Suspension formulations of insulinotropic peptides and uses thereof

• US 8,299,025 B2
• Filed: 04/22/2008
• Issued: 10/30/2012
• Est. Priority Date: 02/03/2005
• Status: Active Grant

• Current Assignee: Intarcia Therapeutics, Inc.
• Original Assignee: Intarcia Therapeutics, Inc.
• Inventors: Alessi, Thomas R., Mercer, Ryan D., Rohloff, Catherine M., Yang, Bing
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US12/148,896
• Publication Number:
  US 20080260840A1
• Time in Patent Office: 1,652 Days
• Field of Search: None
• US Class Current: 514/7.2
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/10 Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/7023 Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 of the pancreatic hormones
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 7/067 Hemoregulatory peptides based on sequence Glp-Glu-Asp-Cys-Lys
• CPC Class Codes: Y10T 29/494 Fluidic or fluid actuated device making

Abstract

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.

Claims

1. A suspension formulation suitable for use in an osmotic delivery device comprising,

a particle formulation comprising an insulinotropic peptide, a disaccharide, methionine, and a buffer;

and

a non-aqueous, single-phase suspension vehicle that consists essentially of about 20 wt % to about 60 wt % benzyl benzoate and about 80 wt % to about 40 wt % polyvinylpyrrolidone, the suspension vehicle having a viscosity of between about 12,000 to about 18,000 poise at 33°

C.;

wherein the suspension vehicle exhibits viscous fluid characteristics, and the particle formulation is dispersed in the vehicle.

2. The formulation of claim 1, wherein the insulinotropic peptide is a glucagon-like peptide-1 (GLP-1), a derivative of GLP-1, or an analogue of GLP-1.

3. The formulation of claim 2, wherein the insulinotropic peptide is GLP-1(7-36) amide.

4. The formulation of claim 1, wherein the insulinotropic peptide is exenatide, a derivative of exenatide, or an analogue of exenatide.

5. The formulation of claim 4, wherein the insulinotropic peptide is exenatide having the amino acid sequence of SEQ ID NO:

2.

6. The formulation of claim 1, wherein the buffer is selected from the group consisting of citrate, histidine, succinate, and mixtures thereof.

7. The formulation of claim 6, wherein the buffer is a citrate buffer.

8. The formulation of claim 1, wherein the disaccharide is selected from the group consisting of lactose, sucrose, trehalose, cellobiose, and mixtures thereof.

9. The formulation of claim 1, wherein the particle formulation is a spray dried preparation of particles.

10. The formulation of claim 1, wherein the vehicle is about 50% solvent and about 50% polymer.

11. The formulation of claim 1, wherein the suspension formulation has an overall moisture content of less than or equal to about 10 wt %.

12. An osmotic delivery device, comprising the suspension formulation of claim 1.

13. A method of manufacturing an osmotic delivery device comprising,

loading the suspension formulation of claim 1 into a reservoir of the osmotic delivery device.

14. A method of treating type II diabetes in a subject in need of such treatment, comprising

delivering the suspension formulation of claim 1 from an osmotic delivery device at a substantially uniform rate for a period of about one month to about a year.

15. The method of claim 14, wherein the insulinotropic peptide is GLP-1(7-36) amide and delivering the suspension formulation is at a substantially uniform rate of between about 100 μ

g/day and about 600 μ

g/day.

16. The method of claim 14, wherein the insulinotropic peptide is exenatide and delivering the suspension formulation is at a substantially uniform rate of between about 5 μ

g/day and about 160 μ

g/day.