Intranasal administration of glucose-regulating peptides

• US 20050143303A1
• Filed: 11/18/2004
• Published: 06/30/2005
• 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.
• Application Number:
  US10/991,597
• Publication Number:
  US 20050143303A1
• Time in Patent Office: Days
• US Class Current: 514/5.300
• 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 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Pharmaceutical compositions and methods are described comprising at least one glucose-regulating peptide, such as amylin, glucagon-like peptide-1 (GLP), pramlintide or exendin-4 and one or more mucosal delivery-enhancing agents for enhanced nasal mucosal delivery of the amylin, for treating a variety of diseases and conditions in mammalian subjects, including obesity and diabetes mellitus.

Claims

1. A transmucosal glucose-regulating peptide formulation wherein the glucose-regulating peptide in the transmucosal glucose-regulating peptide formulation has a permeation in an in vitro permeation assay at least 10-fold greater than the glucose-regulating peptide in a saline formulation, wherein the saline formulation consists of a glucose-regulating peptide, water, sodium chloride and a buffering agent, wherein the transmucosal glucose-regulating peptide formulation and the saline formulation have a pH and osmolarity which are identical.

2. The formulation of claim 1, wherein the glucose-regulating peptide is selected from the group consisting of amylin, an amylin analog, pramlintide, glucagons-like peptide-1 (GLP) and exendin-3, exendin-4.

3. The formulation of claim 1 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, (ii) a phospholipid additive, mixed micelle, liposome, or carrier, (iii) an alcohol, (iv) an enamine, (v) an NO donor compound, (vi) a long-chain amphipathic molecule (vii) a small hydrophobic penetration enhancer;

(viii) sodium or a salicylic acid derivative;

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

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

(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.

4. The formulation of claims 1 wherein the formulation is an intranasal formulation.

5. The formulation of claim 4, wherein the formulation is an aqueous formulation comprised of water and a glucose-regulating peptide.

6. The formulation of claim 5 wherein the glucose-regulating peptide is selected from the group consisting of a amylin peptide, an GLP peptide, and a exendin peptide.

7. The formulation of claim 6 wherein the glucose-regulating peptide is a amylin peptide, wherein the amylin peptide is comprised of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-47.

8. The formulation of claim 4 wherein the formulation is further comprised of at least one transmucosal delivery agent.

9. The formulation of claim 8 wherein the transmucosal delivery agent is 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, (ii) a phospholipid additive, mixed micelle, liposome, or carrier, (iii) an alcohol, (iv) an enamine, (v) an NO donor compound, (vi) a long-chain amphipathic molecule (vii) a small hydrophobic penetration enhancer;

(viii) sodium or a salicylic acid derivative;

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

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

(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.

10. The formulation of claim 4 wherein the formulation is further comprised of at least one polyol.

11. The formulation of claim 10 wherein the polyol is mannitol, lactose or sorbitol.

12. The formulation of claims 4 further comprised of a chelating agent.

13. The formulation of claim 12 wherein the chelating agent is ethylenediamine tetraacetic acid (EDTA).

14. The formulation of claim 4 further comprised of a solubilizing agent.

15. The formulation of claim 14 wherein the solubilizing agent is a cyclodextrin.

16. The formulation of claim 4 further comprised of a surfactant.

17. The formulation of claim 16 wherein the surfactant is L-α

-Phosphatidylcholine didecanoyl (DDPC).

18. The formulation of claims 4 wherein the GRP agonist is exendin-4 peptide.

19. The formulation of claim 4 wherein the formulation has a pH of about of about 2-8.

20. An aqueous glucose-regulating peptide formulation comprising a glucose-regulating peptide, water and a solubilizing agent wherein the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

21. The formulation of claim 20 wherein said solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

22. The aqueous formulation of claim 21 further comprising one or more polyols.

23. The aqueous formulation of claim 22 wherein the polyol is selected from the group consisting of lactose, sorbitol, trehalose, sucrose, mannose, mannitol and maltose and derivatives and homologs thereof.

24. The aqueous glucose-regulating peptide formulation of claim 22 further comprising a surface-active agent and a chelating agent.

25. The aqueous formulation of claims 24 wherein the surface-active agent is 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.

26. The aqueous formulation of claim 20 wherein the GRP is selected from the group consisting of exendin-3, exendin-4, amylin, pramlintide, GLP-1.

27. The aqueous formulation of claim 20 wherein the GRP is a peptide selected from the group consisting of SEQ ID NO:

1-47.

28. The aqueous formulation of claim 27 wherein the peptide has a carboxyl-terminus amino acid residue, wherein said carboxyl-terminus amino acid residue is acetylated.

29. An aqueous glucose-regulating peptide formulation comprised of water, a glucose-regulating peptide, and a chelating agent wherein the pH of the formulation is about 2 to about 8, and the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

30. The aqueous glucose-regulating peptide formulation of claim 29 further comprised of one or more polyols.

31. The aqueous glucose-regulating peptide formulation of claim 29 further comprised of a solubilizng agent.

32. The aqueous glucose-regulating peptide formulation of claim 31 wherein the solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

33. The aqueous glucose-regulating peptide formulation of claim 29 further comprised of a surface-active agent.

34. The aqueous glucose-regulating peptide formulation of claim 33 wherein the surface-active agent is 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.

35. The aqueous glucose-regulating peptide formulation of claim 29 wherein the glucose-regulating peptide is a peptide selected from the group of SEQ ID NOs:

1-47.

36. The formulation of claim 35 wherein the peptide has a carboxyl-terminus amino acid residue, wherein said carboxyl-terminus amino acid residue is acetylated.

37. An aqueous glucose-regulating peptide formulation comprising a glucose-regulating peptide, water, and a solubilizing agent wherein the formulation has a pH of 2.0 to about 8 and the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

38. The aqueous glucose-regulating peptide formulation of claim 37 wherein the solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

39. The aqueous formulation of claim 37 further comprising a chelating agent.

40. The formulation of claim 37 wherein the glucose-regulating peptide is a peptide selected from the group consisting SEQ ID NOs:

1-47.

41. The formulation of claim 40 wherein the peptide has a carboxyl-terminus amino acid residue wherein said carboxyl-terminus amino acid residue is acetylated.

42. An aqueous formulation of glucose-regulating peptide comprising a glucose-regulating peptide, water, a chelatng agent and a surface-active agent wherein the formulation has a pH of 2.0 to about 8 and the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

43. The aqueous formulation of claim 42 wherein the surface-active agent is selected from the group consisting of polysorbate 20, polysorbate 80, PEG, cetyl alcohol, PVP, PVA, L-α

-phosphatidylcholine didecanoyl (DDPC), lanolin alcohol, and sorbitan monooleate.

44. The aqueous glucose-regulating peptide formulation of claim 42 further comprising a solubilizing agent.

45. The aqueous glucose-regulating peptide formulation of claim 44 wherein the solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

46. A method of administering glucose-regulating peptide comprising intranasally administering a transmucosal glucose-regulating formulation, wherein the glucose-regulating peptide in the transmucosal glucose-regulating peptide formulation has a permeation in an in vitro permeation assay at least 10-fold greater than the glucose-regulating peptide in a saline formulation, wherein the saline formulation consists of a glucose-regulating peptide, water, sodium chloride and a buffering agent, wherein the transmucosal glucose-regulating peptide formulation and the saline formulation have a pH and osmolarity which are identical.

47. The method of claim 46, wherein the glucose-regulating peptide is selected from the group consisting of amylin, an amylin analog, pramlintide, glucagons-like peptide-1 (GLP) and exendin-3, exendin-4.

48. The method claim 46 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, (ii) a phospholipid additive, mixed micelle, liposome, or carrier, (iii) an alcohol, (iv) an enamine, (v) an NO donor compound, (vi) a long-chain amphipathic molecule (vii) a small hydrophobic penetration enhancer;

(viii) sodium or a salicylic acid derivative;

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

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

(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.

49. The method of claim 46 wherein the formulation is an aqueous formulation comprised of water and a glucose-regulating peptide.

50. The method of claim 49 wherein the glucose-regulating peptide is selected from the group consisting of a amylin peptide, an GLP peptide, and a exendin peptide.

51. The method of claim 46 wherein the glucose-regulating peptide is a amylin peptide, wherein the amylin peptide is comprised of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-47.

52. The method of claim 49 wherein the formulation is further comprised of at least one transmucosal delivery agent.

53. The method of claim 52 wherein the transmucosal delivery agent is 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, (ii) a phospholipid additive, mixed micelle, liposome, or carrier, (iii) an alcohol, (iv) an enamine, (v) an NO donor compound, (vi) a long-chain amphipathic molecule (vii) a small hydrophobic penetration enhancer;

(viii) sodium or a salicylic acid derivative;

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

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

(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.

54. The method claim 49 wherein the formulation is further comprised of at least one polyol.

55. The formulation of claim 54 wherein the polyol is mannitol, lactose or sorbitol.

56. The method of claim 49 wherein the formulation is further comprised of a chelating agent.

57. The method of claim 56 wherein the chelating agent is ethylenediamine tetraacetic acid (EDTA).

58. The method of claim 49 wherein the formulation is further comprised of a solubilizing agent.

59. The method of claim 58 wherein the solubilizing agent is a cyclodextrin.

60. The method of claim 49 wherein the formulation is further comprised of a surfactant.

61. The method of claim 60 wherein the surfactant is L-α

-Phosphatidylcholine didecanoyl (DDPC).

62. The method of claim 49 wherein the GRP agonist is exendin-4 peptide.

63. The method of claim 49 wherein the formulation has a pH of about of about 2-8.

64. A method for administering a glucose-regulating peptide comprising intranasally administering an aqueous glucose-regulating peptide formulation comprised of a glucose-regulating peptide, water and a solubilizing agent wherein the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

65. The method of claim 64 wherein said solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

66. The method of claim 64 wherein the formulation is further comprised of one or more polyols.

67. The method of claim 66 wherein the polyol is selected from the group consisting of lactose, sorbitol, trehalose, sucrose, mannose, mannitol and maltose and derivatives and homologs thereof.

68. The method of claim 64 wherein the formulation is further comprised of a surface-active agent and a chelating agent.

69. The method of claim 68 wherein the surface-active agent is 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.

70. The method of claim 64 wherein the GRP is selected from the group consisting of exendin-3, exendin-4, amylin, pramlintide, GLP-1.

71. The method of claim 64 wherein the GRP is a peptide selected from the group consisting of SEQ ID NO:

1-47.

72. The method of claim 71 wherein the peptide has a carboxyl-terminus amino acid residue, wherein said carboxyl-terminus amino acid residue is acetylated.

73. A method for administering a glucose-regulating peptide comprising intranasally administering an aqueous glucose-regulating peptide formulation comprised of water, the glucose-regulating peptide, and a chelating agent wherein the pH of the formulation is about 2 to about 8, and the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

74. The method of claim 73 wherein the formulation is further comprised of one or more polyols.

75. The method of claim 73 wherein the formulation is further comprised of a solubilizng agent.

76. The method of claim 75 wherein the solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

77. The method of claim 73 wherein the formulation is further comprised of a surface-active agent.

78. The method of claim 77 wherein the surface-active agent is 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.

79. The method of claim 73 wherein the glucose-regulating peptide is a peptide selected from the group of SEQ ID NOs:

1-47.

80. The method of claim 79 wherein the peptide has a carboxyl-terminus amino acid residue, wherein said carboxyl-terminus amino acid residue is acetylated.

81. A method for administering a glucose-regulating peptide comprising intranasally administering an aqueous glucose-regulating peptide formulation comprised of the glucose-regulating peptide, water, and a solubilizing agent wherein the formulation has a pH of 2.0 to about 8 and the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

82. The method of claim 81 wherein the solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

83. The method of claim 81 wherein the formulation is further comprised of a chelating agent.

84. The method of claim 81 wherein the glucose-regulating peptide is a peptide selected from the group consisting SEQ ID NOs:

1-47.

85. The method of claim 84 wherein the peptide has a carboxyl-terminus amino acid residue wherein said carboxyl-terminus amino acid residue is acetylated.

86. A method for administering a glucose-regulating peptide comprising intranasally administering an aqueous glucose-regulating peptide formulation, wherein said formulation is comprised of the glucose-regulating peptide, water, a chelatng agent and a surface-active agent wherein the formulation has a pH of 2.0 to about 8 and the formulation is substantially free of a stabilizer that is a polypeptide or a protein.

87. The method of claim 86 wherein the surface-active agent is selected from the group consisting of polysorbate 20, polysorbate 80, PEG, cetyl alcohol, PVP, PVA, L-α

-phosphatidylcholine didecanoyl (DDPC), lanolin alcohol, and sorbitan monooleate.

88. The method of claim 86 wherein the formulation is further comprised of a solubilizing agent.

89. The method of claim 88 wherein the solubilizing agent is selected from the group consisting of hydroxypropyl-β

-cyclodextran, sulfobutylether-β

-cyclodextran and methyl-β

-cyclodextrin.

90. A transmucosal glucose-regulating peptide formulation wherein the glucose-regulating peptide in the transmucosal glucose-regulating peptide formulation has bioavailibility of at least 10% when administered intranasally to a human.

91. The formulation of claim 90, wherein the glucose-regulating peptide is selected from the group consisting of amylin, an amylin analog, pramlintide, glucagons-like peptide-1 (GLP) and exendin-3, exendin-4.

92. The formulation of claim 90 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, (ii) a phospholipid additive, mixed micelle, liposome, or carrier, (iii) an alcohol, (iv) an enamine, (v) an NO donor compound, (vi) a long-chain amphipathic molecule (vii) a small hydrophobic penetration enhancer;

(viii) sodium or a salicylic acid derivative;

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

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

(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.

93. The formulation of claims 90 wherein the formulation is an intranasal formulation.

94. The formulation of claim 90, wherein the formulation is an aqueous formulation comprised of water and a glucose-regulating peptide.

95. The formulation of claim 94 wherein the glucose-regulating peptide is selected from the group consisting of a amylin peptide, an GLP peptide, and a exendin peptide.

96. The formulation of claim 95 wherein the glucose-regulating peptide is a amylin peptide, wherein the amylin peptide is comprised of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-47.

97. The formulation of claim 90 wherein the formulation is further comprised of at least one transmucosal delivery agent.

98. A method of administering glucose-regulating peptide comprising intranasally administering a transmucosal glucose-regulating formulation, wherein the glucose-regulating peptide in the transmucosal glucose-regulating peptide formulation has bioavailibility of at least 10% when administered intranasally to a human.

99. The method of claim 98, wherein the glucose-regulating peptide is selected from the group consisting of amylin, an amylin analog, pramlintide, glucagons-like peptide-1 (GLP) and exendin-3, exendin-4.

100. The method claim 99 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, (ii) a phospholipid additive, mixed micelle, liposome, or carrier, (iii) an alcohol, (iv) an enamine, (v) an NO donor compound, (vi) a long-chain amphipathic molecule (vii) a small hydrophobic penetration enhancer;

(viii) sodium or a salicylic acid derivative;

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

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

(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.

101. The method of claim 98 wherein the formulation is an aqueous formulation comprised of water and a glucose-regulating peptide.

102. The method of claim 101 wherein the glucose-regulating peptide is selected from the group consisting of an amylin peptide, an GLP peptide, and a exendin peptide.

103. The method of claim 98 wherein the glucose-regulating peptide is a amylin peptide, wherein the amylin peptide is comprised of an amino acid sequence selected from the group consisting of SEQ ID NOs:

1-47.