CA2437940A1 - Methods of treating diabetes mellitus - Google Patents

Methods of treating diabetes mellitus Download PDF

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CA2437940A1
CA2437940A1 CA002437940A CA2437940A CA2437940A1 CA 2437940 A1 CA2437940 A1 CA 2437940A1 CA 002437940 A CA002437940 A CA 002437940A CA 2437940 A CA2437940 A CA 2437940A CA 2437940 A1 CA2437940 A1 CA 2437940A1
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insulin
moiety
human
patient
conjugate
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CA2437940C (en
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Nnochiri N. Ekwuribe
Christopher H. Price
James Gordon Still
Jennifer Ann Filbey
Balasingam Radhakrishnan
Aslam M. Ansari
Amy L. Odenbaugh
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Biocon Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/62—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Methods of treating diabetes mellitus in a patient in need of such treatment include administering an effective amount of an insulin drug to the patient in order to treat diabetes mellitus in the patient. Methods according to the present invention may "activate" the liver, potentially restoring normal glucose homeostasis to individuals suffering from diabetes mellitus.

Claims (339)

1. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide derivative to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide derivative is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
2. A method according to Claim 1, wherein the oral administration of the effective amount of the insulin polypeptide derivative provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.
3. A method according to Claim 1, wherein the effective amount of the insulin polypeptide derivative is between about 0.05 and about 10 mg per kilogram body weight.
4. A method according to Claim 1, wherein the oral administration of the effective amount of the insulin polypeptide derivative provides a maximum insulin drug concentration in peripheral blood within about 60 minutes.
5. A method according to Claim 1, wherein the oral administration of the effective amount of the insulin polypeptide derivative stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
6. A method according to Claim 1, wherein the insulin polypeptide derivative clears the bloodstream of the patient within about 4 hours following administration.
7. A method according to Claim 1, wherein the administration of the effective amount of the insulin polypeptide derivative reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
8. A method according to Claim 7, wherein the reduction in hepatic glucose production occurs within about 90 minutes of administration.
9. A method according to Claim 1, wherein the insulin polypeptide derivative is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal.
10. A method according to Claim 1, wherein the insulin polypeptide derivative is orally administered less than about one hour prior to ingestion of a meal by the patient.
11. A method according to Claim 1, wherein the insulin polypeptide derivative is orally administered substantially contemporaneously with the ingestion of a meal by the patient.
12. A method according to Claim 1, wherein the insulin polypeptide derivative is orally administered less than about one hour after ingestion of a meal by the patient.
13. A method according to Claim 1, wherein the insulin polypeptide in the insulin polypeptide derivative is insulin.
14. A method according to Claim 1, wherein the insulin polypeptide derivative is an insulin polypeptide-oligomer conjugate.
15. A method according to Claim 14, wherein the insulin polypeptide-oligomer conjugate is an amphiphilically balanced insulin polypeptide-oligomer conjugate.
16. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an amphiphilically-balanced insulin polypeptide-oligomer conjugate to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
17. A method according to Claim 16, wherein the oral administration of the effective amount of the amphiphilically balanced insulin polypeptide-oligomer conjugate provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.
18. A method according to Claim 16, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is between about 0.05 and about 10 mg per kilogram body weight.
19. A method according to Claim 16, wherein the oral administration of the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate provides a maximum insulin drug concentration in peripheral blood within about 60 minutes.
20. A method according to Claim 16, wherein the oral administration of the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
21 . A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate clears the bloodstream of the patient within about 4 hours following administration.
22. A method according to Claim 16, wherein the administration of the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
23. A method according to Claim 22, wherein the reduction in hepatic glucose production occurs within about 90 minutes of administration.
24. A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal.
25. A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate is orally administered less than about one hour prior to ingestion of a meal by the patient.
26. A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate is orally administered substantially contemporaneously with the ingestion of a meal by the patient.
27. A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate is orally administered less than about one hour after ingestion of a meal by the patient.
28. A method according to Claim 16, wherein the insulin polypeptide is insulin.
29. A method according to Claim 28, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
30. A method according to Claim 16, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
31. A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide oligomer conjugate is present as a substantially monodispersed mixture.
32. A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate is present as a monodispersed mixture.
33. A method according to Claim 16, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is present in a pharmaceutical composition.
34. A method according to Claim 16, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate comprises a hydrophilic moiety and a lipophilic moiety.
35. A method according to Claim 34, wherein the hydrophilic moiety is a polyalkylene glycol moiety.
36. A method according to Claim 34, wherein the polyalkylene glycol moiety is a polyethylene glycol moiety.
37. A method according to Claim 34, wherein the polyalkylene glycol moiety has between 1 and 50 polyalkylene glycol subunits.
38. A method according to Claim 34, wherein the polyalkylene glycol moiety has between 3 and 50 polyalkylene glycol subunits.
39. A method according to Claim 34, wherein the polyalkylene glycol moiety has between 2 and 10 polyalkylene glycol subunits.
40. A method according to Claim 34, wherein the polyalkylene glycol moiety has between 4 and 10 polyalkylene glycol subunits.
41. A method according to Claim 34, wherein the polyalkylene glycol moiety has at least 2 polyalkylene glycol subunits.
42. A method according to Claim 34, wherein the lipophilic moiety is an alkyl or fatty acid moiety.
43. A method according to Claim 34, wherein the lipophilic moiety has between and 28 carbon atoms.
44. A method according to Claim 34, wherein the lipophilic moiety has between and 24 carbon atoms.
45. A method according to Claim 34, wherein the lipophilic moiety has between and 18 carbon atoms.
46. A method according to Claim 34, wherein the lipophilic moiety has between and 12 carbon atoms.
47. A method according to Claim 34, wherein the lipophilic moiety has between and 7 carbon atoms.
48. A method according to Claim 34, wherein the lipophilic moiety has between and 14 carbon atoms.
49. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula I:

Insulin Polypeptide~B~L j~G k~R~G'm~R'~G"n~T (I) wherein:
B is a bonding moiety;
L is a linker moiety;
G, G' and G" are individually selected spacer moieties;
R is a lipophilic moiety and R' is a polyalkylene glycol moiety, or R' is the lipophilic moiety and R is the polyalkylene glycol moiety;

T is a terminating moiety; and j, k, m and n are individually 0 or 1;
to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the conjugate of Formula I is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
50. A method according to Claim 49, wherein the oral administration of the effective amount of the conjugate of Formula I provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.
51. A method according to Claim 49, wherein the effective amount of the conjugate of Formula I is between about 0.05 and 10 mg per kilogram body weight.
52. A method according to Claim 49, wherein the oral administration of the effective amount of the conjugate of Formula I provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.
53. A method according to Claim 49, wherein the oral administration of the effective amount of the conjugate of Formula I stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
54. A method according to Claim 49, wherein the conjugate of Formula I clears the bloodstream of the patient within about 4 hours following administration.
55. A method according to Claim 49, wherein the administration of the effective amount of the conjugate of Formula I reduces hepatic glucose production in the patient by at Least about 25 percent when compared to hepatic glucose production in the patient without administration.
56. A method according to Claim 55, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
57. A method according to Claim 49, wherein the conjugate of Formula I is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal.
58. A method according to Claim 49, wherein the conjugate of Formula I is orally administered less than about one hour prior to ingestion of a meal by the patient.
59. A method according to Claim 49, wherein the conjugate of Formula I is orally administered substantially contemporaneously with the ingestion of a meal by the patient.
60. A method according to Claim 49, wherein the conjugate of Formula I is orally administered less than about one hour after ingestion of a meal by the patient.
61. A method according to Claim 49, wherein the insulin polypeptide is insulin.
62. A method according to Claim 61, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
63. A method according to Claim 49, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
64. A method according to Claim 49, wherein the conjugate of Formula I is present as a substantially monodispersed mixture.
65. A method according to Claim 49, wherein the conjugate of Formula I is present as a monodispersed mixture.
66. A method according to Claim 49, wherein the conjugate of Formula I is amphiphilically balanced.
67. A method according to Claim 49, wherein the effective amount of the conjugate of Formula I is present in a pharmaceutical composition.
68. A method according to Claim 49, wherein B is selected from the group consisting of an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety and a covalent bond.
69. A method according to Claim 49, wherein L is selected from the group consisting of alkyl moieties and fatty acid moieties.
70. A method according to Claim 49, wherein G, G' and G" are individually selected from the group consisting of sugar moieties, cholesterol, and glycerine moieties.
71. A method according to Claim 49, wherein T is selected from the group consisting of alkyl and alkoxy.
72. A method according to Claim 49, wherein the polyalkylene glycol moiety is a polyethylene glycol moiety.
73. A method according to Claim 72, wherein the polyethylene glycol moiety has between l and 50 polyethylene glycol subunits.
74. A method according to Claim 72, wherein the polyethylene glycol moiety has between 3 and 50 polyethylene glycol subunits.
75. A method according to Claim 72, wherein the polyethylene glycol moiety has between 2 and 10 polyethylene glycol subunits.
76. A method according to Claim 72, wherein the polyethylene glycol moiety has between 4 and 10 polyethylene glycol subunits.
77. A method according to Claim 72, wherein the polyethylene glycol moiety has at least 2 polyethylene glycol subunits.
78. A method according to Claim 49, wherein the lipophilic moiety is an alkyl or a fatty acid moiety.
79. A method according to Claim 78, wherein the lipophilic moiety has between and 28 carbon atoms.
80. A method according to Claim 78, wherein the lipophilic moiety has between and 24 carbon atoms.
81. A method according to Claim 78, wherein the lipophilic moiety has between and 18 carbon atoms.
82. A method according to Claim 78, wherein the lipophilic moiety has between and 12 carbon atoms.
83. A method according to Claim 78, wherein the lipophilic moiety has between and 7 carbon atoms.
84. A method according to Claim 78, wherein the lipophilic moiety has between and 14 carbon atoms.
85. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula II:

Insulin polypeptide ~ X(CH2)m Y(C2H4O)n R (II) wherein:

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety or a covalent bond;
Y is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety or a covalent bond;
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the conjugate of Formula II is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
86. A method according to Claim 85, wherein the oral administration of the effective amount of the conjugate of Formula II provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.
87. A method according to Claim 85, wherein the effective amount of the conjugate of Formula II is between about 0.05 and 10 mg per kilogram body weight.
88. A method according to Claim 85, wherein the oral administration of the effective amount of the conjugate of Formula II provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.
89. A method according to Claim 85, wherein the oral administration of the effective amount of the conjugate of Formula II stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
90. A method according to Claim 85, wherein the conjugate of Formula II clears the bloodstream of the patient within about 4 hours following administration.
91. A method according to Claim 85, wherein the administration of the effective amount of the conjugate of Formula II reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
92. A method according to Claim 91, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
93. A method according to Claim 85, wherein the conjugate of Formula II is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the patient.
94. A method according to Claim 85, wherein the conjugate of Formula II is orally administered less than about one hour prior to ingestion of a meal by the patient.
95. A method according to Claim 85, wherein the conjugate of Formula II is orally administered substantially contemporaneously with the ingestion of a meal by the patient.
96. A method according to Claim 85, wherein the conjugate of Formula II is orally administered less than one about hour after ingestion of a meal by the patient.
97. A method according to Claim 85, wherein the insulin polypeptide is insulin.
98. A method according to Claim 97, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
99. A method according to Claim 85, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
100. A method according to Claim 85, wherein the conjugate of Formula II is present as a substantially monodispersed mixture.
101. A method according to Claim 85, wherein the conjugate of Formula II is present as a monodispersed mixture.
102. A method according to Claim 85, wherein the conjugate of Formula II is amphiphilically balanced.
103. A method according to Claim 85, wherein the effective amount of the conjugate of Formula II is present in a pharmaceutical composition.
104. A method according to Claim 85, wherein the polyalkylene glycol moiety is a polyethylene glycol moiety.
105. A method according to Claim 85, wherein m is between 3 and 16.
106. A method according to Claim 85, wherein m is between 4 and 14.
107. A method according to Claim 85, wherein m is between 5 and 10.
108. A method according to Claim 85, wherein n is between 3 and 18.
109. A method according to Claim 85, wherein n is between 4 and 14.
110. A method according to Claim 85, wherein n is between 5 and 10.
111. A method according to Claim 85, wherein R is lower alkyl.
112. A method according to Claim 85, wherein R is C1 to C3 alkyl.
113. A method according to Claim $5, wherein R is methyl.
114. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III:

Insulin polypeptide ~ X(CH2)m(OC2H4)n OR (III) wherein:
X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between l and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantine, an alcohol moiety, or a fatty acid moiety;
to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the conjugate of Formula III is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
115. A method according to Claim 114, wherein the oral administration of the effective amount of the conjugate of Formula III provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.
116. A method according to Claim 114, wherein the effective amount of the conjugate of Formula III is between about 0.05 and 10 mg per kilogram body weight.
117. A method according to Claim 114, wherein the oral administration of the effective amount of the conjugate of Formula III provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.
118. A method according to Claim 114, wherein the oral administration of the effective amount of the conjugate of Formula III stabilizes peripheral glucose concentration to within about+/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
119. A method according to Claim 114, wherein the conjugate of Formula III
clears the bloodstream of the patient within about 4 hours following administration.
120. A method according to Claim 114, wherein the administration of the effective amount of the conjugate of Formula III reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
121. A method according to Claim 120, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
122. A method according to Claim 114, wherein the conjugate of Formula III is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the patient.
123. A method according to Claim 114, wherein the conjugate of Formula III is orally administered less than about one hour prior to ingestion of a meal by the patient.
124. A method according to Claim 114, wherein the conjugate of Formula III is orally administered substantially contemporaneously with the ingestion of a meal by the patient.
125. A method according to Claim 114, wherein the conjugate of Formula III is orally administered less than about one hour after ingestion of a meal by the patient.
126. A method according to Claim 114, wherein the insulin polypeptide is insulin.
127. A method according to Claim 126, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
128. A method according to Claim 114, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human;
Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human;
Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human;
Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human;
Leu B28 insulin, human; Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
129. A method according to Claim 114, wherein the conjugate of Formula III is present as a substantially monodispersed mixture.
130. A method according to Claim 114, wherein the conjugate of Formula III is present as a monodispersed mixture.
131. A method according to Claim 114, wherein the conjugate of Formula III is amphiphilically balanced.
132. A method according to Claim 114, wherein the effective amount of the conjugate of Formula III is present in a pharmaceutical composition.
133. A method according to Claim 114, wherein m is between 3 and 16.
134. A method according to Claim 114, wherein m is between 4 and 14.
135. A method according to Claim 114, wherein m is between 5 and 10.
136. A method according to Claim 114, wherein n is between 3 and 18.
137. A method according to Claim 114, wherein n is between 4 and 14.
138. A method according to Claim 114, wherein n is between 5 and 10.
139. A method according to Claim 114, wherein R is lower alkyl.
140. A method according to Claim 114, wherein R is C1 to C3 alkyl.
141. A method according to Claim 114, wherein R is methyl.
142. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula IV:

wherein:

m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the conjugate of Formula IV is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
143. A method according to Claim 142, wherein the oral administration of the effective amount of the conjugate of Formula IV provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.
144. A method according to Claim 142, wherein the effective amount of the conjugate of Formula IV is between about 0.05 and about 10 mg per kilogram body weight.
145. A method according to Claim 142, wherein the oral administration of the effective amount of the conjugate of Formula IV provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.
146. A method according to Claim 142, wherein the oral administration of the effective amount of the conjugate of Formula IV stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
147. A method according to Claim 142, wherein the conjugate of Formula IV
clears the bloodstream of the patient within about 4 hours following administration.
148. A method according to Claim 142, wherein the administration of the effective amount of the conjugate of Formula IV reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
149. A method according to Claim 148, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
150. A method according to Claim 142, wherein the conjugate of Formula IV is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the patient.
151. A method according to Claim 142, wherein the conjugate of Formula IV is orally administered less than about one hour prior to ingestion of a meal by the patient.
152. A method according to Claim 142, wherein the conjugate of Formula IV is orally administered substantially contemporaneously with the ingestion of a meal by the patient.
153. A method according to Claim 142, wherein the conjugate of Formula IV is orally administered less than about one hour after ingestion of a meal by the patient.
154. A method according to Claim 142, wherein the insulin polypeptide is insulin.
155. A method according to Claim 154, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
156. A method according to Claim 142, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human;
Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human;
Gln B3 insulin, human; Gly A21 Glu B3 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human;
Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human;
Leu B28 insulin, human; Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
157. A method according to Claim 142, wherein the conjugate of Formula IV is present as a substantially monodispersed mixture.
158. A method according to Claim 142, wherein the conjugate of Formula IV is present as a monodispersed mixture.
159. A method according to Claim 142, wherein the conjugate of Formula IV is amphiphilically balanced.
160. A method according to Claim 142, wherein the effective amount of the conjugate of Formula IV is present in a pharmaceutical composition.
161. A method according to Claim 142, wherein m is between 3 and 16.
162. A method according to Claim 142, wherein m is between 4 and 14.
163. A method according to Claim 142, wherein m is between 5 and 10.
164. A method according to Claim 142, wherein n is between 3 and 18.
165. A method according to Claim 142, wherein n is between 4 and 14.
166. A method according to Claim 142, wherein n is between 5 and 10.
167. A method according to Claim 142, wherein R is lower alkyl.
168. A method according to Claim 142, wherein R is C1 to C3 alkyl.
169. A method according to Claim 142, wherein R is methyl.
170. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula V:

to the patient within one hour of ingestion of a meal by the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the conjugate of Formula V is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
171. A method according to Claim 170, wherein the oral administration of the effective amount of the conjugate of Formula V provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 30 minutes of administration.
172. A method according to Claim 170, wherein the effective amount of the conjugate of Formula V is between about 0.05 and 10 mg per kilogram body weight.
173. A method according to Claim 170, wherein the oral administration of the effective amount of the conjugate of Formula V provides a maximum insulin drug concentration in peripheral blood within about 60 minutes after administration.
174. A method according to Claim 170, wherein the oral administration of the effective amount of the conjugate of Formula V stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
175. A method according to Claim 170, wherein the conjugate of Formula V
clears the bloodstream of the patient within about 4 hours following administration.
176. A method according to Claim 170, wherein the administration of the effective amount of the conjugate of Formula V reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without .
administration.
177. A method according to Claim 176, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
178. A method according to Claim 170, wherein the conjugate of Formula V is orally administered such that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the patient.
179. A method according to Claim 170, wherein the conjugate of Formula V is orally administered less than about one hour prior to ingestion of a meal by the patient.
180. A method according to Claim 170, wherein the conjugate of Formula V is orally administered substantially contemporaneously with the ingestion of a meal by the patient.
181. A method according to Claim 170, wherein the conjugate of Formula V is orally administered less than about one hour after ingestion of a meal by the patient.
182. A method according to Claim 170, wherein the insulin polypeptide is insulin.
183. A method according to Claim 182, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
184. A method according to Claim 170, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human;
Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human;
Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human;
Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; lys B28 insulin, human;
Leu B28 insulin, human; Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
185. A method according to Claim 170, wherein the conjugate of Formula V is present as a substantially monodispersed mixture.
186. A method according to Claim 170, wherein the conjugate of Formula V is present as a monodispersed mixture.
187. A method according to Claim 170, wherein the effective amount of the conjugate of Formula V is present in a pharmaceutical composition.
188. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide derivative to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide derivative is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
189. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of an insulin polypeptide derivative to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide derivative is administered so that it stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
190. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide derivative to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide derivative is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
191. A method according to Claim 190, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
192. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide derivative to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the insulin polypeptide derivative is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the patient.
193. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an amphiphilically-balanced insulin polypeptide-oligomer conjugate to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and about 1,000 U/ml within about 60 minutes of administration.
194. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an amphiphilically-balanced insulin polypeptide-oligomer conjugate to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
195. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an amphiphilically-balanced insulin polypeptide-oligomer conjugate to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
196. A method according to Claim I95, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
197. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an amphiphilically-balanced insulin polypeptide-oligomer conjugate to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes of ingestion of the meal by the patient.
198. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula I:

Insulin Polypeptide-B-L j-G k-R-G'm-R'-G" n-T (I) wherein:

B is a bonding moiety selected from the group consisting of an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety and a covalent bond;
L is a linker moiety selected from the group consisting of alkyl moieties and fatty acid moieties;

G, G' and G" are spacer moieties individually selected from the group consisting of sugar moieties, cholesterol, and glycerine moieties;

R is a lipophilic moiety and R' is a polyalkylene glycol moiety, or R' is the lipophilic moiety and R is the polyalkylene glycol moiety;

T is a terminating moiety selected from the group consisting of alkyl and alkoxy; and j, k, m and n are individually 0 or 1;

to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
199. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula I:

Insulin Polypeptide-B-L j-G k-R-G'm R'-G"n-T (I) wherein:

B is a bonding moiety selected from the group consisting of an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, and a covalent bond;
L is a linker moiety selected from the group consisting of alkyl moieties and fatty acid moieties;

G, G' and G" are spacer moieties individually selected from the group consisting of sugar moieties, cholesterol, and glycerine moieties;

R is a lipophilic moiety and R' is a polyalkylene glycol moiety, or R' is the lipophilic moiety and R is the polyalkylene glycol moiety;

T is a terminating moiety selected from the group consisting of alkyl and alkoxy; and j, k, m and n are individually 0 or 1;

to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
200. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula I:

Insulin Polypeptide-B-L j-G k-R-G'm-R'-G"n-T (I) wherein:

B is a bonding moiety selected from the group consisting of an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, and a covalent bond;

L is a linker moiety selected from the group consisting of alkyl moieties and fatty acid moieties;
G, G' and G" are spacer moieties individually selected from the group consisting of sugar moieties, cholesterol, and glycerine moieties;

R is a lipophilic moiety and R' is a polyalkylene glycol moiety, or R' is the lipophilic moiety and R is the polyalkylene glycol moiety;

T is a terminating moiety selected from the group consisting of alkyl and alkoxy; and j, k, m and n are individually 0 or 1;
to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
201. A method according to Claim 200, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
202. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula I:

Insulin Polypeptide-B-L j-G k-R-G'm R'-G"n-T (I) wherein:
B is a bonding moiety selected from the group consisting of an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, and a covalent bond;
L is a linker moiety selected from the group consisting of alkyl moieties and fatty acid moieties;

G, G' and G" are spacer moieties individually selected from the group consisting of sugar moieties, cholesterol, and glycerine moieties;

R is a lipophilic moiety and R' is a polyalkylene glycol moiety, or R' is the lipophilic moiety and R is the polyalkylene glycol moiety;

T is a terminating moiety selected from the group consisting of alkyl and alkoxy; and j, k, m and n are individually 0 or 1;

to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes of ingestion of the meal by the patient.
203. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula II:

Insulin polypeptide X(CH2)m Y(C2H4O)n R (II) wherein:

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thin-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

Y is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

m is between 1 and 24;

n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the patient tin order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
204. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula II:

Insulin polypeptide X(CH2)m Y(C2H40)"R (II) wherein:
X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
Y is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between 1 and 24;

n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
205. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula II:

Insulin polypeptide X(CH2)m Y(C2H4O)n R (II) wherein:

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

Y is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between 1 and 24;

n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
206. A method according to Claim 205, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
207. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of an insulin polypeptide-oligomer conjugate comprising the structure of Formula II:

Insulin polypeptide X(CH2)m Y(C2H4O)n R (II) wherein:

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

Y is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;

m is between 1 and 24;

n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes of ingestion of the meal by the patient.
208. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III:

Insulin polypeptide X(CH2)m(OC2H4)n OR (III) wherein:

X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
209. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III:
Insulin polypeptide~X(CH2)m(OC2H4)n OR (III) wherein:
X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
210. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III:
Insulin polypeptide~X(GH2)m(OC2H4)n OR (III) wherein:
X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;

to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
211. A method according to Claim 210, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
212. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula III:
Insulin polypeptide~X(CH2)m(OC2H4)n OR (III) wherein:
X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thin-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes of ingestion of the meal by the patient.
213. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula IV:

wherein:
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
214. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula IV:
wherein:
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
215. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:

orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula IV:
wherein:
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
216. A method according to Claim 215, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
217. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula IV:
wherein:
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes of ingestion of the meal by the patient.
218. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula V:
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it provides an insulin drug concentration in portal vein blood between about 10 and 1,000 U/ml within about 60 minutes of administration.
219. A method according to Claim 218, wherein the insulin polypeptide is insulin.
220. A method according to Claim 219, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
221. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula V:
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it stabilizes peripheral glucose concentration to within about +/- 50 percent of an average peripheral glucose concentration measured over about a one hour time period beginning within about 30 minutes after administration.
222. A method according to Claim 221, wherein the insulin polypeptide is insulin.
223. A method according to Claim 222, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
224. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula V:
to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that it reduces hepatic glucose production in the patient by at least about 25 percent when compared to hepatic glucose production in the patient without administration.
225. A method according to Claim 224, wherein the reduction in hepatic glucose production occurs within about 90 minutes after administration.
226. A method according to Claim 224, wherein the insulin polypeptide is insulin.
227. A method according to Claim 226, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
228. A method of treating diabetes mellitus in a patient in need of such treatment, said method comprising:
orally administering an effective amount of a insulin polypeptide-oligomer conjugate comprising the structure of Formula V:

to the patient in order to treat diabetes mellitus in the patient, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is administered so that at least about 25 percent of post-prandial glucose resulting from ingestion of a meal by the patient is hepatically absorbed within about 120 minutes after ingestion of the meal by the patient.
229. A method according to Claim 228, wherein the insulin polypeptide is insulin.
230. A method according to Claim 229, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
231. The use of an insulin polypeptide derivative for the preparation of an orally administrable medicament for the treatment of diabetes mellitus.
232. The use according to Claim 231, wherein the insulin polypeptide derivative is an insulin polypeptide-oligomer conjugate.
233. The use according to Claim 232, wherein the insulin polypeptide-oligomer conjugate is an amphiphilically balanced insulin polypeptide-oligomer conjugate.
234. The use of an amphiphilically-balanced insulin polypeptide-oligomer conjugate for the preparation of an orally administrable medicament for the treatment of diabetes mellitus.
235. The use according to Claim 234, wherein the insulin polypeptide is insulin.
236. The use according to Claim 235, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
237. The use according to Claim 234, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
238. The use according to Claim 234, wherein the amphiphilically-balanced insulin polypeptide oligomer conjugate is present as a substantially monodispersed mixture.
239. The use according to Claim 234, wherein the amphphilically-balanced insulin polypeptide-oligomer conjugate is present as a monodispersed mixture.
240. The use according to Claim 234, wherein the effective amount of the amphiphilically-balanced insulin polypeptide-oligomer conjugate is present in a pharmaceutical composition.
241. The use according to Claim 234, wherein the amphiphilically-balanced insulin polypeptide-oligomer conjugate comprises a hydrophilic moiety and a lipophilic moiety.
242. The use according to Claim 241, wherein the hydrophilic moiety is a polyalkylene glycol moiety.
243. The use according to Claim 241, wherein the polyalkylene glycol moiety is a polyethylene glycol moiety.
244. The use according to Claim 241, wherein the polyalkylene glycol moiety has between 1 and 50 polyalkylene glycol subunits.
245. The use according to Claim 241, wherein the polyalkylene glycol moiety has between 3 and 50 polyalkylene glycol subunits.
246. The use according to Claim 241, wherein the polyalkylene glycol moiety has between 2 and 10 polyalkylene glycol subunits.
247. The use according to Claim 241, wherein the polyalkylene glycol moiety has between 4 and 10 polyalkylene glycol subunits.
248. The use according to Claim 241, wherein the polyalkylene glycol moiety has at least 2 polyalkylene glycol subunits.
249. The use according to Claim 241, wherein the lipophilic moiety is an alkyl or fatty acid moiety.
250. The use according to Claim 241, wherein the lipophilic moiety has between and 28 carbon atoms.
251. The use according to Claim 241, wherein the lipophilic moiety has between and 24 carbon atoms.
252. The use according to Claim 241, wherein the lipophilic moiety has between and 18 carbon atoms.
253. The use according to Claim 241, wherein the lipophilic moiety has between and 12 carbon atoms.
254. The use according to Claim 241, wherein the lipophilic moiety has between and 7 carbon atoms.
255. The use according to Claim 241, wherein the lipophilic moiety has between and 14 carbon atoms.
256. The use of an insulin polypeptide-oligomer conjugate comprising the structure of Formula I:
Insulin Polypeptide~B~L j~G k~R~G'm~R'~G"n~T (I) wherein:

B is a bonding moiety;
L is a linker moiety;
G, G' and G" are individually selected spacer moieties;
R is a lipophilic moiety and R' is a polyalkylene glycol moiety, or R' is the lipophilic moiety and R is the polyalkylene glycol moiety;
T is a terminating moiety; and j, k, m and n are individually 0 or 1;
for the preparation of an orally administrable medicament for the treatment of diabetes mellitus.
257. The use according to Claim 256, wherein the insulin polypeptide is insulin.
258. The use according to Claim 257, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
259. The use according to Claim 256, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
260. The use according to Claim 256, wherein the conjugate of Formula I is present as a substantially monodispersed mixture.
261. The use according to Claim 256, wherein the conjugate of Formula I is present as a monodispersed mixture.
262. The use according to Claim 256, wherein the conjugate of Formula I is amphiphilically balanced.
263. The use according to Claim 256, wherein the effective amount of the conjugate of Formula I is present in a pharmaceutical composition.
264. The use according to Claim 256, wherein B is selected from the group consisting of an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thin-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety and a covalent bond.
265. The use according to Claim 256, wherein L is selected from the group consisting of alkyl moieties and fatty acid moieties.
266. The use according to Claim 256, wherein G, G' and G" are individually selected from the group consisting of sugar moieties, cholesterol, and glycerine moieties.
267. The use according to Claim 256, wherein T is selected from the group consisting of alkyl and alkoxy.
268. The use according to Claim 256, wherein the polyalkylene glycol moiety is a polyethylene glycol moiety.
269. The use according to Claim 268, wherein the polyethylene glycol moiety has between 1 and 50 polyethylene glycol subunits.
270. The use according to Claim 268, wherein the polyethylene glycol moiety has between 3 and 50 polyethylene glycol subunits.
271. The use according to Claim 268, wherein the polyethylene glycol moiety has between 2 and 10 polyethylene glycol subunits.
272. The use according to Claim 268, wherein the polyethylene glycol moiety has between 4 and 10 polyethylene glycol subunits.
273. The use according to Claim 268, wherein the polyethylene glycol moiety has at least 2 polyethylene glycol subunits.
274. The use according to Claim 256, wherein the lipophilic moiety is an alkyl or a fatty acid moiety.
275. The use according to Claim 274, wherein the lipophilic moiety has between and 28 carbon atoms.
276. The use according to Claim 274, wherein the lipophilic moiety has between and 24 carbon atoms.
277. The use according to Claim 274, wherein the lipophilic moiety has between and 18 carbon atoms.
278. The use according to Claim 274, wherein the lipophilic moiety has between and 12 carbon atoms.
279. The use according to Claim 274, wherein the lipophilic moiety has between and 7 carbon atoms.
280. The use according to Claim 274, wherein the lipophilic moiety has between and 14 carbon atoms.
281. The use of an insulin polypeptide-oligomer conjugate comprising the structure of Formula II:
Insulin polypeptide~X(CH2)m Y(C2H4O)n R (II) wherein:
X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety or a covalent bond;
Y is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, a thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety or a covalent bond;
m is between 1 and 24;

n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantine, an alcohol moiety, or a fatty acid moiety;
for the preparation of an orally administrable medicament for the treatment of diabetes mellitus.
282. The use according to Claim 281, wherein the insulin polypeptide is insulin.
283. The use according to Claim 282, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
284. The use according to Claim 281, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
285. The use according to Claim 281, wherein the conjugate of Formula II is present as a substantially monodispersed mixture.
286. The use according to Claim 281, wherein the conjugate of Formula II is present as a monodispersed mixture.
287. The use according to Claim 281, wherein the conjugate of Formula II is amphiphilically balanced.
288. The use according to Claim 281, wherein the effective amount of the conjugate of Formula II is present in a pharmaceutical, composition.
289. The use according to Claim 281, wherein the polyalkylene glycol moiety is a polyethylene glycol moiety.
290. The use according to Claim 281, wherein m is between 3 and 16.
291. The use according to Claim 281, wherein m is between 4 and 14.
292. The use according to Claim 281, wherein m is between 5 and 10.
293. The use according to Claim 281, wherein n is between 3 and 18.
294. The use according to Claim 281, wherein n is between 4 and 14.
295. The use according to Claim 281, wherein n is between 5 and 10.
296. The use according to Claim 281, wherein R is lower alkyl.
297. The use according to Claim 281, wherein R is C1 to C3 alkyl.
298. The use according to Claim 281, wherein R is methyl.
299. The use of an insulin polypeptide-oligomer conjugate comprising the structure of Formula III:
Insulin polypeptide~X(CH2)m(OC2H4)n OR (III) wherein:
X is an ester moiety, a thio-ester moiety, an ether moiety, a carbamate moiety, thio-carbamate moiety, a carbonate moiety, a thio-carbonate moiety, an amide moiety, a urea moiety, or a covalent bond;
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
for the preparation of an orally administrable medicament for the treatment of diabetes mellitus.
300. The use according to Claim 299, wherein the insulin polypeptide is insulin.
301. The use according to Claim 300, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
302. The use according to Claim 299, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
303. The use according to Claim 299, wherein the conjugate of Formula III is present as a substantially monodispersed mixture.
304. The use according to Claim 299, wherein the conjugate of Formula III is present as a monodispersed mixture.
305. The use according to Claim 299, wherein the conjugate of Formula III is amphiphilically balanced.
306. The use according to Claim 299, wherein the effective amount of the conjugate of Formula III is present in a pharmaceutical composition.
307. The use according to Claim 299, wherein m is between 3 and 16.
308. The use according to Claim 299, wherein m is between 4 and 14.
309. The use according to Claim 299, wherein m is between 5 and 10.
310. The use according to Claim 299, wherein n is between 3 and 18.
311. The use according to Claim 299, wherein n is between 4 and 14.
312. The use according to Claim 299, wherein n is between 5 and 10.
313. The use according to Claim 299, wherein R is lower alkyl.
314. The use according to Claim 299, wherein R is C1 to C3 alkyl.
315. The use according to Claim 299, wherein R is methyl.
316. The use of an insulin polypeptide-oligomer conjugate comprising the structure of Formula IV:
wherein:
m is between 1 and 24;
n is between 1 and 50; and R is an alkyl moiety, a sugar moiety, cholesterol, adamantane, an alcohol moiety, or a fatty acid moiety;
for the preparation of an orally administrable medicament for the treatment of diabetes mellitus.
317. The use according to Claim 316, wherein the insulin polypeptide is insulin.
318. The use according to Claim 317, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
319. The use according to Claim 316, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;

Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
320. The use according to Claim 316, wherein the conjugate of Formula IV is present as a substantially monodispersed mixture.
321. The use according to Claim 316, wherein the conjugate of Formula IV is present as a monodispersed mixture.
322. The use according to Claim 316, wherein the conjugate of Formula IV is amphiphilically balanced.
323. The use according to Claim 316, wherein the effective amount of the conjugate of Formula IV is present in a pharmaceutical composition.
324. The use according to Claim 316, wherein m is between 3 and 16.
325. The use according to Claim 316, wherein m is between 4 and 14.
326. The use according to Claim 316, wherein m is between 5 and 10.
327. The use according to Claim 316, wherein n is between 3 and 18.
328. The use according to Claim 316, wherein n is between 4 and 14.
329. The use according to Claim 316, wherein n is between 5 and 10.
330. The use according to Claim 316, wherein R is lower alkyl.
331. The use according to Claim 316, wherein R is C1 to C3 alkyl.
332. The use according to Claim 316, wherein R is methyl.
333. The use of an insulin polypeptide-oligomer conjugate comprising the structure of Formula V:
for the preparation of an orally administrable medicament for the treatment of diabetes mellitus.
334. The use according to Claim 333, wherein the insulin polypeptide is insulin.
335. The use according to Claim 334, wherein the oligomer is coupled to the lysine at the B29 position of the insulin.
336. The use according to Claim 333, wherein the insulin polypeptide is an insulin analog selected from the group consisting of Gly A21 insulin, human; Gly A21 Gln B3 insulin, human; Ala A21 insulin, human; Ala A21 Gln B3 insulin, human; Gln B3 insulin, human; Gln B30 insulin, human; Gly A21 Glu B30 insulin, human; Gly A21 Gln B3 Glu B30 insulin, human; Gln B3 Glu B30 insulin, human; Asp B28 insulin, human; Lys B28 insulin, human; Leu B28 insulin, human;
Val B28 insulin, human; Ala B28 insulin, human; Asp B28 Pro B29 insulin, human; Lys B28 Pro B29 insulin, human; Leu B28 Pro B29 insulin, human; Val B28 Pro B29 insulin, human; Ala B28 Pro B29 insulin, human.
337. The use according to Claim 333, wherein the conjugate of Formula V is present as a substantially monodispersed mixture.
338. The use according to Claim 333, wherein the conjugate of Formula V is present as a monodispersed mixture.
339. The use according to Claim 333, wherein the effective amount of the conjugate of Formula V is present in a pharmaceutical composition.
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