Method for improving the pharmaceutic properties of microparticles comprising diketopiperazine and an active agent

Abstract

Methods are provided for drying a particle. Specifically, there is provided a spray-dried diketopiperazine-insulin particle formulation having improved aerodynamic performance and in which the active agent is more stabile and efficiently delivered as compared to that of the lyophilized diketopiperazine-insulin formulation. The dry powders have utility as pharmaceutical formulations for pulmonary delivery.

What is claimed is: 
     
         1 . A process for manufacturing a crystalline microparticle of a diketopiperazine loaded with an active agent wherein the diketopiperazine has the formula of 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is a succinyl, glutaryl, maleyl, or fumaryl group comprising the steps of: adding the diketopiperazine in a to water to form an aqueous suspension, maintaining the diketopiperazone solution at a controlled temperature between about 15° C. to about 18° C., adding the active agent to water to form an aqueous solution or suspension of the active, mixing the diketopiperazine aqueous suspension with the active agent aqueous solution or suspension, and then spray-drying the admixture to remove solvent, using a spray dryer having an inlet and outlet, to form a spray-dried powder. 
     
     
         2 . The process of  claim 1 , wherein the inlet of the spray dryer has a temperature of between, or equal, to 105° C. to 140° C. 
     
     
         4 . The process of  claim 1 , wherein the spray dryer produces an atomization pressure of between, or equal, to 0.4 to 1.1 bar. 
     
     
         5 . The process of  claim 1 , wherein the spray dryer produces a spray rate of between, or equal to, 4.4 to 12.2 g/min. 
     
     
         6 . The process of  claim 1 , wherein the spray dryer produces a spray-dried powder of between, or equal to, 0.150 to 0.200 g/cc. 
     
     
         7 . The process of  claim 1 , wherein the spray dryer produces a spray-dried powder that has a tap density of between, or equal to, 0.250 to 0.300 g/cc. 
     
     
         8 . The process of  claim 1 , wherein the active agent is insulin. 
     
     
         9 . The process of  claim 8 , wherein the spray-dried powder has an insulin content of about 3% to about 50% by weight. 
     
     
         10 . The process of  claim 1 , wherein the active agent is selected from the group consisting of: insulin, calcitonin, parathyroid hormone 1-34, or other bioactive fragment of parathyroid hormone, octreotide, leuprolide, and RSV peptide, felbamate, cannabinoid antagonists and/or agonists, muscarinic antagonists and/or agonists, heparin, low molecular weight heparin, cromolyn, sildenafil, vardenafil, tadalafil growth hormone, zidovudine (AZT), didanosine (DDI), granulocyte-colony stimulating factor (GCSF), lamotrigine, chorionic gonadotropin releasing factor, luteinizing release hormone, β-galactosidase, GLP-1, exendins 1-4, ghrelin, and fragments thereof.