Rapid acting injectable insulin compositions

• US 8,933,023 B2
• Filed: 01/15/2014
• Issued: 01/13/2015
• Est. Priority Date: 03/12/2004
• Status: Active Grant

• Current Assignee: Eli Lilly and Company
• Original Assignee: Biodel Inc. (Ipsen Sa)
• Inventors: Pohl, Roderike, Steiner, Solomon S.
• Primary Examiner(s): Bradley, Christina
• Application Number:
  US14/156,307
• Publication Number:
  US 20140135263A1
• Time in Patent Office: 363 Days
• Field of Search: None
• US Class Current: 514/5.9
• 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 38/28 Insulins
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

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. These formulations are rapidly absorbed into the blood stream when administered by subcutaneous injection. In the preferred embodiment, the insulin is provided as a dry 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. An injectable insulin composition comprising an active agent and an effective amount of a dissolution agent and a zinc chelator to dissociate and charge mask the insulin to enhance uptake and transport of the insulin through epithelial cells as compared to insulin in combination with a zinc chelator and HCl,

wherein the active agent consists of insulin hexamers dissociated by the zinc chelator,

wherein the dissolution agent is selected from the group consisting of glutamic, succinic, aspartic, maleic, fumaric, and adipic acid, and

wherein the zinc chelator is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), ethylene-bis(oxyethylene nitro) tetraacetic acid (EGTA), dimercaptosuccinic acid (DMSA), and CDTA (1,2-diaminocyclohexanetetraacetic acid), alone or in combination with ions of a metal.

2. The composition of claim 1, wherein the insulin is selected from the group consisting of human insulin and insulin analogs.

3. The composition of claim 2, wherein the insulin is human insulin.

5. The composition of claim 1 wherein the chelator is present in a concentration range corresponding to between 2.42×

10<sup>−

4</sup> M and 9.68×

10<sup>−

2</sup> M EDTA.

6. The composition of claim 1 wherein the dissolution agent is present in a concentration range corresponding to between 9.37×

10<sup>−

4</sup> M and 9.37×

10<sup>−

2</sup> M citric acid.

8. The composition of claim 1 wherein the insulin is provided in a dry powder in a first container and at least one of the chelator and dissolution agent are provided in a second container containing a diluent.

9. The composition of claim 1 provided as a frozen pharmaceutically acceptable agent for treatment of a diabetic.

4. An injectable insulin composition comprising an active agent and an effective amount of a dissolution agent and ethylenediaminetetraacetic acid (EDTA) to dissociate and charge mask the insulin to enhance uptake and transport of the insulin through epithelial cells as compared to insulin in combination with a zinc chelator and HCl,

wherein the active agent consists of insulin hexamers dissociated by the zinc chelator and

wherein the dissolution agent is selected from the group consisting of glutamic, succinic, aspartic, maleic, fumaric, and adipic acid.

7. The composition of claim 4 wherein the EDTA is present in a concentration of between 2.42×

10<sup>−

4</sup> M and 9.68×

10<sup>−

2</sup> M EDTA and the dissolution agent is present in a concentration corresponding to between 9.37×

10<sup>−

4</sup> M and 9.37×

10<sup>−

2</sup> M citric acid.

10. A method of treating a diabetic individual comprising injecting an effective amount of an injectable insulin composition comprising an active agent, an effective amount of a dissolution agent and a zinc chelator to dissociate and charge mask the insulin to enhance uptake and transport of the insulin through epithelial cells as compared to insulin in combination with a zinc chelator and HCl,

wherein the active agent consists of insulin hexamers dissociated by the zinc chelator, and

wherein the dissolution agent is selected from the group consisting of glutamic, succinic, aspartic, maleic, fumaric, and adipic acid.

11. The method of claim 10, wherein the chelator is selected from the group consisting of alginic acid, and alpha lipoic acid, alone or in combination with ions of a metal.

14. The method of claim 10, wherein the chelator is selected from the group consisting of ethylene-bis(oxyethylene nitro) tetraacetic acid (EGTA), trisodium citrate (TSC), dimercaptosuccinic acid (DMSA), CDTA (1,2-diaminocyclohexanetetraacetic acid) alone or in combination with ions of a metal.

12. A method of treating a diabetic individual comprising injecting an effective amount of an injectable insulin composition comprising an active agent, an effective amount of a dissolution agent and a zinc chelator to dissociate and charge mask the insulin to enhance uptake and transport of the insulin through epithelial cells as compared to insulin in combination with a zinc chelator and HCl,

wherein the active agent consists of insulin hexamers dissociated by the zinc chelator,

wherein the dissolution agent is selected from the group consisting of glutamic, succinic, aspartic, maleic, fumaric, and adipic acid, and

wherein the zinc chelator is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), ethylene-bis(oxyethylene nitro) tetraacetic acid (EGTA), trisodium citrate (TSC), dimercaptosuccinic acid (DMSA), CDTA (1,2-diaminocyclohexanetetraacetic acid) alone or in combination with ions of a metal.

13. The method of claim 12, wherein the chelator is EDTA.