Pharmaceutical composition comprising cyclic somatostatin analogues

Abstract

The present invention describes parenteral pharmaceutical compositions comprising a somatostatin analogue and novel somatostatin analogues.

1 . A pharmaceutical composition for parenteral administration comprising a somatostatin analogue comprising the amino acid sequence of formula I  
       -(D/L)Trp-LYs-X 1 -X 2 -  I  wherein X 1  is a radical of formula (a) or (b)                          wherein R 1  is optionally substituted phenyl,    R 2  is -Z 1 -CH 2 —R 1 , —CH 2 —CO—O—CH 2 R 1 ,                          wherein Z 1  is O or S, and    X 2  is an α-amino acid having an aromatic residue on the C α  side chain, or an amino acid unit selected from Dab, Dpr, Dpm, His,(Bzl)HyPro, thienyl-Ala, cyclohexyl-Ala and t-butyl-Ala, the residue Lys of said sequence corresponding to the residue Lys 9  of the native somatostatin-14    in free form, salt form, or protected form and tartaric acid.    
   
   
       2 . A composition according to  claim 1  wherein the somatostatin analogue is a compound of formula II  
     
       
         
         
             
             
         
       
       wherein the configuration at C-2 is (R) or (S) or a mixture thereof, and  
       wherein R is NR 1 R 2 —C 2-6 alkylene or guanidine-C 2-6 alkylene, and each of R 1  and R 2  independently is H or C 1-4 alkyl,  
       in free form, salt form or protected form.  
     
   
   
       3 . A composition according to  claim 1  wherein the compound of the somatostatin analogue is in aspartate di-salt form.  
   
   
       4 . A composition according to  claim 1  wherein the composition is adjusted to a pH of about 4 to about 4.5.  
   
   
       5 . A composition for parenteral administration buffered at a pH of about 4 to about 4.5 and comprising as active ingredient cyclo[{4-(NH 2 —C 2 H 4 —NH—CO—O—)Pro}-Phg-DTrp-Lys-Tyr(4-Bzl)-Phe] or a pharmaceutically acceptable salt thereof.  
   
   
       6 . A composition according to  claim 5  wherein the composition is buffered by an acetate/acetic acid, lactate/lactic acid, or Glycin/HCl buffer.  
   
   
       7 . Use of a pharmaceutical composition according to  claim 1  for the preparation of a medicament for acromegaly or cancer.  
   
   
       8 . Use according to  claim 6  for the preparation of a medicament for Cushing's Disease.  
   
   
       9 . A method of treating acromegaly or cancer in a subject in need thereof which comprises administering a pharmaceutical composition according to  claim 1  to the subject.  
   
   
       10 . A compound of formula III  
     
       
         
         
             
             
         
       
       wherein R is NR 1 R 2 —C 2-6 alkylene or guanidine-C 2-6 alkylene, and  
       each of R 1  and R 2  independently is H or C 1-4 alkyl,  
       in free form, in salt form or complex form, or in protected form, e.g. cyclo[{4-(NH 2 —C 2 H 4 —NH—CO—O—)Pro}-DPhg-DTrp-Lys-Tyr(4-Bzl)-Phe].