Process for the preparation of pharmaceutical suspensions for inhalation

Abstract

Process for preparing sterile suspensions for inhalation comprising an active ingredient insoluble in water and wherein at least 80% of the particles of said active ingredient have a diameter between 3 and 5 μm, comprising the following stages: dissolving the active ingredient in the minimum quantity of an alcoholic solvent, optionally in the presence of a polyol and adding at least one surfactant, filtering the solution obtained in the previous stage through a sterilizing filter, adding the solution from stage (b) to sterile water under sonication to directly obtain a suspension wherein the particles have a reduced diameter.

1 . Process for preparing sterile suspensions for inhalation for pharmaceutical use comprising a water insoluble active ingredient and wherein at least 80% of the particles of said active ingredient have a diameter between 3 and 5 μm, comprising the following steps: 
 a) dissolving the active ingredient in the minimum quantity of an alcoholic solvent, optionally in the presence of a polyol and adding at least one surfactant,    b) filtering the solution obtained in the previous step through a sterilizing filter,    c) adding the solution from step (b) to sterile water under sonication to directly obtain a suspension wherein the particles have a reduced diameter.    
     
     
         2 . Process as claimed in  claim 1  wherein the temperature of step (c) is controlled by means of cooling system known in the state of the art.  
     
     
         3 . Process as claimed in  claim 1 , wherein the alcoholic solvent is ethanol.  
     
     
         4 . Process as claimed in  claim 1 , wherein the optional polyol is propylene glycol.  
     
     
         5 . Process as claimed in  claim 1 , wherein the surfactant is selected from the group consisting of: ethoxylated castor oil, sorbitan trioleate, oleic alcohol, lecithin oleic acid, Tween.  
     
     
         6 . Process as claimed in  claim 5 , wherein the surfactant is ethoxylated castor oil.  
     
     
         7 . Process as claimed in  claim 1 , wherein the active ingredient is selected from the group consisting of: steroid anti-inflammatory drug, anti-asthma drug.  
     
     
         8 . Process as claimed in  claim 1 , wherein the active ingredient/alcohol weight ratio is between 0.1 and 1.  
     
     
         9 . Process as claimed in  claim 8 , wherein said weight ratio is 1:1.  
     
     
         10 . Process as claimed in  claim 1 , wherein the polyol is added in weight ratios, with respect to the alcohol, between 0.4 and 4.  
     
     
         11 . Process as claimed in  claim 10 , wherein said weight ratio is 3.75.  
     
     
         12 . Process as claimed in  claim 1 , wherein the surfactant is added in weight ratios, with respect to the active ingredient, between 0.4 and 4.  
     
     
         13 . Process as claimed in  claim 12  wherein said ratio is 1:1.  
     
     
         14 . Process as claimed in  claim 1 , wherein the sterile water used in step (c) is sonicated for approximately 15 minutes.  
     
     
         15 . Process as claimed in  claim 1 , wherein the sonication in step (c) is conducted at a frequency between 20 and 40 kHz, wave length between 35 and 70 μm and a power between 500 and 3000 Watts.  
     
     
         16 . Process as claimed in  claim 15  wherein said sonication is conducted at: frequency 20 kHz, power 600 Watts and, finally, wave length of 40 μm.  
     
     
         17 . Process as claimed in  claim 15 , wherein each sonication cycle is conducted for periods of time between 3 and 6 minutes.  
     
     
         18 . Process as claimed in  claim 17  wherein the number of said sonication cycle is an integer ranging from 1 to 50.  
     
     
         19 . Process as claimed in  claim 1 , wherein the suspension for inhalation obtained in step (c) contains the active ingredients in concentrations between 0.01 and 0.1% by weight, alcohol in concentrations between 0.01 and 0.1%, the optional polyol in concentrations between 0.04 and 0.4%, surfactants in concentrations between 0.04 and 0.4%, the remaining to 100 parts by weight consists of sterile water.  
     
     
         20 . Process as claimed in  claim 1  wherein the suspension for inhalation obtained in step (c) contains the active ingredients in concentrations between 0.01 and 0.1% by weight, alcohol in concentrations between 0.01 and 0.4%, the optional polyol in concentrations between 0.04 and 0.4%, surfactants in concentrations between 0.04 and 0.4%, the remaining to 100 parts by weight consists of sterile water.  
     
     
         21 . Process as claimed in  claim 19  wherein said suspension for inhalation for pharmaceutical use has the following concentration: active ingredient 0.04%, ethoxylated castor oil: 0.15%, ethanol: 0.04%, propylene glycol: 0.15%, sterile water q.s. to 100 parts by weight.  
     
     
         22 . Process as claimed in  claim 20 , wherein said suspension for inhalation pharmaceutical use has the following concentration: active ingredient 0.04%, ethoxylated castor oil: 0.15%, ethanol: 0.40%, propylene glycol: 0.15%, sterile water q.s. to 100 parts by weight.  
     
     
         23 . Suspension for inhalation for pharmaceutical use containing an active ingredient in concentrations between 0.01 and 0.1% by weight, an alcohol in concentrations between 0.01 and 0.1%, optionally polyol, in concentrations between 0.04 and 0.4%, a surfactant in concentrations between 0.04 and 0.4%, the remaining to 100 parts by weight consists of sterile water.  
     
     
         24 . Suspension for inhalation as claimed in  claim 23  containing: 0.04% of active ingredient, 0.15% of ethoxylated castor oil, 0.04% of ethanol, 0.15% of propylene glycol, sterile water q.s. to 100 parts by weight.  
     
     
         25 . Suspension for inhalation for pharmaceutical use containing an active ingredient in concentrations between 0.01 and 0.1% by weight, an alcohol in concentrations between 0.01 and 0.4%, optionally polyol, in concentrations between 0.04 and 0.4%, a surfactant in concentrations between 0.04 and 0.4%, the remaining to 100 parts by weight consists of sterile water.  
     
     
         26 . Suspension for inhalation as claimed in  claim 25  containing: 0.04% of active ingredient, 0.15% of ethoxylated castor oil, 0.4% of ethanol, 0.15% of propylene glycol, sterile water q.s. to 100 parts by weight.