Inhalable Pharmaceutical Compositions

Abstract

Methods for making inhalable composite particles comprising a pharmaceutically-active agent, the method comprising: a) providing composite particles comprising a millable grinding matrix and a solid pharmaceutically-active agent, wherein the pharmaceutically-active agent has an median particle size on a volume average basis between 50 nm and 3 μm; and b) milling the composite particles in a mill without milling bodies for a time period sufficient to produce inhalable composite particles having a mass median aerodynamic diameter between 1 μm and 20 μm are described.

1 - 79 . (canceled) 
     
     
         80 . An inhalable pharmaceutically-active composition comprising:
 a millable grinding matrix and a solid pharmaceutically-active agent, wherein the composite particles of the grinding matrix and the pharmaceutically-active agent have a mass median aerodynamic diameter of from about 1 μm to about 20 μm; and wherein the pharmaceutically-active agent has a median particle size, on a particle volume basis, of from about 50 nm to about 3 μm.   
     
     
         81 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the composition comprises a plurality of composite particles comprising the millable grinding matrix and the solid pharmaceutically-active agent. 
     
     
         82 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the solid pharmaceutically-active agent has a median particle size on a volume average basis of between 50 nm and 1 μm. 
     
     
         83 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles have a median particle size on a volume average basis less than or equal to 10,000 nm. 
     
     
         84 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles have a D90, determined on a particle volume basis, of less than or equal to 15,000 nm. 
     
     
         85 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles have a D90, determined on a particle volume basis, greater than or equal to 2000 nm. 
     
     
         86 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles have a volume weighted mean (D4,3) of less than or equal to 10,000 nm. 
     
     
         87 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles have a volume weighted mean (D4,3) greater than or equal to 1000 nm. 
     
     
         88 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles are capable of providing an aerosol with a mass median aerodynamic diameter (MMAD) of the inhalable composite particles between 1 μm and 10 μm when delivered from a dry powder inhaler. 
     
     
         89 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles are capable of providing an aerosol with a fine particle fraction (FPF) of emitted dose of the pharmaceutically active agent of greater than or equal to about 10% when delivered from a dry powder inhaler. 
     
     
         90 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles are capable of providing an aerosol with a relative standard deviation (RSD) of the fine particle fraction FPF of emitted dose of the pharmaceutically active agent of less than or equal to about 10%. 
     
     
         91 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles are capable of providing an aerosol with a fine particle fraction (FPF) of total recovered dose of the pharmaceutically active agent of greater than or equal to about 30% when delivered from a dry powder inhaler. 
     
     
         92 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles when delivered from a dry powder inhaler are capable of providing an aerosol with a mass median aerodynamic diameter (MMAD) of the inhalable composite particles from about 1 μm to about 10 μm and a FPF of the pharmaceutically active agent of at least about 10%. 
     
     
         93 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles are capable of providing an aerosol with an emitted dose (ED) of greater than or equal to about 70% when delivered from a dry powder inhaler. 
     
     
         94 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the composite particles are capable of providing an aerosol with an relative standard deviation (RSD) of less than or equal to about 10% when determined on at least three samples delivered from a dry powder inhaler. 
     
     
         95 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the pharmaceutically-active agent within the provided composite particles has a median size of from about 50 nm to about 1000 nm. 
     
     
         96 . The inhalable pharmaceutically-active composition  claim 80 , wherein the provided composite particles further comprise a milling aid. 
     
     
         97 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the millable grinding matrix is crystalline. 
     
     
         98 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the pharmaceutically-active agent is crystalline. 
     
     
         99 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the content uniformity of the solid pharmaceutically active agent dispersed in the composite particle varies from the average content by a percentage less than or equal to about 5.0%. 
     
     
         100 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the content uniformity of the pharmaceutically active agent throughout the blend has a percent relative standard deviation (RSD) less than or equal to about 5.0%. 
     
     
         101 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the inhalable composite particles have a roughness by surface area ratio greater than or equal to a ratio of about 1.1, wherein the specific surface area is measured using nitrogen absorption; and wherein the surface area is calculated from the spherical equivalent size determined by dry powder laser diffraction. 
     
     
         102 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the composite particles have a roughness root mean square (Rrms) greater than or equal to a height selected about 15 nm and wherein the roughness root mean square (Rrms) is measured using atomic force microscopy or white light interferometry. 
     
     
         103 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the composite particles have a median of force adhesion (F[50]) less than or equal to about 150 nN when measured by atomic force microscopy. 
     
     
         104 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the weight of composite particles when dispensed from an automated or semi-automated filing machine deviates from the average weight dispensed by a percentage less than or equal to about 10%. 
     
     
         105 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the RSD from the average weight is less than or equal to about 10% when the number of samples measured is greater than or equal to 100 samples delivered from an automated or semi-automated filing machine. 
     
     
         106 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the composite particle further comprises a second pharmaceutically active agent, the method producing composite particles of the millable grinding matrix having the solid pharmaceutically active agent and the second pharmaceutically active agent dispersed therein. 
     
     
         107 . The inhalable pharmaceutically-active composition of  claim 106 , wherein the composite particles have a fine particle fraction ratio of the first pharmaceutically active agent and second pharmaceutically active agent less than or equal to about 1.2 when delivered from a dry powder inhaler and analyzed with a Next Generation Impactor (NGI) with an induction port and a preseparator. 
     
     
         108 . The inhalable pharmaceutically-active composition of  claim 106 , wherein the composite particles have a mass median aerodynamic diameter (MMAD) uniformity ratio of less than or equal to about 1.2 when delivered from a dry powder inhaler and analyzed with a Next Generation Impactor (NGI) with an induction port and a preseparator, wherein the distribution of each of the first and second pharmaceutically active agent is assayed and each is used to calculate an mass median aerodynamic diameter (MMAD) for the composite particle. 
     
     
         109 . The inhalable pharmaceutically-active composition of  claim 80 , wherein the composition is formulated in a unit dosage form. 
     
     
         110 . The inhalable pharmaceutically-active composition of  claim 80 , encapsulated in a gelatin capsule. 
     
     
         111 . The inhalable pharmaceutically-active composition of any one of  claim 80 , wherein the composition is suitable for use with a dry powder inhaler. 
     
     
         112 . A dry powder inhaler for use with the inhalable pharmaceutically-active composition of  claim 80 .