Glucagon-like insulinotropic peptides, compositions and methods

• US 6,388,053 B1
• Filed: 10/12/2001
• Issued: 05/14/2002
• Est. Priority Date: 12/09/1993
• Status: Expired due to Fees

• Current Assignee: Eli Lilly and Company
• Original Assignee: Eli Lilly and Company
• Inventors: Galloway, John A., Hoffmann, James A.
• Primary Examiner(s): Jones, Dwayne C.
• Assistant Examiner(s): DELACROIX MUIRHEI, CYBILLE
• Application Number:
  US09/975,905
• Time in Patent Office: 214 Days
• Field of Search: 514/12, 514/866, 530/308, 530/324
• US Class Current: 530/308
• 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 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: Y10S 977/773 Nanoparticle, i.e. structure having three dimensions of 100 nm or less
• CPC Class Codes: Y10S 977/904 for medical, immunological, body treatment, or diagnosis
• CPC Class Codes: Y10S 977/915 Therapeutic or pharmaceutical composition

Abstract

The present invention provides novel complexes consisting of certain GLP-1 molecules associated with a divalent metal cation that is capable of co-precipitating with a GLP-1 molecule. Pharmaceutical compositions and methods of using such complexes for enhancing the expression of insulin in B-type islet cells is claimed, as is a method for treating maturity onset diabetes mellitus in mammals, particularly humans.

Claims

1. A process of preparing a GLP-1 complex, which comprises steps of;

a) mixing a GLP-1 molecule of the formula;

2. The process of claim 1, wherein X is selected from the group consisting of Val, Thr, Ile, and alpha-methyl-Ala.

3. The process of claim 2, wherein the divalent metal cation is zinc.

4. The process of claim 1, wherein R¹ is L-histidine, X is Val, Y is Glu, Z is Glu, and R₂ is Gly-OH.

5. The process of claim 4, wherein the divalent metal cation is zinc.

6. The process of claim 1, wherein R¹ is L-histidine, X is Gly or alpha-methyl-Ala, Y is Glu, Z is Glu, and R₂ is —

NH_2.

7. The process of claim 6, wherein the divalent metal cation is zinc.

8. The process of claim 1, wherein the divalent metal cation is zinc.

9. The process of claim 8, wherein the zinc is provided at a molar ratio of up to about 50 molecules of zinc for each molecule of GLP-1.

10. The process of claim 9, wherein the molar ratio is about 1 molecule of zinc for each molecule of GLP-1.

11. The process of claim 9, wherein the molar ratio is about 0.7 molecules of zinc for each molecule of GLP-1.

12. The process of claim 1, further comprising the step of adding a buffer to the mixture.

13. The process of claim 12 wherein the buffer has a pH in the range of about 6 to about 9.