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 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 of the peptide or peptidomimetic upon mixing without formation of a gel.  
   
   
       2 . The suspension of  claim 1 , wherein the counter-ion is trifluoromethanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, or sulfuric acid.  
   
   
       3 . The suspension of  claim 1 , wherein the counter-ion is a strong acid and the peptide is a GnRH analogue.  
   
   
       4 . The suspension of  claim 3 , wherein the GnRH analogue is a GnRH antagonist.  
   
   
       5 . The suspension of  claim 4 , wherein the GnRH antagonist is Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .  
   
   
       6 . The suspension of  claim 4 , wherein the GnRH antagonist is Azaline B, Abarelix, Antide, Ganirelix, Cetrorelix, or FE200486 and is in the form of an alkylsulfonate, arylsulfonate, trifluoroacetate or sulfate salt.  
   
   
       7 . The suspension of  claim 1 , wherein the peptide is a somatostatin analogue.  
   
   
       8 . The suspension of  claim 7 , wherein the somatostatin analogue is Vapreotide, Octreotide, Lanreotide or SOM 230.  
   
   
       9 . The suspension of  claim 1 , wherein the peptide or peptidomimetic forms a salt with the counter-ion, and the salt is suspended in the aqueous medium at a concentration of equal to or higher than 25 mg/mL.  
   
   
       10 . The suspension of  claim 1 , wherein the aqueous suspension contains an isotonic agent.  
   
   
       11 . The suspension of  claim 10 , wherein the isotonic agent is mannitol.  
   
   
       12 . The suspension of  claim 1 , which further comprises a pharmaceutically acceptable excipient.  
   
   
       13 . The suspension of  claim 10 , wherein the amount of peptide or peptidomimetic ranges from about 0.1 to 5 mg per kg body weight of a mammal or human to which the suspension is to be administered.  
   
   
       14 . The suspension of  claim 1 , wherein the peptide is at least partially in the form of microcrystals having a particle size of from about 1 μm to 150 μm.  
   
   
       15 . A lyophilized composition comprising a dried suspension of  claim 1 .  
   
   
       16 . A method of making the lyophilized composition of  claim 15  which comprises, associating the peptide or peptidomimetic with a counter-ion of a strong proton donor in an amount and at a molar ratio that are sufficient to provide the suspension without formation of a gel, and lyophilizing the suspension to obtain the composition.  
   
   
       17 . A method of preparing a fluid, milky microcrystalline aqueous suspension of a peptide or peptidomimetic which comprises adding water or a buffer solution to the lyophilized composition of  claim 15  with mixing to obtain the suspension.  
   
   
       18 . A method of preparing a fluid, milky microcrystalline aqueous suspension of a peptide or peptidomimetic according to  claim 1 , which comprises associating the peptide or peptidomimetic with the counter-ion in an amount and at a molar ratio with the peptide that are sufficient to provide the fluid, milky microcrystalline aqueous suspension without formation of a gel; lyophilizing the suspension to form a lyophilized composition; and adding water or a buffer solution to the lyophilized composition with mixing to obtain the suspension.  
   
   
       19 . A method of preparing a fluid, milky microcrystalline aqueous suspension of a peptide or peptidomimetic according to  claim 1 , which comprises associating the peptide or peptidomimetic with the counter-ion in an amount and at a molar ratio that are sufficient to provide the fluid, milky microcrystalline aqueous suspension without formation of a gel.  
   
   
       20 . The method of  claim 19 , wherein the suspension is prepared to provide a sustained release formulation of the peptide or peptidomimetic such that, when administered to a subject, the peptide or peptidomimetic is released in vivo over a period of at least two weeks.  
   
   
       21 . The method of  claim 19 , wherein the counter-ion is a trifluoromethanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid or sulfuric acid.  
   
   
       22 . The method of  claim 19 , wherein the counter-ion is a strong acid and the peptide is a GnRH analogue.  
   
   
       23 . The method of  claim 22 , wherein the GnRH analogue is a GnRH antagonist.  
   
   
       24 . The method of  claim 23 , wherein the GNRH antagonist is Ac-D-Nal-DCpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .  
   
   
       25 . The method of  claim 23 , wherein the GnRH antagonist is Azaline B, Abarelix, Antide, Ganirelix, Cetrorelix, or FE200486 and is in the form of an alkylsulfonate, arylsulfonate, trifluoroacetate or sulfate salt.  
   
   
       26 . The method of  claim 19 , wherein the peptide is a somatostatin analogue.  
   
   
       27 . The method of  claim 26 , wherein the somatostatin analogue is Vapreotide, Octreotide, Lanreotide, or SOM 230.  
   
   
       28 . The method of  claim 19 , wherein the peptide or peptidomimetic forms a salt with the counter-ion, and the salt is suspended in the aqueous medium at a concentration of at least 25 mg/mL.  
   
   
       29 . The method of  claim 19 , wherein the aqueous suspension is injected parenterally into a mammal or human subject to obtain a sustained release of the peptide or peptidomimetic over at least one month.  
   
   
       30 . The method of  claim 29 , wherein the amount of peptide or peptidomimetic in the suspension to be injected ranges from about 0.1 to 5 mg per kg body weight of the mammal or human subject.  
   
   
       31 . A sustained release formulation of a peptide or peptidomimetic prepared by the method of  claim 19  which, when administered to a subject, releases the peptide or peptidomimetic in vivo over a period of at least two weeks.