Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus

• US 7,601,688 B2
• Filed: 06/13/2003
• Issued: 10/13/2009
• Est. Priority Date: 06/13/2002
• Status: Active Grant

• Current Assignee: Biocon Limited (Biocon Incorporated)
• Original Assignee: Biocon Limited (Biocon Incorporated)
• Inventors: Kosutic, Gordana, Still, James Gordon
• Primary Examiner(s): Kosar; Andrew D
• Application Number:
  US10/461,199
• Publication Number:
  US 20040038867A1
• Time in Patent Office: 2,314 Days
• Field of Search: None
• US Class Current: 514/1.1
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65

Abstract

The present invention provides compositions and methods for reducing hypoglycemic episodes experienced by a subject in need of treatment for diabetes mellitus, said method comprising orally administering an amount of an insulin polypeptide-oligomer conjugate to the subject, wherein: i) the amount of the insulin polypeptide-oligomer conjugate reduces the number and/or severity of hypoglycemic episodes experienced by the subject during a given time period when compared with the number and/or severity of hypoglycemic episodes that would have been experienced during a similar time period by the subject or by subjects in a control group parenterally administered insulin or an insulin analog in an amount that provides a substantially equivalent level of glycemic control; and ii) the oligomer of the insulin polypeptide-oligomer conjugate comprises a hydrophilic moiety and a lipophilic moiety.

Claims

1. A method for reducing hypoglycemic episodes experienced by a human subject in need of treatment for diabetes mellitus and having a tendency toward hypoglycemic episodes, said method comprising:

orally administering an amount of an insulin polypeptide-oligomer conjugate to the human subject, wherein the insulin polypeptide-oligomer conjugate comprises an insulin polypeptide and an oligomer, wherein the oligomer comprises a hydrophilic moiety and a lipophilic moiety, wherein the insulin polypeptide-oligomer conjugate is a mono-conjugate, wherein the oligomer is coupled to an amino functionality of insulin at Lys^B-29, and wherein the amount of the insulin polypeptide-oligomer conjugate orally administered to the subject maintains the subject'"'"'s blood glucose level between 80 mg/dl and 250 mg/dl and reduces the number and/or severity of hypoglycemic episodes experienced by the human subject during a given time period when compared with the number and/or severity of hypoglycemic episodes that would have been experienced during a similar time period by the human subject parenterally administered insulin or an insulin analog in an amount that provides a substantially equivalent level of glycemic control.

2. The method of claim 1, wherein the amount of the insulin polypeptide oligomer conjugate orally administered to the subject is between 0.05 and 5 mg per kilogram body weight.

3. The method of claim 1, wherein the amount of insulin polypeptide-oligomer conjugate orally administered to the subject reduces the number of hypoglycemic episodes experienced by the subject.

4. The method of claim 1, wherein the amount of insulin polypeptide-oligomer conjugate orally administered to the subject reduces the severity of hypoglycemic episodes experienced by the subject.

5. The method of claim 1, wherein the insulin polypeptide of the insulin polypeptide-oligomer conjugate comprises:

a lysine at B-29;

an A chain having an N terminus;

a B chain having an N terminus; and

wherein the oligomer of the insulin polypeptide-oligomer conjugate is coupled to the lysine at B-29.

6. The method of claim 1, wherein the hydrophilic moiety is a polyalkylene glycol moiety.

7. The method of claim 1, wherein the lipophilic moiety is an alkyl or fatty acid moiety.

8. The method of claim 1, wherein the insulin polypeptide-oligomer conjugate comprises the structure of Formula V:

9. The method of claim 1, wherein the amount of the insulin polypeptide-oligomer conjugate orally administered to the subject maintains the subject'"'"'s blood glucose level between 70 mg/dl and 120 mg/dl when measured before a meal.

10. The method of claim 1, wherein the amount of the insulin polypeptide-oligomer conjugate orally administered to the subject maintains the subject'"'"'s blood glucose level at less than 180 mg/dl but more than 70 mg/dl when measured within two hours after a meal.