Process for Preparing Inhalable Powders

Abstract

The invention relates to a new process for producing powdered preparations for inhalation comprising a substance having a smaller particle size distribution and a substance having a larger particle size distribution, wherein a substance having a smaller particle size distribution and a substance having a larger particle size distribution are continuously metered into a suitable mixing container such that the quotient N of the delivery speed for the metering of the substance having the smaller particle size distribution and the delivery speed for the metering of the substance having the larger particle size distribution is at least as great as the quotient M of the total mass of the substance having the smaller particle size distribution and the total mass of the substance having the larger particle size distribution.

1 - 17 . (canceled)  
   
   
       18 . A process for preparing an inhalable powder comprising a betamimetic selected from the group consisting of bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tulobuterol, mabuterol, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of their racemates, their enantiomers, their diastereomers, as well as optionally their pharmacologically acceptable acid addition salts and hydrates. It is particularly preferable to use, as betamimetics, active substances of this kind selected from among fenoterol, formoterol, salmeterol, mabuterol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, wherein the betamimetic having a smaller particle size distribution and the betamimetic having a larger particle size distribution are continuously metered into a suitable mixing container such that the quotient N of the delivery speed for the metering of the betamimetic having the smaller particle size distribution and the delivery speed for the metering of the betamimetic having the larger particle size distribution is at least as great as the quotient M of the total mass of the betamimetic having the smaller particle size distribution and the total mass of the betamimetic having the larger particle size distribution.  
   
   
       19 . A process for preparing an inhalable powder comprising an anticholinergic selected from the group consisting of tiotropium salts, oxitropium salts and ipratropium salts, wherein the anticholinergic having a smaller particle size distribution and the anticholinergic having a larger particle size distribution are continuously metered into a suitable mixing container such that the quotient N of the delivery speed for the metering of the anticholinergic having the smaller particle size distribution and the delivery speed for the metering of the anticholinergic having the larger particle size distribution is at least as great as the quotient M of the total mass of the anticholinergic having the smaller particle size distribution and the total mass of the anticholinergic having the larger particle size distribution.  
   
   
       20 . A process for preparing an inhalable powder comprising a corticosteroid selected from the group consisting of flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone, wherein the corticosteroid having a smaller particle size distribution and the corticosteroid having a larger particle size distribution are continuously metered into a suitable mixing container such that the quotient N of the delivery speed for the metering of the corticosteroid having the smaller particle size distribution and the delivery speed for the metering of the corticosteroid having the larger particle size distribution is at least as great as the quotient M of the total mass of the corticosteroid having the smaller particle size distribution and the total mass of the corticosteroid having the larger particle size distribution.  
   
   
       21 . A process for preparing an inhalable powder comprising a dopamine antagonist selected from the group consisting of bromocriptine, cabergolin, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan, wherein the dopamine antagonist having a smaller particle size distribution and the dopamine antagonist having a larger particle size distribution are continuously metered into a suitable mixing container such that the quotient N of the delivery speed for the metering of the dopamine antagonist having the smaller particle size distribution and the delivery speed for the metering of the dopamine antagonist having the larger particle size distribution is at least as great as the quotient M of the total mass of the dopamine antagonist having the smaller particle size distribution and the total mass of the dopamine antagonist having the larger particle size distribution.  
   
   
       22 . The process according to any one of claims  18 - 21 , wherein the quotient N is greater than the quotient M.  
   
   
       23 . The process according to any one of claims  18 - 21 , wherein the quotient N/M is in the range from 1<N/M≦1.5.  
   
   
       24 . The process according to any one of claims  18 - 21 , wherein the components of the powder mixture are metered into the mixing container through a suitable screening device.  
   
   
       25 . The process according to any one of claims  18 - 21 , wherein in the resulting inhalable powder the content of the active substance having the smaller particle size distribution is less than 5%.  
   
   
       26 . The process according to any one of claims  18 - 21 , wherein in the resulting inhalable powder the active substance having the smaller particle size distribution has an average particle size of from 0.5 to 10 μm and wherein the active substance having the larger particle size distribution has an average particle size of from 10 to 100 μm.  
   
   
       27 . The process according to any one of claims  18 -21, wherein the quotient N/M is in the range from 1<N/M≦1.5, the components of the powder mixture are metered into the mixing container through a suitable screening device, in the resulting inhalable powder the content of the active substance having the smaller particle size distribution is less than 5%, and in the resulting inhalable powder the active substance having the smaller particle size distribution has an average particle size of from 0.5 to 10 μm and the active substance having the larger particle size distribution has an average particle size of from 10 to 100 μm.  
   
   
       28 . An inhalable powder prepared by a process according to any one of claims  18 - 21 .  
   
   
       29 . The inhalable powder prepared by a process according to  claim 27.