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 - 111 . (canceled) 
     
     
         112 . A method of treating a disease or disorder of the airways in a subject in need thereof, comprising administering via inhalation to the subject an aqueous liquid formulation comprising an aqueous liquid carrier, a sulfoalkyl ether cyclodextrin (SAE-CD), and a dose of corticosteroid dissolved therein, wherein the formulation provides an enhanced pharmacokinetic profile over a suspension based formulation administered under similar conditions. 
     
     
         113 . A system comprising: a nebulizer equipped with a reservoir; and an aqueous liquid formulation comprising an aqueous liquid carrier, solubility enhancer, and a dose of corticosteroid, wherein, during nebulization of the formulation, the nebulizer provides a percentage decrease in the rate of increasing concentration of corticosteroid in the formulation in the reservoir as compared to the rate of increasing concentration of a suspension-based formulation nebulized with the nebulizer under similar conditions. 
     
     
         114 . The method of  claim 112 , wherein the dose of corticosteroid is present in an amount sufficient to provide a mean plasma AUC t  of 160-1600 pg*h/ml, and wherein the molar ratio of SAE-CD to corticosteroid is greater than 10:1. 
     
     
         115 . The method of  claim 112 , wherein the formulation comprises 25-400 μg of a corticosteroid, and wherein the formulation provides a plasma AUC t  of 150-1600 pg*h/ml for the corticosteroid. 
     
     
         116 . The method of  claim 112 , wherein the formulation comprises at least 25 μg of corticosteroid, and wherein the formulation provides a plasma AUC t , normalized for dose of corticosteroid, of at least 6 (pg*h/ml)/μg of corticosteroid. 
     
     
         117 . The method of  claim 112 , wherein the formulation comprises at least 25 μg of corticosteroid, and wherein the formulation provides a plasma AUC i , normalized for dose of corticosteroid, of at least 8 (pg*h/ml)/μg of corticosteroid. 
     
     
         118 . The method of  claim 112 , wherein the SAE-CD is a compound of the Formula I: 
       
         
           
           
               
               
           
         
         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 -R 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. 
       
     
     
         119 . The method of  claim 112 , wherein the SAE-CD is a compound of the Formula II (SAEx-α-CD), wherein “x” ranges from 1 to 18; of the Formula III (SAEy-γ-CD), wherein “y” ranges from 1 to 21; or of the Formula IV (SAEz-γ-CD), wherein “z” ranges from 1 to 24, and wherein “SAE” represents a sulfoalkyl ether substituent, and the values “x”, “y” and “z” represent the average degree of substitution in terms of the number of sulfoalkyl ether groups per CD molecule. 
     
     
         120 . The method of  claim 112 , wherein the Cmax provided by the corticosteroid formulation is at least 1.5 fold higher than the Cmax provided by the suspension-based formulation when the dose of corticosteroid in the formulation is about 2 fold lower than the dose in the suspension. 
     
     
         121 . The method of  claim 112 , wherein the formulation provides a C max  (pg/ml) of 1600 to 1800 on a dose non-normalized basis. 
     
     
         122 . The method of  claim 112 , wherein, on the basis of the normalized nominal dose of corticosteroid, the C max  provided by the corticosteroid formulation is at least 1.7 fold higher than the C max  provided by the suspension-based formulation when the dose of corticosteroid in the formulation and the suspension is approximately the same. 
     
     
         123 . The method of  claim 112 , wherein the formulation provides an AUC inf  (pg*h/ml) of 250 to 2500 on a dose non-normalized basis. 
     
     
         124 . The method of  claim 112 , wherein, on the basis of the non-normalized dose of corticosteroid, the AUC inf  provided by the corticosteroid formulation is 1.5 to 3.5 fold higher than the AUC inf  provided by the suspension-based formulation when the dose of corticosteroid in the formulation and the suspension is approximately the same. 
     
     
         125 . The method of  claim 112 , wherein the AUC inf  provided by the corticosteroid formulation is at least 1.5 fold higher than the AUC inf  provided by the suspension-based formulation when the dose of corticosteroid in the formulation is about 2 fold lower than the dose in the suspension. 
     
     
         126 . The method of  claim 112 , wherein the formulation provides an AUC 0-8 hr  (pg*h/ml) of 2000 to 3000 on a dose non-normalized basis for the corticosteroid. 
     
     
         127 . The method of  claim 112 , wherein the corticosteroid is budesonide. 
     
     
         128 . The method of  claim 112 , wherein the corticosteroid is selected from the group consisting of beclomethasone dipropionate, beclomethasone monopropionate, budesonide, ciclesonide, desisobutyryl-ciclesonide, flunisolide, fluticasone propionate, fluticasone furoate, mometasone furoate, icomethasone enbutate, tixocortol 21-pivalate, and triamcinolone acetonide. 
     
     
         129 . The method of  claim 112 , wherein the formulation is administered with a nebulizer selected from the group consisting of an air jet nebulizer, ultrasonic nebulizer, electronic nebulizer, vibrating membrane nebulizer, vibrating mesh nebulizer, vibrating plate nebulizer, a nebulizer comprising a vibration generator and an aqueous chamber, and a nebulizer comprising a nozzle array. 
     
     
         130 . A method of preparing a corticosteroid formulation, comprising high shear mixing a corticosteroid, SAE-CD, and an aqueous liquid carrier, wherein the SAE-CD is present in an amount sufficient to dissolve the corticosteroid. 
     
     
         131 . The method of  claim 130 , wherein high shear mixing is conducted with a sonicator, narrow gauge syringe(s), mixer/homogenizer, rotor-stator mixer, or saw tooth mixer.