Insulin with a stable basal release profile

• US 8,637,458 B2
• Filed: 05/12/2010
• Issued: 01/28/2014
• Est. Priority Date: 05/12/2010
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Biodel Inc. (Ipsen Sa)
• Inventors: Pohl, Roderike, Kashyap, Nandini, Hauser, Robert, Ozhan, Koray, Steiner, Solomon S.
• Primary Examiner(s): Chandra, Gyan
• Application Number:
  US12/778,719
• Publication Number:
  US 20110281790A1
• Time in Patent Office: 1,357 Days
• Field of Search: None
• US Class Current: 514/5.9
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 47/02 Inorganic compounds
• 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 9/0021 Intradermal administration, e.g. through microneedle arrays, needleless injectors mechanical aspects A61M
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

A basal insulin formulation composed of insulin, preferably insulin glargine, injectable zinc and injectable iron compounds as precipitating and/or stabilizing agents has been developed for subcutaneous, intradermal or intramuscular administration. The formulation is designed to form a precipitate of insulin following injection, creating a slow releasing “basal insulin” over a period of 12 to 24 hours.

Claims

1. A basal insulin formulation comprising

insulin or a modified insulin,

with an injectable zinc compound and

an injectable precipitation enhancing compound in an effective amount to precipitate the insulin and prolong release of solubilized insulin following injection,

wherein precipitation of insulin is enhanced in the formulation comprising zinc and the precipitation enhancing compound as compared to the precipitation of insulin in the presence of the zinc or precipitation enhancing compound,

wherein the precipitation enhancing agent contains an ion selected from the group consisting of, calcium, magnesium, manganese, iron, and copper, used at non-toxic levels, and is in a concentration between 0.1 to 10 mg precipitation enhancing agent/ml of basal insulin formulation.

2. The formulation of claim 1, wherein the zinc compound is selected from the group consisting of zinc acetate, zinc oxide, zinc citrate, zinc carbonate, zinc sulfate, and zinc chloride.

3. The formulation of claim 1, comprising zinc chloride in a concentration between 2 and 3 mg/mL.

4. The formulation of claim 3, comprising an iron compound selected from the group consisting of iron dextran, ferrous gluconate, ferrous sulfate and other injectable iron agents.

5. The formulation of claim 4 wherein the formulation comprises sodium acetate in a concentration between 0.2 and 20 mg/mL.

6. The formulation of claim 1, comprising an iron compound.

7. The formulation of claim 6, wherein the iron compound is selected from the group consisting of iron dextran, ferrous gluconate, ferrous sulfate and other injectable iron agents.

8. The formulation of claim 6, comprising insulin glargine and zinc chloride.

9. The formulation of claim 1, comprising recombinant human insulin further comprising a buffering agent selected from the group consisting of acetate, citrate, phosphate, carbonate, and barbital.

10. The formulation of claim 9, wherein the buffering agent is in a concentration between 1 and 10 mg/mL.

11. The formulation of claim 10, wherein the buffering agent is in a concentration between 5 and 6 mg/mL.

12. The formulation of claim 1, further comprising a solubility modifying agent selected from the group consisting of arginine, histidine, and lysine.

13. The formulation of claim 12 comprising arginine in a concentration between 0.005 and 10 mg/mL.

14. A method of providing a basal insulin to an individual in need thereof comprising administering the formulation of claim 13.

15. The method of claim 14, wherein the formulation is provided in two containers, wherein the insulin or modified insulin is provided in a first container as a lyophilized powder which is reconstituted at the time of administration and the arginine, injectable compound and injectable precipitation enhancing compound are present in one or both the containers.

16. The method of claim 15, wherein the contents of the two containers are mixed to form a clear solution prior to administration.

17. The formulation of claim 1, comprising at least one pH modifying agent selected from the group consisting of sodium hydroxide, citric acid, hydrochloric acid, acetic acid, phosphoric acid, succinic acid, sodium hydroxide, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium hydroxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicates, malic acid, potassium citrate, sodium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, 1,2,3,4-butane tetracarboxylic acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, and combinations thereof.

18. The formulation of claim 1, containing a preservative.

19. The formulation of claim 1, provided in a kit consisting of two or more containers which are mixed at the time of administration to form an insulin solution at the time of injection.

20. The formulation of claim 1, providing a basal effective amount of insulin for a period of 12 to 24 hours following administered by subcutaneous, intramuscular, or intradermal injection.

21. The formulation of claim 1, providing a insulin basal release profile for a short, medium or long duration, wherein the duration is 12 to 16 hours, 16 to 20, or 20 to 24 hours.

22. The formulation of claim 1, in the form of a clear solution which forms a precipitate at physiological pH.

23. A basal insulin formulation comprising

an insulin analog with an injectable zinc compound and an injectable precipitation enhancing compound in an effective amount to precipitate the insulin and prolong release of solubilized insulin following injection,

wherein precipitation of insulin is enhanced in the formulation comprising zinc and the precipitation enhancing compound as compared to the precipitation of insulin in the presence of the zinc or precipitation enhancing compound,

wherein the precipitation enhancing agent contains an ion selected from the group consisting of, calcium, magnesium, manganese, iron, and copper, used at non-toxic levels, and is in a concentration between 0.1 to 10 mg precipitation enhancing agent/ml of basal insulin formulation.

24. The formulation of claim 23, comprising insulin glargine.