Compositions and methods for enhanced mucosal delivery of Y2 receptor-binding peptides and methods for treating and preventing obesity

• US 20040157777A1
• Filed: 12/23/2003
• Published: 08/12/2004
• Est. Priority Date: 12/17/2002
• Status: Active Grant

• Current Assignee: Mdrna Inc. (Adhera Therapeutics, Inc.)
• Original Assignee: Nastech Pharmaceutical Company Inc. (Adhera Therapeutics, Inc.)
• Inventors: Quay, Steven C., Kleppe, Mary S., Brandt, Gordon, MacEvilly, Conor J.
• Granted Patent: US 7,186,691 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/724 Cyclodextrins
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/2271 Neuropeptide Y
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 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 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Pharmaceutical compositions and methods are described comprising at least one Y2 receptor-binding peptide, such as peptide YY(PYY), Neuropeptide Y (NPY) or Pancreatic Peptide (PP) and one or more mucosal delivery-enhancing agents for enhanced nasal mucosal delivery of the peptide YY, for treating a variety of diseases and conditions in mammalian subjects, including obesity.

Claims

1. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a mammal comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the mammal wherein the PYY formulation is comprised of a solubilizing agent, a chelating agent, a polyol and a PYY peptide wherein the PYY peptide is comprised of an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 3 and SEQ ID NOs;

90-105.

2. The method for inducing appetite suppression of claim 1 wherein the formulation is further comprised of at least two polyols.

3. The method for inducing appetite suppression of claim 2 wherein the polyols are selected from the group consisting of sucrose, mannitol, sorbitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, trehalose, D-galactose, lactulose, cellobiose, gentibiose, glycerin and polyethylene glycol.

4. The method of claim 3 wherein the polyols are lactose and sorbitol.

5. The method of claim 1 wherein the chelating agent is ethylene diamine tetraacetic acid (EDTA) or ethylene glycol tetraacetic acid (EGTA).

6. The of claim 5 wherein the chelating agent is ethylenediamine tetraacetic acid (EDTA).

7. The method of claim 1 wherein the solubilizing agent is selected from the group consisting of a cyclodextran, hydroxypropyl-p-cyclodextran, sulfobutylether-p-cyclodextran and methyl-α

-cyclodextrin.

8. The method of claim 7 wherein the solubilizing agent is a cyclodextrin.

9. The method of claims 1 wherein the formulation is further comprised of a surface-active agent.

10. The method of claim 9 wherein the surface-active agent is selected from the group consisting of nonionic polyoxyethylene ether, bile salts such, sodium glycocholate (SGC), deoxycholate (DOC), derivatives of fusidic acid, sodium taurodihydrofusidate (STDHF), L-α

-phospharidycholine didecanoyl (DDPC) polysorbate 80 and polysorbate 20,), polyethylene glycol (PEG), cetyl alcohol, polyvinylpyrolidone (PVP), polyvinyl alcohol (PVA), lanolin alcohol, and sorbitan monooleate.

11. The method of claim 10 wherein the surface-active agent is L-α

-Phospharidycholine didecanoyl (DDPC).

12. The method of claim 1 the formulation is an aqueous PYY formulation further comprised of water.

13. The method of claim 12 wherein the aqueous PYY formulation has a pH of about of about 3-6.

14. The method of claim 13 wherein the pH of the aqueous PYY formulation is 5.0±

0.3.

15. The method of claim 1 wherein a dose containing 50 μ

g to 800 μ

g of a PYY peptide is administered to the mammal.

16. The method of claim 15 wherein a dose containing 100 μ

g to 400 μ

g is administered to the mammal.

17. The method of claim 16 wherein a dose containing 150 μ

g to 200 μ

g is administered to the mammal.

18. The method of claim 1 wherein the mammal is a human.

19. The method of claim 1 wherein the PYY peptide is comprised of PYY(3-36) (SEQ ID NO:

2).

21. The method for inducing appetite suppression of claim 19 wherein the formulation is further comprised of at least two polyols.

22. The method for inducing appetite suppression of claim 21 wherein the polyols are selected from the group consisting of sucrose, mannitol, sorbitol, lactose, L-arabinose, D-erythrose, D-ribose, D-xylose, D-mannose, trehalose, D-galactose, lactulose, cellobiose, gentibiose, glycerin and polyethylene glycol.

23. The method of claim 22 wherein the polyols are lactose and sorbitol.

20. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a mammal comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the mammal wherein the PYY formulation is comprised of a solubilizing agent, a chelating agent, a polyol, a surface active agent and a PYY peptide wherein the PYY peptide is comprised of an amino acid sequence selected from the group consisting of SEQ ID NOs:

2, 3 and SEQ ID NOs;

90-105.

24. The method of claim 20 wherein the chelating agent is ethylene diamine tetraacetic acid (EDTA) or ethylene glycol tetraacetic acid (EGTA).

25. The of claim 24 wherein the chelating agent is ethylenediamine tetraacetic acid (EDTA).

26. The method of claim 20 wherein the solubilizing agent is selected from the group consisting of a cyclodextran, hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-p-cyclodextrin.

27. The method of claim 26 wherein the solubilizing agent is a methyl-p-cyclodextrin.

28. The method of claim 20 wherein the surface-active agent is selected from the group consisting of nonionic polyoxyethylene ether, bile salts such, sodium glycocholate (SGC), deoxycholate (DOC), derivatives of fusidic acid, sodium taurodihydrofusidate (STDHF), L-α

-phospharidycholine didecanoyl (DDPC) polysorbate 80 and polysorbate 20,), polyethylene glycol (PEG), cetyl alcohol, polyvinylpyrolidone (PVP), polyvinyl alcohol (PVA), lanolin alcohol, and sorbitan monooleate.

29. The method of claim 28 wherein the surface-active agent is L-α

-phospharidycholine didecanoyl (DDPC).

30. The method of claim 20 the formulation is an aqueous PYY formulation further comprised of water.

31. The method of claim 30 wherein the aqueous PYY formulation has a pH of about of about 3-6.

32. The method of claim 31 wherein the pH of the aqueous PYY formulation is 5.0±

0.3.

33. The method of claim 20 wherein a dose containing 50 μ

g to 800 μ

g of a PYY peptide is administered to the mammal.

34. The method of claim 33 wherein a dose containing 100 μ

g to 400 μ

g is administered to the mammal.

35. The method of claim 34 wherein a dose containing 150 μ

g to 200 μ

g is administered to the mammal.

36. The method of claim 20 wherein the mammal is a human.

37. The method of claim 20 wherein the PYY peptide is comprised of PYY(3-36) (SEQ ID NO:

2).

39. The method of claim 36 wherein the PYY peptide is comprised of PYY(3-36) (SEQ ID NO:

2).

38. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a mammal comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the mammal wherein the PYY formulation is comprised of methyl-α

-cyclodextrin, EDTA, lactose, sorbitol, DDPC and a PYY peptide wherein the PYY peptide is comprised of an amino acid sequence selected from the group consisting of SEQ ID NOs;

2, 3 and SEQ ID NOs;

90-105.

40. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a human comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the human wherein the PYY formulation is comprised of water, sodium citrate, citric acid, methyl-P-cyclodextrin, EDTA, lactose, sorbitol, DDPC and PYY(3-36) (SEQ ID NO:

2), wherin the formulation has a pH of about 5.0±

0.3.

41. The method of claim 40 wherein the human is administered from 50 μ

g to about 800 μ

g of PYY(3-36) (SEQ ID NO;

     2).

42. The method of claim 40 wherein the human is administered a from 100 μ

g to about 400 μ

g of PYY(3-36) (SEQ ID NO;

     2).

43. The method of claim 40 wherein the human is administered a from 150 μ

g to about 200 μ

g of PYY(3-36) (SEQ ID NO;

     2).

44. The method of claim 40, wherein the formulation is further comprised of a preservative selected from the group consisting of chlorobutanol and benzalkonium chloride.

45. The method of claim 44 wherein the preservative is chlorobutanol.

46. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a human comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the human wherein the PYY formulation is comprised of water, sodium citrate, citric acid, methyl-α

-cyclodextrin, EDTA, lactose, sorbitol, DDPC and PYY(3-36) (SEQ ID NO;

     2), wherein the formulation has a pH of about 5.0+0.3 and wherein the human is administered 150 μ

g to about 200 μ

g of PYY(3-36) (SEQ ID NO;

     2).

47. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a human comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the human wherein the PYY formulation is comprised of water, chlorobutanol, sodium citrate, citric acid, methyl-α

-cyclodextrin, EDTA, lactose, sorbitol, DDPC and PYY(3-36) (SEQ ID NO;

     2), wherein the formulation has a pH of about 5.0±

0.3 and wherein the human is administered 150 μ

g to about 200 μ

g of PYY(3-36) (SEQ ID NO;

     2).

48. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a human comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the human wherein the PYY formulation is comprised of water, benzalkonium chloride, sodium citrate, citric acid, methyl-α

-cyclodextrin, EDTA, lactose, sorbitol, DDPC and PYY(3-36) (SEQ ID NO;

     2), wherein the formulation has a pH of about 5.0±

0.3 and wherein the human is administered 150 μ

g to about 200 μ

g of PYY(3-36) (SEQ ID NO;

     2).

49. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a human comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the human wherein the PYY formulation is comprised of water, chlorobutanol, sodium citrate, citric acid, methyl-α

-cyclodextrin, EDTA, lactose, sorbitol, DDPC and PYY(3-36) (SEQ ID NO;

     2), wherein the formulation has a pH of about 5.0+0.3.

50. A method for treating obesity, inducing weight-loss, inducing satiety or inducing appetite suppression in a human comprising administering intranasally a therapeutically effective amount of a peptide YY (PYY) formulation to the human wherein the PYY formulation is comprised of water, benzalkonium chloride, sodium citrate, citric acid, methyl-β

-cyclodextrin, EDTA, lactose, sorbitol, DDPC and PYY(3-36) (SEQ ID NO;

     2), wherein the formulation has a pH of about 5.0±

0.3.