Sustained release of microcrystalline peptide suspensions

Abstract

The invention relates to a microcrystalline aqueous suspension of a peptide salt selected from the group consisting of Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 trifluoroacetate and Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 sulfate. The invention also relates to methods of preparing the suspension, lyophilized compositions formed from the suspensions, and sustained release formulations that include the suspensions.

1 . A microcrystalline aqueous suspension of a peptide salt selected from the group consisting of Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 trifluoroacetate and Ac—D—Nal—D—pa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 sulfate.  
   
   
       2 . The suspension of  claim 1 , wherein the peptide salt is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 trifluoroacetate.  
   
   
       3 . The suspension of  claim 1 , wherein the peptide salt is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 sulfate.  
   
   
       4 . The suspension of  claim 1 , wherein the peptide salt is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—ProD—Ala—NH 2  trifluoroacetate and is suspended in an aqueous medium at a concentration of equal to or greater than 25 mg/mL.  
   
   
       5 . The suspension of  claim 4 , further comprising an isotonic agent.  
   
   
       6 . The suspension of  claim 5 , wherein the isotonic agent is mannitol.  
   
   
       7 . The suspension of  claim 1 , wherein the peptide salt is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2  sulfate and is suspended in an aqueous medium at a concentration of equal to or greater than 25 mg/mL.  
   
   
       8 . The suspension of  claim 7 , further comprising an isotonic agent.  
   
   
       9 . The suspension of  claim 8 , wherein the isotonic agent is mannitol.  
   
   
       10 . The suspension of  claim 1 , further comprising a pharmaceutically acceptable excipient.  
   
   
       11 . The suspension of  claim 1 , wherein the peptide salt is at least partially in the form of microcrystals in the form of needles having a particle size of from about 1 μm to 150 μm.  
   
   
       12 . A method of preparing the suspension of  claim 1  which comprises, associating the peptide with a counter-ion in an amount and at a molar ratio that are sufficient to provide a fluid, milky microcrystalline aqueous suspension comprising the peptide salt without formation of a gel.  
   
   
       13 . The method of  claim 12 , wherein the counter ion is a trifluoroacetate and the peptide salt that is formed is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 trifluoroacetate.  
   
   
       14 . The method of  claim 12 , wherein the counter ion is a sulfate and the peptide salt that is formed is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 sulfate.  
   
   
       15 . The method of  claim 12  which further comprises, lyophilizing the suspension of  claim 1  to prepare a lyophilized composition.  
   
   
       16 . A lyophilized composition comprising a dried suspension obtained by the method of  claim 15 .  
   
   
       17 . A method of preparing a microcrystalline aqueous suspension which comprises adding water or buffer with mixing to the lyophilized composition of  claim 16 .  
   
   
       18 . A sustained release formulation comprising the suspension of  claim 1  which, when administered to a subject, releases the peptide salt in vivo over a period of at least two weeks.  
   
   
       19 . The formulation of  claim 18 , wherein the peptide salt is Ac—D—Nal—D—pa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH2trifluoroacetate.  
   
   
       20 . The formulation of  claim 18 , wherein the peptide salt is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2  sulfate.  
   
   
       21 . The suspension of  claim 1 , wherein the suspension is a fluid, milky microcrystalline aqueous suspension.  
   
   
       22 . A lyophilized composition formed from a lyophilized suspension, which comprises the suspension of  claim 21 , wherein the peptide salt is Ac—D—Nal—D—Cpa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH2trifluoroacetate, and the suspension further comprises an isotonic agent.  
   
   
       23 . A method of preparing a fluid, milky microcrystalline aqueous suspension of Ac—D—Nal—D—pa—D—Pal—Ser—Tyr—D—Hci—Leu—Ilys—Pro—D—Ala—NH 2 trifluoroacetate comprising, adding water or buffer with mixing to the lyophilized composition of  claim 22.