Oral insulin therapies and protocol

• US 8,324,156 B2
• Filed: 08/24/2009
• Issued: 12/04/2012
• Est. Priority Date: 08/22/2003
• Status: Active Grant

• Current Assignee: NOVO Nordisk North America Operations A/S
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Arbit, Ehud, Goldberg, Michael, Majuru, Shingal
• Primary Examiner(s): NOAKES, SUZANNE MARIE
• Application Number:
  US12/546,283
• Publication Number:
  US 20090318331A1
• Time in Patent Office: 1,198 Days
• Field of Search: None
• US Class Current: 514/5.9
• 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 type II diabetes mellitus and impaired glucose tolerance, resulting in a reduced risk of hvperinsulinemia to said patient, the method comprising orally administering to said human type II diabetic patient one or more oral solid tablets comprising a dose of insulin and an effective amount of the delivery agent 4-[(4-chloro, 2- hydroxybenzoyl)amino] butanoic acid or a pharmaceutically acceptable salt thereof, in an amount that facilitates the absorption of the insulin from the gastrointestinal tract,

wherein the tablets are orally administered to the human type II diabetic patient at a time from about 30 minutes prior to ingestion of a meal to concurrently with ingestion of a meal providing a therapeutically effective reduction in blood glucose after oral administration and a maximum plasma concentration of insulin at a time point from about 5 to about 30 minutes after oral administration,

wherein the tablets are orally administered prior to or with every meal, said total dose being sufficient to replace an endogenous first phase insulin response to an ingested meal in a non-diabetic subject, and

wherein said method comprises chronically administering the one or more oral solid tablets for at least about two weeks.

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

3. 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.

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

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

6. 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).

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