Dry Powder Pharmaceutical Compositions, Its Preparation Process and Stable Aqueous Suspension Obtained from such Composition

Abstract

Pharmaceutical composition in a dry powder form comprising at least one hydrophobic active principle, at least one water-soluble excipient and at least one surfactant, wherein the particles in said dry powder state have a Volume Mean Diameter VMD d greater than the Volume Mean Diameter VMD w of particles in a suspension obtained from said pharmaceutical composition at standard conditions of dispersion in a water-medium. It is also disclosed a process to prepare such dry composition and an extemporaneous suspension for inhalation therapy obtainable from said dry composition.

1 . Pharmaceutical composition in a dry powder form comprising at least one hydrophobic active principle, at least one water-soluble excipient and at least one surfactant, characterized in that the particles in said dry powder state have a Volume Mean Diameter VMD d  greater than the Volume Mean Diameter VMD w  of particles in a suspension obtained from said pharmaceutical composition at standard conditions of dispersion in a water-medium. 
     
     
         2 . Pharmaceutical composition according to  claim 1 , characterized in that said surfactant and said active principle have weight-to-weight ratio between 0.1 and 100. 
     
     
         3 . Pharmaceutical composition according to  claim 2 , characterized in that said surfactant and said active principle have a weight-to-weight ratio between 0.3 and 80. 
     
     
         4 . Pharmaceutical composition according to  claim 3 , characterized in that said surfactant and said active principle have weight-to-weight ratio between 0.6 and 40. 
     
     
         5 . Pharmaceutical composition according to  claim 1 , wherein the particle size of said dry powder pharmaceutical composition expressed as VMD d  is comprised between 0.1 and 175 μm. 
     
     
         6 . Pharmaceutical composition according to  claim 5 , where the particle size of said dry powder pharmaceutical composition expressed as VMD d  is comprised between 0.5 and 30 μm. 
     
     
         7 . Pharmaceutical composition according to  claim 6 , where the particle size of said dry powder pharmaceutical composition expressed as VMD d  is comprised between 1 and 10 μm. 
     
     
         8 . Pharmaceutical composition according to any of the  claims 5 ,  6  and  7 , wherein the size distribution of said particles is substantially mono-modal. 
     
     
         9 . Pharmaceutical composition according to any of the claims from  1  to  4 , wherein said surfactant is a non-ionic surfactant. 
     
     
         10 . Process for the preparation of a dry powder pharmaceutical composition comprising at least one hydrophobic active principle, at least one water-soluble excipient, and at least one surfactant, in which the Volume Mean Diameter VMD d  of the particles in said solid dry composition is greater than the Volume Mean Diameter VMD w  of the particles in a suspension obtained from said pharmaceutical composition at standard conditions of dispersion in a water-medium, said process comprising the following steps:
 a). preparing a first phase (A) in which said hydrophobic active principle is present in a suitable liquid medium;   b). preparing a second phase (B) in which one or more water-soluble excipients are dissolved in an aqueous medium;   c). dissolving the surfactants in either one of phase (A) or phase (B) above, depending on the surfactant preferential solubility;   d). mixing said phases (A) and (B) to obtain a phase (C) in which the liquid medium is homogeneous;   e). drying said phase (C) in controlled conditions in order to obtain a dry powder with particle size between 0.1 and 175 μm;   f). collecting said dry powder and shaping it in a suitable form for an extemporaneous preparation of a suspension.   
     
     
         11 . Process according to  claim 10 , wherein said step a) comprises preparing a phase (A) which is a solution of said hydrophobic active principle in an organic solvent. 
     
     
         12 . Process according to  claim 11 , wherein said organic solvent is miscible with water. 
     
     
         13 . Process according to  claim 12 , wherein said organic solvent is an alcohol. 
     
     
         14 . Process according to  claim 13 , wherein said alcohol is ethyl alcohol. 
     
     
         15 . Process according to  claim 10 , wherein said step a) comprises preparing a phase (A) which is a suspension of said hydrophobic active principle in water. 
     
     
         16 . Process according to  claim 10 , wherein said step d) of drying said phase (C) is a spray drying process. 
     
     
         17 . Process according to any of the claims from  10  to  16 , wherein said particle size, expressed as VMD d , is comprised between 0.1 and 175 μm. 
     
     
         18 . Process according to  claim 17 , wherein said surfactant and active principle have a weight-to-weight ratio in said particles comprised between 0.1 and 100. 
     
     
         19 . Process according to  claim 18 , wherein said surfactant and active principle have a weight-to-weight ratio in said particles comprised between 0.3 and 80. 
     
     
         20 . Process according to  claim 19 , wherein said surfactant and active principle have a weight-to-weight ratio in said particles comprised between 0.6 and 40. 
     
     
         21 . Process according to  claim 17 , wherein said particle size distribution is substantially mono-modal. 
     
     
         22 . Liquid suspension of solid particles comprising a hydrophobic active principle, obtainable by dispersing in an aqueous medium a dry powder pharmaceutical composition comprising said hydrophobic active principle, one or more water-soluble excipients and one or more surfactants, characterized in that the Volume Mean Diameter VMD w  of the particles in said suspension determined under standard conditions of dispersion is lower than the Volume Mean Diameter VMD d  of the particles in said dry powder composition. 
     
     
         23 . Liquid suspension according to  claim 22 , wherein the complete sedimentation time of said suspension is greater than 40 minutes. 
     
     
         24 . Liquid suspension according to  claim 23 , wherein the complete sedimentation time of said suspension is greater than 60 minutes. 
     
     
         25 . Liquid suspension according to  claim 24 , wherein the complete sedimentation time of said suspension is greater than 100 minutes. 
     
     
         26 . Liquid suspension according to  claim 22 , wherein the theoretical mean diameter TMD of said particles is lower than the Volume Mean Diameter VMD w . 
     
     
         27 . Liquid suspension according to  claim 26 , wherein the theoretical mean diameter TMD of said particles fulfils the equation TMD≦0.5 VMD w . 
     
     
         28 . Kit of products for an extemporaneous preparation of a liquid suspension of a hydrophobic active principle, characterized by comprising:
 a) an effective amount of a dry powder pharmaceutical composition comprising said hydrophobic active principle, at least one water-soluble excipient and at least one surfactant,   b) a predetermined volume of a liquid dispersing medium;   wherein said products a) and b) are packaged in physically separated containers, in order to be mixed extemporaneously to form a suspension, in which the particles Volume Mean Diameter VMD w  measured in standard conditions of dispersion is lower than the Volume Mean Diameter VMD d  of the particles in said dry powder pharmaceutical composition.   
     
     
         29 . Kit of products according to  claim 28 , wherein the surfactant and the active principle have a weight-to-weight ratio in said pharmaceutical composition comprised between 0.1 and 100. 
     
     
         30 . Kit of products according to  claim 29 , wherein the surfactant and active principle have a weight-to-weight ratio in said pharmaceutical composition comprised between 0.3 and 80. 
     
     
         31 . Kit of products according to  claim 28 , wherein the surfactant and active principle have a weight-to-weight ratio in said pharmaceutical composition comprised between 0.6 and 40. 
     
     
         32 . Kit of products according to  claim 28 , wherein the Volume Mean Diameter VMD d  of the particles in said dry powder composition is comprised between 0.1 and 175 μm. 
     
     
         33 . Kit of products according to  claim 32 , wherein the Volume Mean Diameter VMD d  of the particles in said solid dry composition is comprised between 0.5 and 30 μm. 
     
     
         34 . Kit of products according to  claim 33 , wherein the Volume Mean Diameter VMD d  of the particles in said solid dry composition is comprised between 1 and 10 μm. 
     
     
         35 . Pharmaceutical composition according to any of the claims from  1  to  9 , wherein said active principle is a steroid molecule. 
     
     
         36 . Pharmaceutical composition according to  claim 35 , wherein said active principle is a glycocorticosteroid. 
     
     
         37 . Pharmaceutical composition according to  claim 36 , wherein said glycocorticosteroid is chosen among budesonide, beclomethasone, fluticasone propionate and their mixtures.