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WO2010022581A1 - Composition pharmaceutique destinée au traitement de l'hyperuricémie et son utilisation - Google Patents

Composition pharmaceutique destinée au traitement de l'hyperuricémie et son utilisation Download PDF

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Publication number
WO2010022581A1
WO2010022581A1 PCT/CN2009/000838 CN2009000838W WO2010022581A1 WO 2010022581 A1 WO2010022581 A1 WO 2010022581A1 CN 2009000838 W CN2009000838 W CN 2009000838W WO 2010022581 A1 WO2010022581 A1 WO 2010022581A1
Authority
WO
WIPO (PCT)
Prior art keywords
febuxostat
probenecid
hyperuricemia
pharmaceutical composition
derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2009/000838
Other languages
English (en)
Chinese (zh)
Inventor
谭明胜
张殿镇
赵健
朱红星
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tianjin Taipu Pharmaceutical Science & Technology Development Co Ltd
Original Assignee
Tianjin Taipu Pharmaceutical Science & Technology Development Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tianjin Taipu Pharmaceutical Science & Technology Development Co Ltd filed Critical Tianjin Taipu Pharmaceutical Science & Technology Development Co Ltd
Publication of WO2010022581A1 publication Critical patent/WO2010022581A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/426—1,3-Thiazoles
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Definitions

  • composition for treating hyperuricemia and use thereof
  • the present invention relates to a pharmaceutical composition for treating hyperuricemia, febuxostat and a uric acid excretion agent for the treatment of hyperuricemia, and more particularly to the treatment of febuxostat or a derivative thereof with probenecid.
  • Hyperuricemia like other metabolic diseases, has increased in recent years and has increased the mortality rate of cardiovascular and cerebrovascular diseases.
  • Hyperuricemia includes primary and secondary hyperuricemia. When hyperuricemia reaches a certain high value, urate is formed, and crystallization accumulates in tissues and joints, causing gout attacks. Hyperuricemia can also cause gouty arthritis, gouty nephropathy, and kidney stones.
  • hyperuricemia is closely related to hypertension, coronary heart disease, diabetes, hyperlipidemia, hypercoagulability, obesity, etc., and is an important component of metabolic syndrome. They can influence each other and form a vicious circle, which is a serious threat to people's health and safety.
  • Drugs that reduce uric acid production such as allopurinol, febuxostat, etc., which reduce uric acid production by inhibiting xanthine oxidase activity, thereby reducing uric acid content in blood and urine.
  • the important difference between febuxostat and allopurinol is that it has a specific inhibitory effect on xanthine oxidase, while allopurinol is only competitive inhibition.
  • high doses of febuxostat have a significant detrimental effect on liver function.
  • Another object of the present invention is to provide use of the pharmaceutical composition for the preparation of a medicament for the treatment of hyperuricemia and its associated various diseases, particularly acute and chronic gout.
  • the present invention provides a pharmaceutical composition for treating hyperuricemia, the composition comprising febuxostat or a derivative thereof and probenecid and a pharmaceutically acceptable carrier; wherein febuxostat or The ratio by weight of the derivative to probenecid is 1: 10-200, preferably 1: 20-100, particularly preferably 1: 30-75; the febuxostat or its derivative and the drug in the pharmaceutical composition of the invention
  • the weight ratio of the carrier used is 1: 0.5-100.
  • the febuxostat derivative of the present invention includes not only a pharmaceutically acceptable salt of febuxostat with an alkali metal and with ammonia or an organic amine, such as a sodium salt, a potassium salt, a calcium salt, an ammonium salt, etc.; Solvents of febuxostat and its pharmaceutically acceptable salts, such as hydrates, alcoholates, and polycrystals of febuxostat and its pharmaceutically acceptable salts, such as febuxostat polycrystals, butethatin sodium salt Polycrystalline, febuxostat potassium salt polycrystalline ⁇
  • the inventive pharmaceutical composition may be in the form of enteral and parenteral administration.
  • the enteral administration forms include: various oral solid and liquid preparations, and the parenteral administration forms include sublingual preparations, transdermal preparations, injections, films or aerosols, and the like.
  • the active ingredient is intimately mixed with any one or several pharmaceutically acceptable carriers to form an oral solid preparation.
  • Preferred oral solid preparations are various tablets, granules, pills, pills or capsules.
  • the pharmaceutically acceptable carrier in the pharmaceutical composition of the present invention is a pharmaceutically commonly used excipient, and includes: a filler such as lactose, sucrose, starch, microcrystalline cellulose, sorbitol or calcium phosphate; a binder, for example, Syrup, gelatin, hydroxypropyl methylcellulose, polyvinylpyrrolidone, PEG (polyethylene glycol), starch or dextrin; disintegrant, for example, microcrystalline cellulose, sodium carboxymethyl starch, carboxymethyl fiber Sodium or cross-linked polyvinylpyrrolidone; a lubricant such as magnesium stearate; a polymeric matrix material, for example, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, carnauba wax, hydrogenated vegetable oil Or an acrylic resin; a film-forming material, for example, hydroxypropylmethylcellulose, polyvinylpyrrolidone or C', another aspect of the invention discloses the pharmaceutical composition for the
  • hyperuricemia includes primary and secondary hyperuricemia.
  • the various conditions associated with hyperuricemia include acute and chronic gout caused by hyperuricemia, gouty arthritis, gouty nephropathy, and kidney stones.
  • the pharmaceutical composition of the present invention is prepared into a unit dose of a tablet or capsule for oral administration once a day, one tablet at a time.
  • the daily dose for administration to an adult is 10-50 mg, preferably 20-40 mg of febuxostat or a derivative thereof, and 200-3000 mg, preferably 300-2000 mg of probenecid.
  • the pharmaceutical composition of the present invention is prepared into tablets, one tablet per day for adults, each tablet containing 20 mg of febuxostat or a derivative thereof; and probenecid 1000 mg.
  • the pharmaceutical composition of the present invention is prepared into capsules, one capsule per day for adults, 40 mg per febustat or a derivative thereof, and 1500 mg of probenecid.
  • the pharmaceutical composition of the present invention is prepared into tablets, one tablet per day for adults, each tablet containing 20 mg of febuxostat or a derivative thereof; and probenecid 800 mg.
  • the pharmaceutical composition of the present invention can rapidly reduce the high uric acid concentration in serum to a normal level or below, thereby effectively treating hyperuricemia and its related diseases, especially acute and chronic. Gout, gouty arthritis, gouty nephropathy and kidney stones.
  • composition of the present invention containing febuxostat 40 mg and probenecid 1500 mg is administered to a patient with hyperuricemia having a serum uric acid concentration of 550-705 ⁇ 1 / ⁇ , 1 tablet per day, 2 weeks later.
  • the serum uric acid concentration dropped to normal or below normal, and no adverse reactions were observed in the patients who were administered.
  • a composition of the present invention containing febuxostat 20 mg and probenecid 800 mg is administered to a patient with chronic spleen having a serum uric acid concentration of 65 ( ⁇ mol / L, 1 tablet per day, 15 serum)
  • the concentration of uric acid was reduced to normal, and the treatment was maintained for 45 days.
  • the gout was cured and no adverse reactions were found in the patient.
  • the pharmaceutical composition of the present invention rapidly and significantly reduces the level of high uric acid in the serum, and the amount of febuxostat is 1/6 to 1/4 of the amount used alone, which greatly reduces the toxicity and side effects of febuxostat. In particular, it reduces the damage of febuxostat on the liver and increases the patient's adaptability and tolerance. Can be used safely for a long time.
  • CMC-Na sodium carboxymethylcellulose
  • CMC-Na sodium carboxymethylcellulose
  • PK121R cryogenic refrigerated centrifuge produced by ALC, Italy.
  • mice were intragastrically administered with a combination of febuxostat and probenecid.
  • the ratio of 1:10 to 1:150 could significantly antagonize the increase of serum uric acid caused by the complex styling agent, and had obvious anti-uric acid effect.
  • the combination of the two drugs has a certain additive and synergistic effect, and statistical analysis shows that there is a significant synergy between 1:10 and 1:100.
  • Table 2 Effect of different ratios of febuxostat and probenecid on serum uric acid in hyperuricemia mice
  • the uric acid production inhibitory drug, febuxostat and the uric acid excretion-promoting drug, probenecid can inhibit serum uric acid in normal mice and hyperuricemia mice.
  • the combination of febuxostat and probenecid has a synergistic effect in the ratio of 1:10 to 1:200, and has a significant synergistic effect in the ratio of 1:10 to 1:100.
  • Debastatin sodium salt (equivalent to 10 g of buprostatin), 600 g of probenecid, 610 g of dextrin, 1830 g of lactose, granulated with pure water, dried, and encapsulated to obtain 1000 capsules.
  • Example 5
  • Fabbutostat potassium salt (equivalent to buprostatil 2g), probenecid 100g, propylene glycol 150ml, and polysorbate 35g.
  • febuxostat potassium salt Take febuxostat potassium salt, probenecid into the water for injection of dissolved sorbitol and propylene glycol, add medicinal base to adjust the pH value to 8-9, dissolve it, make up the injection water to 2000ml, filter, potting , sterilized.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne une composition pharmaceutique, destinée au traitement de l'hyperuricémie ou de maladies associées, et comprenant du febuxotat ou des dérivés de celui-ci, du probénécide et des excipients pharmaceutiquement acceptables, le rapport pondéral entre le febuxotat ou ses dérivés, le probénécide et les excipients pharmaceutiquement acceptables étant de 1/10~200/0,5~100. La présente invention concerne également l'utilisation de ladite composition pharmaceutique et un procédé de traitement de l'hyperuricémie et de maladies associées.
PCT/CN2009/000838 2008-08-26 2009-07-27 Composition pharmaceutique destinée au traitement de l'hyperuricémie et son utilisation Ceased WO2010022581A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN200810054282.8 2008-08-26
CN2008100542828A CN101658520B (zh) 2008-08-26 2008-08-26 用于治疗高尿酸血症的药物组合物

Publications (1)

Publication Number Publication Date
WO2010022581A1 true WO2010022581A1 (fr) 2010-03-04

Family

ID=41720795

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2009/000838 Ceased WO2010022581A1 (fr) 2008-08-26 2009-07-27 Composition pharmaceutique destinée au traitement de l'hyperuricémie et son utilisation

Country Status (2)

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CN (1) CN101658520B (fr)
WO (1) WO2010022581A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112957318A (zh) * 2021-02-02 2021-06-15 河北科星药业有限公司 丙磺舒溶液及其制备方法
CN113995771A (zh) * 2021-12-06 2022-02-01 昆明品品生物科技有限公司 聚乙二醇在制备具有降血尿酸作用的药物中的用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372679A (zh) * 2010-08-27 2012-03-14 北京润德康医药技术有限公司 一种非布司他水溶性衍生物及其制备方法
CN107157943B (zh) * 2017-05-18 2021-02-19 正大制药（青岛）有限公司 一种托匹司他制剂及其制备方法
CN107648195B (zh) * 2017-11-08 2020-07-31 杭州朱养心药业有限公司 稳定的非布司他胶囊剂药物组合物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1954814A (zh) * 2005-10-26 2007-05-02 重庆医药工业研究院有限责任公司 一种具有协同作用治疗痛风的药物组合物及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1954814A (zh) * 2005-10-26 2007-05-02 重庆医药工业研究院有限责任公司 一种具有协同作用治疗痛风的药物组合物及其制备方法

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112957318A (zh) * 2021-02-02 2021-06-15 河北科星药业有限公司 丙磺舒溶液及其制备方法
CN113995771A (zh) * 2021-12-06 2022-02-01 昆明品品生物科技有限公司 聚乙二醇在制备具有降血尿酸作用的药物中的用途

Also Published As

Publication number Publication date
CN101658520A (zh) 2010-03-03
CN101658520B (zh) 2011-07-27

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