Abstract:
Provided are pharmaceutical compositions comprising (1R,5S)-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-(naphthalene-2-yl)-3-azabicyclo[3.1.0]hexane. The compositions are substantially free of the other (−) enantiomer of the compound.

Description:
BACKGROUND 
       [0001]    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is an unbalanced triple reuptake inhibitor with the most potency towards norepinephrine reuptake (NE), one-sixth as much towards dopamine reuptake (DA), and one-fourteenth as much towards serotonin reuptake (5-HT). 
         [0002]    There remains a need for novel pharmaceutical compositions comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form. 
       BRIEF SUMMARY 
       [0003]    Provided is a pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form. 
         [0004]    Further areas of applicability of the present disclosure will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred embodiment of this disclosure, are intended for purposes of illustration only and are not intended to limit the scope of this disclosure. 
     
    
     DETAILED DESCRIPTION 
       [0005]    The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses. 
         [0006]    As used throughout, ranges are used as shorthand for describing each and every value that is within the range. Any value within the range can be selected as the terminus of the range. In addition, all references cited herein are hereby incorporated by referenced in their entireties. In the event of a conflict in a definition in the present disclosure and that of a cited reference, the present disclosure controls. 
         [0007]    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is shown as Formula I below. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0008]    “(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” and “(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” are used interchangeably herein. 
         [0009]    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is an unbalanced triple reuptake inhibitor with the most potency towards norepinephrine reuptake (NE), one-sixth as much towards dopamine reuptake (DA), and one-fourteenth as much towards serotonin reuptake (5-HT). 
         [0010]    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be synthesized as described in U.S. Pat. No. 8,461,196 or International Publication No. WO 2013/019271, both of which are incorporated herein by reference in their entirety. 
         [0011]    As used herein, “substantially free of the corresponding (−) enantiomer” means more of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane than the corresponding (−) enantiomer, i.e., (1S,5R)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. In some embodiments, “substantially free of the corresponding (−) enantiomer” means containing no more than 20% w/w (weight/weight) of the corresponding (−) enantiomer, in free or pharmaceutically acceptable salt form, e.g., no more than 10% w/w of the corresponding (−) enantiomer, in free or pharmaceutically acceptable salt form, e.g., no more than 5% w/w of the corresponding (−) enantiomer, in free or pharmaceutically acceptable salt form, e.g., no more than 2% w/w of the corresponding (−) enantiomer, in free or pharmaceutically acceptable salt form, e.g., no more than 1% w/w of the corresponding (−) enantiomer, in free or pharmaceutically acceptable salt form. 
         [0012]    As used herein, “(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” embraces the compound in any form, for example, free or pharmaceutically acceptable salt form, e.g., as a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable salts are known in the art and include salts that are physiologically acceptable at the dosage amount and form to be administered, for example, hydrochloride salts. 
         [0013]    As used herein, “(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane” is also to be understood as embracing the compound in crystalline and amorphous form including, for example, polymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” may be used interchangeably herein, and are meant to include all crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, including, for example, polymorphs, solvates (including hydrates), unsolvated polymorphs (including anhydrates), and conformational polymorphs, as well as mixtures thereof, unless a particular crystalline form is referred to. 
         [0014]    Crystalline and amorphous forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may be used in any combination or in forms that are substantially free of one or more of the other crystalline forms or free of the amorphous form. 
         [0015]    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane may in some cases also exist in prodrug form. Prodrugs are considered to be any covalently bonded carriers that release the active parent drug in vivo. 
         [0016]    As used herein, “concurrently” means the compounds are administered simultaneously or within the same composition. In some embodiments, the compounds are administered simultaneously. In some embodiments, the compounds are administered within the same composition. 
         [0017]    The nominal viscosity of polymers, e.g., hydroxypropyl methylcellulose may be measured, for example, at a 2% concentration in water at 20° C. according to the U.S. Pharmacopeia and by other techniques known to those skilled in the art. 
         [0018]    Particle size measurements may be made, for example, by laser diffraction and by other techniques known to those skilled in the art. 
         [0019]    In some embodiments, the pharmaceutical compositions disclosed herein comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, may be administered by any suitable route, including orally, parenterally, transdermally, or by inhalation, including by sustained release, although various other known delivery routes, devices and methods can likewise be employed. In some embodiments, provided is a sustained release pharmaceutical composition, e.g., an oral sustained release pharmaceutical composition, comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, which provides therapeutically effective levels of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane over a sustained delivery period of approximately 6 hours or longer, e.g., 8 hours or longer, e.g., 12 hours or longer, e.g., 18 hours or longer, e.g., 24 hours or longer. 
         [0020]    In some embodiments, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is released from a pharmaceutical composition as disclosed herein and delivered into the blood plasma or other target site of activity in the subject (including, but not limited to, areas of the brain such as the prefrontal cortex, frontal cortex, thalamus, striatum, ventral tegmental area, other cortical areas, hippocampus, hypothalamus, or nucleus accumbens) in a sustained release profile characterized in that from about 0% to 20% of the active compound is released and delivered (as determined, e.g., by measuring blood plasma levels) within 0 to 2 hours, from 20% to 50% of the active compound is released and delivered within about 2 to 12 hours, from 50% to 85% of the active compound is released and delivered within about 3 to 20 hours, and greater than 75% of the active compound is released and delivered within about 5 to 18 hours. 
         [0021]    In some embodiments, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is released from a pharmaceutical composition as disclosed herein and delivered into the blood plasma or other target site of activity in the subject (including, but not limited to, areas of the brain such as the prefrontal cortex, frontal cortex, thalamus, striatum, ventral tegmental area, other cortical areas, hippocampus, hypothalamus, or nucleus accumbens) in a sustained release profile characterized in that at least 20% of the active compound is released and delivered (as determined, e.g., by measuring blood plasma levels) within 4 or less hours after administration, e.g., at least about 30%, e.g., at least about 40%, e.g., about 20-80%, e.g., about 30-70%, e.g., about 40-60% is released and delivered within 4 hours or less after administration. 
         [0022]    In some embodiments, (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is released from a pharmaceutical composition as disclosed herein and delivered into the blood plasma or other target site of activity in the subject (including, but not limited to, areas of the brain such as the prefrontal cortex, frontal cortex, thalamus, striatum, ventral tegmental area, other cortical areas, hippocampus, hypothalamus, or nucleus accumbens) in a sustained release profile characterized in that at least 50% of the active compound is released and delivered (as determined, e.g., by measuring blood plasma levels) within 8 hours or less after administration, e.g., at least about 60%, e.g., at least about 70%, e.g., at least about 80%, e.g., about 50-90%, e.g., about 60-90%, e.g., about 60-80% is released and delivered within 8 hours or less after administration. 
         [0023]    In some embodiments, at least 20% of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, e.g., at least about 30%, e.g., at least about 40%, e.g., about 20-80%, e.g., about 30-70%, e.g., about 30-60%, e.g., about 40-60%, e.g., about 50-60%, e.g., about 50%, e.g., about 60%, is released and dissolved within 4 hours or less (e.g., within about 2-4 hours, e.g., about within 3-4 hours, e.g., about 4 hours) from a pharmaceutical composition as disclosed herein as measured in 900 mL water using USP Apparatus 2 paddle, at 50 rpm and at 37° C.±0.5. In addition, in some embodiments, at least 50% of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, e.g., at least about 60%, e.g., at least about 70%, e.g., at least about 80%, e.g., about 50-90%, e.g., about 60-90%, e.g., about 60-80% is released and dissolved within 8 hours or less (e.g., within about 6-8 hours, e.g., within about 7-8 hours, e.g., about 8 hours) from a pharmaceutical composition as disclosed herein as measured in 900 mL water using USP Apparatus 2 paddle, at 50 rpm and 37° C.±0.5. 
         [0024]    In some embodiments, the C max  of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, provided after administration of a sustained release pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, as disclosed herein is less than about 80%, e.g., less than about 75%, e.g., less than about 60%, e.g., less than about 50%, e.g., less than about 40%, e.g., less than about 30% of the C max  obtained after administering an equivalent dose of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in an immediate release pharmaceutical composition. In some embodiments, the C max  of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, provided after administration of a sustained release pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, as disclosed herein is about 20-80%, e.g., is about 30-80%, e.g., is about 20-70% e.g., is about 30-70%, e.g., is about 30-60%, e.g., is about 30-50%, e.g., is about 30-40%, of the C max  obtained after administering an equivalent dose of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in an immediate release pharmaceutical composition. 
         [0025]    (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, provided after administration of a sustained release pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, as disclosed herein is less than about 50%, e.g., less than about 40%, e.g., less than about 30%, of the C max  obtained after administering an equivalent dose of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in an immediate release pharmaceutical composition. In some embodiments, the C max  of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, provided after administration of a sustained release pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, as disclosed herein is about 20-50%, e.g., is about 30-50%, e.g., is about 30-40%, of the C max  obtained after administering an equivalent dose of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in an immediate release pharmaceutical composition. 
         [0026]    In some embodiments, the pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, e.g., a sustained release pharmaceutical composition, comprises a lubricant, e.g., magnesium stearate, a carrier, e.g., lactose monohydrate, or a combination thereof. 
         [0027]    Provided is a pharmaceutical composition (Composition 1), e.g., a sustained release pharmaceutical composition, comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form. 
         [0028]    Further provided is Composition 1 as follows:
   1.1 Composition 1 wherein the composition is sustained release.   1.2 Composition 1 or 1.1 wherein the pharmaceutical composition is substantially free of the corresponding (−) enantiomer.   1.3 Composition 1, 1.1, or 1.2 wherein the composition comprises less than or equal to 20% w/w of the corresponding (−) enantiomer.   1.4 Any of Compositions 1 or 1.1-1.3 wherein the composition comprises less than or equal to 10% w/w of the corresponding (−) enantiomer.   1.5 Any of Compositions 1 or 1.1-1.4 wherein the composition comprises less than or equal to 5% w/w of the corresponding (−) enantiomer.   1.6 Any of Compositions 1 or 1.1-1.5 wherein the composition comprises less than or equal to 2% w/w of the corresponding (−) enantiomer.   1.7 Any of Composition 1 or 1.1-1.6 wherein the composition comprises less than or equal to 1% w/w of the corresponding (−) enantiomer.   1.8 Any of Compositions 1 or 1.1-1.7 wherein (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is in pharmaceutically acceptable salt form.   1.9 Composition 1.8 wherein (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in pharmaceutically acceptable salt form is an acid addition salt.   1.10 Composition 1.9 wherein (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.   1.11 Any of Compositions 1 or 1.1-1.10 comprising 1 mg to 1800 mg, e.g., 10 mg to 1800 mg, e.g., 25 mg to 1800 mg, e.g., 10 mg to 1600 mg, e.g., 10 mg to 1200 mg, e.g., 50 mg to 1200 mg, e.g., 50 mg to 1000 mg, e.g., 75 mg to 1000 mg, e.g., 75 mg to 800 mg, e.g., 75 mg to 500 mg, e.g., 100 mg to 750 mg, e.g., 100 mg to 500 mg, e.g., 100 mg to 400 mg, e.g., 100 mg to 300 mg, e.g., 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.   1.12 Any of Compositions 1 or 1.1-1.11 comprising 75 mg to 1000 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 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.   1.13 Any of Compositions 1 or 1.1-1.11 comprising 50 mg to 600 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg, e.g., 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.   1.14 Any of Compositions 1 or 1.1-1.11 comprising 5 mg to 500 mg, e.g., 5 mg to 10 mg, e.g, 10 mg to 25 mg, e.g., 30 mg to 50 mg, e.g., 10 mg to 300 mg, e.g., 25 mg to 300 mg, e.g., 50 mg to 100 mg, e.g., 100 mg to 250 mg, e.g., 250 mg to 500 mg, of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.   1.15 Any of Compositions 1 or 1.1-1.10 for administration of 0.5 mg/kg to 20 mg/kg per day, e.g., 1 mg/kg to 15 mg/kg per day, e.g., 1 mg/kg to 10 mg/kg per day, e.g., 2 mg/kg to 20 mg/kg per day, e.g., 2 mg/kg to 10 mg/kg per day, e.g., 3 mg/kg to 15 mg/kg per day, of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form.   1.16 Any of Compositions 1 or 1.1-1.15 comprising less than 50% w/w of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, e.g., less than about 40% w/w, e.g., less than about 30% w/w, less than about 20% w/w, e.g., about 1-40% w/w, e.g., about 5-40% w/w, e.g., about 10-30% w/w, e.g., about 15-25% w/w, e.g., about 15-20% w/w, e.g., about 17% w/w, e.g., about 25% w/w.   1.17 Any of Compositions 1 or 1.1-1.16 further comprising hydroxypropyl methylcellulose (e.g., hypromellose HPMC K4M).   1.18 Composition 1.17 wherein the composition comprises at least 10% w/w of the hydroxypropyl methylcellulose, e.g., about 10-50% w/w, e.g., about 10-40% w/w, e.g., about 20-50% w/w, e.g., about 20-40% w/w, e.g., about 30-40% w/w, e.g., about 37% w/w.   1.19 Composition 1.17 or 1.18 wherein the degree of methoxy substitution of the hydroxypropyl methylcellulose is 19-24%.   1.20 Any of Compositions 1.17-1.19 wherein the degree of hydroxypropoxy substitution of the hydroxypropyl methylcellulose is 4-12%.   1.21 Any of Compositions 1.17-1.20 wherein the hydroxypropyl methylcellulose is hypromellose 2208.   1.22 Any of Compositions 1.17-1.21 wherein the hydroxypropyl methylcellulose has a nominal viscosity of 4,000 mPA·s.   1.23 Any of Compositions 1.17-1.21 wherein the hydroxypropyl methylcellulose has a viscosity of 2,000-6,000 mPA·s, e.g., about 2,600 to 5,000 mPA·s, e.g., about 2,663 to 4,970 mPA·s.   1.24 Any of Compositions 1 or 1.1-1.23 wherein the composition further comprises lactose (e.g., alpha-lactose monohydrate).   1.25 Composition 1.24 wherein the composition comprises at least 10% w/w of the alpha-lactose monohydrate, e.g., about 10-80% w/w, e.g., about 20-70% w/w, e.g., about 20-60% w/w, e.g., about 20-50% w/w, e.g., about 20-40% w/w, e.g., about 20-30% w/w, e.g., about 30-70% w/w, e.g., about 30-60% w/w, e.g., about 30-50% w/w, e.g., about 30%-40% w/w, e.g., about 37% w/w.   1.26 Composition 1.24 or 1.25 wherein the composition comprises milled alpha-lactose monohydrate.   1.27 Any of Compositions 1 or 1.1-1.26 wherein the composition comprises a co-processed mixture of hydroxpropyl methylcellulose and alpha-lactose monohydrate (e.g., Retalac).   1.28 Composition 1.27 wherein the mixture comprises equal parts of the hydroxpropyl methylcellulose and alpha-lactose monohydrate.   1.29 Composition 1.27 or 1.28 wherein the mixture comprises particles of hydroxpropyl methylcellulose and alpha-lactose monohydrate with d 50  (median diameter) in the range of 100 μm to 200 μm, e.g., about 125 μm.   1.30 Any of Compositions 1.27-1.29 wherein the mixture comprises particles of hydroxpropyl methylcellulose and alpha-lactose monohydrate wherein the particle size distribution is as follows:
       &lt;63 μm≦25%   &lt;100 μm: 35%   &lt;250 μm≧80%.   
       1.31 Any of Compositions 1.27-1.30 wherein the composition comprises at least 20% w/w of the mixture, e.g., about at least 30% w/w, e.g., at least about 40% w/w, e.g., at least about 50% w/w, e.g., at least about 60% w/w, e.g., at least about 70% w/w, e.g, at least about 80% w/w, e.g., about 20-90% w/w, e.g., about 30-80% w/w, e.g., about 40-80% w/w, e.g., about 50-80% w/w, e.g., about 60-80% w/w, e.g., about 70-80% w/w, e.g., about 75% w/w.   1.32 Any of Compositions 1 or 1.1-1.31 wherein the composition further comprises a lubricant, e.g., magnesium stearate.   1.33 Composition 1.32 wherein the lubricant is one or more of glyceryl behenate, magnesium stearate, talc, and sodium stearyl fumarate, e.g, magnesium stearate.   1.34 Composition 1.32 or 1.33 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.   1.35 Any of Compositions 1.32-1.34 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.   1.36 Any of Compositions 1 or 1.1-1.35 wherein the composition further comprises one or more of a diluent, disintegrant, binder, and modified release agent.   1.37 Composition 1.36 wherein the diluent is one or more of mannitol (e.g., Pearlitol 300 DC), micro-crystalline cellulose (e.g., Avicel pH 102), and pre-gelatinized starch (e.g., Starch 1500).   1.38 Composition 1.36 wherein the disintegrant is one or both of crospovidone (e.g., Polyplasdone XL-10) and sodium starch glycolate (e.g., Explotab).   1.39 Composition 1.36 wherein the binder is polyvinylpyrrolidone (e.g., Povidone K29/32).   1.40 Composition 1.36 wherein the modified release agent is one or more of hydroxypropyl cellulose (e.g., Klucel EXF, Klucel MXF and/or Klucel HXF) and hydroxypropyl methylcellulose (e.g., Methocel K100M, Methocel K4M PREM, Methocel K15M PREM CR).   1.41 Composition 1.36 or 1.40 wherein the composition comprises at least 5% w/w of the modified release agent, e.g., about 5-60% w/w, e.g., about 10-50% w/w, e.g., about 10-40% w/w.   1.42 Composition 1.40 or 1.41 wherein the modified release agent is hydroxypropyl methylcellulose.   1.43 Composition 1.42 wherein the degree of methoxy substitution of the hydroxypropyl methylcellulose is 19-24%.   1.44 Composition 1.42 or 1.43 wherein the degree of hydroxypropoxy substitution of the hydroxypropyl methylcellulose is 4-12%.   1.45 Any of Compositions 1.42-1.44 wherein the hydroxypropyl methylcellulose is hypromellose 2208.   1.46 Any of Compositions 1.42-1.45 wherein the hydroxypropyl methylcellulose has a viscosity of 75,000-140,000 mPA·s.   1.47 Any of Compositions 1.42-1.45 wherein the hydroxypropyl methylcellulose has a viscosity of 2,000-6,000 mPA·s, e.g., about 2,600 to 5,000 mPA·s, e.g., about 2,663 to 4,970 mPA·s.   1.48 Any of Compositions 1.42-1.45 wherein the hydroxypropyl methylcellulose has a viscosity of 12,000-26,000 mPA·s, e.g., about 13,000 to 25,000 mPA·s, e.g., about 13,275 to 24,780 mPA·s.   1.49 Any of Compositions 1.42-1.45 wherein the hydroxypropyl methylcellulose has a viscosity of 100,000 cps.   1.50 Any of Compositions 1.42-1.45 wherein the hydroxypropyl methylcellulose has a viscosity of 3,600 cps.   1.51 Any of Compositions 1.42-1.45 wherein the hydroxypropyl methylcellulose has a viscosity of 18,000 cps.   1.52 Composition 1.36, 1.40, or 1.41 wherein the modified release agent is hydroxypropyl cellulose (e.g., Klucel EXF, Klucel MXF and/or Klucel HXF).   1.53 Any of Compositions 1 or 1.1-1.52 for administration once, twice, three, or four times daily.   1.54 Any of Compositions 1 or 1.1-1.53 further comprising another drug.   1.55 Any of Compositions 1 or 1.1-1.54 wherein the composition further comprises an mGluR1 antagonist, an mGluR2/3 antagonist, an mGluR5 antagonist, an AMPA receptor positive modulator, an NMDA receptor antagonist, a tetracycline antibiotic, an α2-adrenergic agonist, an antipsychotic, an anti-depressant (e.g., a selective serotonin reuptake inhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), or a tricyclic anti-depressant), a benzodiazepine, an anti-convulsant, a mood stabilizer, a gamma-aminobutyric acid (GABA) agonist e.g., a GABA-B agonist, a GABA modulator, a stimulant, a 3-blocker, a hormone, or a combination thereof.   1.56 Any of Compositions 1 or 1.1-1.55 wherein the composition further comprises fenobam, mavoglurant (AFQ056), dipraglurant, R04917523, STX107, 2-methyl-6-phenylethynyl pyridine (MPEP), CX516, memantine, acamprosate, minocycline, clonidine, guanfacine, aripiprazole, risperidone, citalopram, escitalopram, fluoxetine, sertraline, fluovoxamine, paroxetine, trazodone, bupropion, imipramine, amitriptyline, venlafaxine, nefazodone, duloxetine, venlafaxine, carbamazepine, lamotrigine, valproic acid, sodium valproate, lithium, quetiapine, folic acid, L-acetylcarnitine, melatonin, arbaclofen, donepezil hydrochloride, alpha-tocopherol, methylphenidate, amphetamine mixed salts (e.g., Adderall), dextroamphetamine, risperidone, olanzapine, ziprasidone, buspirone, filuzole, metadoxine, primidone, topiramate, estradiol, cyclic medroxyprogesterone, or a combination thereof.   1.57 Any of Compositions 1 or 1.1-1.56 further comprising an mGluR5 antagonist.   1.58 Composition 1.57 further comprising fenobam, mavoglurant (AFQ056), dipraglurant, R04917523, STX107, 2-methyl-6-phenylethynyl pyridine (MPEP), or a combination thereof.   1.59 Composition 1.58 further comprising R04917523, mavoglurant (AFQ056), or a combination thereof.   1.60 Any of Compositions 1 or 1.1-1.59 further comprising a GABA-B agonist.   1.61 Composition 1.60 comprising arbaclofen.   1.62 Any of Compositions 1 or 1.1-1.61 further comprising a GABA modulator.   1.63 Composition 1.62 further comprising acamprosate.   1.64 Any of Compositions 1 or 1.1-1.63 further comprising minocycline.   1.65 Any of Compositions 1 or 1.1-1.64 wherein the C max  of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, provided after administration of the composition is less than about 80%, e.g., less than about 75%, e.g., less than about 60%, e.g., less than about 50%, e.g., less than about 40%, e.g., less than about 30%, e.g., is about 20-80%, e.g., is about 30-80%, e.g., is about 20-70% e.g., is about 30-70%, e.g., is about 30-60%, e.g., is about 30-50%, e.g., is about 30-40%, of the C max  obtained after administering an equivalent dose of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in an immediate release pharmaceutical composition.   1.66 Any of Compositions 1 or 1.1-1.65 wherein the C max  of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, provided after administration of a sustained release pharmaceutical composition comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, is less than about 50%, e.g., less than about 40%, e.g., less than about 30%, e.g., about 20-50%, e.g., about 30-50%, e.g., about 30-40%, of the C max  obtained after administering an equivalent dose of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, in free or pharmaceutically acceptable salt form, in an immediate release pharmaceutical composition.   1.67 Composition 1 wherein the composition comprises 25% w/w (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, 74.5% w/w of an equal parts mixture of hydroxypropyl methylcellulose and alpha-lactose monohydrate, and 0.5% w/w magnesium stearate.   1.68 Any of Compositions 1 or 1.1-1.67 for use in indications as described in U.S. Pat. No. 8,461,196, International Publication No. WO 2013/019271, and International Patent Application No. PCT/US 14/69401, the contents of each of which are hereby incorporated by reference.   
 
       EXAMPLES 
     Example 1 
       [0100]    Sustained release pharmaceutical compositions comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride may be made utilizing a direct blend process, with screening of the excipients and (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride through a Quadro 197S Co-Mil, and blending in a V-shell blender prior to compression on a rotary tablet press. 
       Example 2 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0101]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Tablet Unit 
               
               
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (1R,5S)-1-(naphthalen-2- 
                  25% 
                 100 
               
               
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                 hydrochloride 
               
               
                 Lactose Monohydrate, NF 
                 74.5%  
                 298 
               
               
                 Hypromellose, NF 
               
               
                 (as 50/50 premix - RetaLac ®) 
               
               
                 Magnesium Stearate, NF 
                  0.5% 
                 2 
               
               
                 (Hyqual ® Vegetable source) 
                   
                   
               
               
                 Total 
                 100% 
                 400 
               
               
                   
               
             
          
         
       
     
         [0102]    HPLC conditions for dissolution and dissolution conditions for Examples 3-9 are set forth in Tables 1 and 2. 
         [0000]    
       
         
               
             
               
               
             
               
               
               
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 HPLC Conditions Dissolution 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Item 
                 Setting 
               
               
                   
               
               
                 Column 
                 Waters XBridge C18 3.0 × 150 mm 3.5 μm 
               
               
                 Mobile Phase 
                 MPA: 6 mM Ammonium Formate; 95% Water, 5% CAN 
               
               
                   
                 MPB: 5 mM Ammonium Formate; 5% Water, 95% ACN 
               
               
                 Flow Rate 
                 See Gradient 
               
               
                 Detection 
                 226 nm 
               
               
                 Column Temp. 
                 40° C. 
               
               
                 Run Time 
                 42 minutes 
               
               
                 Injection 
               
               
                 Volume 
                 20 μL 
               
               
                   
               
             
          
           
               
                   
                   
                   
                   
                 Flow Rate 
               
               
                 Gradient 
                 Time 
                 % MPA 
                 % MPB 
                 (mL/min) 
               
               
                   
               
               
                   
                 0 
                 95 
                 5 
                 0.8 
               
               
                   
                 30 
                 50 
                 50 
                 0.8 
               
               
                   
                 30.1 
                 5 
                 95 
                 0.8 
               
               
                   
                 35 
                 5 
                 95 
                 1.2 
               
               
                   
                 35.1 
                 95 
                 5 
                 0.8 
               
               
                   
                 42 
                 95 
                 5 
                 0.8 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Dissolution Testing Conditions 
               
             
          
           
               
                   
                 Item 
                 Setting/Condition 
               
               
                   
                   
               
               
                   
                 Media 
                 Water 
               
               
                   
                 Volume 
                 900 mL 
               
               
                   
                 Speed 
                 50 rpm 
               
               
                   
                 Apparatus 
                 USP, App. 2, Paddle 
               
               
                   
                 Temp. 
                 37° C. ± 0.5 
               
               
                   
                   
               
             
          
         
       
     
       Example 3 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0103]    Manufacture by a direct blend process. Compress on Dynamic Exim rotary tablet press using concave ⅜″ tooling. Compress at a target weight of 300 mg (+15 mg) and target hardness of approximately 8 kp±2 kp. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Tablet Unit 
               
               
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (1R,5S)-1-(naphthalen-2- 
                 16.7% 
                 50 
               
               
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                 hydrochloride 
               
               
                 Lactose Monohydrate, NF 
                 82.8% 
                 248.5 
               
               
                 Hypromellose, NF 
               
               
                 (as 50/50 premix - RetaLac ®) 
               
               
                 Magnesium Stearate, NF 
                  0.5% 
                 1.5 
               
               
                 Total 
                  100% 
                 300 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Dissolution Data: 
               
               
                 12-hour dissolution profile 
               
               
                 Numerical Data 
               
             
          
           
               
                 Vessel 
                 1 hr 
                 2 hr 
                 4 hr 
                 6 hr 
                 8 hr 
                 12 hr 
               
               
                   
               
             
          
           
               
                 1 
                 23 
                 35 
                 52 
                 65 
                 74 
                 84 
               
               
                 2 
                 22 
                 33 
                 51 
                 64 
                 73 
                 84 
               
               
                 3 
                 21 
                 34 
                 50 
                 64 
                 73 
                 84 
               
               
                 Ave 
                 22 
                 34 
                 51 
                 64 
                 73 
                 84 
               
               
                 % RSD 
                 3.0 
                 2.3 
                 1.8 
                 1.0 
                 0.6 
                 0.2 
               
               
                   
               
             
          
         
       
     
       Example 4 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0104]    Manufacture by a direct blend process. Compress on Dynamic Exim rotary tablet press using concave ⅜″ tooling. Compress at a target weight of 300 mg (±15 mg) and target hardness of approximately 8 kp±2 kp. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Tablet Unit 
               
               
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (1R,5S)-1-(naphthalen-2- 
                 16.7% 
                 50 
               
               
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                 hydrochloride 
               
               
                 Lactose Monohydrate, NF 
                 42.8% 
                 128.4 
               
               
                 Hypromellose, NF 
               
               
                 (as 50/50 premix - RetaLac ®) 
               
               
                 Lactose Monohydrate, 315 SD 
                 40.0% 
                 120.0 
               
               
                 Magnesium Stearate, NF 
                  0.5% 
                 1.5 
               
               
                 Total 
                  100% 
                 300 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 4 
               
               
                   
               
               
                 Vessel 
                 1 hr 
                 2 hr 
                 4 hr 
                 6 hr 
                 8 hr 
                 12 hr 
                 24 hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 32 
                 48 
                 66 
                 78 
                 85 
                 94 
                 99 
               
               
                 2 
                 30 
                 45 
                 66 
                 79 
                 90 
                 84 
                 96 
               
               
                 3 
                 33 
                 48 
                 70 
                 79 
                 89 
                 84 
                 89 
               
               
                 Ave 
                 32 
                 47 
                 67 
                 78 
                 88 
                 87 
                 95 
               
               
                 % RSD 
                 3.6 
                 4.6 
                 3.9 
                 0.8 
                 2.6 
                 6.8 
                 5.4 
               
               
                   
               
             
          
         
       
     
       Example 5 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0105]    Manufacture by a direct blend process. Compress on Dynamic Exim rotary tablet press using concave ⅜″ tooling. Compress at a target weight of 300 mg (+15 mg) and target hardness of approximately 8 kp±2 kp. 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Tablet Unit 
               
               
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (1R,5S)-1-(naphthalen-2- 
                 16.7% 
                 50 
               
               
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                 hydrochloride 
               
               
                 Lactose Monohydrate, NF 
                 52.8% 
                 158.5 
               
               
                 Hypromellose, NF 
               
               
                 (as 50/50 premix - RetaLac ®) 
               
               
                 Klucel HXF HPC 
                 30.0% 
                 90.0 
               
               
                 Magnesium Stearate, NF 
                  0.5% 
                 1.5 
               
               
                 Total 
                  100% 
                 300 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 5 
               
               
                   
               
               
                 Vessel 
                 1 hr 
                 2 hr 
                 4 hr 
                 6 hr 
                 8 hr 
                 12 hr 
                 24 hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 29 
                 46 
                 67 
                 75 
                 92 
                 101 
                 105 
               
               
                 2 
                 29 
                 43 
                 65 
                 74 
                 91 
                 94 
                 106 
               
               
                 3 
                 30 
                 43 
                 65 
                 75 
                 87 
                 101 
                 105 
               
               
                 Ave 
                 30 
                 44 
                 66 
                 75 
                 90 
                 99 
                 105 
               
               
                 % RSD 
                 2.0 
                 3.5 
                 1.6 
                 0.7 
                 3.0 
                 4.3 
                 0.6 
               
               
                   
               
             
          
         
       
     
       Example 6 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0106]      
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                   
                 Concentration 
                 Tablet Unit 
               
               
                   
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 (1R,5S)-1-(naphthalen-2- 
                 16.7% 
                 50 
               
               
                   
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                   
                 hydrochloride 
               
               
                   
                 Lactose Monohydrate, 315 SD 
                 41.4% 
                 124.25 
               
               
                   
                 HPMC K4M 
                 41.4% 
                 124.25 
               
               
                   
                 Magnesium Stearate, NF 
                  0.5% 
                 1.5 
               
               
                   
                 Total 
                  100% 
                 300 
               
               
                   
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 6 
               
               
                   
               
               
                 Vessel 
                 1 hr 
                 2 hr 
                 4 hr 
                 6 hr 
                 8 hr 
                 12 hr 
                 24 hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 24 
                 37 
                 55 
                 68 
                 78 
                 88 
                 92 
               
               
                 2 
                 21 
                 33 
                 51 
                 63 
                 76 
                 92 
                 95 
               
               
                 3 
                 22 
                 34 
                 52 
                 62 
                 77 
                 93 
                 100 
               
               
                 4 
                 24 
                 38 
                 56 
                 72 
                 86 
                 100 
                 100 
               
               
                 5 
                 22 
                 34 
                 51 
                 63 
                 71 
                 84 
                 88 
               
               
                 6 
                 23 
                 36 
                 55 
                 66 
                 75 
                 98 
                 104 
               
               
                 Ave 
                 23 
                 35 
                 53 
                 66 
                 77 
                 92 
                 96 
               
               
                 % RSD 
                 5.2 
                 4.9 
                 4.2 
                 5.7 
                 6.4 
                 6.4 
                 6.1 
               
               
                   
               
             
          
         
       
     
       Example 7 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0107]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Tablet Unit 
               
               
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (1R,5S)-1-(naphthalen-2- 
                 33.3% 
                 100 
               
               
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                 hydrochloride 
               
               
                 Lactose Monohydrate, NF 
                 66.2% 
                 198.5 
               
               
                 Hypromellose, NF 
               
               
                 (as 50/50 premix - RetaLac ®) 
               
               
                 Magnesium Stearate, NF 
                  0.5% 
                 1.5 
               
               
                 (Hyqual ® Vegetable source) 
                   
                   
               
               
                 Total 
                  100% 
                 300 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 7 
               
               
                   
               
               
                 Vessel 
                 1 hr 
                 2 hr 
                 4 hr 
                 6 hr 
                 8 hr 
                 12 hr 
                 24 hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 21 
                 33 
                 53 
                 69 
                 84 
                 — 
                 — 
               
               
                 2 
                 21 
                 34 
                 54 
                 68 
                 81 
                 — 
                 — 
               
               
                 3 
                 23 
                 35 
                 57 
                 69 
                 80 
                 — 
                 — 
               
               
                 4 
                 22 
                 31 
                 54 
                 68 
                 83 
                 — 
                 — 
               
               
                 5 
                 22 
                 35 
                 56 
                 71 
                 83 
                 — 
                 — 
               
               
                 6 
                 23 
                 36 
                 57 
                 69 
                 87 
                 — 
                 — 
               
               
                 Ave 
                 22 
                 34 
                 55 
                 69 
                 83 
                 — 
                 — 
               
               
                 % RSD 
                 5.0 
                 4.8 
                 3.6 
                 1.5 
                 3.0 
                 — 
                 — 
               
               
                   
               
               
                 NOTE: 
               
               
                 12 and 24 hour pulls not performed 
               
             
          
         
       
     
       Example 8 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0108]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Tablet Unit 
               
               
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (1R,5S)-1-(naphthalen-2- 
                 25.0% 
                 100 
               
               
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                 hydrochloride 
               
               
                 Lactose Monohydrate, NF 
                 74.5% 
                 298.0 
               
               
                 Hypromellose, NF 
               
               
                 (as 50/50 premix - RetaLac ®) 
               
               
                 Magnesium Stearate, NF 
                  0.5% 
                 2.0 
               
               
                 (Hyqual ® Vegetable source) 
                   
                   
               
               
                 Total 
                  100% 
                 400 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 8 
               
               
                   
               
               
                 Vessel 
                 1 hr 
                 2 hr 
                 4 hr 
                 6 hr 
                 8 hr 
                 12 hr 
                 24 hr 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 20 
                 29 
                 47 
                 60 
                 73 
                 — 
                 — 
               
               
                 2 
                 22 
                 34 
                 53 
                 68 
                 79 
                 — 
                 — 
               
               
                 3 
                 22 
                 33 
                 47 
                 68 
                 79 
                 — 
                 — 
               
               
                 4 
                 20 
                 30 
                 47 
                 64 
                 74 
                 — 
                 — 
               
               
                 5 
                 19 
                 30 
                 43 
                 59 
                 69 
                 — 
                 — 
               
               
                 6 
                 21 
                 31 
                 49 
                 64 
                 76 
                 — 
                 — 
               
               
                 Ave 
                 21 
                 31 
                 48 
                 64 
                 75 
                 — 
                 — 
               
               
                 % RSD 
                 5.5 
                 6.6 
                 7.3 
                 5.7 
                 5.0 
                 — 
                 — 
               
               
                   
               
               
                 NOTE: 
               
               
                 12 and 24 hour pulls not performed 
               
             
          
         
       
     
       Example 9 
     Sustained Release Pharmaceutical Composition Comprising (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride 
       [0109]      
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
               
               
                   
                 Concentration 
                 Tablet Unit 
               
               
                 Ingredient 
                 (% W/W) 
                 Weight (mg) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 (1R,5S)-1-(naphthalen-2- 
                 25.0% 
                 100 
               
               
                 yl)-3-azabicyclo[3.1.0]hexane 
               
               
                 hydrochloride 
               
               
                 Lactose Monohydrate, NF 
                 74.5% 
                 298.0 
               
               
                 Hypromellose, NF 
               
               
                 (as 50/50 premix - RetaLac ®) 
               
               
                 Magnesium Stearate, NF 
                  0.5% 
                 2.0 
               
               
                 (Hyqual ® Vegetable source) 
                   
                   
               
               
                 Total 
                  100% 
                 400 
               
               
                   
               
             
          
         
       
     
         [0110]    Batch has an approximate 50% dissolution release at 4 hours and approximate 80% release at 8 hours.