Dry powder ketamine composition for use in the treatment of depression by pulmonary administration

Abstract

A dry powder inhalable pharmaceutical composition comprising ketamine or its pharmaceutically acceptable salt for use in a method of treatment of depression by administration via pulmonary route. The composition is especially useful for the treatment of treatment-resistant or treatment-refractory depression.

1 . A dry powder pharmaceutical composition comprising ketamine or its pharmaceutically acceptable salt formulated for direct administration to the lungs via pulmonary route. 
     
     
         2 . (canceled) 
     
     
         3 . The composition according to  claim 1  wherein pharmaceutically acceptable salt is hydrochloride. 
     
     
         4 . The composition according to  claim 3  wherein ketamine is esketamine hydrochloride. 
     
     
         5 . The composition according to  claim 1 , wherein the composition comprises from 2 mg to 100 mg of micronized ketamine calculated as a free base per nominal unit dose. 
     
     
         6 . The composition according to  claim 5 , wherein composition comprises from 2 mg to 40 mg of micronized ketamine calculated as a free base per nominal unit dose. 
     
     
         7 . The composition according to  claim 6 , wherein the composition comprises 4 mg of micronized esketamine calculated as a free base per nominal unit dose. 
     
     
         8 . The composition according to  claim 1 , wherein composition comprises one or more additives selected from the group consisting of a carbohydrate bulking agent in the amount of 30 to 95% by weight and a stabilizing agent in the amount of 0.2-3% by weight, with respect to the total weight of the composition. 
     
     
         9 . The composition according to  claim 1 , wherein composition comprises ketamine having median particle diameter d50 of 1-10 μm, d10 of 0.2-5 μm and d90 of 3-35 μm, as measured by laser diffraction technique. 
     
     
         10 . The composition according to  claim 5 , wherein the composition provides emitted dose of at least 1.0 mg of ketamine calculated as a free base, corresponding to 1.2 mg of ketamine hydrochloride. 
     
     
         11 . The composition according to  claim 10 , wherein the fraction of the emitted dose delivered to the lungs is at least 40%. 
     
     
         12 . The composition according to  claim 1 ,
 wherein the composition is formulated for administration via pulmonary route and is comprised in a blister with plurality of individual nominal unit doses premetered and individually sealed,   wherein the composition is formulated for administration via pulmonary route and is comprised in a capsule with a single nominal unit dose,   wherein the composition is formulated for administration via pulmonary route and is comprised in a multi-dose powder reservoir,   wherein ketamine, preferably esketamine, is formulated for self-administered pulmonary administration by a patient by inhalation of a dry powder ketamine composition or in a sequence of administrations consisting of multiple single doses, such as a sequence of at least 3 single doses, each single dose consisting of multiple puffs, such as 1, 2, 3 or 4 puffs, preferably 3 or 4 puffs, said sequences being separated from each other by a break period without any inhalation, or   wherein the composition is formulated for administration in the sequence of esketamine three single doses consisting of 3 or 4 puffs in a period of 30 minutes, single doses being separated by a break periods of 15 minutes, wherein each puff corresponds to esketamine nominal dose of 4 mg in the dry powder composition or formulation.   
     
     
         13 - 16 . (canceled) 
     
     
         17 . A method of treatment of depression in a subject in thereof comprising administering to the subject ketamine or its pharmaceutically acceptable salt by pulmonary route as a inhalable dry powder pharmaceutical formulation. 
     
     
         18 . The method according to  claim 17 ,
 wherein ketamine pharmaceutically acceptable salt is hydrochloride,   wherein ketamine is esketamine hydrochloride,   wherein the composition comprises from 2 mg to 100 mg of micronized ketamine calculated as a free base per nominal unit dose,   wherein composition comprises from 2 mg to 40 mg of micronized ketamine calculated as a free base per nominal unit dose,   wherein the composition comprises 4 mg of micronized esketamine calculated as a free base per nominal unit dose, or   wherein composition comprises one or more additives selected from the group consisting of a carbohydrate bulking agent in the amount of 30 to 95% by weight and a stabilizing agent in the amount of 0.2-3% by weight, with respect to the total weight of the composition.   
     
     
         18 - 23 . (canceled) 
     
     
         24 . The method according to  claim 17 , wherein the ketamine has median particle diameter d50 of 1-10 μm, d10 of 0.2-5 μm and d90 of 3-35 μm, as measured by laser diffraction technique. 
     
     
         25 . The method according to  claim 17 , wherein the administration provides emitted dose of at least 1.0 mg of ketamine calculated as a free base, corresponding to 1.2 mg of ketamine hydrochloride. 
     
     
         26 . The method according to  claim 25 , wherein the fraction of the emitted dose delivered to the lungs is at least 40%. 
     
     
         27 - 29 . (canceled) 
     
     
         30 . The method according to  claim 17 , wherein ketamine, preferably esketamine, is self-administered pulmonary by a patient by inhalation of a dry powder ketamine composition or formulation in a sequence of administrations consisting of multiple single doses, such as a sequence of at least 3 single doses, each single dose consisting of multiple puffs, such as 1, 2, 3 or 4 puffs, preferably 3 or 4 puffs, said sequences being separated from each other by a break period without any inhalation. 
     
     
         31 . The method according to  claim 30 , wherein the administration comprises three esketamine single doses consisting of 3 or 4 puffs in a period of 30 minutes, single doses being separated by a break periods of 15 minutes, wherein each puff corresponds to esketamine nominal dose of 4 mg in the dry powder composition or formulation.