Sustained release of microcrystalline peptide suspensions

Abstract

The invention relates to a fluid, milky microcrystalline aqueous suspension of a peptide or peptidomimetic and a counter-ion of a strong proton donor in water, wherein the peptide or peptidomimetic and counter-ion are present in amounts and at a molar ratio sufficient to form the suspension upon mixing and without formation of a gel. The invention also relates to lyophilized compositions that include a dried suspension, methods of making the lyophilized composition, methods of preparing the suspension, and sustained release formulations prepared by the methods.

1 . A method of preventing gel formation of a hydrophobic peptide which comprises contacting the hydrophobic peptide with a counter-ion derived from a strong acid in an amount and at a molar ratio sufficient to provide a fluid, milky microcrystalline aqueous suspension of the peptide without formation of a gel. 
     
     
         2 . The method of  claim 1  wherein the counter-ion is derived from trifluoroacetic acid or sulfuric acid. 
     
     
         3 . The method of  claim 1  in which the hydrophobic peptide is a GnRH analogue. 
     
     
         4 . The method of  claim 3  in which the GnRH analogue is a GnRH antagonist. 
     
     
         5 . The method of  claim 4  in which the GnRH antagonist is selected from the groups of Azaline B, Abarelix, Antide, Ganirelix, Cetrorelix, or FE200486 in the form of their trifluoroacetate or sulfate salts. 
     
     
         6 . The method of  claim 4  in which the GnRH antagonist is either Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2  trifluoroacetate or Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2  sulfate. 
     
     
         7 . The method of  claim 1  in which the hydrophobic peptide is a somatostatin analogue. 
     
     
         8 . The method of  claim 1  in which the hydrophobic peptide salt is suspended in the aqueous medium at a concentration of equal to or high than 25 mg/ml. 
     
     
         9 . The method of  claim 1  in which the aqueous suspension contains an isotonic agent. 
     
     
         10 . The method of  claim 9  in which the isotonic agent is mannitol. 
     
     
         11 . The method of  claim 1  in which the aqueous suspension contains a pharmaceutically acceptable excipient. 
     
     
         12 . The method of  claim 1  in which the aqueous suspension is obtained extemporaneously from a lyophilized peptide salt. 
     
     
         13 . A fluid, milky microcrystalline aqueous suspension of a hydrophobic peptide and a counter-ion derived from a strong acid in water, wherein the peptide and counter-ion are present in amounts and at a molar ratio sufficient to form, upon mixing, the suspension without formation of a gel. 
     
     
         14 . The suspension of  claim 13  wherein the counter-ion is derived from trifluoroacetic acid or sulfuric acid. 
     
     
         15 . The suspension of  claim 13  in which the hydrophobic peptide is a GnRH analogue. 
     
     
         16 . The suspension of  claim 15  in which the GnRH analogue is a GnRH antagonist. 
     
     
         17 . The suspension of  claim 16  in which the GnRH antagonist is selected from the groups of Azaline B, Abarelix, Antide, Ganirelix, Cetrorelix, or FE200486 in the form of their trifluoroacetate or sulfate salts. 
     
     
         18 . The suspension of  claim 16  in which the GnRH antagonist is either Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2  trifluoroacetate or Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2  sulfate. 
     
     
         19 . The suspension of  claim 13  in which the hydrophobic peptide is a somatostatin analogue. 
     
     
         20 . The suspension of  claim 13  in which the hydrophobic peptide salt is suspended in the aqueous medium at a concentration of equal to or high than 25 mg/ml. 
     
     
         21 . The suspension of  claim 13  in which the aqueous suspension contains an isotonic agent. 
     
     
         22 . The suspension of  claim 21  in which the isotonic agent is mannitol. 
     
     
         23 . The suspension of  claim 13  in which the aqueous suspension contains a pharmaceutically acceptable excipient. 
     
     
         24 . The suspension of  claim 13  wherein the microcrystals are in the form of needles having a particle size of between about 5 and 150 μm. 
     
     
         25 . A lyophilized composition comprising the dried suspension of  claim 13 . 
     
     
         26 . A method of preparing a lyophilized composition according to  claim 25  which comprises a method as claimed in  claim 1  followed by freeze-drying or spray-drying to obtain the composition. 
     
     
         27 . A method of preparing an injectable fluid, milky, microcrystalline aqueous suspension of a hydrophobic peptide which comprises reconstituting with water or a buffer solution the lyophilized composition of  claim 25 . 
     
     
         28 . A method of preparing a sustained release formulation of a hydrophobic peptide which comprises contacting the hydrophobic peptide with a counter-ion derived from a strong acid, wherein the peptide and counter-ion are present in amounts and at a molar ratio sufficient to form, upon mixing, the suspension without formation of a gel. 
     
     
         29 . The method of  claim 28  wherein the counter-ion is derived from trifluoroacetic acid or sulfuric acid. 
     
     
         30 . The method of  claim 28  in which the hydrophobic peptide is a GnRH analogue. 
     
     
         31 . The method of  claim 30  in which the GnRH analogue is a GnRH antagonist. 
     
     
         32 . The method of  claim 31  in which the GnRH antagonist is selected from the groups of Azaline B, Abarelix, Antide, Ganirelix, Cetrorelix, or FE200486 in the form of their trifluoroacetate or sulfate salts. 
     
     
         33 . The method of  claim 31  in which the GnRH antagonist is either Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-llys-Pro-D-Ala-NH 2  trifluoroacetate or Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-llys-Pro-D-Ala-NH 2  sulfate. 
     
     
         34 . The method of  claim 28  in which the hydrophobic peptide is a somatostatin analogue. 
     
     
         35 . The method of  claim 28  in which the hydrophobic peptide salt is suspended in the aqueous medium at a concentration of equal to or high than 25 mg/ml. 
     
     
         36 . The method of  claim 28  in which the aqueous suspension contains an isotonic agent. 
     
     
         37 . The method of  claim 36  in which the isotonic agent is mannitol. 
     
     
         38 . The method of  claim 28  in which the aqueous suspension contains a pharmaceutically acceptable excipient. 
     
     
         39 . The method of  claim 28  in which the aqueous suspension is obtained extemporaneously from a lyophilized peptide salt.