Immunosuppressant formulations

Abstract

The present invention relates to a solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“API”) which is a compound of formula A1 or A2 or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein the API is not exposed to a basic compound.

1 . A solid phase pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and an active pharmaceutical ingredient (“API”) which is a compound of formula A1 or A2 or a pharmacologically acceptable salt, solvate or hydrate thereof, wherein the API is not exposed to a basic compound: 
       
         
           
           
               
               
           
         
       
       wherein
 A is COOR 5 , OPO(OR 5 ) 2 , PO(OR 5 ) 2 , SO 2 OR 5 , POR 5 OR 5  or 1H-tetrazol-5-yl, R 5  being H or an ester-forming group; 
 W is a bond, C 1-3 alkylene or C 2-3 alkenylene; 
 Y is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by 1 to 3 radicals selected from halogen, NO 2 , C 1-6 alkyl, C 1-6 alkoxy; halo-substituted C 1-6 alkyl and halo-substituted 
 C 1-6 alkoxy; 
 Z is chosen from: 
 
       
         
           
           
               
               
           
         
       
       wherein the asterisks of Z indicate the point of attachment between —C(R 3 )(R 4 )— and A of Formula Ia or Ib, respectively; R 6  is chosen from hydrogen and C 1-6 alkyl; and J 1  and J 2  are independently methylene or a heteroatom chosen from S, O and NR 5 ; wherein R 5  is chosen from hydrogen and C 1-6 alkyl; and any alkylene of Z can be further substituted by one to three radicals chosen from halo, hydroxy, C 1-6 alkyl; or R 6  can be attached to a carbon atom of Y to form a 5-7 member ring;
 R 1  is C 6-10 aryl or C 3-9 heteroaryl, optionally substituted by C 1-6 alkyl, C 6-10 aryl, C 6-10 arylC 1-4 alkyl, C 3-9 heteroaryl, C 3-9 heteroarylC 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkylC 1-4 alkyl, C 3-8 heterocycloalkyl or C 3-8 heterocycloalkylC 1-4 alkyl; wherein any aryl, heteroaryl, cycloalkyl or heterocycloalkyl of R 1  may be substituted by 1 to 5 groups selected from halogen, C 1-6 alkyl, C 1-6 alkoxy and halo substituted-C 1-6 alkyl or -C 1-6 alkoxy; 
 R 2  is H, C 1-6 alkyl, halo substituted C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl; and 
 each of R 3  or R 4 , independently, is H, halogen, OH, C 1-6 alkyl, C 1-6 alkoxy or halo substituted C 1-6 alkyl or C 1-6 alkoxy. 
 
     
     
         2 . A composition according to  claim 1  wherein A is COOH. 
     
     
         3 . A composition according to  claim 1  wherein the API is 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid or a pharmaceutically acceptable salt. 
     
     
         4 . A composition according to  claim 1  wherein the API is 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid or a hemifumarate salt thereof. 
     
     
         5 . A composition according to  claim 3  wherein the API is in a mixture of materials which is free of basic compounds. 
     
     
         6 . A solid phase pharmaceutical composition according to  claim 3 , wherein the API is in the form of particles having an X90 diameter of at least 8 μm. 
     
     
         7 . A composition according to  claim 6  wherein the particles have an X90 diameter of from 10 μm to 300 μm. 
     
     
         8 . A composition  claim 6  which is in unit dosage form and complies with the US Pharmacopeia, European Pharmacopeia and Japanese Pharmacopeia harmonised content uniformity requirements as in force on 1 Jan. 2011. 
     
     
         9 . A solid phase pharmaceutical composition according to  claim 3 , wherein the API has a crystallinity of 80% or more. 
     
     
         10 . A tablet comprising a compressed mixture consisting of 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid or a pharmaceutically acceptable salt thereof and one or more non-basic excipients, the 1-{4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid or pharmaceutically acceptable salt being in the form of particles having an X90 diameter of from 10 μm to 200 μm. 
     
     
         11 . A tablet according to  claim 10 , wherein the pharmaceutically acceptable salt is a hemifumarate salt. 
     
     
         12 . A tablet according to  claim 10 , wherein said particles are at least 80% crystalline. 
     
     
         13 . A tablet according to  claim 10 , wherein the compressed mixture includes a desiccant and is coated with a moisture barrier.