RAPID ACTING AND LONG ACTING INSULIN COMBINATION FORMULATIONS

• US 20090137455A1
• Filed: 11/26/2008
• Published: 05/28/2009
• Est. Priority Date: 09/29/2005
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Biodel Inc. (Ipsen Sa)
• Inventors: Steiner, Solomon S., Pohl, Roderike
• Granted Patent: US 8,084,420 B2
• Time in Patent Office: Days
• US Class Current: 514/1.100
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/02 Inorganic compounds
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00

Abstract

An injectable formulation containing a combination of a rapid acting insulin and a long acting insulin has been developed wherein the pH of the rapid acting insulin is adjusted so that the long acting insulin, e.g. insulin glargine, remains soluble when they are mixed together. In the preferred embodiment, this injectable basal bolus insulin is administered before breakfast, provides adequate bolus insulin levels to cover the meal, does not produce hypoglycemia after the meal and provides adequate basal insulin for up to 24 hours. Lunch and dinner can be covered by two bolus injections of a fast acting, or a rapid acting or a very rapid acting insulin. Alternatively, through adjustment of the ratio of rapid acting insulin to long acting insulin, the long acting insulin may be shortened to a 12 hour formulation. This rapid and long acting blend is re-administered to the patient at dinner time, providing a safe and effective basal insulin level until morning. As a result, a patient using intensive insulin therapy should only inject three, rather than four, times a day.

Claims

1. An injectable formulation comprising a fast acting, rapid acting or very rapid acting insulin including a chelator and a dissolution agent in combination with an intermediate acting or long acting insulin in a form suitable for subcutaneous administration.

2. The formulation of claim 1, comprising glargine insulin.

3. The formulation of claim 1, comprising a very rapid acting insulin.

4. The formulation of claim 1, comprising an intermediate acting insulin.

5. The formulation of claim 1, having a pH ranging from 3.0 to 4.2, and wherein the long acting insulin is soluble at the pH of the formulation.

6. The formulation of claim 1, wherein the chelator is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), ethylene-bis(oxyethylene nitro) tetraacetic acid (EGTA), trisodium citrate (TSC), alginic acid, alpha lipoic acid, dimercaptosuccinic acid (DMSA), CDTA (1,2-diaminocyclohexanetetraacetic acid).

7. The formulation of claim 6, wherein the chelator is ethylenediaminetetraacetic acid (EDTA).

8. The formulation of claim 1, wherein the dissolution agent is selected from the group consisting of aspartic acid, glutamic acid, maleic, fumaric, succinic and citric acid.

9. The formulation of claim 1 comprising a zinc chelator and a combination of a very rapid acting insulin and a long acting insulin, wherein the dissolution agent is selected from the group consisting of aspartic, glutamic, succinic, maleic, fumaric or citric acid.

10. The formulation of claim 9, wherein the chelator is EDTA.

11. The formulation of claim 9, wherein the dissolution agent is citric acid.

12. The formulation of claim 9 comprising a very rapid acting insulin and a long acting insulin in a ratio ranging from 1:

0.5 to 1;

20 (units of insulin in rapid acting insulin;

units of insulin in long acting insulin).

13. The formulation of claim 12, comprising a very rapid acting insulin and a long acting insulin in a ratio of 1:

1 (units of insulin in rapid acting insulin;

units of insulin in long acting insulin).

14. The formulation of claim 9, wherein the very rapid acting insulin comprises an insulin selected from the group consisting of native human insulin, recombinant human insulin, porcine insulin, bovine insulin, a derivative of human insulin, or an analog of human insulin suitable for administration to a human.

15. A method of treating a diabetic patient with insulin comprising administering by subcutaneous injection to the patient a formulation comprising a fast acting, rapid acting or very rapid acting insulin including a chelator and a dissolution agent in combination with an intermediate acting or long acting insulin.

16. The method of claim 15, wherein the formulation comprises comprising a zinc chelator and a combination of a very rapid acting insulin and a long acting insulin, wherein the dissolution agent is selected from the group consisting of aspartic, glutamic, succinic, maleic, fumaric or citric acid.

17. The method of claim 16, wherein the chelator is EDTA and wherein the dissolution agent is citric acid.

18. The method of claim 17, wherein the formulation has a duration of action of twelve hours following administration to the patient.

19. A method for stabilizing a diabetic patient'"'"'s blood glucose levels throughout the day comprising administering via subcutaneous injection prior to eating breakfast and prior to eating dinner a formulation comprising a long acting insulin and a very rapid acting insulin, wherein the very rapid acting insulin includes a chelator and a dissolution agent.

20. The method of claim 19, further comprising administering prior to eating lunch a very rapid acting insulin formulation, wherein the formulation comprises a chelator, a dissolution agent and insulin.