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 . An inhalable dry powder with an improved pharmaceutic property comprising microparticles of a diketopiperazine combined with an active agent wherein the pharmaceutic property are improved by increasing the density of powder, increasing the aerodynamic performance of powder, or improving the stability of the active agent and optionally, one or more pharmaceutically acceptable carriers. 
     
     
         2 . The inhalable dry powder of  claim 1 , wherein the one or more pharmaceutically acceptable carriers is diketopiperazine. 
     
     
         3 . The inhalable dry powder of  claim 2 , wherein the diketopiperazine is a diketopiperazine having the formula 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is succinyl, glutaryl, maleyl, or fumaryl. 
     
     
         4 . The inhalable dry powder of  claim 3 , wherein the diketopiperazine is fumaryl diketopiperazine. 
     
     
         5 . The inhalable dry powder of  claim 1 , wherein the active agent is insulin, calcitonin, parathyroid hormone 1-34, bioactive fragment of parathyroid hormone, octreotide, leuprolide, RSV peptide, felbamate, cannabinoid antagonists and/or agonists, muscurinic antagon and/or agonists, heparin, low molecular weight heparin, cromolyn, sildenafil, vardenafil, tadalafil, growth hormone, AZT, DDI, GCSF, lamotrigine, chorionic gonadotropin releasing factor, luteinizing release hormone, .beta.galactosidase, GLP-1, exendins 1-4, or ghrelin. 
     
     
         6 . The inhalable dry powder of  claim 1 , wherein the active agent is a peptide or protein. 
     
     
         7 . The inhalable dry powder of  claim 1 , wherein the active agent is vardenafil or an analogue thereof. 
     
     
         8 . The inhalable dry powder of  claim 1 , further comprises a stabilizing agent. 
     
     
         9 . The inhalable dry powder of  claim 8 , wherein the stabilizing agent is sugars, surface modifying agents, surfactants, hydrophobic amino acids such as tryptophan, tyrosine, leucine, phenylalanine, pharmaceutical carriers, excipients or a combinations thereof. 
     
     
         10 . The inhalable dry powder of  claim 1 , wherein the one or more pharmaceutical acceptable carriers are fructose, galactose, glucose, D-mannose, sorbose, lactose, trehalose, raffinose, maltodextrins, glycine, sodium citrate, tromethamine hydrochloride, human serum albumin, mannitol or a combinations thereof. 
     
     
         11 . The inhalable dry powder of  claim 1 , wherein the aerodynamic performance is measured by the percent respirable fraction on a cartridge fill. 
     
     
         12 . The inhalable dry powder of  claim 11 , wherein the percent respirable fraction is greater than about 40%. 
     
     
         13 . The inhalable dry powder of  claim 1 , wherein the active agent content of the microparticle is about 3% to about 50% by weight of the dry powder formulation. 
     
     
         14 . The inhalable dry powder of  claim 13 , wherein the active agent content of the microparticle is about 7% to about 25% by weight of the dry powder formulation. 
     
     
         15 . The inhalable dry powder of  claim 1 , wherein the improved pharmaceutic property is obtained by removing the solvent by spray drying as compared to removing solvent by lyophilization. 
     
     
         16 . The inhalable dry powder of  claim 15 , wherein the dry powder density is increased to 1.7 to 2.3 times when spray dried as compared to lyophilization. 
     
     
         17 . The inhalable dry powder of claim  20 , wherein the tapped density is from 0.25 to 0.30 g/cc. 
     
     
         18 . The inhalable dry powder of claim  20 , wherein the bulk density is from 0.15 to 0.20 g/cc.