Optimized synthesis of pure, non-polymorphic, crystalline bile acids with defined particle size
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/575
C07J-009/00
C07J-007/00
출원번호
US-0989012
(2011-11-30)
등록번호
US-9512167
(2016-12-06)
우선권정보
EP-10193143 (2010-11-30)
국제출원번호
PCT/EP2011/071406
(2011-11-30)
§371/§102 date
20130806
(20130806)
국제공개번호
WO2012/072689
(2012-06-07)
발명자
/ 주소
Wilhelm, Rudolf
Proels, Markus
Fischer, Erik
Waenerlund Poulsen, Heidi
출원인 / 주소
Dr. Falk Pharma GmbH
대리인 / 주소
Curatolo Sidoti Co., LPA
인용정보
피인용 횟수 :
0인용 특허 :
1
초록▼
The present invention relates to a pure polymorph of Nor-UDCA or Bis-nor-UDCA, or of a pharmaceutically acceptable salt thereof. The invention further provides a pharmaceutical composition comprising the polymorph of the invention, and a method for preparing the polymorph. The invention includes the
The present invention relates to a pure polymorph of Nor-UDCA or Bis-nor-UDCA, or of a pharmaceutically acceptable salt thereof. The invention further provides a pharmaceutical composition comprising the polymorph of the invention, and a method for preparing the polymorph. The invention includes the pharmaceutical use of the polymorph or of the pharmaceutical composition of the invention.
대표청구항▼
1. A chemically pure polymorph of Nor-UDCA or of a pharmaceutically acceptable salt thereof, wherein the total amount of chemical impurities is less than 0.5%, at least 60% of the polymorph particles have a size <10 μm, and wherein said polymorph contains substantially no detectable amorphous Nor-UD
1. A chemically pure polymorph of Nor-UDCA or of a pharmaceutically acceptable salt thereof, wherein the total amount of chemical impurities is less than 0.5%, at least 60% of the polymorph particles have a size <10 μm, and wherein said polymorph contains substantially no detectable amorphous Nor-UDCA. 2. The polymorph of claim 1, wherein the total amount of chemical impurities is less than 0.1%. 3. The polymorph of claim 2, wherein the total amount of chemical impurities is less than 0.05%. 4. The polymorph of claim 1, wherein said Nor-UDCA or pharmaceutically acceptable salt thereof is in its anhydrous form. 5. The polymorph of claim 1, containing no amorphous Nor-UDCA detectable by x-ray powder diffraction. 6. The polymorph of claim 5, containing no amorphous Nor-UDCA. 7. The polymorph of claim 1, having a volume-weighted average particle diameter D50 of less than 10 μm. 8. The polymorph of claim 1, having a volume-weighted average particle diameter D95 of less than 30 μm. 9. A pharmaceutical composition comprising the polymorph according to claim 1. 10. The pharmaceutical composition according to claim 9, which is formulated for oral, parenteral, subcutaneous, intravenous, intramuscular, nasal, topical or rectal administration. 11. The pharmaceutical composition according to claim 9, comprising one or more pharmaceutically acceptable excipients. 12. A method of treating cholestatic liver disease, non-alcoholic steato-hepatitis, alcoholic steato-hepatitis and arteriosclerosis by administering to a subject a pharmaceutical composition comprising a chemically pure polymorph of Nor-UDCA or of a pharmaceutically acceptable salt thereof, wherein the total amount of chemical impurities is less than 0.5%, at least 60% of the polymorph particles have a size <10 μm, and wherein said polymorph contains substantially no detectable amorphous Nor-UDCA. 13. The method of claim 12, wherein the cholestatic liver disease is selected from the group consisting of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH). 14. The method of claim 12, wherein said treating comprises treating arteriosclerosis. 15. The method of claim 12, wherein said treating comprises treating non-alcoholic steato-hepatitis. 16. The method of claim 12, wherein said treating comprises treating alcoholic steato-hepatitis. 17. A method for the preparation of a pure polymorph of Nor-UDCA or of a pharmaceutically acceptable salt thereof containing substantially no detectable amorphous Nor-UDCA, comprising: crystallizing the potassium salt of Nor-UDCA; andoptionally dissolving the potassium salt in a solvent and acidifying the solution to obtain pure Nor-UDCA. 18. The method of claim 17, wherein said solvent is a mixture of water and acetone, and wherein said precipitation is carried out by acidifying the solution to have a pH in the range of 1 to 2. 19. The method of claim 17, further comprising: (a) converting a compound of formula (A) into a compound of formula (B) (b) converting the compound of formula (B) into a compound of formula (C) (c) converting the compound of formula (C) into a compound of formula (D) in crude form and (d) treating the compound of formula (D) in crude form with KOH under conditions to crystallize the potassium salt of Nor-UDCA;wherein n is 1. 20. The method of claim 17, characterized in that it does not comprise a milling step and/or a micronization step.
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이 특허에 인용된 특허 (1)
Enhsen Alfons (Bttelborn DEX) Glombik Heiner (Hofheim DEX) Kramer Werner (Mainz DEX) Wess Gnther (Erlensee DEX), Nor-bile acid derivatives, processes for their preparation and the use of these compounds as medicaments.
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