Enhanced delivery of immunosuppressive drug compositions for pulmonary delivery

Abstract

The present invention includes compositions and methods for making and using a rapid dissolving, high potency, substantially amorphous nanostructured aggregate for pulmonary delivery of tacrolimus and a stabilizer matrix comprising, optionally, a polymeric or non-polymeric surfactant, a polymeric or non-polymeric saccharide or both, wherein the aggregate comprises a surface area greater than 5 m 2 /g as measured by BET analysis and exhibiting supersaturation for at least 0.5 hours when 11-15-times the aqueous crystalline solubility of tacrolimus is added to simulated lung fluid.

What is claimed is: 
     
         1 . A method for preparing a pharmaceutical composition comprising immunosuppressive drug-containing nanoparticles, the nanoparticles comprising an immunosuppressive drug, said method comprising mixing the immunosuppressive drug with a solvent to form a mixture; and ultra-rapid freezing the mixture into a high potency nanoparticle by ultra-rapid freezing on a solid substrate to provide the pharmaceutical composition. 
     
     
         2 . The method of  claim 1 , wherein the drug and solvent mixture further includes a carbohydrate and the mixture is subjected to ultra-rapid freezing on the solid substrate. 
     
     
         3 . The method of  claim 1 , wherein the immunosuppressive drug is amorphous. 
     
     
         4 . The method of  claim 1 , wherein the nanoparticles are free of polymeric surfactants. 
     
     
         5 . The method of  claim 2 , wherein the carbohydrate is mannitol, raffinose, lactose, maltodextrin, trehalose or combinations thereof. 
     
     
         6 . The method of  claim 5 , wherein the carbohydrate is lactose. 
     
     
         7 . The method of  claim 1 , wherein the nanoparticles are free of ethanol and propylene glycol. 
     
     
         8 . The method of  claim 1 , wherein the nanoparticles are further defined as nanostructured particles. 
     
     
         9 . The method of  claim 1 , wherein the pharmaceutical composition is further defined as a dispersion or powder adapted for nebulization or inhalation. 
     
     
         10 . The method of  claim 9 , wherein the pharmaceutical composition is comprised in a nebulizer, an air-jet nebulizer, an ultrasonic nebulizer, a metered dose inhaler, a dry powder inhalation device or a micro-pump nebulizer. 
     
     
         11 . The method of  claim 1 , wherein the immunosuppressive drug is tacrolimus. 
     
     
         12 . The method of  claim 1 , wherein the immunosuppressive drug is cyclosporine. 
     
     
         13 . The method of  claim 1 , wherein the solid substrate is a cryogenic solid substrate. 
     
     
         14 . The method of  claim 1 , wherein the solid substrate is cooled subsequent to the application of the drug mixture thereon. 
     
     
         15 . The method of  claim 1 , wherein the solid substrate is cooled prior to the application of the drug mixture thereon. 
     
     
         16 . A method of treating a pulmonary disease in a subject, the method comprising obtaining a pharmaceutical composition in accordance with  claim 1 , and delivering the composition to the subject by pulmonary delivery to treat one or more pulmonary diseases in an amount effective to treat the pulmonary disease. 
     
     
         17 . The method of  claim 16 , wherein the pulmonary disease is pulmonary fibrosis. 
     
     
         18 . The method of  claim 16 , wherein the pulmonary disease is bronchiolar asthma. 
     
     
         19 . The method of  claim 16 , wherein the pulmonary disease is graft rejection. 
     
     
         20 . The method of  claim 16 , wherein the pharmaceutical composition is delivered to the lungs of the subject by nebulization, metered dose inhalation or dry powder inhalation.