Osmotic delivery device comprising an insulinotropic peptide and uses thereof
A suspension formulation of an insulinotropic peptide (e.g., glucagon-like peptide-1 (GLP-1) or exenatide) is described. The suspension formulation comprises (i) a non-aqueous, single-phase vehicle, comprising one or more polymer and one or more one solvent, wherein the vehicle exhibits viscous fluid characteristics, and (ii) a particle formulation comprising the insulinotropic peptide, wherein the peptide is dispersed in the vehicle. The particle formulation further includes a stabilizing component comprising one or more stabilizers, for example, carbohydrates, antioxidants, amino acids, and buffers. Devices for delivering the suspension formulations and methods of use are also described.
1. A suspension formulation comprising:
a particle formulation comprising:
an insulinotropic peptide, an antioxidant, and a buffer, wherein the insulinotropic peptide is at least one of exenatide, a derivative of exenatide, and an analogue of exenatide; and
a non-aqueous, single-phase suspension vehicle that comprises about 20 wt % to about 60 wt % solvent and about 80 wt % to about 40 wt % pyrrolidone polymer, the suspension vehicle having a viscosity from 5,000 poise to 50,000 poise at 33° C.;
wherein:
the solvent is at least one of lauryl lactate, lauryl alcohol, and benzyl benzoate;
30 to 90% by weight of the particle formulation is the insulinotropic peptide;
the particle formulation has a wt % ratio of insulinotropic peptide to antioxidant of 2.5/1 to 10/1; and
the particle formulation is dispersed in the suspension vehicle.
2. The suspension formulation of claim 1 , wherein the insulinotropic peptide is exenatide.
3. The suspension formulation of claim 1 , wherein the buffer is selected from at least one of citrate, histidine, succinate, and tris.
4. The suspension formulation of claim 3 , wherein the buffer is citrate.
5. The suspension formulation of claim 1 , wherein the antioxidant is methionine.
6. The suspension formulation of claim 1 , wherein the solvent is benzyl benzoate.
7. The suspension formulation of claim 1 , wherein the pyrrolidone polymer is polyvinylpyrrolidone.
8. The suspension formulation of claim 1 , further comprising a carbohydrate.
9. The suspension formulation of claim 8 , wherein the carbohydrate is at least one of lactose, sucrose, trehalose, cellobiose, and raffinose.
10. The suspension formulation of claim 9 , wherein the carbohydrate is sucrose.
11. The suspension formulation of claim 10 , wherein the particle formulation comprises exenatide, sucrose, methionine, and citrate.
12. The suspension formulation of claim 11 , wherein the particle formulation has a wt % ratio of insulinotropic peptide to antioxidant of 5/1 to 10/1.
13. The suspension formulation of claim 12 , wherein the solvent is benzyl benzoate.
14. The suspension formulation of claim 13 , wherein the pyrrolidone polymer is polyvinylpyrrolidone.
15. The suspension formulation of claim 1 , wherein the particle formulation has a moisture content of less than 5 wt %.
16. The suspension formulation of claim 1 , wherein particles of the particle formulation have a diameter of about 3 μm to about 50 μm.
17. A delivery device comprising a suspension formulation, the suspension formulation comprising:
a particle formulation comprising:
an insulinotropic peptide, an antioxidant, and a buffer, wherein the insulinotropic peptide is at least one of exenatide, a derivative of exenatide, and an analogue of exenatide; and
a non-aqueous, single-phase suspension vehicle that consists essentially of about 20 wt % to about 60 wt % solvent and about 80 wt % to about 40 wt % pyrrolidone polymer, the suspension vehicle having a viscosity from 5,000 poise to 50,000 poise at 33° C.;
wherein:
the solvent is at least one of lauryl lactate, lauryl alcohol, and benzyl benzoate;
30 to 90% by weight of the particle formulation is the insulinotropic peptide;
the particle formulation has a wt % ratio of insulinotropic peptide to antioxidant of 2.5/1 to 10/1; and
the particle formulation is dispersed in the suspension vehicle.
18. The delivery device of claim 17 , wherein the delivery device delivers the suspension formulation at least one of osmotically, mechanically, electromechanically, and chemically.
19. The delivery device of claim 17 , wherein the insulinotropic peptide is exenatide.
20. The delivery device of claim 19 , wherein the buffer is selected from at least one of citrate, histidine, succinate, and tris.
21. The delivery device of claim 19 , wherein the buffer is citrate.
22. The delivery device of claim 19 , wherein the antioxidant is methionine.
23. The delivery device of claim 19 , wherein the suspension formulation further comprises a carbohydrate.
24. The delivery device of claim 23 , wherein the carbohydrate is at least one of lactose, sucrose, trehalose, cellobiose, and raffinose.
25. The delivery device of claim 24 , wherein the carbohydrate is sucrose.
26. The delivery device of claim 25 , wherein the particle formulation comprises exenatide, sucrose, methionine, and citrate.
27. A method of treating type II diabetes in a subject in need of such treatment, the method comprising:
delivering a suspension formulation from a delivery device at a substantially uniform rate for a period of about one month to about one year, the suspension formulation comprising:
a particle formulation comprising:
an insulinotropic peptide, an antioxidant, and a buffer, wherein the insulinotropic peptide is at least one of exenatide, a derivative of exenatide, and an analogue of exenatide; and
a non-aqueous, single-phase suspension vehicle that consists essentially of about 20 wt % to about 60 wt % solvent and about 80 wt % to about 40 wt % pyrrolidone polymer, the suspension vehicle having a viscosity from 5,000 poise to 50,000 poise at 33° C.;
wherein:
the solvent is at least one of lauryl lactate, lauryl alcohol, and benzyl benzoate;
30 to 90% by weight of the particle formulation is the insulinotropic peptide;
the particle formulation has a wt % ratio of insulinotropic peptide to antioxidant of 2.5/1 to 10/1; and
the particle formulation is dispersed in the suspension vehicle.
28. The method of claim 27 , wherein the insulinotropic peptide is exenatide.
29. A method for the reduction of at least one of body weight in a subject, glucose concentrations in blood of the subject, and HbA1C levels in the subject, the method comprising:
delivering a suspension formulation from a delivery device at a substantially uniform rate for a period of about one month to about one year, the suspension formulation comprising:
a particle formulation comprising:
an insulinotropic peptide, an antioxidant, and a buffer, wherein the insulinotropic peptide is at least one of exenatide, a derivative of exenatide, and an analogue of exenatide; and
a non-aqueous, single-phase suspension vehicle that consists essentially of about 20 wt % to about 60 wt % solvent and about 80 wt % to about 40 wt % pyrrolidone polymer, the suspension vehicle having a viscosity from 5,000 poise to 50,000 poise at 33° C.;
wherein:
the solvent is at least one of lauryl lactate, lauryl alcohol, and benzyl benzoate;
30 to 90% by weight of the particle formulation is the insulinotropic peptide;
the particle formulation has a wt % ratio of insulinotropic peptide to antioxidant of 2.5/1 to 10/1; and
the particle formulation is dispersed in the suspension vehicle.
30. The method of claim 29 , wherein the insulinotropic peptide is exenatide.