Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus

• US 20040038867A1
• Filed: 06/13/2003
• Published: 02/26/2004
• 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
• Granted Patent: US 7,601,688 B2
• Time in Patent Office: Days
• US Class Current: 514/3
• 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 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 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.

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

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

4. The method of claim 1, wherein the amount of insulin polypeptide-oligomer conjugate 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) a lysine at B-29;

b) an A chain having an N terminus; and

c) a B chain having an N terminus, and

and wherein the oligomer of the insulin polypeptide-oligomer conjugate is coupled to the insulin polypeptide at a site selected from the group consisting of;

a) the lysine at B-29;

b) the N terminus of the A chain; and

c) the N terminus of the B chain.

6. The method of claim 5, wherein the oligomer of the insulin polypeptide-oligomer conjugate is coupled to the lysine at B-29.

7. The method of claim 1, wherein the insulin polypeptide-oligomer conjugate is present as a substantially monodispersed mixture.

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

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

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

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

12. A method 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 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.

13. The method of claim 12, wherein the amount of the insulin polypeptide oligomer conjugate is between about 0.05 and about 5 mg per kilogram body weight.

14. The method of claim 12, wherein the amount of insulin polypeptide-oligomer conjugate reduces the number of hypoglycemic episodes experienced by the subject.

15. The method of claim 12, wherein the amount of insulin polypeptide-oligomer conjugate reduces the severity of hypoglycemic episodes experienced by the subject.

16. The method of claim 12, wherein the insulin polypeptide of the insulin polypeptide-oligomer conjugate comprises:

a) a lysine at B-29;

b) an A chain having an N terminus; and

c) a B chain having an N terminus, and

and wherein the oligomer of the insulin polypeptide-oligomer conjugate is coupled to the insulin polypeptide at a site selected from the group consisting of;

a) the lysine at B-29;

b) the N terminus of the A chain; and

c) the N terminus of the B chain.

17. The method of claim 16, wherein the oligomer of the insulin polypeptide-oligomer conjugate is coupled to the lysine at B-29.

18. The method of claim 12, wherein the insulin polypeptide-oligomer conjugate is present as a substantially monodispersed mixture.

19. The method of claim 12, wherein the hydrophilic moiety is a polyalkylene glycol moiety.

20. The method of claim 12, wherein the lipophilic moiety is an alkyly or fatty acid moiety.

21. The method of claim 12, wherein the insulin polypeptide-oligomer conjugate comprises 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.

22. The method of claim 12, wherein the insulin polypeptide-oligomer conjugate comprises the structure of Formula V: