TWI293290B - - Google Patents
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- TWI293290B TWI293290B TW090126305A TW90126305A TWI293290B TW I293290 B TWI293290 B TW I293290B TW 090126305 A TW090126305 A TW 090126305A TW 90126305 A TW90126305 A TW 90126305A TW I293290 B TWI293290 B TW I293290B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Description
1293290 Α7 Β7 五、發明説明(1 ) 【發明背景】 本發明係有關爲糖尿病藥有用之拿貼利〔化合物名: N -(反式一 4 -異丙基環己烷羰基)一 D -苯基丙氨酸 〕之製造方法。更詳細爲,本發明係有關實質上不含有Η 型.結晶的拿貼利Β型結晶之製造方法。 拿貼利爲,藉由經口投與顯示有良好的降血糖作用, 爲糖尿病治療藥有用而被得知(特公平4 - 1 5 2 2 1號 公報)。 又,拿貼利具有多形結晶,其中Η型結晶因有用而被 得知。惟,爲離析Η型結晶,必須嚴密控制晶析條件,小 心進行晶析,有晶析操作困難的問題(參照特許第 2508949號公報)。 一方面,其他多形結晶之一的Β型結晶,藉由於晶析 時進行冷卻晶析,有容易製造的優點。惟,此Β型結晶於 製造階段有可能轉移成Η型結晶,事實上,以拿貼利的工 業規模進行製造時,判明所取得之Β型結晶中混入了 η型 結晶。爲醫藥品使用的拿貼利’理想爲儘可能避免多形結 晶的混入,因如果可能只以單一結晶形爲最佳,因此期待 開發出可提供只含有其Β型結晶之醫藥製劑,不混入結晶 多形的拿貼利Β型結晶之製造方法。 【發明開示】 本發明係提供無混入其他結晶形的Β型拿貼利結晶於 工業上之製造方法爲目的。 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) 1-----!1#! (請先閲讀背面之注意事項再填寫本頁) 、11 經濟部智慧財產局員工消費合作社印製 -4、 1293290 A7 __ B7 五、發明説明(2) 本發明者等以有效利用拿貼利B型結晶爲目的進行硏 究’藉由選擇於拿貼利的製造階段之條件,發現單一結晶 形的拿貼利B型結晶可以工業規模製造,進而完成本發明 〇 亦即,本發明係提供包含拿貼利的溶媒合物濕潤結晶 於低溫下乾燥至溶媒消失後,使結晶轉移,實質上不含有 Η型結晶的拿貼利B型結晶之製造方法。 本發明之理想係提供包含自含有拿貼利的溶液中,藉 由冷卻晶析,析出取得拿貼利水合物之溶媒合物,於溫度 5 0 °C以下,乾燥至溶媒消失,並且實質上溶媒合物不存 在後,包含加熱至6 0〜1 1 0 °C使結晶轉移至B型結晶 ,實質上不含有Η型結晶的拿貼利B型結晶之製造方法。 【爲實施發明之最佳形態】 使用於本發明之拿貼利的溶媒合物的濕潤結晶爲,甲 醇,乙醇或異丙醇等乙醇類,乙酸甲酯或乙酸乙酯等乙酸 酯類,或水的溶媒合物可被列舉出。拿貼利的溶媒合物的 濕潤結晶通常使甩乙醇混合物及水合物等。乙醇混合物的 場合,例如藉由使拿貼利的濃度成爲5重量%,加入至 6 0 %的乙醇水中,於3 0 °C左右溶解後,使此冷卻至 1 0 °C以下,即可進行調製。 其中,因水合物爲於拿貼利的乙醇溶液,理想爲乙醇 溶液中加入水,冷卻至1 〇 °C以下析出結晶,藉由分離此 而容易取得,因此較理想。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) I-----— If, (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -5- 1293290 A7 B7 五、發明説明(3) 將所取得之溶媒合物的濕潤結晶乾燥至溶媒消失。此 時的溫度雖因附著於結晶上之溶媒種類及量而有所不同, 通常爲6 0 °C以下,理想爲5 0 °C以下。最低溫度雖無特 別指示,但從經濟的觀點看來,通常在2 0 °C以上進行。 乾燥通常於減壓下進行較理想,於工業上儘可能提高減壓 度,較能於短時間內完成乾燥。 於低溫之乾燥,實質上雖持續至溶媒消失,但並不需 至完全消失,即使殘存5重量%左右的溶媒,於結晶轉移 時也會消失,因此不會有問題。 所取得之乾燥結晶,藉由加熱至6 0〜1 1 0 °C,理 想爲7 0〜1 0 0 °C,使其轉移成B型結晶。結晶轉移通 常之理想爲進行0 · 5〜4 8小時,更理想爲1〜2 4小 .時。 B型結晶中的Η型結晶可藉由使用D S C分析。拿貼 利Β型結晶爲,以D S C測定時,Η型結晶爲不被檢測出 者較理想。 乾燥濕潤狀態的拿貼利溶媒合物結晶時,於實驗室規 模的小規模的場合,因分離結晶時的殘存溶媒量少,且又 達到乾燥器之最高減壓的速度快,於最初階段提高乾燥溫 度並無太大問題,但以工業規模,例如一次製造相當於5 k g以上的情況下,自晶析液中所分離出之結晶中所殘存 的溶媒量多,且又因乾燥時達到最高減壓度的時間相較之 下需時較長,藉由本發明之方法,可製造出不含有Η型結 晶之Β型結晶。 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) I-----丨丨丨参丨— (請先閲讀背面之注意事項再填寫本頁) 、1Τ 經濟部智慧財產局員工消費合作社印製 -6 - 1293290 A7 B7 五、發明説明(4) 以下,藉由實施例,進行本發明更具體之說明,惟本 發明並不被限定於此實施例。 實施例1 將拿貼利Η型結晶2 4 . 5 k g加入至乙醇3 6 0 L 中,於室溫下攪拌使其溶解。於此中加入水2 4 0 L,確 認溶解後冷卻至5 °C,更於5 t下使其熟成1小時。分離 所析出之結晶,得到濕結晶4.3 . 0 k g。使此於盤式乾 燥器中,以4 5 °C,乾燥2 4小時(水份含量約1 w t % ),更以9 0 °C加熱1 2小時使結晶轉移,得到乾燥結晶 1 3 · 3 k g。測定此結晶的D S C,因檢測出B型結晶 特有的峰値(熔點約1 3 0 °C ),但無檢測出Η型結晶特 有的峰値(熔點約1 3 9 °C ),得到所取得之結晶只有Β 型結晶,實質上不含有Η型結晶之結論。 比較例1 將拿貼利Η型結晶3 7 . 0 k g加入至乙醇5 4 0 L 中,於室溫下攪拌使其溶解。於此中加入水3 6 0 L,確 認溶解後冷卻至5 °C,更於5 °C下使其熟成1小時。分離 所析出之結晶’得到濕結晶4 6 · 7 k g。使此於錐形乾 燥器中,以3 〇 °C,乾燥3小時(水份含量約1 〇 w t % ),更以9 0 °C加熱1 2小時使結晶轉移,得到乾燥結晶 2 5 . 9 k g。測定此結晶的D S C,除B型結晶之外, 也觀察到Η型結晶的峰値。 本紙張尺度適财關家鮮(CNS ) Α4· ( 21GX297公釐)~' ' I-----111#! (請先閱讀背面之注意事項再填寫本頁) 、1Τ 經濟部智慧財產局員工消費合作社印製 -7 - 1293290 - A7 _—_ B7 ___ 五、發明説明(5) 比較例2 將拿貼利Η型結晶3 7 , 0 k g加入至乙醇5 4 0 L 中,於室溫下攪拌使其溶解。於此中加入水3 6 0 L,確 認溶解後冷卻至5 °C,更於5 °C下使其熟成1小時。分離 所析出之結晶,得到濕結晶4 4 · 5 k g。使此於錐形乾 燥器中,以3 0 °C,乾燥3小時(水份含量約1 0 w t % ),更以9 0 °C加熱15小時使結晶轉移,得到乾燥6型 結晶2 6 · 6 k g。測定此結晶的D S C,除B型結晶之 外,也觀察到Η型結晶的峰値。 藉由使用本發明之條件,可以工業規模製造出不存在 其他結晶形的拿貼利Β型結晶,可提供拿貼利Β型結晶爲 單一拿貼利結晶含有之便宜的醫藥製劑。 ΙΊ---------- (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 率 標 家 國 國 i中 一用 適 釐 π 9 2
Claims (1)
- A8 B8 C8 D8 1293290 六、申[範爆ϋ 第901 26305號專利申請案 中文申請專利範圍修正本 (請先閲·«背面之注意事項再填寫本頁) 民國96年2月14日修正 1 · 一種拿貼利Β型結晶之製造方法,其爲包含將拿 貼利的溶媒合物濕潤結晶於2 0〜6 0 t的低溫下乾燥至 溶媒爲5 w t %以下後,藉由於6 0〜1 1 〇 t:加熱使結 晶轉移至B型結晶者。 2 ·如申請專利範圍第1項之拿貼利B型結晶之製造 方法,其中該溶媒合物濕潤結晶爲水合物。 3 ·如申請專利範圍第1項之拿貼利B型結晶之製造 方法,其中拿貼利溶媒合物濕潤結晶的低溫乾燥與結晶轉 移的兩步驟爲以工業規模進行之步驟。 4 . 一種拿貼利B型結晶之製造方法,其係包含自含 有拿貼利的溶液中,藉由冷卻晶析,析出取得拿貼利水合 物之溶媒合物,於2 0〜6 0 °C的溫度以下,乾燥至溶媒 爲5 w t %以下,於6 0〜1 1 0 °C加熱使結晶轉移至B 型結晶者。 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)-1 -
Applications Claiming Priority (1)
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JP2000324375 | 2000-10-24 |
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TWI293290B true TWI293290B (zh) | 2008-02-11 |
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TW090126305A TWI293290B (zh) | 2000-10-24 | 2001-10-24 |
Country Status (18)
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US (2) | US20030229249A1 (zh) |
EP (1) | EP1334964B1 (zh) |
JP (1) | JP4225057B2 (zh) |
KR (1) | KR100810930B1 (zh) |
CN (1) | CN100422143C (zh) |
AT (1) | ATE370115T1 (zh) |
AU (1) | AU2001296001A1 (zh) |
BR (1) | BR0114846A (zh) |
CA (1) | CA2426745C (zh) |
CY (1) | CY1106839T1 (zh) |
DE (1) | DE60130014T2 (zh) |
DK (1) | DK1334964T3 (zh) |
ES (1) | ES2288997T3 (zh) |
MX (1) | MXPA03003575A (zh) |
PT (1) | PT1334964E (zh) |
RU (1) | RU2275354C2 (zh) |
TW (1) | TWI293290B (zh) |
WO (1) | WO2002034713A1 (zh) |
Families Citing this family (73)
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AU2001241168B2 (en) * | 2000-03-17 | 2005-06-16 | Ajinomoto Co., Inc. | Drugs for complications of diabetes and neuropathy and utilization thereof |
KR100783306B1 (ko) * | 2000-10-18 | 2007-12-10 | 아지노모토 가부시키가이샤 | 아실페닐알라닌의 제조방법 |
CN1232502C (zh) * | 2000-10-18 | 2005-12-21 | 味之素株式会社 | 那格列胺结晶的制备方法 |
MXPA03003685A (es) * | 2000-10-24 | 2004-01-26 | Ajinomoto Kk | Preparaciones que contienen nateglinida. |
KR100829410B1 (ko) * | 2000-10-24 | 2008-05-15 | 아지노모토 가부시키가이샤 | 나테글리니드 함유 친수성 의약 제제 |
WO2003087039A1 (fr) * | 2002-04-15 | 2003-10-23 | Ajinomoto Co., Inc. | Nouveau cristal de nateglinide |
US7411089B2 (en) | 2002-04-15 | 2008-08-12 | Ajinomoto Co., Inc. | Nateglinide crystals |
US6861553B2 (en) | 2002-07-03 | 2005-03-01 | Teva Pharmaceuticals Industries Ltd. | Process for preparing nateglinide and intermediates thereof |
US7534913B2 (en) | 2002-07-18 | 2009-05-19 | Teva Pharmaceutica Industries Ltd. | Crystalline form of nateglinide |
CA2492644A1 (en) * | 2002-07-18 | 2004-01-29 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of nateglinide |
US7358390B2 (en) | 2002-07-18 | 2008-04-15 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of nateglinide |
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CA2563793A1 (en) * | 2004-05-07 | 2005-11-24 | Teva Pharmaceutical Industries Ltd. | Polymorphic forms of nateglinide |
WO2005110395A1 (en) * | 2004-05-19 | 2005-11-24 | University Of South Carolina | System and device for magnetic drug targeting with magnetic drug carrier particles |
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US7425648B2 (en) | 2005-01-03 | 2008-09-16 | A.M.S.A. Anonima Materie Sintetiche E. Affini S.P.A. | Process for the preparation of nateglinide, preferably in B-form |
WO2006080524A1 (ja) * | 2005-01-31 | 2006-08-03 | Ajinomoto Co., Inc. | 血糖降下剤を含有する、耐糖能異常、境界型糖尿病、インスリン抵抗性及び高インスリン血症の改善ないし治療用医薬組成物 |
WO2007135533A1 (en) * | 2006-05-23 | 2007-11-29 | Aurobindo Pharma Limited | Process for preparing nateglinide b-type crystals |
KR100837843B1 (ko) * | 2006-12-26 | 2008-06-13 | 씨제이제일제당 (주) | 나테글리나이드 결정형, 그 제조방법, 및 그를 포함하는약제학적 조성물 |
US9150499B2 (en) | 2010-06-14 | 2015-10-06 | Cipla Limited | Process for the preparation of nateglinide |
WO2014037832A2 (en) | 2012-09-06 | 2014-03-13 | Mahesh Kandula | Compositions and methods for the treatment of epilepsy and neurological diseases |
CN104603096A (zh) | 2012-05-07 | 2015-05-06 | 塞利克斯比奥私人有限公司 | 用于治疗神经肌肉障碍和神经退行性疾病的组合物和方法 |
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JPS6354321A (ja) * | 1985-03-27 | 1988-03-08 | Ajinomoto Co Inc | 血糖降下剤 |
JP2508949B2 (ja) * | 1991-07-30 | 1996-06-19 | 味の素株式会社 | N−(トランス−4−イソプロピルシクロヘキシルカルボニル)−d−フェニルアラニンの結晶及びその製造法 |
US5463116A (en) | 1991-07-30 | 1995-10-31 | Ajinomoto Co., Inc. | Crystals of N- (trans-4-isopropylcyclohexlycarbonyl)-D-phenylalanine and methods for preparing them |
EP2277517A1 (en) * | 1996-11-15 | 2011-01-26 | Ajinomoto Co., Inc. | Nateglinide tablet composition |
US6844006B1 (en) * | 1999-07-09 | 2005-01-18 | Pennfield Oil Company | Process and apparatus for the preparation of chlortetracycline-containing animal feed compositions |
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US7411089B2 (en) * | 2002-04-15 | 2008-08-12 | Ajinomoto Co., Inc. | Nateglinide crystals |
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DK1334964T3 (da) | 2007-09-24 |
US20070232829A1 (en) | 2007-10-04 |
ES2288997T3 (es) | 2008-02-01 |
AU2001296001A1 (en) | 2002-05-06 |
PT1334964E (pt) | 2007-09-20 |
CA2426745A1 (en) | 2003-04-23 |
CA2426745C (en) | 2009-09-15 |
ATE370115T1 (de) | 2007-09-15 |
MXPA03003575A (es) | 2003-07-14 |
BR0114846A (pt) | 2004-02-25 |
CY1106839T1 (el) | 2012-05-23 |
CN100422143C (zh) | 2008-10-01 |
EP1334964A1 (en) | 2003-08-13 |
EP1334964A4 (en) | 2005-09-28 |
US20030229249A1 (en) | 2003-12-11 |
RU2275354C2 (ru) | 2006-04-27 |
JPWO2002034713A1 (ja) | 2004-03-04 |
US7544834B2 (en) | 2009-06-09 |
WO2002034713A1 (fr) | 2002-05-02 |
EP1334964B1 (en) | 2007-08-15 |
CN1483018A (zh) | 2004-03-17 |
KR20030059212A (ko) | 2003-07-07 |
JP4225057B2 (ja) | 2009-02-18 |
DE60130014T2 (de) | 2008-05-08 |
KR100810930B1 (ko) | 2008-03-10 |
DE60130014D1 (de) | 2007-09-27 |
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