Substituted diketopiperazine analogs for use as drug delivery agents

• US 8,906,926 B2
• Filed: 10/11/2012
• Issued: 12/09/2014
• Est. Priority Date: 12/29/2008
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Kraft, Kelly Sullivan
• Primary Examiner(s): Leeser, Erich A
• Application Number:
  US13/649,430
• Publication Number:
  US 20130053309A1
• Time in Patent Office: 789 Days
• Field of Search: 514/255.02, 544/385
• US Class Current: 514/255.02
• CPC Class Codes: A61K 2121/00 Preparations for use in therapy
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• 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 38/26 Glucagons
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms

Abstract

Disclosed are drug delivery systems for the delivery of small molecule and macromolecular drugs. More particularly, disclosed are substituted analogs of 3,6-di(alkyl-4 aminobutyl)-2,5-diketopiperazine (which may also be referred to DKP), their use in the formulation of both small molecule and macromolecular drugs including therapeutic, prophylactic and diagnostic agents, stabilizing agents and systems for their delivery.

Claims

1. A method of treating hyperglycemia in a patient in need thereof, comprising administering to the patient a composition comprising insulin and a substituted diketopiperazine having the general structure of:

2. The method of claim 1 wherein the hyperglycemia comprises diabetes.

3. The method of claim 2 wherein the diabetes is type 1 diabetes.

4. The method of claim 2 wherein the diabetes is type 2 diabetes.

5. The method of claim 1 wherein the administering comprises pulmonary delivery.

6. The method of claim 1 wherein R is hydrogen, n=2, m is C═

C, X is —

NHC(O)—

, and Y is COOH.

7. The method of claim 1 wherein R is isopropyl, n=3, m is C═

C, X is —

NHC(O)—

, and Y is COOH.

8. The method of claim 1 wherein the substituted diketopiperazine is (E)-3-(3-(3,6-dioxopiperazin-2-yl)propyl-carbamoyl)acrylic acid.

9. The method of claim 1 wherein the substituted diketopiperazine is (E)-3-(4-(5-isopropyl-3,6-dioxopiperazin-2-yl)-butylcarbamoyl)acrylic acid.

10. The method of claim 1 wherein the substituted diketopiperazine is (E)-3-(4-(3,6-dioxopiperazin-2-yl)butylcarbamoyl)-acrylic acid.

11. A method of treating hyperglycemia in a patient in need thereof, comprising administering to the patient a composition comprising insulin and a pharmaceutically-acceptable salt of a substituted diketopiperazine having the general structure of:

12. The method of claim 11 wherein the hyperglycemia comprises diabetes.

13. The method of claim 12 wherein the diabetes is type 1 diabetes.

14. The method of claim 12 wherein the diabetes is type 2 diabetes.

15. The method of claim 11 wherein the administering comprises pulmonary delivery.

16. The method of claim 11 wherein R is hydrogen, n=3, m is C═

C, X is —

NHC(O)—

, and Y is COOH.

17. The method of claim 11 wherein R is hydrogen, n=2, m is C═

C, X is —

NHC(O)—

, and Y is COOH.

18. The method of claim 11 wherein R is an isopropyl, n=3, m is C═

C, X is —

NHC(O)—

, and Y is COOH.

19. The method of claim 11 wherein the cation is sodium.