TWI505827B - 治療高尿酸血症及與高尿酸血症有關之新陳代謝疾病之方法及組合物 - Google Patents
治療高尿酸血症及與高尿酸血症有關之新陳代謝疾病之方法及組合物 Download PDFInfo
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- TWI505827B TWI505827B TW101108193A TW101108193A TWI505827B TW I505827 B TWI505827 B TW I505827B TW 101108193 A TW101108193 A TW 101108193A TW 101108193 A TW101108193 A TW 101108193A TW I505827 B TWI505827 B TW I505827B
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- hyperuricemia
- gout
- diacerein
- group
- rhein
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- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- 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
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- 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
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Landscapes
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- Hematology (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
高尿酸血症被定義為男性血尿酸值超過6.8 mg/dL至7.0 mg/dL或女性血尿酸值超過6 mg/dL。高尿酸血症及與高尿酸血症有關之新陳代謝疾病(諸如痛風)在美國影響著三百萬至五百萬個體。在美國，非裔美國人患有痛風之可能性為高加索人美國人之兩倍。此外，痛風及高尿酸血症在中國、日本、玻里尼西亞(Polynesia)及城市撒哈拉以南之非洲地區(urban sub-Saharan Africa)已變得常見，其中痛風比率在1990與2010之間近乎加倍。咸信疾病發生率之此升高係由於預期壽命較長、飲食變化、酒精消耗及與痛風有關之疾病(諸如代謝症候群、腎機能不全及高血壓)的增加。已發現影響痛風比率之許多因素，包括年齡、種族及一年中的季節。在超過30歲之男性及超過50歲之女性中，痛風之發病率約為2%。
與高尿酸血症有關之新陳代謝疾病不僅包括痛風，而且包括歸因於尿酸結晶之急性單關節發炎性關節炎的疼痛侵襲、關節中尿酸鹽結晶之沈積、腎實質中尿酸鹽結晶的沈積、尿石症、腎石病及痛風性腎病。已知長期腎石病及痛風性腎病增加腎損傷及腎衰竭之風險。
痛風為通常特徵在於急性發炎性關節炎反覆發作之醫學病況。大腳趾基部蹠骨-指骨關節最常受影響(約50%個案)。然而，痛風亦可以結節瘤(tophi)、腎結石或尿酸鹽腎病變之形式存在。咸信痛風係由血液中結晶且沈積在關
節、腱及周圍組織中之尿酸含量升高所引起。
高尿酸血症及痛風之當前治療包括利用降尿酸鹽劑來降低血液中之尿酸濃度，該等降尿酸鹽劑諸如有：1)黃嘌呤氧化酶抑制劑，諸如別嘌呤醇(allopurinol)及非布索坦(febuxostat)；2)排尿酸劑，諸如苯磺唑酮(sulphinpyrazone)、苯溴馬隆(benzbromarone)及丙磺舒(probenecid)；3)尿酸鹽氧化酶，諸如聚乙二醇重組尿酸酶(pegloticase)、普瑞凱希(puricase)、拉布立酶(rasburicase)及聚乙二醇化尿酸酶(pegylated uricase)；及4)非諾貝特(fenofibrate)。此外，急性痛風之症狀可用抗發炎劑來控制，該等抗發炎劑諸如有：1)非類固醇抗發炎藥(NSAID)，諸如吲哚美辛(indomethacin)及布洛芬(ibuprofen)；2)皮質類固醇(corticosteroid)；及3)秋水仙鹼(colchicine)。使血尿酸含量回到正常範圍可降低復發性急性痛風之發病率及防止其他與高尿酸血症有關之新陳代謝疾病。
然而，痛風或高尿酸血症之許多目前可用之治療會引起多種不良副作用。舉例而言，黃嘌呤氧化酶抑制劑(諸如別嘌呤醇)會引起過敏性血管炎、史蒂芬-瓊森症候群(Stevens-Johnson syndrome)、剝脫性皮炎、再生不全性貧血及肝功能不全。排尿酸劑(諸如丙磺舒、布可隆(bucolome)及苯溴馬隆)具有諸如腸胃失調、尿石病及特異性體質患者之爆發性肝衰竭的副作用。此外，丙磺舒會影響諸如以下之藥物之排泄：卡托普利(captopril)、吲哚美辛、酮洛芬(ketoprofen)、酮咯酸(ketorolac)、萘普生
(naproxen)、頭孢菌素(cephalosporin)、喹諾酮(quinolone)、青黴素(penicillin)、甲胺喋呤(methotrexate)、齊多夫定(zidovudine)、更昔洛韋(gancyclovir)及阿昔洛韋(acyclovir)。長期使用NSAID會引起包括潰瘍穿孔及上胃腸道出血之副作用。
因此，仍需要開發用於治療痛風及高尿酸血症之新藥劑。
本發明提供治療及/或預防高尿酸血症及與高尿酸血症有關之新陳代謝疾病(諸如痛風、痛風性關節炎、痛風發作(gout flare)、尿酸性腎石病及痛風性腎病)之治療方法。該等方法尤其適用於無充分醫療監控或無法耐受目前可用之降低尿酸鹽及抗發炎之療法的高尿酸血症患者。
特定言之，使用治療有效量之雙醋瑞因(diacerein)、大黃酸(rhein)或其醫藥學上可接受之鹽、類似物、前藥或活性代謝物來治療及/或預防高尿酸血症及與高尿酸血症有關之新陳代謝疾病的方法在降低血尿酸含量方面與使用目前可用之藥劑相比提供料想不到的優勢。
雙醋瑞因([4,5-雙(乙醯氧基)-9,10-二側氧基-2-蒽甲酸])為高度純化之蒽醌衍生物。其已在數個國家中被批准為骨關節炎症狀慢作用藥物(SYmptomatic Slow-Acting Drug in Osteoarthritis，SYSADOA)。大黃酸為雙醋瑞因之主要活性代謝物。已證實雙醋瑞因抑制促炎性細胞激素(諸如介白素-1(IL-1)、TNF-α及介白素-6(IL-6))之合成及活性。
根據本發明，在患有高尿酸血症及與高尿酸血症有關之新陳代謝疾病之患者的治療週期期間，雙醋瑞因可降低血尿酸含量且使血尿酸含量維持在正常範圍內。此外，雙醋瑞因亦可預防急性痛風性關節炎及痛風發作之復發，無論其以單一活性藥物(亦即雙醋瑞因單一療法)形式或以與其他降尿酸鹽劑及/或抗發炎劑之組合形式使用皆然。
相應地，在一個實施例中，本發明提供一種治療及/或預防高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法，其包含向有需要之患者投與治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在另一實施例中，治療及/或預防高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法可另外包含投與該患者至少一種選自由抗發炎劑及降尿酸鹽劑組成之群的其他治療劑。
在另一實施例中，本發明提供一種改善患有痛風、高尿酸血症或與高尿酸血症有關之新陳代謝疾病之患者的血尿酸含量控制之方法，其包含向該患者投與治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在另一實施例中，本發明提供一種治療及/或預防服用降尿酸鹽劑或抗發炎劑之患者的高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法，其包含向該患者投與治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)
大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在另一實施例中，本發明提供一種治療對選自由抗發炎劑及降尿酸鹽劑組成之群的治療劑具有不良耐受性之患者的高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法，其包含向該患者投與治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
根據本發明，雙醋瑞因、大黃酸或其醫藥學上可接受之鹽、類似物、前藥或活性代謝物可用於治療及/或預防高尿酸血症及與高尿酸血症有關之新陳代謝疾病，諸如痛風、痛風性關節炎、痛風發作、尿酸性腎石病及痛風性腎病。
高尿酸血症之治療旨在使血液尿酸含量降低至正常範圍。在人類中，血尿酸含量正常範圍之上端對於女性為約6 mg/dL且對於男性為約7.0 mg/dL。此等範圍可能會視最新臨床指南而變化。痛風之治療旨在緩解急性發作之疼痛及發炎且降低復發性發作之發生率。
使用雙醋瑞因、大黃酸及其醫藥學上可接受之鹽、類似物、前藥或活性代謝物來治療及/或預防高尿酸血症及與高尿酸血症有關之新陳代謝疾病(諸如痛風)與使用習知療法相比提供料想不到的優勢。此等優勢包括降低血尿酸含量及預防痛風症狀復發之能力。此外，在本發明之一些實
施例中，本發明方法允許經口投與藥物，因此避免注射位點之不良反應。
如本文所用，雙醋瑞因(4,5-雙(乙醯氧基)-9,10-二側氧基-2-蒽甲酸)係指具有以下結構式之化合物：
雙醋瑞因直接抑制IL-1β合成及調節IL-1β誘導之活性。雙醋瑞因已在骨關節炎實驗模型中及在患有手指關節及膝關節骨關節炎之人類個體中顯示具有改善疾病之效果(disease modifying effect)。IL-1β在骨關節炎病理生理學及軟骨破壞中起基礎性作用。IL-1β亦促進誘導性氧化氮合成酶之表現，且增加人類骨關節炎軟骨細胞中前列腺素E2(prostaglandin E2)、IL-6、IL-8及TNF-α之釋放。
雙醋瑞因之醫藥學上可接受之鹽、類似物、前藥及活性代謝物亦預期可用於本發明。大黃酸(9,10-二氫-4,5-二羥基-9,10-二側氧基-2-蒽甲酸)及單乙醯基大黃酸為雙醋瑞因之已知活性代謝物。
如本文所用，術語「醫藥學上可接受之鹽」包括酸性或鹼性基團之鹽。醫藥學上可接受之鹽之實例包括源自無機酸之鹽，該等無機酸諸如有鹽酸、氫溴酸、硝酸、碳酸、一氫碳酸(monohydrogencarbonic acid)、磷酸、一氫磷酸、二氫磷酸、硫酸、一氫硫酸、氫碘酸或亞磷酸及其類
似物；以及源自相對無毒的有機酸之鹽，該等有機酸諸如有乙酸、丙酸、異丁酸、順丁烯二酸、丙二酸、苯甲酸、丁二酸、辛二酸、反丁烯二酸、杏仁酸、鄰苯二甲酸、苯磺酸、甲苯磺酸(包括對甲苯磺酸、間甲苯磺酸及鄰甲苯磺酸)、檸檬酸、酒石酸、甲磺酸及其類似物。亦包括胺基酸之鹽(諸如精胺酸鹽及其類似物)及有機酸(諸如葡糖醛酸或半乳糖醛酸及其類似物)之鹽。
如本文所用，術語「前藥」係指活性藥物之藥理學非活性衍生物，其經設計以經由活體內生理作用(諸如水解、代謝及其類似作用)而轉化成活性藥物。
如本文所用，術語「降尿酸鹽劑」係指用於藉由降低血液中之尿酸含量來治療痛風及高尿酸血症之藥物。目前可用之降尿酸鹽劑之實例包括(但不限於)：1)黃嘌呤氧化酶抑制劑，諸如別嘌呤醇及非布索坦；2)排尿酸劑，諸如苯磺唑酮、苯溴馬隆及丙磺舒；3)尿酸鹽氧化酶抑制劑，諸如聚乙二醇重組尿酸酶、普瑞凱希、拉布立酶及聚乙二醇化尿酸酶；及4)非諾貝特。彼等藥物可單獨或以組合方式給予。
如本文所用，術語「抗發炎劑」係指用於治療痛風及高尿酸血症之發炎性症狀之藥物。目前可用之抗發炎劑之實例包括(但不限於)：1)非類固醇抗發炎藥(NSAID)，諸如吲哚美辛及布洛芬；2)皮質類固醇；及3)秋水仙鹼。
如本文所用，術語「治療(treatment/treating)」包括抑制疾病或病況、使症狀之嚴重度及/或發生頻率降低、消除
症狀及/或潛在病因、預防症狀及/或其潛在病因之發生、改善及/或改良患者病況。因此，用本發明之該等組合物「治療」患者包括預防易感個體之特定疾病，以及控制臨床上有症狀之個體以抑制疾病或病症或消退疾病或病症，及維持當前狀態及/或預防疾病或病症之進展。治療可包括預防、醫療或治癒。
如本文所用，本發明之化合物及/或醫藥組合物之「治療有效量」術語係指該化合物及/或組合物足以依適用於任何醫學治療的合理益處/風險比率治療、抑制、改善或預防高尿酸血症或與高尿酸血症有關之新陳代謝疾病時的用量。然而，應瞭解，本發明之化合物及/或組合物之每日總用量將由主治醫師在正確醫學判斷範疇內來決定。針對任何特定患者之特定有效劑量將視多種因素而定，該等因素包括所治療之疾病及該疾病之嚴重性；所用特定化合物之活性；所用特定組合物；患者之年齡、體重、一般健康狀況、性別及飲食；投藥時間、投藥途徑及所用特定化合物之排泄率；治療持續時間；與所用特定化合物組合或同時使用之藥物；及醫學技術中熟知之類似因素。舉例而言，在此項技術之技能範圍內，即可使化合物劑量自低於達成所要治療效果所需之程度起始且逐漸增大劑量，直至達成所要效果為止。
如本文所用，術語「共同投與」包括以單一組合物形式或以獨立組合物形式投與雙醋瑞因及至少一種降尿酸鹽劑及/或抗發炎劑。雙醋瑞因及至少一種降尿酸鹽劑及/或抗
發炎劑可利用相同或不同之投藥途徑及/或以相同或不同之時間或給藥方案投與。
在一個實施例中，本發明提供一種治療及/或預防高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法，其包含向有需要之患者投與治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在一個較佳實施例中，雙醋瑞因之治療有效量為10毫克/日至200毫克/日。在另一實施例中，雙醋瑞因之醫藥學上可接受之鹽、類似物、前藥或活性代謝物之治療有效量等同於每日10毫克至200毫克雙醋瑞因鹼型。
在一個較佳實施例中，雙醋瑞因之活性代謝物為單乙醯基大黃酸或大黃酸。
在一個實施例中，與高尿酸血症有關之新陳代謝疾病係選自由以下組成之群：急性痛風、慢性痛風、痛風性關節炎、痛風發作、尿酸性腎石病及痛風性腎病。
在一個實施例中，治療及/或預防高尿酸血症或與高尿酸血症有關之新陳代謝疾病之方法可另外包含向該患者投與至少一種選自由抗發炎劑及降尿酸鹽劑組成之群的其他治療劑。
在另一實施例中，本發明提供一種改善患有痛風、高尿酸血症或與高尿酸血症有關之新陳代謝疾病之患者的血尿酸含量控制之方法，其包含向該患者投與治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)大黃酸及3)
其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在另一實施例中，本發明提供一種治療或預防服用降尿酸鹽劑或抗發炎劑之患者的高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法，其包含向該患者投與治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在一個較佳實施例中，治療或預防服用降尿酸鹽劑或抗發炎劑之患者的高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法使該患者之血液尿酸含量降低至正常範圍上端以下。
然而，在一些實施例中，所提供之治療及/或預防高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法以及所提供之改善患有痛風、高尿酸血症或與高尿酸血症有關之新陳代謝疾病之患者的血尿酸含量控制之方法不需要且不包含共同投與任何其他治療劑，該等其他治療劑包括(但不限於)降尿酸鹽劑、抗發炎劑、pH值活化型蛋白酶之抑制劑等等。
在另一實施例中，本發明提供一種治療對選自由抗發炎劑及降尿酸鹽劑組成之群的治療劑具有不良耐受性之患者的高尿酸血症或與高尿酸血症有關之新陳代謝疾病的方法，其包含向該患者投與治療有效量的選自以下的化合物：1)雙醋瑞因、2)大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在一個較佳實施例中，抗發炎劑係選自由以下組成之群：非類固醇抗發炎藥(NSAID)、皮質類固醇、秋水仙鹼及其組合。
NSAID之實例包括(但不限於)：芳基烷酸，諸如乙醯胺苯酚(acetaminophen)；2-芳基丙酸，諸如布洛芬、酮咯酸及萘普生；N-芳基鄰胺基苯甲酸，諸如甲芬那酸(mefenamic acid)、甲氯芬那酸(meclofenamic acid)；昔康(oxicam)類，諸如吡羅昔康(piroxicam)、美洛昔康(meloxicam)；芳基烷酸，諸如雙氯芬酸(diclofenac)、依託度酸(etodolac)、吲哚美辛、舒林酸(sulindac)；及COX-2抑制劑，諸如塞內昔布(celecoxib)。
在一個較佳實施例中，降尿酸鹽劑係選自由以下組成之群：黃嘌呤氧化酶抑制劑、排尿酸劑、尿酸鹽氧化酶、尿鹼化劑及非諾貝特。
黃嘌呤氧化酶抑制劑之實例包括(但不限於)：別嘌呤醇、奧昔嘌醇(oxypurinol)及非布索坦。排尿酸劑之實例包括(但不限於)：布可隆、苯磺唑酮、苯溴馬隆及丙磺舒。尿酸鹽氧化酶之實例包括(但不限於)：聚乙二醇重組尿酸酶、普瑞凱希、拉布立酶、尿酸酶及聚乙二醇化尿酸酶。尿鹼化劑之實例包括(但不限於)：碳酸氫鈉、檸檬酸鉀及檸檬酸鈉。
在一個較佳實施例中，治療方法在該患者中降低血液尿酸含量；及/或減少由高尿酸血症誘發之痛風性關節炎及痛風發作的發炎效應；及/或溶解腎結石；及/或降低由高
尿酸血症誘發之急性發炎性關節炎的復發率；及/或預防復發性高尿酸血症；及/或減緩尿酸鹽腎病變之進展。
在另一個較佳實施例中，治療方法在該患者中使血液尿酸含量降低至正常範圍上端以下。
雙醋瑞因及抗發炎劑及/或降尿酸鹽劑可含於單一調配物中或可作為獨立調配物共同投與。
本發明亦提供用於治療及/或預防患者之高尿酸血症或與高尿酸血症有關之新陳代謝疾病的醫藥組合物，其包含治療有效量的選自由以下組成之群的化合物：1)雙醋瑞因、2)大黃酸及3)其醫藥學上可接受之鹽、類似物、前藥或活性代謝物。
在一個較佳實施例中，雙醋瑞因之治療有效量為10毫克/日至200毫克/日。在另一實施例中，雙醋瑞因之醫藥學上可接受之鹽、類似物、前藥或活性代謝物之治療有效量等同於每日10毫克至200毫克雙醋瑞因鹼型。
本發明亦提供醫藥組合物，其包含1)雙醋瑞因、大黃酸或其醫藥學上可接受之鹽、類似物、前藥或活性代謝物及2)至少一種其他治療劑。
在一個實施例中，其他治療劑係選自由抗發炎劑及降尿酸鹽劑組成之群。
在一個較佳實施例中，其他治療劑係選自由以下組成之群：1)黃嘌呤氧化酶抑制劑、2)排尿酸劑、3)尿酸鹽氧化酶抑制劑、4)非諾貝特、5)NSAID、6)皮質類固醇及7)秋水仙鹼。
其他活性成分可呈控制釋放劑型或立即釋放劑型存在。
在投與有需要之患者時，雙醋瑞因、其醫藥學上可接受之鹽、前藥或活性代謝物可製成醫藥組合物之形式。
醫藥組合物可進一步包括醫藥學上可接受之載劑，且可呈固體或液體形式，該固體或液體形式包括(但不限於)：錠劑、散劑、膠囊、丸粒、溶液、懸浮液、酏劑、乳液、凝膠、乳膏劑、貼片劑或栓劑(包括直腸及尿道栓劑)。
如本文所用，術語「醫藥學上可接受之載劑」係指醫藥學上可接受之材料、組合物或媒劑，諸如液體或固體填充劑、稀釋劑、賦形劑、溶劑或囊封材料。醫藥學上可接受之載劑可與組合物之其他成分相容、與投藥模式相容，且對患者無害。醫藥學上可接受之載劑可為水性或非水性。醫藥學上可接受之載劑包括膠類、澱粉、糖類、纖維素材料及其混合物。可充當醫藥學上可接受之載劑之材料的一些實例包括(但不限於)：(a)糖類，諸如乳糖、葡萄糖及蔗糖；(b)澱粉，諸如玉米澱粉及馬鈴薯澱粉；(c)纖維素及其衍生物，諸如羧甲基纖維素鈉、乙基纖維素及乙酸纖維素；(d)黃蓍膠粉末；(e)麥芽；(f)明膠；(g)滑石；(h)賦形劑，諸如可可脂及栓劑蠟；(i)油類，諸如花生油、棉籽油、紅花籽油、芝麻油、橄欖油、玉米油及大豆油；(j)二醇類，諸如丙二醇；(k)多元醇，諸如甘油、山梨糖醇、甘露糖醇及聚乙二醇；(l)酯類，諸如油酸乙酯及月桂酸乙酯；(m)瓊脂；(n)緩衝劑，諸如氫氧化鎂、氫氧化鋁、硼酸及硼酸鈉，以及磷酸鹽緩衝液；(o)海藻酸(alginic
acid)；(p)無熱原質水；(q)等張鹽水；(r)林格氏溶液(Ringer's solution)；(s)乙醇；(t)磷酸鹽緩衝溶液；及(u)其他適用於醫藥組合物之無毒性相容物質。
本發明之組合物可使用此項技術已知之任何方式投與，該等方式包括(但不限於)：經口、經鼻、非經腸、局部、經皮或經直腸途徑投藥。組合物較佳適合於經口或局部投藥。舉例而言，組合物之活性成分可與適合之賦形劑一起調配以製備錠劑、膠囊、丸粒、糖衣錠、口含錠、溶液、散劑或顆粒、懸浮液、硬膠囊或軟膠囊、貼片劑及任何其他適合之形式。製備醫藥組合物之方法及適合賦形劑之選擇已為熟習此項技術者所知。
以下實例展示本發明之一些態樣。該等實例不意欲以任何方式限制本發明。
目的：
評估雙醋瑞因治療患有2型糖尿病之患者之蛋白尿的功效及安全性。
主要終點：
在投與雙醋瑞因或安慰劑24週之後比較尿白蛋白與肌酸酐之比率(UACR)距基線之變化。
個體：
具有微量蛋白尿之男性或女性2型糖尿病患者(BMI35 kg/m2
)。
程序：
此為一項比較雙醋瑞因50 mg每日兩次(bid)對比安慰劑對2型糖尿病患者蛋白尿之影響的II期前瞻性隨機化
雙盲之平行比較研究。
在篩選就診時，使滿足入選標準且給出書面知情同意書之患者進入三至十天的篩選期。在篩選期期間，評估基線UACR。若基線UACR大於50 mg/g，則使患者以1：1比率(雙醋瑞因對比安慰劑)隨機進入48週之治療期。在研究之前，所有參與者需要服用穩定劑量之血管收縮素轉化酶(ACE)抑制劑、血管收縮素受體阻斷劑(ARB)或兩者持續三個月。在試驗期間繼續服用此等藥劑。在研究期期間持續服用低血糖藥物。若有臨床指示，則改變類別及/或劑量。在研究期間經臨床研究者同意，允許向具有低血糖或高血糖可能性之先前存在之協同藥物治療中引入新治療或任何方案變化。
自基線血尿酸含量高於7.0 mg/dL之個體中集合高尿酸血症子組。利用組內變化之成對t試驗法(paired t-test)分析兩個治療組中血尿酸含量之結果。
結果展示於以下表1及表2中。
使患有糖尿病性微量蛋白尿之個體(n=76)以1：1比率隨機服用每日兩次雙醋瑞因50 mg(n=38)或安慰劑(n=38)持續24週。在高尿酸血症子組中，雙醋瑞因組中有9名個體(2名女性及7名男性)及安慰劑組中有12名個體(2名女性及10名男性)的基線血液尿酸含量大於7.0 mg/dL，且平均含量分別為8.06 mg/dL及8.38 mg/dL。
在治療12週及24週之後，與基線相比雙醋瑞因可顯著降低血尿酸含量(表1，在第12週及第24週，p值分別等於0.0037及0.0060)。另外，在治療期期間雙醋瑞因可使血尿酸含量維持在正常範圍上端以下(亦即7.0 mg/dL以下)。與雙醋瑞因治療組對比，在安慰劑治療組中血尿酸含量未得以改善(表2，在第12週及第24週，p值等於0.3887及0.2567)。
如表1及表2顯示，在治療開始時，雙醋瑞因組中有9人且安慰劑組中有12人。在經12週雙醋瑞因治療之後，該9名患者中6人之血尿酸含量達到正常範圍(1名女性血液中之尿酸含量低於6.0 mg/dL且5名男性血液中之尿酸含量低於7.0 mg/dL)。相比之下，在安慰劑組中剩餘11名患者中
僅1人達到正常範圍(1名男性血液中之尿酸含量低於7.0 mg/dL)。在用雙醋瑞因及安慰劑之24週治療中亦觀察到相同趨勢。雙醋瑞因組中剩餘7名患者中4人血液中之尿酸含量達到正常範圍(1名女性血液中之尿酸含量低於6.0 mg/dL且3名男性血液中之尿酸含量低於7.0 mg/dL)，而安慰劑組中剩餘11名患者中僅3人達到正常範圍(3名男性血尿酸含量低於7.0 mg/dL)。圖1及圖2進一步說明研究之結果：圖1為展示用雙醋瑞因或安慰劑治療之男性患者之血尿酸含量的圖；且圖2為展示用雙醋瑞因或安慰劑治療之女性患者之血尿酸含量的圖。
此等結果強烈提示雙醋瑞因可顯著降低高尿酸血症患者之血尿酸含量且在治療期期間使尿酸含量維持在正常範圍內。
在實例1所述之DIA-DM01試驗中，兩名加入雙醋瑞因組之個體具有慢性痛風病史且目前用別嘌呤醇治療。
個案1：具有慢性痛風及高尿酸血症病史之70歲女性自2009年1月2日起用別嘌呤醇治療。在她加入雙醋瑞因試驗之前，她的醫學治療不令人滿意，且她的血液尿酸含量在第一次就診(2009年7月8日)時為8.3 mg/dL。
在24週雙醋瑞因「輔助性(add-on)」治療之後，患者血液尿酸含量降低至7.5 mg/dL。在治療期期間未觀察到急性
發作。
個案2：具有慢性痛風及高尿酸血症病史之66歲男性自2009年8月27日起用別嘌呤醇治療。在他加入雙醋瑞因試驗之前，他的醫學治療亦不令人滿意，且他的血液尿酸含量在第一次就診(2009年12月18日)時為9.5 mg/dL。
在12週雙醋瑞因「輔助性」治療之後，患者血液尿酸含量降低至6.4 mg/dL且維持在正常範圍上端以下。
圖1為展示用雙醋瑞因或安慰劑治療之男性患者之血尿酸含量的圖。
圖2為展示用雙醋瑞因或安慰劑治療之女性患者之血尿酸含量的圖。
Claims (16)
- 一種選自由1)雙醋瑞因(diacerein)、2)大黃酸(rhein)、3)單乙醯基大黃酸及4)其醫藥學上可接受之鹽組成之群的化合物及視需要一種降尿酸鹽治療劑之用途，其用於製造治療高尿酸血症或與高尿酸血症有關之新陳代謝疾病的藥物，該與高尿酸血症有關之新陳代謝疾病係選自由以下組成之群：急性痛風、慢性痛風、痛風發作、尿酸性腎石病及痛風性腎病，且其中該藥物降低血中的尿酸含量。
- 如請求項1之用途，其中該化合物之治療有效量等同於每日10毫克至200毫克雙醋瑞因鹼型。
- 如請求項1之用途，其中該化合物為單乙醯基大黃酸或大黃酸。
- 如請求項1之用途，其中該用途進一步減少由高尿酸血症誘發之痛風性關節炎及痛風發作的發炎效應；及/或溶解腎結石；及/或降低由高尿酸血症誘發之急性發炎性關節炎的復發率；及/或預防復發性高尿酸血症；及/或減緩尿酸鹽腎病變之進展。
- 如請求項1之用途，其中該藥物進一步包含至少一種選自由抗發炎劑及降尿酸鹽治療劑組成之群的其他治療劑。
- 一種選自由1)雙醋瑞因、2)大黃酸、3)單乙醯基大黃酸及4)其醫藥學上可接受之鹽組成之群的化合物及視需要一種降尿酸鹽治療劑之用途，其用於製造在痛風及高尿 酸血症之治療中改善血中尿酸含量之藥物，其中該藥物降低血尿酸含量。
- 如請求項6之用途，其中該化合物之治療有效量等同於每日10毫克至200毫克雙醋瑞因鹼型。
- 如請求項6之用途，其中該化合物為單乙醯基大黃酸或大黃酸。
- 一種降尿酸鹽治療劑及選自由1)雙醋瑞因、2)大黃酸、3)單乙醯基大黃酸及4)其醫藥學上可接受之鹽組成之群的化合物之用途，其用於製造治療高尿酸血症或與高尿酸血症有關之新陳代謝疾病的藥物，該藥物調配為供同時或依序投與，該與高尿酸血症有關之新陳代謝疾病係選自由以下組成之群：急性痛風、慢性痛風、痛風發作、尿酸性腎石病及痛風性腎病，且其中該藥物降低血尿酸含量。
- 如請求項9之用途，其中該化合物之該治療有效量等同於每日10毫克至200毫克雙醋瑞因鹼型。
- 如請求項9之用途，其中該降尿酸鹽劑係選自由以下組成之群：黃嘌呤氧化酶抑制劑、排尿酸劑、尿酸鹽氧化酶、尿鹼化劑及非諾貝特(fenofibrate)。
- 如請求項9之用途，其中該藥物進一步包含抗發炎劑，其係選自由以下組成之群：非類固醇抗發炎藥(NSAID)、皮質類固醇(corticosteroid)、秋水仙鹼(colchicine)及其組合。
- 如請求項9之用途，其中該用途進一步減少由高尿酸血 症誘發之痛風性關節炎及痛風發作的發炎效應；及/或溶解腎結石；及/或降低由高尿酸血症誘發之急性發炎性關節炎的復發率；及/或預防復發性高尿酸血症；及/或減緩尿酸鹽腎病變之進展。
- 一種選自由1)雙醋瑞因、2)大黃酸、3)單乙醯基大黃酸及4)其醫藥學上可接受之鹽組成之群的化合物及視需要一種降尿酸鹽劑之用途，其用於製造治療高尿酸血症或與高尿酸血症有關之新陳代謝疾病的藥物，其中該與高尿酸血症有關之新陳代謝疾病係選自由以下組成之群：急性痛風、慢性痛風、痛風發作、尿酸性腎石病及痛風性腎病，其中該藥物降低對選自由抗發炎劑及降尿酸鹽劑的治療劑具有不良耐受性之患者族群中的血尿酸含量。
- 如請求項14之用途，其中該用途進一步減少該患者中由高尿酸血症誘發之痛風性關節炎及痛風發作的發炎效應；及/或溶解腎結石；及/或降低由高尿酸血症誘發之急性發炎性關節炎的復發率；及/或預防復發性高尿酸血症；及/或減緩尿酸鹽腎病變之進展。
- 如請求項14之用途，其中該化合物之治療有效量等同於每日10毫克至200毫克雙醋瑞因鹼型。
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| AU2011237600B2 (en) * | 2010-04-08 | 2016-06-23 | Twi Biotechnology, Inc. | Methods of using diacerein as an adjunctive therapy for diabetes |
| PT2683372T (pt) | 2011-03-11 | 2017-10-25 | Twi Biotechnology Inc | Métodos e composições para o tratamento da hiperuricemia e distúrbios metabólicos associados com a hiperuricemia |
| CN103638020A (zh) * | 2013-12-20 | 2014-03-19 | 中美华世通生物医药科技（武汉）有限公司 | 一种治疗痛风的新型药物组合物 |
| CN104491839B (zh) * | 2014-11-27 | 2016-06-22 | 青岛大学附属医院 | 丝氨酸蛋白酶抑制剂b3用于治疗痛风性肾病的用途 |
| KR101647348B1 (ko) * | 2014-12-30 | 2016-08-22 | 충남대학교산학협력단 | Shp를 유효성분으로 하는 통풍 예방 및 치료용 조성물 |
| US20160303050A1 (en) * | 2015-04-20 | 2016-10-20 | Twi Biotechnology, Inc. | Formulations containing diacerein and methods of lowering blood levels of uric acid using the same |
| MX2017013489A (es) * | 2015-04-20 | 2018-05-22 | Twi Biotechnology Inc | Formulaciones que contienen diacereina y metodos para la reduccion de los niveles en sangre de acido urico usando los mismos. |
| TWI684465B (zh) * | 2015-04-22 | 2020-02-11 | 安成生物科技股份有限公司 | 含雙醋瑞因之製劑及使用其於降低尿酸血中濃度的方法 |
| US9744131B2 (en) | 2015-07-01 | 2017-08-29 | Twi Biotechnology, Inc. | Diacerein or rhein topical formulations and uses thereof |
| BR112018003212A2 (pt) * | 2015-08-17 | 2018-09-25 | Twi Biotechnology Inc | diacereína ou seus análogos para inibir a expressão de asc, expressão de nlrp3 e / ou formação de complexo inflamassoma nlrp3 |
| KR101863604B1 (ko) | 2016-04-08 | 2018-06-04 | 한국 한의학 연구원 | 익지 추출물을 유효성분으로 함유하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 예방, 개선 또는 치료용 조성물 |
| TW201739448A (zh) * | 2016-05-06 | 2017-11-16 | 安成生物科技股份有限公司 | 用於治療及/或預防血液相關疾病之方法及配方 |
| CN107468955B (zh) * | 2017-09-06 | 2020-07-24 | 大连医科大学 | 治疗痛风性关节炎的中药及制备方法 |
| KR102361526B1 (ko) * | 2019-07-02 | 2022-02-11 | 한국 한의학 연구원 | 난각막을 유효성분으로 함유하는 고요산혈증 또는 고요산혈증 관련 대사 장애의 예방, 개선 또는 치료용 조성물 |
| CN113082012A (zh) * | 2021-04-26 | 2021-07-09 | 北京亿药科技有限公司 | 紫苏烯在制备预防和/或治疗高尿酸血症药物中的应用 |
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| KR20140019795A (ko) | 2014-02-17 |
| TW201249432A (en) | 2012-12-16 |
| AU2012229443B2 (en) | 2017-03-02 |
| KR101567885B1 (ko) | 2015-11-10 |
| EP2683372A1 (en) | 2014-01-15 |
| US8865689B2 (en) | 2014-10-21 |
| AU2012229443A1 (en) | 2013-09-12 |
| RU2603050C2 (ru) | 2016-11-20 |
| PT2683372T (pt) | 2017-10-25 |
| EP2683372B1 (en) | 2017-07-12 |
| WO2012125359A1 (en) | 2012-09-20 |
| CN103429236B (zh) | 2016-09-21 |
| MX350666B (es) | 2017-09-12 |
| NZ614486A (en) | 2014-11-28 |
| MX2013010384A (es) | 2013-10-07 |
| IL228030B (en) | 2018-01-31 |
| JP2014507476A (ja) | 2014-03-27 |
| IL228030A0 (en) | 2013-09-30 |
| US20120232044A1 (en) | 2012-09-13 |
| RU2013145498A (ru) | 2015-04-20 |
| BR112013022332A2 (pt) | 2017-05-30 |
| AR085662A1 (es) | 2013-10-16 |
| CA2829101A1 (en) | 2012-09-20 |
| CN103429236A (zh) | 2013-12-04 |
| ES2634562T3 (es) | 2017-09-28 |
| CA2829101C (en) | 2019-08-20 |
| EP2683372A4 (en) | 2014-08-06 |
| JP6012639B2 (ja) | 2016-10-25 |
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