Diketopiperazine salts for drug delivery and related methods
View Patent ↗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.
1. A microparticulate system for drug delivery comprising a composition comprising:
microparticles of a pharmaceutically acceptable anion of a heterocyclic compound and a biologically active agent, wherein said microparticles release a biologically active agent; and
a cation;
wherein said anion is 3,6-di(citraconate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(oxalate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(malonate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(succinate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(maleate-4-aminobutyl)-2,5-diketopiperazine, 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine or 3,6-di(glutarate-4-aminobutyl)-2,5-diketopiperazine.
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, a 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, beta-galactosidase or Argatroban.
4. The microparticulate system of claim 1 wherein said cation is sodium, potassium, calcium, lithium, triethylamine, butylamine, diethanolamine or triethanolamine.
5. The microparticulate system of claim 1 wherein the anion is 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine.
6. The microparticulate system of claim 1 wherein said microparticles have a diameter between about 0.5 microns and about ten microns.
7. The microparticulate system of claim 1 wherein said composition comprises a suspension for drug delivery.
8. The microparticulate system of claim 7 , wherein said suspension is administered orally.
9. The microparticulate system of claim 1 , wherein said biologically active agent is glucagon-like peptide-1.
10. The microparticulate system of claim 9 , wherein said cation is sodium, potassium, calcium, lithium, triethylamine, butylamine, diethanolamine, or triethanolamine.
11. The microparticulate system of claim 9 wherein the anion is 3,6-di(fumarate-4-aminobutyl)-2,5-diketopiperazine.
12. The microparticulate system of claim 1 , wherein said microparticles have a diameter between about 0.5 microns and about ten microns.
13. The microparticulate system of claim 11 , wherein said composition comprises a suspension for drug delivery.
14. The microparticulate system of claim 13 , wherein said suspension is administered orally.
15. A dry powder composition comprising the microparticles of claim 1 .
16. A dry powder composition comprising the microparticles of claim 9 .