Oral antidepressant formulation with reduced excipient load

Abstract

Provided are methods for reducing the excipient load of pharmaceutical formulations containing 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide as the active pharmaceutical ingredient, and compositions related thereto. In particular, provided is a pharmaceutical product comprising 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide and a stabilizer admixed throughout a solid-form unilamellar matrix, wherein the ratio of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide to stabilizer ranges from about 2:3 to about 1:10, and related methods of forming the pharmaceutical product.

1 . A pharmaceutical product comprising
 a) an admixture of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide; and   b) a stabilizer, wherein the ratio of a) to b) is from about 2:3 to about 1:10.   
     
     
         2 . The pharmaceutical product of  claim 1 , wherein the 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide and stabilizer are a solid-form unilamellar matrix. 
     
     
         3 . The pharmaceutical product of  claim 1 , wherein no more than 10 percent of the total 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide changes morphology when the pharmaceutical product is stored for 40 days at 40° C. under 75% relative humidity. 
     
     
         4 . The pharmaceutical product of  claim 1 , wherein no more than about 10 percent of the total 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide is in crystalline form. 
     
     
         5 . The pharmaceutical product of  claim 1 , wherein the admixture comprises up to 5%, 10%, 15%, 20%, 25%, 30%, 35% or 40% 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide. 
     
     
         6 . The pharmaceutical product of  claim 1 , wherein the product comprises
 a core which comprises active ingredient or ingredients; and   an enteric coating surrounding the core.   
     
     
         7 . The pharmaceutical product of  claim 1 , wherein the product provides plasma levels of phenoxathiin-based MAO-A inhibitor ranging from about 40 ng/ml to about 80 ng/ml. 
     
     
         8 . The pharmaceutical product of  claim 1 , wherein the stabilizer is a copolymer of vinylpyrrolidone and vinyl acetate, poly(vinylpyrrolidone), hydroxypropyl methylcellulose acetate succinate, hydrogenated phosphatidylcholine, a copolymer of methacrylic acid and ethyl acrylate, or a mixture thereof. 
     
     
         9 . A process for making a pharmaceutical product of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide, comprising the steps of:
 i) dissolving about 2 parts by weight or less of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide and about 3 parts by weight of a stabilizer in an organic solvent; and   ii) removing the organic solvent.   
     
     
         10 . The process of  claim 9 , further comprising the steps of:
 iii) adding an aqueous liquid to the product of step ii) and mixing the resultant suspension; and   iv) when step iii) is performed, subsequently removing the aqueous liquid.   
     
     
         11 . The process of  claim 9 , wherein the 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide in step (i) is Form A. 
     
     
         12 . A pharmaceutical product comprising
 an admixture of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide as an active ingredient;   a stabilizer; and   at least one excipient, wherein the ratio of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide to a total at the least one excipient is from about 1:1 to about 1:4.   
     
     
         13 . The pharmaceutical product of  claim 12 , wherein the ratio of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide to a total at the least one excipient ranges from about 1:2 to about 1:3. 
     
     
         14 . A solid-form unilamellar matrix comprising
 an admixture of 3-fluoro-7-(2,2,2-trifluoroethoxy)phenoxathiin 10,10-dioxide as an active ingredient; and   a stabilizer.   
     
     
         15 . A method of inhibiting monoamine oxidase-A (MAO-A) in a mammal identified as being in need of inhibition of MAO-A comprising
 administering a therapeutically effective amount of the pharmaceutical product of  claim 1 .   
     
     
         16 . A method of treating or preventing a psychiatric disorder or psychiatric disease comprising
 administering a therapeutically effective amount of the pharmaceutical product of  claim 1 .   
     
     
         17 . The method of  claim 16 , wherein the psychiatric disorder or psychiatric disease is selected from the group consisting of major depressive disorder, dysthymia, childhood depression, atypical depression, bipolar disorder, mania and hypomania, generalized anxiety disorder, social anxiety disorder, obsessive compulsive disorder, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, panic disorder, anergic depression, and treatment-resistant depression.