Therapeutic formulations for transmucosal administration that increase glucagon-like peptide-1 bioavailability

• US 20060074025A1
• Filed: 12/02/2005
• Published: 04/06/2006
• Est. Priority Date: 12/26/2003
• Status: Abandoned Application

• Current Assignee: Amylin Pharmaceuticals Incorporated (Bristol-Myers Squibb Company)
• Original Assignee: Nastech Pharmaceutical Company Inc. (Adhera Therapeutics, Inc.)
• Inventors: Quay, Steven C., Costantino, Henry R., Kleppe, Mary S.
• Application Number:
  US11/293,676
• Publication Number:
  US 20060074025A1
• Time in Patent Office: Days
• US Class Current: 514/11.700
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/24 containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/2086 Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat active cores with a complete drug-free outer coat A61K9/28

Abstract

What is described is a pharmaceutical formulation for intranasal delivery of glucagon-like protein-1 (GLP-1), comprising an aqueous mixture of GLP-1, a solubilizing agent, a chelator, and a surface active agent.

Claims

1. A pharmaceutical formulation for intranasal delivery of glucagon like peptide-1 (GLP-1), comprising an aqueous mixture of GLP-1, a solubilizing agent, a chelator, and a surface active agent.

2. The GLP-1 formulation of claim 1 wherein the solubilizing agent is selected from the group consisting of a cyclodextran, hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

3. The GLP-1 formulation of claim 2 wherein the solubilizing agent is methyl-β

-cyclodextrin.

4. The GLP-1 formulation of claim 1 wherein the chelating agent is selected from the group consisting of ethylene diamine tetraacetic acid and ethylene glycol tetraacetic acid.

5. The GLP-1 formulation of claim 4 wherein the chelating agent is ethylene diamine tetraacetic acid.

6. The GLP-1 formulation of claim 1, wherein the surface-active agent is selected from the group consisting of nonionic polyoxyethylene ether, fusidic acid and its derivatives, sodium taurodihydrofusidate, L-α

-phosphatidylcholine didecanoyl, polysorbate 80, polysorbate 20, polyethylene glycol, cetyl alcohol, polyvinylpyrolidone, polyvinyl alcohol, lanolin alcohol and sorbitan monooleate.

7. The GLP-1 formulation of claim 6 wherein the surface-active agent is L-α

-phosphatidylcholine didecanoyl.

8. The GLP-1 formulation of claim 1, further comprising a preservative selected from the group consisting of chlorobutanol, methyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, benzethonium chloride, sodium benzoate, sorbic acid, phenol, and ortho-, meta- or para-cresol.

9. The GLP-1 formulation of claim 1, wherein the formulation has a pH of about of about 3 to about 6.

10. The GLP-1 formulation of claim 1 wherein the formulation has a pH of 4.5±

0.50.

11. The GLP-1 formulation of claim 1 further comprised of 20 mM citrate.

12. The GLP-1 formulation of claim 1, wherein a time to maximal concentration in circulation of the animal, T_max, is less than about 45 minutes.

13. The GLP-1 formulation of claim 1, wherein a time to maximal concentration in circulation of the animal, T_max, is less than about 30 minutes.

14. A pharmaceutical formulation for intranasal delivery of an GLP-1, comprising an aqueous mixture of exendin and enhancers, wherein the enhancers increase bioavailability of exendin by at least about 15-fold.

15. The GLP-1 formulation of claim 14, wherein the enhancers increase bioavailability of GLP-1 by at least about 25-fold.

16. The GLP-1 formulation of claim 14, wherein the enhancers increase bioavailability of GLP-1 by at least about 50-fold.

17. The GLP-1 formulation of claim 14, wherein the bioavailability of GLP-1 is at least about 1% relative to a delivery by subcutaneous injection.

18. The GLP-1 formulation of claim 14, wherein the bioavailability of GLP-1 is at least about 5% relative to a delivery by subcutaneous injection.

19. The GLP-1 formulation of claim 14, wherein the bioavailability of GLP-1 is at least about 10% relative to a delivery by subcutaneous injection.

20. A non-sterile pharmaceutical formulation for intranasal delivery of GLP-1 comprised of GLP-1-4, methyl-α

-cyclodextrin, L-α

-phosphatidylcholine didecanoyl and water.

21. The GLP-1 formulation of claim 20 further comprising ethylene diamine tetraacetic acid.

22. The GLP-1 formulation of claim 20 wherein the formulation has a pH of about 3 to about 5.

23. The GLP-1 formulation of claim 20, further comprising a preservative selected from the group consisting of chlorobutanol, methyl paraben, propyl paraben, butyl paraben, benzalkonium chloride, benzethonium chloride, sodium benzoate, sorbic acid, phenol, and ortho-, meta- or para-cresol.