CN1270029A - 可控释活性物质的阿片样止痛药 - Google Patents

可控释活性物质的阿片样止痛药 Download PDF

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CN1270029A
CN1270029A CN00104523A CN00104523A CN1270029A CN 1270029 A CN1270029 A CN 1270029A CN 00104523 A CN00104523 A CN 00104523A CN 00104523 A CN00104523 A CN 00104523A CN 1270029 A CN1270029 A CN 1270029A
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J·巴托洛梅乌斯
J·贝青
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Abstract

本发明涉及一种含有晶体形式的阿片样止痛药的口服控释制剂,其中所述晶体具有的颗粒大小为10μm—3mm,它具有至少一种控释包衣层。

Description

可控释活性物质的阿片样止痛药
本发明涉及一种口服给药的药物制剂，从该制剂中可以控释阿片样止痛活性物质。
从现有技术中可以得知具有控释活性物质的止痛药的许多制剂。
尤其是EP-A-0647448由此已经描述了一种活性物质缓释的止痛活性制剂，它由大量基质组成，所述的基质含有0.1-3mm直径的控释阿片样止痛药作为单一日剂量。适于这种目的的基质可以形成球状体、微珠、小丸或颗粒。这类基质的制备要求相对完善的配制方法，诸如用于小丸的层粘连凝聚法或用于球状体的挤压/成球法。
另一方面，许多阿片样活性物质在它们被制备时以晶体形式出现，使得存在一种直接使用它们的需求，即在药物制备过程中不需要所规定的完善配制方法。
因此，本发明的目的是提供一种含有至少一种阿片样活性物质的口服控释制剂，其中可以直接使用在制备活性物质过程中获得的晶体，即不需要完善的配制步骤。
按照本发明，通过提供控释晶体形式的阿片样止痛药的口服给药制剂可以达到这一目的，其中所述的晶体具有10μm-3mm的颗粒大小，它具有至少一种控释包衣层。
所述的晶体优选具有50μm-1mm的颗粒大小。
本发明的制剂含有至少一种晶形的阿片样止痛药作为止痛活性物质。可以使用的阿片样止痛药是二氢吗啡酮、羟氢可待酮、吗啡、羟甲左吗喃、美沙酮、二氢可待因、可待因、二氢吗啡、哌替啶、芬太尼、氰苯双哌酰胺、丁丙诺啡、胺苯环己乙酯、曲马多、其特定的盐或其混合物。
特别优选将曲马多、盐酸曲马多、吗啡、盐酸吗啡和/或硫酸吗啡用作止痛药。
本发明制剂中的活性物质晶体可以是单晶或具有多晶结构。
除所述的阿片样止痛药外，本发明的制剂可以含有任意与阿片样止痛药表现出协同作用的非阿片样止痛药。这些非阿片样止痛药包括布洛芬、酮基布洛芬、氟比洛芬、异丙基安替比林、对乙酰氨基酚、萘普生、醋炎痛(acematacin)、阿司匹林、安乃近及其盐，优选它们的晶体形式。
本发明所用的制剂以控释、优选缓释所述的止痛药为特征。
通过提供具有至少一种控释包衣层的活性物质晶体可以达到这一目的。这种包衣层可确保所述的活性物质在所需期限内控释或缓释。与常规剂型、即那些没有控释包衣层的剂型相比，在这种方式中，能够有目的地控制起作用的时间期限。优选尽力以这样一种方式调整活性物质的释放，使得需要将所述的制剂每日至多给药两次、优选仅给药一次。
合适的包衣材料是任意的药物上安全的包衣材料，它们对于本领域普通技术人员来说是公知的。优选将天然的、任意修饰的或合成的聚合物用作包衣材料。这些是聚合物，诸如纤维素醚类或丙烯酸树脂类。特别优选的是：不溶于水的或水溶胀的纤维素衍生物，诸如烷基纤维素、优选乙基纤维素；或者不溶于水的丙烯酸树脂，诸如聚(甲基)丙烯酸和/或其衍生物，诸如它们的盐类、酰胺类或酯类。
从现有技术中可以得知这些物质，例如Bauer，Lehmann，Osterwald，Rothgang“Uberzogene Arzneiformen”，Wissenschaftliche VerlagsgesellschaftmbH，Stuttgart，1998，69页及其下的内容中所述，并将该文献的内容引入本文作为参考。
除不溶于水的聚合物和蜡外，还通过优选使用高达30wt.％的非控释、优选诸如聚乙烯吡咯烷酮这样的水溶性聚合物或诸如羟乙基纤维素、羟丙基甲基纤维素或羟丙基纤维素这样的水溶性纤维素衍生物和/或公知的增塑剂也能够任意调整活性物质的释放速率。
除控释包衣层外，所述活性物质的晶体还可以含有另外的包衣层。
例如，可以将这类非控释的包衣材料的包衣材料涂布在所述的晶体表面上作为非控释的中间层。
优选用于这种中间层的包衣材料是纤维素醚类、聚乙烯酮类、聚丙烯酸酯类或者也可以是天然的聚合物。
还能够由活性物质晶体或由优选不同于所述活性物质的阿片样止痛药而优选在控释包衣层上制备另外的包衣层，在口服给药后这种活性物质以一种非控释的方式从该包衣层中被释放出来。通过这种多层包衣，能够在将所述的制剂
给药后提供一种主要用于迅速缓解疼痛的初级剂量，其中由随后延缓释放的活性物质可以维持止痛药的水平。可用于这种目的的包衣材料是药物上安全的物质与最初的活性物质，诸如纤维素醚类、聚乙烯酮类、聚丙烯酸酯类。然而，除活性物质晶体或不同于该活性物质的另外的止痛药(优选阿片样止痛药)外，还能够在非控释包衣层中提供另一种非控释的药物活性物质，或者用这一药物活性物质取代活性物质晶体或不同于该活性物质的另外的止痛药(优选阿片样止痛药)。
除控释包衣层外，所述的晶体还可以另外具有以一种pH依赖性方式溶解的包衣层。因此，例如能够确保制剂中一定比例的晶体以未溶解度方式通过胃道且到达肠道后才释放。
本发明的另一个优选的实施方案是本发明的制剂除包括含有可确保活性物质受控释放的控释包衣层和任意另外的包衣层的活性物质晶体外还包括非控释的活性物质晶体，不过，这些晶体含有一种或多种所述的非控释包衣层。
阿片样活性物质晶体的制备是公知的。在活性物质的必要纯化过程中直接获得这些晶体。
按照下列常规的公知方法在生产时、优选在重晶体后迅速获得的活性物质晶体具有包衣层：诸如通过用溶液、分散液和/或乳浊液喷雾或者通过涂粉法。凝聚法也是一种合适的方法。
为了这一目的，通过在最终的纯化步骤后对所述的活性物质晶体进行包衣而将一种中间层涂布在各晶体上、晶体化并通过用喷雾溶液或优选一种含水包衣分散体喷雾它们而进行干燥。在其上涂布控释包衣层，再次用一种包衣分散体喷涂且随后干燥。这种包衣层的厚度可以根据所到达的释放形态而改变。
如果还涂布另外的包衣层，那么优选用相同的方法制备它们。
本发明还提供了胶囊形式的本发明的口服给药制剂，其中根据所实现的止痛药的各释放期限和释放的量活性物质晶体与受控释放的阿片样止痛药共存。优选将胶囊中活性物质晶体的量进行选择以便使所述的剂量足以每日给药两次、优选一次。如果仅需要将包衣的活性物质晶体包裹在胶囊中，那么不需完善的配制方法也可以获得这种受控释放的胶囊制剂。根据本发明，还可以将所述的活性物质晶体装入小瓶或小袋形式的计量装置中或借助于一种配药器将它们按体积计量。能够添加常规的辅助剂，诸如增充剂、润滑剂或崩解促进剂。此外，本发明的口服给药制剂可以采用片剂形式，其中根据所实现的阿片样止痛药的各释放期限和释放的量将含有或不含常规片剂辅助剂或添加剂的包衣的活性物质晶体压塑成一种片剂。还是在这种情况中，有利的是是否将构成所述片剂的活性物质晶体的量进行选择以便使所实现的止痛药的释放期限和释放的量足以每日给药两次、优选一次。
优选生产含有高比例辅助剂的片剂，使得包衣的活性物质晶体以各种形式得到保留。当所述的片剂快速崩解时，所述的晶体从这种进行受控释放的片剂中被释放出来。甚至当片剂崩解时，受控释放的活性物质晶体的释放形态得到了保持。
还能够生产含有小比例辅助剂的片剂。在这种情况中，在压制时包衣的活性物质晶体相互凝集，从而形成一种附加的受控释放基质。这类片剂不再自发地崩解以便使它们具有比各包衣的晶体具有更高的延缓释放程度。
本发明制剂优选含有的曲马多总浓度以盐酸盐计算为10-1000mg、优选50-800mg。
                            实施例实施例1
将具有颗粒大小为250-500μm的多晶结构的盐酸曲马多晶体在将其制备和纯化后使用，不需进一步的配制步骤。所述乙基纤维素的规定量与使用含水分散体后的干重有关。组成：
    晶体     盐酸曲马多     1.000kg
    包衣层     乙基纤维素(Aquacoat)     0.200kg
  癸二酸二丁酯     0.050kg
    总计     1.250kg
在流化床设备中用热气循环这些盐酸曲马多晶体并借助于一种双相喷嘴将预先拌入癸二酸二丁酯的含水乙基纤维素悬浮液缓慢喷在所述的晶体上。一旦用完该悬浮液，晶体也就被干燥了。实施例2
将按照实施例1包衣的晶体加工制备成胶囊。
为了这一目的，在一种立方体混合器中将包衣的晶体与上述辅助剂混合并使用一种包囊机将其包入硬度为2号的胶囊中。组成：
    胶囊填充物     每粒胶囊     每批
盐酸曲马多晶体，按照实施例1包衣     125mg     1.25kg
    单晶纤维素     75mg     0.75kg
    羧甲基淀粉钠，A型     45mg     0.45kg
    硬脂酸镁     5mg     0.05kg
    总计     250mg     2.50kg
实施例3
将按照实施例1包衣的250g晶体与344g单晶纤维素和6g硬脂酸镁混合并迅速压塑成直径为10mm且重量为300mg的崩解片。实施例4
将具有颗粒大小为250-500μm的多晶结构的盐酸曲马多晶体在将其制备和纯化后使用。涉及中间层和受控释放层的具体内容与使用含水分散体后的干重有关。
在流化床设备中用热气循环这些盐酸曲马多晶体且首先将用于生产中间层的含水分散体喷在其上并干燥。然后，借助于一种双相喷嘴将预先拌入癸二酸二丁酯的乙基纤维素悬浮液缓慢喷在所述的晶体上。一旦用完该悬浮液，晶体也就被干燥了。组成：
    晶体     盐酸曲马多     1.000kg
    中间层     Macrogol 6000     0.025kg
    滑石     0.040kg
羟丙基甲基纤维素，2910型，6mPas     0.100kg
    包衣层     乙基纤维素(Aquacoat)     0.200kg
    癸二酸二丁酯     0.050kg

Claims (16)

1.含有晶体形式的阿片样止痛药的口服控释制剂，其中所述晶体具有的颗粒大小为10μm-3mm，优选50μm-1mm，该制剂具有至少一种控释包衣层。
2.根据权利要求1的制剂，其特征在于所述晶体是单晶或具有多晶结构。
3.根据权利要求1或2的制剂，其特征在于所述的控释包衣层基于一种聚合物。
4.根据权利要求3的制剂，其特征在于所述的控释包衣层含有高达30wt.％的一种非控释的聚合物。
5.根据权利要求3或4的制剂，其特征在于将丙烯酸树脂和/或纤维素衍生物、优选烷基纤维素用作所述的聚合物。
6.根据权利要求3-5之一的制剂，其特征在于将乙基纤维素和/或聚(甲基)丙烯酸和/或其衍生物以及任选地高达30wt.％的羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素或聚乙烯酮类用作所述的聚合物。
7.根据权利要求1-6之一的制剂，其特征在于将二氢吗啡酮、羟氢可待酮、吗啡、羟甲左吗喃、美沙酮、二氢可待因、可待因、二氢吗啡、哌替啶、氰苯双哌酰胺、芬太尼、胺苯环己乙酯、丁丙诺啡、曲马多、它们的特定的盐或它们的混合物用作所述的阿片样止痛药。
8.根据权利要求7的制剂，其特征在于所述阿片样止痛药是曲马多、盐酸曲马多和/或吗啡、盐酸吗啡和/或硫酸吗啡。
9.根据权利要求1-8之一的制剂，其特征在于除控释包衣层外，所述的晶体另有至少一层另外的包衣层。
10.根据权利要求9的制剂，其特征在于所述另外的包衣层包含一种直接涂布于所述晶体表面作为非控释中间层的物质的包衣层而不是控释包衣层。
11.根据权利要求9或10的制剂，其特征在于所述另外的包衣层包括一种耐胃液的包衣层。
12.根据权利要求9-11之一的制剂，其特征在于所述另外的包衣层包括一种含有阿片样止痛药的包衣层，其中所述的阿片样止痛药与所述的晶体止痛药或另一种药物活性物质相同或不同。
13.根据权利要求1-12之一的制剂，其特征在于所述的晶体存在于胶囊、小袋、小瓶、分配器、优选一种计量分配器中。
14.根据权利要求1-12的制剂，其特征在于将所述的晶体与常规的辅助剂和添加剂一起压片。
15.根据权利要求1-12的制剂，其特征在于将所述的晶体任意与非控释的药物活性物质、与或不与辅助剂和添加剂一起压成片剂。
16.根据权利要求1-15之一的制剂，其特征在于以盐酸盐计算曲马多的总浓度为10-1000mg。
CNB001045237A 1999-01-18 2000-01-17 可控释活性物质的阿片样止痛药 Expired - Fee Related CN1244327C (zh)

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