CN1149992C - 活性化合物高度释放的抗真菌凝胶 - Google Patents

活性化合物高度释放的抗真菌凝胶 Download PDF

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CN1149992C
CN1149992C CNB971982643A CN97198264A CN1149992C CN 1149992 C CN1149992 C CN 1149992C CN B971982643 A CNB971982643 A CN B971982643A CN 97198264 A CN97198264 A CN 97198264A CN 1149992 C CN1149992 C CN 1149992C
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M·博恩
K·T·克拉米尔
A·马库斯
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Abstract

本发明涉及含有亲水性胶凝剂、水和式I化合物的药物制剂,其适用于治疗和预防皮肤真菌病。

Description

活性化合物高度释放的抗真菌凝胶
本发明涉及可以局部应用的、活性化合物高度释放的抗真菌制剂,该制剂为凝胶形式,其含有至少一种羟基吡啶酮类型的抗真菌物质和至少一种亲水性胶凝剂。
对于真菌病、特别是皮肤真菌病的局部治疗,各种羟基吡啶酮衍生物的制剂形式如溶液剂、软膏和粉剂是已知的。但由于各种原因,使用目前已知的羟基吡啶酮类化合物的制剂形式很难达到皮肤真菌病的最佳治疗效果。
可以局部应用的液体制剂通常包括透明的水溶液或含水醇溶液。这些制剂或者是涂抹在皮肤表面,或者是用于洗浴。具体地讲,它们用于所有被生长的浓密毛发遮盖的皮肤部位,因为软膏或粉剂不适用于这些部位。此外,它们还用于由于美容上的原因其它药物剂型不适用的皮肤部位如脸部,或经常活动的身体部位(例如肘、膝盖等)。
活性化合物从溶液中释放的速率通常很高,因为在涂抹后由于溶媒的蒸发而在制剂和皮肤之间形成了很高的浓度梯度,这最终导致活性化合物通过皮肤的高度吸收,从而达到很高的效力。
然而,就其应用特性而言,溶液剂是不利的,由于其液体的聚集状态,因而难于处理,特别是在脸上,并且仅施用于限定的皮肤部位是不可能的。
软膏或半固体药物剂型是在室温至皮肤温度的温度范围内可以分散的给药形式,因此可以同液体给药形式和固体给药形式区分开。基于皮肤载体物质的物质特性,软膏通常是指无水的脂肪基质或由油相和水相组成的乳液,该乳液用乳化剂稳定。
由于其半固体的质地,与溶液剂相比,软膏制剂可以非常特异性地涂抹于限定的皮肤部位。但是,由于含有脂肪成分,亲脂性的羟基吡啶酮衍生物从软膏组分中的释放受到了很大的限制。此外,软膏通常不能在皮肤上形成耐擦拭的膜,这也会对涂抹软膏后的治疗效果产生不利影响。因此,在与衣服或床单接触时,涂抹的产品很容易被擦去,从而不能得到有效的治疗。
粉剂主要用于吸附增加的分泌液并保持皮肤干燥;这一点对于治疗尤其是皮肤真菌病是非常重要的。由于实际应用的原因,粉剂的应用几乎完全局限于足真菌病的治疗。
现已发现,含有溶剂和亲水性胶凝剂以及常规制剂辅料的羟基吡啶酮衍生物的凝胶制剂可以高度释放活性化合物,并且由于可以在皮肤内达到活性化合物的高浓度而使效果得到改善。基于本发明制剂的半固体质地,很容易将其特异性地涂抹于感染的皮肤部位并表现出所需的干燥(dry-out)效果,特别是在治疗足真菌病时。
因此,本发明涉及含有亲水性胶凝剂、水和式I化合物或式I化合物的生理可耐受盐的药物制剂,
Figure C9719826400051
其中R1、R2和R3彼此相同或不同,分别是氢原子或含有1-4个碳原子的烷基,R4是含有6-9个碳原子的饱和烃基。
优选的药物制剂是:其中,R4是含有6-9个碳原子的饱和烃基,基团R1和R3之一是氢原子,另一个是氢原子、甲基或乙基,R2是含有1或2个碳原子烷基。
特别优选的药物制剂是,其中,式I化合物在R4位置含有环状基团。
更优选的药物制剂是,其中,R4是环己基或-CH2-CH(CH3)-CH2-C(CH3)3
其中,术语“饱和的”是指这些基团不含脂族多重键、即不含烯键或炔键。
可以提到的适宜的式I化合物是,例如:1-羟基-4-甲基-6-正己基-、-6-异己基-、-6-正庚基-或-6-异庚基-2-吡啶酮,1-羟基-4-甲基-6-辛基-或-6-异辛基-2-吡啶酮,特别是1-羟基-4-甲基-6-(2,4,4-三甲基戊基)-2-吡啶酮、1-羟基-4-甲基-6-环己基-2(-吡啶酮、1-羟基-4-甲基-6-环己基甲基-或-6-环己基乙基-2-吡啶酮,其中的各环己基还可以带有一个甲基,1-羟基-4-甲基-6-(2-二环[2.2.1]庚基)-2-吡啶酮,1-羟基-3,4-二甲基-6-苄基-或-6-二甲基-苄基-2-吡啶酮和1-羟基-4-甲基-6-(β-苯乙基)-2-吡啶酮。
本发明还涉及药物制剂用于生产用于治疗和预防皮肤真菌病的药物的用途。
使用本发明的药物治疗皮肤真菌病时,可以迅速治愈。本发明的药物还适用于对皮肤真菌病的预防性应用。
本发明的药物制剂中,式I化合物的含量取决于各式I化合物的结构,因此取决于式I化合物从凝胶的释放、其在皮肤中的渗透行为及其抗真菌特性。
在本发明的药物制剂中,式I化合物的含量通常为0.05-2%(重量),优选0.1-1%(重量)。
可以使用的亲水性胶凝剂是天然物质如明胶、果胶、角叉菜胶、琼脂、西黄蓍胶和藻酸盐,半合成胶凝剂如纤维素醚(甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羧甲基纤维素钠)、淀粉衍生物和果胶衍生物以及全合成的胶凝剂如聚丙烯酸酯、聚甲基丙烯酸酯、聚乙烯醇和聚乙烯吡咯烷酮。特别优选聚丙烯酸酯作为亲水性胶凝剂。其用量为最终产品的0.3-2.0重量份至100重量份。
适宜的溶剂是水以及所有可与水混溶的溶剂。适宜的溶剂是,例如链烷醇(其选自乙醇和/或异丙醇),以及丙二醇和二甲亚砜。在制备本发明的制剂时,可以使用一种或多种溶剂。
适用于本发明药物制剂的增溶剂是:苄醇、2-辛基十二醇、己二酸酯、丙二醇和甘油。这些增溶剂在本发明制剂中的含量为1-15%(重量)。
适宜的其他辅料是乳化剂、湿润剂和分散剂。
所述制剂根据已知的方式通过将各成分混合进行制备,如需要,可进行适于具体制剂的进一步加工。
通过以下实施例对本发明进一步进行说明,但本发明并不仅限于此。若无相反说明,以下数据是就重量而言的。
实施例1
本发明的制剂具有如下组成:
1-羟基-4-甲基-6-(2,4,4-三甲基戊基)-2-(1H)-吡啶酮    0.50%
羟乙基纤维素                                          1.50%
聚乙二醇-7甘油椰油酸酯(glycerylcocoate)               5.00%
1,2-丙二醇                                          10.00%
异丙醇                                               20.00%
去离子水                                             63.00%
实施例2
本发明的制剂具有如下组成:
1-羟基-4-甲基-6-环己基-2-(1H)-吡啶酮                  1.00%
聚丙烯酸聚合物(例如卡波姆934P)                        0.70%
氢氧化钠                                              0.20%
二辛基磺基琥珀酸钠                                    0.05%
2-辛基十二醇                                          7.50%
异丙醇                                               25.00%
去离子水                                             65.55%
实施例3
本发明的制剂具有如下组成:
1-羟基-4-甲基-6-环己基-2-(1H)-吡啶酮        0.50%
聚丙烯酸聚合物(例如卡波姆940)               0.50%
氢氧化钠                                    0.20%
聚氧乙烯(20)脱水山梨醇单硬脂酸酯            3.50%
肉豆蔻酸异丙酯                             10.00%
乙醇                                       20.00%
去离子水                                   65.30%
实施例4
现有技术的软膏制剂具有如下组成:
1-羟基-4-甲基-6-环己基-2-(1H)-吡啶酮        1.00%
凡士林                                     20.00%
硬脂醇                                     15.00%
2-辛基十二醇                               10.00%
聚氧乙烯(20)脱水山梨醇单硬脂酸酯            3.50%
脱水山梨醇单硬脂酸酯                        1.50%
去离子水                                   49.00%
实施例5
现有技术的软膏制剂具有如下组成:
1-羟基-4-甲基-6-环己基-2-(1H)-吡啶酮        1.00%
凡士林                                     20.00%
硬脂醇                                     15.00%
2-辛基十二醇                               10.00%
聚氧乙烯(20)脱水山梨醇单硬脂酸酯            3.50%
脱水山梨醇单硬脂酸酯                        1.50%
去离子水                                   49.00%
实施例6
活性试验
在使用切除的猪皮肤的渗透模型中测试本发明药物制剂的活性化合物释放。
通过渗透模型在切除的猪皮肤上测试本发明组合物中活性化合物的释放。于是,通过用微生物测定方法测定渗透深度可以直接评估本发明组合物中活性化合物的释放。试验方法如下:
在将杀死的动物用沸水烫之前,从屠宰的猪上切下较大块背部皮肤,用湿纸和塑料薄膜包裹并于-20℃下深度冷冻直至试验。
试验前,除去皮肤表面的脂肪组织,刮去毛并用异丙醇处理60分钟进行消毒。每次试验使用不同的皮肤(约2×3cm)。将皮肤表面用含有各种式I化合物的制剂处理。在各作用时间(0.5、1和4小时)结束后,从皮肤表面洗去产品。为了研究活性化合物的不同渗透力,或各制剂的不同释放能力,将皮肤用Scotch膜在三个相邻的轨道上剥离2次、6次和10次。然后将各轨道以点状的方式用须发癣菌100/25悬浮液接种10下(每个接种点约200个小分生孢子)。然后将皮肤块在加有青霉素、链霉素和放线菌酮的水和琼脂上于28℃保温7天。从接种第4天起,每日用肉眼观察结果。
结果:
与相应的安慰剂制剂相比,用实施例1-4的含活性化合物的凝胶制剂作用4小时后,在皮肤块的所有截面均没有肉眼可见的真菌。
对于根据现有技术制备的实施例5的含活性化合物的软膏制剂,4小时的作用时间不足以在接种的部分杀死大分生孢子。

Claims (12)

1.含有亲水性胶凝剂、水、二辛基磺基琥珀酸酯钠盐和2-辛基十二醇,以及式I化合物或式I化合物的生理可耐受盐的药物制剂用于制备治疗和预防皮肤真菌病的药物的用途,
Figure C9719826400021
其中R1、R2和R3彼此相同或不同,分别是氢原子或含有1-4个碳原子的烷基,R4是含有6-9个碳原子的饱和烃基;
其中,所用的亲水性胶凝剂是天然物质包括:明胶、果胶、角叉菜胶、琼脂、西黄蓍胶或藻酸盐,半合成化合物:包括纤维素醚、淀粉衍生物或果胶衍生物,以及全合成的胶凝剂包括:聚丙烯酸酯、聚甲基丙烯酸酯、聚乙烯醇或聚乙烯吡咯烷酮,或它们的混合物。
2.权利要求1所述的用途,其中,R4是含有6-9个碳原子的饱和烃基,基团R1和R3之一是氢原子,另一个是氢原子、甲基或乙基,R2是含有1或2个碳原子烷基。
3.权利要求1或2所述的用途,其中,式I化合物在R4位置含有环状基团。
4.权利要求3所述的用途,其中,R4是环己基或-CH2-CH(CH3)-CH2-C(CH3)3
5.权利要求1或2所述的用途,其中所述纤维素醚选自甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素或羧甲基纤维素钠。
6.权利要求1或2所述的用途,其中,使用聚丙烯酸酯作为亲水性胶凝剂。
7.权利要求1或2所述的用途,其中的药物制剂中还加有选自苄醇、2-辛基十二醇、丙二醇、己二酸酯和甘油的增溶剂。
8.权利要求1或2所述的用途,其中的药物制剂中还加有可与水混溶的溶剂包括链烷醇以及丙二醇或二甲亚砜。
9.权利要求8的用途,其中所述链烷醇选自乙醇和/或异丙醇。
10.权利要求1或2所述的用途,药物制剂中式I化合物的含量通常为0.05-2%重量,亲水性胶凝剂的含量为0.3-2%重量。
11.权利要求10的用途,药物制剂中式I化合物的含量为0.1-1%重量。
12.权利要求1的用途,药物制剂中还含有聚氧乙烯(20)脱水山梨醇单硬脂酸酯。
CNB971982643A 1996-09-27 1997-09-16 活性化合物高度释放的抗真菌凝胶 Expired - Lifetime CN1149992C (zh)

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