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 - 42 . (canceled)  
   
   
       43 . The invention according to any one of claims  71 ,  72 ,  101 ,  104 ,  105 ,  106 , or  107 , wherein the cyclodextrin 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 -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.  
 
   
   
       44 . The invention according to any one of claims  71 ,  72 ,  101 ,  104 ,  105 ,  106 , or  107 , wherein the cyclodextrin is a compound of the Formula II (SAEx-α-CD), wherein “x” ranges from 1 to 18; of the Formula III (SAEy-β-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.  
   
   
       45 . The invention according to  claim 44 , wherein the cyclodextrin 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.    
   
   
       46 - 70 . (canceled)  
   
   
       71 . A method of treating a disease or disorder of the airways, in a subject in need thereof, comprising administering or delivering, via inhalation, to the subject an aqueous liquid formulation comprising an aqueous liquid carrier, a sulfoalkyl ether cyclodextrin, and a dose of corticosteroid dissolved therein, wherein the formulation provides an enhanced pharmacokinetic profile over a suspension based formulation administered under similar conditions.  
   
   
       72 . A method of administering or delivering a dose of corticosteroid to the air passageways of a subject in need thereof, the method comprising administering or delivering the corticosteroid with a nebulizer comprising a charge of an aqueous liquid formulation, the formulation comprising an aqueous liquid carrier, sulfoalkyl ether cyclodextrin, and the corticosteroid dissolved therein, wherein, during operation, the system provides enhanced drug delivery, increased rate of drug administration, reduced treatment time, reduced toxicity, improved stability, enhanced bioabsorption, increased output rate, increased total output, enhanced pharmacokinetic profile, reduced corticosteroid-related side effects, enhanced pulmonary deposition, reduced oropharyngeal deposition, and/or improved nebulization performance over another system comprising the nebulizer and a suspension based formulation of the corticosteroid.  
   
   
       73 . The method of  claim 71 , wherein the formulation provides enhanced drug delivery, increased rate of drug administration, reduced treatment time, reduced toxicity, improved stability, enhanced bioabsorption, increased output rate, increased total output, enhanced pharmacokinetic profile, reduced corticosteroid-related side effects, enhanced pulmonary deposition, reduced oropharyngeal deposition, and/or improved nebulization performance over a suspension based formulation administered under similar conditions.  
   
   
       74 . The method of  claim 71 , wherein the dose of corticosteroid is at least 25 μg, 40 μg, at least 45 μg, at least 48 μg, 45-1000 μg, about 1 μg to 20 mg, or 1 μg to 10 mg, 0.01 mg to 10 mg, 0.025 mg to 10 mg, 0.05 mg to 5 mg, 0.1 mg to 5 mg, 0.125 mg to 5 mg, 0.25 mg to 5 mg, 0.5 mg to 5 mg, 0.05 mg to 2 mg, 0.1 mg to 2 mg, 0.125 mg to 2 mg, 0.25 mg to 2 mg, 0.5 mg to 2 mg, 1 μg, 10 μg, 25 μg, 50 μg, 100 μg, 125 μg, 200 μg, 250 μg, 25 to 66 μg, 48 to 81 μg, 73 to 125 μg, 40 μg, 64 μg, 95 μg, 35 to 95 μg, 25 to 125 μg, 60 to 170 μg, 110 μg, 170 μg, 45 to 220 μg, 45 to 85 μg, 48 to 82 μg, 85 to 160 μg, 140 to 220 μg, 120 to 325 μg, 205 μg, 320 μg, 325 μg, 90 to 400 μg, 95 to 170 μg, 165 to 275 μg, 275 to 400 μg.  
   
   
       75 . The method of  claim 71 , wherein the liquid has a volume of 10 μl to 100 ml, 50 μl to 50 ml, 50 μl to 10 ml, 0.1 to 10 ml, 0.1 ml to less than 10 ml, 0.1 ml to 7.5 ml, 0.1 ml to 5 ml, 0.1 ml to 3 ml, 0.1 ml to 2 ml, 0.1 ml to 1 ml, 0.05 ml to 7.5 ml, 0.05 ml to 5 ml, 0.05 ml to 3 ml, 0.05 ml to 2 ml, or 0.05 ml to 1 ml.  
   
   
       76 . The method of  claim 71 , wherein the step of delivering or administering is conducted over a period of less than 30 min, less than 20 min, less than 10 min, less than 7 min, less than 5 min, less than 3 min, or less than 2 min, or the time is about 0.05 to 10 min, about 0.1 to 5 min, about 0.1 to 3 min, about 0.1 to 2 min, about 0.1 to 1.5 min, about 0.5 min to about 1.5 min, or about 1 min, or the time is about the time it takes for a subject to take a single breath (about 1 to 3 or 1 to 5 sec).  
   
   
       77 . The method of  claim 71 , wherein the enhanced pharmacokinetic profile is an enhancement of 1.5 to 8 fold higher, 1.5 to 6 fold higher, 1.5 to 4 fold higher, 1.5 to 2 fold higher, 1.64 to 3.55 fold higher for Cmax, 1.48 to 6.25 fold higher for Cmax, 1.59 to 3.55 or 1.19 to 6.11 fold higher for AUC inf , 1.69-3.67 or 1.21 to 7.66 fold higher for AUC last  as compared to administration of the suspension formulation.  
   
   
       78 . The method of  claim 71 , wherein 20% to 85%, or 30% to 80%, or at least 30%, at least 40%, at least 56%, at least 59%, at least 62% of the dose of corticosteroid is delivered to the lungs of the subject.  
   
   
       79 . The method of  claim 71 , wherein the method provides in the subject a C max  (pg of corticosteroid/ml) of 90 to 900, 200 to 600, 200 to 550, 200 to 250, 400 to 450, 500 to 600, 225, 437, or 545 on a dose non-normalized basis.  
   
   
       80 . The method of  claim 71 , wherein the method provides in the subject a dose normalized C max  (pg/ml/μg) of: 1) 0.3 to 2, 0.35 to 2, 0.6 to 1.5, 0.5 to 1.2, 0.8 to 1, 0.8 to 0.9, 0.7 to 0.8, 0.4, 1.9, 0.6, 1.5, 0.5, 1.2, 0.35, 2, 0.7, 0.8, or 0.9 on a nominal available dose normalized basis; 2) 3.4 to 9.2, 3.5 to 8.5, 5.5 to 9.2, 4.5 to 7.5, 5.8 to 7, 3.4, 3.5, 4.5, 5.5, 9.2, 8.5, 7.5, 5.8, 5.9, 6, or 7 on a dose to lung normalized basis; 3) 1.7 to 7.5, 3.2 to 4.1, 1.9 to 6, 3.2 to 7.5, 1.7 to 5.2, 3.6, 4.1, 3.2, 1.9, 6, 3.2, 7.4, 7.5, 1.7, 5.2 or 5.3 on a dose to subject normalized basis; 4) 0.9 to 3.3, 1.7 to 2.2, 0.9 to 3, 1 to 3, 1.7 to 3.3, 1 to 2.7, 1.9, 2.1, 2.2, 1.7, 0.9, 1, 2, 3, 2.9, 3.2, 3.3, or 2.7 on an emitted dose normalized basis.  
   
   
       81 . The method of  claim 71 , wherein the, on the basis of the non-normalized dose of corticosteroid, the Cmax provided by the formulation is 1.6 to 2, 1.5 to 3, 1.5 to 2.5, 1.5 to 2, 1.5, 1.6, 2, 2.5, or 3 fold higher than the Cmax provided by the suspension-based formulation when the dose of corticosteroid in the formulation and the suspension is approximately the same amount loaded.  
   
   
       82 . The method of  claim 71 , wherein, on the basis of normalization to the nominal available dose of corticosteroid, the Cmax provided by the corticosteroid formulation is 1.8 to 6.2, 1.5 to 6.5, 2 to 6.5, 1.5 to 5.5, 2 to 4, 1.5 to 4, 1.5 to 3, 2.7, 3.3, 3.4, 1.5, 6.5, 2, 5.5, 4, or 3 fold higher than the Cmax provided by the suspension-based formulation.  
   
   
       83 . The method of  claim 71 , wherein, on the basis of normalization to the dose of corticosteroid to lung, the Cmax provided by the corticosteroid formulation is 1.4 to 4.3, 1.4 to 4.5, 1.5 to 4.5, 1.5 to 3.5, 1.5 to 3, 1.4 to 3, 1.5 to 2.5, 1.5 to 2, 2, 2.3, 1.4, 4/5, 3.5, 3, 1.5 or 2.5 fold higher than the Cmax provided by the suspension-based formulation.  
   
   
       84 . The method of  claim 71 , wherein, on the basis of normalization to the dose of corticosteroid to subject, the Cmax provided by the corticosteroid formulation is 2 to 3.5, 2 to 5, 1.7 to 3.8, 1.7 to 5, 2.7, 3, 2.4, 2, 3.5, 5, 1.7, or 3.8 fold higher than the Cmax provided by the suspension-based formulation.  
   
   
       85 . The method of  claim 71 , wherein, on the basis of normalization to the emitted dose of corticosteroid, the Cmax provided by the corticosteroid formulation is 1.9 to 6.3, 1.75 to 6.5, 2.2 to 4.2, 2.2 to 6.3, 1.9 to 4.2, 3.2, 3.5, 3.6, 2.8, 1.75, 6.5, 2.2, 4.2, or 6.3 fold higher than the Cmax provided by the suspension-based formulation.  
   
   
       86 . The method of  claim 71 , wherein the Cmax provided by the corticosteroid formulation is at least 1.5, 1.6, 2, 2.6, and 3 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.  
   
   
       87 . The method of  claim 71 , wherein the method provides a C max  (pg/ml) of 1600 to 1800, 1650 to 1750, or 1700 on a dose non-normalized basis.  
   
   
       88 . The method of  claim 71 , wherein the method provides a dose normalized C max  (pg/ml/μg) of: 1) 1 to 2, 1.6 to 1.8, or 1.7 on a loaded dose nominal normalized basis; 2) 2 to 2.5, or 2.2 on an emitted dose normalized basis.  
   
   
       89 . The method of  claim 71 , wherein, on the basis of the normalized nominal dose of corticosteroid, the C max  provided by the corticosteroid formulation is at least 1.7, 1.8, 1.9, or 2 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.  
   
   
       90 . The method of  claim 71 , wherein, on the basis of normalization to the emitted dose of corticosteroid, the C max  provided by the corticosteroid formulation is at least 1.5, 1.6, to 2 fold higher than the C max  provided by the suspension-based formulation.  
   
   
       91 . The method of  claim 71 , wherein the method provides in the subject an AUC inf  (pg*h/ml) of 500 to 1700, 530 to 1650, 250 to 2500, 280 to 1300, 780 to 1300, 980 to 2450, 275, 775, 980, 2400, 2500, 1300, 1290, 530, 1650, 250, 280 or 780 on a dose non-normalized basis.  
   
   
       92 . The method of  claim 71 , wherein the method provides in the subject a dose normalized AUC inf  (pg/ml/μg) of: 1) 1 to 5.5, 2 to 2.2, 1 to 5.3, 1.1 to 5.2, 1.5 to 2.6, 1.3 to 3.3, 2, 2.1, 2.2, 1, 5.5, 5.3, 5.2, 1.5, 2.6, 1.3 or 3.3 on a nominal available dose normalized basis; 2) 10 to 25, 14 to 18, 10.2 to 20, 13.6 to 18.8, 11.2 to 24.7, 10.2, 20, 13.6, 14, 19, 18.8, 11, 11.2, 25, 24.7, 14.2, 16.2, 17.3 on a dose to lung normalized basis; 3) 4 to 16, 4.2 to 16.1, 8 to 12.2, 5.4 to 16, 5.4 to 17, 8.5 to 9.6, 8.5, 9.5, 9.6, 4.2, 16.1, 8, 12.2, 12, 5.4, 16, 17, or 16.5 on a dose to subject normalized basis; 4) 2.5 to 9, 2.6 to 8.5, 4.5 to 5.1, 2.5 to 8, 2.6 to 7.9, 4.2 to 6.7, 3.1 to 8.5, 3.2 to 8.5, 4.5, 4.6, 5, 5.1, 2.5, 2.6, 4.2, 3.1, 9, 8.5, 5.1, 8, 7.9, or 6.7 to on an emitted dose normalized basis.  
   
   
       93 . The method of  claim 71 , wherein, on the basis of the non-normalized dose of corticosteroid, the AUC inf  provided by the corticosteroid formulation is 1.6 to 2.5, 1.6 to 3.1, 1.5 to 3.5, 1.5 to 3.3, 2.5 to 3.3, 3.1, 1.5, 3.3, 1.6, or 2.5 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.  
   
   
       94 . The method of  claim 71 , wherein, on the basis of normalization to the nominal available dose of corticosteroid, the AUC inf  provided by the corticosteroid formulation is 1.75 to 6.5, 1.75 to 6.1, 2 to 6.5, 2 to 6.1, 2 to 4.5, 2 to 4.4, 3.3, 3.2, 3.5, 3.4, 1.75, 6.5, 6.1, 2, 4.5, or 4.4 fold higher than the AUC inf  provided by the suspension-based formulation.  
   
   
       95 . The method of  claim 71 , wherein, on the basis of normalization to the dose of corticosteroid to lung, the AUC inf  provided by the corticosteroid formulation is 1.2 to 3.5, 1.2 to 4, 1.2 to 3, 1.2 to 2.85, 1.5 to 3.5, 1.4 to 3.5, 2, 2.2, 2.3, 2.4, 1.2, 3, 4, 2.85, 1.5, 3.5, or 1.4 fold higher than the AUC inf  provided by the suspension-based formulation.  
   
   
       96 . The method of  claim 71 , wherein, on the basis of normalization to the dose of corticosteroid to subject, the AUC inf  provided by the corticosteroid formulation is 1.6 to 4.9, 1.5 to 5, 1.6 to 5, 1.6 to 3.7, 1.6 to 3.6, 2 to 4.9, 1.9 to 4, 2.6, 1.5, 5, 1.6, 3.7, 3.6, 2, 4.9, 1.9, or 4 fold higher than the AUC inf  provided by the suspension-based formulation.  
   
   
       97 . The method of  claim 71 , wherein, on the basis of normalization to the emitted dose of corticosteroid, the AUC inf  provided by the corticosteroid formulation is 1.5 to 6, 1.7 to 6, 1.9 to 6, 1.9 to 5.4, 2.3 to 5.8, 1.9 to 5.5, 1.9 to 5.8, 1.5, 6, 1.7, 1.9, 5.4, 2.3, 5.8, 5.8, 3.2, 3.5, or 3.6 fold higher than the AUC inf  provided by the suspension-based formulation.  
   
   
       98 . The method of  claim 71 , wherein the AUC inf  provided by the corticosteroid formulation is at least 1.5, 1.6, 2, 2.5, 3 and 3.1 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.  
   
   
       99 . The method of  claim 71 , wherein the method provides in the subject an AUC 0-8 hr  (pg*h/ml) of 2000 to 3000, 2500 to 2700, 2000, 3000, or 2600 on a dose non-normalized basis for the corticosteroid.  
   
   
       100 . The method of  claim 71 , wherein the method provides in the subject a dose normalized AUC inf  (pg/ml/μg) of: 1) 2 to 3, 2.5 to 2.7, or 2.6 on a loaded dose nominal normalized basis; and/or 2) 3 to 4, 3.4 to 3.5, or 3.4 on an emitted dose normalized basis.  
   
   
       101 . 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.  
   
   
       102 . The system of  claim 101 , wherein the percentage decrease in the rate of increasing concentration is 10% to 60%, 15% to 60%, 20% to 60%, 30% to 60%, or 40% to 60%.  
   
   
       103 . The system of  claim 101 , wherein the system provide a rate of increasing concentration of 0 to 40, 1 to 40, 5 to 30, or 10 to 30 mcg of corticosteroid/mL of formulation volume per min of nebulization.  
   
   
       104 . A method of treating a disease or disorder of the airways, in a subject in need thereof, comprising administering via inhalation to the subject a liquid formulation comprising an aqueous liquid carrier, a sulfoalkyl ether cyclodextrin, and a dose of corticosteroid dissolved therein, 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.  
   
   
       105 . A method of providing a corticosteroid to a subject, the method comprising: administering to the subject, via nebulization, 25-400 μg of a corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin to provide a plasma AUC t  of 150-1600 pg*h/ml for the corticosteroid.  
   
   
       106 . A method of providing in a subject a plasma AUC t , normalized for dose of corticosteroid, of at least 6 (pg*h/ml)/μg of corticosteroid, comprising: administering to the subject, via nebulization, a dose of at least 25 μg of corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin.  
   
   
       107 . A method of providing in a subject an AUC i , normalized for dose of corticosteroid, of at least 8 (pg*h/ml)/μg of corticosteroid, comprising: administering to the subject, via nebulization, a dose of at least 25 μg of corticosteroid dissolved in an aqueous liquid carrier comprising sulfoalkyl ether cyclodextrin.  
   
   
       108 . The invention according to any one of claims  71 ,  72 ,  101 ,  104 ,  105 ,  106 , or  107 , wherein the corticosteroid is budesonide.  
   
   
       109 . The invention according to any one of claims  71 ,  72 ,  101 ,  104 ,  105 ,  106 , or  107 , wherein the corticosteroid has a lipophilicity approximating or exceeding that of flunisolide.  
   
   
       110 . The invention according to  claim 109 , 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.  
   
   
       111 . The invention according to any one of claims  71 ,  72 ,  101 ,  104 ,  105 ,  106 , or  107 , wherein the step of administering or delivering is conducted 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.