WO2012075473A1 - Preparation and use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in the treatment of conditions affected by monoamine neurotransmitters - Google Patents

Preparation and use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in the treatment of conditions affected by monoamine neurotransmitters Download PDF

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WO2012075473A1
WO2012075473A1 PCT/US2011/063193 US2011063193W WO2012075473A1 WO 2012075473 A1 WO2012075473 A1 WO 2012075473A1 US 2011063193 W US2011063193 W US 2011063193W WO 2012075473 A1 WO2012075473 A1 WO 2012075473A1
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dichlorophenyl
azabicyclo
hexane
agent
pharmaceutically acceptable
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PCT/US2011/063193
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English (en)
French (fr)
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Anthony Alexander Mckinney
Frank Bymaster
Walter Piskorski
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Euthymic Bioscience, Inc.
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Priority to CA2834713A priority Critical patent/CA2834713A1/en
Priority to BR112013013572A priority patent/BR112013013572A2/pt
Priority to AU2011336318A priority patent/AU2011336318A1/en
Priority to EP11844214.4A priority patent/EP2646019A4/en
Priority to JP2013542235A priority patent/JP2013544850A/ja
Priority to KR1020137017462A priority patent/KR20140053822A/ko
Publication of WO2012075473A1 publication Critical patent/WO2012075473A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring

Definitions

  • the present invention relates to selective inhibition of the reuptake of monoamine neurotransmitters.
  • the present invention relates to compositions comprising (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and their use in the treatment of conditions affected by monoamine neurotransmitters.
  • Triple reuptake inhibitors selectively inhibit the reuptake of multiple monoamine neurotransmitters. Specifically, they inhibit the reuptake of 5-hydroxytryptamine (serotonin), norepinephrine and dopamine by blocking the action of the serotonin transporter, norepinephrine transporter and dopamine transporter.
  • 5-hydroxytryptamine serotonin
  • norepinephrine transporter norepinephrine transporter and dopamine transporter.
  • triple reuptake inhibitors under investigation for use in the treatment of a variety of conditions including depression, anxiety, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, schizophrenia and allied disorders,addiction, obesity, tic disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, chronic pain and Alzheimer's disease.
  • ADHD attention deficit hyperactivity disorder
  • l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is a triple reuptake inhibitor currently under investigation. It exhibits chirality and has two enantiomers. Enantiomers may have the same or different effects on biological entities and many pharmaceutical agents are sold as racemates even though the desired or any pharmacological activity resides in only one enantiomer. For example, the S(+)- methacholine enantiomer is 250 times more potent than the R(-) enantiomer. With ketamine, the (S)-enantiomer is an anesthetic, but the (R)-enantiomer is a hallucinogen. Administration of a racemic mixture of any drug can be disadvantageous in that racemic mixtures may be less
  • compositions and methods using an unbalanced triple reuptake inhibitor (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane as shown below, and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane, for the treatment of mammals, including humans, suffering from signs and symptoms of disorders generally treated with triple reuptake inhibitors including, but not limited to, depression, anxiety, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, schizophrenia and allied disorders, addiction, obesity, tic disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, chronic pain states, and Alzheimer's disease.
  • ADHD attention deficit hyperactivity disorder
  • Unbalanced as used herein refers to the relative effects on each of the monoamine transporters. In this case reference is made to a triple reuptake inhibitor with the most activity against the serotonin transporter, half as much to the norepinephrine transporter and one eighth to the dopamine transporter. In contrast, a balanced triple reuptake inhibitor would have similar activity against each of the three monoamine transporters.
  • (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents as used herein are substantially free of the corresponding (-) enantiomer, (-)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1. OJhexane.
  • (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .OJhexane exists in at least three polymorphic forms, labeled herein polymorphs A, B and C.
  • the polymorphs may be used in pharmaceutical compositions in combination or in forms that are substantially free of one or more of the other polymorphic forms.
  • (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.OJhexane may furthermore be in the form of pharmaceutically acceptable active salts, glycosylated derivatives, metabolites, solvates, hydrates and/or prodrugs.
  • pharmaceutically acceptable active salts for example, many pharmacologically active organic compounds regularly crystallize incorporating second, foreign molecules, especially solvent molecules, into the crystal structure of the principal pharmacologically active compound to form pseudopolymorphs.
  • the second molecule is a solvent molecule, the pseudopolymorphs can also be referred to as solvates.
  • pharmaceutically acceptable forms may include inorganic and organic acid addition salts such as
  • compositions and coordinate treatment means using additional or secondary psychotherapeutic agents in combination with (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents including (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane.
  • Suitable secondary psychotherapeutic agents in combination with (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents including (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, and pharmaceutically acceptable active salts, polymorphs, glycosyl
  • psychotherapeutic drugs for use in the compositions and methods herein include, but are not limited to, drugs from the general classes of anti-convulsant, mood-stabilizing, antipsychotic, anxiolytic, benzodiazepines, calcium channel blockers, anti-inflammatories, and antidepressants.
  • drugs from the general classes of anti-convulsant include, but are not limited to, drugs from the general classes of anti-convulsant, mood-stabilizing, antipsychotic, anxiolytic, benzodiazepines, calcium channel blockers, anti-inflammatories, and antidepressants.
  • antidepressants include, for example, tri-cyclic antidepressants (TCAs), specific monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, selective norepinephrine or noradrenaline reuptake inhibitors, selective dopamine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, multiple monoamine reuptake inhibitors, monoamine oxidase inhibitors, atypical antidepressants, atypical antipsychotics, anticonvulsants, or opiate agonists.
  • TCAs tri-cyclic antidepressants
  • (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.Ojhexane agents ((+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.OJhexane, and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) are effective in treating, preventing, alleviating, or moderating disorders affected by monoamine neurotransmitters or biogenic amines, specifically disorders that are alleviated by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake.
  • compositions of the present invention may increase monoamine neurotransmitter levels and/or selectively inhibit reuptake of monoamine neurotransmitters and/or biogenic amines.
  • norepinephrine side effects such as elevated heart rate, increased blood pressure, gastrointestinal (nausea/vomiting and constipation/diarrhea) effects, dry mouth, insomnia, anxiety, and hypomania seen in similar dosages of balanced triple reuptake inhibitors or unbalanced triple reuptake inhibitors with different inhibition ratios.
  • compositions herein are also unexpectedly useful in the treatment of individuals who have previously been treated one or more times for disorders affected by monoamine neurotransmitters, particularly depression.
  • (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agents have shown unexpected efficacy in the treatment of individuals who have been refractory to previous treatments for disorders affected by monoamine neurotransmitters, i.e.
  • anti-depressants such as, but not limited to, tri-cyclic antidepressants (TCAs), specific monoamine reuptake inhibitors, selective serotonin reuptake inhibitors including citalopram, selective norepinephrine or noradrenaline reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, selective dopamine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, multiple monoamine reuptake inhibitors, monoamine oxidase inhibitors, atypical antidepressants, atypical antipsychotics, anticonvulsants, ant-inflammatories or opiate agonists.
  • TCAs tri-cyclic antidepressants
  • specific monoamine reuptake inhibitors selective serotonin reuptake inhibitors including citalopram, selective norepinephrine or noradrenaline reuptake inhibitors, serotonin-norepinep
  • refractory individuals may have failed to respond or failed to respond sufficiently to a previous treatment.
  • a refractory individual may have treatment resistant depression.
  • a refractory individual may have responded to the initial treatment, but not succeed in entering remission from the treatment.
  • refractory individuals may have been unable to continue taking the medication due to intolerance of the medication including side effects such as, but not limited to, sexual dysfunction, weight gain, insomnia, dry mouth, constipation, nausea and vomiting, dizziness, memory loss, agitation, anxiety, sedation, headache, urinary retention, or abdominal pain.
  • Unsatisfactory or failed responses may be determined by any means generally used, including patient self-reporting, clinical observation and depression rating scales.
  • compositions comprising (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents including (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.OJhexane and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane in effective amounts will be effective to improve an individual's score on a depression rating scale such as, but not limited to, Montgomery Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Depression (HAMD- 17), the Clinical Global Impression-Severity Scale (CG1-S) and the Clinical Global Impression-Improvement Scale (CGI-1).
  • MADRS Montgomery Asberg Depression Rating Scale
  • HAMD- 17 Hamilton Rating Scale for Depression
  • administering will be sufficient to place an individual into remission.
  • Remission may be measured by any of a variety of ways, for example, remission from depression may be determined with a MADRS score of ⁇ 12, HAMD-17 score of ⁇ 7 or CGI-S score of ⁇ 2.
  • a dosage form has been developed for the sustained or extended release delivery of an active ingredient of (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.
  • OJhexane agents including (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane in effective amounts to treat disorders affected by monoamine neurotransmitters, particularly depression, for a long period of time.
  • the active ingredient can be administered in an effective amount to provide sustained relief of depression by utilizing a dosage regimen of from about 25 mg. to about 200 mg. once or twice daily in an oral unit dosage form containing as its composition this amount of the active ingredient, 30% to 50% by weight of the composition of a pharmaceutically acceptable carrier, and from about 15% to 45% by weight of the composition of a hydroxypropyl methyl cellulose slow release matrix, with the carrier and the active ingredient dispersed in the slow release matrix.
  • Figure 1 is a graph showing a decrease in patients' scores on the
  • HAM-D Hamilton Depression Rating Scale
  • n modified intent-to-treat
  • CG1-I Clinical Global Impression - Improvement Scale
  • CGI-S Clinical Global Impression-Severity
  • Figure 5 is a graph showing that treatment with EB-1010 ((+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane) resulted in significantly greater remission rates than treatment with placebo as measured by the Clinical Global Impressions-Severity (CGI- S) scale (Last Observation Carried Forward (LOCF)).
  • CGI- S Clinical Global Impressions-Severity
  • LOCF Long Observation Carried Forward
  • Figure 6 is a graph showing that treatment with EB- 1010 ((+)-l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane) resulted in statistically significant
  • Figure 7 is a graph showing that Derogatis Interview for Sexual
  • DISF-SR Functioning-Self Report
  • Described herein is an enantiomer of ( ⁇ )-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane which provides therapeutic efficacy in the treatment of conditions affected by monoamine neurotransmitters including, but not limited to, depression, anxiety, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, schizophrenia and allied disorders, obesity, tic disorders, addiction, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, chronic pain and
  • Alzheimer's disease Further described herein are coordinate treatment methods and combined drug compositions, dosage forms, packages, and kits for preventing or treating conditions affected by monoamine neurotransmitters including, but not limited to, depression.
  • ( ⁇ )-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is a triple reuptake inhibitor (TRI), or serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI). It was previously described in U.S. Patent No. 4,435,419 to Epstein et al for use as an
  • antidepressant It possesses a desirable unbalanced triple monoamine uptake inhibition ratio, with highly potent serotonin reuptake inhibition and lesser norepinephrine and, particularly, dopamine reuptake inhibition in a ratio of ⁇ 1 :2:8, respectively (IC50 values of 12, 23, and 96 nM, respectively in human embryonic kidney (HEK) 293 cells expressing the corresponding human recombinant transporters for [3H]serotonin,
  • an unbalanced triple reuptake inhibitor may provide a lower side effect profile than a balanced triple reuptake inhibitor and allow for higher concentrations of an unbalanced inhibitor such as (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane to be used without incurring the dopaminergic and/or noradrenergic side effects frequently seen in the use of balanced triple reuptake inhibitors or unbalanced triple reuptake inhibitors that have different inhibition ratios.
  • an unbalanced inhibitor such as (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane
  • compositions and methods using (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1 .0]hexane as shown below, and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .Ojhexane, for the treatment of mammals, including humans, suffering from signs and symptoms of disorders generally treated with triple reuptake inhibitors including, but not limited to, depression, anxiety, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, schizophrenia and allied disorders, addiction, obesity, tic disorders, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, chronic pain and Alzheimer's disease.
  • ADHD attention deficit hyperactivity disorder
  • (+)- 1 -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane is particularly useful in treating depression in those who have been previously treated for a condition affected by monoamine neurotransmitters, specifically those who have failed an initial course of antidepressant therapy, such as selective serotonin reuptake inhibitor therapy.
  • (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be prepared by any means generally used for preparing such a compound.
  • the (+) enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • An efficient means of preparing (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane is described in U.S. Patent Application No.1 1/740,667, incorporated herein by reference in its entirety.
  • (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be isolated from ( ⁇ )-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane by any means generally used.
  • Methods for preparing ( ⁇ )- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane may be found, for example, in U.S. Patent No. 4,435,419 and U.S. Patent Application Nos. 10/920,748, 1 1/205,956; 12/208,284; 12/428,399 each of which is incorporated herein by reference in their entirety.
  • the enantiomers of ( ⁇ )- l - (3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane may be separated by any means generally used to separate enantiomeric forms including, but not limited to,
  • the compositions refer to an enantiomeric excess greater than 80%, preferably greater than 90%, more preferably greater than 95%, and most preferably greater than 98% of the (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane as determined by configuration and/or optical activity.
  • the compositions contain no more than about 5% w/w of the corresponding (-) enantiomer, more preferably no more than about 2%, more preferably no more than about 1% w/w of the corresponding (-) enantiomer of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.OJhexane.
  • (+)-l -(3, 4-dichlorophenyl)-3-azabicyclo[3.1. OJhexane is polymorphic.
  • the present invention comprises use of one or more polymorphic forms of (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1. OJhexane, specifically forms A, B and C as disclosed in U.S. Patent Application Nos. 1 1/205,956, 12/208, 284 and 12/428,399 incorporated herein by reference in their entirety.
  • Polymorph form A may be characterized as the hemi-hydrate of acid addition salts of (+)-l -(3,4-dichlorophenyl) -3-azabicyclo[3.1.0]hexane.
  • the polymorphs of acid addition salts of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be characterized by their X-ray powder diffraction patterns (XRPD) and/or their Raman spectroscopy peaks.
  • XRPD X-ray powder diffraction patterns
  • a Bragg-Brentano instrument which includes the Shimadzu system, used for the X-ray powder diffraction pattern measurements reported herein, gives a systematic peak shift (all peaks can be shifted at a given "°2 ⁇ ” angle) which result from sample preparation errors as described in Chen et al.; J Pharmaceutical and Biomedical Analysis, 2001 ; 26, 63. Therefore, any "°2 ⁇ " angle reading of a peak value is subject to an error of about ( ⁇ ) 0.2°.
  • Table 1 shows the values for the relative intensities for peaks of the X-ray powder diffraction pattern of purified polymorph form A of the hydrochloride salt of (+)- 1 -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
  • Io represents the value of the maximum peak determined by XRPD for the sample for all "°2 ⁇ " angles
  • I represents the value for the intensity of a peak measured at a given ⁇ '°2 ⁇ " angle".
  • the angle ⁇ '°2 ⁇ " is a diffraction angle which is the angle between the incident X-rays and the diffracted X-rays.
  • Table 2 shows the relative intensities for peaks of the X- ray powder diffraction pattern of purified polymorph form B of the hydrochloride salt of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
  • Table 3 shows the values of the relative intensities of the peaks of the X-ray powder diffraction pattern of purified polymorph form C of the hydrochloride salt of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane having a crystal size of from about 10 to 40 microns.
  • polymorph form B the "°20" angles of these major peaks which characterize polymorph form B, subject to the error set forth above, are as follows: 15.58; 17.52; 21.35; 23.04; 25.43; and 30.72.
  • polymorph form C the "°2 ⁇ " angles of these major peaks which characterize polymorph form C, subject to the error set forth above, are as follows: 13.34; 17.64; 20.07; 21.32; 22.97; 24.86; 26.32; and 27.90. Any of these major peaks, either alone or in any distinguishing combination, are sufficient to distinguish a polymorph from the other polymorph forms.
  • Table 4 provides the complete patterns of the Raman peak positions with respect to the hydrochloride salts of polymorph forms A, B and C respectively. However, there are certain key peaks within these patterns which are unique to each of the hydrochloride salts of these polymorphs. Any of these key peaks, either alone or in any distinguishing combination, are sufficient to distinguish one of the polymorph forms from the other two polymorph forms.
  • These peak positions, expressed in wavenumbers (cm " ') for the hydrochloride salt of polymorph form A are: 762; 636; 921 ; 959; 1393; 1597; 2890; 2982; and 3064.
  • the characterizing peak positions expressed in wavenumbers (cm "1 ) for the hydrochloride salt of polymorph form B are: 1245; 1380; 2963; 2993; 3027; and 3066.
  • the characterizing peak positions expressed in wavenumbers (cm "1 ) for the hydrochloride salt of polymorph form C are: 1059; 1094; 1266; 1343; 1595; 2900; 2966; and 3070. Any of these key peaks, either alone or in any distinguishing combination, are sufficient to distinguish each polymorph form from the other two polymorph forms.
  • Polymorph forms A, B and C of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .0]hexane, particularly as hydrochloride acid addition salts, can each be prepared substantially free of its other enantiomeric, geometric and polymorphic isomeric forms through re-crystallization of a mixture of the A and B polymorph forms produced in accordance with prior art procedures.
  • any means generally used to separate polymorphs may be used.
  • crystallization from a mixture of A and B may be utilized.
  • the crystallization technique with regard to producing each of these polymorph forms substantially free of other polymorph forms is different.
  • polymorph form A which is the hemi- hydrate of the acid addition salt of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
  • the preferred organic solvents that can be utilized in this procedure include lower alkanol solvents such as methanol, butanol, ethanol or isopropanol as well as other solvents such as acetone, dichloromethane and tetrahydrofuran.
  • Polymorph form B is the anhydrous form of the acid addition salt of (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
  • Polymorph form B of the acid addition salt of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3, 1.0]hexane can be prepared from a solid containing polymorph form A or a mixture of polymorph forms A and B by dissolving the polymorph form A or the mixture of polymorph forms A and B, preferably as the hydrochloride salt, utilizing anhydrous conditions.
  • Polymorph form C can be prepared from either polymorph form A or polymorph form B or mixtures thereof.
  • Polymorph form C is prepared by extensive heating of either polymorph form A or polymorph form B, or mixtures thereof, at temperatures of at least 50°C, preferably from 60°C to 80°C. Heating can be continued until polymorph form C substantially free of other polymorph forms is formed.
  • mixtures containing specific percentages of the individual polymorphic forms of the acid addition salt of (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane can be obtained.
  • mixtures containing from about 10% to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85- 95% and up to 95-99%) or greater (by weight) of polymorph form A, with the remainder of the mixture being either or both polymorph form B and polymorph form C, can be prepared.
  • mixtures containing from about 10% to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85-95% and up to 95-99% or greater (by weight) of polymorph form B, with the remainder of the mixture being either or both polymorph form A and polymorph form C can be prepared.
  • mixtures containing from about 10% to about 10-20%, 20-35%, 35-50%, 50-70%, 70-85%, 85- 95% and up to 95-99%o or greater (by weight) of polymorph form C, with the remainder of the mixture being either or both polymorph form A and polymorph form B can be prepared.
  • pseudopolymorphs can also be referred to as solvates. All of these additional forms of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are likewise contemplated for use within the present invention.
  • the polymorph forms A, B and C of the present invention can be prepared as acid addition salts formed from an acid and the basic nitrogen group of (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3. 1.0]hexane.
  • Suitable acid addition salts are formed from acids, which form non-toxic salts, examples of which are hydrochloride, hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate.
  • Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts.
  • the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, ⁇ , ⁇ '-dibenzylethylenediamine salt and the like; organic acid salts such as acetate, citrate, lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and the like; and amino acid salts such as arginate, asparginate, glutamate, tartrate, gluconate and the like.
  • hydrochloride salt formed with hydrochloric acid is an exemplary useful salt.
  • (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents ((+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane and pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) are effective in treating a variety of conditions including, but not limited to, depression, anxiety, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, schizophrenia and allied disorders, addiction, obesity, tic disorders, Parkinson's disease, ADHD, chronic pain and Alzheimer's disease.
  • combinatorial formulations are provided that use substantially pure (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane alone or in combination with other psychotherapeutic drugs to modulate, prevent, alleviate, ameliorate, reduce or treat symptoms or conditions influenced by monoamine neurotransmitters or biogenic amines.
  • Subjects amenable to treatment according to the invention include mammalian subjects, including humans, suffering from or at risk for any of a variety of conditions including, but not limited to, depression, anxiety, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, schizophrenia and allied disorders, obesity, tic disorders, addiction, ADHD, Parkinson's disease, chronic pain and Alzheimer s disease.
  • pharmaceutically acceptable active salt, polymorph, glycosylated derivative, metabolite, solvate, hydrate, and/or prodrug of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be administered alone or in combination with one or more other psychotherapeutic drugs including, but not limited to, drugs from the general classes of anti-convulsant, mood-stabilizing, anti-psychotic, anxiolytic, benzodiazepines, calcium channel blockers, and antidepressants. (See, e.g., R J. Baldessarini in Goodman & Oilman's The
  • (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable active salt, polymorph, glycosylated derivative, metabolite, solvate, hydrate, and/or prodrug of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane may be administered in combination with an anti-inflammatory.
  • the secondary therapeutic and/or psychotherapeutic drug is administered concurrently or sequentially with (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable active salt, polymorph, glycosylated derivative, metabolite, solvate, hydrate, and/or prodrug of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane to treat or prevent one or more symptoms of the targeted disorder.
  • (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is administered concurrently or sequentially with (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, or a pharmaceutically acceptable active salt, polymorph, glycosylated derivative, metabolite, solvate, hydrate, and/or prodrug of (+)-l -(3,4-
  • the additional therapeutic and/or psychotherapeutic agent and (+)- l-(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable active salt, polymorph, glycosylated derivative, metabolite, solvate, hydrate, and/or prodrug of (+)-l- (3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane may be combined in a single composition or combined dosage form.
  • the combinatorial ly effective additional therapeutic and/or psychotherapeutic drug and (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .Ojhexane agents may be administered at the same time in separate dosage forms.
  • the additional therapeutic and/or psychotherapeutic agent and (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent may each exert biological activities and therapeutic effects over different time periods, although a distinguishing aspect of all coordinate treatment methods of the invention is that treated subjects exhibit positive therapeutic benefits.
  • (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane a pharmaceutically acceptable active salt, polymorph, glycosylated derivative, metabolite, solvate, hydrate, and/or prodrug of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or the coordinate treatment method or combinatorial drug composition of the invention to suitable subjects will yield a reduction in one or more target symptom(s) associated with the selected disorder or development of the disorder by at least 2%, 5%, 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95% or greater, compared to placebo-treated or other suitable control subjects.
  • Comparable levels of efficacy are contemplated for the entire range of disorders described herein, including all contemplated neurological and psychiatric disorders, and related conditions and symptoms, for treatment or prevention using the compositions and methods of the invention. These values for efficacy may be determined by comparing accepted therapeutic indices or clinical values for particular test and control individuals over a course of treatment/study, or more typically by comparing accepted therapeutic indices or clinical values between test and control groups of individuals using standard human clinical trial design and implementation.
  • prevention and preventing when referring to a disorder or symptom, refers to a reduction in the risk or likelihood that a mammalian subject will develop said disorder, symptom, condition, or indicator after treatment according to the invention, or a reduction in the risk or likelihood that a mammalian subject will exhibit a recurrence or relapse of said disorder, symptom, condition, or indicator once a subject has been treated according to the invention and cured or restored to a normal state (e.g., placed in remission from a targeted disorder).
  • treatment or “treating,” when referring to the targeted disorder, refers to inhibiting or reducing the progression, nature, or severity of the subject condition or delaying the onset of the condition.
  • compounds disclosed herein are administered to mammalian subjects, for example a human patient, to treat or prevent one or more symptom(s) of a disorder alleviated by inhibiting dopamine reuptake, and/or norepinephrine reuptake, and/or serotonin reuptake.
  • treatment or “treating” refers to amelioration of one or more symptom(s) of a disorder, whereby the symptom(s) is/are alleviated by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake.
  • treatment refers to an amelioration of at least one measurable physical parameter associated with a disorder.
  • treatment refers to inhibiting or reducing the progression or severity of a disorder (or one or more symptom(s) thereof) alleviated by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake, e.g., as discerned based on physical, physiological, and/or psychological parameters.
  • treatment refers to delaying the onset of a disorder (or one or more symptom(s) thereof) alleviated by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake.
  • an "effective amount,” “therapeutic amount,” “therapeutically effective amount,” or “effective dose” of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) and/or an additional psychotherapeutic agent as used herein means an effective amount or dose of the active compound as described herein sufficient to elicit a desired pharmacological or therapeutic effect in a human subject.
  • antidepressant therapeutic agents these terms most often refer to a measureable, statistically significant reduction in an occurrence, frequency, or severity of one or more symptom(s) of a specified disorder, including any combination of neurological and/or psychological symptoms, diseases, or conditions, associated with or caused by the targeted disorder and/or reduction in the development of depression in a target population.
  • Therapeutic efficacy can alternatively be demonstrated by a decrease in the frequency or severity of symptoms associated with the treated condition or disorder, or by altering the nature, occurrence, recurrence, or duration of symptoms associated with the treated condition or disorder.
  • psychotherapeutic drugs and (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents include pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3. l .OJhexane) within the invention can be readily determined by ordinarily skilled artisans following the teachings of this disclosure and employing tools and methods generally known in the art, often based on routine clinical or patient-specific factors.
  • Efficacy of the coordinate treatment methods and drug compositions of the invention will often be determined by use of conventional patient surveys or clinical scales to measure clinical indices of disorders in subjects.
  • the methods and compositions of the invention will yield a reduction in one or more scores or selected values generated from such surveys or scales completed by test subjects (indicating for example an incidence or severity of a selected disorder), by at least 5%, 10%, 20%, 30%, 50% or greater, up to a 75-90%), or 95% compared to correlative scores or values observed for control subjects treated with placebo or other suitable control treatment.
  • the methods and compositions of the invention will yield a stable or minimally variable change in one or more scores or selected values generated from such surveys or scales completed by test subjects. More detailed data regarding efficacy of the methods and compositions of the invention can be determined using alternative clinical trial designs.
  • Useful patient surveys and clinical scales for comparative measurement of clinical indices of psychiatric disorders in subjects treated using the methods and compositions of the invention can include any of a variety of widely used and well known surveys and clinical scales.
  • these useful tools are the Mini International Neuropsychiatric Interview ⁇ (MINI) (Sheehan et al., 1998); Clinical Global Impression scale (CGI) (Guy, W., ECDEU Assessment Manual for Psychopharmacology, DHEW Publication No. (ADM) 76-338, rev. 1976); Clinical Global Impression Severity of Illness (CGI-S) (Guy, 1976); Clinical Global Impression Improvement (CGI-I) (Guy, et al. 1976); Beck
  • BDI Depression Inventory
  • RHRSD Revised Hamilton Rating Scale for Depression
  • MDI Major Depressive Inventory
  • CDI Children's Depression Index
  • HDRS Hamilton Depression Rating Scale ⁇
  • the methods and compositions of the invention will yield a reduction in one or more scores or values generated from these clinical surveys (using any single scale or survey, or any combination of one or more of the surveys described above) by at least 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95%) compared to correlative scores or values observed for control subjects treated with placebo or other suitable control treatment.
  • the methods and compositions of the invention will yield a stabilization or diminished change in the scores or values generated from these clinical surveys.
  • administration of the pharmaceutical compositions contemplated herein will be sufficient to place an individual into remission for a condition, specifically depression.
  • Remission from depression may be measured by any of a variety of ways, for example with patient surveys and clinical scales.
  • An indication of remission for example would be scores on the MADRS ⁇ 12, HAMD-17 ⁇ 7 or CGI-S ⁇ 2.
  • the unbalanced reuptake inhibition profile of (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3. l .OJhexane allows for higher doses of (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane to be used without incurring the side effects that limit the effectiveness of balanced triple reuptake inhibitors such as GS 372475.
  • (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is well tolerated and has a similar adverse event profile as placebo.
  • (+)- l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane use also did not lead to the noradrenergic side effects such as significantly elevated heart rate and increased systolic and diastolic blood pressure seen with GSK37425 (See Tables 1 1 and 12 and Graff, 2009) or dopaminergic side effects such as nausea, vomiting, and hypomania.
  • (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane will have substantially fewer dopaminergic or noradrenergic side effects than use of similar doses of balanced triple reuptake inhibitors.
  • the use of substantially pure (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1 .0]hexane will reduce adverse effects including side effects by 1 %, 3%, 10%, 20%, 30%, 50% or greater, up to a 75%, 80%, 90%, or 95% or greater over use of a balanced triple reuptake inhibitor.
  • (+)- l - (3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane will have fewer dopaminergic or noradrenergic side effects than triple reuptake inhibitors with higher rates of inhibition for dopamine or noradrenaline reuptake.
  • (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane will result in reuptake inhibition of the 5-HT transporter in individuals of about 1 0%, 15 %, 20%, 30%, 50% or greater, up to a 75%, 80%, 90%, or 95% or greater than reuptake inhibition of the NE transporter or the DA transporter.
  • reuptake inhibition of the 5HT transporter will be more than about 100% greater than reuptake inhibition of the DA or NE transporter in a particular individual.
  • reuptake inhibition of the 5-HT transporter w ill be two, three, four, five, six, seven or eight fold greater than the reuptake inhibition of the DA transporter. In other
  • reuptake inhibition of the 5-HT transporter will be one and half or twice that of the NE transporter.
  • Reuptake inhibition of the NE transporter may be about 10%, 15%, 20%, 30%, 50% or greater, up to a 75%, 80%, 90%, or 95% or greater than reuptake inhibition of the DA transporter.
  • reuptake inhibition of the NE transporter may be two, three or four times greater than the reuptake inhibition of the DA transporter.
  • (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane will result in binding of the 5-HT transporter in in dividuals at levels of about 10%, 15 %, 20%, 30%), 50% or greater, up to a 75%, 80%, 90%, or 95% or greater than binding of the NE transporter or the DA transporter.
  • binding of the 5-HT transporter will be more than about 100% greater than the binding of the NE transporter or the DA transporter.
  • binding of the 5-HT transporter will be two, three, four, five, six, seven or eight fold greater than the binding of the DA transporter.
  • binding of the 5-HT transporter will be one and half or twice that of the NE transporter. Binding of the NE transporter may be about 10%, 15%, 20%, 30%, 50% or greater, up to a 75%, 80%, 90%, or 95% or greater than binding of the DA transporter in treated individuals. In some embodiments, binding of the NE transporter may be two, three or four times greater than binding of the DA transporter in an individual.
  • the relative binding as determined by K, of 5-HT may be slightly higher, substantially higher, or significantly higher than the binding of the DA transporter or NE transporter alone or in combination.
  • pharmaceutically acceptable active salts, polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .0]hexane are useful for treating or preventing endogenous disorders alleviated by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake.
  • Such disorders include, but are not limited to, attention-deficit disorder, depression, anxiety disorder, panic disorder, post-traumatic stress disorder, obsessive compulsive disorder, schizophrenia and allied disorders, anxiety, obesity, tic disorders, Parkinson's disease, tic disorders, Parkinson's disease, chronic pain, attention deficit hyperactivity disorder (ADHD) and addictive and substance abuse disorders.
  • ADHD attention deficit hyperactivity disorder
  • disorders alleviated by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake are not limited to the specific disorders described herein, and the compositions and methods of the invention will be understood or readily ascertained to provide effective treatment agents for treating and/or preventing a wide range of additional disorders and associated symptoms.
  • the compounds of the invention will provide promising candidates for treatment and/or prevention of depression, attention deficit hyperactivity disorder and related symptoms, as well as forms and symptoms of alcohol abuse, drug abuse, cognitive disorders, obsessive compulsive behaviors, learning disorders, reading problems, gambling addiction, manic symptoms, phobias, panic attacks, oppositional defiant behavior, conduct disorder, academic problems in school, smoking, abnormal sexual behaviors, schizoid behaviors, somatization, depression, sleep disorders, general anxiety, stuttering, and tic disorders (See, for example, U.S. Pat. No. 6, 132,724).
  • Cognitive disorders for treatment and/or prevention according to the invention include, but are not limited to, Attention- Deficit/Hyperactivity Disorder, Predominately Inattentive Type; Attention- Deficit/Hyperactivity Disorder, Predominately Hyperactivity-Impulsive Type; Attention- Deficit/Hyperactivity Disorder, Combined Type; Attention-Deficit/Hyperactivity Disorder not otherwise specified (NOS); Conduct Disorder; Oppositional Defiant Disorder; and Disruptive Behavior Disorder not otherwise specified (NOS).
  • Depressive disorders amenable for treatment and/or prevention according to the invention include, but are not limited to, Major Depressive Disorder, Recurrent; Dysthymic Disorder;
  • Addictive disorders amenable for treatment and/or prevention employing the methods and compositions of the invention include, but are not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, and opioid-related disorders, all of which are further sub-classified as listed below.
  • Substance abuse disorders include, but are not limited to alcohol-related disorders, nicotine-related disorders, Amphetamine- related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-use disorders, inhalant-related disorders, and opioid-related disorders.
  • novel compounds of the present invention are thus useful in a wide range of veterinary and human medical applications, in particular for treating and/or preventing a wide array of disorders and/or associated symptom(s) alleviated by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake.
  • the unbalanced serotonin-norepinephrine-dopamine reuptake inhibition ratio of -1 :2:8, respectively of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane provides several advantages in comparison to a balanced triple reuptake inhibitor and allows for higher dosages of (+)- 1 -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane to be used without triggering the dopaminergic or norepinephrine side effects such as elevated heart rate, increased blood pressure, nausea, vomiting, insomnia and hypomania seen in similar dosages of balanced triple reuptake inhibitors.
  • compositions of the present invention are effective in the treatment of those who have been previously treated for disorders affected by monoamine neurotransmitters such as depression.
  • the compositions are additionally effective in the treatment of those who have had refractory experiences with prior treatments, i.e.
  • monoamine neurotransmitters such as anti-depressants including, but not limited to, tri-cyclic antidepressants (TCAs), specific monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, selective norepinephrine or noradrenaline reuptake inhibitors, selective dopamine reuptake inhibitors, serotonin- norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, multiple monoamine reuptake inhibitors, monoamine oxidase inhibitors, atypical antidepressants, atypical antipsychotics, anticonvulsants, or opiate agonists.
  • TCAs tri-cyclic antidepressants
  • specific monoamine reuptake inhibitors selective serotonin reuptake inhibitors, selective norepinephrine or noradrenaline reuptake inhibitors, selective dopamine reuptake inhibitors, serotonin- norepineph
  • refractory individuals may have failed to respond or failed to respond sufficiently to a previous treatment.
  • a refractory individual may have treatment resistant depression.
  • a refractory individual may have responded to the initial treatment, but not succeed in entering remission from the treatment.
  • refractory individuals may have been unable to continue taking the medication due to intolerance of the medication including side effects such as, but not limited to, sexual dysfunction, weight gain, insomnia, dry mouth, constipation, nausea and vomiting, dizziness, memory loss, agitation, anxiety, sedation, headache, urinary retention, or abdominal pain.
  • combinatorial formulations and coordinate administration methods employ an effective amount of a (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (or a pharmaceutically effective salt, solvate, hydrate, polymorph, or prodrug thereof), and one or more additional active agent(s) that is/are combinatorially formulated or coordinately administered with the compound of the invention— yielding a combinatorial formulation or coordinate administration method that is effective to modulate, alleviate, treat or prevent a targeted disorder, or one or more symptom(s) thereof, in a mammalian subject.
  • Exemplary combinatorial formulations and coordinate treatment methods in this context comprise a therapeutic compound of the invention in combination with one or more additional or adjunctive treatment agents or methods for treating the targeted disorder or symptom(s), for example one or more antidepressant or anxiolytic agent(s) and/or therapeutic method(s).
  • the compounds disclosed herein can be used in combination therapy with at least one other therapeutic agent or method.
  • compounds of the invention can be administered concurrently or sequentially with administration of a second therapeutic agent, for example a second agent that acts to treat or prevent the same, or different, disorder or symptom(s) for which the compound of the invention is administered.
  • the compound of the invention and the second therapeutic and/or psychotherapeutic agent can be combined in a single composition or administered in different compositions.
  • the second therapeutic and/or psychotherapeutic agent may also be effective for treating and/or preventing a disorder or associated symptom(s) by inhibiting dopamine and/or norepinephrine and/or serotonin reuptake.
  • the coordinate administration may be done simultaneously or sequentially in either order, and there may be a time period while only one or both (or all) active therapeutic agents, individually and/or collectively, exert their biological activities and therapeutic effects.
  • the compound of the invention exerts at least some detectable therapeutic activity toward alleviating or preventing the targeted disorder or symptom(s), as described herein, and/or elicit a favorable clinical response, which may or may not be in conjunction with a secondary clinical response provided by the secondary therapeutic agent.
  • the coordinate administration of a compound of the invention with a secondary therapeutic agent as contemplated herein will yield an enhanced therapeutic response beyond the therapeutic response elicited by either or both the compound of the invention and/or secondary therapeutic agent alone.
  • combination therapy involves alternating between administering a compound of the present invention and a second therapeutic agent (i.e., alternating therapy regimens between the two drugs, e.g., at one week, one month, three month, six month, or one year intervals).
  • alternating therapy regimens between the two drugs, e.g., at one week, one month, three month, six month, or one year intervals.
  • Alternating drug regimens in this context will often reduce or even eliminate adverse side effects, such as toxicity, that may attend long- term administration of one or both drugs alone.
  • the additional psychotherapeutic agent is an antidepressant drug, which may include, for example, any species within the broad families of tri-cyclic antidepressants (TCAs) including, but not limited to, amitriptyline, imipramine, clomipramine, or desipramine; specific monoamine reuptake inhibitors; selective serotonin reuptake inhibitors (SSRIs) including, but not limited to, escitalopram, fluoxetine, fluvoxamine, sertraline, citalopram, vilazodone, and paroxetine; selective norepinephrine or noradrenaline reuptake inhibitors including but not limited to, tertiary amine tricyclics such as amitriptyline, clomipramine, doxepin, imipramine, (+)- trimipramine, and secondary amine tricyclics including amoxapine, atomoxetine, desipramine, maprotiline,
  • TCAs tri-cyclic antide
  • the additional psychotherapeutic agent may additionally include atypical antipsychotics including, but not limited to, aripiprazole, ziprasidone, risperidone, quetiepine, or olanzapine or anticonvulsants including but not limited to gabopentin, pregabalin, lamotrigine, carbamazepine, oxcarbazepine, valproate, levetriacetam, and topiramate.
  • Additional psychotherapeutic agents may additionally include opiate agonists including, but not limited to, buprenorphine, methadone and LAAM.
  • Exemplary anxiolytics include, but are not limited to, buspirone, ben2:odiazepines, selective serotonin reuptake inhibitors, azapirones, barbiturates, hydroxyzine, and pregabalin.
  • the secondary psychotherapeutic agent is an anti- attention-deficit-disorder treatment agent.
  • useful anti -attention-deficit- disorder agents for use in these embodiments include, but are not limited to,
  • methylphenidate methylphenidate
  • dextroamphetamine and other amphetamines tricyclic antidepressants, such as imipramine, desipramine, and nortriptyline
  • psychostimulants such as pemoline and deanol.
  • the secondary psychotherapeutic agent is an anti- addictive-disorder or anti-substance abuse agent.
  • useful anti-addictive- disorder agents include, but are not limited to, tricyclic antidepressants; glutamate antagonists, such as ketamine HCl, dextromethorphan, dextrorphan tartrate and dizocilpine (MK801 ); degrading enzymes, such as anesthetics and aspartate antagonists; GABA agonists, such as baclofen and muscimol HBr; reuptake blockers; degrading enzyme blockers; glutamate agonists, such as D-cycIoserine, carboxyphenylglycine, L- glutamic acid, and cis-piperidine-2,3-dicarboxylic acid; aspartate agonists; GABA antagonists such as gabazine (SR-9553 1 ),
  • the secondary therapeutic agent is an appetite suppressant.
  • useful appetite suppressants include, but are not limited to, fenfluramine, phenylpropanolamine, bupropion, and mazindol.
  • the secondary therapeutic agent is an anti- Parkinson's-disease agent.
  • useful anti-Parkinson's-disease agents include, but are not limited to dopamine precursors, such as levodopa, L-phenylalanine, and L- tyrosine; neuroprotective agents; dopamine agonists; dopamine reuptake inhibitors;
  • anticholinergics such as amantadine and memantine; and 1,3,5-trisubstituted
  • adamantanes such as l -amino-3,5-dimethyl-adamantane.
  • the secondary therapeutic agent is an anti- inflammatory agent.
  • useful anti -inflammatory agents included, but are not limited to celecoxib, ibuprofen, ketoprofen, naproxen sodium, piroxicam, sulindac, aspirin, and nabumetone.
  • Suitable routes of administration for a (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent include, but are not limited to, oral, buccal, nasal, aerosol, topical, transdermal, transdermal patch, mucosa], injectable, slow release, controlled release, iontophoresis, sonophoresis, and other conventional delivery routes, devices and methods. Injectable delivery methods are also contemplated, including but not limited to, intravenous, intramuscular,
  • intraperitoneal intraspinal, intrathecal, intracerebroventricular, intraarterial, and subcutaneous injection.
  • Suitable effective unit dosage amounts of a (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent may range from about 5 to about 1800 mg, about 10 to about 1800 mg, 25 to about 1800 mg, about 50 to about 1000 mg, about 75 to about 900 mg, about 100 to about 750 mg, or about 150 to about 500 mg.
  • the effective dosage will be selected within narrower ranges of, for example, about 5 to about 10 mg, 10 to about 25 mg, about 30 to about 50 mg, about 10 to about 300 mg, about 25 to about 300 mg, about 75 to about 100 mg, about 100 to about 250 mg, or about 250 to about 500 mg.
  • These and other effective unit dosage amounts may be administered in a single dose, or in the form of multiple daily, weekly or monthly doses, for example in a dosing regimen comprising from 1 to 5, or 2-3, doses administered per day, per week, or per month.
  • dosages of about 10 to about 25 mg, about 30 to about 50 mg, about 25 to about 150, about 75 to about 100 mg, about 100 to about 250 mg, or about 250 to about 500 mg are administered one, two, three, or four times per day.
  • dosages of about 50-75 mg, about 100-200 mg, about 250-400 mg, or about 400-600 mg are administered once or twice daily.
  • dosages are calculated based on body weight, and may be administered, for example, in amounts from about 0.5 mg/kg to about 20 mg/kg per day, 1 mg/kg to about 15 mg kg per day, 1 mg/kg to about 10 mg/kg per day, 2 mg/kg to about 20 mg/kg per day, 2 mg/kg to about 10 mg/kg per day or 3 mg/kg to about 15 mg/kg per day.
  • a (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .0]hexane agent including pharmaceutically acceptable active
  • An effective dose or multi-dose treatment regimen for the compounds of the invention will ordinarily be selected to approximate a minimal dosing regimen that is necessary and sufficient to substantially prevent or alleviate one or more symptom(s) of a neurological or psychiatric condition in the subject, as described herein.
  • a (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3. 1.0]hexane agent following administration of a (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3. 1.0]hexane agent
  • test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75- 90%, or 95% or greater, reduction, in one or more symptoms associated with a targeted monoamine neurotransmitter influenced disorder or other neurological or psychiatric condition, compared to placebo-treated or other suitable control subjects.
  • Pharmaceutical dosage forms of a compound of the present invention may optionally include excipients recognized in the art of pharmaceutical compounding as being suitable for the preparation of dosage units as discussed above.
  • excipients include, without intended limitation, binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents and other conventional excipients and additives.
  • Pharmaceutical dosage forms of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane may include inorganic and organic acid addition salts.
  • the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, ⁇ , ⁇ '- dibenzylethylenediamine salt and the like; organic acid salts such as acetate, citrate, lactate, succinate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the like; sulfonates such as methanesulfonate, benzenesulfonate, benz
  • OJhexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
  • An additional psychotherapeutic compound and/or (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1 .OJhexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .OJhexane) of the present invention will often be formulated and administered in an oral dosage form, optionally in
  • pharmaceutical formulation technology include, but are not limited to, microcrystalline cellulose, lactose, sucrose, fructose, glucose dextrose, or other sugars, di-basic calcium phosphate, calcium sulfate, cellulose, methylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, or other sugar alcohols, dry starch, dextrin, maltodextrin or other polysaccharides, inositol, or mixtures thereof.
  • Exemplary unit oral dosage forms for use in this invention include tablets and capsules, which may be prepared by any conventional method of preparing pharmaceutical oral unit dosage forms can be utilized in preparing oral unit dosage forms.
  • Oral unit dosage forms such as tablets or capsules, may contain one or more conventional additional formulation ingredients, including, but are not limited to, release modifying agents, glidants, compression aides, disintegrants, lubricants, binders, flavors, flavor enhancers, sweeteners and/or
  • Suitable lubricants include stearic acid, magnesium stearate, talc, calcium stearate, hydrogenated vegetable oils, sodium benzoate, leucine carbowax, magnesium lauryl sulfate, colloidal silicon dioxide and glyceryl monostearate.
  • Suitable glidants include colloidal silica, fumed silicon dioxide, silica, talc, fumed silica, gypsum and glyceryl monostearate.
  • Substances which may be used for coating include hydroxypropyl cellulose, titanium oxide, talc, sweeteners and colorants. The aforementioned effervescent agents and disintegrants are useful in the formulation of rapidly disintegrating tablets known to those skilled in the art.
  • effervescent agent typically an organic acid and a carbonate or bicarbonate.
  • Such rapidly acting dosage forms would be useful, for example, in the prevention or treatment of acute episodes of mania.
  • the additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.OJhexane agent can be prepared and administered in any of a variety of inhalation or nasal delivery forms known in the art.
  • Devices capable of depositing aerosolized formulations of an additional psychotherapeutic compound and/or (+)- ] -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent include pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane) of the invention in the sinus cavity or pulmonary alveoli of a patient include metered dose inhalers, nebulizers, dry powder generators, sprayers, and the like.
  • Pulmonary delivery to the lungs for rapid transit across the alveolar epithelium into the blood stream may be particularly useful in treating impending episodes of depression.
  • Methods and compositions suitable for pulmonary delivery of drugs for systemic effect are well known in the art.
  • Suitable formulations, wherein the carrier is a liquid, for administration, as for example, a nasal spray or as nasal drops, may include aqueous or oily solutions of a compound of the present invention, and any additional active or inactive ingredient(s).
  • Intranasal delivery permits the passage of active compounds of the invention into the blood stream directly after administering an effective amount of the compound to the nose, without requiring the product to be deposited in the lung.
  • intranasal delivery can achieve direct, or enhanced, delivery of the active additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane to the central nervous system.
  • intranasal administration of the compounds of the invention may be advantageous for treating disorders influenced by monoamine neurotransmitters, by providing for rapid absorption and delivery.
  • a liquid aerosol formulation will often contain an active compound of the invention combined with a dispersing agent and/or a physiologically acceptable diluent.
  • dry powder aerosol formulations may contain a finely divided solid form of the subject compound and a dispersing agent allowing for the ready dispersal of the dry powder particles. With either liquid or dry powder aerosol formulations, the formulation must be aerosolized into small, liquid or solid particles in order to ensure that the aerosolized dose reaches the mucous membranes of the nasal passages or the lung.
  • aerosol particle is used herein to describe a liquid or solid particle suitable of a sufficiently small particle diameter, e.g., in a range of from about 2-5 microns, for nasal or pulmonary distribution to targeted mucous or alveolar membranes.
  • Other considerations include the construction of the delivery device, additional components in the formulation, and particle characteristics. These aspects of nasal or pulmonary administration of drugs are well known in the art, and manipulation of formulations, aerosol ization means, and construction of delivery devices, is within the level of ordinary skill in the art.
  • compositions and methods of the invention are provided for topical administration of an additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1 .0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) of the present invention.
  • an additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1 .0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
  • Topical compositions may comprise a compound of the present invention and any other active or inactive component(s) incorporated in a dermatological or mucosal acceptable carrier, including in the form of aerosol sprays, powders, dermal patches, sticks, granules, creams, pastes, gels, lotions, syrups, ointments, impregnated sponges, cotton applicators, or as a solution or suspension in an aqueous liquid, non-aqueous liquid, oil-in-water emulsion, or water-in-oil liquid emulsion.
  • These topical compositions may comprise a compound of the present invention dissolved or dispersed in water or other solvent or liquid to be incorporated in the topical composition or delivery device.
  • transdermal route of administration such as by a transdermal patch
  • a dermal penetration enhancer known to those skilled in the art.
  • Formulations suitable for such dosage forms incorporate excipients commonly utilized therein, particularly means, e.g. structure or matrix, for sustaining the absorption of the drug over an extended period of time, for example 24 hours.
  • compositions of a compound of the present invention are provided for parenteral administration, including aqueous and non-aqueous sterile injection solutions which may optionally contain anti-oxidants, buffers, bacteriostats and/or solutes which render the formulation isotonic with the blood of the mammalian subject; aqueous and non-aqueous sterile suspensions which may include suspending agents and/or thickening agents; dispersions; and emulsions.
  • the formulations may be presented in unit- dose or multi-dose containers.
  • Pharmaceutically acceptable formulations and ingredients will typically be sterile or readily sterilizable, biologically inert, and easily administered.
  • Parenteral preparations typically contain buffering agents and preservatives, and may be lyophilized for reconstitution at the time of administration.
  • Parental formulations may also include polymers for extended release following parenteral administration. Such polymeric materials are well known to those of ordinary skill in the pharmaceutical compounding arts. Extemporaneous injection solutions, emulsions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit, daily sub-dose, as described herein above, or an appropriate fraction thereof, of the active ingredient(s).
  • the additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3. 1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) for treating disorders disclosed herein is/are administered in an extended release or sustained release formulation.
  • the sustained release composition of the formulation provides therapeutically effective plasma levels of the additional psychotherapeutic compound and/or (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane) over a sustained delivery period of approximately 8 hours or longer, or over a sustained delivery period of approximately 18 hours or longer, up to a sustained delivery period of approximately 24 hours or longer.
  • the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including
  • pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) is/are combined with a sustained release vehicle, matrix, binder, or coating material.
  • sustained release vehicle, matrix, binder, or coating material refers to any vehicle, matrix, binder, or coating material that effectively, significantly delays dissolution of the active compound in vitro, and/or delays, modifies, or extends delivery of the active compound into the blood stream (or other in vivo target site of activity) of a subject following administration (e.g., oral administration), in comparison to dissolution and/or delivery provided by an "immediate release” formulation, as described herein, of the same dosage amount of the active compound. Accordingly, the term
  • sustained release vehicle, matrix, binder, or coating material as used herein is intended to include all such vehicles, matrices, binders and coating materials known in the art as “sustained release”, “delayed release”, “slow release”, “extended release”, “controlled release”, “modified release”, and “pulsatile release” vehicles, matrices, binders and coatings.
  • the current invention comprises an oral sustained release dosage composition for administering an additional psychotherapeutic compound and/or (+)- l -(3,4-dichIorophenyl)-3-azabicyclo[3. 1 .0]hexane agent (including (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane and pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) according to the invention.
  • an additional psychotherapeutic compound and/or (+)- l -(3,4-dichIorophenyl)-3-azabicyclo[3. 1 .0]hexane agent including (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane and
  • the invention comprises a method of reducing one or more side effects that attend administration of an oral dosage form of an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including
  • pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) compound by employing a sustained release formulation.
  • an additional psychotherapeutic compound and/or (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabiicyclo[3.1.0]hexane) is provided in a sustained release oral dosage form and the dosage form is introduced into a gastrointestinal tract of a mammalian subject presenting with a disorder amenable to treatment using the subject therapeutic drug, by having the subject swallow the dosage form.
  • the method further includes releasing the active additional psychotherapeutic compound and/or (+)-l - (3,4-dichlorophenyl)-3-azabicyclo[3.1.OJhexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .OJhexane) in a sustained, delayed, gradual or modified release delivery mode into the gastrointestinal tract (e.g., the intestinal lumen) of the subject over a period of hours, during which the active additional psychotherapeutic compound and/or (+)- 1 -(3,4-dichloropheny l)-3- azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-
  • OJhexane reach(es), and is/are sustained at, therapeutic concentration(s) in a blood plasma, tissue, organ or other target site of activity (e.g., a central nervous system tissue, fluid or compartment) in the patient.
  • a blood plasma, tissue, organ or other target site of activity e.g., a central nervous system tissue, fluid or compartment
  • the side effect profile of the additional psychotherapeutic compound and/or (+)-l -(3,4-dichIorophenyl)-3-azabicyclo[3.1 When following this method, the side effect profile of the additional psychotherapeutic compound and/or (+)-l -(3,4-dichIorophenyl)-3-azabicyclo[3.1 .
  • OJhexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3, 4-dichIorophenyl)-3-azabicyclo[3.1 .OJhexane
  • is less than a side effect profile of an equivalent dose of the additional psychotherapeutic compound and/or (+)-l -(3, 4-dichlorophenyl)-3-azabicyclo[3.1 .OJhexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichIorophenyl)-3- azabicyclo[3.1. OJhexane) administered in an immediate release oral dosage form.
  • the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .OJhexane is/are released from the sustained release compositions and dosage forms of the invention and delivered into the blood plasma or other target site of activity in the subject at a sustained therapeutic level over a period of at least about 6 hours, often over a period of at least about 8 hours, at least about 12 hours, or at least about 18 hours, and in other embodiments over a period of about 24 hours or greater.
  • sustained therapeutic level is meant a plasma concentration level of at least a lower end of a therapeutic dosage range as exemplified herein.
  • the sustained release compositions and dosage forms will yield a therapeutic level of an additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane) following
  • a desired dosage amount e.g., 5, 10, 25, 50, 100 200, 400, 600, or 800 mg
  • a desired dosage amount e.g., 5, 10, 25, 50, 100 200, 400, 600, or 800 mg
  • a minimum plasma concentration of at least a lower end of a therapeutic dosage range as exemplified herein over a period of at least about 6 hours, at least about 8 hours, at least about 12 hours, at least about 18 hours, or up to 24 hours or longer.
  • the sustained release compositions and dosage forms will yield a therapeutic level of additional dosage amount
  • psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane) following administration to a mammalian subject in a desired dosage amount (e.g., 5, 10, 25, 50, 100, 200, 400, 600, or 800 mg) that yields a minimum plasma concentration that is known to be associated with clinical efficacy, over a period of at least about 6 hours, at least about 8 hours, at least about 12 hours, at least about 18 hours, or up to 24 hours or longer.
  • a desired dosage amount e.g., 5, 10, 25, 50, 100, 200, 400, 600, or 800 mg
  • the active additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane agent including
  • pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.
  • compositions and dosage forms of the invention is/are released from the compositions and dosage forms of the invention 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 thalamus, striatum, ventral tegmental area, 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 in 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.
  • compositions and oral dosage forms of an additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents are provided, wherein the compositions and dosage forms, after ingestion, provide a curve of concentration of the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.
  • the curve having an area under the curve (AUC) which is approximately proportional to the dose of the additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents administered, and a maximum concentration (C max ) that is proportional to the dose of the additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl!)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) administered.
  • AUC area under the curve
  • C max maximum concentration
  • the C max of the active additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .OJhexane agents provided after oral delivery of a composition or dosage form of the invention is less than about 80%, often less than about 75%, in some embodiments less than about 60%, or 50%, of a C max obtained after administering an equivalent dose of the active compound in an immediate release oral dosage form.
  • compositions and dosage forms containing the additional psychotherapeutic compound and/or (+)- 1 -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane
  • a sustained release vehicle, matrix, binder, or coating will yield sustained delivery of the active compound such that, following administration of the composition or dosage form to a mammalian treatment subject, the C max of the additional psychotherapeutic compound and/or (+)-l - (3,4-dichlorophenyl)-3-azabicyclo[3.1.
  • OJhexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) in the treatment subject is less than about 80% of a C max provided in a control subject after administration of the same amount of the additional psychotherapeutic compound and/or (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) in an immediate release formulation.
  • immediate release dosage form refers to a dosage form of an additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dich!orophenyl)-3-azabicyclo[3.1 .0]hexane) wherein the active compound readily dissolves upon contact with a liquid physiological medium, for example phosphate buffered saline (PBS) or natural or artificial gastric fluid.
  • PBS phosphate buffered saline
  • an immediate release formulation will be characterized in that at least 70% of the active compound will be dissolved within a half hour after the dosage form is contacted with a liquid physiological medium, in alternate embodiments, at least 80%), 85%o, 90% or more, or up to 100%), of the active compound in an immediate release dosage form will dissolve within a half hour following contact of the dosage form with a liquid physiological medium in an art-accepted in vitro dissolution assay.
  • a liquid physiological medium in alternate embodiments, at least 80%), 85%o, 90% or more, or up to 100%
  • These general characteristics of an immediate release dosage form will often relate to powdered or granulated compositions of an additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.
  • the immediate release dosage form may be provided in the form of a compressed tablet, granular preparation, powder, or even liquid dosage form, in which cases the dissolution profile will often be even more immediate (e.g., wherein at least 85%>-95% of the active compound is dissolved within a half hour).
  • an immediate release dosage form will include compositions wherein the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) is not admixed, bound, coated or otherwise associated with a formulation component that substantially impedes in vitro or in vivo dissolution and/or in vivo bioavailability of the active compound.
  • the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or pro
  • the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) will be provided in an immediate release dosage form that does not contain significant amounts of a sustained release vehicle, matrix, binder or coating material.
  • the term "significant amounts of a sustained release vehicle, matrix, binder or coating material” is not intended to exclude any amount of such materials, but an amount sufficient to impede in vitro or in vivo dissolution of an additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents in a formulation containing such materials by at least 5%, often at least 10%, and up to at least 15%-20% compared to dissolution of the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents when provided in a composition that is essentially free of such materials.
  • an immediate release dosage form of an additional psychotherapeutic compound and/or -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent may be any dosage form comprising the active compound which fits the FDA Biopharmaceutics Classification System (BCS) Guidance definition (see, e.g., http://www.fda.gov/cder/OPS/BCS_guidance.htm) of a "high solubility substance in a rapidly dissolving formulation.”
  • BCS Biopharmaceutics Classification System
  • an immediate release formulation of an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.
  • compositions, dosage forms and methods of the invention thus include novel tools for coordinate treatment of disorders involving monoamine neurotransmitters by providing for sustained release and/or sustained delivery of the additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) in the formulation will go into a test solution within about 30 minutes at pH 1 , pH 4.5, and pH 6.8.
  • the compositions, dosage forms and methods of the invention thus include novel tools for coordinate treatment of disorders involving monoamine neurotransmitters by providing for sustained release and/or sustained delivery of the additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.
  • sustained release and sustained delivery are evinced by a sustained, delayed, extended, or modified, in vitro or in vivo dissolution rate, in vivo release and/or delivery rate, and/or in vivo pharmacokinetic value(s) or profile.
  • the sustained release dosage forms of the present invention can take any form as long as one or more of the dissolution, release, delivery and/or pharmacokinetic property(ies) identified above are satisfied.
  • the composition or dosage form can comprise an additional psychotherapeutic compound and/or (+)- 1 -(3, 4-dichlorophenyl)-3-azabicyclo[3.1 .OJhexane agents combined with any one or combination of: a drug-releasing polymer, matrix, bead, microcapsule, or other solid drug-releasing vehicle; drug-releasing tiny timed-release pills or mini-tablets; compressed solid drug delivery vehicle; controlled release binder; multi-layer tablet or other multi-layer or multi-component dosage form; drug-releasing lipid; drug-releasing wax; and a variety of other sustained drug release materials as contemplated herein, or formulated in an osmotic dosage form.
  • the present invention thus provides a broad range of sustained release compositions and dosage forms comprising an additional psychotherapeutic agent and/or(+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1. OJhexane agent (including
  • active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.
  • OJhexane which in certain embodiments are adapted for providing sustained release of the active compound(s) following, e.g., oral administration.
  • Sustained release vehicles, matrices, binders and coatings for use in accordance with the invention include any biocompatible sustained release material which is inert to the active agent and which is capable of being physically combined, admixed, or incorporated with the active compound.
  • Useful sustained release materials may be dissolved, degraded, disintegrated, and/or metabolized slowly under physiological conditions following delivery (e.g., into a gastrointestinal tract of a subject, or following contact with gastric fluids or other bodily fluids).
  • Useful sustained release materials are typically non-toxic and inert when contacted with fluids and tissues of mammalian subjects, and do not trigger significant adverse side effects such as irritation, immune response, inflammation, or the like. They are typically metabolized into metabolic products which are biocompatible and easily eliminated from the body.
  • sustained release polymeric materials are employed as the sustained release vehicle, matrix, binder, or coating
  • sustained release vehicle see, e.g., "Medical Applications of Controlled Release,” Langer and Wise (eds.), CRC Press., Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, N.Y. ( 1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem. 23:61 ; see also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25:351 ; Howard et al, 1989, J.
  • useful polymers for co-formulating with the additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agents to yield a sustained release composition or dosage form include, but are not limited to, ethylcellulose, hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxypropylmethyl cellulose phthalate; hydroxypropylmethylcellulose acetate succinate;
  • hydroxypropylmethylcellulose acetate phthalate sodium carboxymethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate; polyoxyethylene stearates; polyvinyl pyrrolidone; polyvinyl alcohol; copolymers of polyvinyl pyrrolidone and polyvinyl alcohol; polymethacrylate copolymers; and mixtures thereof.
  • Example XII a formulation is provided for an oral unit dosage extended release tablet of an HC1 salt of (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
  • HC1 salt of (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane.
  • hydroxypropylmethyl cellulose is used as a sustained release vehicle, while microcrystalline cellulose and starch is used as a carrier.
  • formulation of a 350 mg tablet contains 100 mg of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane (HC1 salt), 105 mg of Methocel Premium CR 4 or 100, 71.5 mg Microcrystalline Cellulose, 70 mg pregelatinized starch 1500, 1 .75 mg colloidal silicon dioxide, 1 .75 mg magnesium stearate, and an optional coating, such as Opadry II White.
  • HC1 salt (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane
  • Methocel Premium CR 4 or 100 71.5 mg Microcrystalline Cellulose
  • 70 mg pregelatinized starch 1500 1 .75 mg colloidal silicon dioxide, 1 .75 mg magnesium stearate
  • an optional coating such as Opadry II White.
  • that formulation uses 30% hydroxypropylmethyl cellulose (% of total weight of the tablet ingredients).
  • an oral extended release tablet of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HC1 or other pharmaceutically acceptable salt will include an amount of about 15-45%, 25-35%, or 30% of hydroxypropyl methyl cellulose of total weight of the tablet ingredients.
  • An oral extended release tablet of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HC1 or other pharmaceutically acceptable salt will further contain about 25 to 200 mg, 50 to 150 mg, or 100 mg of an active ingredient of (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane HC1 or other pharmaceutically acceptable salt.
  • An oral extended release tablet of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane HC1 or other pharmaceutically acceptable salt will additionally contain from about 30-50% or 40% of pharmaceutically acceptable carrier.
  • Additional polymeric materials for use as sustained release vehicles, matrices, binders, or coatings within the compositions and dosage forms of the invention include, but are not limited to, additional cellulose ethers, e.g., as described in Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1 -9 (incorporated herein by reference).
  • Other useful polymeric materials and matrices are derived from copolymeric and homopolymeric polyesters having hydrolysable ester linkages. A number of these are known in the art to be biodegradable and to lead to degradation products having no or low toxicity.
  • Exemplary polymers in this context include polyglycolic acids (PGAs) and polylactic acids (PLAs), poly(DL-lactic acid-co-glycolic acid)(DL PLGA), poly(D-lactic acid-coglycolic acid)(D PLGA) and poly(L-lactic acid-co-glycolic acid)(L PLGA).
  • Other biodegradable or bioerodable polymers for use within the invention include such polymers as poly(e- caprolactone), poly(8-aprolactone-CO-lactic acid), poly(s-aprolactone-CO-glycolic acid), poly(B-hydroxy butyric acid), poly(alkyl-2-cyanoacrilate), hydrogels such as
  • Methods for preparing pharmaceutical formulations using these polymeric materials are generally known to those skilled in the art (see, e.g., Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978, incorporated herein by reference).
  • compositions and dosage forms comprise an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agents coated on a polymer substrate.
  • the polymer can be an erodible or a nonerodible polymer.
  • the coated substrate may be folded onto itself to provide a bilayer polymer drug dosage form.
  • psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents can be coated onto a polymer such as a polypeptide, collagen, gelatin, polyvinyl alcohol, polyorthoester, polyacetyl, or a polyorthocarbonate, and the coated polymer folded onto itself to provide a bilaminated dosage form.
  • a polymer such as a polypeptide, collagen, gelatin, polyvinyl alcohol, polyorthoester, polyacetyl, or a polyorthocarbonate
  • the coated polymer folded onto itself to provide a bilaminated dosage form In operation, the bioerodible dosage form erodes at a controlled rate to dispense the active compound over a sustained release period.
  • biodegradable polymers for use in this and other aspects of the invention can be selected from, for example, biodegradable poly(amides), poly (amino acids), poly(esters), poly(lactic acid), poly(glycolic acid), poly(carbohydrate), poly(orthoester), poly (orthocarbonate), poly(acetyl), poly(anhydrides), biodegradable poly(dehydropyrans), and poly(dioxinones) which are known in the art (see, e.g., Rosoff, Controlled Release of Drugs, Chap. 2, pp. 53-95 (1989); and U.S. Pat. Nos. 3,81 1 ,444; 3,962,414; 4,066,747, 4,070,347; 4,079,038; and 4,093,709, each incorporated herein by reference).
  • the dosage form comprises an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3- azabicycIo[3.1 .OJhexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3. 1 .0]hexane) loaded into a polymer that releases the drug(s) by diffusion through a polymer, or by flux through pores or by rupture of a polymer matrix.
  • the drug delivery polymeric dosage form comprises the active compound contained in or on the polymer.
  • the dosage form comprises at least one exposed surface at the beginning of dose delivery.
  • the non-exposed surface when present, can be coated with a pharmaceutically acceptable material impermeable to the passage of a drug.
  • the dosage form may be manufactured by procedures known in the art, for example by blending a pharmaceutically acceptable carrier like polyethylene glycol, with a pre-determined dose of the active compound(s) at an elevated temperature (e.g., 37°C), and adding it to a silastic medical grade elastomer with a cross-linking agent, for example, octanoate, followed by casting in a mold. The step is repeated for each optional successive layer. The system is allowed to set for 1 hour, to provide the dosage form.
  • Representative polymers for manufacturing such sustained release dosage forms include, but are not limited to, olefin, and vinyl polymers, addition polymers, condensation polymers, carbohydrate polymers, and silicon polymers as represented by polyethylene, polypropylene, polyvinyl acetate, polymethylaerylate, polyisobutylmethacrylate, poly alginate, polyamide and polysilicon.
  • These polymers and procedures for manufacturing them have been described in the art (see, e.g., Coleman et al., Polymers 1990, 31 , 1 187-1231 ; Roerdink et al., Drug Carrier Systems 1989, 9, 57-10; Leong et al., Adv. Drug Delivery Rev. 1987, 1, 199-233; and Roff et al., Handbook of Common Polymers 1971 , CRC Press; U.S. Pat. No. 3,992,51 8).
  • compositions and dosage forms comprise an additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.
  • the drug- releasing beads may have a central composition or core comprising an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents and a pharmaceutically acceptable carrier, along with one or more optional excipients such as a lubricants, antioxidants, dispersants, and buffers.
  • the beads may be medical preparations with a diameter of about 1 to 2 mm. In exemplary embodiments they are formed of non-cross-linked materials to enhance their discharge from the
  • the beads may be coated with a release rate-controlling polymer that gives a timed release pharmacokinetic profile.
  • the beads may be manufactured into a tablet for therapeutically effective drug administration.
  • the beads can be made into matrix tablets by direct compression of a plurality of beads coated with, for example, an acrylic resin and blended with excipients such as hydroxypropylmethyl cellulose.
  • the manufacture and processing of beads for use within the invention is described in the art (see, e.g., Lu, Int. J. Pharm,, 1994, 1 12, 1 17- 124; Pharmaceutical Sciences by Remington, 14 th ed, ppl 626-1628 (1970); Fincher, J. Pharm. Sci. 1968, 57, 1825-1835 ; and U.S. Pat. No. 4,083,949, each incorporated by reference) as has the manufacture of tablets (Pharmaceutical Sciences, by Remington, 17 th Ed, Ch. 90, ppl 603- 1625, 1985, incorporated herein by reference).
  • the dosage form comprises a plurality of tiny pills or mini-tablets.
  • the tiny pills or mini-tablets provide a number of individual doses for providing various time doses for achieving a sustained-release drug delivery profile over an extended period of time up to 24 hours.
  • the tiny pills or mini- tablets may comprise a hydrophilic polymer selected from the group consisting of a polysaccharide, agar, agarose, natural gum, alkali alginate including sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum, pectin, arnylopectin, gelatin, and a hydrophilic colloid.
  • a hydrophilic polymer selected from the group consisting of a polysaccharide, agar, agarose, natural gum, alkali alginate including sodium alginate, carrageenan, fucoidan, furcellaran, laminaran, hypnea, gum arabic, gum ghatti, gum karaya, gum tragacanth, locust bean gum, pectin, arnylopectin, gelatin,
  • the hydrophilic polymer may be formed into a plurality (e.g., 4 to 50) tiny pills or mini- tablet, wherein each tiny pill or mini-tablet comprises a pre-determined dose of the additional psychotherapeutic agent and/or (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.
  • 1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .OJhexane) agent, e.g., a dose of about 10 ng, 0.5 mg, 1 mg, 1 .2 mg, 1.4 mg, 1.6 mg, 5.0 mg etc.
  • the tiny pills and mini-tablets may further comprise a release rate-controlling wall of 0.001 up to 10 mm thickness to provide for timed release of the active compound.
  • Representative wall forming materials include a triglyceryl ester selected from the group consisting of glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl laureate, glyceryl didecenoate and glyceryl tridenoate.
  • Other wall forming materials comprise polyvinyl acetate, phthalate,
  • the tiny pills and mini-tablets may further comprise a blend of particles, which may include particles of different sizes and/or release properties, and the particles may be contained in a hard gelatin or non-gelatin capsule or soft gelatin capsule.
  • drug-releasing lipid matrices can be used to formulate therapeutic compositions and dosage forms comprising an additional psychotherapeutic agent and/or (+)- l-(3,4-dichlorophenyl)-3- azabicyclo[3.1 .OJhexane agents.
  • solid microparticles of the active compound are coated with a thin controlled release layer of a lipid (e.g., glyceryl behenate and/or glyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat. No.
  • the lipid-coated particles can optionally be compressed to form a tablet.
  • Another controlled release lipid-based matrix material which is suitable for use in the sustained release compositions and dosage fonns of the invention comprises polyglycolized glycerides, e.g., as described in Roussin et al., U.S. Pat. No. 6, 171 ,615 (incorporated herein by reference).
  • drug-releasing waxes can be used for producing sustained release compositions and dosage forms comprising an additional psychotherapeutic agent and/or (+)-l -(3,4-dichlorophenyI)-3-azabicyclo[3.1 .0]hexane agents.
  • suitable sustained drug-releasing waxes include, but are not limited to, carnauba wax, candedilla wax, esparto wax, ouricury wax, hydrogenated vegetable oil, bees wax, paraffin, ozokerite, castor wax, and mixtures thereof (see, e.g., Cain et al., U.S. Pat. No. 3,402,240; Shtohryn et al. U.S. Pat. No. 4,820,523; and Walters, U.S. Pat. No.
  • osmotic delivery systems are used for sustained release delivery of an additional psychotherapeutic compound and/or (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) (see, e.g., Verma et al., Drug Dev. Ind. Pharm., 2000, 26:695-708, incorporated herein by reference).
  • the osmotic delivery system is an OROS® system (Alza
  • the dosage form comprises an osmotic dosage form, which comprises a semi -permeable wall that surrounds a therapeutic composition comprising the additional psychotherapeutic agent and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane).
  • a therapeutic composition comprising the additional psychotherapeutic agent and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-
  • the osmotic dosage form comprising a homogenous composition imbibes fluid through the semipermeable wall into the dosage form in response to the concentration gradient across the semipermeable wall.
  • the therapeutic composition in the dosage form develops osmotic energy that causes the therapeutic composition to be administered through an exit from the dosage form over a prolonged period of time up to 24 hours (or even in some cases up to 30 hours) to provide controlled and sustained prodrug release.
  • These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • the dosage form comprises another osmotic dosage form comprising a wall surrounding a compartment, the wall comprising a semipermeable polymeric composition permeable to the passage of fluid and substantially impermeable to the passage of the active compound present in the compartment, a drug-containing layer composition in the compartment, a hydrogel push layer composition in the compartment comprising an osmotic formulation for imbibing and absorbing fluid for expanding in size for pushing the additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl!-3-azabicyclo[3.1 .0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) composition layer from the dosage form, and at least one passageway in the wall for releasing
  • This osmotic system delivers the active compound by imbibing fluid through the semipermeable wall at a fluid imbibing rate determined by the permeability of the semipermeable wall and the osmotic pressure across the semipermeable wall causing the push layer to expand, thereby delivering the active compound through the exit passageway to a patient over a prolonged period of time (up to 24 or even 30 hours).
  • the hydrogel layer composition may comprise 10 mg to 1000 mg of a hydrogel such as a member selected from the group consisting of a polyalkylene oxide of 1 ,000,000 to 8,000,000 which are selected from the group consisting of a polyethylene oxide of 1 ,000,000 weight-average molecular weight, a polyethylene oxide of 2,000,000 molecular weight, a polyethylene oxide of 4,000,000 molecular weight, a polyethylene oxide of 5,000,000 molecular weight, a polyethylene oxide of 7,000,000 molecular weight and a polypropylene oxide of the 1 ,000,000 to 8,000,000 weight-average molecular weight; or 10 mg to 1000 mg of an alkali carboxymethylcellulose of 10,000 to 6,000,000 weight average molecular weight, such as sodium carboxymethylcellulose or potassium carboxymethylcellulose.
  • the hydrogel expansion layer may comprise a hydroxyalkylcellulose of 7,500 to 4,500,00 weight-average molecular weight (e.g., hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
  • hydroxybutylcellulose or hydroxypentylcellulose an osmagent, e.g., selected from the group consisting of sodium chloride, potassium chloride, potassium acid phosphate, tartaric acid, citric acid, raffinose, magnesium sulfate, magnesium chloride, urea, inositol, sucrose, glucose and sorbitol, and other agents such a hydroxypropylalkylcellulose of 9,000 to 225,000 average-number molecular weight (e.g., hydroxypropylethylcellulose,
  • hydropropylbutylcellulose ferric oxide
  • antioxidants e.g., ascorbic acid, butylated hydroxyanisole, butylatedhydroxyquinone, butylhydroxyanisol, hydroxycomarin, butylated hydroxytoluene, cephalm, ethyl gallate, propyl gallate, octyl gallate, lauryl gallate, propyl- hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol, dibutylphenol, vitamin E, lecithin and ethanolamine), and/or lubricants (e.g., calcium stearate, magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate, sodium suberate, potassium laureate, salts of fatty acids, salts of alicyclic acids, salts of aromatic acids, stearic acid, oleic acid, palmitic acid, a mixture of a salt of a fatty, alicyclic or aromatic acid, and
  • the semipermeable wall comprises a composition that is permeable to the passage of fluid and impermeable to passage of the additional psychotherapeutic agent and/or (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane).
  • the wall is nontoxic and comprises a polymer selected from the group consisting of a cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate.
  • the wall typically comprises 75 wt % (weight percent) to 100 wt % of the cellulosic wall- forming polymer; or, the wall can comprise additionally 0.01 wt % to 80 wt % of polyethylene glycol, or 1 wt % to 25 wt % of a cellulose ether (e.g., hydroxypropylcellulose or a hydroxypropylalkycellulose such as hydroxypropylmethylcellulose).
  • a cellulose ether e.g., hydroxypropylcellulose or a hydroxypropylalkycellulose such as hydroxypropylmethylcellulose.
  • the total weight percent of all components comprising the wall is equal to 100 wt %.
  • the internal compartment comprises the drug-containing composition alone or in layered position with an expandable hydrogel composition.
  • the expandable hydrogel composition in the compartment increases in dimension by imbibing the fluid through the semipermeable wall, causing the hydrogel to expand and occupy space in the compartment, whereby the drug composition is pushed from the dosage form.
  • the therapeutic layer and the expandable layer act together during the operation of the dosage form for the release of drug to a patient over time.
  • the dosage form comprises a passageway in the wall that connects the exterior of the dosage form with the internal compartment.
  • the osmotic powered dosage form delivers the additional psychotherapeutic compound and/or (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) from the dosage form to the patient at a zero order rate of release over a period of up to about 24 hours.
  • (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexan
  • the expression "passageway” comprises means and methods suitable for the metered release of an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.OJhexane agents from the compartment of an osmotic dosage form.
  • the exit means comprises at least one passageway, including orifice, bore, aperture, pore, porous element, hollow fiber, capillary tube, channel, porous overlay, or porous element that provides for the osmotic controlled release of the active compound.
  • the passageway includes a material that erodes or is leached from the wall in a fluid environment of use to produce at least one control Ied-release dimensioned passageway.
  • Representative materials suitable for forming a passageway, or a multiplicity of passageways comprise a leachable poly(glycolic) acid or poly(lactic) acid polymer in the wall, a gelatinous filament, poly(vinyl alcohol), leach-able polysaccharides, salts, and oxides.
  • a pore passageway, or more than one pore passageway can be formed by leaching a leachable compound, such as sorbitol, from the wall.
  • the passageway possesses control led-release dimensions, such as round, triangular, square and elliptical, for the metered release of prodrug from the dosage form.
  • the dosage form can be constructed with one or more passageways in spaced apart relationship on a single surface or on more than one surface of the wall.
  • fluid environment denotes an aqueous or biological fluid as in a human patient, including the gastrointestinal tract.
  • Passageways and equipment for forming passageways are disclosed in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,063,064; 4,088,864; 4,816,263;
  • microparticle, microcapsule, and/or microsphere drug delivery technologies can be employed to provide sustained release delivery of an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) within the compositions, dosage forms and methods of the invention.
  • an additional psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-
  • an additional psychotherapeutic compound and/or (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l-(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane
  • a biocompatible, biodegradable wall- forming material e.g., a polymer
  • the active compound is typically dissolved, dispersed, or emulsified in a solvent containing the wall fonning material. Solvent is then removed from the microparticles to form the finished microparticle product.
  • solvent is then removed from the microparticles to form the finished microparticle product.
  • psychotherapeutic compound and/or (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1 .Ojhexane) in a sustained release formulation according to the invention.
  • a microparticle formulation can be made in which the resulting microparticles exhibit both diffusional release and biodegradation release properties.
  • the active agent is released from the microparticles prior to substantial degradation of the polymer.
  • the active agent can also be released from the microparticles as the polymeric excipient erodes.
  • US. Pat. No. 6,596,316 (incorporated herein by reference) discloses methods for preparing microparticles having a selected release profile for fine tuning a release profile of an active agent from the microparticles.
  • enteric-coated preparations can be used for oral sustained release administration.
  • Preferred coating materials include polymers with a pH-dependent solubility (i.e., pH-controlled release), polymers with a slow or pH- dependent rate of swelling, dissolution or erosion (i.e., time-controlled release), polymers that are degraded by enzymes (i.e., enzyme-controlled release) and polymers that form firm layers that are destroyed by an increase in pressure (i.e., pressure-controlled release).
  • Enteric coatings may function as a means for mediating sustained release of the additional psychotherapeutic compound and/or (+)-l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)- 3-azabicyclo[3.1.0]hexane) by providing one or more barrier layers, which may be located entirely surrounding the active compound, between layers of a multi-layer solid dosage form (see below), and/or on one or more outer surfaces of one or multiple layers of a multilayer solid dosage form (e.g., on end faces of layers of a substantially cylindrical tablet).
  • barrier layers which may be located entirely surrounding the active compound, between layers of a multi-layer solid dosage form (see below), and/or on one or more outer surfaces of one or multiple layers of a multilayer solid dosage form (
  • barrier layers may, for example, be composed of polymers which are either substantially or completely impermeable to water or aqueous media, or are slowly erodible in water or aqueous media or biological liquids and/or which swell in contact with water or aqueous media.
  • Suitable polymers for use as a barrier layer include acrylates,
  • barrier layers comprising polymers which swell in contact with water or aqueous media may swell to such an extent that the swollen layer forms a relatively large swollen mass, the size of which delays its immediate discharge from the stomach into the intestine.
  • the barrier layer may itself contain active material content, for example the barrier layer may be a slow or delayed release layer.
  • Barrier layers may typically have an individual thickness of 10 microns up to 2 mm.
  • Suitable polymers for barrier layers which are relatively impermeable to water include the MethocelTM series of polymers, used singly or combined, and EthocelTM polymers. Such polymers may suitably be used in combination with a plasticizer such as hydrogenated castor oil.
  • the barrier layer may also include conventional binders, fillers, lubricants and compression acids etc such as Polyvidon 30 (trade mark), magnesium stearate, and silicon dioxide.
  • Additional enteric coating materials for mediating sustained release of an additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent include coatings in the form of polymeric membranes, which may be semipermeable, porous, or asymmetric membranes (see, e.g., US Patent No. 6,706,283, incorporated herein by reference).
  • Coatings of these and other types for use within the invention may also comprise at least one delivery port, or pores, in the coating, e.g., formed by laser drilling or erosion of a plug of water-soluble material.
  • Other useful coatings within the invention including coatings that rupture in an environment of use (e.g., a gastrointestinal compartment) to form a site of release or delivery port:.
  • Exemplary coatings within these and other embodiments of the invention include poly(acrylic) acids and esters; poly(methacrylic) acids and esters; copolymers of poly(acrylic) and poly(methacrylic) acids and esters; cellulose esters; cellulose ethers; and cellulose ester/ethers.
  • Additional coating materials for use in constructing solid dosage forms to mediate sustained release of an additional psychotherapeutic compound and/or (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent include, but are not limited to, polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, poly(vinylpyrrolidone), ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylethyl cellulose, starch, dextran, dextrin, chitosan, collagen, gelatin, bromelain, cellulose
  • sustained release of the additional psychotherapeutic compound and/or (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent is provided by formulating the active compound in a dosage form comprising a multi-layer tablet or other multi-layer or multi-component dosage form.
  • the active compound is formulated in layered tablets, for example having a first layer which is an immediate release layer and a second layer which is a slow release layer.
  • Other multi-layered dosage forms of the invention may comprise a plurality of layers of compressed active ingredient having variable (i.e., selectable) release properties selected from immediate, extended and/or delayed release mechanisms.
  • Multi-layered tablet technologies useful to produce sustained release dosage forms of an additional psychotherapeutic compound and/or (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent include pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .Ojhexane) are described, for example, in International Publications WO 95/20946; WO 94/06416; and WO 98/05305 (each incorporated herein by reference).
  • Other multi-component dosage forms for providing sustained delivery of an additiona l psychotherapeutic compound and/or (+)-l - (3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane agent include pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) include tablet formulations having a core containing the active compound coated with a release retarding agent and surrounded by an outer casing layer (optionally containing the active compound) (see, e.g., International Publication WO 95/28148, incorporated herein by reference).
  • the release retarding agent is an enteric coating, so that there is an immediate release of the contents of the outer core, followed by a second phase from the core which is delayed until the core reaches the intestine.
  • International Publication WO 96/04908 (incorporated herein by reference) describes tablet formulations which comprise an active agent in a matrix, for immediate release, and granules in a delayed release form comprising the active agent. Such granules are coated with an enteric coating, so release is delayed until the granules reach the intestine.
  • International Publication WO 96/04908 (incorporated herein by reference) describes delayed or sustained release formulations formed from granules which have a core comprising an active agent, surrounded by a layer comprising the active agent.
  • bilayer tablet for sustained delivery of additional psychotherapeutic compound and/or (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1 .0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) is described in US Patent No. 6,878,386 (incorporated herein by reference). Briefly, the bilayer tablet comprises an immediate release and a slow release layer, optionally with a coating layer.
  • the immediate release layer may be, for example, a layer which disintegrates immediately or rapidly and has a composition similar to that of known tablets which disintegrate immediately or rapidly.
  • An alternative type of immediate release layer may be a swellable layer having a composition which incorporates polymeric materials which swell immediately and extensively in contact with water or aqueous media, to form a water permeable but relatively large swollen mass. Active material content may be immediately leached out of this mass.
  • the slow release layer may have a composition comprising the additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)- l -(3,4-dichlorophenyl)- 3-azabicyclo[ 3. 1.Ojhexane) with a release retarding vehicle, matrix, binder, coating, or excipient which allows for slow release of the active compound.
  • a release retarding vehicle, matrix, binder, coating, or excipient which allows for slow release of the active compound.
  • Suitable release retarding excipients include pH sensitive polymers, for instance polymers based upon methacrylic acid copolymers, which may be used either alone or with a plasticiser; release-retarding polymers which have a high degree of swelling in contact with water or aqueous media such as the stomach contents; polymeric materials which form a gel on contact with water or aqueous media; and polymeric materials which have both swelling and gelling characteristics in contact with water or aqueous media.
  • Release retarding polymers which have a high degree of swelling include, inter alia, cross-linked sodium
  • carboxymethylcellulose cross-linked hydroxypropylcellulose, high-molecular weight hydroxypropylmethylcellulose, carboxymethylamide, potassium
  • release retarding gellable polymers include methylcellulose, carboxymethylcellulose, low-molecular weight hydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols,
  • release retarding polymers simultaneously possessing swelling and gelling properties include medium-viscosity hydroxypropylmethylcellulose and medium-viscosity polyvinylalcohols.
  • An exemplary release-retarding polymer is xanthan gum, in particular a fine mesh grade of xanthan gum, preferably pharmaceutical grade xanthan gum, 200 mesh, for instance the product Xantural 75 (also known as eltrol CRTM Monsanto, 800 N Lindbergh Blvd, St Louis, Mo. 63167, USA).
  • Xanthan gum is a polysaccharide which upon hydration forms a viscous gel layer around the tablet through which the active has to diffuse. It has been shown that the smaller the particle size, the slower the release rate. In addition, the rate of release of active compound is dependent upon the amount of xanthan gum used and can be adjusted to give the desired profile. Examples of other polymers which may be used within these aspects of the invention include Methocel 4MTM, Methocel E5TM, Methocel E50TM, Methocel E4MTM, Methocel K15MTM and Methocel K100MTM.
  • release- retarding polymers which may be incorporated within this and other embodiments of the invention to provide a sustained release composition or dosage form of an additional psychotherapeutic compound and/or (+)- l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agents include, hydrocolloids such as natural or synthetic gums, cellulose derivatives other than those listed above, carbohydrate-based substances such as acacia, gum tragacanth, locust bean gum, guar gum, agar, pectin, carrageenan, soluble and insoluble alginates, carboxypolymethylene, casein, zein. and the like, and proteinaceous substances such as gelatin.
  • hydrocolloids such as natural or synthetic gums, cellulose derivatives other than those listed above, carbohydrate-based substances such as acacia, gum tragacanth, locust bean gum, guar gum, agar, pectin, carrageenan, soluble and insoluble
  • a sustained release delivery device or system is placed in the subject in proximity of the target of the active compound, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in "Medical
  • an oral sustained release pump may be used (see, e.g., Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201 ; and Saudek et al., 1989, N. Engl. J. Med. 321 :574, each incorporated herein by reference).
  • compositions and dosage forms of the current invention will typically be provided for administration in a sterile or readily sterilizable, biologically inert, and easily administered form.
  • kits for reducing symptoms in a human subject suffering from a disorder affected by monoamine neurotransmitters, including depression comprise the additional
  • psychotherapeutic agent and (+)- l-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane) therapeutic agent in an effective amount, and a container means for containing the additional psychotherapeutic agent and (+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane agent (including pharmaceutically acceptable active salts polymorphs, glycosylated derivatives, metabolites, solvates, hydrates, and/or prodrugs of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane) for coordinate administration to the said subject (for example a container, divided bottle, or
  • the container means can include a package bearing a label or insert that provides instructions for multiple uses of the kit contents to treat the disorder and reduce symptoms in the subject.
  • the additional psychotherapeutic agent and (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane agent are admixed or co- formulated in a single, combined dosage form, for example a liquid or solid oral dosage form.
  • the additional psychotherapeutic agent and (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1 .OJhexane agent are contained in the kit in separate dosage forms for coordinate administration.
  • An example of such a kit is a so- called blister pack.
  • Blister packs are well-known in the packaging industry and are widely used for the packaging of pharmaceutical dosage forms (tablets, capsules and the like).
  • This product is converted to diethyl cis-l -(3,4-dichlorophenyl)- l ,2- cyclopropanedicarboxylate by the method of L. L. McCoy, J.A.C.S., 80, 6568 (1958).
  • a mixture of 150 g of this diester and 66 g of 85% KOH in 500 ml of water and 500 ml of ethanol is refluxed for 6 hours and then chilled in ice.
  • the oily material is extracted into ether and the aqueous layer is made acidic with 100 ml of 12 N hydrochloric acid.
  • the oily lower layer crystallizes slowly to give a colorless crystalline cake. This is recrystallized from a mixture of ethanol and ethyl acetate to give colorless crystals of l -(3,4-dichlorophenyl)-l ,2-cyclopropanedicarboxylic acid.
  • the precipitated crystals are collected by filtration and are recrystallized from isopropyl alcohol to give 1 .70 g of 1 -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane hydrochloride as colorless crystals, m.p. 180°- 181° C.
  • the solution was concentrated to a volume of 6 mL using a stream of helium gas, and six 1 -mL portions of the concentrate were subjected to high- performance liquid chromatography using an HPLC instrument equipped with a 1 cm x 25 cm Daicel CHIRALPA AD column (Chiral Technologies, Inc., Exton, Pa.). Elution was carried out at ambient temperature using 95:5 (v/v) hexane: isopropyl alcohol solution containing 0.05% diethylamine as a mobile phase at a flow rate of 6 mL/min. The fraction eluting at about 21.5 to 26 minutes was collected and concentrated to provide a first residue, which was dissolved in a minimal amount of ethyl acetate.
  • aqueous i-PrOAc was azeotropically concentrated in vacuum to ca. 24.5 L. Methylcyclohexane ( 17.5 L) was added dropwise over 2 h. The wet cake was displacement-washed with 7 L of 40% methylcyclohexane/l -PrOAc followed by a slurry wash (7 L, i-PrOAc) and a displacement wash (7 L, i-PrOAc). Typical isolated yield: 57- 60% corrected with wt %: 87-99.5% (based on HC1 salt).
  • the wet cake was displacement-washed with 10 L of 30% i-PrOH in MeOBu-t followed by 2x7.5 L 10% i-PrOH in MeOBu-t (slurry wash, then displacement wash).
  • the wet cake was suction dried under N 2 (10-50 RH %) at ambient temperature to give the hemihydrate HC1 salt of (lR,5S)-(+)-l-(3,4-dichlorophenyl)-3- azabicyclo[3, 10]hexane. Typical yield: 92%.
  • (+)- 1 -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0] hexane hydrochloride may also be manufactured according to the procedure described in U.S. Patent Application No. 12/428,399 as follows:
  • Step 1 Synthesis of a-bromo-3.4-dichlorophenylacetic acid methyl ester
  • the lower organic phase was separated, and the aqueous phase washed with 2 x 150 L ethylene dichloride.
  • the combined organic phases were washed with 100 L water and then with aqueous sodium carbonate (3 kg sodium carbonate in 100 L water).
  • the solution of crude ester was azeotropically "dried" in vacuo at 60-620C, resulting in the collection of 100 L ethylene dichloride. A theoretical yield was assumed without isolation and the solution was used "as is" in the following bromination reaction.
  • Step 2 Synthesis of l -(3,4-dlchlorophenyl- l ,2-cyclopropane-dicarboxylic
  • the lower aqueous phase was separated, and 150 L water and 1.0 kg potassium carbonate were added to the organic phase. The mixture was agitated 5 minutes and stratified. The lower aqueous phase was separated and discarded, as well as the interfacial emulsion, and the organic phase was washed with 100 L water containing 1 L 32% hydrochloric acid. After stratification and separation of the lower aqueous phase, the organic phase was line-filtered and distilled in vacuo to "dryness" (full vacuum at 65°C). To the hot residue was added 70 kg methanol with agitation. The mix was cooled (seeding at +10°C) to -5°C and maintained at this temperature overnight.
  • the cold thick suspension was suction-filtered (Nutsche), and the cake of l-(3,4-dichlorophenyl)-l ,2-cyclopropane-dicarboxylic acid dimethyl ester was suction dried, washed with 2 x 20 L hexane, suction dried for 30 minutes and air-dried on paper (racks) for 2 days at ambient conditions.
  • Step 3 Synthesis of l -(3.4-dichloropheriyl)- l ,2-cyclopropane-dicarboxylic acid
  • the 1 -(3,4- dichlorophenyl)-l ,2-cyclopropane-dicarboxylic acid cake was washed with cold ethylene dichloride (2 x 5 L), followed by ambient ethylene dichloride (4 x 5 L).
  • the dicarboxylic acid product was suction dried for 15 minutes and air-dried on paper (racks).
  • the free dicarboxylic acid was precipitated with 31 kg of 32% hydrochloric acid and extracted with 100 kg ethyl acetate.
  • the lower aqueous phase was separated and washed with 20 kg ethyl acetate.
  • the combined organic phases were washed with 50 L water, and then saturated aqueous sodium chloride. Distillation in vacuo to 80°C with full vacuum yielded a concentrate of l -(3,4-dichlorophenyl)-l ,2-cyclopropane-dicarboxylic acid, which was used "as is" for the next step, cyclization to the imide. A quantitative yield from the diester was assumed for calculation purposes.
  • Step 4 Synthesis and Recrystallization of 1 -(3,4-dichlorophenyl)-3-azabicyclor3.1.0] hexane-2,4-dione
  • BH3-THF complex is charged into a 2 L addition funnel (9 x 2 L, then 1 x
  • reaction mixture is then transferred to a 10 L Buchi flask,
  • the filtrate is then transferred into a 40 L separatory funnel and the phases are allowed to separate. Each phase is then drained into separate 5-gallon containers. The aqueous layer is returned to the 40 L separatory funnel and extracted with ethyl acetate (2 2 L). The organic phases are combined. The aqueous layer is discarded.
  • HCI gas is bubbled through a 12 L flask containing 10 L of ethyl acetate to make an approximately 2.3 M solution of HCI/ethyL acetate.
  • This HCI/ethyl acetate solution is added to the oil dropwise at a rate that maintains a temperature of ⁇ 20°C using an ice/water bath.
  • the solution is then stirred at ⁇ 10°C for a minimum of 2 hours in the ice/water bath.
  • the material is chilled in a cold room overnight.
  • the material is then filtered through a 18.5 cm funnel utilizing a filter pad and transferred to a 22 L flask.
  • the solution is then stirred at room temperature for 1 hour. After stirring, the solution is chilled to 4°C with an ice/water bath and stirred for 3.75 hours. The product is then placed in a cold room overnight.
  • Step 6 Resolution of ( ⁇ )- l -(S3,4-dichlorophenyI)-3-azabicyclor[3.1.01hexane hydrochloride into (+)- l -(3.4-dichlorophenyl)-3-azabicyclo[3.1.01hexane hydrochloride
  • the mixture is then cooled to 15-20°C and stirred at this temperature for approximately 2 hours.
  • the resulting solids are filtered onto a plate filter using a polypropylene filter cloth.
  • the cake is washed with methanol (3 x 5 L) and pressed dry.
  • the solids are transferred to a tarred 5-gallon container and weighed (yield ⁇ 20 kg).
  • HC1 gas is bubbled through 12 L of ethyl acetate to make an approximately 2.3 M solution of HCI/ethyl acetate. After titration assay, the solution is adjusted to exactly 2.3 M by adding either ethyl acetate or HCI gas. [00166] 8.2 L of the 2.3 M solution of HCI/ethyl acetate is added (over a period of approx. 1.5 hours) to the filtrate (above), maintaining the temperature at ⁇ 20°C and ensuring that a pH of 2 is obtained. Once the addition is complete, the mixture is stirred at 0 to -5°C for a period of 16 hours.
  • Step 6a Recrystallization of (+)-1 -(3.4-dichloroPhenyl)-3-azabicyclor3.1.01 hexane hydrochloride from isopropanol
  • the norepinephrine binding assay was performed according to the methods described in Raisman et al., Eur. J. Pharmacol. 78:345-351 (1 82) and Langer et al., Eur. J. Pharmacol. 72:423 ( 198 1 ).
  • the receptor source was rat forebrain membranes; the radioligand was [ 3 H]-nisoxetine (60-85 Ci/mmol) at a final ligand concentration of 1.0 nM; the non-specific determinant [ 1.0 ⁇ ]; reference compound and positive control were ( ⁇ )-desmethylimipramine HCl.
  • (+)-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .0]hexane HCl was obtained according to the method of Example 1 , above. Reactions were carried out in 50 mM TRIS-HCl (pH 7.4), containing 300 niM NaCl and
  • (+)-l - (3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof will be significantly more active than ( ⁇ )- l -(3,4-dichlorophenyl)-3- azabicyclo[3.1 .OJhexane or a pharmaceutically acceptable salt thereof for treating or preventing depression in a patient.
  • the serotonin binding assay was performed according to the methods described in D'Amato et al., J. Pharmacol. Exp. Ther. 242:364-371 (1987) and Brown et al., Eur. J. Pharmac. 123: 161 - 165 (1986).
  • the receptor source was rat forebrain membranes; the radioligand was [ 3 H]-citalopram (70-87 Ci/mmol) with a final ligand concentration of 0.7 nM; the non-specific determinant was clomipramine [10 ⁇ ]; and the reference compound and positive control were ( ⁇ )-desmethylimipramine.
  • (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane HCl was obtained according to the method of Example 5, above. Reactions were carried out in 50 mM TRIS-HCl (pH 7.4) containing 120 mM NaCl and 5 mM KG at 25° C. for 60 minutes. The reaction was terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped in the filters was determined using liquid scintillation spectrometry and compared to control values in order to ascertain any interactions of test compound with the serotonin transporter binding site. The data are reported in Table 6 below.
  • (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof will be significantly more active than ( ⁇ )-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.0]hexane or a pharmaceutical salt thereof for treating or preventing depression in a patient.
  • (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane or a pharmaceutical salt thereof for treating or preventing depression in a patient.
  • Subjects were identified who were between the ages of 1 8-65 (inclusive), and met criteria for Major Depressive Disorder in accordance with the Diagnostic and Statistical manual of Mental Disorders-IV-TR and confirmed by the MINI International Neuropsychiatric Interview.
  • subjects had a baseline Hamilton Depression Rating Scale (HAMD- 17) >22 and a severity of >2 on item 1 and a rating on the Hamilton Anxiety Scale (HAM-A) ⁇ 1 7. They were also required to have a BMI ⁇ 35 and body weight > 45 kg at the Screening Visit.
  • anticonvulsants including gabapentin and pregabalin, neuroleptics, MAO inhibitors, barbiturates, benzodiazepines, stimulants, antipsychotics, lithium, anxiolytics and beta blockers starting two weeks prior to the study and continuing until after the follow-up visit.
  • Subjects were evaluated for safety parameters prior to and throughout the trial by a variety of measures including electrocardiogram, physical examination, vital signs and body weight, and clinical laboratory testing including a lipid panel, CBC with differential and urinalysis, Samples were drawn to assess total bilirubin, alkaline phosphatase, ALT (SGPT), AST (SGOT), blood urea nitrogen (BUN), creatinine, glucose, uric acid, calcium, phosphorus, total protein, albumin, total cholesterol, LDL,
  • HDL high-density polyethylene glycol
  • triglycerides sodium, potassium, bicarbonate, chloride, GGT and creatine kinase
  • EB-1010 mean baseline scores on the main outcome measures: MADRS (31 .4)
  • HAMD- 17 29.6
  • DISF-SR 25.38
  • the sixty-three subjects were randomized to receive either 25 mg of ( ⁇ )-l -(3,4-dichlorophenyl)-3- azabicyclo[3.1.Ojhexane twice a day for two weeks and then 50 mg twice a day for four weeks or placebo according to the following schedule:
  • Visit 1 Screening Visit:
  • Visit 2 Placebo Run-in Visit:
  • HAMD- 17 To be eligible for the study, the total HAMD- 17 score must be > 22 and the score on HAMD- 17 item 1 must be > 2.
  • Patient Medication Diary Patients were provided with a diary at the Placebo Run-in Visit (Visit 2) and at each subsequent visit except the last visit (the Follow-Up Visit, Visit 9). Patients recorded the date, time and dosage of each study medication dose using the diary. The diary was collected at the next scheduled visit, reviewed for dosing compliance, and a new diary dispensed.
  • Efficacy was determined by measuring the change from baseline in the Montgomery- Asberg Depression Rating Scale (MADRS), the HAMD-17, the Clinical Global Impression Global Improvement Scale (CGI-I), the Clinical Global Impression- Severity scale (CGI-S) and the Derogatis Interview for Sexual Functioning Self-Report (DISF-SR).
  • MADRS Montgomery- Asberg Depression Rating Scale
  • CGI-I Clinical Global Impression Global Improvement Scale
  • CGI-S Clinical Global Impression- Severity scale
  • DISF-SR Derogatis Interview for Sexual Functioning Self-Report
  • MADRS the primary efficacy parameter
  • HAMD-17 the primary efficacy parameter
  • Anhedonia D1SF-SR
  • CGI-1 and CGI-S scores were analyzed using a mixed- repeated measures (MMRM) analysis model including factors for Subject, Visit, Treatment Arm and Baseline value as a covariate.
  • Adjusted least- squares means from these models are presented. Comparisons between groups were made at each post-baseline visit using model-based contrasts and adjusted degrees of freedom. For these analyses no explicit data imputations were made prior to the analysis. Response and remission categorical data were analyzed using chi-square tests. Inferential analyses of safety data were conducted with ANOVA models or chi-square tests. Two- tail alpha was set to 0.05. All analyses were conducted using SAS version 9.2.
  • MADRS 31 .4
  • HAMD-17 (29.5)
  • D1SF-SR 25.8.
  • MADKS Montgomery Asberg Depression Rating Scale
  • 1 IAMD- 1 Hamilton Rating Scale for Depression
  • CGI-I Clinical Global Impressions - Improvement
  • CGI-S Clinical Global Impressions - Severity
  • MMRM Mixed Effect Models for Repeated Measures
  • MITT Modified Intcnt-to-treat
  • CI Confidence Interval
  • SE Standard Error.
  • MADRS Montgomery Asberg Depression Rating Scale
  • HAM D- 1 Hamilton Rating Scale for Depression
  • CGI-I Clinical Global Impressions - Improvement
  • LOC F Last Observation Carried Forward
  • Response 50% reduction or more of the baseline total score ol " MADRS or HAMD-17 at endpoint; Remission, MADRS ⁇ 12 or HAMD- 1 7 ⁇ 7 or CGI-S ⁇ 2.
  • Treatment-emergent adverse events defined as events reported by at least 5% of EB- 1010-treated patients and at least twice the rate of placebo
  • BP blood pressure BP blood pressure
  • HDL high density lipoprotein HDL high density lipoprotein
  • LDL low density lipoprotein Safety population. All randomized patients who received study drug ; P values were calculated by using ANOVA with treatment group as main effect
  • (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1 .0]hexane was not associated with significant weight gain or sexual dysfunction (See, for example, Figure7).
  • Immediate release tablets containing 50 mg of the HCI salt of -(3,4- dichlorophenyl)-3-azabicyclo[3. 1.0]hexane are prepared using the following ingredients.
  • the "% composition” is the % by weight of the ingredient based upon the total weight of the composition.
  • Each tablet may also be coated with 6.00 mg of Opadry II White
  • Immediate release capsules containing 50 mg of the HCI salt of (+)- l -(3,4- dichlorophenyl)-3-azabicyclo[3.1 .OJhexane are prepared using the following ingredients.
  • the "% composition” is the % by weight of the ingredient based upon the total weight of the composition.
  • extended release tablets containing 100 mg of the HCl salt of (+)-l -(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane are prepared using the following ingredients.
  • the "% composition” is the % by weight of the ingredient based upon the total weight of the composition.
  • the tablets are manufactured by direct compression into 3/8" round, standard biconvex tablets.
  • the microcrystalline cellulose used is 90 micron grade.
  • a pregelatinized starch is used in the tablets.
  • the Methocel Premium CR can be Methocel 4 or Methocel 100.
  • Each tablet may also be coated, such as with 5.5% Opadry II White (85F 18422).
  • Dissolution testing of tablets manufactured according to Example XII was performed on tablets containing either Methocel K4 or 100, and tablets were either coated or uncoated. Dissolution Testing was performed using USP Apparatus 2, 50 rpm, 900ml water, 37°C. Table 16
  • results of the dissolution testing confirm that a slow dissolution profile was achieved for an extended release tablet of (+)- l -(3,4-dichlorophenyl)-3- azabicyclo[3. l .0]hexane, HCI salt form.
  • results further show that the (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane was released at or nearly at a continuous or nearly same rate over 24 hours, and in particular was released at a continual or nearly continual/same rate between 2-12 hours ( 120-720 minutes).
  • the amount of (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1 .0]hexane released over 24 hours was from about 65% (68%o in the 100M coated example) to 100%>, and overall averaged about 83%> released, with 3 samples of tablets having released 78, 83, and 100% of the (+)-l -(3,4- dichlorophenyl)-3-azabicyclo[3.1.0]hexane initially contained therein.
  • hexane released after 12 hours following administration was from about 55% to about 70%.
  • Fava M Rush AJ, Thase ME, Clayton A, Stahl SM, Pradko JF, Johnston JA. 15 years of clinical experience with bupropion HC1: from bupropion to bupropion SR to bupropion XL. Prim Care Companion J Clin Psychiatry. 2005;7(3): 106-13 Fava M. Diagnosis and definition of treatment-resistant depression. Biol Psychiatry. 2003;53(8):649-59
  • C CASA Columbia Classification Algorithm of Suicide Assessment
  • Van Londen L Molenaar RP
  • Goekoop JG Goekoop JG
  • Zwinderman AH Rooijmans HG.Three- to 5- year prospective follow-up of outcome in major depression.

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PCT/US2011/063193 2010-12-03 2011-12-02 Preparation and use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in the treatment of conditions affected by monoamine neurotransmitters WO2012075473A1 (en)

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CA2834713A CA2834713A1 (en) 2010-12-03 2011-12-02 Preparation and use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in the treatment of conditions affected by monoamine neurotransmitters
BR112013013572A BR112013013572A2 (pt) 2010-12-03 2011-12-02 métodos para tratar depressão, para aumentar níveis neurotransmissores de monoamina, e para inibir seletivamente a recaptação de amina biogênica, agente, composição, e, forma de dosagem oral unitária
AU2011336318A AU2011336318A1 (en) 2010-12-03 2011-12-02 Preparation and use of (+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane in the treatment of conditions affected by monoamine neurotransmitters
EP11844214.4A EP2646019A4 (en) 2010-12-03 2011-12-02 PREPARATION AND USE OF (+) - 1- (3,4-DICHLOROPHENYL) -3-AZABICYCLO- [3.1.0] HEXANE IN THE TREATMENT OF DISEASES AFFECTED BY MONOAMINE-TYPE NEUROTRANSMITTERS
JP2013542235A JP2013544850A (ja) 2010-12-03 2011-12-02 モノアミン神経伝達物質によって影響を受ける病態の処置における（＋）−１−（３，４−ジクロロフェニル）−３−アザビシクロ［３．１．０］ヘキサンの調製および使用
KR1020137017462A KR20140053822A (ko) 2010-12-03 2011-12-02 (+)-1-(3,4-디클로로페닐)-3-아자비시클로[3.1.0]헥산의 제조방법 및 모노아민 신경전달물질에 의해 영향을 받는 병태를 치료하기 위한 용도

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JP2016518406A (ja) * 2013-05-07 2016-06-23 ユーシミクス・バイオサイエンス・インコーポレイテッドＥｕｔｈｙｍｉｃｓ Ｂｉｏｓｃｉｅｎｃｅ，Ｉｎｃ． 嗜癖障害およびアルコール関連障害を治療するための（＋）−１−（３，４−ジクロロフェニル）−３−アザビシクロ［３．１．０］へキサンの使用
WO2015070156A1 (en) * 2013-11-11 2015-05-14 Impax Laboratories, Inc. Rapidly disintegrating formulations and methods of use
US11701323B2 (en) 2016-06-28 2023-07-18 Trichomeshell Ltd. Dosage form for vaporization and smoking
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US11911513B2 (en) 2018-05-23 2024-02-27 Shanghai Wd Pharmaceutical Co., Ltd Controlled-release system of active pharmaceutical ingredient and preparation method therefor
CN116813547A (zh) * 2023-06-29 2023-09-29 爱斯特（成都）生物制药股份有限公司 一种制备3-氮杂双环[3，2，1]辛烷盐酸盐的方法

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US20140039029A1 (en) 2014-02-06
CA2834713A1 (en) 2012-06-07
EP2646019A4 (en) 2014-05-21
AU2011336318A1 (en) 2013-07-04
US20180256542A1 (en) 2018-09-13
EP2646019A1 (en) 2013-10-09
US20210161863A1 (en) 2021-06-03
US20190358199A1 (en) 2019-11-28
US20120258994A1 (en) 2012-10-11
BR112013013572A2 (pt) 2016-10-11
KR20140053822A (ko) 2014-05-08
JP2019031502A (ja) 2019-02-28
JP2013544850A (ja) 2013-12-19

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