可以按照常规方法将本发明的药物组合物制成各种药物制剂，例如散剂、颗粒剂、片剂、包衣的制剂和液体制剂。例如，硬胶囊可以通过如下方法制备：向药物组合物中加入润滑剂和其它药物添加剂，将混合物加工成粉末或颗粒，然后将粉末或颗粒填充到硬明胶胶囊中；片剂可以通过向药物组合物中加入适宜的添加剂然后将混合物压片来制备；液体制剂可以通过将药物组合物溶于水中来制备；包衣的制剂可以通过将药物组合物的溶液涂覆在糖珠例如Non-pareil(Edward Mendell Co.，UK)上来制备。
如上所述，含有伊曲康唑和磷酸的熔凝混合物的本发明组合物可以达到很高的伊曲康唑体内生物利用度。此外，本发明的制备含有伊曲康唑的本发明抗真菌组合物的方法与现有技术方法相比的优点在于它的加工温度较低而生产效率很高。
以下实施例是用来进一步说明本发明的，并不限定本发明的范围。
此外，以下给出的固体在固体混合物中、液体在液体中以及固体在液体中的百分比分别是基于wt/wt、vol/vol和wt/vol，除非另有具体说明。
实施例1：硬胶囊的制备
用如下成分制备硬胶囊：
                              量(mg/胶囊)
伊曲康唑                         100
磷酸85％                         150
Poloxamer407                  30
CremophorRH40                 10
羟丙甲基纤维素                   20
水滑石                           70
二氧化硅                         20
将伊曲康唑和磷酸混合并将混合物加热至160℃得到熔化了的熔化物。在使混合物冷却的同时向其中加入除二氧化硅之外的其它成分。然后，将形成的混合物冷却至室温得到熔凝的固体。将固体与二氧化硅混合，粉碎然后填充到硬明胶胶囊中。
实施例2：硬胶囊的制备
用如下成分通过实施例1的方法制备硬胶囊：
                              量(mg/胶囊)
伊曲康唑                         100
磷酸85％                         100
Poloxamer407                  30
Tween80                       10
羟丙甲基纤维素                   20
水滑石                           70
二氧化硅                         20
实施例3：硬胶囊的制备
用如下成分通过实施例1的方法制备硬胶囊：
                          量(mg/胶囊)
伊曲康唑                     100
磷酸85％                     100
Poloxamer407              30
CremophorRH40             10
水滑石                       100
二氧化硅                     20
实施例4：硬胶囊的制备
用如下成分通过实施例1的方法制备硬胶囊：
                           量(mg/胶囊)
伊曲康唑                      100
磷酸85％                      150
Tween80                    20
CremophorRH40              10
水滑石                        70
二氧化硅                      20
实施例5：硬胶囊的制备
用如下成分通过实施例1的方法制备硬胶囊：
                            量(mg/胶囊)
伊曲康唑                       100
磷酸85％                       50
Poloxamer407                40
CremophorRH40               20
水滑石                         70
二氧化硅                       20
实施例6：硬胶囊的制备
用如下成分通过实施例1的方法制备硬胶囊：
                                 量(mg/胶囊)
伊曲康唑                            100
磷酸85％                            150
Poloxamer407                     30
CremophorRH40                    10
聚乙二醇(PEG)20000                  150
二氧化硅                            20
实施例7：硬胶囊的制备
用如下成分制备硬胶囊：
                                 量(mg/胶囊)
伊曲康唑                            100
磷酸85％                            100
乙醇                                500
Poloxamer407                     100
CremophorRH40                    50
聚乙二醇(PEG)20000                  200
将伊曲康唑和磷酸混合，向混合物中加入乙醇得到溶液。向其中加入其它成分，将形成的溶液加热至100℃蒸除乙醇，然后冷却至室温得到固体。将固体粉碎然后填充到硬明胶胶囊中。
实施例8：含有包衣珠的硬胶囊的制备
用如下成分制备含有包衣珠的硬胶囊：
                                 量(mg/胶囊)
伊曲康唑                            100
磷酸85％                            200
乙醇                                500
聚乙二醇(PEG)20000                   100
CremophorRH40                     20
糖珠                                 400
用实施例7的方法制备含有除乙醇之外的其它成分的混合物，其中含有一半的PEG 20000。将混合物均匀地涂覆在糖珠上，然后在其上涂覆剩余部分的PEG 20000。然后将制得的包衣糖珠填充到硬明胶胶囊中。
比较实施例：硬胶囊的制备
按照实施例1的方法用如下成分制备硬胶囊，但不使用磷酸：
                                  量(mg/胶囊)
伊曲康唑                              100
Poloxamer407                       30
CremophorRH40                      10
羟丙甲基纤维素                        20
水滑石                                70
二氧化硅                              20
试验实施例1：溶解试验
按照《韩国药典》的“一般试验”一章中描述的溶出试验方法II(桨法)在下述条件下测定本发明实施例1至3的制剂；比较实施例的制剂；Sporanox胶囊和Sporanox片剂(Janssen Korea)的伊曲康唑溶出速率：
试验装置：Erweka DT80(Erweka，德国)
试验溶液：900ml 0.1N HCl
试验溶液的温度：37±0.5℃
旋转速度：100±4rpm
分析方法：液相色谱
-柱：Cosmosil C18(150mm×4.6mm；Nacalai tesque，日本)
-流动相：乙腈/磷酸盐缓冲液(pH7.0)＝60∶40
-流速：1.2ml/分钟
-检测器：UV 255nm
-注射体积：10μl
溶出的伊曲康唑的量用45分钟内洗脱的伊曲康唑的累积量表示，结果如表1中所示。
                                 表1
  样品   实施例1   实施例2   实施例3   比较实施例   Sporanox胶囊   Sporanox片剂
  溶出的量(45分钟)   94％   91％   96％   15％   50％   92％
从表1可以看出，实施例1至3的制剂显示出明显高于比较实施例和Sporanox胶囊的伊曲康唑的溶解量。该结果证实，通过使用本发明的伊曲康唑和磷酸的熔凝混合物可以大大提高伊曲康唑在水中的溶解度。
此外，虽然Sporanox片剂显示出类似于实施例1至3的伊曲康唑的高水平溶出，但本发明制剂的生产方法比Sporanox片剂简单得多，并且生产效率更高。此外，如试验实施例2所示，Sporanox片剂的伊曲康唑体内生物利用度显著低于本发明的组合物。
试验实施例2：体内吸收试验
为了研究本发明制剂中所含的伊曲康唑的生物利用度，进行了如下体内吸收试验。
将30只体重均为大约300g的14或15周龄的雄性Sprague-Dawly大鼠禁食48小时并同时可以使其随意地接近水，然后将其分成每组含10只大鼠的两组。
向两组大鼠分别口服给药本发明实施例1的制剂和Sporanox片剂，剂量为20mg伊曲康唑/kg大鼠体重。在给药前和给药2、4、6、8和24小时后直接从大鼠的心脏获取血样，然后从其中分离出血清。
向500μl各血清样品中加入50μl内标物溶液(含有500μg/ml益康唑的甲醇溶液)和200μl 1M碳酸盐缓冲液(pH10.0)。向其中加入7ml提取溶剂(正庚烷∶异戊醇＝9∶1)并将形成的混合物于80rpm振摇5分钟得到提取物。将提取物以3,000rpm离心10分钟，然后在氮气氛下于50℃蒸除溶剂。向形成的残余物中加入200μl 0.05％三乙胺的65％含水乙腈溶液并将该混合物在如下条件下进行HPLC：
-柱：Inertsil ODS2(250×4.6mm，5μm；GL科学，日本)
-流动相：含有0.05％三乙胺的65％乙腈水溶液
-检测器：UV 258nm
-流速：1.2ml/分钟
-注射体积：100μl
表1中的结果证实，用本发明制剂所观察到的伊曲康唑的生物利用度远远高于Sporanox片剂。
虽然就上述具体实施方案对本发明进行了描述，但应当理解，本领域技术人员可以对本发明进行各种修饰和改变，这些修饰和改变也落在所附权利要求所定义的本发明的范围之内。

Claims (5)

1.用于口服给药的抗真菌组合物，该组合物含有伊曲康唑和磷酸、可药用载体和表面活性剂的熔凝混合物。
2.按照权利要求1的抗真菌组合物，其中在熔凝混合物中伊曲康唑和磷酸的重量比为1∶0.1至1∶10。
3.按照权利要求1的抗真菌组合物，其中所述可药用载体选自：乳糖、糊精、淀粉、微晶纤维素、羟丙甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素、甲基纤维素、聚乙二醇、二氧化硅、水滑石、硅酸镁铝、氢氧化铝、硅酸铝、硅酸镁铝、膨润土及其混合物。
4.按照权利要求1的抗真菌组合物，其中所述表面活性剂选自：聚氧乙烯乙二醇化的天然或氢化植物油、聚氧乙烯-脱水山梨醇-脂肪酸酯、聚氧乙烯脂肪酸酯、聚氧乙烯-聚氧丙烯嵌段共聚物、二辛基磺基琥珀酸钠、十二烷基硫酸钠、磷脂、丙二醇单-或二-脂肪酸酯、天然植物油甘油三酯和聚亚烷基多元醇的反式酯化的产物、单甘油酯、二甘油酯、单/二-甘油酯和脱水山梨醇脂肪酸酯。
5.权利要求1所述的抗真菌组合物的制备方法，该方法包括：
(a)将伊曲康唑和磷酸混合，
(b)将混合物加热至100至170℃得到均匀的熔融混合物，
(c)向其中加入可药用载体和表面活性剂，
(d)将形成的熔融混合物冷却得到固体，和
(e)将固体粉碎。
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