Inhalant Formulation Containing Sulfoalkyl Ether Cyclodextrin and Corticosteroid

Abstract

An inhalable formulation containing SAE-CD and corticosteroid is provided. The formulation is adapted for administration to a subject by nebulization with any known nebulizer. The formulation can be included in a kit. The formulation is administered as an aqueous solution; however, it can be stored as a dry powder, ready-to-use solution, or concentrated composition. The formulation is employed in an improved nebulization system for administering corticosteroid by inhalation. SAE-CD present in the formulation significantly enhances the chemical stability of budesonide. A method of administering the formulation by inhalation is provided. The formulation can also be administered by conventional nasal delivery apparatus.

1 . An aqueous liquid formulation comprising a therapeutically effective amount of corticosteroid dissolved therein, SAE-CD, and an aqueous liquid carrier, wherein the molar ratio of SAE-CD to corticosteroid is greater than 10:1. 
     
     
         2 . The formulation of  claim 1 , wherein the corticosteroid is selected from the group consisting of beclomethasone, beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone, fluticasone propionate, mometasone, mometasone furoate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide 
     
     
         3 . The formulation of  claim 1 , wherein the molar ratio of SAE-CD to corticosteroid is greater than about 10:1 to about 10,000:1. 
     
     
         4 . The formulation of  claim 1 , wherein the formulation is a substantially clear solution comprising less than 5% wt. undissolved corticosteroid. 
     
     
         5 . The formulation of  claim 1 , comprising 21.5±2% wt./wt. or less of SAE-CD. 
     
     
         6 . The formulation of  claim 1 , wherein the SAE-CD is present at a concentration of about 10 mg to about 500 mg of SAE-CD per ml of formulation. 
     
     
         7 . The formulation of  claim 1 , wherein the formulation has a shelf-life of at least 6 months. 
     
     
         8 . The formulation of  claim 1  further comprising one or more therapeutic agents independently selected at each occurrence from the group consisting of a β2-adrenoreceptor agonist, a dopamine (D2) receptor agonist, a topical anesthetic, an anticholinergic agent, IL-5 inhibitor, antisense modulator of IL-5, milrinone (1,6-dihydro-2-methyl-6-oxo-[3,4′-bipyridine]-5-carbonitrile), milrinone lactate, tryptase inhibitor, tachykinin receptor antagonist, leukotriene receptor antagonist, 5-lypoxygenase inhibitor, and anti-IgE antibody. 
     
     
         9 . The formulation of  claim 8 , wherein the corticosteroid is present in a molar excess over the other therapeutic agent. 
     
     
         10 . The formulation of  claim 8 , wherein the other therapeutic agent is present in a molar excess over the corticosteroid. 
     
     
         11 . The formulation of  claim 8 , wherein the SAE-CD is present in a molar excess over the other therapeutic agent. 
     
     
         12 . The formulation of  claim 1 , wherein the SAE-CD is a compound of the Formula 1: 
       
         
           
           
               
               
           
         
         wherein: 
         n is 4, 5 or 6; 
         R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8  and R 9  are each, independently, —O— or a —O—(C 2 -C 6  alkylene)-SO 3   −  group, wherein at least one of R 1 - 9  is independently a —O—(C 2 -C 6  alkylene)-SO 3   − group, a —O—(CH 2 ) m SO 3   −  group wherein m is 2 to 6, —OCH 2 CH 2 CH 2 SO 3   − , or —OCH 2 CH 2 CH 2 CH 2 SO 3   − ); and 
         S 1 , S 2 , S 3 , S 4 , S 5 , S 6 , S 7 , S 8  and S 9  are each, independently, a pharmaceutically acceptable cation. 
       
     
     
         13 . The formulation of  claim 12 , wherein the SAE-CD is selected from the group consisting of: 
       
         
           
                 
                 
                 
                 
               
                     
                     
                 
                     
                   SAEx-α-CD 
                   SAEy-β-CD 
                   SAEz-γ-CD 
                 
                     
                     
                 
                     
                   SEEx-α-CD 
                   SEEy-β-CD 
                   SEEz-γ-CD 
                 
                     
                   SPEx-α-CD 
                   SPEy-β-CD 
                   SPEz-γ-CD 
                 
                     
                   SBEx-α-CD 
                   SBEy-β-CD 
                   SBEz-γ-CD 
                 
                     
                   SPtEx-α-CD 
                   SPtEy-β-CD 
                   SPtEz-γ-CD 
                 
                     
                   SHEx-α-CD 
                   SHEy-β-CD 
                   SHEz-γ-CD. 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
               
            
           
         
       
     
     
         14 . A solid composition prepared by drying a formulation according to  claim 1 . 
     
     
         15 . A liquid formulation according to  claim 1 , wherein the formulation is adapted for nasal, oral, ophthalmic, otic, or topical administration. 
     
     
         16 . A method of treating a disease or disorder of the airways, in a subject in need thereof, comprising administering via inhalation the formulation of  claim 1 , the corticosteroid being present in an amount sufficient to provide a mean plasma AUCt of 160-1600 pg*h/ml. 
     
     
         17 . A method of providing in a subject:
 (a) a mean plasma AUCt of 150-1600 pg*h/ml for the corticosteroid in an individual subject comprising: administering to the subject, via nebulization, 48-220 μg, as dose to subject, of a corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin; or   (b) a mean plasma AUCt, normalized for dose of corticosteroid to subject, of at least 6 (pg*h/ml)/μg of corticosteroid delivered, as dose to subject, comprising: administering to the subject, via nebulization, at least 45 μg of corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin; or   (c) a mean AUCi, normalized for dose of corticosteroid to subject, of at least 8 (pg*h/ml)/μg of corticosteroid delivered, as dose to subject, comprising: administering to the subject, via nebulization, at least 45 μg of corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin.   
     
     
         18 . A method of reducing the amount of time required to provide a therapeutically effective amount of corticosteroid to a subject by inhalation of a corticosteroid-containing composition with a nebulizer, the method comprising the steps of: including SAE-CD in the composition in an amount sufficient to solubilize the corticosteroid to form an inhalable aqueous corticosteroid-containing solution; and
 administering the solution to the subject by inhalation with a nebulizer, wherein the amount of time required to provide a therapeutically effective amount of corticosteroid to the subject with the solution is reduced as compared to the amount of time required to provide a therapeutically effective amount of corticosteroid to the subject with a corticosteroid-containing suspension comprising the same amount or concentration of corticosteroid when the suspension and solution are administered under otherwise similar nebulization conditions.