Diketopiperazine salts for drug delivery and related methods

Patent metadata

Field	Value
Publication number	US-9259471-B2
Application number	US-201414150474-A
Country	US
Kind code	B2
Filing date	Jan 8, 2014
Priority date	Aug 23, 2004
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

Drug delivery systems have been developed based on the formation of diketopiperazine carboxylate salts and microparticles containing the same. The systems may further comprise a bioactive agent. Related methods for making and using the biologically active agent delivery compositions are also provided. In certain embodiments, the pharmaceutically acceptable salts described can be formed by removal of solvent by methods including distillation, evaporation, spray drying or lyophilization.

First claim

What is claimed is:

1. A microparticulate system for drug delivery comprising a composition comprising:
microparticles of a pharmaceutically acceptable anion of a diketopiperazine compound comprising a carboxylate group, a divalent cation, and a biologically active agent,
wherein the diketopiperazine compound is represented by the following general formula:

wherein E 1 and E 2 are NH, and R 1 and R 2 are independently selected from succinate-4-aminobutyl, glutarate-4-aminobutyl, maleate-4-aminobutyl, citraconate-4-aminobutyl, malonate-4-aminobutyl, oxalate-4-aminobutyl, and fumarate-4-aminobutyl.

2. The microparticulate system of claim 1 wherein said biologically active agent is a hormone, an anticoagulant, an immunomodulating agent, a cytotoxic agent, an antibiotic, an antiviral, an antisense, an antigen, an antibody or an active fragment or an analog thereof.

3. The microparticulate system of claim 1 wherein said biologically active agent is insulin, a cannabinoid, heparin, calcitonin, felbamate, parathyroid hormone or a fragment thereof, growth hormone, erythropoietin, glucagon-like peptide-1, somatotrophin-releasing hormone, follicle stimulating hormone, cromolyn, adiponectin, RNAse, ghrelin, zidovudine, didanosine, tetrahydrocannabinol, atropine, granulocyte colony stimulating factor, lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β-galactosidase, or Argatroban.

4. The microparticulate system of claim 3 wherein said biologically active agent is insulin.

5. The microparticulate system of claim 3 wherein said biologically active agent is glucagon-like peptide-1.

6. The microparticulate system of claim 1 wherein said anion comprises 3,6-di(succinate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(maleate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(citraconate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(glutarate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(malonate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(oxalate-4-aminobutyl)-2,5-diketopiperazine, or 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine.

7. The microparticulate system of claim 6 wherein said anion is 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine.

8. The microparticulate system of claim 1 wherein said microparticles have a diameter between about 0.5 microns and about ten microns.

9. The microparticulate system of claim 1 wherein said composition comprises a suspension for drug delivery.

10. The microparticulate system of claim 9 , wherein said suspension is administered orally.

11. The microparticulate system of claim 3 wherein said anion is 3,6-di(succinate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(maleate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(citraconate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(glutarate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(malonate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(oxalate-4-aminobutyl)-2,5-diketopiperazine, or 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine.

12. The microparticulate system of claim 11 , wherein said biologically active agent is glucagon-like peptide-1.

13. The microparticulate system of claim 11 , wherein said biologically active agent is insulin.

14. The microparticulate system of claim 13 wherein said anion is 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine.

15. The microparticulate system of claim 3 , wherein said microparticles have a diameter between about 0.5 microns and about ten microns.

16. The microparticulate system of claim 6 , wherein the divalent cation comprises Mg++ or Ca++.

17. The microparticulate system of claim 16 wherein said cation comprises Mg++.

18. The microparticulate system of claim 17 , wherein said biologically active agent is glucagon-like peptide-1.

19. The microparticulate system of claim 17 , wherein said biologically active agent is insulin.

20. The microparticulate system of claim 16 , wherein said microparticles are suitable for pulmonary administration.

21. The microparticulate system of claim 1 , wherein said divalent cation is calcium or magnesium.

Assignees

• Mannkind Corp

Inventors

• Leone-Bay Andrea
• Moye-Sherman Destardi
• Wilson Bryan R

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K47/22 Primary

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title

• A61K31/357

  having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel · CPC title

• A61K31/4965

  Non-condensed pyrazines · CPC title

• C07D241/08 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title