Method of treatment of a metabolic disease using intranasal administration of exendin peptide

• US 20060210614A1
• Filed: 05/04/2006
• Published: 09/21/2006
• Est. Priority Date: 12/26/2003
• Status: Abandoned Application

• Current Assignee: Nastech Pharmaceutical Company Inc. (Adhera Therapeutics, Inc.)
• Original Assignee: Nastech Pharmaceutical Company Inc. (Adhera Therapeutics, Inc.)
• Inventors: Quay, Steven C., Costantino, Henry R., Leonard, Alexis Kays
• Application Number:
  US11/418,982
• Publication Number:
  US 20060210614A1
• Time in Patent Office: Days
• US Class Current: 424/448
• 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
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00

Abstract

Methods for treating metabolic diseases are described for intranasal delivery of an exenatide, comprising an aqueous mixture of exendin, and a delivery enhancer selected from the group consisting of a solubilizer, a chelator, and a surfactant, and the pharmaceutical formulations used therein.

Claims

1. A method of administering glucose-regulating peptide comprising intranasally administering a transmucosal glucose-regulating formulation comprising exendin-4, wherein the glucose-regulating peptide in the transmucosal glucose-regulating peptide formulation has bioavailability of at least 10% when administered intranasally to a mammal.

2. The method claim 1 wherein the formulation is further comprised of at least one mucosal delivery-enhancing agent selected from the group consisting of:

a. a solubilization agent;

b. a charge-modifying agent;

c. a pH control agent;

d. a degradative enzyme inhibitory agent;

e. a mucolytic or mucus clearing agent;

f. a ciliostatic agent;

g. a membrane penetration-enhancing agent selected from (i) a surfactant, (ii) a bile salt, (iii) a phospholipid additive, mixed micelle, liposome, or carrier, (iv) an alcohol, (v) an enamine, (vi) an NO donor compound, (vii) a long-chain amphipathic molecule (viii) a small hydrophobic penetration enhancer;

(ix) sodium or a salicylic acid derivative;

(x) a glycerol ester of acetoacetic acid (xi) a cyclodextrin or beta-cyclodextrin derivative, (xii) a medium-chain fatty acid, (xiii) a chelating agent, (xiv) an amino acid or salt thereof, (xv) an N-acetylamino acid or salt thereof, (xvi) an enzyme degradative to a selected membrane component, (xvii) an inhibitor of fatty acid synthesis, or (xviii) an inhibitor of cholesterol synthesis;

or (xix) any combination of the membrane penetration enhancing agents recited in (i)-(xix);

h. a modulatory agent of epithelial junction physiology;

i. a vasodilator agent;

j. a selective transport-enhancing agent; and

k. a stabilizing delivery vehicle, carrier, support or complex-forming species.

3. The method of claim 1 wherein the formulation is an aqueous formulation comprised of water and exendin-4.

4. The method of claim 3 wherein the formulation is an intranasal formulation.

5. The method of claim 4, wherein the formulation is an aqueous formulation comprised of water and exendin-4

6. A method of regulating glucose levels in a mammal comprising intranasally administering a transmucosal glucose-regulating formulation comprising exendin-4, wherein the glucose-regulating peptide in the transmucosal glucose-regulating peptide formulation has bioavailability of at least 10% when administered intranasally to a mammal

23. The method of claim 6, wherein the bioavailability of exendin is at least about 1% relative to a delivery by subcutaneous injection.

24. The method of claim 6, wherein the bioavailability of exendin is at least about 5% relative to a delivery by subcutaneous injection.

25. The method of claim 6 wherein the bioavailability of exendin is at least about 10% relative to a delivery by subcutaneous injection.

7. A method for treating metabolic disease comprising administering intranasally delivery of an exenatide formulation, comprising an aqueous mixture of exendin, a solubilizing agent, a chelating agent, and a surface active agent

8. The method of claim 7 wherein the exendin is exendin-4.

9. The method of claim 7 wherein the solubilizing agent is selected from the group consisting of a cyclodextran, hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

10. The method of claim 9 wherein the solubilizing agent is methyl-β

-cyclodextrin.

11. The method of claim 10 wherein the chelating agent is selected from the group consisting of ethylene diamine tetraacetic acid and ethylene glycol tetraacetic acid.

12. The method of claim 7 wherein the chelating agent is ethylene diamine tetraacetic acid.

13. The method of claim 7, 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.

14. The method of claim 13 wherein the surface-active agent is L-α

-phosphatidylcholine didecanoyl.

15. The method of claim 7, wherein the formulation further comprises 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.

16. The method of claim 7, wherein the formulation has a pH of about of about 3 to about 6.

17. The method of claim 7 wherein the formulation has a pH of 4.5±

50.

18. The method of claim 7 further comprised of 20 mM citrate.

19. The method of claim 7, wherein a time to maximal concentration in circulation of the animal, T_max, is less than about 45 minutes.

20. The method of claim 7, wherein a time to maximal concentration in circulation of the animal, T_max, is less than about 30 minutes.

21. The method of claim 7, wherein the exendin-4 formulation further comprises a viscosity enhancer.

22. The method of claim 21, wherein the exendin-4 formulation has a viscosity of about 1.5 to about 10.0 cps.

26. A pharmaceutical formulation for intranasal administration of a glucose-regulating peptide formulation to a mammal, comprising exendin-4, and a delivery enhancer selected from the group consisting of a chelator, a solubilizer, and a surfactant.

27. The formulation of claim 26, further comprised of at least one polyol.

28. The aqueous formulation of claim 27 wherein the polyol is selected from the group consisting of lactose, sorbitol, trehalose, sucrose, mannose, mannitol and maltose and derivatives and homologs thereof.

29. The formulation of claim 27, wherein the polyol is mannitol, lactose or sorbitol.

30. The formulation of claim 26, wherein the formulation comprises a chelator, ethylenediamine tetraacetic acid.

31. The formulation of claim 26, wherein the formulation comprises a solubilizer selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

32. The formulation of claim 31, wherein the solubilizer is a cyclodextrin.

33. The formulation of claim 26, wherein the formulation comprises a surfactant selected from the group consisting of polysorbate 20, polysorbate 80, PEG, cetyl alcohol, PVP, PVA, lanolin alcohol, L-α

-phosphatidylcholine didecanoyl (DDPC) and sorbitan monooleate.

34. The formulation of claim 33 wherein the surfactant is DDPC.

35. The formulation of claim 26 wherein the formulation has a pH of about of about 2 to about 8.

36. The formulation of claim 26, further comprising a viscosity enhancer.

37. The formulation of claim 36, wherein the viscosity is about 1.5 to about 10.0 cps.