Sustained release pharmaceutical compositions comprising (1r, 5s)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane

Abstract

Provided are pharmaceutical compositions comprising (1R,55)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form. The compositions are formulated for providing a sustained release of enantiomerically pure (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.O)]hexane. The compositions are substantially free of the other (—) enantiomer of the compound.

1 . An oral sustained release pharmaceutical composition, wherein the composition is a tablet comprising about 1 to 40% w/w (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, 30-50% w/w of hydroxypropyl methylcellulose, 30-50% w/w alpha-lactose monohydrate, and a lubricant, wherein 40-60% of the (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is released and dissolved within 4 hours, and 60-90% is released in 6-8 hours, as measured in 900 mL water using USP Apparatus 2 paddle at 50 rpm and at 37° C.±0.5° C. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
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         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The composition of  claim 1 , wherein the composition comprises less than or equal to 2% w/w of the corresponding (—) enantiomer. 
     
     
         8 . The composition of  claim 1 , wherein the composition comprises less than or equal to 1% w/w of the corresponding (—) enantiomer. 
     
     
         9 . The composition of  claim 1 , wherein (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is in pharmaceutically acceptable salt form. 
     
     
         10 . The composition of  claim 9 , wherein the (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is an acid addition salt. 
     
     
         11 . The composition of  claim 10 , wherein the (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 
     
     
         12 . The composition of  claim 1  comprising 1 mg to 1800 mg, or 10 mg to 1800 mg, or 25 mg to 1800 mg, or 10 mg to 1600 mg, or 10 mg to 1200 mg, or 50 mg to 1200 mg, or 50 mg to 1000 mg, or 75 mg to 1000 mg, or 75 mg to 800 mg, or 75 mg to 500 mg, or 100 mg to 750 mg, or 100 mg to 500 mg, or 100 mg to 400 mg, or 100 mg to 300 mg, or 100 mg to 200 mg, of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form. 
     
     
         13 . (canceled) 
     
     
         14 . The composition of  claim 1 , comprising 100 mg to 200 mg of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form. 
     
     
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         17 . The composition of  claim 1 , comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in an amount less than about 30% w/w, or less than about 20% w/w, or about 1-40% w/w, or about 5-40% w/w, or about 10-30% w/w, or about 15-25% w/w, or about 15-20% w/w, or about 17% w/w, or about 25% w/w. 
     
     
         18 . (canceled) 
     
     
         19 . The composition of  claim 1 , wherein the composition comprises the hydroxypropyl methylcellulose, in an amount of about 30-40% w/w, or of about 37% w/w. 
     
     
         20 . (canceled) 
     
     
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         24 . The composition of  claim 1 , wherein the hydroxypropyl methylcellulose has a viscosity of 2,000-6,000 mPA·s, or of about 2,600 to 5,000 mPA·s, c.g., or of about 2,663 to 4,970 mPA·s. 
     
     
         25 . (canceled) 
     
     
         26 . The composition of  claim 1 , wherein the composition comprises the alpha-lactose monohydrate in an amount of abput 30%-40% w/w, e.g., abput 37% w/w. 
     
     
         27 . The composition of  claim 1 , wherein the alpha-lactose monohydrate is milled alpha-lactose monohydrate. 
     
     
         28 . The composition of  claim 1 , wherein the composition comprises a co-processed mixture of hydroxypropyl methylcellulose and alpha-lactose monohydrate (e.g., Retalac®). 
     
     
         29 . The composition of  claim 28 , wherein the mixture comprises equal parts of the hydroxypropyl methylcellulose and alpha-lactose monohydrate. 
     
     
         30 . (canceled) 
     
     
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         32 . The composition of  claim 28 , wherein the composition comprises about 60-80% w/w, e.g., about 70-80% w/w, e.g., about 75% w/w of the co-processed mixture of hydroxpropyl methylcellulose and alpha-lactose monohydrate. 
     
     
         33 . (canceled) 
     
     
         34 . The composition of  claim 1 , wherein the lubricant is one or more of glyceryl behenate, magnesium stearate, talc, and sodium stearyl fumarate, e.g, magnesium stearate. 
     
     
         35 . The composition of  claim 33 , wherein the composition comprises less than 10% w/w of the lubricant, e.g., less than about 5% w/w, less than about 3% w/w, less than about 1% w/w, e.g., about 0.1 to 1% w/w, e.g., about 0.1 to 0.8% w/w, e.g., about 0.5% w/w. 
     
     
         36 . The composition of  claim 33 , wherein the composition comprises less than 10% w/w of magnesium stearate, e.g., less than about 5% w/w, less than about 3% w/w, less than about 1%, e.g., about 0.1 to 1% w/w, e.g., about 0.1 to 0.8% w/w, e.g., about 0.5% w/w. 
     
     
         37 . (canceled) 
     
     
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         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . The composition of  claim 1 , wherein the composition comprises a co-processed mixture of hydroxpropyl methylcellulose and alpha-lactose monohydrate comprising equal parts of the hydroxpropyl methylcellulose and alpha-lactose monohydrate.