Method of preparing a pharmaceutical composition

Abstract

The present disclosure provides a method of preparing a pharmaceutical composition. The method includes transferring a predetermined quantity of an excipient mixture from a second vessel to a first vessel. The excipient mixture transferred from the second vessel includes a liquid-state second quantity of a hydrofluoroalkane propellant and a first solubilized excipient comprising a low-molecular weight poly(ethylene oxide) polymer. The method further includes contacting at least one pharmaceutically-active compound with the excipient mixture under conditions that facilitate forming an intermixture comprising the propellant, the polymer, and the compound. Before transferring the excipient mixture, the first vessel contains a vapor-phase first quantity of the hydrofluoroalkane propellant and an effective amount of the at least one pharmaceutically-active compound.

1 . A method, comprising:
 transferring a predetermined quantity of an excipient mixture from a second vessel to a first vessel;
 wherein the excipient mixture transferred from the second vessel comprises a liquid-state second quantity of a hydrofluoroalkane propellant and a first solubilized excipient; 
 wherein the first solubilized excipient comprises a low-molecular weight poly(ethylene oxide) polymer; 
 wherein, before transferring the excipient mixture, the first vessel contains a vapor-phase first quantity of the hydrofluoroalkane propellant and an effective amount of at least one pharmaceutically-active compound; and 
   contacting the at least one compound with the excipient mixture under conditions that facilitate forming an intermixture comprising the propellant, the first solubilized excipient, and the pharmaceutically-active compound.   
     
     
         2 . The method of  claim 1 , wherein forming the intermixture comprises forming a pharmaceutical composition. 
     
     
         3 . The method of  claim 1 , wherein the method further comprises mixing a liquid-state third quantity of the hydrofluoroalkane propellant with the intermixture to form a pharmaceutical composition. 
     
     
         4 . The method of  claim 1  wherein, before transferring the excipient mixture, the first vessel is substantially free of liquid-state propellant in fluid contact with the at least one pharmaceutically-active compound. 
     
     
         5 . The method of  claim 1 , wherein the hydrofluoroalkane propellant is selected from a group consisting of HFA-227, HFA-134A, and mixtures thereof. 
     
     
         6 . The method of  claim 1 , wherein the excipient mixture comprises about 0.01 weight percent to about 3 weight percent of the poly(ethylene oxide) polymer. 
     
     
         7 . The method of  claim 1 , wherein the pharmaceutical composition comprises about 0.01 weight percent to about 3.0 weight percent poly(ethylene oxide) polymer. 
     
     
         8 . The method of  claim 1 , wherein the excipient mixture further comprises a second solubilized excipient. 
     
     
         9 . The method of  claim 8 , wherein the second solubilized excipient comprises a polyvinylpyrrolidone polymer. 
     
     
         10 . The method of  claim 1 , wherein the at least one pharmaceutically-active compound is selected from a group consisting of formoterol fumarate and hydrates thereof, budesonide, fluticasone propionate, fluticasone furoate, salmeterol xinafoate, mometasone furoate, albuterol sulfate, beclomethasone, ipratropium bromide, tiotropium bromide, ciclesonide, indacaterol, vilanterol, glycopyrrolate, a generally long acting beta agonist, steroids, long acting muscarinic agonists, and a combination of any of the foregoing pharmaceutically-active compounds. 
     
     
         11 . The method of  claim 1 , wherein the at least one pharmaceutically-active compound comprises formoterol fumarate dihydrate and budesonide. 
     
     
         12 . The method of  claim 1 , wherein the at least one pharmaceutically-active compound comprises albuterol sulfate. 
     
     
         13 . The method of  claim 1 , wherein the at least one pharmaceutically-active compound comprises particles, wherein the particles have an average particle diameter of less than or equal to 10 microns. 
     
     
         14 . The method of  claim 1 :
 wherein transferring a predetermined quantity of an excipient mixture from a second vessel to a first vessel comprises placing the first and second vessels in fluid communication;   wherein, while the first and second vessels are in fluid communication, the first vessel has a first internal pressure and the second vessel has a second internal pressure;   wherein the first internal pressure is not more than about 210 kPa below the second internal pressure.   
     
     
         15 . The method of  claim 1 , further comprising forming the excipient mixture, wherein forming the excipient mixture comprises:
 contacting the poly(ethylene oxide) polymer with the second quantity of the propellant, wherein at least a portion of the poly(ethylene oxide) polymer contacted with the second quantity is solid state poly(ethylene oxide) polymer; and   heating the propellant.   
     
     
         16 . The method of  claim 1 , further comprising forming the excipient mixture, wherein forming the excipient mixture comprises:
 heating the poly(ethylene oxide) polymer; and   after heating the poly(ethylene oxide) polymer, contacting the poly(ethylene oxide) polymer with the second quantity of the propellant.   
     
     
         17 . The method of  claim 1 , further comprising transferring a predefined mass of the intermixture to a vessel that is configured to be used in a metered-dose inhaler. 
     
     
         18 . The method of  claim 1 , further comprising transferring a predefined mass of the pharmaceutical composition to a vessel that is configured to be used in a metered-dose inhaler. 
     
     
         19 . The method of  claim 1  wherein, prior to transferring a predetermined quantity of an excipient mixture from a second vessel to a first vessel, the first vessel and the second vessel are substantially free of an alcoholic solvent. 
     
     
         20 . The method of  claim 1  wherein, prior to transferring a predetermined quantity of an excipient mixture from a second vessel to a first vessel, the first vessel and the second vessel are substantially free of a polar co-solvent.