Dry powder formulation of azole derivative for inhalation

Abstract

A spray dried-powder composition for inhalation comprising particles (X) containing (a) between 5 and 50% by weight of at least one azole derivative in amorphous state but not in crystalline structure and (b) at least one matricial agent to the composition selected from a group consisting of polyol such as sorbitol, mannitol and xylitol; a monosaccharides such as glucose and arabinose; disaccharide such as lactose, maltose, saccharose and dextrose; cholesterol, and any mixture thereof, wherein the composition provides a dissolution rate of said azole derivative of at least, 5% within 10 minutes, 10% within 20 minutes and 40% within 60 minutes when tested in the dissolution apparatus type 2 of the United States Pharmacopoeia at 50 rotation per minute, 37° C. in 900 milliliters of an aqueous dissolution medium adjusted at pH 1.2 and containing 0.3% of sodium laurylsulfate.

1 . Spray dried particles for inhalation composition comprising:
 a) between 5 to 50% by weight of at least one azole compound in an amorphous state; and   b) at least one matricial agent to the composition selected from the group consisting of polyol including one of sorbitol, mannitol or xylitol; a monosaccharide including one of glucose or arabinose; disaccharide including one of lactose, maltose, saccharose or dextrose; cholesterol, and any mixture thereof.   
     
     
         2 . The particles according to  claim 1 , wherein the matricial agent is mannitol or cholesterol. 
     
     
         3 . The particles according to  claim 1 , wherein the weight ratio of the at least one azole compound/at least one matricial agent is between 0.5/99.5 and 40/60. 
     
     
         4 . The particles according to  claim 1  further comprising a surfactant. 
     
     
         5 . The particles according to  claim 4  comprising between 0.1 and 5% by weight of the surfactant. 
     
     
         6 . The particles according to  claim 4 , wherein said surfactant comprises lecithin, phospholipids derivatives including phosphatic acids, phosphatidyl choline (saturated and unsaturated), phoshpatidyl ethanol amine, phosphatidyl glycerol, phosphatidyl serine, phosphatidyl inositol, dioleoylphosphatidylcholine, dimyristoyl phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoyl phosphatidylcholine, diarachidoyl phosphatidylcholine, dibenoyl phosphatidylcholine, ditricosanoyl phosphatidylcholine, dilignoceroylphatidylcholine, dimiristoylphosphatidylethanolamine, dipalmitoyl-phosphatidylethanoalamine, pipalmitoleoylphasphatidylethanolamine, distearoyl-phosphatidylethanolamine, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidyl glycerol, dipalmitolcoylphosphatidylglycerol and hydrogenated derivates or modified vitamins comprise α-tochopherols derivates. 
     
     
         7 . The spray dried-powder composition for inhalation comprising particles (X) according to  claim 1 , wherein said composition comprises at least 50% of the matricial agent and provides a dissolution rate of said azole derivative of at least, 5% within 10 minutes, 10% within 20 minutes and 40% within 60 minutes when tested in the dissolution apparatus type 2 of the United States Pharmacopoeia at 50 rotation per minute, 37° C. in 900 milliliters of an aqueous dissolution medium adjusted at pH 1.2 and containing 0.3% of sodium laurylsulfate. 
     
     
         8 . The spray dried-powder composition according to  claim 7  providing a Fine Particle Fraction of the azole derivative of at least 35% of the total nominal dose of the azole in the powder following the method “preparations for inhalation: assessment of fines particles” using the Multi-stage Liquid Impinger, Apparatus C-chapter 2.9.18 of the European Pharmacopoeia. 
     
     
         9 . The spray dried-powder composition according to  claim 7  further comprising particles (Y) according to  claim 4 . 
     
     
         10 . The spray dried-powder composition according to  claim 9 , wherein the particles (Y) contain between 0.5 and 5% by weight of the surfactant(s). 
     
     
         11 . The spray dried-powder composition according to  claim 7  further comprising particles (Z) containing up to 20% by weight of nanoparticles of the at least one azole compound in crystalline structure having a mean size between 0.1 and 1 μm. 
     
     
         12 . The spray dried-powder composition according to  claim 9  providing a dissolution rate of the at least one azole compound of 5 to 50% within 5 minutes, 10 to 60% within 10 minutes, 15 to 90% within 20 minutes and 40 to 100% after 60 minutes. 
     
     
         13 . The spray dried-powder composition according to  claim 7 , wherein the at least one azole compound is selected from the group consisting of iconazole, fluconazole, itraconazole, posaconazole, voriconazole, isoconazole, ketoconazole, oxiconazole, bifonazole, fenticonazole, tioconazole, terconazole, sulconazole, ravuconazole, econazole, terconazole, and itraconazole and mixtures thereof. 
     
     
         14 . A method for preparing spray dried particles comprising the steps of:
 a) preparing a liquid composition comprising:
 i. a liquid carrier comprising a class 3 solvent according to European Pharmacopoeia including acetic acid, heptane, acetone, isobutyl acetate, anisole, isopropyl acetate,1-Butanol, methyl acetate, 2-Butanol, 3-Methyl-1-butanol, Butyl acetate, methylethylketone, tert-Butylmethyl ether, methylisobutylketone, cumene, 2-Methyl-1-propanol, dimethyl sulfoxide, pentane, 
 ii. ethanol, 1-Pentanol, Ethyl acetate, 1-Propanol, ethyl ether, 2-Propanol, ethyl formate, propyl acetate, or formic acid, or mixtures thereof, or the mixture of any of the above with water; 
 iii. at least one azole compound in solution in said liquid carrier; and 
 iv. at least one matricial agent in solution in said liquid carrier, 
 wherein the weight ratio of the at least one azole compound/at least one matricial agent is between 0.5/99.5 and 40/60, and 
   b) spray drying the liquid composition thereby producing particles for the dry powder composition.   
     
     
         15 . The method according to  claim 14  further comprising the steps of:
 c) preparing another liquid composition comprising a liquid carrier comprising a class 3 solvent or any mixture of two or more of such solvents with or without water and at least one matricial agent in solution in said liquid carrier, wherein the liquid composition further comprises:
 i. at least one azole compound in solution in said liquid carrier and at least one surfactant; and/or 
 ii. nanoparticles of at least one azole compound having a mean size between 0.1 and 1 μm, and 
 
 d) spray drying said liquid composition provided by step (c) thereby producing particles for the dry powder composition. 
 
     
     
         16 . The method according to  claim 15  comprising a step of physically blending the particles obtained by steps (b) with the particles obtained by step (d). 
     
     
         17 . A liquid composition prepared according to the method of  claim 14 . 
     
     
         18 . The liquid composition according to  claim 17  further comprising at least one surfactant and/or nanoparticles of at least one azole compound having a mean size between 0.1 and 1 μm. 
     
     
         19 . The spray dried-powder composition according to  claim 13 , wherein the at least one azole compound is itraconazole.