ORAL INSULIN THERAPIES AND PROTOCOL

• US 20090318331A1
• Filed: 08/24/2009
• Published: 12/24/2009
• Est. Priority Date: 08/22/2003
• Status: Active Grant

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Ehud Arbit, Michael Goldberg, Shingal Majuru
• Inventors: Majuru, Shingal, Goldberg, Michael, ARBIT, Ehud
• Granted Patent: US 8,324,156 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• 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 38/28 Insulins
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

Methods for treating impaired glucose tolerance and early and late stage diabetes in mammals, for prophylactically sparing β-cell function, aiding in preventing β-cell death, preventing the onset of overt diabetes in a mammal with type 2 diabetes, treating the current level of glycemic control dysfunction of a mammal with impaired glucose tolerance or diabetes, comprising orally administering insulin and a delivery agent that facilitates insulin absorption from the gastrointestinal tract at the time of or shortly before mealtime, e.g., within about 10 minutes prior to ingestion of a meal, on a chronic basis. The methods also comprise, in addition to administering a rapid-acting insulin to provide a first insulin peak, administering a slow acting insulin to provide a second insulin peak occurring at a later time but of a longer duration. These methods achieve improved glycemic control without the risks of hypoglycemia, hyperinsulinemia and weight gain and the need for frequent blood glucose monitoring that are normally associated with insulin therapy.

Claims

1. A method of treating a human patient with diabetes mellitus comprising orally administering to said human diabetic patient an oral solid tablet comprising a dose of insulin and an effective amount of a delivery agent of the formula or a pharmaceutically acceptable salt thereof,

2. The method of claim 1, wherein X is a halogen, or wherein R═

C3, or both.

3. The method of claim 1, wherein said halogen is chlorine.

4. The method of claim 1, wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid (4-CNAB).

5. The method of claim 1, which provides a maximum plasma insulin concentration at from about 5 minutes to about 25 minutes after oral administration.

6. The method of claim 1, which provides a maximum blood glucose concentration reduction caused by said dose of insulin at from about 10 to about 20 minutes after oral administration.

7. The method of claim 1, wherein the amount of insulin contained in said tablet is from about 100 Units to about 450 Units.

8. The method of claim 1, wherein the amount of delivery agent contained in said tablet is from about 20 mg to about 600 mg.

9. The method of claim 1, wherein the ratio of Insulin (Units) to delivery agent (mg) ranges from 10:

1 (Units;

mg) to 1;

10 (Units;

mg).

10. The method of claim 1, wherein said insulin is unmodified.

11. A method of treating a human patient with diabetes mellitus comprising orally administering to said human diabetic patient a substantially homogeneous oral tablet comprising a therapeutically effective dose of insulin, a delivery agent of the formula or a pharmaceutically acceptable salt thereof,

12. The method of claim 11, wherein said substantially homogeneous oral tablet further comprises per dosage unit a dose of insulin within the range of from about 10 Units to about 600 Units, the delivery agent in an amount that facilitates absorption of insulin from the gastrointestinal tract within the range of from about 20 mg to about 600 mg, and at least one pharmaceutically acceptable excipient, such that an effective dose comprising one or more of said tablets upon administration to said human diabetic patient providing a therapeutically effective reduction in blood glucose of said patient.

13. The method of claim 11, wherein X is a halogen, or wherein R═

C3, or both.

14. The method of claim 11, wherein said halogen is chlorine.

15. The method of claim 11, wherein said delivery agent is 4-[(4-chloro, 2-hydroxybenzoyl)amino]butanoic acid (4-CNAB).

16. The method of claim 11, which provides a maximum plasma insulin concentration at from about 5 minutes to about 25 minutes after oral administration.

17. The method of claim 11, which provides a maximum blood glucose concentration reduction caused by said dose of insulin at from about 10 to about 30 minutes after oral administration.

18. The method of claim 11, wherein the amount of insulin contained in said tablet is from about 100 Units to about 450 Units.

19. The method of claim 11, wherein the amount of delivery agent contained in said tablet is from about 20 mg to about 600 mg.

20. The method of claim 11, wherein the ratio of Insulin (Units) to delivery agent (mg) ranges from 10:

1 (Units;

mg) to 1;

10 (Units;

mg).