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CN1150898C - 富马酸单烷基酯在制备微型片剂药物组合物中的应用 - Google Patents

富马酸单烷基酯在制备微型片剂药物组合物中的应用

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CN1150898C
CN1150898C CNB988138344A CN98813834A CN1150898C CN 1150898 C CN1150898 C CN 1150898C CN B988138344 A CNB988138344 A CN B988138344A CN 98813834 A CN98813834 A CN 98813834A CN 1150898 C CN1150898 C CN 1150898C
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fumarate
neurodermatitis
psoriatic arthritis
micro
treating psoriasis
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K����ϣ
拉金德拉·K·乔希
˵á�ʩ���ױ���
汉斯－彼得·施特雷贝尔
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Bio Gene International Ltd
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Fumapharm AG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract

本发明涉及一种或多种以下通式的富马酸单烷基酯，其中R是C1-5烷基，任选地与以下式的二烷基富马酸酯以及任选的常规药物学上可接受的赋形剂和载体混合，在制备微型片剂或者微型丸剂形式的、用于治疗牛皮癣、牛皮癣性关节炎、神经性皮炎和节段性肠炎的药物组合物中的应用。

Description

富马酸单烷基酯在制备微型片剂药物组合物中的应用
技术领域
本发明涉及游离酸形式的某些富马酸单烷基酯在单独或者与富马酸二烷基酯组合时在制备微型片剂药物组合物中的应用，该药物组合物可用于治疗牛皮癣、牛皮癣性关节炎、神经性皮炎和Crohn节段性肠炎。
背景技术
给药后由于生物降解而进入柠檬酸循环或者属于该循环的药物制剂在通常高剂量时正逐渐取得更高的重要性，这是因为在它们的帮助下可以缓解或者治愈隐原性疾病。
因此，富马酸抑制鼠中Ehrlich腹水肿瘤的生长，降低丝裂霉素C和黄曲霉毒素的毒性(参考：K.Kuroda，M.Akao，Biochem.Pharmacol.29，2839-2844(1980)/Gann.72，777-782(1981)/Cancer Res.36，1900-1903(1976))，而且还具有抗牛皮癣和抗微生物作用(C.N.Huhtsnen，J.Food Sci.48，1574(1983)/M.N.Islam，US-A-4,346,118/C.A.97，161317b(1982))。
当通过非胃肠道、皮肤而且特别是经口给药时，高剂量的用于此目的的已知富马酸衍生物，如二羟基富马酸、富马酰胺和反式丁烯二腈，具有令人不可接受的副作用和高毒性(P.Holland，R.G.White，Brit.J.Dermatol.85，259-263(1971)/M.Hagedom，K.W.Kalkoff，G.Kiefer，D.Baron，J.Hug，J.Peteres，Arch.Derm.Res.254，67-73(1975))，使得该治疗通常不得不被放弃。
EP-A-0 188 749已描述了用于治疗牛皮癣的富马酸衍生物(盐)和包含该衍生物的药物组合物。
从DE-A-25 30 372中可知包含富马酸和其他富马酸衍生物之混合物的药物组合物，该组合物可用于治疗牛皮癣。富马酸的含量是强制性的。
DE-A-26 21 214描述了用于治疗牛皮癣的药物，该药物包含富马酸单乙基酯及其矿物盐作为活性成分。另外，EP-A-0 312 697描述了各种富马酸单烷基酯盐在治疗牛皮癣、牛皮癣性关节炎、神经性皮炎和Crohn节段性肠炎中的应用。
富马酸单乙基酯盐(Ca、Zn、Mg)和富马酸二甲基酯在治疗牛皮癣中的应用从出版物“Hautarzt”(1987，279-285)中是已知的。
因为在牛皮癣性表皮中，磷脂酶A2的活性被改变，富马酸刺激该酶的事实是对本发明组合物之机理的一个可能解释。
发明内容
令人惊奇的是，我们已经发现，用富马酸单烷基酯治疗牛皮癣，即使在没有形成盐的情况下，也可用包含游离酸形式的一种或多种C1-5富马酸单烷基酯的药物组合物来实现，该组合物还可任选地包含药物学上可接受的赋形剂和载体，而且该组合物为微型片剂或者微型丸剂。任选地，这些组合物也可包含一种或多种富马酸二烷基酯。
具体实施方式
微型片剂或者微型丸剂的组合物使得能够给药游离酸来代替盐，并且不发生已知的副作用、特别是形成溃疡。这有可能是因为以下事实：微型片剂或者微型丸剂使药物能够均匀地分散在胃中，由此避免了游离酸形式的单富马酸单烷基酯的局部刺激浓度。
包含20-300mg富马酸单烷基酯的组合物特别适合于口服给药，而活性成分的总重量为100-300mg。
对于开始全身治疗或者停止该治疗，包含100-120mg活性成分的低剂量，例如30.0-35.0mg的富马酸二甲基酯和70-90mg富马酸单甲基酯，是有利的。
190-210mg的活性成分，例如120.0mg的富马酸二甲基酯和90.0mg富马酸单乙基酯的形式，是初始阶段后的治疗剂量的一个例子。
根据本发明的组合物可以微型片剂或者经包胶的微型片剂或微型丸剂的形式经口给药，固体单个剂量药物剂型在几分钟内溶解在胃中，并由药物制剂中均匀地释放活性成分。低剂量对于开始或者停止全身给药是必须的，而初始阶段后对于治疗则需要更高的剂量。
根据本发明的微型片剂是用本领域已知的技术制造的，例如制粒、筛选、挤出/成球等。除活性成分外，它们还可包含常规的赋形剂和载体，如乳糖、PVP等。微型片剂或者微型丸剂的尺寸优选为300-2000μm，更优选为500-1500μm，并最优选为1000μm。
为便于给药单个剂量，微型片剂或者微型丸剂可进行包胶，例如包胶在明胶胶囊中。任选地，微型片剂或者微型丸剂可包覆耐胃酸的包衣。此等包衣可用已知方法包覆，例如在流化床装置中涂敷或者喷涂，或者是薄膜包衣。
实施例
制造包含50.0mg富马酸单甲基酯(相当于总共44.6mg的富马酸)并经 包胶的微型丸剂
采取必要的防范措施(呼吸面罩、手套、保护衣)，用#400筛网粉碎5000kg的富马酸单甲基酯，并均化。另外，制备2升的20％(m/v)聚乙烯吡咯烷酮(Kollidon K30)乙醇溶液。在包衣锅中引入7.250kg的Nonpareilles丸，并喷洒部分Kollidon K-30溶液直至略微湿润。然后加入部分活性成分混合物，直至丸剂干燥。继续进行该湿润/干燥步骤，直至加入所有的活性成分混合物。最后，在锅中摇动丸剂直至完全干燥。然后将丸剂填入硬明胶胶囊中(126.5mg丸剂/胶囊)。
发现对于各种临床形式的牛皮癣、牛皮癣性关节炎、神经性皮炎和Crohn节段性肠炎(Crohn病)，与包含已知成盐形式的富马酸衍生物的制剂相比，根据本发明的制剂具有类似的作用，但是没有给药游离酸时的已知副作用。
急性毒性的检查
在临床实验前，通过向鼠口服给药来检查富马酸单甲基酯的急性毒性。结果表明所用的富马酸具有非常低的毒性(见表1)。
             表1：鼠中的急性毒性(口服给药)
    性别     富马酸单甲基酯
LD50     雄性     2606.8
    雌性     1777.8
最低致死量(mg/kg)     雄性     2150.0
    雌性     1470.0
药物效力
分别比较Fumaderm forte(欧洲专利0 312 697 B1中的实施例4)和富马酸单甲基酯或者富马酸单乙基酯钙盐的药代动力学数据。
                             表2：效力
给药的物质   动物种类     剂量(mg/kg体重)   富马酸单甲基酯浓度(Cmax)/(μg/ml)
Fumaderm forte     鼠     30   8.99
富马酸单甲基酯     鼠     100   雄性：69.9雌性：84.5
富马酸单甲基酯钙盐     鼠     100   雄性：51.3雌性：107.0
Fumaderm forte：该混合物包含120mg的富马酸二甲基酯、87mg的富马酸单乙基酯钙盐、5mg的富马酸单乙基酯镁盐、3mg的富马酸单乙基酯锌盐。

Claims (5)

1、一种或多种以下通式的富马酸单烷基酯
Figure C9881383400021
其中R是C1-5烷基，任选地与以下式的二烷基富马酸酯
Figure C9881383400022
以及任选的常规药物学上可接受的赋形剂和载体混合，在制备微型片剂或者微型丸剂形式的、用于治疗牛皮癣、牛皮癣性关节炎、神经性皮炎和Crohn节段性肠炎的药物组合物中的应用，其中所述微型片剂或者微型丸剂的尺寸为300-2000μm。
2、如权利要求1所述的应用，其特征在于使用富马酸单甲基酯。
3、如权利要求1所述的应用，其特征在于使用富马酸单甲基酯和富马酸二甲基酯的混合物。
4、如权利要求1所述的应用，其是用于制备微型片剂或者微型丸剂形式的口服给药的药物组合物，其特征在于活性成分的总重量为20-300mg。
5、如权利要求1-4之一所述的应用，其是用于制备口服给药的药物组合物，其特征在于所述微型片剂或者微型丸剂具有肠溶包衣。
CNB988138344A 1998-03-31 1998-12-08 富马酸单烷基酯在制备微型片剂药物组合物中的应用 Expired - Fee Related CN1150898C (zh)

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DE19814358A DE19814358C2 (de) 1998-03-31 1998-03-31 Verwendung von Alkylhydrogenfumaraten zur Behandlung von Psoriasis, psoriatischer Arthritis, Neurodermitis und Enteritis regionalis Crohn
DE19814358.3 1998-03-31

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