Suspension formulation comprising an insulinotropic peptide
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, a carbohydrate, and a buffer, wherein the insulinotropic peptide is at least one of exenatide, a derivative of exenatide, or 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;
the pyrrolidone polymer is polyvinylpyrrolidone;
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 plus carbohydrate of 1/2 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 1 , wherein the carbohydrate is sucrose.
5. The suspension formulation of claim 1 , wherein the solvent is benzyl benzoate.
6. The suspension formulation of claim 1 , wherein the antioxidant is at least one of methionine, ascorbic acid, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), citric acid, and butylated hydroxyltoluene.
7. The suspension formulation of claim 1 , wherein the particle formulation comprises exenatide, sucrose, methionine, and citrate.
8. The suspension formulation of claim 1 , wherein the particle formulation has a wt % ratio of insulinotropic peptide to antioxidant plus carbohydrate of 5/1 to 10/1.
9. The suspension formulation of claim 1 , wherein the particle formulation has a moisture content of less than 5 wt %.
10. A delivery device comprising a suspension formulation, the suspension formulation comprising:
a particle formulation comprising:
an insulinotropic peptide, an antioxidant, a carbohydrate, and a buffer, wherein the insulinotropic peptide is at least one of exenatide, a derivative of exenatide, or 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;
the pyrrolidone polymer is polyvinylpyrrolidone;
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 plus carbohydrate of 1/2 to 10/1; and
the particle formulation is dispersed in the suspension vehicle.
11. The delivery device of claim 10 , wherein the insulinotropic peptide is exenatide.
12. The delivery device of claim 10 , wherein the buffer is selected from at least one of citrate, histidine, succinate, and tris.
13. The delivery device of claim 10 , wherein the carbohydrate is sucrose.
14. The delivery device of claim 10 , wherein the antioxidant is at least one of methionine, ascorbic acid, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), citric acid, and butylated hydroxyltoluene.
15. The delivery device of claim 10 , wherein the particle formulation comprises exenatide, sucrose, methionine, and citrate.
16. A method of treating type II diabetes in a subject in need of such treatment, the method comprising:
delivering the suspension formulation from the delivery device of claim 10 at a substantially uniform rate for a period of about one month to about one year.
17. 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 the suspension formulation from the delivery device of claim 10 at a substantially uniform rate for a period of about one month to about one year.