Sustained release of microcrystalline peptide suspensions
View Patent ↗The invention relates to a method of preventing gel formation of a hydrophobic peptides by contacting the hydrophobic peptide with a counter-ion in an amount and at a molar ratio with the peptide that are sufficient to provide a fluid, milky microcrystalline aqueous suspension of the peptide without formation of a gel. The invention also relates to a fluid, milky microcrystalline aqueous suspension of a hydrophobic peptide and a counter-ion 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.
1. A fluid, milky microcrystalline aqueous suspension comprising Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .trifluoroacetate and an isotonic agent.
2. The suspension of claim 1 , wherein the amount of Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .trifluoracetate 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.
3. The suspension of claim 1 , which provides, when administered to a subject, a sustained release of peptide in vivo.
4. The suspension of claim 3 , wherein the sustained release is over a period of two weeks.
5. The suspension of claim 1 , wherein Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .trifluoroacetate is suspended in an aqueous medium at a concentration of equal to or greater than 25 mg/mL.
6. The suspension of claim 1 , wherein the isotonic agent is mannitol.
7. The suspension of claim 1 , further comprising a pharmaceutically acceptable excipient.
8. The suspension of claim 1 , wherein microcrystals are in the form of needles having a particle size of between 1 and 150 μm.
9. A method of preparing the suspension of claim 1 comprising, associating Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 with trifluoroacetate counter-ion in an amount and at a molar ratio that are sufficient to provide a fluid, milky microcrystalline aqueous suspension without formation of a gel.
10. A method of preparing a lyophilized composition comprising Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .trifluoroacetate comprising, lyophilizing the suspension of claim 1 .
11. A method of preparing the suspension of claim 1 comprising, associating Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 with trifluoroacetate counter-ion in an amount and at a molar ratio that are sufficient to provide a fluid, milky microcrystalline aqueous suspension without formation of a gel; lyophilizing to form a lyophilized composition; and adding water or buffer with mixing.
12. A method of preparing a sustained release formulation of Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .trifluoroacetate comprising, associating Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 with the trifluoroacetate counter-ion in an amount and at a molar ratio that are sufficient to provide the fluid, milky microcrystalline aqueous suspension of claim 1 , such that, when administered to a subject, the peptide is released in vivo over a period of at least two weeks.
13. The method of claim 12 , wherein the aqueous suspension is injected parenterally into a mammal or human subject to obtain a sustained release of Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .trifluoroacetate for at least one month to about 45 days.
14. The method of claim 12 , wherein the amount of Ac-D-Nal-D-Cpa-D-Pal-Ser-Tyr-D-Hci-Leu-Ilys-Pro-D-Ala-NH 2 .trifluoroacetate in the suspension to be injected ranges from about 0.1 to 5 mg per kg body weight of the mammal or human subject.