CN1323206A - 富马酸微型片剂 - Google Patents
富马酸微型片剂 Download PDFInfo
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- CN1323206A CN1323206A CN99812007A CN99812007A CN1323206A CN 1323206 A CN1323206 A CN 1323206A CN 99812007 A CN99812007 A CN 99812007A CN 99812007 A CN99812007 A CN 99812007A CN 1323206 A CN1323206 A CN 1323206A
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- fumaric acid
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- alkyl ester
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 title claims abstract description 86
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 239000001530 fumaric acid Substances 0.000 title claims abstract description 41
- 201000004681 Psoriasis Diseases 0.000 claims abstract description 8
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 8
- 150000001768 cations Chemical class 0.000 claims abstract description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 5
- 208000011231 Crohn disease Diseases 0.000 claims abstract description 4
- 201000009053 Neurodermatitis Diseases 0.000 claims abstract description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims abstract description 4
- 229910052749 magnesium Inorganic materials 0.000 claims abstract description 4
- 229910052742 iron Inorganic materials 0.000 claims abstract description 3
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 3
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical class COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 claims description 37
- -1 monomethyl ester Chemical class 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 26
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- 125000000217 alkyl group Chemical group 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 8
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- NKHAVTQWNUWKEO-NSCUHMNNSA-N monomethyl fumarate Chemical group COC(=O)\C=C\C(O)=O NKHAVTQWNUWKEO-NSCUHMNNSA-N 0.000 description 5
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
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- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
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- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
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- 230000000996 additive effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
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- 235000019359 magnesium stearate Nutrition 0.000 description 2
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- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229940005650 monomethyl fumarate Drugs 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- QBBTZXBTFYKMKT-UHFFFAOYSA-N 2,3-diacetyloxypropyl acetate Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O.CC(=O)OCC(OC(C)=O)COC(C)=O QBBTZXBTFYKMKT-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- LBQUJVJZHVBJTO-UHFFFAOYSA-M C(C=CC(=O)[O-])(=O)OC.[Ca+] Chemical compound C(C=CC(=O)[O-])(=O)OC.[Ca+] LBQUJVJZHVBJTO-UHFFFAOYSA-M 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- NEDGUIRITORSKL-UHFFFAOYSA-N butyl 2-methylprop-2-enoate;2-(dimethylamino)ethyl 2-methylprop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound COC(=O)C(C)=C.CCCCOC(=O)C(C)=C.CN(C)CCOC(=O)C(C)=C NEDGUIRITORSKL-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000084 colloidal system Substances 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
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- 239000002662 enteric coated tablet Substances 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
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- 239000007888 film coating Substances 0.000 description 1
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- 206010016766 flatulence Diseases 0.000 description 1
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Chemical class 0.000 description 1
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 1
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- 150000002505 iron Chemical class 0.000 description 1
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- 239000004922 lacquer Substances 0.000 description 1
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- 210000005087 mononuclear cell Anatomy 0.000 description 1
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- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
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- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
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Classifications
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- 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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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
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- A61P19/00—Drugs for skeletal disorders
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A—HUMAN NECESSITIES
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Abstract
本发明涉及一种或多种以下通式(Ⅰ)的烷基氢富马酸酯，任选地与以下式(Ⅱ)的二烷基富马酸酯，其中A是选自于Ca、Mg、Zn或Fe的二价阳离子或者是选自于Li、Na或K的单价阳离子,而n根据阳离子的类型代表1或2,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局限性肠炎的药物组合物中的应用。
Description
本发明涉及某些富马酸单烷基酯盐在单独或者与富马酸二烷基酯组合时在制备微型片剂中的应用，该微型片剂可用于治疗牛皮癣性关节炎、神经性皮炎、牛皮癣、和Crohn局限性肠炎。
EP-A-0 188 749已描述了用于治疗牛皮癣的富马酸衍生物和包含该衍生物的药物组合物。同样，从DE-A-2530372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。游离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。富马酸单乙基酯的钙、锌和镁盐以及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。
最后，EP-A-0 312 697公开了包含选自于富马酸单甲基酯之钙、镁、锌和铁盐中的一种或多种化合物的药物组合物，这些化合物可单独使用或者优选与C1-5烷基富马酸酯混合使用。根据该文献之实施例4的制剂包含87.5mg富马酸单乙基酯钙盐、120.0mg的富马酸二甲酯、5.0mg的富马酸单乙基酯镁盐、以及3.0mg的富马酸单乙基酯锌盐，这相当于164mg的富马酸。该制剂为肠溶片剂，而且已被批准在德国市场上销售，其商标为Fumaderm。
早在该产品的3期临床试验以及销售后的研究中发现，在Fumaderm的初始治疗期间，约60％的患者产生胃肠道症状，其形式为腹泻、胃痛和胀气。其他副作用是所谓的潮红，即、脸红，以及对热敏感。
即使通常情况下可较好地耐受片剂，但是上述症状仍然发生，特别是在治疗开始时。在治疗过程中，这些不令人希望的副作用经常减少。但是，服用Fumaderm在一些患者中导致严重的胃肠道不适。这些胃肠道中的症状影响患者的适应性，而且对于患者是非常不愉快的，以致于有时中断治疗。
因此，本发明的目的是提供一种药物制剂，该药物制剂在给药相同的药物成分时可避免上述副作用、特别是胃肠道不适。
本发明的申请人所进行的实验表明，构成Fumaderm制剂之主要成分的富马酸二甲酯的代谢物是甲基氢富马酸酯，其开始时增加人周边血单核细胞(周边血单核细胞=PBMC)以及经分离的单核细胞中的内毒素刺激的TNF-α分泌。在多次重复接触时，内毒素诱导的TNF-α分泌增加被降低，即、产生适应性。
有可能的情况是，初始诱导产生TNF-α是Fumaderm制剂之已知副作用的原因，所述副作用例如是胃肠道不适或潮红症状。重复接触甲基氢富马酸酯后减少内毒素诱导的TNF-α分泌的趋势可用于解释适应性作用，即、持续的Fumaderm治疗后副作用减少。因此，其他实验的首要目的是用其他药物抑制TNF-α分泌，并由此控制给药Fumaderm的副作用。
令人惊奇而且出乎意料的是，在这些实验的过程中发现微型片剂形式的活性成分制剂显著减少胃肠道症状。因此，本发明的目的可通过使用以下通式的一种或多种富马酸单烷基酯盐制备用于治疗牛皮癣性关节炎、神经性皮炎、牛皮癣、和Crohn局限性肠炎的微型片剂或微型丸剂形式的药物组合物来实现，
该富马酸单烷基酯盐任选地与以下通式的富马酸二烷基酯混合，
其中A是选自于Ca、Mg、Zn或Fe的二价阳离子或者是选自于Li、Na或K的单价阳离子，而n根据阳离子的类型代表1或2，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。
微型片剂或者微型丸剂的尺寸或者平均直径优选为300-2000μm，更优选为500-1500μm，并最优选为1000μm。
微型片剂或微型丸剂可填在胶囊或扁囊(sachet)中，并以此形式给药。另外，微型片剂本身或者胶囊可具有用常规方法包敷的肠溶包衣。胶囊可以是硬明胶或软明胶胶囊。
根据本发明的优选组合物包含富马酸单甲酯钙盐和/或富马酸单乙酯钙盐，并任选地混合富马酸二甲酯。活性成分的总重量为10-300mg。优选的是，微型片剂形式的组合物包含10-290重量份的富马酸单烷基酯(钙盐)和290-10重量份的富马酸二甲酯。根据另一个实施方案，该组合物还可包含1-50重量份的富马酸单烷基酯锌盐。
微型片剂形式的另一个优选实施方案包含1-250重量份的富马酸单烷基酯(钙盐)、250-10重量份的富马酸二甲酯、1-50重量份的富马酸单烷基酯(镁盐)以及1-50重量份的富马酸单烷基酯(锌盐)，而活性成分的总重量为30-300mg。
全身初始治疗以及治疗终止(降低剂量)时，低剂量是有利的。此等剂量例如可包括30mg的富马酸二甲酯、20mg的富马酸单乙酯(钙盐)以及3mg的富马酸单乙酯或富马酸单甲酯(锌盐)。初始期后的治疗剂量可例如包括20mg的富马酸二甲酯、87mg的富马酸单乙酯(钙盐)以及3.0mg的富马酸单乙酯或富马酸单甲酯(锌盐)。
例如，本发明中所用的富马酸衍生物可根据EP0 312 697中所述的方法来制得。
不希望囿于任何理论，假设胃肠道症状是由于局部刺激肠的上皮细胞而产生的，这诱导TNF-α分泌。在给药常规片剂时，这些片剂的成分在肠道中释放的浓度过高，对肠粘膜产生局部刺激作用。该局部刺激作用的结果是，在短时间内释放非常高浓度的TNF-α，这有可能对胃肠道的副作用负责。另一方面，当给药在胶囊中的肠溶包衣的微型片剂时，活性成分在肠上皮细胞处的浓度较低。由于胃的蠕动作用，微型片剂逐渐地被移至小肠中，增加了活性成分的分布。
换言之，相同剂量的肠溶包衣的微型片剂分散在胃中，并分批地进入肠道，其中活性成分以更小的剂量被释放。其结果是，避免了肠道上皮细胞的局部刺激以及TNF-α的释放。这是与常规片剂相比微型片剂的耐受性增强的一种可能的解释。但是，没有想到制剂方面的小变化可导致副作用如此巨大地减少。
以下实施例将说明根据本发明之微型片剂的制备和作用。
实施例1制备在胶囊中的肠溶包衣微型片剂，其包含87.0mg的富马酸单乙基酯钙盐、120.0mg的富马酸二甲酯和5.0mg的富马酸单乙基酯镁盐，这相当于总共164mg的富马酸
采取必要的防范措施(呼吸面罩、手套、保护衣等)，粉碎8.700kg的富马酸单乙基酯钙盐、12.000kg的富马酸二甲酯、0.500kg的富马酸单乙基酯镁盐和0.30kg的富马酸单乙基酯锌盐，然后充分混合并用800筛网均化。制备如下组成的赋形剂混合物：18.00kg的淀粉衍生物(STA-RX1500)、0.30kg的微晶纤维素(AvicelPH 101)、0.75kg的PVP(Kollidon120)、4.00kg的Primogel、0.25kg的胶体硅酸(Aerosil)。将整个粉末混合物添加至活性成分混合物中，用200筛网使其均化，然后用2％聚乙烯吡咯烷酮(KollidonK25)的水溶液按常规方法处理成粘合颗粒，接着再在干燥状态下与外相混合，所述外相由0.50kg的硬脂酸镁和1.50kg的滑石组成。然后用常规方法将该粉末混合物压制成凸形微型片剂，其重量为10.0mg，直径为2.0mm。除该典型的压片法外，也可使用其他方法来制备片剂，如直接压片或根据熔化和喷雾干燥法的固体分散法。
将耐胃酸的包衣倾倒或喷雾在典型的包衣锅中或者在合适的流化床中施用。为实现耐胃酸性，将2.250kg邻苯二甲酸羟丙基甲基纤维素(HPMCP，PharmacoatHP50)的溶液部分地溶解在由13.00升丙酮、13.50升乙醇(94重量％，已用2％酮变性)和1.50升去离子水组成的溶剂混合物中。在上述溶液中添加0.240kg的蓖麻油作为软化剂，然后按照常规方法部分地涂敷在片剂芯上。
完成干燥后，在相同的装置中涂敷以下组成的悬浮液作为薄膜包衣：滑石0.340kg、氧化钛(Ⅵ)Cronus RN 56 0.400kg、着色漆L红漆868370.324kg、Eudragit E 12.5％4.800kg、和聚乙二醇6000 pH11 Ⅺ 0.120kg，它们在由8.170kg的2-丙醇、0.200kg的去离子水和0.600kg的甘油三乙酸酯(Triacetin)组成的溶剂混合物中。
然后将耐胃酸的微型片剂填充在硬明胶胶囊中，至其净重为500.0mg，然后密封。
实施例2制备在胶囊中的肠溶包衣微型片剂，其包含87.0mg的富马酸单乙基酯钙盐、120.0mg的富马酸二甲酯和5.0mg的富马酸单乙基酯镁盐，这相当于总共164mg的富马酸
采取必要的防范措施(呼吸面罩、手套、保护衣等)，粉碎8.700kg的富马酸单乙基酯钙盐、12.000kg的富马酸二甲酯、0.500kg的富马酸单乙基酯镁盐和0.30kg的富马酸单乙基酯锌盐，然后充分混合并用800筛网均化。制备如下组成的赋形剂混合物：24.70kg的微晶纤维素(AvicelPH 200)、3.00kg的羧甲基纤维素钠(AC-Di-SOL-SD-711)、2.50kg的滑石、0.10kg的无水二氧化硅(Aerosil200)、和1.00kg的硬脂酸镁。将整个赋形剂混合物添加至活性成分混合物中，然后使其均化。用直接压片法将该混合物压制成凸形微型片剂，其重量为10.0mg，直径为2.0mm。除该典型的压片法外，也可使用其他方法来制备片剂，如直接压片或根据熔化和喷雾干燥法的固体分散法。
将耐胃酸的包衣倾倒或喷雾在典型的包衣锅中或者在合适的流化床中施用。例如，制备0.94kg的EudragitL在异丙醇中的溶液，该溶液还包含0.07kg的邻苯二甲酸二丁酯。将该溶液喷雾在片剂芯上。
之后，制备17.32kg的EudragitLD-55与2.80kg微细滑石、2.00kg的Macrogol 6000及0.07kg的Dimetican在水中的分散液，然后喷雾在片剂芯上。
然后将肠溶包衣的微型片剂填充在硬明胶胶囊中，至其净重为760.0mg，然后密封。治疗例
根据上述制备实施例制备四种活性成分以及它们的量都与市售产品Fumaderm相同的微型片剂。Fumaderm片剂的肠溶包衣约相当于102片相同组成的肠溶包衣微型片剂。如上述制备实施例所述，这些微型片剂填入胶囊中，以更方便给药。两个胶囊相当于一片Fumaderm。
为便于比较，两位在用Fumadem片剂治疗期间产生严重胃肠道症状的患者用根据本发明的肠溶包衣微型片剂治疗。在给药这些微型片剂后，令人惊奇地发现这些患者不再有用常规片剂治疗时观察到的胃肠道不适。对于牛皮癣，观察到了与现有技术中Fumaderm片剂相同的改善。在某些情况下，当给药微型片剂时，更小的剂量就足以实现临床成功。
上述治疗的结果列于下表中：
*Fumaderm片剂相当于两个Fumaderm P mikro胶囊GI=胃肠道
| 患者1 | 患者2 | 产品 | |
| 初始 | M.M. | W.F. | |
| 年龄 | 63 | 54 | |
| 性别 | 女性 | 男性 | |
| 剂量 | 1998.1.1-4.1,Fumaderm初始 | 1985:3片Fumaderm/天 | Fumaderm初始/Fumaderm |
| GI症状 | 痉挛，疼痛 | 上腹区疼痛 | ″ |
| GI症状的严重程度 | 严重 | 严重 | ″ |
| 牛皮癣的临床评估 | 满意 | 满意 | ″ |
| 治疗中断 | 无 | 1985-1988.5.12 | ″ |
| 剂量 | 1998.4.1-6:3个胶囊/天1998.4.7-5.10:9个胶囊/天1998.5.11-8.31:3个胶囊/天 | 1998.5.13-20:3个胶囊/天1998.5.21-7.1:6个胶囊/天 | FumadermPmikro |
| GI症状 | 无 | 1998.5.15-18肠气 | ″ |
| 症状的严重程度 | - | 轻 | ″ |
| 牛皮癣的临床评估 | 非常好 | 好 | ″ |
这些片剂表明，即使增加微型片剂的剂量(每日9个胶囊)，仍没有或者仅有非常轻微的副作用，而低剂量的市售产品Fumaderm在更低的剂量时就已产生严重的胃肠道症状。
该治疗的结果还表明，微型片剂对牛皮癣的治疗效果，即使不优于市售产品，至少也是相同的。总之，微型片剂形式的富马酸衍生物制剂比常规制剂具有明显的治疗改善作用。
Claims (11)
1、一种或多种以下通式的烷基氢富马酸酯任选地与以下式的二烷基富马酸酯
其中A是选自于Ca、Mg、Zn或Fe的二价阳离子或者是选自于Li、Na或K的单价阳离子，而n根据阳离子的类型代表1或2，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局限性肠炎的药物组合物中的应用。
2、如权利要求1所述的应用，其特征在于使用富马酸单乙酯或单甲酯的钙盐。
3、如权利要求1或2所述的应用，其特征在于使用富马酸单烷基酯钙盐和富马酸二甲基酯的混合物。
4、如权利要求1所述的应用，其特征在于使用富马酸单烷基酯钙盐和锌盐与富马酸二甲基酯的混合物。
5、如权利要求1所述的应用，其特征在于使用富马酸单乙基酯钙盐、镁盐和锌盐与富马酸二甲基酯的混合物。
6、如权利要求1-5之一所述的应用，其特征在于富马酸单烷基酯钙盐的用量为10-300重量份，而活性成分的总重量为10-300mg。
7、如权利要求3所述的应用，其特征在于使用10-290重量份的富马酸单烷基酯钙盐和290-10重量份的富马酸二甲酯，而活性成分的总重量为20-300mg。
8、如权利要求4所述的应用，其特征在于使用10-250重量份的富马酸单烷基酯钙盐、1-50重量份的富马酸二甲酯以及1-50重量份的富马酸单烷基酯锌盐，而活性成分的总重量为20-300mg。
9、如权利要求1-5之一所述的应用，其特征在于使用1-250重量份的富马酸单烷基酯钙盐、250-10重量份的富马酸二甲酯、1-50重量份的富马酸单烷基酯镁盐以及1-50重量份的富马酸单烷基酯锌盐，而活件成分的总重量为30-300mg。
10、如任一前述权利要求所述的应用，其特征在于所述微型片剂或者微型丸剂具有肠溶包衣。
11、如任一前述权利要求所述的应用，其特征在于所述微型片剂或者微型丸剂填入在胶囊或扁囊中。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490849A (zh) * | 2014-11-24 | 2015-04-08 | 广东东阳光药业有限公司 | 一种高密度的富马酸二甲酯肠溶颗粒及其制备方法 |
| CN110898164A (zh) * | 2019-12-19 | 2020-03-24 | 赣州安宏环保科技有限公司 | 根除胃肠病幽门螺杆菌感染的富马酸单乙酯钙盐及其用途 |
Families Citing this family (53)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19853487A1 (de) * | 1998-11-19 | 2000-05-25 | Fumapharm Ag Muri | Verwendung von Dialkylfumaraten |
| US20020044962A1 (en) * | 2000-06-06 | 2002-04-18 | Cherukuri S. Rao | Encapsulation products for controlled or extended release |
| EP1372634B1 (de) | 2001-01-12 | 2009-11-11 | Biogen Idec International GmbH | Verwendung von fumarsäureamiden |
| DE10101307A1 (de) * | 2001-01-12 | 2002-08-01 | Fumapharm Ag Muri | Fumarsäurederivate als NF-kappaB-Inhibitor |
| US6613800B1 (en) * | 2001-12-03 | 2003-09-02 | Steven A. Smith | Method and compositions for treating psoriasis, eczema, seborrhea and arthritis |
| DE10217314A1 (de) * | 2002-04-18 | 2003-11-13 | Fumapharm Ag Muri | Carbocyclische und Oxacarboncyclische Fumarsäure-Oligomere |
| EP1663197B1 (en) * | 2003-09-09 | 2007-12-05 | Fumapharm AG | The use of fumaric acid derivatives for treating cardiac insufficiency, and asthma |
| PL2801354T3 (pl) * | 2004-10-08 | 2017-08-31 | Forward Pharma A/S | Kompozycje farmaceutyczne o kontrolowanym uwalnianiu zawierające ester kwasu fumarowego |
| US20080004344A1 (en) * | 2004-11-10 | 2008-01-03 | Aditech Pharma Ab | Novel Salts of Fumaric Acid Monoalkylesters and Their Pharmaceutical Use |
| ITBO20050123A1 (it) * | 2005-03-07 | 2005-06-06 | Alfa Wassermann Spa | Formulazioni farmaceutiche gastroresistenti contenenti rifaximina |
| ATE455783T1 (de) * | 2005-07-07 | 2010-02-15 | Aditech Pharma Ag | Neue glucopyranoseester und glucofuranoseester von fumarsäurealkylestern und deren pharmazeutische verwendung |
| US20080227847A1 (en) * | 2005-07-07 | 2008-09-18 | Aditech Pharma Ab | Novel Salts of Fumaric Acid Monoalkylesters and Their Pharmaceutical Use |
| PT1762231E (pt) * | 2005-08-19 | 2010-12-13 | Verla Pharm | Microcomprimidos de magnésio de libertação retardada |
| EP1940382A2 (en) * | 2005-10-07 | 2008-07-09 | Aditech Pharma AB | Combination therapy with fumaric acid esters for the treatment of autoimmune and/or inflammatory disorders |
| JP2009510137A (ja) * | 2005-10-07 | 2009-03-12 | アディテック・ファルマ・アクチボラゲット | フマル酸エステルを含む制御放出医薬組成物 |
| RS63489B1 (sr) | 2007-02-08 | 2022-09-30 | Biogen Ma Inc | Kompozicije i upotrebe za tretiranje multiple skleroze |
| WO2008096271A2 (en) * | 2007-02-08 | 2008-08-14 | Ralf Gold | Neuroprotection in demyelinating diseases |
| DK2334378T3 (da) | 2008-08-19 | 2014-07-07 | Xenoport Inc | Prodrugs af methylhydrogenfumarat, farmaceutiske sammensætninger deraf og fremgangsmåder til anvendelse |
| EP3295936A1 (en) * | 2009-01-09 | 2018-03-21 | Forward Pharma A/S | Pharmaceutical formulation comprising one or more fumaric acid esters in an erosion matrix |
| US9422226B2 (en) | 2011-06-08 | 2016-08-23 | Biogen Ma Inc. | Process for preparing high purity and crystalline dimethyl fumarate |
| RU2014125430A (ru) | 2011-11-24 | 2015-12-27 | Синтон Бв | Контролируемое высвобождение частиц, содержащих диметилфумарат |
| US9504679B2 (en) | 2011-12-19 | 2016-11-29 | Bjoern Colin Kahrs | Pharmaceutical compositions comprising glitazones and Nrf2 activators |
| US20130158077A1 (en) | 2011-12-19 | 2013-06-20 | Ares Trading S.A. | Pharmaceutical compositions |
| EP2811994A4 (en) | 2012-02-07 | 2016-01-13 | Biogen Ma Inc | PHARMACEUTICAL COMPOSITIONS CONTAINING DIMETHYL FUMARATE |
| TWI486339B (zh) | 2012-02-07 | 2015-06-01 | Xenoport Inc | □啉烷基反丁烯二酸化合物、醫藥組成物以及使用之方法 |
| US20140056973A1 (en) | 2012-08-22 | 2014-02-27 | Xenoport, Inc. | Oral Dosage Forms Having a High Loading of a Methyl Hydrogen Fumarate Prodrug |
| CA2882713A1 (en) * | 2012-08-22 | 2014-02-27 | Xenoport, Inc. | Methods of administering monomethyl fumarate and prodrugs thereof having reduced side effects |
| US20140171504A1 (en) * | 2012-12-14 | 2014-06-19 | Georgia Regents Research Institute, Inc. | Methods of Treating Sickle Cell Disease and Related Disorders Using Fumaric Acid Esters |
| US20140179779A1 (en) | 2012-12-21 | 2014-06-26 | Biogen Idec Ma Inc. | Deuterium Substituted Fumarate Derivatives |
| US8669281B1 (en) | 2013-03-14 | 2014-03-11 | Alkermes Pharma Ireland Limited | Prodrugs of fumarates and their use in treating various diseases |
| SG11201507371RA (en) | 2013-03-14 | 2015-10-29 | Alkermes Pharma Ireland Ltd | Prodrugs of fumarates and their use in treating various deseases |
| US10179118B2 (en) | 2013-03-24 | 2019-01-15 | Arbor Pharmaceuticals, Llc | Pharmaceutical compositions of dimethyl fumarate |
| WO2014197860A1 (en) | 2013-06-07 | 2014-12-11 | Xenoport, Inc. | Method of making monomethyl fumarate |
| US9421182B2 (en) | 2013-06-21 | 2016-08-23 | Xenoport, Inc. | Cocrystals of dimethyl fumarate |
| US20160206587A1 (en) | 2013-08-26 | 2016-07-21 | Forward Pharma A/S | Pharmaceutical composition containing dimethyl fumarate for administration at a low daily dose |
| JP2016534133A (ja) | 2013-09-06 | 2016-11-04 | ゼノポート，インコーポレイティド | （ｎ，ｎ−ジエチルカルバモイル）メチル メチル（２ｅ）ブト−２−エン−１，４−ジオエートの結晶形態、その合成方法及び使用 |
| US20150079180A1 (en) | 2013-09-18 | 2015-03-19 | Xenoport, Inc. | Nanoparticle compositions of dimethyl fumarate |
| KR102335289B1 (ko) | 2013-12-12 | 2021-12-06 | 알미랄, 에스.에이. | 디메틸 푸마레이트를 포함하는 약학적 조성물 |
| JP6337135B2 (ja) | 2014-02-24 | 2018-06-06 | アルカーメス ファーマ アイルランド リミテッド | フマル酸エステルのスルホンアミドプロドラッグ及びスルフィンアミドプロドラッグ並びに種々の疾患の治療におけるその使用 |
| EP3501510B1 (en) | 2014-02-28 | 2020-07-01 | Banner Life Sciences LLC | Controlled release enteric soft capsules of fumarate esters |
| US10098863B2 (en) | 2014-02-28 | 2018-10-16 | Banner Life Sciences Llc | Fumarate esters |
| US9636318B2 (en) | 2015-08-31 | 2017-05-02 | Banner Life Sciences Llc | Fumarate ester dosage forms |
| US9326947B1 (en) | 2014-02-28 | 2016-05-03 | Banner Life Sciences Llc | Controlled release fumarate esters |
| US9999672B2 (en) | 2014-03-24 | 2018-06-19 | Xenoport, Inc. | Pharmaceutical compositions of fumaric acid esters |
| WO2016061393A1 (en) | 2014-10-15 | 2016-04-21 | Xenoport, Inc. | Fumarate compounds, pharmaceutical compositions, and methods of use |
| US10213411B2 (en) | 2015-08-27 | 2019-02-26 | Vijaykumar Rajasekhar | Use of prodrugs of fumarates in treating heart failure diseases |
| WO2017060400A1 (en) | 2015-10-07 | 2017-04-13 | Neurovive Pharmaceutical Ab | Protected carboxylic acid-based metabolites for the treatment of disesases related to mitochondrial dysfunctions |
| US10463642B2 (en) | 2016-02-01 | 2019-11-05 | Vijaykumar Rajasekhar | Methods of treating heart failure diseases using prodrugs of methyl hydrogen fumarate |
| WO2020094767A1 (en) | 2018-11-08 | 2020-05-14 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of nrf2 activators for the treatment of staphylococcus aureus infections |
| AU2020283238B2 (en) | 2019-05-31 | 2022-07-07 | Curacle Co., Ltd. | Enteric tablet containing dimethyl fumarate |
| US11903918B2 (en) | 2020-01-10 | 2024-02-20 | Banner Life Sciences Llc | Fumarate ester dosage forms with enhanced gastrointestinal tolerability |
| KR20220133807A (ko) | 2021-03-25 | 2022-10-05 | 주식회사 큐라클 | 특정 약동학적 매개변수를 나타내는 디메틸푸마레이트를 유효성분으로 함유한 약학적 조성물 |
| WO2024047248A1 (en) | 2022-09-02 | 2024-03-07 | Institut National de la Santé et de la Recherche Médicale | Use of nrf2 activators for the treatment of cerebral small vessel disease |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2530372A1 (de) * | 1975-07-08 | 1977-01-13 | Walter Dr Schweckendiek | Pharmazeutische zubereitungen zur behandlung von psoriasis |
| DE2621214C3 (de) * | 1976-05-13 | 1981-11-12 | Koronis Gmbh Chemisch-Pharmazeutische Praeparate, 5441 Sassen | Verwendung von Stabilisatoren in Arzneimitteln mit Fumarsäuremonoäthylester und desen Mineralsalzen |
| US5149695A (en) * | 1985-01-15 | 1992-09-22 | Speiser Peter P | Fumaric acid derivatives, process for the production thereof and pharmaceutical compositions containing same |
| CH664150A5 (de) * | 1985-01-15 | 1988-02-15 | Peter Paul Prof Dr Speiser | Fumarsaeureprodrug, verfahren zu seiner herstellung und dieses enthaltende darreichungsformen. |
| US4959389A (en) * | 1987-10-19 | 1990-09-25 | Speiser Peter P | Pharmaceutical preparation for the treatment of psoriatic arthritis |
| US5424332A (en) * | 1987-10-19 | 1995-06-13 | Speiser; Peter P. | Pharmaceutical composition and process for the production thereof |
| DE3834794A1 (de) | 1988-10-12 | 1990-04-19 | F Schielein | Oral zu verabreichendes mittel zur behandlung von psoriasis |
| DE19721099C2 (de) * | 1997-05-20 | 1999-12-02 | Fumapharm Ag Muri | Verwendung von Fumarsäurederivaten |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490849A (zh) * | 2014-11-24 | 2015-04-08 | 广东东阳光药业有限公司 | 一种高密度的富马酸二甲酯肠溶颗粒及其制备方法 |
| CN110898164A (zh) * | 2019-12-19 | 2020-03-24 | 赣州安宏环保科技有限公司 | 根除胃肠病幽门螺杆菌感染的富马酸单乙酯钙盐及其用途 |
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