Pharmaceutical compositions comprising 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione

Abstract

Disclosed herein is pharmaceutical compositions of Compound 1, and/or the hydroquinone form thereof, and methods useful for treating or suppressing a disease or disorder such as an α-synucleinpathy, a tauopathy, an autistic spectrum disorder, a pervasive developmental disorder, a liver disease, and liver damage in a subject using such pharmaceutical compositions.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 a) about 48 wt/wt % to about 70 wt/wt % of a pharmaceutically acceptable oil, about 12 wt/wt % to about 25 wt/wt % of a propylene glycol laurates composition, and about 8 wt/wt % to about 20 wt/wt % of a polysorbate 80;   b) about 1 wt/wt % to about 15 wt/wt % of Compound 1:   
       
         
           
           
               
               
           
         
          and/or the hydroquinone form thereof; wherein Compound 1, and/or the hydroquinone thereof is optionally a hydrate thereof, and/or solvate thereof; and wherein when Compound 1, and/or hydroquinone thereof, is in the form of a hydrate and/or solvate, then the about 1 wt/wt % to about 15 wt/wt % of Compound 1, and/or its hydroquinone, does not include the weight of the water in the hydrate or the weight of the solvent in the solvate; and 
         c) 0 wt/wt % to about 2% wt/wt % of an optional flavorant; 
       
       wherein the wt/wt % of Compound 1, the pharmaceutically acceptable oil, the propylene glycol laurates composition, the polysorbate 80, and optional flavorant total 100%. 
     
     
         2 . The pharmaceutical composition of  claim 1 , comprising:
 a) about 52 wt/wt % to about 65 wt/wt % of a pharmaceutically acceptable oil, about 17 wt/wt % to about 20 wt/wt % of a propylene glycol laurates composition, and about 13 wt/wt % to about 20 wt/wt % of a polysorbate 80;   b) about 1 wt/wt % to about 12 wt/wt % of Compound 1:   
       
         
           
           
               
               
           
         
          and/or the hydroquinone form thereof; wherein Compound 1, and/or the hydroquinone thereof is optionally a hydrate thereof, and/or solvate thereof; and wherein when Compound 1, and/or hydroquinone thereof, is in the form of a hydrate and/or solvate, then the about 1 wt/wt % to about 12 wt/wt % of Compound 1, and/or its hydroquinone, does not include the weight of the water in the hydrate or the weight of the solvent in the solvate; and 
         c) 0 wt/wt % to about 2% wt/wt % of an optional flavorant; 
       
       wherein the wt/wt % of Compound 1, the pharmaceutically acceptable oil, the propylene glycol laurates composition, the polysorbate 80, and optional flavorant total 100%. 
     
     
         3 . The pharmaceutical composition of  claim 1  or  2 , wherein the ratio of the pharmaceutically acceptable oil to propylene glycol laurates composition to polysorbate 80 is about 55-75 parts by weight of the pharmaceutically acceptable oil,
 about 15-25 parts by weight of the propylene glycol laurates composition, 
 about 10-20 parts by weight of the polysorbate 80, or 
 
       wherein the ratio is 55-75:15-25:10-20 by weight; and 
       wherein the parts in the ratio of the pharmaceutically acceptable oil to propylene glycol laurates composition to polysorbate 80 total 100. 
     
     
         4 . The pharmaceutical composition of any one of  claims 1 - 3 , wherein the ratio of the pharmaceutically acceptable oil to propylene glycol laurates composition to polysorbate 80 is
 about 60-65 parts by weight of the pharmaceutically acceptable oil,   about 20-25 parts by weight of the propylene glycol laurates composition,   about 15-20 parts by weight of the polysorbate 80, or   
       wherein the ratio is 60-65:20-25:15-20; and 
       wherein the parts in the ratio of the pharmaceutically acceptable oil to propylene glycol laurates composition to polysorbate 80 total 100. 
     
     
         5 . The pharmaceutical composition of any one of  claims 1 - 4 , wherein the ratio of the pharmaceutically acceptable oil to propylene glycol laurates composition to polysorbate 80 is
 about 60 parts by weight of the pharmaceutically acceptable oil,   about 20 parts by weight of the propylene glycol laurates composition,   about 20 parts by weight of the polysorbate 80, or   
       wherein the ratio is 60:20:20. 
     
     
         6 . The pharmaceutical composition of any one of  claims 1 - 4 , wherein the ratio of the pharmaceutically acceptable oil to propylene glycol laurates composition to polysorbate 80 is
 about 65 parts by weight of the pharmaceutically acceptable oil,   about 20 parts by weight of the propylene glycol laurates composition,   about 15 parts by weight of the polysorbate 80, or   
       wherein the ratio is 60:20:15. 
     
     
         7 . The pharmaceutical composition of any one of  claims 1 - 6 , wherein the pharmaceutically acceptable oil is
 selected from the group consisting of one or more of: a Labrafac-like oil (Labrafac WL 1349 or Labrafac PG), sesame oil, cottonseed oil, soybean oil, olive oil, and corn oil; or   selected from the group consisting of one or more of: a Labrafac-like oil (Labrafac WL 1349 or Labrafac PG), cottonseed oil, soybean oil, and corn oil; and   
       optionally wherein one pharmaceutically acceptable oil is selected. 
     
     
         8 . The pharmaceutical composition of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable oil is a Labrafac-like oil (Labrafac WL 1349 or Labrafac PG). 
     
     
         9 . The pharmaceutical composition of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable oil is sesame oil. 
     
     
         10 . The pharmaceutical composition of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable oil is soybean oil. 
     
     
         11 . The pharmaceutical composition of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable oil is Labrafac WL 1349. 
     
     
         12 . The pharmaceutical composition of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable oil is olive oil. 
     
     
         13 . The pharmaceutical composition of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable oil is corn oil. 
     
     
         14 . The pharmaceutical composition of any one of  claims 1 - 7 , wherein the pharmaceutically acceptable oil is cottonseed oil. 
     
     
         15 . The pharmaceutical composition of any one of  claims 1 - 14 , wherein the propylene glycol laurates composition is Lauroglycol 90. 
     
     
         16 . The pharmaceutical composition of any one of  claims 1 - 15 , wherein the polysorbate 80 is Tween 80. 
     
     
         17 . The pharmaceutical composition of any one of  claims 1 - 16 , wherein the pharmaceutical composition comprises about 1 wt/wt % to about 12 wt/wt %, about 4 wt/wt % to about 12 wt/wt %, or about 5 wt/wt % to about 10 wt/wt % of Compound 1. 
     
     
         18 . The pharmaceutical composition of any one of  claims 1 - 17 , wherein the pharmaceutical composition comprises about 5 wt/wt %, about 6 wt/wt %, about 7 wt/wt %, about 8 wt/wt %, about 9 wt/wt %, or about 10 wt/wt % of Compound 1. 
     
     
         19 . The pharmaceutical composition of any one of  claims 1 - 18 , wherein the pharmaceutical composition comprises about 5 wt/wt % of Compound 1. 
     
     
         20 . The pharmaceutical composition of any one of  claims 1 - 18 , wherein the pharmaceutical composition comprises about 6 wt/wt % of Compound 1. 
     
     
         21 . The pharmaceutical composition of any one of  claims 1 - 18 , wherein the pharmaceutical composition comprises about 10 wt/wt % of Compound 1. 
     
     
         22 . The pharmaceutical composition of any one of  claims 1 - 21 , wherein the pharmaceutical composition contains about 50 mg to about 120 mg of Compound 1 in the composition, about 50 mg to about 100 mg of Compound 1 in the composition, about 60 mg to about 100 mg of Compound 1 in the composition, about 100 mg to about 120 mg of Compound 1 in the composition, about 50 mg of Compound 1 in the composition, about 60 mg of Compound 1 in the composition, or about 100 mg of Compound 1 in the composition. 
     
     
         23 . The pharmaceutical composition of  claim 1 - 22 , wherein the pharmaceutical composition is stable when stored at about 15° C. to about 25° C. or at about 25° C. and about 60% relative humidity or at about 40° C. and about 75% relative humidity for a duration of time of at least about one month, at least about three months, or at least about six months. 
     
     
         24 . The pharmaceutical composition of any one of  claims 1 - 22 , wherein the pharmaceutical composition shows no birefringent crystals when stored at about 15° C. to about 25° C. or at about 25° C. and about 60% relative humidity or at about 40° C. and about 75% relative humidity for a duration of time of at least about one month. 
     
     
         25 . The pharmaceutical composition of any one of  claims 1 - 22 , wherein the pharmaceutical composition shows no birefringent crystals when stored at about 15° C. to about 25° C. or at about 25° C. and about 60% relative humidity for a duration of at least about one month or at least about six months. 
     
     
         26 . The pharmaceutical composition of any one of  claims 1 - 22 , wherein the pharmaceutical composition shows no birefringent crystals when stored at about 40° C. and about 75% relative humidity for a duration of at least about one month. 
     
     
         27 . The pharmaceutical composition of any one of  claims 1 - 26 , wherein the total impurity level increases by 25% or less from an initial total impurity level to a subsequent total impurity level, when stored at about 40° C. and about 75% relative humidity for at least about three months, optionally wherein the initial total impurity level is measured on the day the pharmaceutical composition is prepared and before it is stored on the same day as it is prepared; and wherein the subsequent total impurity level is tested after about 3 months in storage. 
     
     
         28 . The pharmaceutical composition of any one of  claims 1 - 27 , wherein the subsequent total impurity level is about 1% or less, about 0.5% or less, or about 0.4% or less. 
     
     
         29 . The pharmaceutical composition of  claim 27  or  28 , wherein the pharmaceutical composition shows about 2% or less change in potency from an initial potency after storing at about 15° C. to 25° C. or at about 25° C. and about 60% relative humidity or at about 40° C. and about 75% relative humidity for a duration of time of at least one month; optionally wherein the initial potency is measured on the day the pharmaceutical composition is prepared and before it is stored on the same day as it is prepared. 
     
     
         30 . The pharmaceutical composition of  claim 27  or  28 , wherein the pharmaceutical composition shows about 1% or less degradation from an initial degradation level after storing at about 15° C. to 25° C. or at about 25° C. and about 60% relative humidity or at about 40° C. and about 75% relative humidity for a duration of time of at least one month; optionally wherein the initial degradation level is measured on the day the pharmaceutical composition is prepared and before it is stored on the same day as it is prepared. 
     
     
         31 . The pharmaceutical composition of any one of  claims 1 - 22 , wherein the pharmaceutical composition is stable when stored at about 5° C. for a period of at least about 4 weeks. 
     
     
         32 . The pharmaceutical composition of any one of  claims 1 - 31 , wherein b) is 
       
         
           
           
               
               
           
         
       
       or one or more members selected from the group consisting of hydrates thereof and solvates thereof. 
     
     
         33 . The pharmaceutical composition of any one of  claims 1 - 32 , wherein b) is 
       
         
           
           
               
               
           
         
       
     
     
         34 . The pharmaceutical composition of any one of  claims 1 - 31 , wherein b) is the hydroquinone form of 
       
         
           
           
               
               
           
         
       
       or one or more members selected from the group consisting of hydrates thereof, and solvates thereof. 
     
     
         35 . The pharmaceutical composition of any one of  claims 1 - 31 , and  34 , wherein b) is the hydroquinone form of 
       
         
           
           
               
               
           
         
       
     
     
         36 . The pharmaceutical composition of any one of  claims 1 - 35 , wherein the pharmaceutical composition is an oral pharmaceutical composition. 
     
     
         37 . The pharmaceutical composition of  claim 36 , wherein the oral pharmaceutical composition is in a capsule. 
     
     
         38 . The pharmaceutical composition of  claim 37 , wherein the capsule is a hard gelatin capsule. 
     
     
         39 . The pharmaceutical composition of  claim 40 , wherein any water content in the gelatin of the hard gelatin capsule is about 20% or less, about 10% to about 20%, or about 11% to about 16%, when stored for about one month, about one or more months, about three months, or about three or more months. 
     
     
         40 . The pharmaceutical composition of  claims 1 - 36 , wherein the oral pharmaceutical composition is a solution. 
     
     
         41 . The pharmaceutical composition of any one of  claims 36 - 40 , wherein the pharmaceutical composition has bioavailability when administered with a Low-fat Food for Testing which differs from bioavailability when administered with a Medium-fat Food for Testing by a percentage difference of about 90% or less, about 85% or less, about 80% or less, about 75% or less, about 70% or less, or about 65% or less; optionally wherein the pharmaceutically acceptable oil is a Labrafac-like oil (preferably, Labrafac WL 1349), the propylene glycol laurates composition is Lauroglycol 90, and the polysorbate 80 is Tween 80; additionally optionally wherein the ratio by weight of the pharmaceutically acceptable oil to the propylene glycol laurates composition to the polysorbate 80 is about 65:20:15. 
     
     
         42 . The pharmaceutical composition of any one of  claims 36 - 40 , wherein oral bioavailability for Medium-fat Food for Testing is about 45% to about 55%, about 40 to about 50%, about 49%; optionally wherein the pharmaceutically acceptable oil is a Labrafac-like oil (preferably, Labrafac WL 1349), the propylene glycol laurates composition is Lauroglycol 90, and the polysorbate 80 is Tween 80; additionally optionally wherein the ratio by weight of the Labrafac-like oil (preferably, Labrafac WL 1349) to the Lauroglycol 90 to the polysorbate 80 is about 60:20:20. 
     
     
         43 . The pharmaceutical composition of  claims 36 - 40  and  42 , wherein oral bioavailability for Low-fat Food for Testing is about 10% to about 15%, in some embodiments, about 13%; optionally wherein the pharmaceutically acceptable oil is a Labrafac-like oil (preferably, Labrafac WL 1349), the propylene glycol laurates composition is Lauroglycol 90, and the polysorbate 80 is Tween 80; additionally optionally wherein the ratio by weight of the pharmaceutically acceptable oil to the propylene glycol laurates composition to the polysorbate 80 is about 60:20:20. 
     
     
         44 . The pharmaceutical composition of any one of  claims 36 - 40 , wherein oral bioavailability for Medium-fat Food for Testing is about 15% to about 40%, 25% to about 35%, about 29%; optionally wherein the ratio by weight of the pharmaceutically acceptable oil to the propylene glycol laurates composition to the polysorbate 80 is about 65:20:15; and additionally optionally wherein the pharmaceutically acceptable oil is a Labrafac-like oil (Labrafac WL 1349 or Labrafac PG), cottonseed oil, soybean oil, olive oil, or corn oil; the propylene glycol laurates composition is Lauroglycol 90; and the polysorbate 80 is Tween 80. 
     
     
         45 . The pharmaceutical composition of  claims 36 - 40  and  44 , wherein oral bioavailability for Low-fat Food for Testing is about 10% to about 15%, in some embodiments, about 14%; optionally wherein the pharmaceutically acceptable oil is a Labrafac-like oil (preferably, Labrafac WL 1349), the propylene glycol laurates composition is Lauroglycol 90, and the polysorbate 80 is Tween 80; additionally optionally wherein the ratio by weight of the pharmaceutically acceptable oil to the propylene glycol laurates composition to the polysorbate 80 is about 65:20:15. 
     
     
         46 . The pharmaceutical composition of any one of  claims 1 - 45 , wherein the pharmaceutical composition comprises a flavorant. 
     
     
         47 . The pharmaceutical composition of  claims 1 - 46 , wherein the amount of the flavorant is less than 1% wt/wt %. 
     
     
         48 . The pharmaceutical composition of  claims 46  and  47 , wherein the flavorant is selected from the group consisting of natural flavors, natural fruit flavors, artificial flavors, artificial fruit flavors, flavor enhancers and mixtures thereof. 
     
     
         49 . The pharmaceutical composition of any one of  claims 46 - 48 , wherein the flavorant is oil soluble. 
     
     
         50 . The pharmaceutical composition of any one of  claims 46 - 49 , wherein the flavorant has flavor selected from the group consisting of raspberries, punch, cherry, strawberries, and blueberries. 
     
     
         51 . The pharmaceutical composition of any one of  claims 46 - 50 , wherein the flavorant has odor selected from the group consisting of raspberries, punch, cherry, strawberries, and blueberries. 
     
     
         52 . The pharmaceutical composition of any one of  claims 1 - 45 , wherein the pharmaceutical composition does not comprise a flavorant. 
     
     
         53 . The pharmaceutical composition of any one of  claims 1 - 35 , wherein the pharmaceutical composition is a transdermal pharmaceutical composition. 
     
     
         54 . A method of preparing a pharmaceutical composition of any one of  claims 1 - 53 , comprising:
 step a) mixing about 48 wt/wt % to about 70 wt/wt % of a pharmaceutically acceptable oil, about 12 wt/wt % to about 25 wt/wt % of a propylene glycol laurates composition, about 8 wt/wt % to about 20 wt/wt % of a polysorbate 80, and 0 wt/wt % to about 2% wt/wt % of an optional flavorant;   step b) adding about 1 wt/wt % to about 15%, of Compound 1 and/or the hydroquinone form thereof, wherein Compound 1 and/or the hydroquinone form thereof is optionally a hydrate and/or solvate thereof; to the mixture from step a) and mixing,   and wherein when the Compound 1, and/or hydroquinone thereof, is in the form of a hydrate and/or solvate, then the about 1 wt/wt % to about 15 wt/wt % of Compound 1 and/or its hydroquinone, does not include the weight of any the water in the hydrate or the weight of the solvent in the solvate; and   wherein the wt/wt % of Compound 1, the pharmaceutically acceptable oil, the propylene glycol laurates composition, the polysorbate 80, and optional flavorant total 100%.   
     
     
         55 . The method of  claim 54 , wherein step b) occurs at room temperature. 
     
     
         56 . The method of  claim 54  or  55 , wherein Compound 1 in step b) is a polymorph of an anhydrate of 2,3,5-trimethyl-6-nonylcyclohexa-2,5-diene-1,4-dione, wherein a powder X-ray diffraction pattern for the polymorph comprises characteristic peaks at least at the following angular positions, wherein the angular positions may vary by ±0.2:4.10, 12.12, and 16.14, and wherein the characteristic peaks are measured with a Cu Kα1 source, a wavelength of 1.540598 Å, and at room temperature or at a temperature of 23-25° C. 
     
     
         57 . The method of any one of  claims 54 - 56 , wherein the mixing occurs until a clear formulation solution forms. 
     
     
         58 . The method of  claim 57 , wherein the solution is assessed visually and under microscope for the absence of crystals of Compound 1. 
     
     
         59 . The method of any one of  claims 54 - 58 , wherein Compound 1 is added and mixed under light protection or yellow light. 
     
     
         60 . A pharmaceutical composition prepared by the method of any one of  claims 54 - 58 . 
     
     
         61 . A method for treating or suppressing a disease or disorder selected from the group consisting of an α-synucleinpathy, a tauopathy, an autistic spectrum disorder, a pervasive developmental disorder, a liver disease, liver damage, dementia, and reperfusion injury, comprising administering a pharmaceutical composition of any one of  claims 1 - 53  or a pharmaceutical composition of  claim 60  to a patient in need thereof. 
     
     
         62 . The method of  claim 61 , wherein the α-synucleinpathy is selected from the group consisting of: Parkinson's Disease (idiopathic and genetic), Parkinson's Disease with dementia (PDD), multisystem atrophy (MSA), Frontotemporal Dementia, Dementia with Lewy Bodies (DLB), Gaucher's disease (GD), Neurodegeneration with Brain Iron Accumulation (NBIA), and neuroaxonal dystrophies (PLA2G6-associated neurodegeneration). 
     
     
         63 . The method of  claim 62 , wherein the Parkinson's Disease is that wherein the patient has a mutation in one or more of the following genes: MAPT (Microtubule-associated protein tau), PRKN (parkin), PINK1 (PINK1), LRRK2 (leucine-rich repeat kinase 2), GBA (glucocerebrosidase), SNCA (alpha synuclein), PARK7 (DJ-1), and/or UCHL1 (ubiquitin carboxyl-terminal esterase L1). 
     
     
         64 . The method of  claim 61 , wherein the tauopathy is selected from the group consisting of: Alzheimer's disease, dementia pugilistica, Guam Amyotrophic lateral sclerosis-Parkinsonism-Dementia (Guam ALS/PD), Pick Disease, Argyrophilic grain dementia, Nieman-Pick type C, Subacute sclerosing panencephalitis (SSPE), Progressive supranuclear palsy (PSP), multisystem atrophy (MSA), Corticobasoganlionic degeneration, Frontotemporal dementia with parkinsonism-17 (FTDP-17), Postencephalitic Parkinsonism (PEP), and Autosomal recessive Parkinsonism. 
     
     
         65 . The method of  claim 61 , wherein the liver disease is selected from the group consisting of NASH/NAFL, pediatric NAFLD, alcoholic hepatitis, cholestatic liver disease, viral hepatitis, drug-induced liver toxicity, hemachromatosis, Wilson's disease, liver transplant reperfusion injury, hepatic insufficiency where the hepatic insufficiency is due to injury, SIRS, sepsis, or severe illness; and drug-induced liver toxicity, such as cisplatin-induced liver toxicity and acetaminophen-induced liver toxicity. 
     
     
         66 . The method of  claim 61 , wherein the autistic spectrum disorder or pervasive developmental disorder is selected from the group consisting of autistic disorder, Asperger's syndrome, childhood disintegrative disorder (CDD), Rett's disorder, Rett syndrome (RTT), PDD-not otherwise specified (PDD-NOS), and attention deficit/hyperactivity disorder (ADHD). 
     
     
         67 . The method of  claim 61 , wherein the reperfusion injury is selected from the group consisting of cardiac reperfusion injury, renal reperfusion injury, and stroke. 
     
     
         68 . The method of any one of  claims 61 - 67 , wherein the pharmaceutical composition is administered orally. 
     
     
         69 . The method of any one of  claims 61 - 68 , wherein the pharmaceutical composition is administered for at least 24 weeks or for at least 28 weeks. 
     
     
         70 . The method of  claim 69 , wherein the pharmaceutical composition is administered at a dose selected from 150 mg BID and 250 mg BID. 
     
     
         71 . The method of  claim 70 , wherein the pharmaceutical composition is administered at a dose of 10 capsules total per day, wherein the weight of Compound 1 in each capsule is 50 mg. 
     
     
         72 . The method of  claim 70 , wherein the pharmaceutical composition is administered at a dose of 6 capsules total per day, wherein the weight of Compound 1 in each capsule is 50 mg. 
     
     
         73 . The method of any one of  claims 61 - 72 , wherein the patient does not experience any emergent serious adverse events (TEAEs), no TEAEs leading to discontinuation of the pharmaceutical composition, and/or no TEAEs leading to death. 
     
     
         74 . The method of any one of  claims 61 - 68 , wherein the pharmaceutical composition is administered at a dose ranging from about 100 mg to about 1000 mg daily dose for a period of at least 14 days. 
     
     
         75 . The method of any one of  claims 61 - 74 , wherein the pharmaceutical composition does not comprise the optional flavorant and the pharmaceutical composition is administered in or with food. 
     
     
         76 . The method of  claim 75 , wherein the food is a Low-fat Food or a Medium fat Food. 
     
     
         77 . The method of  claim 76 , wherein the food is a Low-fat Food. 
     
     
         78 . The method of  claim 76 , wherein the food is a Medium fat Food.