WO2007048332A1 - Composition pharmaceutique pour le traitement de la goutte et sa preparation et son utilisation - Google Patents

Composition pharmaceutique pour le traitement de la goutte et sa preparation et son utilisation Download PDF

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Publication number
WO2007048332A1
WO2007048332A1 PCT/CN2006/002827 CN2006002827W WO2007048332A1 WO 2007048332 A1 WO2007048332 A1 WO 2007048332A1 CN 2006002827 W CN2006002827 W CN 2006002827W WO 2007048332 A1 WO2007048332 A1 WO 2007048332A1
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Prior art keywords
pharmaceutical composition
febuxostat
composition according
benzbromarone
group
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PCT/CN2006/002827
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English (en)
French (fr)
Inventor
Jie Deng
Bin Fan
Caihua Mu
Yanye Zou
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Shanghai Fosun Pharmaceutical Group Co Ltd
Chongqing Pharmaceutical Research Institute Co Ltd
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Shanghai Fosun Pharmaceutical Group Co Ltd
Chongqing Pharmaceutical Research Institute Co Ltd
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Priority to CNA2006800400510A priority Critical patent/CN101296696A/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents

Definitions

  • the present invention relates to a pharmaceutical composition for treating gout, in particular a pharmaceutical composition comprising a therapeutically effective amount of febuxostat or a pharmaceutically acceptable salt thereof, or a solvate thereof and a uric acid excretion agent, and a process for the preparation thereof, and Use of the composition in the manufacture of a medicament for the treatment of gout.
  • a pharmaceutical composition for treating gout in particular a pharmaceutical composition comprising a therapeutically effective amount of febuxostat or a pharmaceutically acceptable salt thereof, or a solvate thereof and a uric acid excretion agent
  • Gout is a heterogeneous disease of tissue damage caused by increased blood uric acid. Increased blood uric acid is mainly associated with long-term dyslipidemia and/or reduced uric acid excretion. Earthworm is a component of the nucleus. As long as the food containing cells contains strontium, animal foods and legumes contain more strontium. Therefore, the occurrence of gout has a lot to do with people's diet. As the consumption of animal foods increases, the incidence of gout increases.
  • the cause of gout is that the sputum metabolism disorder causes the uric acid concentration in the blood to be too high, and the formation of uric acid crystals is deposited in the tissue.
  • Hyperuricemia is a prelude to gout. When gout occurs, the small joints of the big toe, the back of the foot, the heel, the ankle, the finger, the wrist, etc. may be red and swollen. Repeated episodes cause the joint to become deformed, resulting in a "goutstone.”
  • Gout is the most common arthritic disease in men over 40 years old and has been listed by the United Nations Health Organization as one of the top ten chronic diseases in the 20th century.
  • the latest domestic report by the Chinese Ministry of Health and the China Gout Alliance shows that in China, the incidence of gout is higher than the world average (3-9%) due to climate, eating habits, etc., and the number of gout patients in the country exceeds 0.9 billion.
  • anti-inflammatory drugs for treating acute gout mainly include colchicine, non-steroidal anti-inflammatory drugs and hormones.
  • the acute phase i1 ⁇ 2 needs to control the concentration of blood uric acid in the body.
  • drugs used to control blood uric acid levels in the body one of which is a drug that inhibits uric acid synthesis for decades.
  • the products available to patients on the market are only allopurinol, which have many side effects and are difficult for patients to tolerate, such as allergic rash, abdominal pain, diarrhea, white blood cells and thrombocytopenia, and even side effects such as liver damage.
  • One type of drug is uric acid excretion.
  • the drug has the advantage of not affecting the metabolism of purines and pyrimidines.
  • the clinical drugs are mainly benzbromarone and probenecid.
  • Probenecid also known as probalan
  • probalan is used to treat gout and has no effect on acute gout.
  • the drug is completely absorbed in the gastrointestinal tract, and its metabolites still have a uric acid action. Therefore, its maximum therapeutic effect occurs several days after taking the drug, and may have gastrointestinal reactions, fever of the rash, and few side effects such as liver and kidney dysfunction and blood system damage.
  • Benzbronarone also known as gout, is a derivative of benzofuran.
  • the drug has a strong blood uric acid lowering effect, and the mechanism of action is mainly to reduce the uric acid concentration in the blood by inhibiting the reabsorption of uric acid by the renal tubule.
  • Benzolamazole does not block the metabolism of purine nucleotides and is suitable for long-term treatment of hyperuricemia and gout. Less side effects can occasionally cause severe hepatitis and neutropenia.
  • the benzbromarone was first developed by the French company Labaz in the 1960s. It was listed in Germany in 1971 and has since been listed in Australia, Belgium, France, China and other countries.
  • Sulfinpyrazone is a potent uric acid excretion agent that lasts for 10 hours after one administration.
  • the drug is suitable for the treatment of chronic gout, has a weak anti-inflammatory and analgesic effect, and can inhibit platelet coagulation.
  • Febuxastat (English name: febuxostat) is another blood-lowering uric acid drug that inhibits uric acid synthesis. It is also a non-xanthine-based xanthine oxidase inhibitor. Its chemical structure is as follows:
  • U.S. Patent No. 5,614,520 discloses the use of febuxostat and its methods of preparation, as well as for the treatment of gout due to elevated blood uric acid.
  • Febuxostat reduces blood uric acid by inhibiting the activity of xanthine oxidase and preventing or reducing the synthesis of uric acid from hypoxanthine and xanthine.
  • Benzobromarone, probenecid and sulfinpyrazone mainly control blood uric acid level through uric acid excretion, so as to achieve the purpose of treating gout.
  • Ibubbuttan is used to treat gout by controlling the production of uric acid by inhibiting the production of uric acid.
  • the present invention provides a synergistic pharmaceutical composition for treating gout comprising a therapeutically effective amount of febuxostat or a pharmaceutically acceptable salt thereof or a solvate thereof and a uric acid excretion agent, and may also comprise a pharmaceutically acceptable Excipient or carrier.
  • the uric acid excretion agent of the present invention is selected from at least one of the following drugs: benzbromarone, c Hengshu, dipyridone.
  • a preferred uric acid excretion agent is at least one of benzbromarone and probenecid.
  • a more preferred acid excretion agent is benzbromarone.
  • a specific pharmaceutical composition of the present invention is a preparation containing febuxostat and benzbromarone.
  • the pharmaceutically acceptable salt of febuxostat may be an alkali metal or alkaline earth metal salt such as a sodium salt, a potassium salt, a calcium salt or the like, or an ammonium salt or an organic amine salt.
  • the weight ratio of febuxostat to the uric acid excretion agent is from 1:50 to 10:1, preferably from 1:25 to 3:1, more preferably from 1:7 to 2:1. Further preferably, it is 1:5-2:1.
  • the weight ratio of febuxostat to benzbromarone is from 1:2.5 to 4.8:1, preferably from 1:2.5 to 2.4:1, more preferably 1:2-2: 1.
  • the content of febuxostat may be 20 mg, 40 mg, 80 mg, 120 mg per 1 dose of the pharmaceutical composition, and the content of benzbromarone may be 25 mg, 40 mg> 50 mg, 80 mg, 100 mg, the amounts of the two active ingredients can be arbitrarily combined.
  • the non-buxostat is 80 mg or 120 mg, and the corresponding benzbromarone is 50 mg.
  • the content of febuxostat may be, for example, 20 mg, 40 mg, 80 mg, 120 mg per 1 dose of the pharmaceutical composition, and the content of the propionate may be 250 mg, 500 mg, of the two active ingredients.
  • the optional dosage can be combined in any combination.
  • febuxostat is 80 mg or 120 mg, and the corresponding propanol is 250 mg.
  • the content of febuxostat may be, for example, 20 mg, 40 mg, 80 mg, 120 mg per 1 dose of the pharmaceutical composition, and the content of the pirulone may be 100 mg, 200 mg, of the two active ingredients.
  • the optional dosage can be combined in any combination.
  • the above-mentioned dose of 1 can be understood as 1 tablet, 1 capsule, 1 bag, and 1 injection for different dosage forms.
  • the pharmaceutical composition of the present invention may be in the form of a tablet or a capsule, a buccal tablet, or an oral cavity.
  • Disintegrating tablets, oral instant tablets, tablets, chewables, granules, dry suspensions, injections, solutions, etc. may also be slow-translation agents, controlled release agents, immediate release sustained release preparations, such as sustained release tablets, glues Hey.
  • a preferred dosage form is a tablet or capsule.
  • the adjuvant or carrier is selected from the group consisting of fillers, disintegrators, binders, lubricants, wetting agents, and combinations thereof.
  • Other excipients may also contain flavoring agents, other surfactants, and excipients or carriers that can be used for injection.
  • the respective excipients can be selected according to different dosage forms of the pharmaceutical composition, and the preparation of the corresponding dosage forms can be carried out according to the conventional conventional techniques in the preparation of the preparation, and if necessary, coating can also be carried out.
  • the filler may be starch, modified starch, mannitol, sorbitol, lignocellulose, microcrystalline cellulose, lactose and carbonated hooks, which may be used alone or in combination. It is used in an amount of from 10% to 95.4%, preferably from 20% to 94.%, more preferably from 40% to 92.4%, based on the total weight of the pharmaceutical composition.
  • the binder may be hydroxypropylmethylcellulose, polyvinylpyrrolidone or polyvinyl alcohol, which may be used singly or in combination, in an amount of from 0 to 20%, preferably 0, based on the total weight of the pharmaceutical composition. %-15%, more preferably 0% -10%.
  • the disintegrant may be low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, sodium carboxymethyl starch, calcium carboxymethyl cellulose, starch, modified starch, croscarmellose sodium and Divinylpyrrolidone, which may be used singly or in combination, preferably low-substituted hydroxypropylcellulose and cross-linked polyvinylpyrrolidone, in an amount of from 0% to 40%, preferably from 1% to 30% based on the total weight of the pharmaceutical composition. %, more preferably 3% to -20%.
  • the lubricant may be magnesium stearate, stearic acid, palmitic acid, copper stearate and talc, which may be used singly or in combination, in an amount of about 0.01% by weight based on the total weight of the pharmaceutical composition. % is more preferably 0.1% to 3%.
  • the wetting agent may be water or ethanol; a flavoring agent such as aspartame or saccharin and its sodium salt
  • the present invention also provides a method of preparing a pharmaceutical composition of the present invention, comprising: stirring a mixture comprising a therapeutically effective amount of febuxostat or a pharmaceutically acceptable salt thereof or a solvate thereof and a uric acid excretion agent, and preparing the desired In the form of a formulation, wherein the mixture may also comprise a pharmaceutically acceptable adjuvant or carrier.
  • Another object of the present invention is to provide a use of the pharmaceutical composition of the present invention for the preparation of a medicament for treating gout. It can be used to treat gout caused by elevated blood uric acid levels and other causes.
  • Animal test demonstrates the administration of a formulation containing febuxostat and a urinary excretion drug (benbromumone, propyl sulphate or piracetone)
  • Febuxostat can be obtained by the method disclosed in U.S. Patent No. 5,614,520, and benzbromarone, probenecid, and sulfinpyrazone are commercially available. The resulting preparation can be administered only once a day, 1 dose unit at a time. detailed description
  • Example 1 Preparation of a formulation comprising benzbromarone and febuxostat
  • Example 3 Preparation of a formulation comprising sulfinpyrazone and febuxostat
  • Example 4 Preparation of a formulation containing sulfinpyrazone and febuxostat febuxostat 120g
  • Magnesium stearate 3 g was made into 1000 tablets. A tablet was prepared according to the procedure of Example 1.
  • Example 5 Preparation of a formulation containing probenecid and febuxostat febuxostat 80g
  • mice Seventy healthy male Wistar rats weighing (200 ⁇ 20) g were randomly divided into 7 groups (10 in each group): negative control group, hyperuricemia group (model group), benzene Bromomaron + febuxostat group A (low dose group), benzbromarone + febuxostat group B (middle dose group), benzbromarone + febuxostat group C (high dose group), The benzbromarone (positive drug) group and the febuxostat (positive drug) group. Animals were adapted to the environment for 1 week.
  • the negative control group was given CMC-Na emulsion (0.8%) 1 ml/100 g body weight ip (prepared in physiological saline) for 5 days, and the rats in each group were given 2.5% potassium oxonate 1 ml/100 g ip. After 1 hour, the same dose was administered by intragastric administration. One hour after the intragastric administration, each rat was sacrificed for blood sampling. The blood sample was placed in a 1.5 ml EP tube, incubated at 37 ° C for 30 minutes, and centrifuged at 2500 g X for 15 minutes. The supernatant was used for uric acid determination.
  • Potassium oxonate preparation 0.5% CMC-Na was used to prepare a 2.5% physiological saline emulsion, and was intraperitoneally injected at 250 mg/kg.
  • Blood uric acid was measured by a phytase-EHSPT method using a biochemical analyzer.
  • the serum uric acid level in the hyperuricemia group was significantly higher (P ⁇ 0.001), indicating successful modeling.
  • the middle dose group high The blood uric acid levels in the dose group, the benzbromarone group and the febuxostat group were significantly lower (P ⁇ 0.01, P ⁇ 0.001, P ⁇ 0.05, and P ⁇ 0.05, respectively), as shown in Table 1.
  • Low dose group blood Although the uric acid level decreased but not statistically significant ( ⁇ >0.05), the lowering of serum uric acid level in the middle and high dose groups was stronger than that of the benzbromarone or febuxostat alone.
  • the doses of benzbromarone or febuxostat in the group were lower than those in the group using benzbromarone or febuxostat, respectively, indicating that the effect of blood uric acid level in the combination was lower than that of phenyl bromide. Marlon group or febuxostat group.
  • Negative control group 10 ⁇ 135.65 ⁇ 9.27 Simple hyperuricemia group 10 ⁇ 274.38 ⁇ 21.34*** Low dose group 10 7.5 5:2.5 250.47 ⁇ 19.86 ⁇ medium dose group 10 15 10:5 242.56 ⁇ 21 ⁇ 45 ⁇ high dose group 10 30 20:10 221.59 ⁇ 16.32 ⁇ benzbromarone group 10 7 252 ⁇ 12 ⁇ 18.65 ⁇ His group 10 14 -254.32 ⁇ 19.43 ⁇ in the hyperuricemia group compared with the negative control group, ***: ⁇ ⁇ 0.001; compared with the group of hyperuricemia alone, ⁇ : ⁇ ⁇ 0.05; ⁇ : ⁇ 0.01; ⁇ : ⁇ ⁇ 0.001.
  • Formulations containing benzbromarone and febuxostat showed a strong lowering of uric acid, which was better than either benzbromarone or febuxostat alone, indicating a combination of febuxostat and benzbroma
  • the dragon has a synergistic effect and enhances the effect of lowering blood uric acid.

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Description

一种用于治疗痛风的药物组合物及其制备方法和用途 技术领域
本发明涉及一种用于治疗痛风的药物组合物， 具体是含有治疗有效 量的非布司他或其可药用盐或其溶剂化物和促尿酸排泄剂的药物组合 物及其制备方法， 以及该组合物在制备治疗痛风的药物中的用途。 背景技术
痛风（ GOUT )是因为血尿酸增高导致組织损伤的一組异质性疾病。 血尿酸增高主要是与长期嘌呤代谢障碍和 /或尿酸排泄减少有关。嘌呤是 细胞核中的一种成分， 只要含有细胞的食物就含有嘌呤， 动物性食品和 豆类食品中嘌呤含量较多。因此，痛风的发生与人们的饮食有很大关系。 随着动物性食品的食用量增大， 痛风发病率升高。
痛风的发病原因是嘌呤代谢紊乱导致血液中的尿酸浓度过高， 形成 尿酸结晶沉积在組织中。 高尿酸血症是痛风的前奏。痛风发作时，拇趾、 足背、 足跟、 踝、 指、 腕等小关节都有可能红肿剧痛。 反复发作致使关 节变畸形， 从而形成"痛风石"。
痛风是 40岁以上男性最常见的关节炎疾病，被联合国卫生组织列为 20世纪人类十大顽症之一。 中国国家卫生部、 中国痛风联盟组织的国内 最新报告显示： 在中国， 由于气候、 饮食习惯等问题， 痛风的发病率高 于世界平均水平 (3-9%), 全国痛风患者超过 0.9亿人。
目前治疗急性痛风的抗炎类药物主要有秋水仙碱、 非甾体类抗炎药 和激素。 急性期 i½需要控制体内血尿酸的浓度。 目前， 主要有 2类药 物用于控制体内血尿酸水平， 其中之一是抑制尿酸合成的药物， 几十年 来市场上可供病人选择的产品只有别嘌呤醇， 药物副作用较多且病人难 以耐受， 如别嘌呤醇过敏性皮疹、 腹痛、 腹泻、 白细胞及血小板减少， 甚而有肝功能损害等副作用； 另一类是促尿酸排泄的药物。 该药物的优 点是不影响嘌呤和嘧啶代谢。 临床用药以苯溴马隆和丙磺舒为主。
丙磺舒 ( probenecid )又称为羧苯磺胺 (probalan), 用于治疗曼性痛 风， 对急性痛风无作用。 该药物在胃肠吸收完全， 其代谢物仍有排尿酸 作用。故其最大治疗作用发生于服药后数日，可有胃肠反应，皮疹发热， 很少有肝肾功能损害及血液系统损害等副作用。
苯溴马隆 (benzbronarone)又称为痛风利仙， 是苯并呋喃的衍生物。 该药物有很强的降低血尿酸作用，作用机制主要是通过抑制肾小管对尿 酸的重吸收，从而降低血中尿酸浓度。苯溴马隆不阻挠嘌呤核苷酸代谢， 适用于长期性治疗高尿酸血症及痛风病。 副作用较少， 偶尔可引起重型 肝炎及粒细胞减少。 苯溴马隆最早由法国 Labaz公司于六十年代研制， 1971年在德国上市， 此后分别在澳大利亚、 比利时、 法国、 中国等多国 上市。
磺吡酮（Sulfinpyrazone )是强效的促进尿酸排泄剂， 一次服用后 排尿酸作用可持续 10小时。 该药物适用于治疗慢性痛风， 有微弱的抗 炎镇痛作用， 能抑制血小板凝结。
非布司他 (英文通用名为： febuxostat)是另一种抑制尿酸合成的降血 尿酸药物， 也是笫一种非黄嘌醇类的黄嘌呤氧化酶抑制剂， 其化学结构 式如下：
Figure imgf000003_0001
化学名为: 2-[3-氰基 -4-(2-甲基丙氧基)苯基】 -4-甲基 -5 -噻唑羧酸。 美国专利 US 5,614,520公开了非布司他及其制备方法， 以及用于治 疗因血尿酸升高所致的痛风的用途。 非布司他是通过抑制黄嘌呤氧化酶 的活性、 阻止或降低由次黄嘌呤、 黄嘌呤合成尿酸， 从而达到降低血尿 酸的作用。 体外对比试验和临床试验显示， 降血尿酸（ SUA )作用比别 嘌呤醇强， 耐受性好， 能有效控制血尿酸水平， 从而达到治疗痛风的目 的。 非布司他由日本帝人药物公司开发， 正在美国 FDA注册上市。
苯溴马隆、 丙磺舒、磺吡酮三者主要通过促尿酸排泄来控制血尿酸 水平， 从而达到治疗痛风的目的。 非布司他则是通过抑制尿酸的生成来 控制血尿酸水平， 而达到治疗痛风的作用。 虽然单独施用它们都能降低 血尿酸水平， 但其单独施用的效果无法达到令人满意的程度， 而且给药 量较大， 引起许多副作用， 使得病人耐受性差， 因此不利于较长时间的 治疗方案。 因此， 临床需要疗效更好、 副作用少， 耐受性更好， 以适合 病人长期服用的药品。
经本发明人进行的研究证明，施用含有非布司他与^ ^酸排泄药物 的复方制剂来降低血中尿酸水平所得到的效果明显优于施用各单独剂 量药物的效果。 非布司他与促尿酸排泄药物组合得到的药物组合物使两 类不同作用机制的药物协同作用， 可提高药效， 同时减少活性药物的剂 量， 降低药物的副作用， 由此完成了本发明。 发明内容
本发明提供了一种具有协同作用的用于治疗痛风的药物组合物， 包 含治疗有效量的非布司他或其药用盐或其溶剂化物和促尿酸排泄剂， 还 可以包含药物上可接受的辅料或载体。
本发明的促尿酸排泄剂选自下述药物中的至少一种： 苯溴马隆、 丙 橫舒、 橫吡酮。
优选的促尿酸排泄剂为苯溴马隆和丙磺舒中的至少一种。 更优选的 ^^酸排泄剂为苯溴马隆。本发明的具体药物组合物是含有非布司他和 苯溴马隆的制剂。
非布司他的药用盐可为碱金属或碱土金属盐如钠盐、钾盐、钙盐等， 或铵盐、 有机胺盐。
在本发明的药物組合物中， 非布司他与促尿酸排泄剂的重量比为 1:50-10:1 , 优选为 1:25-3:1， 更优选为 1:7-2:1 , 再优选为 1 :5-2:1。
在本发明的优选药物组合物中， 非布司他与苯溴马隆的重量比为 1:2.5-4.8:1 , 优选为 1:2.5-2.4:1 , 更优选为 1:2-2:1。
依据上述的重量比， 每 1剂量药物组合物中， 非布司他的含量例如 可为 20mg、 40 mg、 80 mg、 120mg,苯溴马隆的含量可为 25 mg、 40 mg> 50 mg, 80 mg、 lOOmg, 这两种活性成分的用量可任意组合。 优选非布 司他为 80 mg或 120 mg， 对应的苯溴马隆为 50 mg。
依据上述的重量比， 每 1剂量药物组合物中， 非布司他的含量例如 可为 20mg、 40 mg、 80 mg、 120mg, 丙續舒的含量可为 250mg、 500mg, 这两种活性成分的可选择用量可任意组合。 优选非布司他为 80 mg或 120 mg, 对应的丙横舒为 250 mg。
依据上述的重量比， 每 1剂量药物组合物中， 非布司他的含量例如 可为 20mg、 40 mg, 80 mg, 120mg,續吡酮的含量可为 100mg、 200mg, 这两种活性成分的可选择用量可任意组合。
上述所说的 1剂量根据不同的剂型可理解为 1片、 1粒胶曩、 1袋、 注射液可为 1支等。
本发明的药物组合物， 其制剂形式可为片剂或胶嚢、 口含片、 口腔 崩解片、 口腔速溶片、 片、 咀嚼剂、 颗粒剂、 干混悬剂、 注射剂、 溶液剂等， 也可为緩译剂、控释剂、速释緩释制剂， 如緩释片、胶嚢等。 优选的剂型为片剂或胶嚢。
在本发明的药物组合物中， 所述的辅料或载体选自： 填充剂、 崩解 剂、粘合剂、润滑剂、润湿剂和它们的组合。其它辅料还可包含矫味剂， 其它表面活性剂以及可用于注射的辅料或载体。根据药物组合物的不同 剂型可选择相应的辅料，根据制剂制备方面的现有常规技术可以实现相 应剂型的制备， 必要时还可进行包衣。
在本发明的药用组合物中， 所述的填充剂可为淀粉、 变性淀粉、 甘 露醇、 山梨醇、 木质纤维素、 微晶纤维素、 乳糖和碳酸钩， 它们可以单 独使用也可以混合使用， 其用量约为药物组合物总重量的 10%-95.4%, 优选为 20%-94.2%, 更优选为 40%-92.4%。
所述的粘合剂可为羟丙甲基纤维素、 聚乙烯吡咯烷酮、 聚乙烯醇， 它们可以单独使用也可以混合使用， 其用量约为药物组合物总重量的 0-20%, 优选为 0%-15%， 更优选为 0 % -10%。
所述的崩解剂可为低取代羟丙纤维素、羧甲基纤维素钠、羧甲基淀 粉钠、 羧甲基纤维素钙、 淀粉、 变性淀粉、 交联羧甲基纤维素钠和交联 聚乙烯吡咯烷酮， 它们可以单独使用也可以混合使用， 优选低取代羟丙 纤维素和交联聚乙烯吡咯烷酮， 其用量约为药物组合物总重量的 0%-40% , 优选为 1%-30%， 更优选为 3 % -20%。
所述的润滑剂可为硬脂酸镁、硬脂酸、棕榈酸、硬脂酸铜和滑石粉， 它们可以单独使用也可以混合使用， 其用量约为药物组合物总重量的 0.01%-10% , 更优选为 0.1%-3%。
所述的润湿剂可为水或乙醇； 矫味剂如阿斯巴甜或糖精及其钠盐 本发明还提供制备本发明的药物组合物的方法， 包括将包含治疗有 效量的非布司他或其药用盐或其溶剂化物和促尿酸排泄剂的混合物搅 拌均匀， 并制成所需要的制剂形式， 其中所述混合物还可以包含药物上 可接受的辅料或载体。
本发明的另一目的是提供本发明的药物组合物在制备治疗痛风的 药物中的应用。 可用于治疗因血中尿酸浓度升高以及其它原因引起的痛 风症。
动物试验证明：施用包含非布司他与促尿酸排泄药物 (苯溴马隆、丙 橫舒或續吡酮)的制剂
和快捷。 非布司他可以按照美国专利 US 5,614,520公开的方法制得， 苯 溴马隆、 丙磺舒、 磺吡酮可从市场上购得。 所得制剂每日可以只给药 1 次， 每次 1剂量单位。 具体实施方式
以下实施例用以详细阐明和理解本发明 , 但并不限制本发明的范 围。
实施例 1: 包含苯溴马隆和非布司他的制剂的制备
非布司他 80g
苯溴马隆 50g
乳糖 80g
微晶纤维素 30g
10%聚乙烯吡咯垸酮溶液 适量
羧甲基淀粉钠 10g 硬脂酸镁 2.5g
制成 1000片
将非布司他、苯溴马隆、乳糖和微晶纤维素混合，然后加入适量 10% 聚乙烯吡咯烷酮溶液， 搅拌均匀， 过筛后烘干， 加入羧曱基淀粉钠和硬 脂酸镁混合均匀后压片。 实施例 2 包含苯溴马隆和非布司他的制剂的制备
非布司他 120g
苯溴马隆 50g
乳糖 80g
微晶纤维素 30g
10%聚乙烯吡咯坑酮溶液 适量
羧曱基淀粉钠 10g
硬脂酸镁 2.9g
制成 1000片
按实施例 1的工艺制备成片剂。 实施例 3 包含磺吡酮和非布司他的制剂的制备
非布司他 80g
橫吡酮 100g
乳糖 80g
微晶纤维素 30g
10%聚乙烯吡咯烷酮溶液 适量
羧曱基淀粉钠 10g 硬脂酸镁
制成 1000片 按实施例 1的工艺制备成片剂。 实施例 4 包含磺吡酮和非布司他的制剂的制备 非布司他 120g
續吡酮 100g
乳糖 80g
微晶纤维素 30g
10%聚乙烯吡咯垅酮溶液 适量
羧甲基淀粉钠 10g
硬脂酸镁 3g 制成 1000片 按实施例 1的工艺制备成片剂。 实施例 5 包含丙磺舒和非布司他的制剂的制备 非布司他 80g
丙磺舒 250g
L 80g
微晶纤维素 60g
10%聚乙烯吡咯燒酮溶液 适量
羧甲基淀粉钠 20g
硬脂酸镁 5g 制成 1000片
按实施例 1的工艺制备成片剂。 药效试验
材料和方法
1、 动物：选取体重为（ 200 ± 20 ) g的健康雄性 Wistar大鼠 70只， 随机分为 7组（每组 10只）： 阴性对照组、单纯高尿酸血症组（模型组）、 苯溴马隆 +非布司他组 A (低剂量组）、 苯溴马隆 +非布司他组 B (中剂量 组）、 苯溴马隆 +非布司他組 C (高剂量组）、 苯溴马隆（阳性药）组和非 布司他（阳性药）组。 动物取回后适应环境 1周。
2、 试验药物和仪器：
试验药物：包含苯溴马隆和非布司他的制剂【非布司他:苯溴马隆 =2:1 (重量比) 1。
苯溴马隆和非布司他均由重庆医药工业研究院有限责任公司提供。 氧漆酸钾，由 Aldrich Chemical Compan 提供，批号: 04328DO-231。 羧甲基纤维素钠（CMC-Na， 分析纯）， 由中国上海亨 ¾ 细化学品 有限公司提供。
日立 7020全自动生化分析仪， 日本生产。
3、 实验前 1 天称取大鼠体重， 确定给药剂量。 低剂量组给药
7.5mg/kg (非布司他为 5 mg/kg、 苯溴马隆为 2.5 mg/kg )、 中剂量組给药 15mg/kg (非布司他为 10 mg/kg、 苯溴马隆为 5 mg/kg )、 高剂量组给药 30mg/kg (非布司他为 20 mg/kg、 苯溴马隆为 10 mg/kg) (均用 0.8%的 CMC-Na配制成浓度分别为 0.75mg/ml、 1.5mg/mK 3.0mg/ml的悬液）； 阴性对照组、单纯高尿酸血症组给予 0.8%CMC-Na乳剂；苯溴马隆组给 药 7mg/kg (用 0.8%的 CMC-Na配制成浓度为 0.7mg/ml的悬液)， 非布司 他组给药 14mg/kg (用 0.8%的 CMC-Na配制成浓度为 1.4mg/ml的悬液), 给药体积为 lml/lOOg体重， 连续给药 4天。 于笫 5天对阴性对照组给予 CMC-Na乳剂 (0.8%)lml/100g体重 i.p (生理盐水配制）， 其佘各组给予 2.5%氧嗪酸钾 lml/100g i.p。 1小时后同前灌胃给药，灌胃给药后 1小时， 将各只大鼠断尾取血，血样置于 1.5ml EP管中， 37°C温育 30分钟， 2500g X 15min离心取上清液用于尿酸测定。
4、 氧嗪酸钾配制：用 0.8%CMC-Na配成终浓度 2.5%的生理盐水 乳悬液， 按 250mg/kg腹腔注射。
5、 采用生化分析仪按照尿酸酶 -EHSPT法测定血尿酸。
试验结果
单纯高尿酸血症组与阴性对照组相比血尿酸水平有明显升高 ((P< 0.001)， 说明造模成功。 经药物处理后， 与单纯高尿酸血症组比较， 中剂 量组、 高剂量组、 苯溴马隆组和非布司他组的血尿酸水平有明显降低 (分 别为 P<0.01、 P<0.001、 P<0.05和 P<0.05) , 见下表 1。 低剂量组血尿酸 水平虽有下降但无统计学意义 (Ρ>0. 05 )， 中、 高剂量组的血尿酸水平降 低效果较单独使用苯溴马隆或非布司他的组都强。 此外， 中剂量组中的 苯溴马隆或非布司他的剂量分别小于单独使用苯溴马隆或非布司他的组 中的剂量， 表明复方制剂的血尿酸水平降 4氏效果实际上分别大于苯溴马 隆组或非布司他组。
同时， 试验结果表明复方制剂組没有明显的毒性和副作用。
此外，在包含苯溴马隆和非布司他的制剂中也未发现苯溴马隆和非 布司他之间存在反应， 制剂稳定性好。 絲明二者之间的相容性良好。 表 1.血尿酸水平的比较
动物数 剂量 非布司他:苯溴马隆 血尿酸水平 组别
(只） ( mg/kg ) (mg/kg: mg/kg) (μιηοΙ/L) 阴性对照组 10 ― ― 135.65±9.27 单纯高尿酸血症组 10 ― ― 274.38±21.34*** 低剂量组 10 7.5 5:2.5 250.47±19.86Δ 中剂量组 10 15 10:5 242.56±21·45ΔΔ 高剂量组 10 30 20:10 221.59±16.32ΔΔΑ 苯溴马隆组 10 7 一 252·12±18.65Δ 非布司他组 10 14 一 254.32±19.43Δ 单纯高尿酸血症组与阴性对照组比较， ***:Ρ<0.001; 各组与单纯高尿酸血症组 比较， Δ:Ρ<0.05; ΔΔ:Ρ<0.01; ΔΔΔ:Ρ<0.001。 包含苯溴马隆和非布司他的制剂表现出较强的降血尿酸作用， 其作 用比单独使用苯溴马隆或非布司他都要好，表明联合使用非布司他与苯 溴马隆具有协同作用， 增强了降低血液尿酸的效果。

Claims

权 利 要 求
1、 一种用于治疗痛风的药物组合物， 包含治疗有效量的非布司他 或其药用盐或其溶剂化物和促尿酸排泄剂。
2、 根据权利要求 1 所述的药物组合物， 其中所述促尿酸排泄剂是 选自苯溴马隆、 丙磺舒和磺吡酮中的至少一种。
3、 根据权利要求 2 所述的药物组合物， 其中所述^ ^酸排泄剂是 选自苯溴马隆和丙磺舒中的至少一种。
4、 根据权利要求 3所述的药物组合物， 其中所述促尿酸排泄剂是 苯溴马隆。
5、 根据权利要求 1所述的药物组合物， 其中所述非布司他的药用 盐是选自碱金属或碱土金属盐、 铵盐、 有机胺盐中的至少一种。
6、 根据权利要求 5所述的药物组合物， 其中所述非布司他的碱金 属或碱土金属盐是选自钠盐、 钾盐和钙盐中的至少一种。
7、 根据权利要求 1 所述的药物组合物， 其中非布司他与促尿酸排 泄剂的重量比为 1:50-10:1。
8、 根据权利要求 7所述的药物组合物， 其中非布司他与促尿酸排 泄剂的重量比为 1:25-3:1。
9、 根据权利要求 8所述的药物组合物， 其中非布司他与促尿酸排 泄剂的重量比为 1:7-2:1。
10、根据权利要求 4所述的药物组合物，其中非布司他与苯溴马隆 的重量比为 1:2.5-4.8:1。
11、 根据权利要求 10所述的药物组合物， 其中非布司他与苯溴马 隆的重量比为 1:2.5-2.4:1。
12、 根据权利要求 11所述的药物組合物， 其中非布司他与苯溴马 隆的重量比为 1:1-2:1。
13、根据权利要求 1所述的药物组合物， 还包含药物上可接受的辅 料或载体。
14、 根据前述权利要求任一项所述的药物组合物， 其制剂形式为片 剂、 胶嚢、 口含片、 口腔崩解片、 口腔速溶片、 ^^片、 咀嚼剂、 颗粒 剂、 干混悬剂、 注射剂、 溶液剂、 緩释剂、 控释剂或速释緩释制剂。
15、根据前述权利要求任一项所述的药物组合物在制备用于治疗痛 风的药物中的用途。
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