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CN1198623C - 含环索奈德的含水药物组合物 - Google Patents

含环索奈德的含水药物组合物 Download PDF

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CN1198623C
CN1198623C CNB00814253XA CN00814253A CN1198623C CN 1198623 C CN1198623 C CN 1198623C CN B00814253X A CNB00814253X A CN B00814253XA CN 00814253 A CN00814253 A CN 00814253A CN 1198623 C CN1198623 C CN 1198623C
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A·纳加诺
Y·尼施贝
K·塔卡纳施
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Abstract

本发明提供一种含环索奈德及羟丙基甲基纤维素的含水药物组合物,其中环索奈德是以固体颗粒的形式分散在水介质中的。该组合物能够避免生产过程中环索奈德浓度的改变,并避免环索奈德回收率的降低。

Description

含环索奈德的含水药物组合物
技术领域
本发明涉及一种可用于药物疗法的含环索奈德的含水药物组合物,其包含环索奈德及羟丙基甲基纤维素,其中所述的环索奈德是以固体颗粒的形式分散在水介质中的。更特别的是,本发明涉及这样一种含环索奈德的含水药物组合物,与传统的含水药物组合物相比,其在生产过程中具有极好的环索奈德分散性。
背景技术
环索奈德含水药物组合物,其含有以固体颗粒形式分散在水介质中的环索奈德,预期代表了一种有益的药物形式,原因包括1)无需完全溶解环索奈德,2)可通过喷雾等方法将其直接给予受损害的部位,用于治疗局部疾病,如鼻粘膜,眼及表皮的那些疾病,及3)它们比片剂或颗粒剂等更易于吞咽。
当存在于水介质中时,环索奈德可抗润湿并易于聚集。在现有技术中,为了能够在水介质中稳定的分散具有这种性质的药物,可在生产过程中加入湿润剂如聚山梨醇酯80,并用力搅拌。
有关通过加入纤维素基聚合物来改善含水药物组合物的药物分散性的内容已经在Morishima等的WO99-37286专利说明书中公开,其中的含水药物组合物含有以固体颗粒形式分散在水介质中的药物。然而,此专利涉及在贮存过程中沉降的药物的再分散问题,且其与本发明根本不同,本发明涉及需克服环索奈德向气泡迁移的问题,其中该气泡是由生产过程中的有力搅拌而形成的,还需克服环索奈德在生产装置壁上的吸附问题。此外,在Morishima等的专利说明书中,纤维素基聚合物的浓度为0.0001-0.003%,且对于纤维素基聚合物可用甲基纤维素代替羟丙基甲基纤维素,同时还需添加非离子表面活性剂。从这个专利很难推导出本发明,在所述专利中,羟丙基甲基纤维素的浓度的最佳值是0.01%w/w-0.5%w/w,且无需表面活性剂。
发明内容
在环索奈德含水药物组合物的生产过程中,需要高剪切力来分散环索奈德,且必需用力搅拌含环索奈德的含水药物组合物。环索奈德迁移到在此时形成的气泡中。因为这导致环索奈德含水药物组合物上部的环索奈德浓度提高,并高于下部的环索奈德浓度,并导致所生产环索奈德含水药物组合物的环索奈德浓度的改变。此外,由于环索奈德吸附在生产装置的壁等上,导致回收率降低。
环索奈德浓度的这些改变及环索奈德在生产装置上的吸附几乎根本不可能通过在现有技术中所用过的加入湿润剂如聚山梨醇酯80来改善。相反,还导致促进环索奈德浓度进一步改变的所形成气泡的量增加。
因此,广泛地需要研制一种环索奈德含水药物组合物,其能够避免生产过程中环索奈德浓度的改变及环索奈德回收率的降低。
即,本发明的目的是提供一种环索奈德含水药物组合物,其可避免生产过程中环索奈德浓度的改变及环索奈德回收率的降低。
作为解决上述问题的最早期研究的结果,本发明人发现通过使用含环索奈德及羟丙基甲基纤维素的环索奈德含水药物组合物,可避免生产过程中环索奈德浓度的改变及环索奈德回收率的降低,而可以提供环索奈德含水药物组合物,从而完成了本发明。
即,本发明涉及一种含环索奈德及羟丙基甲基纤维素的含水药物组合物,其中所述的环索奈德是以固体颗粒的形式分散在水介质中的。
本发明的具体实施方式
本发明的组合物含有环索奈德是必需的,而除环索奈德之外,还可加入水溶性,低水溶性或水不溶性药物。这些药物的具体例子包括血管收缩药,支气管扩张药,抗-变应性药和祛痰药。
虽然可用于本发明的环索奈德颗粒可以是任意大小,但它们优选在10nm-100μm,特别优选10nm-10μm范围内。
虽然任意物质均可用于本发明可用的水不溶性或低水溶性物质,但优选的例子是纤维素,特别优选的例子是结晶纤维素。
在本发明中,以固体颗粒形式存在的水不溶性物质和/或低水溶性物质在水介质中的浓度相对于组合物总量为优选0.3%w/w及以上,特别优选1%w/w-10%w/w。
此外,还可将含水聚合物加入到本发明的药物组合物中。这种含水聚合物的具体例子包括丙二醇藻酸酯,果胶,低甲氧基果胶,瓜尔胶(gua gum),阿拉伯树胶,角叉菜胶(carrageenan),甲基纤维素,羧甲基纤维素钠,黄原胶(xanthan gum)及羟丙基纤维素,而特别优选的例子包括羧甲基纤维素钠,聚乙二醇和羟丙基纤维素。此外,结晶纤维素羧甲基纤维素钠是这些可用于本发明的水溶性物质及水不溶性物质的组合,它由羧甲基纤维素钠和结晶纤维素的混合物组成。另外,在加入这些水溶性聚合物的情况下,所述聚合物相对于水不溶性物质和/或低水溶性物质的浓度优选1%w/w-30%w/w。
本发明含环索奈德的含水药物组合物还需包含羟丙基甲基纤维素。尽管其可以是任意级的,但具体的例子是羟丙基甲基纤维素2910。
虽然所述羟丙基甲基纤维素可以任意浓度存在,但其相对于组合物总量的浓度优选0.01%w/w-30%w/w,特别优选0.01%w/w-5%w/w,更特别优选0.01%w/w-1%w/w,最优选0.01%w/w-0.5%w/w。
虽然本发明不是必需加入湿润剂,但还是可以加入湿润剂,其具体例子包括聚山梨醇酯80,单硬脂酸甘油酯,硬脂酸酯-聚烃氧基酯,月桂基聚乙二醇(lauromacrogol),脱水山梨糖醇油酸酯,及蔗糖脂肪酸酯。
在本发明中,还可加入调节渗透压的物质(渗透压调节剂)以调节渗透压,其具体例子包括盐如氯化钠和水溶性糖类如葡萄糖,其中葡萄糖是特别优选的。
本发明所用环索奈德的有效量可根据各疾病的类型和程度,及患者的年龄和体重等来确定。
本发明环索奈德相对于组合物总量的浓度优选0.01%w/w-1%w/w,特别优选0.05%w/w-0.5%w/w。
在水介质中分散水不溶性物质和/或低水溶性物质的任意方法均可用于生产本发明含环索奈德的含水药物组合物,其具体实施例是使用均相混合机的方法。
为了改善制剂的物理性质,外观或气味等,必要时可向本发明组合物中加入已知的抗菌剂,pH调节剂,防腐剂,缓冲剂,着色剂,矫味剂等。抗菌剂的例子包括苯扎氯铵,pH调节剂的例子包括盐酸和氢氧化钠,防腐剂的例子包括抗坏血酸,缓冲剂的例子包括磷酸及其盐,着色剂的例子包括2号红色染料,矫味剂的例子包括薄荷醇。
根据如上所述,本发明提供一种环索奈德含水药物组合物,与现有技术的含水药物组合物相比,其可更有效地避免生产过程中环索奈德浓度的改变及环索奈德回收率的降低。由于较高的回收率,这些结果还可提高质量并降低生产成本。
因此,本发明在环索奈德含水药物组合物生产的质量和经济效益方面均具有极高的意义。
实施例
下面,通过实施例说明本发明。
本发明所用的环索奈德是由Byk Gulden Co.生产的,结晶纤维素羧甲基纤维素钠是由Asahi Chemical Industry Co.,Ltd.(AvicelTMRC-A591NF)生产的,羟丙基甲基纤维素2910是由Shin-EtsuChemical Co.,Ltd.(TC-5RWTM或Metrose 60SH-4000TM)生产的,聚山梨醇酯80是由Nippon Surfactant Co.,Ltd生产的,脱水山梨糖醇油酸三酯是由Nikko Chemical Co.,Ltd生产的,所用的均相搅拌机ROBOMICSTM是由Tokushu Kika Kogyo Co.,Ltd生产的。
实施例1
含下列组分的环索奈德含水药物组合物是通过使用均相搅拌机处理而在300ml规模制备的。均相搅拌机在6000rpm下处理30分钟。
组合物(1)
环索奈德:0.1%w/w
结晶纤维素羧甲基纤维素钠:1.7%w/w
羟丙基甲基纤维素2910(TC-5RWTM):0.01%w/w
组合物(2)
环索奈德:0.1%w/w
结晶纤维素羧甲基纤维素钠:1.7%w/w
羟丙基甲基纤维素2910(TC-5RWTM):0.1%w/w
组合物(3)
环索奈德:0.1%w/w
结晶纤维素羧甲基纤维素钠:1.7%w/w
羟丙基甲基纤维素2910(TC-5RWTM):1%w/w
组合物(4)
环索奈德:0.1%w/w
结晶纤维素羧甲基纤维素钠:1.7%w/w
羟丙基甲基纤维素2910(Metrose 60SH-4000TM):0.01%w/w
组合物(5)
环索奈德:0.1%w/w
结晶纤维素羧甲基纤维素钠:1.7%w/w
羟丙基甲基纤维素2910(Metrose 60SH-4000TM):0.1%w/w
用均相混合机处理组合物1-5之后,立即从乳化罐的上部和下部收集环索奈德含水药物组合物,接着通过HPLC量化环索奈德的浓度。以乳化罐下部的环索奈德浓度作为100%来计算乳化罐上部的值。
接着,通过HPLC量化从乳化罐回收的环索奈德含水药物组合物中环索奈德的浓度,并根据环索奈德浓度的理论值确定环索奈德的回收率,其中环索奈德的浓度是根据投料量计算的。
那些值在表1中列出。
对照实施例1
含下列组分的环索奈德含水药物组合物是使用均相搅拌机处理而在300ml规模制备的。均相搅拌机在6000rpm下处理30分钟。
组合物(6)
环索奈德:0.1%w/w
结晶纤维素羧甲基纤维素钠:1.7%w/w
聚山梨醇酯80:0.1%w/w
组合物(7)
环索奈德:0.1%w/w
结晶纤维素羧甲基纤维素钠:1.7%w/w
脱水山梨糖醇油酸三酯:0.1%w/w
用均相混合机处理组合物6-7后,立即从乳化罐的上部和下部收集环索奈德含水药物组合物,接着通过HPLC量化环索奈德的浓度。以乳化罐下部的环索奈德浓度作为100%来计算乳化罐上部的值。
接着,通过HPLC量化从乳化罐回收的环索奈德含水药物组合物中环索奈德的浓度,并根据环索奈德浓度的理论值确定环索奈德的回收率,其中环索奈德的浓度是根据投料量计算的。
那些值在表1中列出。
                                                   表1
制剂        刚处理后的环索奈德浓度(%)   回收率(%)
乳化罐上部   乳化罐下部
实施方案1   组合物1     138.1     100.0     104.2
组合物2 100.3 100.0     100.7
  组合物3     99.6     100.0     101.5
  组合物4     147.9     100.0     98.4
  组合物5     100.4     100.0     100.8
对照实施例1   组合物6     131.1     100.0     78.2
  组合物7     438.7     100.0     43.0
在含0.1-1%w/w羟丙基甲基纤维素2910的组合物2,3和5中,用均相搅拌机刚处理后的乳化罐中环索奈德的浓度是均匀的,且回收率几乎为100%。此外,在含0.01%w/w羟丙基甲基纤维素2910的组合物1和4中,用均相搅拌机刚处理后的乳化罐中环索奈德的浓度虽然不太均匀,但回收率几乎为100%。相反地,在含0.1%w/w聚山梨醇酯80的组合物6中,用均相搅拌机刚处理后的乳化罐上部环索奈德的浓度比乳化罐下部的浓度高30%以上。此外,回收率降低约20%。在含0.1%w/w脱水山梨糖醇油酸三酯的组合物7中,用均相搅拌机刚处理后的乳化罐上部环索奈德的浓度比乳化罐下部的浓度高40%以上,且回收率的降低超过一半。
根据这些结果可知,使用含羟丙基甲基纤维素的组合物可避免生产过程中环索奈德浓度的改变及避免环索奈德回收率的降低。

Claims (14)

1.一种含环索奈德及羟丙基甲基纤维素的含水药物组合物,其中所述的环索奈德是以固体颗粒的形式分散在水介质中的。
2.根据权利要求1所述的含水药物组合物,其中所述的羟丙基甲基纤维素相对于组合物总量的浓度为0.01%重量-30%重量。
3.根据权利要求1所述的含水药物组合物,其中所述的羟丙基甲基纤维素相对于组合物总量的浓度为0.01%重量-5%重量。
4.根据权利要求1所述的含水药物组合物,其中所述的羟丙基甲基纤维素相对于组合物总量的浓度为0.01%重量-1%重量。
5.根据权利要求1所述的含水药物组合物,其中所述的羟丙基甲基纤维素相对于组合物总量的浓度为0.01%重量-0.5%重量。
6.根据权利要求1-5任意一项所述的含水药物组合物,其中还含有一种或多种类型的水不溶性物质和/或低水溶性物质。
7.根据权利要求6所述的含水药物组合物,其中所述的水不溶性物质和/或低水溶性物质是纤维素。
8.根据权利要求7所述的含水药物组合物,其中所述的纤维素是结晶纤维素。
9.根据权利要求1所述的含水药物组合物,其中还含有水溶性聚合物。
10.根据权利要求9所述的含水药物组合物,其中所述的水溶性聚合物是一种或多种类型的选自聚乙二醇,丙二醇藻酸酯,果胶,低甲氧基果胶,瓜尔胶,阿拉伯树胶,角叉菜胶,甲基纤维素,羧甲基纤维素钠,黄原胶及羟丙基纤维素的物质。
11.根据权利要求9所述的含水药物组合物,其中所述的水溶性聚合物是羧甲基纤维素钠。
12.根据权利要求9所述的含水药物组合物,其中所述的水溶性聚合物是聚乙二醇。
13.根据权利要求9所述的含水药物组合物,其中所述的水溶性聚合物是羟丙基纤维素。
14.根据权利要求1所述的含水药物组合物,其中存在水不溶性物质与水溶性聚合物的组合,其为结晶纤维素羧甲基纤维素钠。
CNB00814253XA 1999-10-20 2000-10-20 含环索奈德的含水药物组合物 Expired - Lifetime CN1198623C (zh)

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