Insulin formulations for rapid uptake

• US 9,060,927 B2
• Filed: 03/03/2009
• Issued: 06/23/2015
• Est. Priority Date: 03/03/2009
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Biodel Inc. (Ipsen Sa)
• Inventors: Steiner, Solomon S., Pohl, Roderike, Li, Ming, Hauser, Robert
• Primary Examiner(s): Kemmerer, Elizabeth C
• Assistant Examiner(s): Deberry, Regina M
• Application Number:
  US12/397,219
• Publication Number:
  US 20100227795A1
• Time in Patent Office: 2,303 Days
• Field of Search: 530/303, 530/399, 514/5.9, 514/6.4, 514/6.5, 514/6.7, 514/6.8, 514/6.9
• US Class Current: 1/1
• 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 38/28 Insulins
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/50 for increasing or potentiating the activity of insulin
• CPC Class Codes: C07K 14/62 Insulins

Abstract

Injectable insulin formulations with improved stability and rapid onset of action are described herein. The formulations may be for subcutaneous, intradermal or intramuscular administration. In the preferred embodiment, the formulations are administered via subcutaneous injection. The formulations contain insulin in combination with a chelator and dissolution agent, and optionally additional excipients. In the preferred embodiment, the formulation contains human insulin, a zinc chelator such as EDTA and a dissolution agent such as citric acid or sodium citrate. These formulations are rapidly absorbed into the blood stream when administered by subcutaneous injection. In the preferred embodiment, the insulin is provided as a clear liquid, neutral pH, in a multi-use sterile vial. In an alternative embodiment, the insulin is provided as a powder in a sterile vial. This is mixed with a diluent containing a pharmaceutically acceptable carrier, such as water, a zinc chelator such as EDTA and a dissolution agent such as citric acid shortly before or at the time of administration. In another embodiment, the insulin is stored as a frozen mixture, ready for use upon thawing.

Claims

1. A clear insulin solution having a pH of between greater than 7.0 and 7.6, consisting of insulin, one or more zinc chelators one or more dissolution agents and one or more excipients,

wherein the insulin comprises dissociated insulin monomers produced by chelation of the zinc in insulin hexamers which are not soluble at a pH of between greater than 7.0 and 7.6,

the dissociated insulin monomers have bound thereto charge masking agents which stabilize the dissociated insulin monomers,

wherein the solution is prepared by raising the pH of an insulin solution from about pH 4.0 to a pH between a pH greater than 7.0 and a pH about 7.6, and

wherein the insulin has an enhanced rate of uptake and transport through epithelial cells relative to the solution without the zinc chelator and dissolution agent.

2. The solution of claim 1, wherein the zinc 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), and CDTA (1,2-diaminocyclohexanetetraacetic acid).

3. The solution of claim 2, wherein the zinc chelator is ethylenediaminetetraacetic acid (EDTA).

4. The solution of claim 1, wherein the dissolution agent is acetic acid, ascorbic acid, citric acid, glutamic, succinic, aspartic, maleic, fumaric, adipic acid, or a salt thereof.

5. The solution of claim 1 wherein the dissolution agent is citric acid or sodium citrate.

6. The solution of claim 1 wherein the pH is between 7.4 and 7.5.

7. The solution of claim 1, wherein the insulin is selected from the group consisting of human insulin, insulin analogs and combinations thereof.

8. The solution of claim 7 wherein the insulin is recombinant human insulin.

9. The solution of claim 7, wherein the insulin analog is selected from the group consisting of insulin lispro, insulin glargine, insulin aspart, insulin glulisine, and insulin detemir.

10. The solution of claim 1 provided as a frozen pharmaceutically acceptable solution for treatment of a diabetic.

11. The solution of claim 1 provided as a clear aqueous solution at 4°

C.

12. A method of treating a diabetic individual comprising

injecting an effective amount of a clear insulin solution having a pH of between greater than 7.0 and 7.6, consisting of insulin, a one or more zinc chelators, one or more dissolution agents and one or more excipients,

wherein the insulin comprises dissociated insulin monomers produced by chelation of the zinc in insulin hexamers which are not soluble at a pH of between greater than 7.0 and 7.6 by a zinc chelator,

the dissociated insulin monomers have bound thereto charge masking agents which stabilize the dissociated insulin monomers,

wherein the solution is prepared by raising the pH of an insulin solution from about pH 4.0 to a pH between a pH greater than 7.0 and a pH about 7.6, and

wherein the insulin has an enhanced rate of uptake and transport through epithelial cells relative to the solution without the zinc chelator and dissolution agent.

13. The method of claim 12 wherein the zinc 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), and CDTA (1,2-diaminocyclohexanetetraacetic acid).

14. The method of claim 12 wherein the zinc chelator is ethylenediaminetetraacetic acid (EDTA).

15. The method of claim 12 wherein the dissolution agent-is acetic acid, ascorbic acid, citric acid, glutamic, succinic, aspartic, maleic, fumaric, adipic acid, or a salt thereof.

16. The method of claim 15 wherein the dissolution agent is citric acid or sodium citrate.

17. The method of claim 12 wherein the pH is between 7.4 and 7.5.

18. The method of claim 12 wherein the insulin is selected from the group consisting of human insulin, insulin analogs and combinations thereof.

19. The method of claim 12 wherein the insulin is recombinant human insulin.

20. A clear insulin solution having a pH of between a pH greater than 7 and a pH of 7.6, wherein the solution consists of insulin, zinc chelator, dissolution agent and one or more excipients, wherein the solution is prepared by raising the pH of an insulin solution from about pH 4.0 to a pH of between a pH greater than 7.0 and a pH of 7.6.