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CN1054745C - 抗菌组合物 - Google Patents

抗菌组合物 Download PDF

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CN1054745C
CN1054745C CN94107507A CN94107507A CN1054745C CN 1054745 C CN1054745 C CN 1054745C CN 94107507 A CN94107507 A CN 94107507A CN 94107507 A CN94107507 A CN 94107507A CN 1054745 C CN1054745 C CN 1054745C
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dapsone
aminometradine
preparation
actinomycetes
nocardia
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CN1105563A (zh
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I·康皮斯
R·特恩
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F Hoffmann La Roche 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis

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  • Veterinary Medicine (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
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Abstract

一种含有氨嘧啶和氨苯砜的药用制剂，它可用于治疗因分支杆菌、放线菌和弓形体病病原体所引起的传染病。

Description

抗菌组合物
本发明涉及抗菌活性组合制剂，该制剂包含2，4-二氨基-5-[3，5-二乙氧基-4-(吡咯-1-基)苄基]嘧啶(氨嘧啶)和4，4′-二氨基-二苯砜(氨苯砜)。本发明还涉及氨嘧啶和氨苯砜的用途，它们可作为活性物质用于药物制剂的制备以治疗因分支杆菌、放线菌、特别是诺卡菌和弓形体病病原体引起的传染病，以及含氨嘧啶和氨苯砜的商品包装，其中的药品说明书涉及联合用药以治疗因分支杆菌、放线菌、特别是诺卡菌和弓形体病病原体引起的传染病的方法。
二氨基苄基嘧啶的使用，包括氨嘧啶和氨苯砜或抗菌活性磺胺任意组合的使用，能对抗因真菌卡氏肺囊虫引起的传染病，可从专利公告WO 9208461中得知。我们惊奇的发现，氨嘧啶和氨苯砜的组合适用于治疗因分支杆菌、特别是M.marinum、M.smegmatis、M.avivm和M.leprac；和弓形体病病原体，特别是兔弓形虫；和放线菌，特别是诺卡菌引起的传染病。
活性物质可单独或以组合制剂的形式同时或以一定间隔给药，优选同时给药。
活性物质可于直肠内、肠道外或局部给药。片剂、胶囊、糖衣丸、糖浆、混悬液、溶液和栓剂等适用于肠内给药。输注或注射溶液适用于肠道外给药。
活性物质给药剂量按照使用方式和使用途径以及病人的需要而不同。
活性物质可以氨嘧啶∶氨苯砜比率为1∶100到100∶1(重量)用于控制上述命名的传染病或病原体。治疗因分支杆菌引起的传染病优选氨嘧啶∶氨苯砜比率为1∶1到1∶5(重量)。治疗因弓形体病病原体引起的传染病优选1∶2到2∶1的比率。若是诺卡菌传染病优选氨嘧啶∶氨苯砜比率为4∶1到1∶1(重量)。
若是口服给药，活性物质的剂量一般等于每天每公斤体重0.5到50毫克，对于氨嘧啶优选每天每公斤体重0.5-3毫克，对于氨苯砜优选每天每公斤体重0.5-2毫克。
若是片剂形式，活性物质的量例如为每片片剂中有20-200毫克的氨嘧啶和20-100毫克的氨苯砜。
制剂可含有惰性或药用活性添加剂。例如片剂或颗粒剂可含有一系列粘合剂、填充剂、载体或稀释剂。液体制剂可以无菌水溶性溶液的形式存在。除了活性物质之外，胶囊中足可含有填充剂或增稠剂。此外，还可以有调味添加剂和常用保鲜剂、稳定剂、保湿剂和乳化剂以及用来改变渗透压的盐、缓冲剂和其它添加剂。
上述提到的载体和稀释剂可包含有机或无机的物质，例如水、明胶、乳糖、淀粉、硬脂酸镁、滑石、阿拉伯树胶、聚亚烷基二醇等等。前提是用于制剂制备的所有辅助剂都是无毒的。
对于局部给药，活性物质一般以软膏、药酒、霜剂、溶液、洗剂、喷洒剂、悬浮液等形式使用。优选软膏、霜剂和溶液。用作局部给药的这些制剂可通过作为活性成份的过程产品和无毒、惰性固体或液体载体混合而制得。该载体适用于局部治疗并且常用于这类制剂。
一般约0.1-5％，优选0.3-2％的溶液和约0.1-5％，优选0.3-2％的软膏或霜剂适用于局部给药。
若需要，抗氧剂例如生育酚、N-甲基-γ-生育胺和叔丁基-羟基茴香醚或叔丁基-羟基甲苯可与制剂混合。
本发明中的组合制剂的活性可从下表所给的数据中显示出来。
表1和2显示了单独的和组合的活性物质在体内对各种分支杆菌和放线菌的最小抑制浓度(MIC)和FIC(部分抑制浓度)的活性。FIC可表示协同效应的大小(参见J.Bio，.Chem.1954.298，477)。FIC指数越小，则协同效应越大。
表3显示了M.lufu培养物的抑制百分率，该培养物为测试抗麻风药剂公认的标样，得到了单独的活性物质和它们的组合物给药的确定浓度。
表4和5显示了诺卡菌和弓形菌传染病在体内的活性。用病原体RH兔弓形虫10000个菌落单位腹膜内给药传染实验动物。传染后24小时将所示活性物质的剂量通过除鲠器每隔一天施入动物体内，用14天。“治愈”代表动物大脑中未发现囊肿。
                          表1
       抗不同分支 杆菌交错 滴定法
病原体                单独的MIC氨苯砜             氨嘧啶[μg/ml]               组合的MIC氨苯砜      +      氨嘧啶[μg/ml] FIC指数
 M.avium SN 304     ＞30     ＞30     63     1518     ＜0.7＜0.7
 M.intracellulareSN 403     ＞30     8     3     1     ＞0.23
 M.kansasii     ＞20     ＞20     86     1011     ＜0.9＜0.9
 M.lufu L 209     0.012     ＞6     0.002     1.2     ＜0.36
 M.marinumSN 1254     3     16     0.5     2     ≤0.3
 M.smegmatisATCC 607     0.4     2.5     0.08     0.5     ≤0.4
                                 表2
                          体外抗放线杆菌活性
病原体 培育时间(天数)             单独MICp氨苯砜           氨苯砜[μg/ml]          组合的MIC氨苯砜     +    氨嘧啶[μg/ml] FIC指数
Nocardia asteroides N1Nocardia asteroidesN10Nocardia brasiliensisN2Streptomyces sp.N31Actinomadura maduraeN3     37377377   ＞100＞100255012.5＞100＞100＞100     100＞1002550＞10025100＞100     3.1256＜336.253350     36＜336.2561250   0.06250.125＜0.250.1250.53＜0.281＜0.186＜0.5
                  表3玻璃试管中氨嘧啶和氨苯砜组合物抗Lufu分支杆菌
    μg/ml ％抑制百分数
氨嘧啶     52560     143473
氨苯砜     0.20.4     2222
氨嘧啶      +氮苯砜     0.2+50.4+25     8496
                   表4
          小鼠体内抗诺卡菌的活性
剂量       [mg/kg] ％存活百分数 平均存活期(天数)
氨苯砜     氨嘧啶1-          30-          1001          301          1003          303          100 000204060100 2.61.726.613.212.2＞20
                    表5
             体内抗弓形体病活性：
剂量(毫克) 存活数 存活率％中治愈的动物：
氨苯砜氨苯砜   50100    1/1010/10     00
氨嘧啶   100    0/10     -
氨嘧啶氨苯砜   25/2550/50100/50100/100    0/1010/1010/1010/10 302050
对照组   0/30    0/30
本发明的活性物质组合例如可用于治疗诺卡菌、放线菌、和分支杆菌。该分支杆菌因放线菌例如以色到放线菌、A.naeslundii等、brasiliensis诺卡菌、N.asteroides等和链霉菌例如madurae链霉菌。S.someliensis、S.pelleiieri、Madarella mycetomi而引起；还可治疗因分支杆菌引起的综合传染病，特别是因对病人免疫系统有破坏功能的M.avivm和M.intracellulave引起的一般性传染病；和治疗麻风和大脑弓形体病。
下面是一个典型剂量配方的例子：片剂：氨苯砜                                 100毫克氨嘧啶                                 200PRIMOJEL(淀粉衍生物)                   6Povidone K30(聚乙烯吡咯烷酮)           8硬脂酸镁                               6

Claims (7)

1.一种药用制剂，它包含氨嘧啶和氨苯砜及常用的药用载体。
2.权利要求1的制剂，它所包含的氨嘧啶和氨苯砜的重量比率为1∶100到100∶1。
3.权利要求1的制剂，它所包含的氨嘧啶和氨苯砜的重量比率为1∶1到1∶5。
4.氨嘧啶和氨苯砜在制备用于治疗因分支杆菌、放线菌和弓形体病痛原体引起的传染病的药物制剂方面的用途。
5.按照权利要求4所述的用途，其中所述的放线菌是诺卡菌。
6.一种商品包装，它包含将氨嘧啶和氨苯砜结合使用治疗因分支杆菌、放线菌和弓形体病病原体引起的传染病的说明。
7.按照权利要求6的商品包装，其中所述的放线菌是诺卡菌。
CN94107507A 1993-06-17 1994-06-16 抗菌组合物 Expired - Fee Related CN1054745C (zh)

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CA2030129A1 (en) * 1989-11-29 1991-05-30 Thomas Saupe 1,8-napthalenedicarboximides as antidotes
JP4048054B2 (ja) * 2000-04-27 2008-02-13 バジリア ファルマスーチカ アーゲー 抗菌活性を有するピリミジニルメチルインドール誘導体
JP2007533606A (ja) * 2003-08-13 2007-11-22 キューエルティー・ユーエスエイ・インコーポレーテッド ダプソンを含む乳化組成物
WO2010079224A1 (en) * 2009-01-12 2010-07-15 Intervet International B.V. Pharmaceutical composition to protect an animal against a disorder arising from an infection with a bacterium that belongs to the group of nocardioform actinomycetes
MX2009004635A (es) * 2009-04-29 2010-10-29 Univ Autonoma Metropolitana Formas farmaceúticas solubles de la n,n´-diamino-difenilsulfona para su uso óptimo en el tratamiento de diversas enfermedades.
RU2638926C2 (ru) * 2016-06-02 2017-12-19 федеральное государственное бюджетное образовательное учреждение высшего образования "Волгоградский государственный медицинский университет" Министерства здравоохранения Российской Федерации Противолепрозное средство, обладающее бактериостатической и бактерицидной активностью в отношении m. lufu, представляющее собой производное o-бензоиламинобензойной кислоты
JP7446594B2 (ja) * 2017-07-21 2024-03-11 学校法人東京薬科大学 好中球細胞外トラップ形成促進剤

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CA2125121A1 (en) 1994-12-18
ES2122085T3 (es) 1998-12-16
EP0629403B1 (de) 1998-09-09
ATE170751T1 (de) 1998-09-15
JP2650852B2 (ja) 1997-09-10
JPH072672A (ja) 1995-01-06
CN1105563A (zh) 1995-07-26
RU94019991A (ru) 1996-04-27
RU2136272C1 (ru) 1999-09-10
AU685449B2 (en) 1998-01-22
DK0629403T3 (da) 1999-06-07
EP0629403A1 (de) 1994-12-21
NZ260721A (en) 1997-03-24
MY110998A (en) 1999-07-31
DE59406863D1 (de) 1998-10-15
US5721242A (en) 1998-02-24

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