Pharmaceutical compositions

Abstract

This invention provides a pharmaceutical composition comprising a eutectic composition of two pharmacologically active ingredients for delivery to the lung by inhalation. This invention also provides a pharmaceutical composition comprising a eutectic composition of two pharmacologically active ingredients for the treatment of respiratory disease.

1 - 44 . (canceled) 
     
     
         45 . A pharmaceutical composition comprising two pharmacologically active ingredients in a eutectic composition, wherein a first pharmacologically active ingredient is selected from corticosteroids and salts, esters, polymorphs, hydrates or solvates thereof and a second pharmacologically active ingredient is selected from β2 agonists, methylxanthine compounds and antihistamines and salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         46 . A pharmaceutical composition comprising a eutectic composition of two pharmacologically active ingredients for delivery to the lung by inhalation, wherein a first pharmacologically active ingredient is selected from corticosteroids and salts, esters, polymorphs, hydrates or solvates thereof and a second pharmacologically active ingredient is selected from β2 agonists, methylxanthine compounds and antihistamines and salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         47 . A pharmaceutical composition comprising a eutectic composition of two pharmacologically active ingredients for the treatment of respiratory disease, wherein a first pharmacologically active ingredient is selected from corticosteroids and salts, esters, polymorphs, hydrates or solvates thereof and a second pharmacologically active ingredient is selected from β2 agonists, methylxanthine compounds and antihistamines and salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         48 . A composition according to  claim 47  wherein the respiratory disease is chronic respiratory disease. 
     
     
         49 . A composition according to  claim 47  wherein the respiratory disease is infection. 
     
     
         50 . A composition according to  claim 45 , wherein the pharmacologically active ingredients are a corticosteroid and a methylxanthine compound or salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         51 . A composition according to  claim 50  wherein the methylxanthine compound is theophylline, aminophylline or oxtriphylline and salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         52 . A composition according to  claim 45 , wherein the pharmacologically active ingredients are a corticosteroid and a β 2  agonist or salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         53 . A composition according to  claim 52 , wherein the β 2  agonist is selected from the group consisting of formoterol, salmeterol, carmoterol, indacaterol, vilanterol, arformoterol, bambuterol, isoproterenol, milveterol, clenbuterol, olodaterol, fenoterol, salbutamol, levalbuterol, procaterol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol, or ritodrine, albuterol and salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         54 . A composition according to  claim 45 , wherein the pharmacologically active ingredients are a corticosteroid and an antihistamine or salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         55 . A composition according to  claim 54 , wherein the antihistamine is selected from acrivastine, cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine, mizolastine, alimemazine, chlorphenamine, clemastine, cyproheptadine, hydroxyzine, ketotifen and promethazine, cimetadine, azatadine, brompheniramine, carbinoxamine or pyrilamine and salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         56 . A composition according to  claim 45 , wherein the corticosteroid is selected from the group consisting of mometasone, beclomethasone, budesonide, fluticasone, cliclesonide or triamcinolone and salts, esters, polymorphs, hydrates or solvates thereof. 
     
     
         57 . A composition according to  claim 45 , further comprising an excess of at least one of the pharmacologically active ingredients, wherein the excess forms less than 50% by weight of the total weight of the said pharmacologically active ingredients present in the composition. 
     
     
         58 . A composition according to  claim 45 , further comprising an excess of at least one of the pharmacologically active ingredients, wherein the excess forms less than 50 mol % of the amount of the said pharmacologically active ingredients present in the eutectic composition. 
     
     
         59 . A composition according to claim  1 , wherein 90% by weight of at least one of the pharmacologically active ingredients is in the eutectic composition. 
     
     
         60 . A composition according to  claim 45 , wherein the molar ratio of the two pharmacologically active ingredients is 10:1 to 1:1. 
     
     
         61 . A composition according to  claim 45  wherein the eutectic composition is in particulate form, preferably wherein the mass median aerodynamic diameter is up to 10 μm. 
     
     
         62 . A process for making a composition according to  claim 45  comprising:
 providing two pharmacologically active ingredients wherein the first pharmacologically active ingredient is selected from corticosteroids and salts, esters, polymorphs, hydrates or solvates thereof and the second pharmacologically active ingredient is selected from β2 agonists, methylxanthine compounds and antihistamines and salts, esters, polymorphs, hydrates or solvates thereof and: 
 i) dissolving the two pharmacologically active ingredients in a solvent, removing the solvent; and forming particles of the eutectic composition; or 
 ii) forming a melt of the two pharmacologically active ingredients, solidifying the melt and forming particles of the eutectic composition; or 
 iii) forming a melt of a first pharmacologically active ingredient and introducing a solution of a second pharmacologically active ingredient into the melt, solidifying the resulting composition; and forming particles of the eutectic composition; or 
 iv) subjecting the two pharmacologically active ingredients to mechanical comminution to form particles of the eutectic composition. 
 
     
     
         63 . A process according to  claim 62 , wherein the process further comprises treating the particles of the eutectic composition with a non-solvent therefor and applying ultrasound to the particles when they are in contact with said non-solvent. 
     
     
         64 . A process according to  claim 62 , wherein the process comprises:
 (i) forming a solution of the two pharmacologically active ingredients in a solvent;   (ii) subjecting the solution to a process selected from the group consisting of rapid precipitation, freeze drying, lyophilisation, rapid expansion of supercritical solutions, spray drying or mixtures thereof, wherein the said dissolved pharmacologically active ingredients are converted into a substantially dry solid material;   (iii) optionally isolating the solid material from the liquid and/or gaseous components of the process of step (ii);   (iv) treating said dry solid material from step (ii) or step (iii) with a non-solvent therefor;   (v) applying ultrasound to the solid material from step (iv) when it is in contact with said non-solvent; and   (vi) optionally separating and/or drying the resultant solid material from step (v).   
     
     
         65 . A process according to  claim 64 , wherein the process is sequential, and steps (iv) and (v) take place immediately after step (ii). 
     
     
         66 . A process according to  claim 62 , wherein the process comprises:
 (a) subjecting the two pharmacologically active ingredients to mechanical comminution, preferably by mechanical micronization, milling, jet milling, grinding or mixtures thereof;   (b) treating said pharmacologically active ingredients from step (a) with a non-solvent therefor;   (c) applying ultrasound to the solid composition from step (b) when it is in contact with said non-solvent; and   (d) optionally separating and/or drying the resultant solid composition from step (c).   
     
     
         67 . A process according to  claim 62 , wherein the molar ratio of the two pharmacologically active ingredients is 10:1 to 1:1. 
     
     
         68 . A dry powder inhaler containing a composition according to  claim 45 . 
     
     
         69 . A pressurized metered-dose inhaler (pMDI) containing a composition according to  claim 45 . 
     
     
         70 . A breath activated nasal inhaler containing a composition according to  claim 45 .