WO2012118562A1 - Compositions and methods for treating depression, adhd and other central nervous system disorders employing novel bupropion compounds, and methods for production and use of novel bupropion compounds and formulations - Google Patents

Compositions and methods for treating depression, adhd and other central nervous system disorders employing novel bupropion compounds, and methods for production and use of novel bupropion compounds and formulations Download PDF

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WO2012118562A1
WO2012118562A1 PCT/US2012/000117 US2012000117W WO2012118562A1 WO 2012118562 A1 WO2012118562 A1 WO 2012118562A1 US 2012000117 W US2012000117 W US 2012000117W WO 2012118562 A1 WO2012118562 A1 WO 2012118562A1
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bupropion
disorder
cns
subject
treatment
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PCT/US2012/000117
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French (fr)
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Arifulla Khan
John Frederick Reinhard, Jr.
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Rhine Pharmaceuticals, Llc
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

Definitions

  • the present invention relates to pharmaceutical compositions and methods for therapeutic use of bupropion. More specifically, the invention relates to enantiomeric brupropion compositions and formulations and methods for manufacturing them and using these materials in therapeutic methods for treating central nervous system disorders.
  • bupropion was discovered over forty five years ago, it is demonstrated by the discoveries presented herein as a heretofore underutilized and incompletely developed psychotropic agent. Bupropion was initially approved for depression and later for facilitating smoking cessation based on a serendipitous discovery. Generic bupropion is commonly used in clinical practice for these approved indications and has also been reported for non- approved indications, including attention deficit hyperactivity disorder (ADHD), tardive dyskinesia, brain disorders, sexual dysfunction, addiction, hypercholesterolemia, ethanol conditions and weight disorders.
  • ADHD attention deficit hyperactivity disorder
  • Bupropion is an atypical antidepressant that has fewer side effects than many antidepressents; however, as noted above the use of bupropion is attended by increased risk of seizures, particularly in certain formulations and at higher dosages. Previous attempts to address this issue focused on development of a slow release bupropion formulation, however continued safety issues perist, including unacceptable increased siezure risk, which have prevented assessment and development of bupropion for many prospective beneficial uses beyond the limited approved uses for depression and smoking cessation, and at elevated dosing ranges and/or frequency.
  • bupropion toxicity may reside unequally in one of the isomeric hydroxylated bupropion metabolites, little is known about the actual in vivo metabolism of bupropion and its enantiomers, or about the metabolism and in vivo pharmacological activity of the various metabolic derivatives thereof.
  • the instant invention fulfills these needs and satisfies additional objects and advantages by providing novel compositions and methods employing an isolated (R)(-) enantiomeric form of bupropion for treating a range of central nervous system (CNS) disorders amenable to treatment using bupropion compounds and drugs that modulate one or more monoamine transporter activity(ies) in vertebrate subjects.
  • CNS central nervous system
  • compositions, formulations and methods of the invention typically employ a stable, often substantially pure, (R)(-) bupropion compound as an effective pharmaceutical agent that is effective to treat or prevent a variety of CNS disorders.
  • (R)(-)bupropion is effective to treat (e.g., to prevent the occurrence or recurrence of, alleviate the severity or duration of, or moderate one or more symptoms of) a CNS disorder affected by a defect, disturbance or imbalance in monoamine neurotransmitter receptor or biogenic amine physiology, including CNS disorders treatable by inhibiting norepinephrine and/or dopamine reuptake.
  • compositions and formulations described herein are useful for as a therapeutic agent against (i.e., for the prevention, treatment, amelioration, alleviation and/or reduction of symptoms of) a variety of CNS disorders in vertebrate subjects, most typically mammalian subjects such as humans suffering from a CNS disorder.
  • CNS disorders and related conditions amenable to treatment using the methdos and compositions of the invention include, but not limited to, depression, treatment resistant depression (TRD), seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder (HSDD), addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity.
  • TRD depression, treatment resistant depression
  • TRD seasonal affective disorder
  • bipolar disorder epsy
  • cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome
  • male and female sexual dysfunction including male and female hyposexual desire disorder (HSDD)
  • addictive disorders including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid
  • compositions and methods herein are effectively employed to enhance cognitive function and/or memory, to alleviate cognitive and other symptoms associated with Parkinson's disease, Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
  • novel compositions and methods are provided that employ substantially pure (R)(-)bupropion to treat a targeted CNS condition in a mammalian subject, while reducing the incidence or severity of one or more adverse effects associated with bupropion therapy.
  • the achievement of therapeutic effects and attendant reduction in side effects elicited by (R)(-)bupropion is interrelated with a reduction in the presence and/or level of 2(R)(-) hydroxybupropion, an undesirable metabolite with limited activity and/or unacceptable toxicity, in treated individuals.
  • the invention employs substantially pure (R)(-) bupropion to treat a CNS condition in a mammalian subject while increasing the presence and/or level of 2(S)(+) hydroxybupropion, a highly therapeutic metabolite with desired safety characteristics, in the subject.
  • administering a selected therapeutic dose of (R)(-)bupropion to patients with a CNS condition will exhibit at least a 10%-20%, 25%-50%, 50%-75%, or even 90-100% reduction in measurable symptoms or other indices of therapeutic efficacy for treating the CNS condition, and a concomitant reduction, by at least 10%-20%, 25%-50%, 50%-75%, or even 90-100% of observed side effects compared to therapeutic and side effects observed for the same dose of racemic or (S)(+) bupropion.
  • Symptoms of CNS disorders that can be included as indices for determining therapeutic efficacy of the methods and compositions of the invention include, but are not limited to, any one or more symptoms or suittes of symptoms considered diagnostic in the clinical arts, for example in the case of ADHD, depression and other mental disorders those presented in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (2000), Text Revision (DSM-IV-TR), American Psychiatric Association, Washington, D.C., incorporated herein by reference.
  • the methods and compositions of the invention allow for reduced dosing of patients to achieve an equivalent therapeutic benefit and/or side effect profile compared to therapeutic effects exhibited by racemic or (S)(+) bupropion.
  • the invention includes novel dosage forms comprising a therapeutically effective dose of (R)(-) bupropion that is 10%-20%, 25%-50%, 50%-75%, or even more than 75% reduced in comparison to a therapeutically equivalent dose of racemic bupropion.
  • substantially pure (R)(-) bupropion in combination with one or more additional therapeutic agents effective to prevent, treat, ameliorate, alleviate or reduce signs and symptoms of a targeted CNS disorder in a vertebrate subjects amenable to treatemtn with bupropion.
  • Exemplary combinatorial formulations and coordinate treatment methods employ (R)(-) bupropion in combination with one or more secondary therapeutic agent(s), typically psychotherapeutic agent(s), including, but not limited to, drugs from the general classes of antidepressants, mood-stabilizing, anxiolytic, anticonvulsant, antipsychotic, antiaddictive, stimulants, muscle relaxants and sleep medications, antiepileptics, medications for Parkinson's disease, Alzheimer's medications, medications for ADHD, opioids, and appetite suppressant drugs in combination with substantially pure (R)(-) bupropion.
  • substantially pure (R)(-) bupropion and the secondary therapeutic agent(s) are administered concurrently, or sequentially in any order, to prevent or P T/US2012/000117
  • the (R)(-) bupropion compositions and the additional or secondary therapeutic agent(s) may be combined in a novel, combinatorial formulation or combined dosage form, or administered at the same time in separate dosage forms in amounts collectively effective to treat the target CNS condition.
  • Figure 1 is a graph illustrating the relationship between R-bupropion concentration and velocity of metabolism of the R-hydroxybupropion and S-hydroxybupropion metabolites in a standard human liver microsome assay (results measured at ten minutes).
  • Figure 2 is a multipanel graphic illustration of enantioselective inhibition of
  • Figure 3 is a graph depicting the racemization over time at different pH conditions of bupropion preparations including enantiomerically purified (R)(-) bupropion, demonstrating the criticality of pH for stable formulation of (R)(-) bupropion for clinical use within the invention.
  • the instant invention provides novel methods and compositions employing an isolated (R)(-) enantiomer of bupropion which is more therapeutically effective with fewer side effects than clinically-established, racemic forms of bupropion, along with methods for using (R)(-) bupropion compositions and formulations to treat important diseases and conditions of the central nervous system (CNS) in vertebrate subjects, particularly humans and other mammalian subjects.
  • CNS central nervous system
  • Bupropion ( ⁇ )-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-propanone, is described for example in U.S. Pat. Nos. 3,819,706 and 3,885,046. Bupropion is widely reported on as an atypical antidepressant possessing norepinephrine reuptake inhibitory and nicotinic acetylcholine receptor antagonistic activities. Currently, bupropion is primarily used clinically to treat depression and as an aid in smoking cessation. It has also been reportedly investigated for use to treat seasonal affective disorder, treatment resistant T US2012/000117
  • depression restless leg syndrome
  • bipolar disorder attention deficit hyperactivity disorder (ADHD)
  • sexual dysfunction Parkinson's disease
  • addiction hypercholesterolemia
  • narcolepsy neuropathic pain
  • obesity obesity
  • Additional side effects reported for bupropion include: severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue, unusual hoarseness); blurred vision or other vision changes; reduced sexual desire or impaired sexual performanc; chest pain; confusion; dark urine; delusions; fainting; fast or irregular heartbeat; fever, chills, or sore throat; hallucinations; hearing problems; menstrual changes; new or worsening mental or mood changes; agitation; restlessness; red, swollen, blistered, or peeling skin; seizures; severe headache or dizziness; severe or persistent joint or muscle pain; severe or persistent nausea, vomiting, or stomach pain; severe or persistent nervousness, restlessness, or trouble sleeping; shortness of breath; suicidal thoughts or attempts; tremor; unusual swelling; yellowing of the skin or eyes, among others (See, The Physician's Desk Reference, PDR network, LLC (2009)).
  • Bupropion and its principal metabolites are chiral molecules, however, none of the isomeric forms of bupropion or any of its metabolites have been developed for clinical use.
  • Bupropion enantiomers can be labeled structurally (R or S), optically (+, d or -, 1) or by their relative spatial configuration (D/L).
  • substituents are each assigned a priority based on atomic number according to the Cahn-Ingold-Prelog priority rules.
  • An enantiomer can also be named for the direction it rotates polarized light. If it rotates the light clockwise, that enantiomer is labeled (+) or (d) for dextrotatory.
  • an enantiomer can be labeled by its relative configuration to glyceraldehyde using the D/L system. Enantiomers may have the same, or entirely different, activities from the corresponding racemate and/or from the alternate enantiomer, and these disparate activity profiles cannot be predicted or determined without careful, detailed and successful experimentation.
  • ibuprofen is a mixture of the (S) and (R) enantiomers, with the (S) enantiomer being the most effective and the (R) enantiomer only being used after conversion to the (S) enantiomer by 2-arylpropionyl-CoA epimerase. With ketamine, the (S)-enantiomer is an anesthetic, but the (R)-enantiomer is a hallucinogen.
  • a surprising discovery of the present invention is that an isolated, substantially pure and stable (-)- 1 -(3-chlorophenyl)-2-[(l , 1 - dimethylethyl)amino]-l-propanone (hereafter (R)(-) bupropion, as shown below) composition is an unexpectedly potent and safe drug agent for the treatment of a wide range of important CNS disorders in humans and other subjects.
  • (R)((-) bupropion is useful to prevent, eliminate or alleviate symptoms of targeted CNS conditions amenable to treatment by modulation of biogenic amine reuptake and/or using racemic bupropion, with enhanced potency and reduced side effects compared to racemic bupropion.
  • Subjects amenable to treatment employing the methods and compositions of the invention include, but are not limited to, humans and other mammals suffering from CNS disorders selected from depression, treatment resistant depression, seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder, addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity.
  • ADHD attention deficit hyperactivity disorder
  • R e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation
  • gambling addiction e.g., and sex addiction
  • R)(-) bupropion compositions and methods herein are effectively employed to enhance cognitive function and/or memory
  • Parkinson's disease Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
  • Bupropion is a chiral compound with two enantiomers, (+)-l-(3-chlorophenyl)-2- [(1,1 -dimethylethyl)amino] - 1 -propanone and (-)- 1 -(3 -chlorophenyl)-2- [(1,1- dimethylethyl)amino]-l -propanone ((S)(+) and (R)(-) bupropion, respectively, as shown below): (S)(+) Bupropion (R)(-) Bupropion
  • the methods and compositions of the invention employ substantially pure (R)(-) bupropion or compositions and formulations that are artificially enantiomerically enriched for (R)(-) bupropion.
  • substantially pure (R)(-) bupropion or “enantiomerically pure (R)(-)bupropion” refers to a composition that is artificially enriched to contain, in stable form, more (R)(-) bupropion than (S)(+) bupropion, wherein the (R)(-) bupropion occurs in an enantiomeric excess (ee) of at least about 60%, 70%, 75%, 80%, up to approximately 90% or greater, up to 95% or greater ee.
  • compositions of the invention employ highly purified or isolated (R)(-) buproprion (at least as a starting material prior to administration, formulation or storage) in an enantiomeric excess of up to 98% or greater, e.g., as determined by chiral chromatography and/or optical purity assay.
  • Preparations of (R)(-) bupropion in enantiomeric excess greater than 80% or 90% are considered substantially free of the corresponding (S)(+) bupropion enantiomer and are highly desired drug preparations for clinical use.
  • pharmaceutical compositions of the invention for treating CNS disorders as described herein will contain no more than about 5% w/w, and in some embodiments no more than about 2% or even 1% w/w, of the
  • (S)(+) bupropion enantiomer i.e., measured as a percent of all bupropion, including racemate and (R)(-) and (S)(+) enantiomers, present in the composition).
  • At equivalent dosing with racemic and/or (S)(+) bupropion, (R)(-) bupropion within the compositions and methods of the invention will show relative increased therapeutic efficacy of least 10%, 20%, 30%, or 50%, up to 75-95%, 100% or even 200% than observed for the racemic and/or (S)(+) bupropion, and a reduction in occurrence and/or severity of side effects of as much as 10%, 20%, 30%, or 50%, up to 75-95% or more compared to observed side effect values for racemic or (S)(+) bupropion.
  • bupropion creates a complex array of compounds whose enantiomeric forms are poorly known, particularly in terms of their therapeutic efficacy and side effect profiles.
  • bupropion is extensively metabolized by cytochrome P450 2B6 (CyP2B6) and forms several active metabolites including hydroxybupropion, threo- hydrobupropion and ery/Aro-hydrobupropion, all of which contain at least one chiral center as shown below.
  • Threohydrobupropion HCI 0% 10% 90%
  • bHydroxybupropion is metabolized and present in human plasma following dosing of the parent compound bupriopion HCI
  • Bupropion 100 100 0 Bupropion 300 100 80
  • R-Hydroxybupropion 300 100 100 S-Hydroxybupropion 100 0 0 S-Hydroxybupropion 300 100 0
  • hydroxybupropion arises metabolically from the (R)(-) isomer of bupropion.
  • racemic bupropion and its two isomers were incubated in increasing concentrations of racemic bupropion, (R)(-) bupropion, and (S)(+) bupropion in human liver microsomes using conventional liver microsomal incubation and assay methods.
  • Table 3 below, both bupropion and S-bupropion led to the formation of R, R-hydroxybupropion, whereas R-bupropion surprisingly yielded detectable levels of only the S,S-hydroxybupropion metabolite.
  • these findings are consistent with data reported by Kharash et al. (2008) examining stereoselective bupropion hydroxylation as a phenotypic probe for CYP2B6 activity.
  • R-Bupropion 3110 2A 0 aMetabolites were placed in human hepatic microsomes for 30 minutes and 37 degrees C using 200 g of microsomal protein per sample in vitro.
  • Circling stereotyped movement around the periphery of the test chamber. Hypo- and hyperactivity was observed within a one hour post-administration observation period.
  • neurotransmitter reuptake are strongly enantioselective for bupropion, with the (R)(-) enantiomer being a substantially more potent inhibitor of dopamine and norepinephrine transporters (see Figure 2).
  • Non-Specific Ligand 10 ⁇ Nomifensine
  • Non-Specific Ligand 10 ⁇ Desipramine
  • Coefficients significantly different than 1.0 may suggest that the binding displacement does not follow the laws of mass action with a single binding site.
  • (R)(-) bupropion was the most potent with an apparent Ki of 9.77 ⁇ , a value ⁇ 65-fold higher than inhibition of the dopamine transporter by this distinctly therapeutically active enantiomer.
  • (S)(+)-Bupropion was approximately half as potent as the (R)(-) enantiomer at the dopamine transporter, with an apparent Ki of 20.3 ⁇ , while racemic bupropion had an intermediate value of 14.7 ⁇ .
  • racemic bupropion administration of racemic bupropion and the attendant high toxicity associated with elevated levels of that molecule.
  • compositions, formulations and methods employing an isolated (R)(-) enantiomer of bupropion to treat a range of central nervous system (CNS) disorders in vertebrate subjects amenable to treatment with drugs that modulate monoamine transporter activity(ies).
  • CNS central nervous system
  • compositions, formulations and methods are provided that employ a stable, substantially pure (R)(-) bupropion compound as an effective pharmaceutical agent for treating a variety of CNS disorders.
  • (R)(-) bupropion including pharmaceutically acceptable salts, solvates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of (R)(-) bupropion, is effective for treating (e.g., preventing or alleviating symptoms, or moderating the length and/or severity of) CNS disorders affected by
  • the pharmaceutical agents comprising purified (R)(-) bupropion as described herein are useful for the prevention, treatment, amelioration, alleviation and reduction of one or more symptoms of a variety of CNS disorders in vertebrate, most typically mammalian, subjects suffering from central nervous system disorders including those generally treated with bupropion, such as, but not limited to, depression, treatment resistant depression, seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder, addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity.
  • ADHD attention deficit hyperactivity disorder
  • sex addiction e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and
  • compositions and methods herein are effectively employed to enhance cognitive function and/or memory, to alleviate cognitive and other symptoms associated with Parkinson's disease, Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
  • Efficacy of the pharmaceutical agents and methods of the invention employing purified (R)(-) bupropion can be demonstrated using any known, art-accepted index that docoments the incidence or records or determines the severity, symptomology, or therapeutic efficacy of drug agents and methods for treating CNS disorders.
  • Many such methods and tools for determining therapeutic efficacy are known and routinely utilized for clinical assessment of the full array of treated CNS conditions in humans, and comparable indices and tools are routinely employed for non-human vertebrate treatment assessment in the veterinary arts.
  • a purified (R)(-) bupropion composition, formulation or method according to the invention will be administered to a mammalian submect in a therapeutically effective amount and or dosing regimen to yield a clinically significant thereapeutic benefit against a targeted CNS disorder, condition or symptom(s) in the subject.
  • (R)(-) bupropion compositions, formulations and methods of the invention will yield at least a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30-50% reduction, 50-75% reduction, up to at least a 75-90% reduction, and as much as a 95% reduction ranging to complete elimination prevention, remission of the individual incidence, symptom occurrence or severity, adverse sequelae, disease recurrence, population disease rate indices between treated and non-treated groups, or any other clinically useful index or suite of observational statistics sufficient to reasonably quantify disease risk, occurrence, status, severity, recurrence, or remission, or otherwise quantitatively assess drug therapeutic efficacy for prevention, treatment, amelioration, alleviation and or reduction of one or more symptom(s) associated with a targeted CNS disorder or condition.
  • compositions and methods that employ substantially pure (R)(-) bupropion in a therapeutically amount effective to treat a CNS condition (e.g., by reducing one or more adverse symptoms of a CNS condition) in a vertebrate subject, while reducing the incidence or severity of one or more adverse effects associated with bupropion therapy in comparison to the incidence or severity of the same side effect(s) in a comparative test subject administered the same amount of racemic bupropion or substantially pure (S)(+) bupropion.
  • Adverse effects are harmful or undesirable effects of pharmaceuticals that may occur at any point during a treatment period. They may range from irritating to fatal side effects, and can result from individual patient physiology or
  • a purified ( )(-) bupropion composition, formulation or method according to the invention will be administered in a side-effect ameliorating effective amount and/or dosing regimen to a mammalian subject to yield a clinically significant reduction of one or more of the foregoing adverse effects known in the art to be associated with racemic bupropion drug treatment.
  • (R)(-) bupropion compositions, formulations and methods of the invention will yield at least a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30- 50% reduction, 50-75% reduction, up to at least a 75-90% reduction, and as much as a 95% reduction ranging to total elimination prevention, remission of the individual incidence, occurrence or severity, or of population adverse event rates, including but not limited to: seizure; allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue, unusual hoarseness); blurred vision or other vision changes; reduced sexual desire or impaired sexual performanc; chest pain; confusion; dark urine; delusions; fainting; fast or irregular heartbeat; fever, chills, or sore throat;
  • the enhanced therapeutic efficacy of (R)(-) bupropion over efficacy profiles determined for other CNS-therapeutic drugs, including racemic bupropion and (S)(+), is demonstrated by side-by-side efficacy comparisons employing any of the clinical efficacy methods and tools described herein.
  • a selected therapeutic dose of (R)(-)bupropion administered to a patient presenting with a targeted CNS disorder will elicit increased therapeutic effects, for example as demonstrated by at least a 10%-20% comparative reduction in measurable symptoms of targeted CNS disorder (or other index of therapeutic efficacy for treating the targeted CNS condition in the patient) after an effective treatment period.
  • (R)(-) bupropion-treated patients ehibit at least a 50%-75% comparative reduction in measurable symptoms of the targeted CNS disorder compared to symptom reduction or other therapeutic efficacy value determined for racemic bupropion- or (S)(+) bupropion administered at an equal dosage and comparable treatment period to control subjects.
  • compositions and methods employing substantially pure (R)(-) bupropion in an amount effective to treat a targeted CNS condition while at the same time reducing an incidence and/or level of 2(R)(-) hydroxybupropion in a plasma or CNS compartment of the individual selected for bupropion treatment.
  • administering yields a lower incidence and/or level of 2(R)(-) hydroxybupropion detected in a sample from blood or a selected CNS compartment (e.g., CNS tissue, a targeted CNS organ such as the brain, or cerebrospinal fluid) at a predetermined time after administration, than will be detected in a sample collected contemporaneously from a test subject administered the same amount of racemic bupropion or substantially pure (S)(+) bupropion.
  • a selected CNS compartment e.g., CNS tissue, a targeted CNS organ such as the brain, or cerebrospinal fluid
  • FIG. 1 A block diagram illustrating an exemplary computing environment in accordance with the invention.
  • FIG. 1 A block diagram illustrating an exemplary computing environment in accordance with the invention.
  • FIG. 1 A block diagram illustrating an exemplary computing environment in accordance with the invention.
  • FIG. 1 A block diagram illustrating an exemplary computing environment in accordance with the invention.
  • FIG. 1 A block diagram illustrating an exemplary computing environment in accordance with the invention.
  • (R)(-) bupropion is administered to the subject in a therapeutic dose which yields an attendant increased incidence and/or level of 2(S)(+) hydroxybupropion in a blood or CNS sample at a predetermined time after administration compared to the incidence or level detected in a comparable sample from a test subject administered the same amount, or an equivalent therapeutic amount (i.e., an amount that yields essentially equivalent therapeutic results, irrespective of dosage and side effects) of racemic bupropion or (S)(+) bupropion.
  • an equivalent therapeutic amount i.e., an amount that yields essentially equivalent therapeutic results, irrespective of dosage and side effects
  • administration of (R)(-) bupropion yields an incidence and/or level of 2(S)(+) hydroxybupropion in a blood or CNS sample of a subject that is increased by at least 10%-20%, 25%-35%, 40%-60%, 75%-95%, up to 100% and even two- fold or greater than the incidence and/or level of 2(S)(+) hydroxybupropion observed in a comparable sample from a test subject administered the same amount, or an equivalent therapeutic amount of racemic bupropion or (S)(+)bupropion.
  • administering (R)(-)bupropion within the compositions and methods described herein of the invention yields therapeutic effects with attendant reduction of effects, mediated in part by a reduction in the presence and/or level of 2(R)(-) hydroxybupropion in the treated individual (e.g., as measured comparatively in blood plasma or CNS samples between individuals dosed equivalently with either (R)(-)bupropion, or racemic or (S)(+) bupropion).
  • the reduced side effects are correlated qualitatively or even quantitatively with the reduction in incidence and or levels of 2(R)(-) hydroxybupropion detected in comparative test samples.
  • subjects administered a dose of (R)(-)bupropion that is therapeutic for treating a selected CNS disorder e.g., depression, ADHD, addiction
  • a selected CNS disorder e.g., depression, ADHD, addiction
  • subjects administered a dose of (R)(-)bupropion that is therapeutic for treating a selected CNS disorder who exhibit a 10-25%, 30-50%, or even 75% or greater reduction in adverse effects of bupropion compared to those observed in individuals administered the same (therapeutic or subtherapeutic) dose of racemic bupropion or substantially pure (S)(+)bupropion
  • will exhibit a qualitatively or quantitavely related or even directly proportionate e.g., generally in a dose-responsive relationship
  • reduced incidence or level of 2(R)(-) hydroxybupropion in plasma or CNS test samples compared to the incidence or level of 2(R)(-) hydroxybupropion detected in comparable test samples from subjects receiving the same amount, or equivalent therapeutic amount, of racemic or (S)(+)
  • administration of (R)(-)bupropion yields an incidence and/or level of 2(R)(-) hydroxybupropion in a blood or CNS sample of a subject that is decreased by at least 10%-20%, 25%-35%, 40%-60%, up to 75%-95%, or even as much as 100% compared to the incidence and/or level of 2(R)(-) hydroxybupropion observed in a comparable sample from a test subject administered the same amount, or an equivalent therapeutic amount of racemic bupropion or (S)(+)bupropion.
  • compositions and methods that employ a therapeutically effective dose of substantially pure (R)(-)bupropion that reduces first-pass formation of 2(R)(-) hydroxybupropion in a plasma or CNS sample of a treated individual in comparison to first-pass formation of 2(R)(-) hydroxybupropion in plasma or CNS sample from a subject administered the same amount, or a therapeutically equivalent dose, of racemic bupropion.
  • the first-pass formation of 2(R)(-) hydroxybupropion in plasma or CNS samples of (R)(-)bupropion-treated individuals will be reduced by at least 10-25%, 30-50%, 75%-90% or even 95% or greater compared to the first-pass formation of 2(R)(-) hydroxybupropion detected in like-treated individuals receiving bupropion racemate or (S)(+)bupropion.
  • the novel properties of (R)(-) bupropion compositions and methods of the invention yield a combination of beneficial pharmacological effects, including: a measurable increase in therapeutic effects; reduction of adverse effects; and coordinate increase of thereapeutic 2(S)(+) hydroxybupropion and decrease of 2(R)(-) hydroxybupropion incidence and/or levels, compared to therapeutic effects, side effects and relative 2(S)(+) hydroxybupropion and 2(R)(-) hydroxybupropion incidence and or levels observed after administering the same amount of racemic or substantially pure (S)(+)bupropion.
  • the (R)(-)bupropion compositions and methods of the invention provide enhanced therapeutic effects at lower bupropion dosages in comparison to the dosage/efficacy of racemic bupropion or (S)(+) bupropion, also yielding reduced side effects at the same, or even higher, dosages compared to racemic or (S)(+) bupropion.
  • administering a selected therapeutic dose of (R)(-)bupropion to a patient presenting with a CNS condition as described herein will yield at least a 10%-20%, 25%-50%, 50%-75%, or even 90-100% reduction in the patient of measurable symptoms of the CNS disorder, or other indices of therapeutic efficacy for treating the targeted CNS condition, attended by at least a 10%-20%, 25%-50%, 50%-75%, or even 90-100% reduction in observed side effects (e.g., seizure incidence, loss of sexual desire, occurrence/severity of allergic reaction) compared to a therapeutic efficacy and side effect profile determined after administration of a same dose of racemic or (S)(+) bupropion.
  • the methods and compositions of the invention provide for reduced dosing of patients while achieving an equivalent therapeutic benefit and/or side effect profile compared to therapeutic and side effects exhibited by racemic or (S)(+) bupropion.
  • the invention provides novel dosage forms of bupropion comprising a therapeutically effective dosage (with acceptable side effect profile) of (R)(-)bupropion that is 10%-20%, 25%-50%, 50%-75%, or even more than 75% reduced (e.g., by weight of active compound) compared to an established, equivalently therapeutic dose (with equal or greater adverse effect profile) of racemic or (S)(+) bupropion.
  • novel therapeutic dosages of (R)(-)bupropion will typically be selected that are within the aforementioned ranges of reduced weight of active compound in comparison to a predetermined relative amount of racemic bupropion tested and shown to yield approximately equivalent therapeutic efficacy (e.g., by reduction in measurable symptoms or other indices of the incidence or severity of a targeted CNS condition) and side effect profile.
  • a dose of 200 mg of a sustained release (SR) formulation of racemic bupropion administered twice daily is determined to yield a baseline therapeutic efficacy (i.e., minimum efficacy considered satisfactory by physicians for positive treatment effectiveness) against, e.g., depression, ADHD, stimulant addiction, or male or female hyposexual desire disorder
  • a twice daily dosage of ( )(-) bupropion that is, for example, 150 mg - 200 mg, 150 mg or less, 100 mg - 150 mg, 100 mg or less, 50 mg - 100 mg, or even 50 mg or 25 mg or less.
  • the invention provides for reduced dosing in accordance with the foregoing by lowering the frequency of dosing, thus in the preceding example an equivalent therapeutic benefit to a 200 mg twice daily dose of racemic bupropion will be achieved by a once daily dosing regimen of between about 200 mg and 400 mg or less, for example 250 mg - 400 mg, 200 mg - 300 mg, 150 mg - 250 mg, 150 mg or less, or even less than or equal to 100 mg or 50 mg.
  • substantially pure (R)(-) bupropion in combination with one or more additional therapeutic agents effective to prevent, treat, ameliorate, alleviate or reduce signs and symptoms of a targeted CNS disorder in a vertebrate subjects amenable to treatemtn with bupropion.
  • Exemplary combinatorial formulations and coordinate treatment methods employ (R)(-) bupropion in combination with one or more secondary therapeutic agent(s), typically psychotherapeutic agent(s), including, but not limited to, drugs from the general classes of antidepressants, mood-stabilizing, anxiolytic, anticonvulsant, antipsychotic, antiaddictive, stimulants, muscle relaxants and sleep medications, antiepileptics, medications for Parkinson's disease, Alzheimer's medications, medications for ADHD, opioids, and appetite suppressant drugs.
  • substantially pure (R)(-) bupropion and the secondary therapeutic agent(s) are administered concurrently, or sequentially in any order, to prevent or treat one or more symptoms of the targeted CNS disorder.
  • the (R)(-) bupropion compositions and the additional or secondary therapeutic agent(s) may be combined in a novel, combinatorial formulation or combined dosage form, or administered at the same time in separate dosage forms in amounts collectively effective to treat the target CNS condition.
  • Substantially pure (R)(-) bupropion enantiomer for use within the invention may be prepared by any means generally used to separate enantiomeric forms including, but not limited to, crystallization, the use of chiral acids, oxidation of corresponding chiral amino alcohols (Berrang, B.D., et al, 1982), reduction with BH 3 -THF, liquid chromatography, gas- liquid chromatography, chiral columns, high performance liquid chromatography (HPLC), the use of an ovomucoid column, electrokinetic chromatography, selective reaction of one reaction of one enantiomer with an enantiomer-specific reagent, and the use of highly sulfated cyclodextrins among others.
  • specific enantiomers 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.
  • the (R)(-) enantiomer of bupropion can reportedly be prepared by asymmetric synthesis as described previously (Musso et al. 1993, Fang et al. 2000, each incorporated herein by reference). However, the enantiomeric composition and purity of the products produced within these reports are not certain or fully characterized, while attempts to reproduce the reported assymetric synthetic method of Fang et al. were unsuccessful for yielding usable drug product to administer to study subjects.
  • bupropion enantiomers can be prepared by successful by chiral chromatography, e.g. supercritical fluid chromatography.
  • novel assmetric synthetic methods for obtaining a purified (R)(-) enantiomer of bupropion is provided, characterized by incorporating non-basic conditions, for example between a pH of 0.5 and 2.0 for crystallization of the (R)(-) bupropion.
  • novel assmetric synthetic methods are provided for obtaining a purified (R)(-) enantiomer bupropion characterized in that the crystallization of the (R)(-) enantiomer is carried out at a substantially reduced temperature, e.g., between about 2°C and 10°C.
  • substantially pure (R)(-) bupropion compositions having a demonstrated chiral purity, as expressed in terms of enantiomeric excess (ee), of at least 90% ee, and in certain embodiments up to at least 95% ee, 96% ee, 97% ee or greater.
  • the assymetric synthesis methods of the invention generated highly enantiomerically pure (R)(-) bupropion compositions that were greater than 97% ee in purity.
  • Racemic bupropion hydrochloride (24.9 g, 90.2 mmol) was suspended in ethyl acetate (400 mL) with magnetically stirring. To the stirred suspension was added at 25°C an aqueous solution of sodium hydrogencarbonate (17.0 g in 300 mL HPLC quality water; 202.5 mmol, 2.25 equivalents) in several portion over 5 min. The resulting two phase system was stirred for further 5 min and then transferred into a separation funnel. The organic layer was isolated and dried over anhydrous MgS04 (30 g). The solution was filtered and the drying agent washed with several portion of fresh ethyl acetate (2 x 50 mL).
  • Feed solution preparation Bupropion trifluoroacetate (31.7 g), prepared as described above, was dissolved in 1.40 L of a mixture of hexane:2-propanol (80:20 (v/v)).
  • Residual solvent was also determined by GC, with results are as follows:
  • (R)(-) bupropion has been formulated in a stable capsular form, with novel pH and moisture content characteristics, that exhibited 100% stability at room temperature after three months.
  • compositions remained stably enantiomerically enriched.
  • test solutions of (R)(-) bupropion were prepared at various graded, buffered pH levels. These solutions were subsequently assayed for changes in (R)(-) bupropion enantiomeric excess (% ee) values over time, empoying the following materials and conditions according to conventional protocols.
  • an acidic excipient may be added as a buffer to maintain an acidic pH to avoid racemization.
  • a suitable pH for a stable, clinically useful (R)(-) bupropion should never be higher than about pH 4.0, or pH 3.5, and in most circumstances (R)(-) bupropion should not be exposed to a less acidic pH than at or below about pH 3.0. Indeed, for stable isolation, synthesis, formulation, manufacture and storage, to yield a stable (R)(-) bupropion product free of unacceptable levels of
  • (R)(-) bupropion was combined with a suitable amount of a citric acid carrier/buffering agent, along with a silica filler/handling agent, yielding a stable pH of the formulation below about pH 2.0, and this formulation maintained a substantially enantiomerically pure state of the (R)(-) bupropion for extended storage periods, up to six weeks or longer.
  • Suitable pH stabilizing carriers/buffering agents for formulating (R)(-) bupropion in an enantiomerically stable formulation include, in addition to citric acid, any suitable, physiologically acceptable acid that is compatable with (R)(-) bupropion to preclude reaction or degradation and which will help prevent racemization of the (R)(-) bupropion by buffering the pH of the formulation within the accepted acidic ranges noted above, preferably between about pH 0.5 and pH 2.0, and in certain embodiments at or below about pH 1.5, or pH 1.0.
  • Exemplary candidates in this context include, but are not limited to, salicylic acid, tartaric acid, succinic acid, and fumaric acid.
  • suitable buffering/carrier candidates in this context include, but are not limited to, glycopyrrolate, sorbitol, and tween 80.
  • Inclusion of one or more of these and other prospective suitable buffering carrier agents within (R)(-) bupropion formulations of the invention provide for maintenance of enantiomeric stability of the formulation for extended periods, for example more than two weeks, up to a month or longer, up to two months or longer, up to three to four months or longer, six months or longer, and even for periods of up to six months to a year, during which time substantially pure (R)(-) bupropion remains essentially stable, such that it maintains (R)(-) bupropion purity at 90% ee or greater throughout the subject stability period.
  • the invention provides pH stabilized and substantially anhydrously produced, formulated and packaged, pharmaceutical compositions having, in exemplary embodiments, an enantiomeric purity of the (R)(-) bupropion of 95% ee or greater after a stability period (i.e., a storage period after isolation and crystallization of the (R)(-) bupropion at room temperature or higher temperature conditions) of at least two weeks.
  • a stability period i.e., a storage period after isolation and crystallization of the (R)(-) bupropion at room temperature or higher temperature conditions
  • pharmaceutical compositions are provided which have enantiomeric purity of (R)(-) bupropion of at least 75% ee or greater after an extended stability period of four-six weeks.
  • the pharmaceutical compositions of the invention exhibit an enantiomeric purity of (R)(-) bupropion of 85% ee or greater after a stability period of four-six months.
  • pharmaceutical compsitions can be provided according to the teachings herein which have a documented long-term stability as reflected by enantiomeric purity of (R)(-) bupropion of at least 60% ee, 75% ee, 80% ee, 85% ee, or even 90% ee or greater after an extended stability period of six months, even under high temperature storage conditions above room temperature up to 40 degrees centigrade or higher.
  • compositions of the invention should be maintained under as anhydrous conditions as possible, preferably to exclude even trace quantities of water altogether.
  • (R)(-) bupropion was formulated as described above, and sealed in water-tight container, optionally with a dessicant present in a sufficient amount to absorb all incidental moisture present in the formulation and container (and any other ingredients and/or packing materials) upon sealing of the drug product within the container.
  • the invention provides pharmaceutical kits for treating a CNS disorder comprising (R)(-) bupropion in an enantiomerically stable form.
  • (R)(-) bupropion is provided in combination with container means to stably contain the (R)(-) bupropion in a water-tight, essentially anhydrous enclosure.
  • the container is a water-resistant plastic or other suitable, sealable container that includes water- barrier means to effectively seal the (R)(-) bupropion (and optional secondary therapeutic agent) in a water-proof container chamber, which is thereafter sealed to maintain the (R)(-) bupropion essentially free of exogenous water and in an essentially enantiomerically stable 000117
  • the container is a high density plastic, such as a PTFE or other polyethylene plastic, and the lip and lid of the container are sealable against one another to anhydrously seal the container chamber upon closure of the (R)(-) bupropion therein.
  • sealing means of the container include use of a heat-resistant, sealable undersurface (e.g., a foil undersurface) comprising the sealing gasket means or undersurface of the lid, which is placed in contact with the lip of the lid upon closure/sealing of the sealable container.
  • the sealing gasket or sealable undersurface of the lid is seated under heat and optionally pressurized conditions to form a thermal seal against the lip of the container, optionally leaving a partial vacuum within the container after sealing and cooling to further preclude exposure of the (R)(-) bupropion within the container to water.
  • suitable packaging methods, materials and devices are provided within the invention, suitable packaging materials and products are provided to maintain essential enantiomeric stability of (R)(-) bupropion formulations for extended periods, for two weeks or more, up to a month or longer, up to two months or longer, up to three to four months or longer, six months or longer, and for periods of up to six months to a year, during which stability periods the substantially pure (R)(-) bupropion originally packaged in the container remains essentially stable with the (R)(-) bupropion purity remaining at or above 90% ee.
  • compositions and methods of the invention employing (R)(-) bupropion) are therapeutically useful for treating a broad range of CNS disorders amenable to treatment using bupropion and/or by modulation of monoamine neurotransmitter and/or monoamine neurotransmitter receptor levels or physiology.
  • Subjects amenable to treatment according to the invention include mammalian subjects, including humans, suffering from or at risk for any of a variety of CNS disorders, including CNS disorders previously approved for treatment using racemic bupropion, namely depression and smoking cessation difficulties, and some conditions incidently addressed in off-label bupropion racemate use reports, including attention deficit hyperactivity disorder (ADHD), sexual dysfunction, addiction, and eating and weight disorders.
  • ADHD attention deficit hyperactivity disorder
  • (R)(-) bupropion) refers to enantiomerically enriched isolates of (R)(-) bupropion as described herein, including (R)(-) bupropion compositions and products produced by a process according to any of the synthetic, purification, handling, formulation or packaging processes described herein.
  • (R)(-) bupropion compostions for use within the invention will include pharmaceutically acceptable salts, solvates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of (R)(-) bupropion.
  • salts include inorganic and organic acid addition salts, base salts and metal salts, including but not limited to 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, benz
  • Suitable base salts are formed from bases which form nontoxic salts and include, for example, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts.
  • pharmaceutically compatable solvates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of (R)(-) bupropion can be selected and developed or use within the invention without undue experimentation.
  • Prodrugs of (R)(-) bupropion are particularly useful wihin 000117
  • (R)( ⁇ ) bupropion covalently bonded with a carriers which releases the active parent drug in vivo examples include, for example, esters or amides of (R)(-) bupropion with hydroxyalkyl or aminoalkyl as a substituent, though a wide range of useful alternative prodrugs can be routinely identified and developed according to the teachings herein.
  • compositions and methods employing (R)(-) bupropion) described herein are therapeutically effective for treating a novel expanded range of CNS disorders amenable to treatment using bupropion and/or by modulation of biogenic amine and/or monoamine receptor levels and/or physiology including, but not limited to, depression, treatment resistant depression, seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder, addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity.
  • ADHD attention deficit hyperactivity disorder
  • sex addiction e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation
  • compositions and methods of the invention are effectively employed to enhance cognitive function and/or memory, to alleviate cognitive and other symptoms associated with Parkinson's disease, Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
  • neuropathy such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
  • Additional CNS disorders contemplated for effective treatment employing the methods of the invention include additional CNS disorders amenable to treatment by modulation of monoamine neurotransmitter and/or monoamine neurotransmitter receptor levels and/or physiology, as described, for example, in the Quick Reference to the Diagnostic Criteria from DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), The American Psychiatric Association, Washington, D.C., 1994.
  • 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 central nervous system disorder, symptom, condition, or indicator after treatment according to the invention, or a reduction in the risk or likelihood that a
  • treatment when referring to a targeted CNS disorder, refers to inhibiting or reducing the progression, nature, or severity of the subject condition or delaying the onset of the condition.
  • an "effective amount,” “therapeutic amount,” “therapeutically effective amount,” or “effective dose” of (R)(-) bupropion agents and/or a secondary therapeutic agent as used herein means an effective amount or dose of the active compound(s) as described herein sufficient to elicit a desired pharmacological or therapeutic effect in a human subject. 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 CNS disorder, including any combination of neurological and/or psychological symptoms associated with or caused by the targeted CNS disorder.
  • Therapeutic efficacy can alternatively be demonstrated by a decrease in the frequency or severity of symptoms associated with the treated central nervous system condition or disorder, or by altering the nature, occurrence, recurrence, or duration of symptoms associated with the treated condition or disorder.
  • effective amounts “therapeutic amounts,” “therapeutically effective amounts,” and
  • the methods and compositions herein employing (R)(-) bupropion are additionally effective in the treatment of CNS disorders in patients who have been determined to be refractory to prior drug treatment, including prior with an antidepressant drug, an anti-ADHD drug, an anti-addiction drug, and in certain cases drug treatment using bupropion racemate.
  • (R)(-) bupropion will often be employed as an effective treatment in individuals who have failed first-line drug treatment for the targeted CNS disorder, e.g., individuals who have not responded, who have responded insufficiently, or who have been unable to tolerate previous treatment(s) due to adverse effects or who have otherwise responded in an unsatisfactory manner to prior drug treatment, typically prior drug treatment aimed at modulating physiology and/or levels or activity of monoamine neurotransmitters and/or their receptors (such as 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, monoamine oxidase inhibitors, atypical antide
  • TCAs tri-cyclic antide
  • refractory individuals may have failed to respond or failed to respond sufficiently to a previous treatment.
  • a refractory individual may have treatment resistant depression or treatment resistant ADHD.
  • a refractory individual may have responded to an initial treatment, but not succeed in maintaining remission following one or more initial courses of drug treatment.
  • refractory individuals may have been unable to continue taking the medication due to intolerance of the medication including side effects such as seizure, allergic reactions, blurred vision or other vision changes, reduced sexual desire or impaired sexual performanc, chest pain confusion, dark urine, delusions, fainting, fast or irregular heartbeat, fever, chills, or sore throat, hallucinations, hearing problems, menstrual changes, mental or mood changes, agitation, restlessness, skin reactions, headache or dizziness, joint or muscle pain, persistent nausea, vomiting, or stomach pain, nervousness, restlessness, agitation or trouble sleeping, shortness of breath, suicidal thoughts or attempts, tremor, unusual swelling, yellowing of the skin or eyes, changes in metabolism, eating behavior and/or body weight, drowsiness, memory loss, and/or decreased cognitive function.
  • side effects such as seizure, allergic reactions, blurred vision or other vision changes, reduced sexual desire or impaired sexual performanc, chest pain confusion, dark urine, delusions, fainting, fast or irregular heartbeat, fever, chill
  • the novel compositions and methods of the invention will be therapeutically effective against the target CNS disorder to yield at least a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30-50% reduction, 50-75% reduction, up to at least a 75-90% reduction, and as much as a 95% reduction ranging to complete elimination/prevention, remission of the individual incidence, symptom occurrence or severity, adverse sequelae, disease recurrence, population disease rate indices between treated and non-treated groups, or another clinically useful index or suite of observational data statistics sufficient to reasonably quantify disease risk, occurrence, status, severity, recurrence, or remission, or otherwise quantitatively assess drug therapeutic efficacy for preventing, treating, ameliorating, alleviating and/or reducting of one or more symptoms of, the
  • Efficacy of the individual or 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 CNS disorder, such as depression, ADHD, cognitive deficiency, sexual dysfunction), by at least 5%, 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95% or greater, up to stable remission, compared to correlative scores or values observed for control subjects treated with placebo or other a suitable postive control drug treatment (e.g., racemic bupropion).
  • a selected CNS disorder such as depression, ADHD, cognitive deficiency, sexual dysfunction
  • 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. In other embodiments of the invention, clinical or therapeutic efficacy will be determined by direct observation of disease symptoms, including by physician observation, physical, cognitive or physiological testing, blood, tissue or other biological sample biochemical testing (e.g.,as particularly suited for assessing drug addiction treatment efficacy), or any other useful, qualitative or quantitative parameters for determining absolute or relative therapeutic efficacy of the (R)(-) bupropion compositions and methods disclosed herein.
  • the methods and compositions of the invention empoying (R)(-) bupropion are therapeutically effective for treating a range of cognitive disorders, including but not limited to Attention-Deficit/Hyperactivity Disorder (ADHD) Predominately Inattentive Type, ADHD Predominately Hyperactivity-Impulsive Type;
  • ADHD Attention-Deficit/Hyperactivity Disorder
  • ADHD Combined Type, ADHD not otherwise specified (NOS); Conduct Disorder;
  • the methods and compositions of the invention are therapeutically effective for treating Parkinson's disease (including via modulation of dopamine/dopamine transporter and/or norepinephrine/norepinephrine transporter
  • ADHD is a CNS disorder characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity (Buitelaar et al., 2010; Spencer et ah, 2007). It is one of the most common developmental disorders in children, with 5-10% prevalence (Scahill et al., 2000; Polanczyk et al., 2007). ADHD can continue through adolescence and into adulthood, such that a still substantial percentage of the adult population presents with continuing or adult ADHD (Kessler et al., 2006; Faraone and Biederman, 2005).
  • (R)(-) bupropion compositions of the invention including pharmaceutically acceptable active salts, polymorphs, hydrates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of ( )(-) bupropion, are effectively employed treat both pediatric and adult ADHD diseases and symptoms.
  • NE norepinephrine
  • DA dopamine
  • these monoamine neurotransmitters are targets of specific methods and compositions of the invention that employ (R)(-) bupropion in an amount and dosing regimen effective to therapeutically modulate levels and/or activity of one or both of the biogenic amines, NA and DA, and/or to modulate levels or monoamine reuptake activity by one or more of the cognate receptors for these biogenic amines, the norepinephrine transporter (NET) and dopamine transporter (DAT), respectively.
  • NET norepinephrine transporter
  • DAT dopamine transporter
  • the methods and compositions of the invention will frequently employ (R)(-) bupropion in a biogenic amine physiology modulatory effective amount, for example which is effective to ihibit NE reuptake and/or DA reuptake by at least about a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30-50% reduction, up to a 50-75% or greater reduction (in an accepted in vitro assay of NE and/or DAtransporter inhibition, or in actual test samples (e.g., plasma or cerebrospinal fluid) from subjects treated with (R)(-) bupropion assayed to quantitatively assess in vivo NET and/or DAT inhibitory activity in comparison to endogenous activity values).
  • a biogenic amine physiology modulatory effective amount for example which is effective to ihibit NE reuptake and/or DA reuptake by at least about a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30-50% reduction, up to a 50-75%
  • Pharmacotherapy is a primary form of treatment for ADHD.
  • ADHD There are currently eight drugs in the US approved for treatment of ADHD: Amphetamine- dextroamphetamine (Adderall®), Dexmethylphenidate (Focalin®), Dextroamphetamine (Dexedrine®, Dextrostat®), Lisdexametamine (Vyvanse®), Methylphenidate (Ritalin®, Concert®a, Metadate®, Daytrana®), Atomexetine (Straterra®), Guanfacine (Intuniv®, Tenex®), and Cloonidine (Catapres®). Stimulants such as methylphenidate and
  • amphetamines are commonly used for ADHD.
  • the major mechanism of action of the stimulants is inhibition of DA and NE transporters.
  • the stimulants are reportedly effective against core symptoms of ADHD.
  • major concerns about stimulants include risk of abuse, dependency, and diversion as well as potential neurotoxic effects of amphetamines (Berman et al, 2009).
  • the abuse potential of stimulants is particularly problematic in adults because substance abuse is a common co-morbidity with adult ADHD (Levin and leber, 1995; Ohlmeier, 2008).
  • the (R)(-) bupropion compositions of the invention are therapeutically effective against pediatric and adult ADHD as determined, for example, by the drug-mediated alleviation of one or more ADHD symptoms in treated patients, including but not limited to symptoms of inattention, disorganization, lack of concentration, impulsivity, difficulty functioning, learning disabilities, low educational attainment, under-achievement in vocational pursuits, and poor social and/or family relations. Many alternative means of selecting ADHD patients for treatment and for determining therapeutic efficacy of the methods and
  • indices determined in conventional psychoanalytic or behavioral scales or scoring tests include scales, questionnaires or tests that assess attributes or symptoms of the disorder, such as: difficulty paying attention to details, difficulty keeping attention on tasks, difficulty following instructions, difficulty organizing activities, difficulty following conversations, being easily distracted, being forgetful of daily routines.
  • the subject indices for selecting candidates for treatment with (R)(-) bupropion compositions, or for quantifying therapeutic efficacy of this novel drug can include disruptive and age-inappropriate symptoms, such as: fidgeting often, inappropriate running about, trouble playing or enjoying leisure activities quietly, excessive talking, blurting out answers, trouble waiting turn, and interrupting others, whereas combinations of these various indices of inattentive and hyperactive-impulsive symptoms may be present in combined type ADHD.
  • WURS Wender Utah Rating Scale
  • ARS Adult Rating Scale
  • CSS Curent Symptoms Scale
  • CAARS Conners Adult ADHD Rating Scale
  • APQ Adult Problems Questionnaire
  • 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% or greater compared to correlative scores or values observed for control subjects treated with placebo or other suitable control treatment, which comparative data can also demonstrate efficacy for prophylactic
  • substantially pure (R)(-) bupropion employed therapeutically to treat a variety of addictive disorders, particularly addictive disorders amenable to treatment by modulation of biogenic amine and/or monoamine transporter levels or activity.
  • Addictive disorders amenable for treatment and/or prevention employing the methods and compositions of the invention include, but are not limited to, behavioral addictions such as gambling addiction, sex addiction, certain eating disorders, impulse control disorders including obsessive compulsive shopping and hording disorders, and drug addictions such as amphetamine addiction, nicotine addiction, cocaine addiction, and opiate addiction, among other drug addictions.
  • compositions of the invention are therapeutically effective to treat and/or prevent the incidence, severity and recurrence/relapse of targeted symptoms of these addictive disorders by at least 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95% or greater compared to correlative values observed for control subjects treated with placebo or other suitable control treatment.
  • Amphetamine-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions of the invention include, but are not limited to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine-Induced Psychotic Disorders with hallucinations, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,
  • Amphetamine Related Disorder not otherwise specified NOS
  • Amphetamine Intoxication Amphetamine Intoxication
  • Amphetamine Withdrawal Symptoms associated with these amphetamine-related disorders are well described in the literature to allow for reliable patient selection for treatment and ready assessment of efficacy and dosage optimization for the (R)(-) bupropion methods and compositions of the invention.
  • Cocaine-related disorders include amenable to treatment using the (R)(-) bupropion methods and compositions of the invention include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine
  • Opioid-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Intoxication, Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder with delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid- Induced Anxiety Disorder, Opioid Related Disorder not otherwise specified (NOS), Opioid Intoxication, and Opioid Withdrawal.
  • Nicotine-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related Disorder not otherwise specified (NOS).
  • Alcohol-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Alcohol-Induced
  • Impulse control disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, and Impulse Control Disorder not otherwise specified (NOS).
  • compositions and methods that effectively treat sexual dysfunction conditions, including male and female hyposexual desire disorder (HSDD).
  • HSDD hyposexual desire disorder
  • R (-) bupropion compositions and methods are provided that effectively treat eating disorders and weight disorders, including obesity.
  • Eating disorders in this context include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Eating Disorder not otherwise specified (NOS); and eating disorders associated with weight disorders, including obesity and other adverse health effects.
  • (R)(-) bupropion compositions and methods are provided that effectively treat depressive disorders, including but not limited to, Major Depressive Disorder, Recurrent; Dysthymic Disorder; Depressive Disorder not otherwise specified (NOS); and Major Depressive Disorder, Single Episode
  • Additional useful patient surveys and clinical scales for selection of patients amenable to treatment using (R)(-) bupropion compositions and methods of the invention, and/or for assessing clinical efficacy of individual or combinatorial treatment compositions and methods provided herein can include any of a variety of widely used and well known patient psychiatric assessment surveys and other CNS disease-diagnostic clinical scales as set forth below (all of which clinical assessment tools are incorporated herein by reference for economy of description).
  • MINI Mini International Neuropsychiatric Interview ⁇
  • CGI Clinical Global Impression scale
  • IES-R Event Scale-Revised
  • CGI-S Clinical Global impression Severity of Illness
  • CGI-I Clinical Global Impression Improvement
  • DGRP Duke Global Rating for PTSD scale
  • SI-PTSD Structured Interview for PTSD
  • PTSD-I PTSD Interview
  • PSS-I PTSD Symptom Scale
  • BDI Beck Depression Inventory
  • RHRSD Revised Hamilton Rating Scale for Depression
  • MDI Major Depressive Inventory
  • CDI Children's Depression Index
  • exemplary scales for assessing efficacy of the invention include, for example, the Hamilton Depression Rating Scale ⁇ (HDRS) (Hamilton, M., J. Neurol. Neurosurg. Psychiatr. 23:56-62, 1960; Hamilton, M., Br. J. Soc. Clin. Psychol. 6:278-296, 1967); Montgomery- Asberg Depression Rating Scale ⁇ (MADRS) (Montgomery and Asberg, 1979); Beck Scale for Suicide Ideation® (BSS) (Beck and Steer, 1991 Columbia-Suicide Severity Rating Scale ⁇ (C-SSRS) or Columbia Classification Algorithm
  • HDRS Hamilton Depression Rating Scale ⁇
  • MADRS Montgomery- Asberg Depression Rating Scale ⁇
  • BSS Beck Scale for Suicide Ideation®
  • C-SSRS Columbia-Suicide Severity Rating Scale ⁇
  • C CASA Suicide Assessment ⁇
  • S-SST Sheehan-Suicidality Tracking Scale ⁇
  • BHS Beck Hopelessness Scale ⁇
  • GDS Geriatric Depression Scale
  • HAM-D scale for depression Hamilton, 1960
  • YBOCS Yale-Brown Obsessive Compulsive Scale
  • PANSS Positive and Negative Syndrome Scale
  • schizophrenia Kay et al., 1987
  • YMRS YMRS rating scale for mania
  • Liebowitz Social Anxiety Scale Heimburg et al, 2002.
  • 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 often yield a percentage increase in stabilization in the scores or values generated from these clinical surveys.
  • score changes indicating stabilization, or acquisition of a "normal” or “moderately symptomatic” status for a targeted CNS condition may occur more often in subjects treated according to the invention, e.g., by a factor of at least 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95%, compared to a frequency of the same stabilized, normal or moderately symptomatic scores or values observed for placebo or positive control (e.g., racemic bupropion-treated) subjects completing the same survey(s).
  • placebo or positive control e.g., racemic bupropion-treated
  • (R)(-) bupropion may be beneficially combined with one or more secondary therapeutic agents, often a secondary, psychotherapeutic agent, in a coordinate treatment method or combinatorial drug formulation or treatment regimen.
  • secondary therapeutic agent is one or more
  • psychotherapeutic drugs these may include, but are not limited to, drugs from the general classes of anticonvulsant, mood-stabilizing, antipsychotic, anxiolytic, anti-addictive, stimulants, muscle relaxants and sleep medications, antiepileptics, medications for
  • Parkinson's disease medications for ADHD, opioids, and appetite suppressant drugs benzodiazepines, calcium channel blockers, thyroid medications, and antidepressants.
  • benzodiazepines include benzodiazepines, calcium channel blockers, thyroid medications, and antidepressants.
  • R J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, Chapters 19 and 21, McGraw-Hill, 2001 for a review of useful secondary CNS therapeutic drugs, incorporated herein by reference.
  • (R)(-) bupropion is coordinately administered with a secondary psychotherapeutic agent that is is an anti-ADHD drug.
  • the secondary, anti-ADHD drug is selected from amphetamine- dextroamphetamine, dexmethylphenidate, dextroamphetamine, lisdexametamine, methylphenidate, atomexetine, guanfacine, clonidine, atomoxetine and a2-adrenergic agonists.
  • (R)(-) bupropion is administered alone as a singularly-effective treatment agent, or coordinately with a secondary psychotherapeutic agent, to effectively treat a CNS disorder selected from psychotic disorders, epilepsy, seizure disorders, tic disorders, abnormal sexual behaviors, schizoid behaviors, somatization, sleep disorders, autism spectrum disorders, certain eating disorders and other mood disorders and mental illnesses that are categorized and treated distinctly from other CNS disorders, such as depressive, anxiety, eating and addictive disorders.
  • a CNS disorder selected from psychotic disorders, epilepsy, seizure disorders, tic disorders, abnormal sexual behaviors, schizoid behaviors, somatization, sleep disorders, autism spectrum disorders, certain eating disorders and other mood disorders and mental illnesses that are categorized and treated distinctly from other CNS disorders, such as depressive, anxiety, eating and addictive disorders.
  • Exemplary psychotic disorders amenable to treatment employing the methods and compositions of the invention include, but are not limited to, schizophrenia, schizophreniform diseases, acute mania, schizoaffective disorders, depression with psychotic features, and other psychotic disorders known in the art and associated with increased risks of suicide.
  • (R)(-) bupropion treatment may be coordinated with administration of secondary CNS therapeutic agents including drugs from the general classes of antidepressant, mood-stabilizing, anxiolytic, anticonvulsant, antipsychotic, anti- addictive, and appetite suppressant drugs.
  • (R)(-) bupropion is coordinately administered with an antipsychotic drug, which may be known as a typical or atypical antipsychotic drug, many of which are dual categorized as having multiple, e.g., including antidepressant, activities and are elsewhere described herein.
  • the antipsychotic secondary drug is selected from Typical Antipsychotics, for example, chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone, and loxapine, or Atypical
  • Antipsychotics for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, and anticonvulsants (e.g., lamotrigine, carbamazepine,
  • ( )(-) bupropion is beneficially combined in a coordinate treatment method or combinatorial drug formulation with a secondary psychotherapeutic agent that is is an antidepressant drug, which may include, for example, any species within the broad families of tricyclic antidepressants (TCAs) including, but not limited to, amitriptyline, imipramine, or desipramine; specific monoamine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs) including, but not limited to, escitalopram, fluoxetine, fluvoxamine, sertraline, vilazodone, and paroxetine, selective norepinephrine reuptake inhibitors, selective dopamine reuptake inhibitors, multiple monoamine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), noradrenaline reuptake inhibitors (NRIs), multiple monoamine reuptake inhibitors, e.g.,
  • the additional or secondary 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 lamotrigine, carbamazepine, oxcarbazepine, valproate, levetriacetam, and topiramate).
  • Secondary therapeutic agents may additionally include opiate agonists including, but not limited to, buprenorphine, methadone and LAAM.
  • Lexapro® escitalopram oxalate
  • Symbyax® olanzepine and fluoxetine
  • Zoloft® sertraline
  • the additional or secondary psychotherapeutic agent is an anxiolytic drug agent including, but not limited to, benzodiazepines, such as alaprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam and prazepam; non-benzodiazepine agents, such as buspirone; and tranquilizers, such as barbituates.
  • benzodiazepines such as alaprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam and prazepam
  • non-benzodiazepine agents such as buspirone
  • tranquilizers such as barbituates.
  • the additional or secondary psychotherapeutic agent is a stimulant including, but not limited to, modafinil, methylphenidate, dextroamphetamine, methamphetamine.
  • Sodium oxybate may also be used in the combinatorial treatment of narcolepsy.
  • the additional or secondary psychotherapeutic agent is a muscle relaxant or sleep medication, including, but not limited to, clonazepam, triazolam, eszopiclone, ramelteon, temazepam, zaleplon and Zolpidem.
  • combinatorial formulations and coordinate treatment methods employ an additional or secondary psychotherapeutic agent that is antiepileptic, such as lamotrigen or gabapentin.
  • the additional or secondary psychotherapeutic agent is an anti-Parkinson's agents, including, but not limited to, dopamine, ropinirole and pramipexole.
  • the additional psychotherapeutic agent is an opioid, including but not limited to, codeine, oxycodone and hydrocodone.
  • the secondary therapeutic drug typically a psychotherapeutic drug
  • (R)(-) bupropion is administered concurrently or sequentially with (R)(-) bupropion to treat or prevent one or more symptoms of the targeted CNS disorder.
  • the secondary therapeutic agent and (R)(-) bupropion may optionally be combined in a single composition or combined dosage form.
  • the combinatorially effective psychotherapeutic drug and (R)(-) bupropion agents may be administered at the same time in separate dosage forms.
  • the psychotherapeutic agent and (R)(-) bupropion 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.
  • compositions of the invention comprising an effective amount of a psychotherapeutic compound and an effective amount of (R)(-) bupropion agents will be routinely adjusted on an individual basis, depending on such factors as weight, age, gender, and condition of the individual, the acuteness of the targeted anxiety disorder and/or related symptoms, whether the administration is prophylactic or therapeutic, and on the basis of other factors known to effect drug delivery, absorption, pharmacokinetics, including half-life, and efficacy.
  • the dosage of (R)(-) bupropion agents will be the same or different than the dosage of the racemate generally used. In one embodiment, the amount of (R)(-) bupropion agent will be lower.
  • the suitable oral dose range for use is from about 5mg to about 1500mg per day, preferably from about 10 mg to about 1500 mg per day, about lOOmg to about 1500mg a day, about 150mg to about 1500mg a day, about lOmg to about 900 mg per day, 10 mg to 500 mg per day, 75mg to 450mg per day, 150mg to 400mg per day, about 300mg to about 1500mg per day, about 600 to about 1500mg per day.
  • (R)(-) bupropion will depend on the CNS condition being treated and the desired general pharmacokinetics (e.g. immediate release kinetics, sustained release kinetics, biphasic release, etc.), and will consider such factors as major PK parameters (e.g., as for the racemate of bupropion, which has a a C max of approximately 160ng/ml, and a t ma of approximately 1.50 hours.
  • major PK parameters e.g., as for the racemate of bupropion, which has a a C max of approximately 160ng/ml, and a t ma of approximately 1.50 hours.
  • the timing of C max and AUC for (R)(-) bupropion will influence optimization of pharmacokinetic parameters, including for hydroxybupropion metabolites after (R)(-) bupropion is administered.
  • the rate of appearance of therapeutically effective metabolites following administration of (R)(-) bupropion, including radafaxine will further guide optimization of (R)(-) bupropion dosing, including dosage amount and frequency.
  • (R)(-) bupropion dosing optimization include: 1) seizure risk, 2) abuse liability, and 3) safety profile for potential bupropion polypharmacy with secondary thereapetic agents, such as amphetamines that may be used as a secondary therapeutic in treating ADHD.
  • an (R)(-) bupropion dose of 100-900 mgs, typically between 150-600 mgs, in certain
  • embodiments 200-400 mgs, optionally 150 mg, 200 mg, 250 mg, or 300 mg, PO qD will exhibit therapeutic effects for a wide range of targeted CNS conditions compared to placebo, without unacceptable adverse effects.
  • An effective dose or multi-dose treatment regimen for (R)(-) bupropion compositions and methods 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 the targeted CNS disorder as described herein.
  • sub-therapeutic amounts may be used.
  • Exemplary suggested dosage ranges for selected drugs for use within ccoordinate treatment methods and combinatorial formulations of the invention are provided below in Table 9, below, for illustrative purposes.
  • Lexapro® escitalopram oxalate 10-20 mg
  • Effective unit dosage amounts of either or both (R)(-) bupropion and secondary therapeutic agent(s) 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.
  • a dosing regimen comprising from 1 to 5, or 2-3, doses administered per day, per week, or per month.
  • exemplary dosages of selected drugs as illustrated above are administered one, two, three, or four times per day.
  • specific dosages within the specified exemplary ranges above are administered once, twice, or three times daily.
  • dosages are calculated based on body weight, and may be
  • 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.
  • the psychotherapeutic agent and (R)(-) bupropion agent may each be administered by any of a variety of delivery routes and modes, which may be the same or different for each agent.
  • the delivery routes and modes may be the same or different for each agent.
  • psychotherapeutic agent and (R)(-) bupropion agent is administered by a mode of delivery selected from oral, buccal, nasal, aerosol, topical, transdermal, mucosal, or injectable.
  • both the psychotherapeutic agent and (R)(-) bupropion agent are administered orally.
  • one or both of the psychotherapeutic agent and (R)(-) bupropion agent is/are delivered in a sustained or extended release formulation, for example in a sustained release, oral or intravenous formulation.
  • compositions of the invention comprising an effective amount of a psychotherapeutic compound and an effective amount of a (R)(-) bupropion agent will be routinely adjusted on an individual basis, depending on such factors as weight, age, gender, and condition of the individual, the acuteness of the targeted disorder and/or related symptoms, whether the administration is prophylactic or therapeutic, and on the basis of other factors known to effect drug delivery, absorption, pharmacokinetics, including half-life, and efficacy.
  • compositions of the invention for treating the disorders herein can thus include any one or combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art.
  • additional formulation additives and agents will often be biologically inactive and can be administered to patients without causing deleterious side effects or interactions with the active agent.
  • (R)(-) bupropion agent of the present invention will often be formulated and administered in an oral dosage form, optionally in combination with a carrier or other additive(s).
  • suitable carriers common to 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 may also contain one or more acids or acid salts including, but not limited to, glycine HC1, cysteine HC1, cysteine dihydrochloride, tartaric acid, citric acid, ascorbic acid, isoascorbic acid, and malic acids as a stabilizing agent. (See, for example, U.S. Patent No. 5,731 ,000).
  • 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 preservatives.
  • 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. These typically disintegrate in the mouth in less than one minute, and preferably in less than thirty seconds.
  • effervescent agent is meant a couple, 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.
  • (R)(-) bupropion can also be administered in any of a variety of inhalation or nasal delivery forms known in the art.
  • Devices capable of depositing aerosolized formulations of a psychotherapeutic compound and or (R)(-) bupropion agent 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 mania or 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 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 R(-) bupropion agent to the central nervous system.
  • intranasal administration of the compounds of the invention may be advantageous for treating disorders generally treated by bupropion, by providing for rapid absorption and delivery.
  • a liquid aerosol formulation will often contain a dispersing agent and/or a physiologically acceptable diluent.
  • dry powder aerosol formulations may contain a finely divided solid form of (R)(-) bupropion and a dispersing agent allowing for the ready dispersal of the dry powder particles.
  • 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.
  • Topical compositions may comprise (R)(-) bupropion 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.
  • 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
  • transdermal route of administration may be enhanced by the use of 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 (R)(-) bupropion over an extended period of time, for example 24 hours.
  • compositions of (R)(-) bupropion 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;
  • compositions 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.
  • the (R)(-) bupropion is administered, optionally together with a secondary therapeutic agent, in an extended release or sustained release formulation.
  • the sustained release composition of the formulation provides therapeutically effective plasma levels of the (R)(-) bupropion agent 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 (R)(-) bupropion agent is combined with a sustained release vehicle, matrix, binder, or coating material.
  • 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
  • sustained release formulation as described herein, of the same dosage amount of the active compound.
  • 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 (R)(-) bupropion is released from the sustained release compositions and dosage forms 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 (R)(-) bupropion following administration to a mammalian subject in a desired dosage amount (e.g., 200, 400, 600, or 800 mg) that yields 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.
  • a desired dosage amount e.g. 200, 400, 600, or 800 mg
  • the sustained release compositions and dosage forms will yield a therapeutic level of (R)(-) bupropion following administration to a mammalian subject in a desired dosage amount 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.
  • the invention provides pharmaceutical kits for reducing symptoms in a human subject suffering from a CNS disorder.
  • the kits comprise (R)(-) bupropion therapeutic agent in an effective amount in a container means for containing the (R)(-) bupropion agent in a stable form.
  • a simple combinatorial formulation of (R)(-) bupropion and a secondary therapeutic agent as described herein is provided.
  • a formulation of (R)(-) bupropion (optionally admixed with a secondary therapeutic agent) is provided in combination with container means to stably contain the (R)(-) bupropion therein.
  • the container will be a plastic or other suitable, sealable container that includes water-barrier means to effectively seal the (R)(-) bupropion and optional secondary therapeutic agent in an enclosed, water-proof container chamber that can be maintained over an extended period of time essentially free of exogenous water.
  • the container is a high density plastic, such as a PTFE or other polyethylene plastic, and the lip and lid of the contrainer are sealable against one another to anhydrously seal the container chamber upon closure of the (R)(-) bupropion therein.
  • a combinatorial formulation of (R)(-) bupropion and a secondary therapeutic agent is anhydrously sealed within the container prior to storage and use.
  • a suitable amount of a dessicant is included in the container to absorb any incidental water that may be present in the container and or enclosed additional drug products and packaging materials upon orginal closure/sealing.
  • sealing means of the container include use of a heat-resistant, sealable undersurface (e.g., a foil undersurface) comprising the seal gasket or undersurface of the lid, that is in contact with the lip of the lid upon closure/sealing of the sealable container.
  • the seal gasket or sealable undersurface of the lid is seated under heat and optionally pressurized conditions to form a thermal seal against the lip of the container, optionally leaving a partial vacuum within the container after sealing and cooling to further preclude exposure of the (R)(-) bupropion and any other incredients within the container to water.
  • Other water-tight containers, bottles, foil packs and like sealing means are examples of the seal gasket or undersurface of the lid, that is in contact with the lip of the lid upon closure/sealing of the sealable container.
  • Blister packs are multi- dose packages that have recesses in a container portion of the blister pack the size and shape of the tablets or capsules contained therein. The tablets or capsules are placed in the recesses and the container portion is closd by juxtaposition against a sealing plastic or foil closure means that forms a sealable closure against the openings of the recesses in the container portion.
  • both the container portion and closure surface or lid of the blister pack must be impervious to water. Tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses, whereby an opening is formed in the sealing surface sheet above the recess.
  • a memory aid may be provided on the kit, such as in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Other variations of memory aids will be readily apparent.
  • the package kits or associated packaging may optionally bear a product-use label or insert that provides instructions for multiple uses of the kit contents to treat the targeted CNS disorder and identify symptoms and side effects associated with the disorder and drug.
  • Hamilton M A rating scale for depression. J. Neurol. Neurosurg. Psychiat., 1960, 23, 56. Hamilton, M. (1959). The assessment of anxiety states by rating. British Journal of Medical Psychology, 32, 50-55.
  • C CASA classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 2007; 165:1035-1043.

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Abstract

Compositions and methods are disclosed using a purified (R)(-) enantiomer of bupropion to treat central nervous system disorders with fewer side effects compared to those seen in subjects treated with racemic bupropion. Additionally disclosed are methods and intermediates for producing enantiomerically purified (R)(-) bupropion, stable pharmaceutical formulations of (R)(-) bupropion, and pharmaceutical products and kits comprising (R)(-) bupropion for clinical use.

Description

Compositions And Methods For Treating Depression, ADHD And Other Central Nervous System Disorders Employing Novel Bupropion Compounds, And Methods For Production
And Use of Novel Bupropion Compounds and Formulations
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority from United States Provisional patent application Serial No. 61/448,625, filed March 2, 2011, and United States Provisional patent application Serial No. 61/454,946, filed March 21, 2011, each of which is incorporated herein by reference in its entirety for all purposes.
TECHNICAL FIELD
[0002] The present invention relates to pharmaceutical compositions and methods for therapeutic use of bupropion. More specifically, the invention relates to enantiomeric brupropion compositions and formulations and methods for manufacturing them and using these materials in therapeutic methods for treating central nervous system disorders.
BACKGROUND OF THE INVENTION
[0003] Although bupropion was discovered over forty five years ago, it is demonstrated by the discoveries presented herein as a heretofore underutilized and incompletely developed psychotropic agent. Bupropion was initially approved for depression and later for facilitating smoking cessation based on a serendipitous discovery. Generic bupropion is commonly used in clinical practice for these approved indications and has also been reported for non- approved indications, including attention deficit hyperactivity disorder (ADHD), tardive dyskinesia, brain disorders, sexual dysfunction, addiction, hypercholesterolemia, ethanol conditions and weight disorders. However, such off-label uses of bupropion have not been fully and reliably investigated, while in general off-label uses of this drug must be considered carefully in view of dosing and side effects concerns— whereby the risk/benefit ratio of off- label bupropion is often suspect, and no formal guidelines are presently available for such uses of buproprion in the United States and many other jurisdictions.
[0004] Developing the full therapeutic potential of bupropion has been severely limited by adverse effect reports, including toxicity concerns and other safety considerations for this compound. Among these noted hazards, there is a substantial increased risk of seizure and numerous other serious side effects associated with bupropion use in human subjects.
[0005] Bupropion is an atypical antidepressant that has fewer side effects than many antidepressents; however, as noted above the use of bupropion is attended by increased risk of seizures, particularly in certain formulations and at higher dosages. Previous attempts to address this issue focused on development of a slow release bupropion formulation, however continued safety issues perist, including unacceptable increased siezure risk, which have prevented assessment and development of bupropion for many prospective beneficial uses beyond the limited approved uses for depression and smoking cessation, and at elevated dosing ranges and/or frequency.
{0006] Notably, the mechanisms by which bupropion exerts its positive biological effects and by which it causes adverse events such as seizures are poorly understood. There has been little progress, and in fact some prior attempts have failed or been abandoned, to develop comprehensive and proven methods to isolate, characterize, formulate and clinically develop enantiomers of bupropion or its major metabolites, and to date there have been no successful reported attempts to develop any isomer of bupropion or a metabolic derivative thereof for clinical use. With respect to bupropion enantiomers, one US company, Sepracor, filed several US patents (McCullough, et al., USPN 6,495,605, Jerussi, et al., USPN
6,342,496, Young, J. W., USPN 6,451,860, Young, J. W., USPN 6,369,113, Young, J. W., USPN 6,277,887, Young, J. W., USPN 6,110,973, and Young, J. W., USPN 6,451,860) purporting to describe the use of either the (+) or (-) enantiomer of bupropion to treat a wide array of prospective CNS disorders. However, all of these Sepracor patents are now abandoned, and the description of each of these patents fails to demonstrate any use of an isolated (+) or (-) enantiomer of bupropion in an actual assay that would validate therapeutic efficacy and/or safety of either enantiomer for any contemplated, unapproved medical use. Among the limited, actual and peer-reviewed studies of bupropion enantiomers to date, Musso and colleagues (1993) found no significant differences in the potencies of (R) and (S) bupropion enantiomers to reduce tetrabenazine-induced sedation in mice or in their IC50 values as inhibitors of biogenic amine uptake (norepinephrine, dopamine and serotonin) uptake in a murine model (see also, Fang et al., 2000). While it has been postulated that bupropion toxicity may reside unequally in one of the isomeric hydroxylated bupropion metabolites, little is known about the actual in vivo metabolism of bupropion and its enantiomers, or about the metabolism and in vivo pharmacological activity of the various metabolic derivatives thereof.
[0007] In view of the foregoing, there is a long unmet need in the art for improved techniques and materials to synthesize and characterize enantiomers of bupropion, to establish their purity and stability, to demonstrate the metabolic pathways by which the distinct enantiomeric forms of bupropion are processed in vivo to potentially toxic derivatives, and to generate data to support safe and effective use of this drug and selected enantiomeric compositions thereof for clinical treatment of central nervous system (CNS) disorders without unacceptable side effects.
SUMMARY OF EXEMPLARY EMBODIMENTS
[0008] The instant invention fulfills these needs and satisfies additional objects and advantages by providing novel compositions and methods employing an isolated (R)(-) enantiomeric form of bupropion for treating a range of central nervous system (CNS) disorders amenable to treatment using bupropion compounds and drugs that modulate one or more monoamine transporter activity(ies) in vertebrate subjects.
[0009] The compositions, formulations and methods of the invention typically employ a stable, often substantially pure, (R)(-) bupropion compound as an effective pharmaceutical agent that is effective to treat or prevent a variety of CNS disorders.
[0010] Within exemplary embodiments of the invention, (R)(-)bupropion is effective to treat (e.g., to prevent the occurrence or recurrence of, alleviate the severity or duration of, or moderate one or more symptoms of) a CNS disorder affected by a defect, disturbance or imbalance in monoamine neurotransmitter receptor or biogenic amine physiology, including CNS disorders treatable by inhibiting norepinephrine and/or dopamine reuptake.
[0011] The pharmaceutical compositions and formulations described herein are useful for as a therapeutic agent against (i.e., for the prevention, treatment, amelioration, alleviation and/or reduction of symptoms of) a variety of CNS disorders in vertebrate subjects, most typically mammalian subjects such as humans suffering from a CNS disorder. CNS disorders and related conditions amenable to treatment using the methdos and compositions of the invention include, but not limited to, depression, treatment resistant depression (TRD), seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder (HSDD), addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity. In additional aspects of the invention (R)(-)bupropion compositions and methods herein are effectively employed to enhance cognitive function and/or memory, to alleviate cognitive and other symptoms associated with Parkinson's disease, Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
[0012] Within more detailed aspects of the invention, novel compositions and methods are provided that employ substantially pure (R)(-)bupropion to treat a targeted CNS condition in a mammalian subject, while reducing the incidence or severity of one or more adverse effects associated with bupropion therapy. Within these aspects of the invention, the achievement of therapeutic effects and attendant reduction in side effects elicited by (R)(-)bupropion is interrelated with a reduction in the presence and/or level of 2(R)(-) hydroxybupropion, an undesirable metabolite with limited activity and/or unacceptable toxicity, in treated individuals.
[0013] Within other detailed embodiments the invention employs substantially pure (R)(-) bupropion to treat a CNS condition in a mammalian subject while increasing the presence and/or level of 2(S)(+) hydroxybupropion, a highly therapeutic metabolite with desired safety characteristics, in the subject.
[0014] Within related embodiments of the invention, therapeutic use of (R)(-)bupropion with attendant reduction in side effects is associated with a reduction of harmful 2(R)(-) hydroxybupropion, and attendant increase of thereapeutic 2(S)(+) hydroxybupropion, in treated subjects. These novel findings provide therapeutic benefits of (R)(-)bupropion at lower dosages with fewer side effects compared to either racemic bupropion or (S)(+) bupropion. Thus, within certain methods and compositions of the invention administration of a selected therapeutic dose of (R)(-)bupropion to patients with a CNS condition will exhibit at least a 10%-20%, 25%-50%, 50%-75%, or even 90-100% reduction in measurable symptoms or other indices of therapeutic efficacy for treating the CNS condition, and a concomitant reduction, by at least 10%-20%, 25%-50%, 50%-75%, or even 90-100% of observed side effects compared to therapeutic and side effects observed for the same dose of racemic or (S)(+) bupropion. Symptoms of CNS disorders that can be included as indices for determining therapeutic efficacy of the methods and compositions of the invention include, but are not limited to, any one or more symptoms or suittes of symptoms considered diagnostic in the clinical arts, for example in the case of ADHD, depression and other mental disorders those presented in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (2000), Text Revision (DSM-IV-TR), American Psychiatric Association, Washington, D.C., incorporated herein by reference.
[0015] In related aspects, the methods and compositions of the invention allow for reduced dosing of patients to achieve an equivalent therapeutic benefit and/or side effect profile compared to therapeutic effects exhibited by racemic or (S)(+) bupropion. For example, the invention includes novel dosage forms comprising a therapeutically effective dose of (R)(-) bupropion that is 10%-20%, 25%-50%, 50%-75%, or even more than 75% reduced in comparison to a therapeutically equivalent dose of racemic bupropion.
[0016] Additionally provided herein are combinatorial formulations which employ
substantially pure (R)(-) bupropion in combination with one or more additional therapeutic agents effective to prevent, treat, ameliorate, alleviate or reduce signs and symptoms of a targeted CNS disorder in a vertebrate subjects amenable to treatemtn with bupropion.
Exemplary combinatorial formulations and coordinate treatment methods employ (R)(-) bupropion in combination with one or more secondary therapeutic agent(s), typically psychotherapeutic agent(s), including, but not limited to, drugs from the general classes of antidepressants, mood-stabilizing, anxiolytic, anticonvulsant, antipsychotic, antiaddictive, stimulants, muscle relaxants and sleep medications, antiepileptics, medications for Parkinson's disease, Alzheimer's medications, medications for ADHD, opioids, and appetite suppressant drugs in combination with substantially pure (R)(-) bupropion. Within related, coordinate administration methods of the invention, substantially pure (R)(-) bupropion and the secondary therapeutic agent(s) are administered concurrently, or sequentially in any order, to prevent or P T/US2012/000117
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treat one or more symptoms of the targeted CNS disorder. When administered simultaneously, the (R)(-) bupropion compositions and the additional or secondary therapeutic agent(s) may be combined in a novel, combinatorial formulation or combined dosage form, or administered at the same time in separate dosage forms in amounts collectively effective to treat the target CNS condition.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] Figure 1 is a graph illustrating the relationship between R-bupropion concentration and velocity of metabolism of the R-hydroxybupropion and S-hydroxybupropion metabolites in a standard human liver microsome assay (results measured at ten minutes).
[0018] Figure 2 is a multipanel graphic illustration of enantioselective inhibition of
monoamine reuptake by (R)(-) bupropion. Top Panel, inhibition of dopamine (DA) transporter. Bottom Panel, inhibition of norepinephrine (NE) transporter.
[0019] Figure 3 is a graph depicting the racemization over time at different pH conditions of bupropion preparations including enantiomerically purified (R)(-) bupropion, demonstrating the criticality of pH for stable formulation of (R)(-) bupropion for clinical use within the invention.
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
[0020] The instant invention provides novel methods and compositions employing an isolated (R)(-) enantiomer of bupropion which is more therapeutically effective with fewer side effects than clinically-established, racemic forms of bupropion, along with methods for using (R)(-) bupropion compositions and formulations to treat important diseases and conditions of the central nervous system (CNS) in vertebrate subjects, particularly humans and other mammalian subjects.
[0021] Bupropion, (±)-l-(3-chlorophenyl)-2-[(l,l-dimethylethyl)amino]-l-propanone, is described for example in U.S. Pat. Nos. 3,819,706 and 3,885,046. Bupropion is widely reported on as an atypical antidepressant possessing norepinephrine reuptake inhibitory and nicotinic acetylcholine receptor antagonistic activities. Currently, bupropion is primarily used clinically to treat depression and as an aid in smoking cessation. It has also been reportedly investigated for use to treat seasonal affective disorder, treatment resistant T US2012/000117
7
depression, restless leg syndrome, bipolar disorder, attention deficit hyperactivity disorder (ADHD), sexual dysfunction, Parkinson's disease, addiction, hypercholesterolemia, narcolepsy, neuropathic pain, and obesity.
[0022] Development of the full potential utility of bupropion has long been limited by these adverse effects and related safety and dosing concerns that have attended clinical use of the drug to date. Current clinical preparations of racemic bupropion are widely reported to increase the risk of seizures in patients, with potentially highly morbid or even fatal results. Additional side effects reported for bupropion include: severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue, unusual hoarseness); blurred vision or other vision changes; reduced sexual desire or impaired sexual performanc; chest pain; confusion; dark urine; delusions; fainting; fast or irregular heartbeat; fever, chills, or sore throat; hallucinations; hearing problems; menstrual changes; new or worsening mental or mood changes; agitation; restlessness; red, swollen, blistered, or peeling skin; seizures; severe headache or dizziness; severe or persistent joint or muscle pain; severe or persistent nausea, vomiting, or stomach pain; severe or persistent nervousness, restlessness, or trouble sleeping; shortness of breath; suicidal thoughts or attempts; tremor; unusual swelling; yellowing of the skin or eyes, among others (See, The Physician's Desk Reference, PDR network, LLC (2009)).
[0023] Bupropion and its principal metabolites are chiral molecules, however, none of the isomeric forms of bupropion or any of its metabolites have been developed for clinical use. Bupropion enantiomers can be labeled structurally (R or S), optically (+, d or -, 1) or by their relative spatial configuration (D/L). In the R or S system, substituents are each assigned a priority based on atomic number according to the Cahn-Ingold-Prelog priority rules. An enantiomer can also be named for the direction it rotates polarized light. If it rotates the light clockwise, that enantiomer is labeled (+) or (d) for dextrotatory. Its mirror-image is labeled (-) or (1) for levorotatory. Additionally, an enantiomer can be labeled by its relative configuration to glyceraldehyde using the D/L system. Enantiomers may have the same, or entirely different, activities from the corresponding racemate and/or from the alternate enantiomer, and these disparate activity profiles cannot be predicted or determined without careful, detailed and successful experimentation. For example, ibuprofen is a mixture of the (S) and (R) enantiomers, with the (S) enantiomer being the most effective and the (R) enantiomer only being used after conversion to the (S) enantiomer by 2-arylpropionyl-CoA epimerase. With ketamine, the (S)-enantiomer is an anesthetic, but the (R)-enantiomer is a hallucinogen.
[0024] With these and other considerations in mind, a surprising discovery of the present invention is that an isolated, substantially pure and stable (-)- 1 -(3-chlorophenyl)-2-[(l , 1 - dimethylethyl)amino]-l-propanone (hereafter (R)(-) bupropion, as shown below) composition is an unexpectedly potent and safe drug agent for the treatment of a wide range of important CNS disorders in humans and other subjects. In substantially pure form, (R)((-) bupropion is useful to prevent, eliminate or alleviate symptoms of targeted CNS conditions amenable to treatment by modulation of biogenic amine reuptake and/or using racemic bupropion, with enhanced potency and reduced side effects compared to racemic bupropion. Subjects amenable to treatment employing the methods and compositions of the invention include, but are not limited to, humans and other mammals suffering from CNS disorders selected from depression, treatment resistant depression, seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder, addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity. In additional aspects of the invention (R)(-) bupropion compositions and methods herein are effectively employed to enhance cognitive function and/or memory, to alleviate cognitive and other symptoms associated with
Parkinson's disease, Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
[0025] Bupropion is a chiral compound with two enantiomers, (+)-l-(3-chlorophenyl)-2- [(1,1 -dimethylethyl)amino] - 1 -propanone and (-)- 1 -(3 -chlorophenyl)-2- [(1,1- dimethylethyl)amino]-l -propanone ((S)(+) and (R)(-) bupropion, respectively, as shown below): (S)(+) Bupropion (R)(-) Bupropion
Figure imgf000011_0001
The identity and quantification of a particular bupropion enantiomer within the invention may be determined by a variety of means. For example, it may be determined using conventional chiral chromatography and/or polarimitry (e.g., using an [α]ο20 α= -39.64 for (R) bupropion and an [C.]D20°c = +40.21 for (S) bupropion, as described by Musso et al., 1993). The methods and compositions of the invention employ substantially pure (R)(-) bupropion or compositions and formulations that are artificially enantiomerically enriched for (R)(-) bupropion. As used herein the term "substantially pure (R)(-) bupropion" or "enantiomerically pure (R)(-)bupropion" refers to a composition that is artificially enriched to contain, in stable form, more (R)(-) bupropion than (S)(+) bupropion, wherein the (R)(-) bupropion occurs in an enantiomeric excess (ee) of at least about 60%, 70%, 75%, 80%, up to approximately 90% or greater, up to 95% or greater ee. In certain aspects the methods and compositions of the invention employ highly purified or isolated (R)(-) buproprion (at least as a starting material prior to administration, formulation or storage) in an enantiomeric excess of up to 98% or greater, e.g., as determined by chiral chromatography and/or optical purity assay. Preparations of (R)(-) bupropion in enantiomeric excess greater than 80% or 90% are considered substantially free of the corresponding (S)(+) bupropion enantiomer and are highly desired drug preparations for clinical use. Typically, pharmaceutical compositions of the invention for treating CNS disorders as described herein will contain no more than about 5% w/w, and in some embodiments no more than about 2% or even 1% w/w, of the
(S)(+) bupropion enantiomer (i.e., measured as a percent of all bupropion, including racemate and (R)(-) and (S)(+) enantiomers, present in the composition).
[0026] The use of substantially pure (R)(-) bupropion or enantiomerically enriched formulations including (R)(-) bupropion will provide enhanced therapeutic efficacy and reduced side effects at equivalent dosages (by weight) at comparable dosages, and equivalent therapeutic efficacy at lower or less frequent dosages compared to racemic and (S)(+) bupropion. In certain aspects, at equivalent dosing with racemic and/or (S)(+) bupropion, (R)(-) bupropion within the compositions and methods of the invention will show relative increased therapeutic efficacy of least 10%, 20%, 30%, or 50%, up to 75-95%, 100% or even 200% than observed for the racemic and/or (S)(+) bupropion, and a reduction in occurrence and/or severity of side effects of as much as 10%, 20%, 30%, or 50%, up to 75-95% or more compared to observed side effect values for racemic or (S)(+) bupropion.
[0027] Metabolism of bupropion creates a complex array of compounds whose enantiomeric forms are poorly known, particularly in terms of their therapeutic efficacy and side effect profiles. When ingested, bupropion is extensively metabolized by cytochrome P450 2B6 (CyP2B6) and forms several active metabolites including hydroxybupropion, threo- hydrobupropion and ery/Aro-hydrobupropion, all of which contain at least one chiral center as shown below.
n
Figure imgf000012_0001
[0028] There are also profound differences in the metabolites of bupropion created among different species (Welch et al., 1987). As an example, mice and humans form the metabolite hydroxybupropion (OHB), while this product is a minor metabolite in rats (Welch et al., 1987). In humans dosed with racemic bupropion, the circulating levels of
hydroxybupropion, by chiral chromatography, were reported to be 96% as the (-)
diastereomer of hydroxybupropion (Suckow et al., 1997). In a separate study, metabolism of bupropion by recombinant, human CyP2B6 and in human microsomal preparations reportedly yielded three-fold faster metabolism of (S)(+) bupropion, relative to the (R)(-) enantiomer (Coles and Kharasch, 2008). In a human clinical trial, healthy volunteers were dosed with racemic bupropion and chiral chromatography of subject plasma samples revealed predominantly the 2(R) hydroxybupropion that was elimination rate limited. Small amounts of the 2(S) hydroxybupropion were reported to be formation rate limited (Kharasch et al., 2008). Adding further complexity to the metabolic picture for bupropion, under physiologic conditions, 42% of the (R)(-) isomer was reportedly converted to a mixture of isomers in 2 hours (Fang et al., 2000). Because the process is base-catalyzed, it would not start until the compound reached the small intestine.
[0029] There have been reports that certain metabolites of bupropion, and/or enantiomeric forms thereof, may predominate with respect to side effect risk. For example, Silverstone and colleagues evaluated convulsive effects of buproprion and three bupropion metabolites (erythrohydrobupropion, threohydrobupropion, and hydroxybupropion), and attributed most of the observed convulsive effects to hydroxybupropion, as shown in Table 1 below
Table 1
Metabolite Percentage of Convulsing Mice Based on Dose Levef
25mg/kg 50 mg/kg 75MG/KG
Bupropion HCI 0% 0% 10%
Erythrohydrobupropion HC1 0% 0% 10%
Threohydrobupropion HCI 0% 10% 90%
Hydroxybupropion HClb 0% 100% 100% aData from Silverstone et al., 2008
bHydroxybupropion is metabolized and present in human plasma following dosing of the parent compound bupriopion HCI
CA11 animals were observed continuously for 2 hours.
[0030] Morgan and coworkers working at SmithKline Beecham also investigated the potentially divergent roles of bupropion metabolites in eliciting seizure effects in murine subjects, and reported that a majority of seizure-inducing risk potential resided with the R- hydroxybupropion metabolite (see Table 2, below)
Table 2 Data from Toxicity Study in Mice Reporting Seizure Induction and Mortality
Associated with S- and R-Hydroxybupropion Metabolites.8
Metabolite Dose in mg/kg % Seizing % Died
Bupropion 100 100 0 Bupropion 300 100 80
R-Hydroxybupropion 100 100 0 R-Hydroxybupropion 300 100 100 S-Hydroxybupropion 100 0 0 S-Hydroxybupropion 300 100 0
"Data from WSA Patent No. 6,391,875 B2 (SmithKline Beecham) Filed by Morgan et al., 2002
[0031] Despite these and other reports concerning the nature and risk potential of specific metabolites of bupropion, and/or enantiomeric forms thereof, the relationships between these metabolites and bupropion enantiomers, and the nature and mechanisms of metabolic conversion and efficacy and toxicity between buproprion enantiomers and metabolic derivatives of bupropion, have not heretofore been adequately comprehended.
[0032] As shown in Reaction Scheme 1, below, it has been determined herein that (-) R hydroxybupropion originates from the (S)(+) isomer of bupropion and that (+) S
hydroxybupropion arises metabolically from the (R)(-) isomer of bupropion.
(S)(+) Bupropion (2R)(-) Hydroxybupropion
Figure imgf000014_0001
(R)(-) Bupropion (2S)(+) Hydroxybupropion
Scheme 1
[0033] These novel findings support the related, unexpected determination herein that (R)(-) bupropion posesses uniquely potent biological activity and a surprisingly safe side effect P T/US2012/000117
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profile—by virtue that R-bupropion is metabolized to the S, S-hydroxyl bupropion metabolite, and not to R, R-hydroxybupropion. To further elucidate the nature and implications of these novel metabolic discoveries for (R)(-) bupropion, the following working examples are provided.
EXAMPLE I
Formation of Hydroxybupropion Isomers from Bupropion and its Isolated Enantiomers by
Human Hepatic Microsomes In vitro
[0034] In a first investigative approach, racemic bupropion and its two isomers were incubated in increasing concentrations of racemic bupropion, (R)(-) bupropion, and (S)(+) bupropion in human liver microsomes using conventional liver microsomal incubation and assay methods. As shown in Table 3, below, both bupropion and S-bupropion led to the formation of R, R-hydroxybupropion, whereas R-bupropion surprisingly yielded detectable levels of only the S,S-hydroxybupropion metabolite. Interestingly, these findings are consistent with data reported by Kharash et al. (2008) examining stereoselective bupropion hydroxylation as a phenotypic probe for CYP2B6 activity.
Table 3. Bupropion Metabolites Generated by (R)(-) Bupropion, and (S)(+) Bupropion in Human Liver Microsomes
nM of Bupropion Isomers formed at 30 Minutes
Metabolite [μΜ) S, S-Hydroxy R, R-Hydroxy
Bupropion [nM] Bupropion [nM]
Bupropion 85.79 0 0.6
Bupropion 85.79 0 0.3
Bupropion 373.04 0 1.3
Bupropion 373.04 0 1.1
Bupropion 800.42 0 1.0
Bupropion 800.42 0 1.0
S-Bupropion 404 0 1.5
S-Bupropion 404 0 1.9
S-Bupropion 1557 0 2.7
S-Bupropion 1557 0 2.7
S-Bupropion 2897 0 2.6
S-Bupropion 2897 0 3.5
R-Bupropion 350 2.2 0
R-Bupropion 350 2.2 0 R-Bupropion 1496 2.0 0
R-Bupropion 1496 2.4 0
R-Bupropion 3110 3.2 0
R-Bupropion 3110 2A 0 aMetabolites were placed in human hepatic microsomes for 30 minutes and 37 degrees C using 200 g of microsomal protein per sample in vitro.
EXAMPLE II
Formation of Hydroxybupropion Isomers from Bupropion
and its Isolated Enantiomers In vivo
[0035] To further elucidate the nature and mechanisms of metabolic conversion and efficacy and toxicity between buproprion enantiomers and metabolic derivatives of bupropion, blood levels of bupropion, its isomers, and isomeric hydroxybupropion metabolites were measured after administration of racemic bupropion and (R)(-) and (S)(+) bupropion to mice using conventional methods. As shown in Table 4, below, the metabolic pattern demonstrated in the above, in vitro experiments was confirmed in vivo in murine model subjects.
Table 4. Analysis of Bupropion and Hydroxybupropion Isomers in Mice
Figure imgf000016_0001
Data are the means ± SEM of groups of 5-6 animals per group
EXAMPLE III
Formation of Hydroxybupropion Isomers From Increasing Doses
of (R)(-) Bupropion Enantiomer In vivo
[0036] Additional investigation was undertaken to clarify the novel patterns of metabolic conversion observed for (R)(-) bupropion, employing human liver microsomes incubated with increasing doses of (R)(-) bupropion. As shown in Figure 1 , after ten minutes of incubation only S, S-hydroxybupropion was detected at various dosage levels of (R)(-) bupropion. Thus, even with increasing dosing the (R)(-) enantiomer of bupropion enantioselectively yields exclusively the S, S-hydroxybupropion metabolite. EXAMPLE IV
Therapeutic Efficacy of Hydroxybupropion Isomers in a Murine Pre-Clinical Model
[0037] To further explore the unexpected therapeutic potential of (R)(-) bupropion within the methods and compositions of the invention, additional experiments employing an accepted animal model predictive of human bupropion therapeutic efficacy were undertaken examining behavioral and pharmacokinetic data for bupropion and its two isomers. More specifically, murine behavioral indices correlated with bupropion therapeutic efficacy for treating CNS conditions in humans were measured according to conventional methods following administration of indicated doses of racemic bupropion, (R)(-) bupropion, and (S)(+) bupropion. As shown in Table 5, below, racemic bupropion and R-bupropion exhibited significant therapeutic potential as demonstrated by correlative behavioral effects in mice, whereas (S)(+) bupropion showed relatively low behavioral activity.
Table 5. Gross Behavioral Effects of Bupropion and Its Isomers in Mice
Figure imgf000017_0001
Circling = stereotyped movement around the periphery of the test chamber. Hypo- and hyperactivity was observed within a one hour post-administration observation period.
EXAMPLE V
Potent Enantioselective Inhibition of Biogenic Amine Reuptake by (R)(-) Bupropion
[0038] The instant example provides yet additional compelling evidence of the unexpectedly potent pharmacological properties of (R)(-) bupropion within the methods and compositions of the invention, particularly for treating CNS disorders mediated by defects, impairments or imbalances in monoamine metabolism and/or transport. Briefly, the data herein demonstrate that monoamine transporter modulation, as exemplified by inhibition of monoamine
neurotransmitter reuptake, are strongly enantioselective for bupropion, with the (R)(-) enantiomer being a substantially more potent inhibitor of dopamine and norepinephrine transporters (see Figure 2).
[0039] The isomers of bupropion were initially evaluated against a broad panel of receptors known to be involved in mediating CNS disorders. These broad-spectral assays
demonstrated modulatory activity of the (R(-) enantiomer of bupropion at a broad array of candidate receptor targets, but the most significant reuptake inhibitory activity was observed at dopamine and norepinephrine transporters (DAT and NET, respectively). A subsequent study was undertaken to identify the affinities of the isomers for the two transporters.
[0040] This study used [125I]-RTI 55 to label these human transporters stably expressed in mammalian cell lines according to the following protocol and conditions.
Transporter. Dopamine (DAT)
Source: Human recombinant CHO-K1 cells
Vehicle: 1% DMSO
Incubation Time/Temp: 3 hours @ 4°C
Incubation Buffer: 50 mN Tris-HCl, pH 7.4, 100 m
NaCl, 1 μΜ Leupeptin, 10 μΜ PMSF
Kd: 0.58 nM*
Ligand: 0.15 nM[,25l]RTl-55
Non-Specific Ligand: 10 μ Nomifensine
Specific Binding: 90% *
Quantiation Method: Radioligand Binding
Significance Criteria: >50% of max stimulation or inhibition
Bmax: 0.047 pmole/mg Protein* Transporter. Norepineph iirine (NET)
Source: Human recombinant MDCK cells
Vehicle: 1% DMSO
Incubation Time/Temp: 3 hours @ 4°C
Incubation Buffer: 50 mN Tris-HCl, pH 7.4, 100 mM
NaCl, 1 μΜ Leupeptin, 10 μΜ PMSF
d: 0.024 μΜ*
Ligand: 0.2 nM[,25l]RTl-55
Non-Specific Ligand: 10 μΜ Desipramine
Specific Binding: 75%*
Quantiation Method: Radioligand Binding
Significance Criteria: >50% of max stimulation or inhibition
Bmax: 2.5 pmole/mg Protein*
* Demonstrated Values
[0041] The materials and methods employed in this study were mofidifed from conventional methods to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure validity of the results obtained. Where presented, IC50 values were determined by a non-linear, least squares regression analysis using Math IQ™ (ID Business Solutions Ltd., US). Where inhibition constants (Ki) are presented, the Ki values were calculated using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W. H., Biochem. Pharmacol. 22:3309-3108, 1973) using the observed IC50 of the tested compound, the concentration of radioligand employed in the assay, and demonstrated values of the KD of the ligand obtained experimentally. Where presented, the Hill coefficient (nH), defining the scope of the competitive binding curve, was calculated using Math IQ™. Hill
Coefficients significantly different than 1.0 may suggest that the binding displacement does not follow the laws of mass action with a single binding site.
[0042] The results of this investigation are depicted graphically in Figure 2, appended below. These data surprisingly demonstrate relatively potent inhibition of the dopamine transporter by the (R)(-) bupropion enantiomer, with an apparent Ki of 0.15 μΜ. By comparison, the apparent Ki of the (S)(+) enantiomer was 2.88 μΜ, approximately 20-fold weaker. Racemic bupropion was approximately 2- to 3-fold weaker than the (R)(-) enantiomer with an apparent Ki of 0.45 μΜ.
[0043] The norepinephrine transporter was inhibited by the racemate and both isomers.
However, (R)(-) bupropion was the most potent with an apparent Ki of 9.77 μΜ, a value ~65-fold higher than inhibition of the dopamine transporter by this distinctly therapeutically active enantiomer. (S)(+)-Bupropion was approximately half as potent as the (R)(-) enantiomer at the dopamine transporter, with an apparent Ki of 20.3 μΜ, while racemic bupropion had an intermediate value of 14.7 μΜ.
[0044] The foregoing data are regarded as unexpected in light of numerous unpredictable factors that attend the art pertaining to the invention. Consistent with this observation, the data presented herein are in marked contrast to data on biogenic amine uptake inhibition reported by Musso and colleagues (Musso et al. 1993), in which the (R)(-) enantiomer (identified as the levorotatory) was reportedly approximately half as potent as the (S)- enantiomer for inhibiting synaptosomal dopamine uptake and approximately 2.5-fold weaker than the (S)(+) enantiomer for inhibiting norepinephrine uptake into synaptosomes. The present data are, however, consistent with the behavioral studies herein which demonstrate stimulant activity in a murine model predictive of CNS therapeutic efficacy with the (R)(-) enantiomer but not with the (S)(+) enantiomer.
[0045] Further studies by the instant inventors confirm that the the (R)(-) enantiomer of bupropion generates exclusively a therapeutically active 2(S)(+) hydroxybupropion metabolite, which retains therapeutic efficacy consistent with bupropion, while 2(R)(-) hydroxybupropion contributes primarily to the toxicity of bupropion and hence increases its adverse effect profile while having little therapeutic benefit. Therefore, the instant invention includes the additional important discoveries that administration of (R)(-) bupropion will result in elevated levels of 2(S)(+) hydroxybupropion and lower levels of 2(R)(-)
hydroxybupropion, yielding enhanced therapeutic efficacy and reduced side effects compared to racemic bupropion or the (S)(+) bupropion enantiomer. Additionally, since the first pass absorption and metabolism of bupropion appears faster than the process of interconversion, (R)(-) hydroxybupropion does not appear to emerge as a metabolic byproduct of (R)(-) bupropion, administering (R)(-) bupropion according to the invention will reduce the first- pass formation of (R)(-) hydroxybupropion (in comparison to that observed after
administration of racemic bupropion) and the attendant high toxicity associated with elevated levels of that molecule.
[0046] In light of the foregoing discoveries, the invention herein provides powerful new compositions and methods employing an isolated (R)(-) enantiomer of bupropion to treat a range of central nervous system (CNS) disorders in vertebrate subjects amenable to treatment with drugs that modulate monoamine transporter activity(ies). Within certain aspects of the invention, compositions, formulations and methods are provided that employ a stable, substantially pure (R)(-) bupropion compound as an effective pharmaceutical agent for treating a variety of CNS disorders.
[0047] As described herein (R)(-) bupropion (including pharmaceutically acceptable salts, solvates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of (R)(-) bupropion), is effective for treating (e.g., preventing or alleviating symptoms, or moderating the length and/or severity of) CNS disorders affected by
monoamine neurotransmitter receptor or biogenic amine levels and/or activities—typically CNS disorders alleviated by inhibiting norepinephrine and/or dopamine reuptake.
[0048] The pharmaceutical agents comprising purified (R)(-) bupropion as described herein are useful for the prevention, treatment, amelioration, alleviation and reduction of one or more symptoms of a variety of CNS disorders in vertebrate, most typically mammalian, subjects suffering from central nervous system disorders including those generally treated with bupropion, such as, but not limited to, depression, treatment resistant depression, seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder, addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity. In additional aspects of the invention (R)(-)bupropion compositions and methods herein are effectively employed to enhance cognitive function and/or memory, to alleviate cognitive and other symptoms associated with Parkinson's disease, Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy.
[0049] Efficacy of the pharmaceutical agents and methods of the invention employing purified (R)(-) bupropion can be demonstrated using any known, art-accepted index that docoments the incidence or records or determines the severity, symptomology, or therapeutic efficacy of drug agents and methods for treating CNS disorders. Many such methods and tools for determining therapeutic efficacy are known and routinely utilized for clinical assessment of the full array of treated CNS conditions in humans, and comparable indices and tools are routinely employed for non-human vertebrate treatment assessment in the veterinary arts. Within exemplary embodiments of the invention a purified (R)(-) bupropion composition, formulation or method according to the invention will be administered to a mammalian submect in a therapeutically effective amount and or dosing regimen to yield a clinically significant thereapeutic benefit against a targeted CNS disorder, condition or symptom(s) in the subject. For example, (R)(-) bupropion compositions, formulations and methods of the invention will yield at least a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30-50% reduction, 50-75% reduction, up to at least a 75-90% reduction, and as much as a 95% reduction ranging to complete elimination prevention, remission of the individual incidence, symptom occurrence or severity, adverse sequelae, disease recurrence, population disease rate indices between treated and non-treated groups, or any other clinically useful index or suite of observational statistics sufficient to reasonably quantify disease risk, occurrence, status, severity, recurrence, or remission, or otherwise quantitatively assess drug therapeutic efficacy for prevention, treatment, amelioration, alleviation and or reduction of one or more symptom(s) associated with a targeted CNS disorder or condition.
[0050] In related aspects of the invention, compositions and methods are provided that employ substantially pure (R)(-) bupropion in a therapeutically amount effective to treat a CNS condition (e.g., by reducing one or more adverse symptoms of a CNS condition) in a vertebrate subject, while reducing the incidence or severity of one or more adverse effects associated with bupropion therapy in comparison to the incidence or severity of the same side effect(s) in a comparative test subject administered the same amount of racemic bupropion or substantially pure (S)(+) bupropion. Adverse effects are harmful or undesirable effects of pharmaceuticals that may occur at any point during a treatment period. They may range from irritating to fatal side effects, and can result from individual patient physiology or
biochemistry, allergic reactions, dosing incompatibilities, interactions with other
medications, age, gender or racial differences, and many other factors, and are often the due to an intrinsic biological activity of the drug itself. Adverse effects may diminish or disappear with continued drug use, continue indefinitely during treatment, or increase in number and/or severity during a prolonged course of treatment. Many adverse effects are dose-dependent, limiting the potential of numerous pharmaceuticals by confining their use to a particular dosage range, frequency or duration of use, thereby preventing their full clinical utility from being explored. This is the case for many psychiatric medications, which have well documented therapeutic efficacy for treating psychiatric disorders, but often have substantial adverse effects, such as sexual dysfunction, seizure, changes in metabolism, eating behavior and body weight, drowsiness, memory loss, nausea, insomnia, dizziness, blurred vision, and agitation, among others. Much the same can be said for bupropion, a drug which has approved clinical utility for treating depression and aiding in nicotine cessation, but has numerous documented adverse effects, some very serious, and thereby has met with very limited further clinical development. Within exemplary embodiments of the invention a purified ( )(-) bupropion composition, formulation or method according to the invention will be administered in a side-effect ameliorating effective amount and/or dosing regimen to a mammalian subject to yield a clinically significant reduction of one or more of the foregoing adverse effects known in the art to be associated with racemic bupropion drug treatment.
[0051] For example, (R)(-) bupropion compositions, formulations and methods of the invention will yield at least a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30- 50% reduction, 50-75% reduction, up to at least a 75-90% reduction, and as much as a 95% reduction ranging to total elimination prevention, remission of the individual incidence, occurrence or severity, or of population adverse event rates, including but not limited to: seizure; allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue, unusual hoarseness); blurred vision or other vision changes; reduced sexual desire or impaired sexual performanc; chest pain; confusion; dark urine; delusions; fainting; fast or irregular heartbeat; fever, chills, or sore throat;
hallucinations; hearing problems; menstrual changes; new or worsening mental or mood changes; agitation; restlessness; red, swollen, blistered, or peeling skin; severe headache or dizziness; severe or persistent joint or muscle pain; severe or persistent nausea, vomiting, or stomach pain; severe or persistent nervousness, restlessness, agitation or trouble sleeping; shortness of breath; suicidal thoughts or attempts; tremor; unusual swelling; yellowing of the skin or eyes; changes in metabolism, eating behavior and/or body weight, drowsiness, memory loss, and/or decreased cognitive function (e.g., as compared to these values observed in a subject or population receiving the same, or therapeutically equivalent, dosage and dosing frequency of racemic bupropion or (S)(+) bupropion).
[0052] In more detailed aspects of the invention, the enhanced therapeutic efficacy of (R)(-) bupropion over efficacy profiles determined for other CNS-therapeutic drugs, including racemic bupropion and (S)(+), is demonstrated by side-by-side efficacy comparisons employing any of the clinical efficacy methods and tools described herein. In exemplary embodiments, a selected therapeutic dose of (R)(-)bupropion administered to a patient presenting with a targeted CNS disorder will elicit increased therapeutic effects, for example as demonstrated by at least a 10%-20% comparative reduction in measurable symptoms of targeted CNS disorder (or other index of therapeutic efficacy for treating the targeted CNS condition in the patient) after an effective treatment period. These comparative results are determined in side-by-side comparison to an observed treatment efficacy for a compared drug, for example by measuring the same symptoms or indices in suitable control subjects after a comparable treatment period following administration of an equal or greater dose of racemic bupropion or (S)(+) bupropion. In related embodiments, (R)(-)bupropion-treated patients will ehibit at least a 25%-50% comparative reduction in measurable symptoms of a targeted CNS disorder compared to symptom reduction or other therapeutic efficacy value determined for racemic bupropion- or (S)(+) bupropion administered at an equal dosage and comparable treatment period to control subjects. In other related embodiments, (R)(-) bupropion-treated patients ehibit at least a 50%-75% comparative reduction in measurable symptoms of the targeted CNS disorder compared to symptom reduction or other therapeutic efficacy value determined for racemic bupropion- or (S)(+) bupropion administered at an equal dosage and comparable treatment period to control subjects.
[0053] Within the aspects of the invention relating to minimization of adverse effects, novel compositions and methods are provided employing substantially pure (R)(-) bupropion in an amount effective to treat a targeted CNS condition while at the same time reducing an incidence and/or level of 2(R)(-) hydroxybupropion in a plasma or CNS compartment of the individual selected for bupropion treatment. According to these aspects of the invention, administration of (R)(-) bupropion to a human or non-human vertebrate subject in a therapeutic dose yields a lower incidence and/or level of 2(R)(-) hydroxybupropion detected in a sample from blood or a selected CNS compartment (e.g., CNS tissue, a targeted CNS organ such as the brain, or cerebrospinal fluid) at a predetermined time after administration, than will be detected in a sample collected contemporaneously from a test subject administered the same amount of racemic bupropion or substantially pure (S)(+) bupropion.
[0054] Other related aspects of the invention employ substantially pure (R)(-) bupropion in an amount effective to treat a CNS condition, while increasing the presence and/or level of 2(S)(+) hydroxybupropion in the plasma or a CNS sample of an individual taking bupropion therapeutically relative to the presence and/or level of 2(S)(+) hydroxybupropion measured in a comparable test subject administered the same, or a therapeutically equivalent, amount of racemic or (S)(+) bupropion. Within these aspects of the invention (R)(-) bupropion is administered to the subject in a therapeutic dose which yields an attendant increased incidence and/or level of 2(S)(+) hydroxybupropion in a blood or CNS sample at a predetermined time after administration compared to the incidence or level detected in a comparable sample from a test subject administered the same amount, or an equivalent therapeutic amount (i.e., an amount that yields essentially equivalent therapeutic results, irrespective of dosage and side effects) of racemic bupropion or (S)(+) bupropion. In exemplary aspects of the invention, administration of (R)(-) bupropion yields an incidence and/or level of 2(S)(+) hydroxybupropion in a blood or CNS sample of a subject that is increased by at least 10%-20%, 25%-35%, 40%-60%, 75%-95%, up to 100% and even two- fold or greater than the incidence and/or level of 2(S)(+) hydroxybupropion observed in a comparable sample from a test subject administered the same amount, or an equivalent therapeutic amount of racemic bupropion or (S)(+)bupropion.
[0055] Within additional related apsects of the invention, administering (R)(-)bupropion within the compositions and methods described herein of the invention yields therapeutic effects with attendant reduction of effects, mediated in part by a reduction in the presence and/or level of 2(R)(-) hydroxybupropion in the treated individual (e.g., as measured comparatively in blood plasma or CNS samples between individuals dosed equivalently with either (R)(-)bupropion, or racemic or (S)(+) bupropion). The reduced side effects are correlated qualitatively or even quantitatively with the reduction in incidence and or levels of 2(R)(-) hydroxybupropion detected in comparative test samples. Thus, subjects administered a dose of (R)(-)bupropion that is therapeutic for treating a selected CNS disorder (e.g., depression, ADHD, addiction), who exhibit a 10-25%, 30-50%, or even 75% or greater reduction in adverse effects of bupropion compared to those observed in individuals administered the same (therapeutic or subtherapeutic) dose of racemic bupropion or substantially pure (S)(+)bupropion, will exhibit a qualitatively or quantitavely related or even directly proportionate (e.g., generally in a dose-responsive relationship) reduced incidence or level of 2(R)(-) hydroxybupropion in plasma or CNS test samples compared to the incidence or level of 2(R)(-) hydroxybupropion detected in comparable test samples from subjects receiving the same amount, or equivalent therapeutic amount, of racemic or (S)(+) bupropion. In exemplary aspects of the invention, administration of (R)(-)bupropion yields an incidence and/or level of 2(R)(-) hydroxybupropion in a blood or CNS sample of a subject that is decreased by at least 10%-20%, 25%-35%, 40%-60%, up to 75%-95%, or even as much as 100% compared to the incidence and/or level of 2(R)(-) hydroxybupropion observed in a comparable sample from a test subject administered the same amount, or an equivalent therapeutic amount of racemic bupropion or (S)(+)bupropion.
[0056] In more detailed embodiments of the invention, compositions and methods are provided that employ a therapeutically effective dose of substantially pure (R)(-)bupropion that reduces first-pass formation of 2(R)(-) hydroxybupropion in a plasma or CNS sample of a treated individual in comparison to first-pass formation of 2(R)(-) hydroxybupropion in plasma or CNS sample from a subject administered the same amount, or a therapeutically equivalent dose, of racemic bupropion. Within these embodiments, the first-pass formation of 2(R)(-) hydroxybupropion in plasma or CNS samples of (R)(-)bupropion-treated individuals (receiving any enantiomerically enriched (R)(-)bupropion composition or formulation described herein) will be reduced by at least 10-25%, 30-50%, 75%-90% or even 95% or greater compared to the first-pass formation of 2(R)(-) hydroxybupropion detected in like-treated individuals receiving bupropion racemate or (S)(+)bupropion.
[0057] In further detailed embodiments of the invention, the novel properties of (R)(-) bupropion compositions and methods of the invention yield a combination of beneficial pharmacological effects, including: a measurable increase in therapeutic effects; reduction of adverse effects; and coordinate increase of thereapeutic 2(S)(+) hydroxybupropion and decrease of 2(R)(-) hydroxybupropion incidence and/or levels, compared to therapeutic effects, side effects and relative 2(S)(+) hydroxybupropion and 2(R)(-) hydroxybupropion incidence and or levels observed after administering the same amount of racemic or substantially pure (S)(+)bupropion.
[0058] By virtue of the foregoing effects and advantages, the (R)(-)bupropion compositions and methods of the invention provide enhanced therapeutic effects at lower bupropion dosages in comparison to the dosage/efficacy of racemic bupropion or (S)(+) bupropion, also yielding reduced side effects at the same, or even higher, dosages compared to racemic or (S)(+) bupropion. In certain methods and compositions of the invention, administration of a selected therapeutic dose of (R)(-)bupropion to a patient presenting with a CNS condition as described herein will yield at least a 10%-20%, 25%-50%, 50%-75%, or even 90-100% reduction in the patient of measurable symptoms of the CNS disorder, or other indices of therapeutic efficacy for treating the targeted CNS condition, attended by at least a 10%-20%, 25%-50%, 50%-75%, or even 90-100% reduction in observed side effects (e.g., seizure incidence, loss of sexual desire, occurrence/severity of allergic reaction) compared to a therapeutic efficacy and side effect profile determined after administration of a same dose of racemic or (S)(+) bupropion. In related aspects, the methods and compositions of the invention provide for reduced dosing of patients while achieving an equivalent therapeutic benefit and/or side effect profile compared to therapeutic and side effects exhibited by racemic or (S)(+) bupropion.
[0059] Thus, the invention provides novel dosage forms of bupropion comprising a therapeutically effective dosage (with acceptable side effect profile) of (R)(-)bupropion that is 10%-20%, 25%-50%, 50%-75%, or even more than 75% reduced (e.g., by weight of active compound) compared to an established, equivalently therapeutic dose (with equal or greater adverse effect profile) of racemic or (S)(+) bupropion. Within these aspects of the invention, novel therapeutic dosages of (R)(-)bupropion will typically be selected that are within the aforementioned ranges of reduced weight of active compound in comparison to a predetermined relative amount of racemic bupropion tested and shown to yield approximately equivalent therapeutic efficacy (e.g., by reduction in measurable symptoms or other indices of the incidence or severity of a targeted CNS condition) and side effect profile. Thus, if a dose of 200 mg of a sustained release (SR) formulation of racemic bupropion administered twice daily is determined to yield a baseline therapeutic efficacy (i.e., minimum efficacy considered satisfactory by physicians for positive treatment effectiveness) against, e.g., depression, ADHD, stimulant addiction, or male or female hyposexual desire disorder, therapeutically equivalent or improved results with comparable or reduced side effects will be obtained by administering a twice daily dosage of ( )(-) bupropion that is, for example, 150 mg - 200 mg, 150 mg or less, 100 mg - 150 mg, 100 mg or less, 50 mg - 100 mg, or even 50 mg or 25 mg or less. In other exemplary embodiments the invention provides for reduced dosing in accordance with the foregoing by lowering the frequency of dosing, thus in the preceding example an equivalent therapeutic benefit to a 200 mg twice daily dose of racemic bupropion will be achieved by a once daily dosing regimen of between about 200 mg and 400 mg or less, for example 250 mg - 400 mg, 200 mg - 300 mg, 150 mg - 250 mg, 150 mg or less, or even less than or equal to 100 mg or 50 mg.
[0060] Additionally provided herein are combinatorial formulations which employ
substantially pure (R)(-) bupropion in combination with one or more additional therapeutic agents effective to prevent, treat, ameliorate, alleviate or reduce signs and symptoms of a targeted CNS disorder in a vertebrate subjects amenable to treatemtn with bupropion.
Exemplary combinatorial formulations and coordinate treatment methods employ (R)(-) bupropion in combination with one or more secondary therapeutic agent(s), typically psychotherapeutic agent(s), including, but not limited to, drugs from the general classes of antidepressants, mood-stabilizing, anxiolytic, anticonvulsant, antipsychotic, antiaddictive, stimulants, muscle relaxants and sleep medications, antiepileptics, medications for Parkinson's disease, Alzheimer's medications, medications for ADHD, opioids, and appetite suppressant drugs. Within related, coordinate administration methods of the invention, substantially pure (R)(-) bupropion and the secondary therapeutic agent(s) are administered concurrently, or sequentially in any order, to prevent or treat one or more symptoms of the targeted CNS disorder. When administered simultaneously, the (R)(-) bupropion compositions and the additional or secondary therapeutic agent(s) may be combined in a novel, combinatorial formulation or combined dosage form, or administered at the same time in separate dosage forms in amounts collectively effective to treat the target CNS condition.
[0061] Substantially pure (R)(-) bupropion enantiomer for use within the invention may be prepared by any means generally used to separate enantiomeric forms including, but not limited to, crystallization, the use of chiral acids, oxidation of corresponding chiral amino alcohols (Berrang, B.D., et al, 1982), reduction with BH3-THF, liquid chromatography, gas- liquid chromatography, chiral columns, high performance liquid chromatography (HPLC), the use of an ovomucoid column, electrokinetic chromatography, selective reaction of one reaction of one enantiomer with an enantiomer-specific reagent, and the use of highly sulfated cyclodextrins among others. Alternatively, specific enantiomers 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.
[0062] The (R)(-) enantiomer of bupropion can reportedly be prepared by asymmetric synthesis as described previously (Musso et al. 1993, Fang et al. 2000, each incorporated herein by reference). However, the enantiomeric composition and purity of the products produced within these reports are not certain or fully characterized, while attempts to reproduce the reported assymetric synthetic method of Fang et al. were unsuccessful for yielding usable drug product to administer to study subjects. Alternatively for use within the invention, bupropion enantiomers can be prepared by successful by chiral chromatography, e.g. supercritical fluid chromatography.
[0063] Assymetric synthetic methodologies previously contemplated for production of bupropion enantiomers have been substantially modified and expanded to yield successful results within the methods of the invention, as described below.
EXAMPLE VI
Exemplary Assymetric Synthesis of (R -) Bupropion
[0064] In general aspects and with reference to the foregoing detailed passages, an exemplary synthetic protocol with generalized steps and conditions for generating clinical grade/quantity (R)(-) bupropion useful within the methods and compositions of the invention is summarized below in Reaction Scheme 2. Scherae2: S nthetic Overview for R(-)Bupropion HCl salt
Figure imgf000030_0001
i 1 ) Swern
Oxidation on (+)-free base
2) HCl
(S)-(+)-bupropion HCl Salt
(biologically less active)
Musso-(+M
Musso, D. L., Mehta, N. B., et al., Chirality, 1993, 5, 495-500.
Figure imgf000030_0002
(R)-(-)-bupropion HCl Salt
Musso-(-)-1
Musso mp 188-190°C
Musso (a]D -39.64°
J. J. Partridge Consulting, Inc.
09 June 2011 Reductio /Step 1 / 1971-11-1
Reaction conditions
• 500 g, racemic Bupropion HC1 salt (lot #R05-27l 1-53)
• BH3*THF(2 eq)
• THF (5 L)
Observations/Notes
• Slowly added BH3*THF at temp below 3C and stirred for 18 hours at rt; clear solution was observed.
• HPLC showed no S .
• Added NaOH to pH ~ 10 and stirred at reflux for 1.5 hours.
• Concentrated reaction mixture to ~7 vol. and added TBE
• Separated organic phase and washed aq phase with MTBE (2x)
• Combined organic phases, washed with brine, and dried over MgS04.
• Filtered, concentrated - yellow oil with some crystals.
Isolated Material
• Yield: 485 g (crude oil)
• Lot#: 1971-11-1
• HPLC: diastereomeric: 29/71
Purification /Step 1 /1971-13-1
Reaction conditions
• 485 g , aminoalcohol crude (lot #1971-11-1)
• L(+)-Tartaric acid ( 1.2 eq)
• water (3 L)
Observations/Notes
• Free amine stirred with L(+)-Tartaric acid at 95C to lOOC for 1 hour.
• Reaction mixture was cooled to rt and stirred for 18 h.
• Solids were filtered, washed with water.
Isolated Material
o Yield: 325 g white solids (wet)
o Lot#: 1971-13-1
o HPLC: diastereomeric// ee: 1.6/7.7// 88/2.2 (only 10% of desired enantiomer in the filtrate)
Recrystallization IP A/water:
• Lot 1971-13-1 (wet) dissolved in IP A/water (500 ml/ 200 ml) at 70C in jacketed reactor.
• Mixture cooled to 40C, stirred for 4 hours and cooled to 15C.
• Currently is stirring at 15C.
o Yield: TBD
o Lot#: 1971-13-3
o HPLC: diastereomeric// ee: TBD
Reduction /Step 1 /1971-15-1
Reaction conditions
308 g, rac. Bupropion HC1 salt (lot #R05-271 1-53)
BH3*THF (2 eq)
THF (5 L)
Observations/Notes
Slowly added BH3*THF at temp below 3C and stirred for 18 hours at rt.
Reaction in progress.
Isolated Material
Yield: TBD
Lotf: 1971-15-1
HPLC: TBD
Purification /Step 1 / 1971-9-1
Reaction conditions
• 25 , aminoalcohol (lot #1971-6-1) • L(+)-Tartaric acid ( 1.2 eq)
• water (50 mL)
Observations/Notes
• Free amine stirred with L(+)-Tartaric acid at 95C to lOOC for 20 minutes and filtered.
• Filtrate was concentrated to approximately 2 vol and stirred at it for 18 h
• Solids was filtered, washed with water.
Isolated Material
o Yield: 12.3 g white solids
o Lot#: 1971-9-2
o HPLC: diastereomeric / ee: 1.8/5.7//74.1/18.4.
• Lot 1971-9-1 dissolved in IPA water (5/1) at reflux (cloudy solution)
• Mixture cooled to rt and stirred for 18 hours.
• Solids were filtered and dried.
Isolated Material
• Yield: 9.75 g
• Lot#: 1971-9-3
• HPLC: diastereomeric / ee: 0.11//99.8/0.1.
Additional Comments/Notes
• Lot 1971-9-3 was converted to free amine (5 g).
• Some recrystallization methods were tested:
o EtOH/MTBE - diastereomeric// ee: 0//1.2/97
o IPA/water - diastereomeric// ee: 0.9//91.2/6
Oxydation /StepS / 1971-12-1
Reaction conditions
• 5 g, alcohol (+) (lot #1971-9-3)
• (COCl)2 (2.5 eq), DMSO (5 eq), Et3N (5.4 eq)
• DCM (170 ml)
Observations/Notes
• Slowly added DMSO at temp below -70C into (COCl)2 in DCM and stirred for 20 minutes.
• Added alcohol solution at temp below -60C and stirred for 209 minutes.
• Reaction mixture was heated to -15C and slowly added TEA. Stirred at -15C to -IOC fro 30 minutes.
• Heated reaction mixture to -5C and added cold water, (extracted at temp below 5C).
• Separated organic phase and extracted inorganic with DCM (2x50 ml).
• Combined organic phases washed with brine and dried over MgS04 at temp, below 5C.
• Mixture was filtered and immediately added HCl/diethyl ether 2M solution.
• Reaction mixture was concentrated and coevaporated with heptanes.
• Added heptanes, stirred for 2 hours and filtered.
Isolated Material
• Yield: 6.5 g, crude
• Lot#: 1971-12-1
• HPLC: 97.7%
Additional Comments/Notes
• Recrystallizations tests showed that material do not crystallize from IPA/water, EtOH/water.
Product crystallized from EtOH diethyl ether (Mussso method).
• 6.2 g crude lot 1971 - 12- 1 dissolved in 20 ml EtOH at 50C, added Et20 (60 ml) and stirred at rt for 18 hours.
• Product was filtered and currently is drying under high vacuum at 60C.
[0065] In reference to the foregoing general schematic and exemplary synthetic protocol steps and conditions, the published methodology of Musso et al. was considered somewhat problematic for the purposes of the invention, in part because racemic bupropion could not easily be split into its two enantiomers using conventional techniques such as separation by using tartaric acid isomers. In an attempt to overcome this problem the Musso laboratory first reduced racemic bupropion using BH3.THF. This led to the formation of two compounds - threo and erythro bupropion. Attempts at isolating versions of erythro bupropion into its enatiomers were not successful. However, they were successful in isolating the two enatiomers of threo bupropion. Following this second step, Musso and coworkers used Swern oxidation to reform specific enantiomers of bupropion.
[0066] Although much of the assymetric separation strategy described by Musso et al could be replicated within the invention, four unexpected modifications were required for successful implementation to yield the enantiomerically purified (R)(-) compositions and methods of the invention. First, Swern oxidation at below -60°C and re-crystallization required the complete exclusion of sample exposure to basic conditions. Any such exposure led to unacceptable racemization. The pH needed to prevent unacceptable racemization was decidedly acidic, for example below approximately pH 2.5, more acceptably at or below approximately pH 1.0, or between pH 0.5 and pH 1.0. Accordingly, within certain aspects of the invention novel assmetric synthetic methods for obtaining a purified (R)(-) enantiomer of bupropion is provided, characterized by incorporating non-basic conditions, for example between a pH of 0.5 and 2.0 for crystallization of the (R)(-) bupropion.
[0067] Additional modifications required for successful (R)(-) bupropion synthesis for use within the methods and compositions of the invention relate to temperature conditions that are reduced well below those described for conventional assymetric synthetic protocols, win particular, successful crystallization of enantiomerically purified (R)(-) bupropion required temperature conditions to be maintained below approximately 10°C-15°C, more acceptably below about 10°C, in certain embodiments below about 5°C or 6°C, and in other
embodiments between about 2°C-5°C. Accordingly, within certain aspects of the invention novel assmetric synthetic methods are provided for obtaining a purified (R)(-) enantiomer bupropion characterized in that the crystallization of the (R)(-) enantiomer is carried out at a substantially reduced temperature, e.g., between about 2°C and 10°C.
[0068] Yet a third modification over conventional assymetric syntheses such as the method of Musso et al. for successful isolation of (R)(-) bupropion within the invention consisted of dissolving the extract from the Swern reaction into acetonitrile, in order to reduce or eliminate triethyl amine content. This important step of re-crystallization from acetonitrile is neither described nor contemplated by Musso et al., and is critical for production of clinical grade/quantity (R)(-) bupropion for use within the invention. A fourth substantial modification for producing (R)(-) bupropion for use within the invention involved the important removal of triethyl amine contaminant by multiple, e.g., two or three, cold washes, prior to recrystallizing.
[0069] In accordance with the foregoing, novel preparations of substantially pure (R)(-) bupropion were obtained and confirmed and characterized according to standard methods, as illustrated by the Analytic Report below.
Product: (2R)-2-[(½r/-Butyl)amino]-l-(3-chlorophenyl)propan-l-one HC1 salt
Product Code: R(-)Bupropion HC1 Salt
Lot Number: 1791-23-1
Log No.: Rl 1-1528, Rl 1-1533
Formula: C,3H19Cl2NO
Molecular Weight: 276.2 g mol
Appearance: Off-white solid
HNMR (DMSO-d6): Conforms to structure
,3CNMR (DMSO-d6): Conforms to structure
Karl Fischer: 0.15%
Optical Rotation: -39.7° (95% ethanol, 1.4039 g/ 100 ml, 589 nm, 1 dm)
IR: Conforms to expectations for purified crystal product
LCMS: 240.1 [M+H]
MP: 237.2 °C
DSC: Onset @ 232.74 °C, 250.98 °C, 299.72 °C
Exotherm: 235.86 °C, 251.64 °C, 309.24 °C
HPLC (area%): 99.8%
HPLC chiral (area %): 98.1%
XRPD: Conforms to expectations for purified crystal product
Heavy Metals: <20 ppm
ROI: 0.02%
TGA: 0.06% @ 100 °C
Element Analysis: Actual: 56.87 %C 7.08 %H 5.08 %N 24.95 %C1 [0070] Summarizing the foregoing data and discoveries, assymetric synthetic methodologies previously contemplated for production of bupropion enantiomers were unsuccessful for use within then invention, and novel methods incorporating substantial modifications and expansions of steps and conditions were required to obtain successful results to implement the objects and advantages of the invention. Employing these novel procedures and conditions allowed for production of clinical grade/quanity, substantially pure (R)(-) bupropion compositions having a demonstrated chiral purity, as expressed in terms of enantiomeric excess (ee), of at least 90% ee, and in certain embodiments up to at least 95% ee, 96% ee, 97% ee or greater. In one exemplary embodiment, the assymetric synthesis methods of the invention generated highly enantiomerically pure (R)(-) bupropion compositions that were greater than 97% ee in purity.
EXAMPLE V
Exemplary Chiral Chromatographic Purification of (POM Bupropion
[0071] In general aspects and with reference to the foregoing detailed passages, an exemplary protocol with generalized steps and conditions for generating clinical
grade/quantity (R)(-) bupropion useful within the methods and compositions of the invention employing chiral chromatographic techniques has been developed. As demonstrated herein, bupropion exhibits severe chemical and stereochemical instability under basic mobile phase conditions, which requires fundamental departures from conventional chiral chromatographic techniques in order to achieve the objects of the invention. As a first modification directive, a more conservative HPLC separation approach was selected. Additionally, neutral nonpolar ion pairing conditions were selected which was shown to enhance bupropion stereochemical stability in a milder HPLC regime. Column screening experiments conducted with hexane- alcohol based mobile phases containing mixtures of trifluoroacetic acid and various amines returned still further-enhanced separation results on a CHIRALCEL OD-H CSP. Stability studies carried out with isolated enantiomer fractions indicated unexpected improvements in chemical and stereochemical stability employing these methods. However, some degree of racemization and chemical degradation was still seen upon prolonged standing in the mobile phase media, even at ambient temperature. Subsequent investigations focusing on optimization of the additive concentration and the molar acid/base ratio led to still further improvements concerning the stability characteristics.
[0072] Within these novel expanded chromatographic methods, a highly apolar mobile phase system was devised as exemplified by a hexane/2-pronaol 90:10 (v/v) system containing acidic and basic ion pairing agents in an exemplary 1 :l-stoichiometry (see Table 6). This proved to be a particularly favorable environment, such that racemization was not observed even after 2 days of storage at ambient temperature. With respect to chemical stability, only minor amounts of degradation products were detected after storage of the fraction for 2 days at room temperature.
Figure imgf000036_0001
[0073] Despite these unexpectedly advantageous results, additional barriers were required to be overcome in order to obtain a useful chiral chromatographic method for preparative scale separation of bupropion enantiomers. In particular, the limited solubility of bupropion hydrochloride in the novel mobile phase system of the invention presented a formidable barrier to this objective. To address this problem, a more lipophilic triflouroacetate salt was prepared from the corresponding hydrochloride via the free base and tested as an alternative racemic starting material. Major enhancements in solubility were achieved by the anion replacement and use of a modified injection solvent. The significant improvements in solubility allowed high loads of racemic sample able to be applied onto the column to allow preparative scale implementation of the inventive methods, without sacrificing resolution due to volume overload phenomena.
[0074] In order to achieve the objects of the invention, it was further essential to develop an integral process, addressing in addition to the chromatographic challenges all chemical steps required for stable and high-yield/purity isolation of the subject (R)(-) bupropion enantiomer of interest. After considerable experimentation, an exemplary protocol fully compatible with the sensitive stereochemical nature of bupropion was determined. Exemplary novel aspects of this integrated methodology include important steps of: 1) preparation of the
trifluoroacetate from the commercially available racemic hydrochloride; 2) chromatographic separation of the enantiomers on a suitable column, exemplified by a CHIRALCEL OD-H, column under optimized chromatographic conditions as illustrated above; 3) post-processing of the enantiomer fractions to achieve removal of basic/acidic additives; 4) reformation of the hydrochloride; and 5) final organic washing to remove chemical impurities formed during the individual processing steps. A detailed description of exemplary procedures illustrative of the forgoing general protocol is provided as follows.
(R,S) Bupropion Trifluoroacetate from the Corresponding Hydrochloride
[0075] Racemic bupropion hydrochloride (24.9 g, 90.2 mmol) was suspended in ethyl acetate (400 mL) with magnetically stirring. To the stirred suspension was added at 25°C an aqueous solution of sodium hydrogencarbonate (17.0 g in 300 mL HPLC quality water; 202.5 mmol, 2.25 equivalents) in several portion over 5 min. The resulting two phase system was stirred for further 5 min and then transferred into a separation funnel. The organic layer was isolated and dried over anhydrous MgS04 (30 g). The solution was filtered and the drying agent washed with several portion of fresh ethyl acetate (2 x 50 mL). To the combined organic phases was added a solution of trifluoroacetic acid (8.0 mL, 12.3 g, 0.108 mmol, 1.20 equivalents) in 100 mL ethyl acetate. The resultant colorless solution was evaporated under reduced pressure at a bath temperature of 25°C to yield an off-white solid (31.7 g, quantitative) after drying in vacuum.
Preparative Separation of (R,S)-Burpropion TFA salt on CHIRALPAK OD-H.
[0076] Feed solution preparation: Bupropion trifluoroacetate (31.7 g), prepared as described above, was dissolved in 1.40 L of a mixture of hexane:2-propanol (80:20 (v/v)).
Column Conditioning: A column packed with CHIRACLCEL OD-H CSP (250 x 50 mm i.d., 5 micron particles) was washed with a mixture of hexane:2-propanol:trifluoroacetic acid 90:10:0.1 (v/v) for 20 min at a flow rate of 120 mL/min. Subsequently, the column was conditioned with a mobile phase system consisting of hexane:2-propanol:2- propylamine:trifluoroacetic acid 90:10:0.025:0.03 (v/v) for 20 min at a flow rate of 120 mL/min. A typical preparative chromatogram is depicted in Figure 4. After this treatment, the chromatographic separation was carried out using the conditions summarized in Table 7 Table 7 Nonpolar Ion Paring Conditions Used for the Separation of Bupropion Trifluoroacetate Enantiomers on CHIRALCEL OD-H CSP
Column CHIRALCEL OD-H (250 x 50 mm i.d., packed with 5.0 micron
CSP particles
Mobile Phase Hexane:2-Propanol:Trifluoroacetic acid:2-Propylamine
90:10:0.025:0.03
Flow Rate 120 mL/min
System 64 bar
Pressure
Detection UV 280 nm
Temperature 25 C
Sample 22.6 g Bupropion Trifluoroacetate / L in mobile phase
Inject. Volume 25 mL (565 mg)
Cycle Time 3.7 min/cycle
Isolation of Bupropion Hydrochlorides from the Chromatographic Fractions
[0077] The pooled fractions of Enantiomer 2 (ca. 8.0 L) were evaporated under reduced pressure using at an external bath temperature of 25°C. To the resultant oily residue ethyl acetate (1.0 L) was added and the mixture was mechanically stirred until a clear solution was obtained. After transferring a separation funnel, an aqueous solution of sodium hydrogen carbonate (17.0 g in 300 mL HPLC quality water; 202.5 mmol) was added in several portions. The solution was extracted and the aqueous layer was discarded. The organic layer was washed with water (0.4 L) and then dried over anhydrous magnesium sulphate (30 g). The solution was filtered and the drying agent washed with fresh ethyl acetate (2 x 100 mL). The combined filtrates were concentrated under reduced pressure at 25°C. The resulting oil was taken into a mixture of hexane:2-propanol (90:10 (v/v); 300 mL). A freshly prepared anhydrous solution of hydrogen chloride in hexane:2-propanol was added in excess to convert the free base into the corresponding hydrochloride. Evaporation under reduced pressure at 25°C furnished an off-white solid. To facilitate filtration and removal of colored impurities a final washing step with an inert organic solvents was performed. Specifically, methyl-tert. butyl-ether (200 mL) was added, and the crude hydrochloride adhering to the wall of the flask was broken and homogenized with a spatula. The resultant slurry was filtered and the solid was washed repeatedly with of hexane (3 x 200 mL). Yield after drying at 25°C in vacuum: 9.9 g (35.8 mmol mmol, 80%) of a white solid. The pooled fractions of Enantiomer 1 (ca. 5 L) were treated as described above to yield 9.9 g of a white solid (25.8 mmol, 80%).
[0078] The practical feasibility of the general process outlined above was further demonstrated via a further study employing a 25g amount of racemic bupropion hydrochloride. All individual process steps detailed above were implemented successfully with excellent results, ultimately producing both (R)(-) and (S)(+) bupropion enantiomers in an 80% or better yield, with excellent levels of optical purity, with an estimated ee greater than 98% for both enanatiomers, and comparable chemical purity.
Analytical Characterization of the Isolated Enantiomers
[0079] Chiral purity: Fractions were examined by LC, with results as follows:
Sample Chiral LC purity
Racemate 50.0 / 50.0%
(R)(-) bupropion 99.44% (98.9%e.e.)
(S)(+) bupropion 99.72% (99.4%e.e.)
Residual solvent was also determined by GC, with results are as follows:
Figure imgf000039_0001
[0080] Considering the preceding disclosure, conventional chiral chromatographic methods previously considered for obtaining bupropion enantiomers were not practicable to fulfill the uses and purposes of the invention, whereby novel methods incorporating substantial modifications and expansions of steps and conditions were required to obtain successful chiral chromatography methods and results to fulfill the objects and advantages of the invention. Employing these novel procedures involving modified high pressure liquid chromatography yielded (R)(-) bupropion compositions with an enantiomeric purity of at least 90% ee or greater, up to at least 95% ee, 96% ee, 97% ee, or greater. In one exemplary embodiment, the chiral chromatographic methods of the invention generated (R)(-) bupropion compositions having at least 99% ee or greater enantiomeric purity.
[0081] In conjunction with the foregoing, and respective of all preparative methods and compositions for producing purified, stable (R)(-) bupropion contemplated herein, it is important to note that acceptable methods for producing (R)(-) bupropion, particularly for clinical uses and practices including stable encapsulation and formulation, must be consistent with the unexpectedly reduced pH requirements described herein for production and maintenance of useful, stable (R)(-) bupropion formulations (see below).
[0082] In other embodiments of the invention described herein, (R)(-) bupropion has been formulated in a stable capsular form, with novel pH and moisture content characteristics, that exhibited 100% stability at room temperature after three months.
EXAMPLE VI
Stable Pharmaceutical Formulation, Packaging and Storage
of (R)(-) Bupropion for Clinical Use
[0083] In all aspects of its handling and production, consistent with the investigations and results described herein, enantiomerically-enriched (R)(-) bupropion compositions exhibit surprisingly rapid and extensive racemization under a broad range of previously undescribed conditions. This finding presents many serious obstacles to the clinical development of (R)(-) bupropion within the invention. These challenges and uncertainties attributable to (R)(-) bupropion racemization accord with the previous failure by others to evaluate and clinically develop (R)(-) bupropion as a prospective drug candidate.
[0084] The nature and extent of instability of (R)(-) bupropion was discovered and documented herein by numerous independent investigations. Initially, the rapid racemization of (R)(-) bupropion was determined generally, and in more detailed studies (R)(-) bupropion racemization was investigated for a range of enantiomerically purified (R)(-) bupropion compositions under different pH conditions. These studies, summarized below, led to the identification of an unexpected critical conditions for stable (R)(-) bupropion formulation, namely an exceptionally low pH, and extreme intolerance to the presence of water.
[0085] Based on our initial findings that isomers of buropion racemized quickly under general laboratory, preparative and formulation conditions we formulated a sample pharmaceutical preparation comprising 50 mg capsules of R-bupropion, and these capsules were evaluated the purity and stability over three months. These initial (R)(-) bupropion were found to have racemized in an accelerated stability chamber after only 14 days of exposure. Capsules from a room temperature humidity chamber were then analyzed, and were found to have partially racemized.
[0086] Further studies were conducted employing crystalline (R)(-) bupropion stored in airtight sample tubes at room temperature, and under these strict storage conditions the (R)(-) bupropion was observed to be resistant to racemization. Additionally, samples of (R)(-) bupropion dissolved in 0.1 M HC1 (pH ~ 1.2) showed no apparent racemization. Therefore, racemization of (R)(-) bupropion only appeared to be occurring in the presence of water, and at higher pH values. Based on these observations additional studies were designed to test the hypothesis that moisture absorption occurring under conventional lab and storage conditions was contributing to (R)(-) bupropion racemization, possibly by allowing pH-dependent racemization of R-bupropion to occur inside capsules and unsealed assay containers.
[0087] In further stodies to elucidate the mechanisms and possible controls to prevent (R)(-) bupropion raceiztion, additional studies were undertaken wherein the pH of enantiomerically enriched (R)(-) bupropion compositions was maintained at a pH of 2.0 or less in tightly sealed containers, and under these conditions the experimental (R)(-) bupropion
compositions remained stably enantiomerically enriched.
[0088] In order to more discretely determine the effects of water and pH on (R)(-) bupropion racemization, test solutions of (R)(-) bupropion were prepared at various graded, buffered pH levels. These solutions were subsequently assayed for changes in (R)(-) bupropion enantiomeric excess (% ee) values over time, empoying the following materials and conditions according to conventional protocols.
Materials:
(R)(-) Bupropion
Agilent 1260 Infinity HPLC
15-mL Celstar sample tubes
Methods:
HPLC method AM06- 50/50 A/B; 0.5 mlJmin; 20 uL loop; Chiralpak IA® column (4.6mm x 150 mm, 5 micron pores)
A = 90: 10 acetonitrile:H20 B = 0.05 M KP04 (pH 7.5), 0.05% triethylamine, 10% acetonitrile
[0089] Four buffer solutions were prepared of pH 5 (50 mM acetate), pH 4 (50 mM acetate), pH 2 (50 mM phosphate), and pH 1.2 (0.1 M HC1). Sample tubes were stored at room temperature in clear plastic Cellstar 15 mL sample tubes. The HPLC method used was AM02, with the ChiralPak IA column and operated under reverse phase conditions. The mobile phase concentrations of the organic modifier (MeCN) were adjusted slightly each day for relative resolution. Pure crystalline (R)(-) bupropion and (S)(+) bupropion samples were dissolved in separate 0.01 M HC1 sample tubes. These were then diluted to 10 mL, 0.2 mM solutions of each enantiomer in each pH buffer, for 8 total sample tubes. The 8 samples were prepared one at a time and assayed immediately for time-zero %ee. The samples were then assayed once daily for an initial one week study period. Thereafter, once racemization trends became apparent, monitoring assay frequency was attenuated until final % ee assays was conducted after 45 days. The results of this pH/stability assay are presented in Figure 3, appended below.
[0090] The racemization trendlines shown in Figure 3 demonstrate that both (R)(-) bupropion and (S)(+) bupropion enantiomers racemize more rapidly as solution pH increases. As noted earlier, crystalline preparations that were moisture-free were shown to be enantiomerically stable. Accordingly, the findings above reveal that racemization of bupropion enantiomers remains a critical obstacle to stable clinical preparation of this compound under ordinary hydrous conditions across a broad range of conventional drug formulation and physiological pH conditions.
[0091] Therefore there are two important aspects of drug purification, formulation and maintenance for (R)(-) bupropion compositions of the invention, which include a requirement to keep the surrounding environment as anhydrous as possible, and a need to maintain an acidic pH during synthesis/purification, drug product preparation, and storage.
[0092] To control pH within stable preparative compositions and products containing (R)(-) bupropion, an acidic excipient may be added as a buffer to maintain an acidic pH to avoid racemization. As determined by the investigations herein, a suitable pH for a stable, clinically useful (R)(-) bupropion should never be higher than about pH 4.0, or pH 3.5, and in most circumstances (R)(-) bupropion should not be exposed to a less acidic pH than at or below about pH 3.0. Indeed, for stable isolation, synthesis, formulation, manufacture and storage, to yield a stable (R)(-) bupropion product free of unacceptable levels of
racemization, all relevant compositions described herein should optimally be maintained below approximately pH 3.0, more desirably below about pH 2.5. Even greater stability of enantiomerically purified (R)(-) bupropion formulations of the invention can be obtained with pH conditions are artificially lowered to below about pH 2.0, more acceptably at or below approximately pH 1.5 or 1.0, between pH 0.5 and pH 1.0, or even at or below pH 0.5. Within related aspects of the invention novel purified (R)(-) bupropion compositions are provided which feature an added pH stabilizing agent, such as an acidic buffering agent, to maintain a stable pH and substantially prevent racemization of the (R)(-) bupropion over an extended time period. In one exemplary embodiment, (R)(-) bupropion was combined with a suitable amount of a citric acid carrier/buffering agent, along with a silica filler/handling agent, yielding a stable pH of the formulation below about pH 2.0, and this formulation maintained a substantially enantiomerically pure state of the (R)(-) bupropion for extended storage periods, up to six weeks or longer.
[0093] Suitable pH stabilizing carriers/buffering agents for formulating (R)(-) bupropion in an enantiomerically stable formulation include, in addition to citric acid, any suitable, physiologically acceptable acid that is compatable with (R)(-) bupropion to preclude reaction or degradation and which will help prevent racemization of the (R)(-) bupropion by buffering the pH of the formulation within the accepted acidic ranges noted above, preferably between about pH 0.5 and pH 2.0, and in certain embodiments at or below about pH 1.5, or pH 1.0. Exemplary candidates in this context include, but are not limited to, salicylic acid, tartaric acid, succinic acid, and fumaric acid. Other suitable buffering/carrier candidates in this context include, but are not limited to, glycopyrrolate, sorbitol, and tween 80. Inclusion of one or more of these and other prospective suitable buffering carrier agents within (R)(-) bupropion formulations of the invention provide for maintenance of enantiomeric stability of the formulation for extended periods, for example more than two weeks, up to a month or longer, up to two months or longer, up to three to four months or longer, six months or longer, and even for periods of up to six months to a year, during which time substantially pure (R)(-) bupropion remains essentially stable, such that it maintains (R)(-) bupropion purity at 90% ee or greater throughout the subject stability period. [0094] Based on these and additional experiments and findings, the invention provides pH stabilized and substantially anhydrously produced, formulated and packaged, pharmaceutical compositions having, in exemplary embodiments, an enantiomeric purity of the (R)(-) bupropion of 95% ee or greater after a stability period (i.e., a storage period after isolation and crystallization of the (R)(-) bupropion at room temperature or higher temperature conditions) of at least two weeks. In related embodiments, pharmaceutical compositions are provided which have enantiomeric purity of (R)(-) bupropion of at least 75% ee or greater after an extended stability period of four-six weeks. In other related embodiments, the pharmaceutical compositions of the invention exhibit an enantiomeric purity of (R)(-) bupropion of 85% ee or greater after a stability period of four-six months. In yet additional embodiments, it has been shown that low pH-stabilized, essentially anhydrously formulated and stored, pharmaceutical compsitions can be provided according to the teachings herein which have a documented long-term stability as reflected by enantiomeric purity of (R)(-) bupropion of at least 60% ee, 75% ee, 80% ee, 85% ee, or even 90% ee or greater after an extended stability period of six months, even under high temperature storage conditions above room temperature up to 40 degrees centigrade or higher.
[0095] As noted above, stable formulation and storage of (R)(-) bupropion also requires that compositions of the invention should be maintained under as anhydrous conditions as possible, preferably to exclude even trace quantities of water altogether. Thus, in exemplary formulations and kits of the invention, (R)(-) bupropion was formulated as described above, and sealed in water-tight container, optionally with a dessicant present in a sufficient amount to absorb all incidental moisture present in the formulation and container (and any other ingredients and/or packing materials) upon sealing of the drug product within the container. In this context, the invention provides pharmaceutical kits for treating a CNS disorder comprising (R)(-) bupropion in an enantiomerically stable form. In certain aspects, (R)(-) bupropion is provided in combination with container means to stably contain the (R)(-) bupropion in a water-tight, essentially anhydrous enclosure. In exemplary embodiments, the container is a water-resistant plastic or other suitable, sealable container that includes water- barrier means to effectively seal the (R)(-) bupropion (and optional secondary therapeutic agent) in a water-proof container chamber, which is thereafter sealed to maintain the (R)(-) bupropion essentially free of exogenous water and in an essentially enantiomerically stable 000117
form over an extended period of time. In more detailed embodiments the container is a high density plastic, such as a PTFE or other polyethylene plastic, and the lip and lid of the container are sealable against one another to anhydrously seal the container chamber upon closure of the (R)(-) bupropion therein. In optional products kits, a combinatorial
formulation of (R)(-) bupropion and a secondary therapeutic agent is anhydrously sealed within the container prior to storage and use. In additional detailed embodiments, a suitable amount of a dessicant is included in the container prior to sealing to absorb any incidental water that may be present in the container and or in other drug or packaging materiasl also enclosed in the container upon orginal container closure/sealing. In yet additional detailed embodiments, sealing means of the container include use of a heat-resistant, sealable undersurface (e.g., a foil undersurface) comprising the sealing gasket means or undersurface of the lid, which is placed in contact with the lip of the lid upon closure/sealing of the sealable container. In exemplary embodiments, the sealing gasket or sealable undersurface of the lid is seated under heat and optionally pressurized conditions to form a thermal seal against the lip of the container, optionally leaving a partial vacuum within the container after sealing and cooling to further preclude exposure of the (R)(-) bupropion within the container to water. According to these teachings, suitable packaging methods, materials and devices are provided within the invention, suitable packaging materials and products are provided to maintain essential enantiomeric stability of (R)(-) bupropion formulations for extended periods, for two weeks or more, up to a month or longer, up to two months or longer, up to three to four months or longer, six months or longer, and for periods of up to six months to a year, during which stability periods the substantially pure (R)(-) bupropion originally packaged in the container remains essentially stable with the (R)(-) bupropion purity remaining at or above 90% ee.
[0096] As noted above, the compositions and methods of the invention employing (R)(-) bupropion) are therapeutically useful for treating a broad range of CNS disorders amenable to treatment using bupropion and/or by modulation of monoamine neurotransmitter and/or monoamine neurotransmitter receptor levels or physiology. Subjects amenable to treatment according to the invention include mammalian subjects, including humans, suffering from or at risk for any of a variety of CNS disorders, including CNS disorders previously approved for treatment using racemic bupropion, namely depression and smoking cessation difficulties, and some conditions incidently addressed in off-label bupropion racemate use reports, including attention deficit hyperactivity disorder (ADHD), sexual dysfunction, addiction, and eating and weight disorders.
[0097] As used herein, "(R)(-) bupropion)" refers to enantiomerically enriched isolates of (R)(-) bupropion as described herein, including (R)(-) bupropion compositions and products produced by a process according to any of the synthetic, purification, handling, formulation or packaging processes described herein. Those skilled in the art will likewise understand that (R)(-) bupropion compostions for use within the invention will include pharmaceutically acceptable salts, solvates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of (R)(-) bupropion. For example numerous additional salts of (R)(-) bupropion that are useful in preparative and/or clinical compositions of the invention are contemplated herein that can be produced and implemented within the invention without undue experimentation following the teachings herein. Thus, useful (R)(-) bupropion compostions within the invention can be prepared as alternative acid addition salts in addition to the exemplary hydrochloride salt employed in the foregoing examples
(including, e.g., hydrobromide, hydroiodide, sulphate, hydrogen sulphate, nitrate, phosphate, and hydrogen phosphate salts). Other examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts, base salts and metal salts, including but not limited to 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, Ν,Ν'- 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. Suitable base salts are formed from bases which form nontoxic salts and include, for example, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and diethanolamine salts. In a similar manner, pharmaceutically compatable solvates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of (R)(-) bupropion can be selected and developed or use within the invention without undue experimentation. Prodrugs of (R)(-) bupropion are particularly useful wihin 000117
the invention, and are generally considered to be include (R)(~) bupropion covalently bonded with a carriers which releases the active parent drug in vivo. Examples of useful (R)(-) bupropion prodrugs include, for example, esters or amides of (R)(-) bupropion with hydroxyalkyl or aminoalkyl as a substituent, though a wide range of useful alternative prodrugs can be routinely identified and developed according to the teachings herein.
[0098] In more detailed aspects of the invention, the compositions and methods employing (R)(-) bupropion) described herein are therapeutically effective for treating a novel expanded range of CNS disorders amenable to treatment using bupropion and/or by modulation of biogenic amine and/or monoamine receptor levels and/or physiology including, but not limited to, depression, treatment resistant depression, seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female sexual dysfunction including male and female hyposexual desire disorder, addictive disorders, including drug addiction (e.g., addictions to stimulants, including amphetamines, cocaine addiction, opioid addiction, and nicotine addiction and/or nicotine withdrawal symptoms to assist smoking cessation), gambling addiction, and sex addiction, among others, impulse control disorders, eating disorders and weight disorders such as obesity. In related aspects of the invention (R)(-) bupropion compositions and methods of the invention are effectively employed to enhance cognitive function and/or memory, to alleviate cognitive and other symptoms associated with Parkinson's disease, Alzheimer's disease, senile dementia and traumatic and other pathogenic brain injury, and to treat pain and other symptoms associated with neuropathy, such as neuropathic pain associated with nerve compression or traumatic, surgical or pathogenic neuropathy, including diabetic neuropathy. In yet additional aspects of the invention. Additional CNS disorders contemplated for effective treatment employing the methods of the invention include additional CNS disorders amenable to treatment by modulation of monoamine neurotransmitter and/or monoamine neurotransmitter receptor levels and/or physiology, as described, for example, in the Quick Reference to the Diagnostic Criteria from DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), The American Psychiatric Association, Washington, D.C., 1994.
[0099] Administration of (R)(-) bupropion agents alone or in a 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 central nervous system disorder or development of the disorder by at least 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.
[00100] As used herein, the terms "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 central nervous system 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 an incidence or recurrence of said central nervous system 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 CNS disorder). As used herein, the terms "treatment" or "treating," when referring to a targeted CNS disorder, refers to inhibiting or reducing the progression, nature, or severity of the subject condition or delaying the onset of the condition.
[00101] An "effective amount," "therapeutic amount," "therapeutically effective amount," or "effective dose" of (R)(-) bupropion agents and/or a secondary therapeutic agent as used herein means an effective amount or dose of the active compound(s) as described herein sufficient to elicit a desired pharmacological or therapeutic effect in a human subject. 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 CNS disorder, including any combination of neurological and/or psychological symptoms associated with or caused by the targeted CNS disorder. Therapeutic efficacy can alternatively be demonstrated by a decrease in the frequency or severity of symptoms associated with the treated central nervous system condition or disorder, or by altering the nature, occurrence, recurrence, or duration of symptoms associated with the treated condition or disorder. In this context, "effective amounts," "therapeutic amounts," "therapeutically effective amounts," and
"effective doses" of psychotherapeutic drugs and ( )(-) bupropion agents 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.
[00102] In related aspects of the invention, the methods and compositions herein employing (R)(-) bupropion are additionally effective in the treatment of CNS disorders in patients who have been determined to be refractory to prior drug treatment, including prior with an antidepressant drug, an anti-ADHD drug, an anti-addiction drug, and in certain cases drug treatment using bupropion racemate. For each of the targeted CNS disorders identified herein, (R)(-) bupropion will often be employed as an effective treatment in individuals who have failed first-line drug treatment for the targeted CNS disorder, e.g., individuals who have not responded, who have responded insufficiently, or who have been unable to tolerate previous treatment(s) due to adverse effects or who have otherwise responded in an unsatisfactory manner to prior drug treatment, typically prior drug treatment aimed at modulating physiology and/or levels or activity of monoamine neurotransmitters and/or their receptors (such as 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, monoamine oxidase inhibitors, atypical antidepressants, atypical antipsychotics, anticonvulsants, or opiate agonists).
Individuals may have been refractory to previous treatment(s) for any reason. In some embodiments, refractory individuals may have failed to respond or failed to respond sufficiently to a previous treatment. In one embodiment of the invention, a refractory individual may have treatment resistant depression or treatment resistant ADHD. In other embodiments, a refractory individual may have responded to an initial treatment, but not succeed in maintaining remission following one or more initial courses of drug treatment. In some embodiments, refractory individuals may have been unable to continue taking the medication due to intolerance of the medication including side effects such as seizure, allergic reactions, blurred vision or other vision changes, reduced sexual desire or impaired sexual performanc, chest pain confusion, dark urine, delusions, fainting, fast or irregular heartbeat, fever, chills, or sore throat, hallucinations, hearing problems, menstrual changes, mental or mood changes, agitation, restlessness, skin reactions, headache or dizziness, joint or muscle pain, persistent nausea, vomiting, or stomach pain, nervousness, restlessness, agitation or trouble sleeping, shortness of breath, suicidal thoughts or attempts, tremor, unusual swelling, yellowing of the skin or eyes, changes in metabolism, eating behavior and/or body weight, drowsiness, memory loss, and/or decreased cognitive function.
[00103] In all aspects of CNS disorder treatment contemplated herein, including first- and second-line treatment, and combinatorial therapy using coordinate treatment and/or combinatorial formulations of (R)(-) bupropion with a second CNS therapeutic drug, the novel compositions and methods of the invention will be therapeutically effective against the target CNS disorder to yield at least a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30-50% reduction, 50-75% reduction, up to at least a 75-90% reduction, and as much as a 95% reduction ranging to complete elimination/prevention, remission of the individual incidence, symptom occurrence or severity, adverse sequelae, disease recurrence, population disease rate indices between treated and non-treated groups, or another clinically useful index or suite of observational data statistics sufficient to reasonably quantify disease risk, occurrence, status, severity, recurrence, or remission, or otherwise quantitatively assess drug therapeutic efficacy for preventing, treating, ameliorating, alleviating and/or reducting of one or more symptoms of, the targeted CNS disease or condition. Efficacy of the individual or 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 CNS disorder, such as depression, ADHD, cognitive deficiency, sexual dysfunction), by at least 5%, 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95% or greater, up to stable remission, compared to correlative scores or values observed for control subjects treated with placebo or other a suitable postive control drug treatment (e.g., racemic bupropion). In at risk populations, 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. In other embodiments of the invention, clinical or therapeutic efficacy will be determined by direct observation of disease symptoms, including by physician observation, physical, cognitive or physiological testing, blood, tissue or other biological sample biochemical testing (e.g.,as particularly suited for assessing drug addiction treatment efficacy), or any other useful, qualitative or quantitative parameters for determining absolute or relative therapeutic efficacy of the (R)(-) bupropion compositions and methods disclosed herein.
[00104] In more detailed embodiments, the methods and compositions of the invention empoying (R)(-) bupropion are therapeutically effective for treating a range of cognitive disorders, including but not limited to Attention-Deficit/Hyperactivity Disorder (ADHD) Predominately Inattentive Type, ADHD Predominately Hyperactivity-Impulsive Type;
ADHD Combined Type, ADHD not otherwise specified (NOS); Conduct Disorder;
Oppositional Defiant Disorder; and Disruptive Behavior Disorder not otherwise specified (NOS). In related embodiments, the methods and compositions of the invention are therapeutically effective for treating Parkinson's disease (including via modulation of dopamine/dopamine transporter and/or norepinephrine/norepinephrine transporter
physiology), autism, traumatic brain injury, cognitive impairment, schizophrenia (particularly for cognition), mild cognitive impairment, cognitive and/or memory loss associated with Parkinson's disease, Alzheimer's disease, and brain injury or pathology, and for enhancing cognitive function and memory in general.
[00105] ADHD is a CNS disorder characterized by developmentally inappropriate inattention, hyperactivity, and impulsivity (Buitelaar et al., 2010; Spencer et ah, 2007). It is one of the most common developmental disorders in children, with 5-10% prevalence (Scahill et al., 2000; Polanczyk et al., 2007). ADHD can continue through adolescence and into adulthood, such that a still substantial percentage of the adult population presents with continuing or adult ADHD (Kessler et al., 2006; Faraone and Biederman, 2005). (R)(-) bupropion compositions of the invention, including pharmaceutically acceptable active salts, polymorphs, hydrates, chemically modified derivatives or conjugates, metabolites, polymorphs and prodrugs of ( )(-) bupropion, are effectively employed treat both pediatric and adult ADHD diseases and symptoms.
[00106] The exact causes of ADHD are not known, but a dysfunction of the prefrontal cortex and its associated circuitries has been posited as a key deficit in ADHD (Arnsten, 2009). Consistent with this notion is the finding that abnormal catecholaminergic function plays a key role, particularly in prefrontal cortical regions (Arnsten 2009). The
catecholamines norepinephrine (NE) and dopamine (DA) are highly involved in several domains of cognition including working memory, attention, and executive function.
Accordingly, these monoamine neurotransmitters are targets of specific methods and compositions of the invention that employ (R)(-) bupropion in an amount and dosing regimen effective to therapeutically modulate levels and/or activity of one or both of the biogenic amines, NA and DA, and/or to modulate levels or monoamine reuptake activity by one or more of the cognate receptors for these biogenic amines, the norepinephrine transporter (NET) and dopamine transporter (DAT), respectively.
[00107] In these and other aspects and CNS disease treatment methods of the invention, the methods and compositions of the invention will frequently employ (R)(-) bupropion in a biogenic amine physiology modulatory effective amount, for example which is effective to ihibit NE reuptake and/or DA reuptake by at least about a 5-10% reduction, 10-20% reduction, 20-30% reduction, 30-50% reduction, up to a 50-75% or greater reduction (in an accepted in vitro assay of NE and/or DAtransporter inhibition, or in actual test samples (e.g., plasma or cerebrospinal fluid) from subjects treated with (R)(-) bupropion assayed to quantitatively assess in vivo NET and/or DAT inhibitory activity in comparison to endogenous activity values).
[00108] Pharmacotherapy is a primary form of treatment for ADHD. There are currently eight drugs in the US approved for treatment of ADHD: Amphetamine- dextroamphetamine (Adderall®), Dexmethylphenidate (Focalin®), Dextroamphetamine (Dexedrine®, Dextrostat®), Lisdexametamine (Vyvanse®), Methylphenidate (Ritalin®, Concert®a, Metadate®, Daytrana®), Atomexetine (Straterra®), Guanfacine (Intuniv®, Tenex®), and Cloonidine (Catapres®). Stimulants such as methylphenidate and
amphetamines are commonly used for ADHD. The major mechanism of action of the stimulants is inhibition of DA and NE transporters. The stimulants are reportedly effective against core symptoms of ADHD. However, major concerns about stimulants include risk of abuse, dependency, and diversion as well as potential neurotoxic effects of amphetamines (Berman et al, 2009). The abuse potential of stimulants is particularly problematic in adults because substance abuse is a common co-morbidity with adult ADHD (Levin and leber, 1995; Ohlmeier, 2008). Although some non-stimulant drugs are available for use in the US to treat adult ADHD, including atomoxetine and a2-adrenergic agonists, doubts about the therapeutic utility of these agents have been reported (see, e.g., Faraone, 2009).
[00109] The (R)(-) bupropion compositions of the invention (including salts, polymorphs, solvates, derivatives, metabolites, prodrugs of (R)(-) bupropion), are therapeutically effective against pediatric and adult ADHD as determined, for example, by the drug-mediated alleviation of one or more ADHD symptoms in treated patients, including but not limited to symptoms of inattention, disorganization, lack of concentration, impulsivity, difficulty functioning, learning disabilities, low educational attainment, under-achievement in vocational pursuits, and poor social and/or family relations. Many alternative means of selecting ADHD patients for treatment and for determining therapeutic efficacy of the methods and
compositiosn of the invention, including the incidence of indices determined in conventional psychoanalytic or behavioral scales or scoring tests. Such indices for ADHD alternatively include scales, questionnaires or tests that assess attributes or symptoms of the disorder, such as: difficulty paying attention to details, difficulty keeping attention on tasks, difficulty following instructions, difficulty organizing activities, difficulty following conversations, being easily distracted, being forgetful of daily routines. In the case of predominantly hyperactive- impulsive type ADHD, the subject indices for selecting candidates for treatment with (R)(-) bupropion compositions, or for quantifying therapeutic efficacy of this novel drug, can include disruptive and age-inappropriate symptoms, such as: fidgeting often, inappropriate running about, trouble playing or enjoying leisure activities quietly, excessive talking, blurting out answers, trouble waiting turn, and interrupting others, whereas combinations of these various indices of inattentive and hyperactive-impulsive symptoms may be present in combined type ADHD.
[00110] Efficacy of the treatment methods and drug compositions of the invention for ADHD and often be assessed by conventional patient surveys or clinical scales that measure clinical indices of ADHD subjects. Several useful surveys are available for ADHD, 117
including assessments for adults, children, those rated by clinical investigators, and those rated by subjects treated. Among these useful tools are the Wender Utah Rating Scale (WURS) (Ward et al, 1993); Adult Rating Scale (ARS) (Weyandt et al, 1995); Curent Symptoms Scale (CSS) (Barkley and Murphy, 1998); Conners Adult ADHD Rating Scale (CAARS) (Conners et al, 1999); Adult Problems Questionnaire (APQ) (De Quiros and
Kinsboume, 2001); Young Adult Rating Scale (YARS) (Du Paul et al, 2001); Assessment of Hyperactivity and Attention (AHA) (Mehringer et al, 2002); Attention Deficit Scales for Adults (ADSA) (Triolo and Murphy, 1996); ADHD Rating Scale (ADHD-RS) (Du Paul et al, 1998); Brown Attention Deficict Disorder Series (BADDS) (Brown, 1996); Symptom Inventory (SI) (McCann and Roy-Byrne, 2004); Young Adult Questionnaire (YAQ) (Young, 2004); Adult Self Report Scale (ASRS) (Adler et al, 2006), and the Caterino Scale (Caterino et al, 2009), each incorporated herein by reference.
[00111] 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% or greater compared to correlative scores or values observed for control subjects treated with placebo or other suitable control treatment, which comparative data can also demonstrate efficacy for prophylactic
treatment/preventive uses of (R)(-) bupropion described herein (in contexts of prevention of ADHD or its symptoms, prevention of drug addictive behavior in recovering addicts and/or subjects genetically predisposed to addiction, etc.)
[00 12] Within other embodiments of the invention, substantially pure (R)(-) bupropion employed therapeutically to treat a variety of addictive disorders, particularly addictive disorders amenable to treatment by modulation of biogenic amine and/or monoamine transporter levels or activity. Addictive disorders amenable for treatment and/or prevention employing the methods and compositions of the invention include, but are not limited to, behavioral addictions such as gambling addiction, sex addiction, certain eating disorders, impulse control disorders including obsessive compulsive shopping and hording disorders, and drug addictions such as amphetamine addiction, nicotine addiction, cocaine addiction, and opiate addiction, among other drug addictions. The methods and
compositions of the invention are therapeutically effective to treat and/or prevent the incidence, severity and recurrence/relapse of targeted symptoms of these addictive disorders by at least 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95% or greater compared to correlative values observed for control subjects treated with placebo or other suitable control treatment.
[00113] Amphetamine-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions of the invention include, but are not limited to, Amphetamine Dependence, Amphetamine Abuse, Amphetamine Intoxication, Amphetamine Withdrawal, Amphetamine Intoxication Delirium, Amphetamine-Induced Psychotic Disorder with delusions, Amphetamine-Induced Psychotic Disorders with hallucinations, Amphetamine-Induced Mood Disorder, Amphetamine-Induced Anxiety Disorder,
Amphetamine-Induced Sexual Dysfunction, Amphetamine-Induced Sleep Disorder,
Amphetamine Related Disorder not otherwise specified (NOS), Amphetamine Intoxication, and Amphetamine Withdrawal. Symptoms associated with these amphetamine-related disorders are well described in the literature to allow for reliable patient selection for treatment and ready assessment of efficacy and dosage optimization for the (R)(-) bupropion methods and compositions of the invention.
[00114] Cocaine-related disorders include amenable to treatment using the (R)(-) bupropion methods and compositions of the invention include, but are not limited to, Cocaine Dependence, Cocaine Abuse, Cocaine Intoxication, Cocaine Withdrawal, Cocaine
Intoxication Delirium, Cocaine-Induced Psychotic Disorder with delusions, Cocaine- Induced Psychotic Disorders with hallucinations, Cocaine-Induced Mood Disorder, Cocaine- Induced Anxiety Disorder, Cocaine-Induced Sexual Dysfunction, Cocaine-Induced Sleep Disorder, Cocaine Related Disorder not otherwise specified (NOS), Cocaine Intoxication, and Cocaine Withdrawal. Symptoms associated with these cocaine-related disorders are likewise well known to allow ready clinical application and assessment of the (R)(-) bupropion methods and compositions provided herein.
[00115] Opioid-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Opioid Dependence, Opioid Abuse, Opioid Intoxication, Opioid Intoxication Delirium, Opioid-Induced Psychotic Disorder with delusions, Opioid-Induced Psychotic Disorder with hallucinations, Opioid- Induced Anxiety Disorder, Opioid Related Disorder not otherwise specified (NOS), Opioid Intoxication, and Opioid Withdrawal.
[00116] Nicotine-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Nicotine Dependence, Nicotine Withdrawal, and Nicotine-Related Disorder not otherwise specified (NOS).
[00117] Alcohol-related disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Alcohol-Induced
Psychotic Disorder, with delusions; Alcohol Abuse; Alcohol Intoxication; Alcohol
Withdrawal; Alcohol Intoxication Delirium; Alcohol Withdrawal Delirium; Alcohol- Induced Persisting Dementia; Alcohol-Induced Persisting Amnestic Disorder; Alcohol Dependence; Alcohol-Induced Psychotic Disorder, with hallucinations; Alcohol-Induced Mood Disorder; Alcohol-Induced Anxiety Disorder; Alcohol-Induced Sexual Dysfunction; Alcohol-Induced Sleep Disorders; Alcohol-Related Disorders not otherwise specified (NOS); Alcohol Intoxication; and Alcohol Withdrawal.
[00118] Impulse control disorders amenable to treatment using the (R)(-) bupropion methods and compositions invention include, but are not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, and Impulse Control Disorder not otherwise specified (NOS).
[00119] In other embodiments of the invention (R)(-) bupropion compositions and methods are provided that effectively treat sexual dysfunction conditions, including male and female hyposexual desire disorder (HSDD).
[00120] In yet addional embodiments of the invention (R)(-) bupropion compositions and methods are provided that effectively treat eating disorders and weight disorders, including obesity. Eating disorders in this context include, but are not limited to, Bulimia Nervosa, Nonpurging Type; Bulimia Nervosa, Purging Type; Eating Disorder not otherwise specified (NOS); and eating disorders associated with weight disorders, including obesity and other adverse health effects.
[00121] In other embodiments of the invention, (R)(-) bupropion compositions and methods are provided that effectively treat depressive disorders, including but not limited to, Major Depressive Disorder, Recurrent; Dysthymic Disorder; Depressive Disorder not otherwise specified (NOS); and Major Depressive Disorder, Single Episode [00122] Additional useful patient surveys and clinical scales for selection of patients amenable to treatment using (R)(-) bupropion compositions and methods of the invention, and/or for assessing clinical efficacy of individual or combinatorial treatment compositions and methods provided herein, can include any of a variety of widely used and well known patient psychiatric assessment surveys and other CNS disease-diagnostic clinical scales as set forth below (all of which clinical assessment tools are incorporated herein by reference for economy of description). Among 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); HAM-A rating scale for anxiety (Hamilton, 1959); Clinician- Administered Post-traumatic Stress Disorder Scale (CAPS) (Weathers et al., 1999); Clinician-Administered PTSD Scale Part 2 (CAPS-2) (Blake et al, 1995); Clinician- Administered PTSD Scale for Children and Adolescents (CAPS-CA)(Nader et al, 1996); Impact of Event Scale (IES) (Horowitz et al. 1979); Impact of Event Scale-Revised (IES-R) (Weiss et al 1996); Clinical Global impression Severity of Illness (CGI-S) (Guy, 1976); Clinical Global Impression Improvement (CGI-I) (Guy, et al 1976); Duke Global Rating for PTSD scale (DGRP) (Davidson et al, 1998); Duke Global Rating for PTSD scale Improvement (DGRP-I); Structured Interview for PTSD (SI-PTSD) (Davidson, et al. 1990); PTSD Interview (PTSD-I) (Watson et al, 1991); PTSD Symptom Scale (PSS-I) (Foa et al, 2006); Beck Depression Inventory (BDI) (Beck, 2006); Revised Hamilton Rating Scale for Depression (RHRSD) (Warren, 1994); Major Depressive Inventory (MDI) (Olsen et al. 2003); and Children's Depression Index (CDI) (Kovacs, et al 1981). Any of these scales, alone or in combination, can be effectively employed to determine efficacy of the methods and compositions of the invention. Additionally, a variety of other scales and methods for assessing comparative anxiety disorder symptoms or status, are widely used and well known in the art for use within the invention. Other exemplary scales for assessing efficacy of the invention include, for example, the Hamilton Depression Rating Scale© (HDRS) (Hamilton, M., J. Neurol. Neurosurg. Psychiatr. 23:56-62, 1960; Hamilton, M., Br. J. Soc. Clin. Psychol. 6:278-296, 1967); Montgomery- Asberg Depression Rating Scale© (MADRS) (Montgomery and Asberg, 1979); Beck Scale for Suicide Ideation® (BSS) (Beck and Steer, 1991 Columbia-Suicide Severity Rating Scale© (C-SSRS) or Columbia Classification Algorithm
ss of Suicide Assessment© (C CASA) (Posner, K, et al., 2007); Sheehan-Suicidality Tracking Scale© (S-SST) (Coric et al., 2009); Beck Hopelessness Scale© (BHS) (Beck, Steer, 1988); Geriatric Depression Scale (GDS) (Yesavage, J. A. et al., J. Psychiatr. Res. 17:37-49, 1983). HAM-D scale for depression (Hamilton, 1960); the Yale-Brown Obsessive Compulsive Scale (YBOCS) (Goodman et al., 1989); The Positive and Negative Syndrome Scale (PANSS) for schizophrenia (Kay et al., 1987); the YMRS rating scale for mania (Young et al., 1978); the Liebowitz Social Anxiety Scale (Heimburg et al, 2002). 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. In prophylactic treatment, the methods and compositions of the invention will often yield a percentage increase in stabilization in the scores or values generated from these clinical surveys. For example, score changes indicating stabilization, or acquisition of a "normal" or "moderately symptomatic" status for a targeted CNS condition may occur more often in subjects treated according to the invention, e.g., by a factor of at least 10%, 20%, 30%, 50% or greater, up to a 75-90%, or 95%, compared to a frequency of the same stabilized, normal or moderately symptomatic scores or values observed for placebo or positive control (e.g., racemic bupropion-treated) subjects completing the same survey(s).
[00123] In certain embodiments of the invention, as may be clinically advantageous within any of the CNS disorder treatment methdos of the invention, (R)(-) bupropion may be beneficially combined with one or more secondary therapeutic agents, often a secondary, psychotherapeutic agent, in a coordinate treatment method or combinatorial drug formulation or treatment regimen. When the secondary therapeutic agent is one or more
psychotherapeutic drugs, these may include, but are not limited to, drugs from the general classes of anticonvulsant, mood-stabilizing, antipsychotic, anxiolytic, anti-addictive, stimulants, muscle relaxants and sleep medications, antiepileptics, medications for
Parkinson's disease, medications for ADHD, opioids, and appetite suppressant drugs benzodiazepines, calcium channel blockers, thyroid medications, and antidepressants. (See, e.g., R J. Baldessarini in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, Chapters 19 and 21, McGraw-Hill, 2001 for a review of useful secondary CNS therapeutic drugs, incorporated herein by reference.)
[00124] In certain embodiments of the invention, (R)(-) bupropion is coordinately administered with a secondary psychotherapeutic agent that is is an anti-ADHD drug. In more detailed aspects, the secondary, anti-ADHD drug is selected from amphetamine- dextroamphetamine, dexmethylphenidate, dextroamphetamine, lisdexametamine, methylphenidate, atomexetine, guanfacine, clonidine, atomoxetine and a2-adrenergic agonists.
In certain embodiments of the invention, (R)(-) bupropion is administered alone as a singularly-effective treatment agent, or coordinately with a secondary psychotherapeutic agent, to effectively treat a CNS disorder selected from psychotic disorders, epilepsy, seizure disorders, tic disorders, abnormal sexual behaviors, schizoid behaviors, somatization, sleep disorders, autism spectrum disorders, certain eating disorders and other mood disorders and mental illnesses that are categorized and treated distinctly from other CNS disorders, such as depressive, anxiety, eating and addictive disorders. Exemplary psychotic disorders amenable to treatment employing the methods and compositions of the invention include, but are not limited to, schizophrenia, schizophreniform diseases, acute mania, schizoaffective disorders, depression with psychotic features, and other psychotic disorders known in the art and associated with increased risks of suicide. Within related coordinate treatment methods and combinatorial formulations of the invention, (R)(-) bupropion treatment may be coordinated with administration of secondary CNS therapeutic agents including drugs from the general classes of antidepressant, mood-stabilizing, anxiolytic, anticonvulsant, antipsychotic, anti- addictive, and appetite suppressant drugs. In certain combinatorial formulations and coordinate treatment protocols of the invention (R)(-) bupropion is coordinately administered with an antipsychotic drug, which may be known as a typical or atypical antipsychotic drug, many of which are dual categorized as having multiple, e.g., including antidepressant, activities and are elsewhere described herein. In certain exemplary embodiments, the antipsychotic secondary drug is selected from Typical Antipsychotics, for example, chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone, and loxapine, or Atypical
Antipsychotics, for example clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, and anticonvulsants (e.g., lamotrigine, carbamazepine,
oxcarbazepine, valproate, levetriacetam, and topiramate).
[00125] In other coordinate treatment embodiments of the invention, ( )(-) bupropion is beneficially combined in a coordinate treatment method or combinatorial drug formulation with a secondary psychotherapeutic agent that is is an antidepressant drug, which may include, for example, any species within the broad families of tricyclic antidepressants (TCAs) including, but not limited to, amitriptyline, imipramine, or desipramine; specific monoamine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs) including, but not limited to, escitalopram, fluoxetine, fluvoxamine, sertraline, vilazodone, and paroxetine, selective norepinephrine reuptake inhibitors, selective dopamine reuptake inhibitors, multiple monoamine reuptake inhibitors, monoamine oxidase inhibitors (MAOIs), noradrenaline reuptake inhibitors (NRIs), multiple monoamine reuptake inhibitors, e.g., that inhibit both serotonin and norepinephrine reuptake (SNRIs) including, but not limited to, venlafaxine and duloxetine, and indeterminate (atypical) antidepressants. The additional or secondary 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 lamotrigine, carbamazepine, oxcarbazepine, valproate, levetriacetam, and topiramate). Secondary therapeutic agents may additionally include opiate agonists including, but not limited to, buprenorphine, methadone and LAAM. A more comprehensive list of suitable antidepressant drugs for use with (R)(-) bupropion in combinatorial formulations and coordinate treatment methods of the invention is provided in Table 8, below.
Table 8
EXEMPLARY ANTIDEPRESSANT DRUGS FOR COORDINATE ADMINISTRATION WITH ΠΟΜ BUPROPION
SSRIs
Celexa® (citalopram)
Lexapro® (escitalopram oxalate)
Luvox® (fluvoxamine)
Paxil® (paroxetine)
Prozac® (fluoxetine)
Symbyax® (olanzepine and fluoxetine) Zoloft® (sertraline)
SNRIs
Cymbalta® (duloxetine)
Ef exor® (venlafaxine)
Pristiq® (desvenlafaxine)
Tricyclics
Adapin® (doxepin)
Anafranil® (clomipramine)
Elavil® (amitriptyline)
Endep® (amitriptyline)
Ludiomil® (maprotiline)
Norpramin® (desipramine)
Pamelor® (nortryptyline)
Pertofrane® (desipramine)
Sinequan® (doxepin)
Surmontil® (trimipramine)
Tofranil® (imipramine)
Vivactil® (protriptyline)
Other Approved Antidepressants
Remeron® (mirtazapine)
Vilazodone®
Pending FDA Approval
Agomelatine®
[00126] In other detailed combinatorial formulations and coordinate treatment methods of the present invention, the additional or secondary psychotherapeutic agent is an anxiolytic drug agent including, but not limited to, benzodiazepines, such as alaprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam and prazepam; non-benzodiazepine agents, such as buspirone; and tranquilizers, such as barbituates.
[00127] In further combinatorial formulations and coordinate treatment methods of the present invention, the additional or secondary psychotherapeutic agent is a stimulant including, but not limited to, modafinil, methylphenidate, dextroamphetamine, methamphetamine. Sodium oxybate may also be used in the combinatorial treatment of narcolepsy.
[00128] In additional combinatorial formulations and coordinate treatment methods of the present invention, the additional or secondary psychotherapeutic agent is a muscle relaxant or sleep medication, including, but not limited to, clonazepam, triazolam, eszopiclone, ramelteon, temazepam, zaleplon and Zolpidem.
[00129] In yet another embodiment of the invention, combinatorial formulations and coordinate treatment methods employ an additional or secondary psychotherapeutic agent that is antiepileptic, such as lamotrigen or gabapentin.
[00130] In other combinatorial formulations and coordinate treatment methods of the invention, the additional or secondary psychotherapeutic agent is an anti-Parkinson's agents, including, but not limited to, dopamine, ropinirole and pramipexole.
[00131] In further combinatorial formulations and coordinate treatment methods of the present invention, the additional psychotherapeutic agent is an opioid, including but not limited to, codeine, oxycodone and hydrocodone.
[00132] Within the coordinate administration methods of the invention, the secondary therapeutic drug, typically a psychotherapeutic drug, is administered concurrently or sequentially with (R)(-) bupropion to treat or prevent one or more symptoms of the targeted CNS disorder. When administered together the secondary therapeutic agent and (R)(-) bupropion may optionally be combined in a single composition or combined dosage form. Alternatively, the combinatorially effective psychotherapeutic drug and (R)(-) bupropion agents may be administered at the same time in separate dosage forms. When the coordinate administration is conducted simultaneously or sequentially, the psychotherapeutic agent and (R)(-) bupropion 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.
[00133] The amount, timing and mode of delivery of compositions of the invention comprising an effective amount of a psychotherapeutic compound and an effective amount of (R)(-) bupropion agents will be routinely adjusted on an individual basis, depending on such factors as weight, age, gender, and condition of the individual, the acuteness of the targeted anxiety disorder and/or related symptoms, whether the administration is prophylactic or therapeutic, and on the basis of other factors known to effect drug delivery, absorption, pharmacokinetics, including half-life, and efficacy. In some embodiments, the dosage of (R)(-) bupropion agents will be the same or different than the dosage of the racemate generally used. In one embodiment, the amount of (R)(-) bupropion agent will be lower. In other embodiments, higher dosages of (R)(-) bupropion agent may be used without incurring significant adverse effects or adverse effects that exceed the profile of the currently used racemic mixture. In exemplary embodiments, the suitable oral dose range for use is from about 5mg to about 1500mg per day, preferably from about 10 mg to about 1500 mg per day, about lOOmg to about 1500mg a day, about 150mg to about 1500mg a day, about lOmg to about 900 mg per day, 10 mg to 500 mg per day, 75mg to 450mg per day, 150mg to 400mg per day, about 300mg to about 1500mg per day, about 600 to about 1500mg per day.
[00134] Dosing of (R)(-) bupropion will depend on the CNS condition being treated and the desired general pharmacokinetics (e.g. immediate release kinetics, sustained release kinetics, biphasic release, etc.), and will consider such factors as major PK parameters (e.g., as for the racemate of bupropion, which has a a Cmax of approximately 160ng/ml, and a tma of approximately 1.50 hours. In this context, the timing of Cmax and AUC for (R)(-) bupropion will influence optimization of pharmacokinetic parameters, including for hydroxybupropion metabolites after (R)(-) bupropion is administered. The rate of appearance of therapeutically effective metabolites following administration of (R)(-) bupropion, including radafaxine will further guide optimization of (R)(-) bupropion dosing, including dosage amount and frequency. Within this context, there additional areas that will be studied for (R)(-) bupropion dosing optimization include: 1) seizure risk, 2) abuse liability, and 3) safety profile for potential bupropion polypharmacy with secondary thereapetic agents, such as amphetamines that may be used as a secondary therapeutic in treating ADHD. Based on our preliminary assessments of these and additional dosing factors, it is contemplated that at least in certain embodiments an (R)(-) bupropion dose of 100-900 mgs, typically between 150-600 mgs, in certain
embodiments 200-400 mgs, optionally 150 mg, 200 mg, 250 mg, or 300 mg, PO qD will exhibit therapeutic effects for a wide range of targeted CNS conditions compared to placebo, without unacceptable adverse effects.
[00135] An effective dose or multi-dose treatment regimen for (R)(-) bupropion compositions and methods 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 the targeted CNS disorder as described herein. In some embodiments, sub-therapeutic amounts may be used. Exemplary suggested dosage ranges for selected drugs for use within ccoordinate treatment methods and combinatorial formulations of the invention are provided below in Table 9, below, for illustrative purposes.
[00136]
Table 9
Exemplary Effective Dosage Ranges For Selected Oral Antidepressant Medications
SSRIs
Celexa® (citalopram) 20-40 mg
Lexapro® (escitalopram oxalate) 10-20 mg
Luvox® (fluvoxamine) 100 mg
Paxil® (paroxetine) 20-40 mg
Prozac® (fluoxetine) 20 mg
Symbyax® (Zyprexa & Prozac) 12.5-50 mg
Zoloft® (sertraline) 50-200 mg
SNRIs
Cymbalta® (duloxetine) 60- 120 mg
Effexor® (venlafaxine) 75-375 mg
Pristiq® (desvenlafaxine) 50 mg
Tricyclics
Adapin® (doxepin) 150 mg
Anafranil® (clomipramine) 150 mg
Elavil® (amitriptyline) 150 mg
Endep® (amitriptyline) 150 mg
Ludiomil® (maprotiline) 100 mg
Norpramin® (desipramine) 150 mg
Pamelor® (nortryptyline) 75 mg
Pertofrane® (desipramine) 150 mg
Sinequan® (doxepin) 150 mg
Surmontil® (trimipramine) 150 mg
Tofranil® (imipramine) 150 mg
Vivactil® (protriptyline) 75 mg
Other Approved Antidepressants
Remeron® (mirtazapine) 20-40 mg
Vilazodone® 40 mg
Pending FDA Approval
Agomelatine® 50- 100 mg [00137] Effective unit dosage amounts of either or both (R)(-) bupropion and secondary therapeutic agent(s) 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. In exemplary
embodiments, exemplary dosages of selected drugs as illustrated above are administered one, two, three, or four times per day. In more detailed embodiments, specific dosages within the specified exemplary ranges above are administered once, twice, or three times daily. In alternate embodiments, dosages are calculated based on body weight, and may be
administered, for example, in amounts as exemplified above adjusted for body weight.
[00138] 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. Such 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.
[00139] Within various aspects of the invention, the psychotherapeutic agent and (R)(-) bupropion agent may each be administered by any of a variety of delivery routes and modes, which may be the same or different for each agent. In alternate embodiments, the
psychotherapeutic agent and (R)(-) bupropion agent is administered by a mode of delivery selected from oral, buccal, nasal, aerosol, topical, transdermal, mucosal, or injectable. In exemplary embodiments, both the psychotherapeutic agent and (R)(-) bupropion agent are administered orally. In other embodiments, one or both of the psychotherapeutic agent and (R)(-) bupropion agent is/are delivered in a sustained or extended release formulation, for example in a sustained release, oral or intravenous formulation.
[00140] The amount, timing and mode of delivery of compositions of the invention comprising an effective amount of a psychotherapeutic compound and an effective amount of a (R)(-) bupropion agent will be routinely adjusted on an individual basis, depending on such factors as weight, age, gender, and condition of the individual, the acuteness of the targeted disorder and/or related symptoms, whether the administration is prophylactic or therapeutic, and on the basis of other factors known to effect drug delivery, absorption, pharmacokinetics, including half-life, and efficacy.
[00141] The compositions of the invention for treating the disorders herein, can thus include any one or combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art. These additional formulation additives and agents will often be biologically inactive and can be administered to patients without causing deleterious side effects or interactions with the active agent.
[00142] (R)(-) bupropion agent of the present invention will often be formulated and administered in an oral dosage form, optionally in combination with a carrier or other additive(s). Suitable carriers common to 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 may also contain one or more acids or acid salts including, but not limited to, glycine HC1, cysteine HC1, cysteine dihydrochloride, tartaric acid, citric acid, ascorbic acid, isoascorbic acid, and malic acids as a stabilizing agent. (See, for example, U.S. Patent No. 5,731 ,000). Additionally, 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 preservatives. 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. These typically disintegrate in the mouth in less than one minute, and preferably in less than thirty seconds. By effervescent agent is meant a couple, 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.
[00143] (R)(-) bupropion can also be administered in any of a variety of inhalation or nasal delivery forms known in the art. Devices capable of depositing aerosolized formulations of a psychotherapeutic compound and or (R)(-) bupropion agent 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 mania or 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 and any additional active or inactive ingredient(s).
[00144] 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. In addition, intranasal delivery can achieve direct, or enhanced, delivery of R(-) bupropion agent to the central nervous system. In these and other embodiments, intranasal administration of the compounds of the invention may be advantageous for treating disorders generally treated by bupropion, by providing for rapid absorption and delivery. For intranasal and pulmonary administration, a liquid aerosol formulation will often contain a dispersing agent and/or a physiologically acceptable diluent. Alternative, dry powder aerosol formulations may contain a finely divided solid form of (R)(-) bupropion 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. The term "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. [00145] Yet additional compositions and methods of the invention are provided for topical administration of a psychotherapeutic compound and/or (R)(-)bupropion agent of the present invention. Topical compositions may comprise (R)(-) bupropion 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. It can be readily appreciated that the transdermal route of administration may be enhanced by the use of 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 (R)(-) bupropion over an extended period of time, for example 24 hours.
[00146] Yet additional formulations of (R)(-) bupropion 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.
[00147] Within exemplary compositions and dosage forms of the invention, the (R)(-) bupropion is administered, optionally together with a secondary therapeutic agent, in an extended release or sustained release formulation. In these formulations, the sustained release composition of the formulation provides therapeutically effective plasma levels of the (R)(-) bupropion agent 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.
[00148] In exemplary embodiments, the (R)(-) bupropion agent is combined with a sustained release vehicle, matrix, binder, or coating material. As used herein, the term
"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. In certain embodiments, the (R)(-) bupropion is released from the sustained release compositions and dosage forms 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. By sustained therapeutic level is meant a plasma concentration level of at least a lower end of a therapeutic dosage range as exemplified herein. In more detailed embodiments of the invention, the sustained release compositions and dosage forms will yield a therapeutic level of (R)(-) bupropion following administration to a mammalian subject in a desired dosage amount (e.g., 200, 400, 600, or 800 mg) that yields 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. In alternate embodiments of the invention, the sustained release compositions and dosage forms will yield a therapeutic level of (R)(-) bupropion following administration to a mammalian subject in a desired dosage amount 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. [00149] In some embodiments, the invention provides pharmaceutical kits for reducing symptoms in a human subject suffering from a CNS disorder. The kits comprise (R)(-) bupropion therapeutic agent in an effective amount in a container means for containing the (R)(-) bupropion agent in a stable form. In optional products/kits, a simple combinatorial formulation of (R)(-) bupropion and a secondary therapeutic agent as described herein is provided. In related products/kits, a formulation of (R)(-) bupropion (optionally admixed with a secondary therapeutic agent) is provided in combination with container means to stably contain the (R)(-) bupropion therein. Typically the container will be a plastic or other suitable, sealable container that includes water-barrier means to effectively seal the (R)(-) bupropion and optional secondary therapeutic agent in an enclosed, water-proof container chamber that can be maintained over an extended period of time essentially free of exogenous water. In more detailed embodiments the container is a high density plastic, such as a PTFE or other polyethylene plastic, and the lip and lid of the contrainer are sealable against one another to anhydrously seal the container chamber upon closure of the (R)(-) bupropion therein. In optional products/kits, a combinatorial formulation of (R)(-) bupropion and a secondary therapeutic agent is anhydrously sealed within the container prior to storage and use. In additional detailed embodiments, a suitable amount of a dessicant is included in the container to absorb any incidental water that may be present in the container and or enclosed additional drug products and packaging materials upon orginal closure/sealing. In yet additional detailed embodiments, sealing means of the container include use of a heat-resistant, sealable undersurface (e.g., a foil undersurface) comprising the seal gasket or undersurface of the lid, that is in contact with the lip of the lid upon closure/sealing of the sealable container. In exemplary embodiments, the seal gasket or sealable undersurface of the lid is seated under heat and optionally pressurized conditions to form a thermal seal against the lip of the container, optionally leaving a partial vacuum within the container after sealing and cooling to further preclude exposure of the (R)(-) bupropion and any other incredients within the container to water. Other water-tight containers, bottles, foil packs and like sealing means are
contemplated within the invention, including water-tight blister packs. Blister packs are multi- dose packages that have recesses in a container portion of the blister pack the size and shape of the tablets or capsules contained therein. The tablets or capsules are placed in the recesses and the container portion is closd by juxtaposition against a sealing plastic or foil closure means that forms a sealable closure against the openings of the recesses in the container portion. In this context both the container portion and closure surface or lid of the blister pack must be impervious to water. Tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses, whereby an opening is formed in the sealing surface sheet above the recess. In all packaging kits of the invention, a memory aid may be provided on the kit, such as in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Other variations of memory aids will be readily apparent. The package kits or associated packaging may optionally bear a product-use label or insert that provides instructions for multiple uses of the kit contents to treat the targeted CNS disorder and identify symptoms and side effects associated with the disorder and drug.
[00150] The invention now having been fully described, it will be apparent that many changes and modifications can be made in accordance with the description above by applying ordinary knowledge and skill in the art without departing from the spirit or scope of the appended claims which are offered by way of illustration and exemplification, not limitation. All publications, patents and patent applications referenced herein are incorporated herein by reference for all purposes, particularly those pertaining to practice, description and use of the invention.
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Claims

What is Claimed is:
1. A method of treating a central nervous system (CNS) disorder in a mammalian subject comprising administering a composition comprising an effective amount of a substantially pure (R)(-) bupropion agent to said subject sufficient to treat the CNS disorder.
2. The method of claim 1, wherein the CNS disorder is selected from the group consisting of depression, treatment resistant depression (TRD), seasonal affective disorder, bipolar disorder, narcolepsy, cognitive disorders including attention deficit hyperactivity disorder (ADHD), restless leg syndrome, male and female and female hyposexual desire disorder (HSDD), addictive disorders, cognitive disorders, psychotic disorders eating disorders, and neuropathic conditions.
3. The method of claim 1, wherein the CNS disorder is ADHD
4. The method of claim 1, wherein the CNS disorder is depression.
5. The method of claim 4, wherein the CNS disorder is treatment resistant depression.
6. The method of claim 1 , wherein the CNS disorder is narcolepsy.
7. The method of claim 1, wherein the CNS disorder is an addictive disorder.
8. The method of claim 7, wherein the addictive disorder is selected from the group consisting of drug addiction, gambling addiction, and sex addiction.
9. The method of claim 7, wherein the addictive disorder is drug addiction selected from addictions to stimulants, cocaine addiction, opioid addiction, nicotine addiction, and alcohol addiction.
10. The method of claim 1, wherein the CNS disorder is stimulant addiction.
11. The method of claim 1 , wherein the CNS disorder is amphetamine addiction.
12. The method of claim 1, wherein the CNS disorder is cognitive impairment associated with ADHD, Parkinson's disease, Alzheimer's disease, senile dementia, or traumatic or pathogenic brain injury, non-specific impairment of cognitive function or memory.
13. The method of claim 1, wherein the CNS disorder is pain or another symptom associated with neuropathy selected from nerve compression injury and traumatic, surgical, anatomic or pathogenic neuropathy, including diabetic neuropathy.
14. The method of claim 1, wherein the CNS disorder is an eating disorder or weight disorder, including obesity.
15. The method of claim 1 , wherein the CNS disorder is male or female and female hyposexual desire disorder (HSDD).
16. The method of claim 1 , wherein the CNS disorder is a cognitive disorder.
17. The method of claim 1, wherein the CNS disorder is a psychotic disorder.
18. The method of claim 1, wherein the psychotic disorder is selected from schizophrenia, schizophreniform diseases, acute mania, schizoaffective disorders, and depression with psychotic features.
19. The method of claim 1, wherein the CNS disorder is selected from epilepsy, abnormal sexual behaviors, schizoid behaviors, somatization, sleep disorders, autism spectrum disorders, and eating disorders.
20. The method of claim 1 , wherein the CNS disorder is Parkinson's disease.
21. A method for treating attention deficit hyperactivity disorder (ADHD) or a related behavioral disorder or condition in a human subject comprising administering to said subject an effective amount of a substantially pure (R)(-) bupropion agent.
22. The method of claim 21 , wherein the ADHD is selected from the group consisting of Attention Deficit Hyperactivity Disorder-predominantly hyperactive-impulsive subtype, Attention Deficit Hyperactivity Disorder-predominantly inattentive subtype, and Attention Deficit Hyperactivity Disorder-combined subtype.
23. The method according to claim 21 , wherein the related behavioral disorder is selected from the group consisting of Conduct Disorder and Oppositional Defiant Disorder.
24. The method according to claim 21 , wherein the subject is a human child, adolescent, or adult presenting with ADHD symptomology.
25. The method according to claim 24, wherein the subject is an adult.
26. The method according to claim 24, wherein the subject is a child.
27. A method according to claims 1 or 21 , further comprising coordinately administering to the subject a secondary therapeutic agent selected from an antidepressant, antipsychotic, anticonvulsant or anxiolytic agent.
28. A method according to claims 1 or 21, further comprising coordinately administering to the subject a secondary therapeutic agent that is an anti-ADHD drug.
29. The method of claim 28, wherein the anti-ADHD drug is selected from amphetamine-dextroamphetamine, dexmethylphenidate, dextroamphetamine,
lisdexametamine, methylphenidate, atomexetine, guanfacine, clonidine, atomoxetine and a2- adrenergic agonists.
30. A method according to claims 1 or 21, further comprising coordinately administering to the subject a secondary therapeutic agent that is an antipsychotic drug.
31. The method of claim 30, wherein the antipsychotic drug is selected from Typical Antipsychotics and Atypical Antipsychotics.
32. The method of claim 31, wherein the antipsychotic is selected from
chlorpromazine, thioridazine, mesoridazine, fluphenazine, perphenazine, prochlorperazine, trifluoperazine, thiothixine, haloperidol, molindone, loxapine, clozapine, olanzapine, risperidone, quetiapine, aripirazole, ziprasidone, amisulpride, and anticonvulsants.
33. The method of claim 32, wherein the anticonvulsant is selected from lamotrigine, carbamazepine, oxcarbazepine, valproate, levetriacetam, and topiramate.
34. A method according to claims 1 or 21, further comprising coordinately administering to the subject a secondary therapeutic agent which is an antidepressant.
35. The method of claim 34, wherein the antidepressant is selected from the group consisting of tri-cyclic antidepressants, specific monoamine reuptake inhibitors, selective serotonin reuptake inhibitors, selective norepinephrine or noradrenaline reuptake inhibitors, selective dopamine reuptake inhibitors, multiple monoamine reuptake inhibitors, monoamine oxidase inhibitors, and atypical antidepressants.
36. The method of claim 1, further comprising coordinately administering to the subject a secondary therapeutic agent that is an appetite supressant
37. The method according to claim 1 or 21, wherein the substantially pure (R)(-) bupropion is administered in a composition comprising no more than no more than 5% w/w of the corresponding (S)(+) bupropion enantiomer.
38. The method according to claim 1 or 21 , wherein the substantially pure (R)(-) bupropion is administered in a composition comprising no more than no more than 2% w/w of the corresponding (S)(+) bupropion enantiomer.
39. The method according to claim 1 , wherein the substantially pure (R)(-) bupropion is a pharmaceutically acceptable salt hydrochloride salt.
40. The method of claim 1 or 21, wherein administration of the (R)(-) bupropion causes fewer side effects in the subject than administration of racemic bupropion or (S)(+) bupropion.
41. The method of claim 1 or 21, wherein administration of the (R)(-) bupropion results in a lower risk, occurrence, and/or severity of seizure effects in the subject than administration of racemic bupropion or (S)(+) bupropion.
42. The method of claim 1 or 21, wherein the composition has an enantiomeric purity of the (R)(-) bupropion of 60% enantiomeric excess (ee) or greater.
43. The method of claim 1 or 21, wherein the composition has an enantiomeric purity of the (R)(-) bupropion of 95% enantiomeric excess (ee) or greater.
44. The method of claim 1 or 21, wherein the (R)(-) bupropion is administered by oral, buccal, nasal, aerosol, topical, transdermal, mucosal, or injectable delivery.
45. The method of claim 1 or 21, wherein the (R)(-) bupropion is administered in a sustained release formulation or by a sustained release topical formulation or delivery device.
46. The method of claim 45, wherein the sustained release formulation or device provides therapeutically effective plasma levels of (R)(-) bupropion over a sustained delivery period of approximately 8 hours or longer.
47. The method of claim 1 or 21, wherein the (R)(-) bupropion is administered in a therapeutically effective dosage of between about 100 mg to about 900 mg per day.
48. The method of claim 1 or 21, wherein the (R)(-) bupropion is administered in a therapeutically effective dose selected from a 50 mg dose, a 100 mg dose, a 150 mg dose, a 200 mg dose, and a 400 mg dose, administered 1-3 times per day.
49. A pharmaceutical composition for the treatment of a targeted central nervous system (CNS) disorder in a mammalian subject comprising a therapeutically effective dosage amount of enantiomerically purified (R)(-) bupropion effective to treat the targeted CNS condition in said subject.
50. The pharmaceutical composition of claim 49, having an enantiomeric purity of the (R)(-) bupropion of 60% enantiomeric excess (ee) or greater.
51. The pharmaceutical composition of claim 49, having an enantiomeric purity of the (R)(-) bupropion of 95% enantiomeric excess (ee) or greater.
52. The pharmaceutical composition of claim 49, comprising enantiomerically purified (R)(-) bupropion in a formulation having a pH of less than or equal to pH 3.0.
53. The pharmaceutical composition of claim 49, comprising enantiomerically purified (R)(-) bupropion in a formulation having a pH of less than or equal to pH 2.0.
54. The pharmaceutical composition of claim 49, comprising enantiomerically purified (R)(-) bupropion in a formulation having a pH of between pH 0.5 and pH 1.5.
55. The pharmaceutical composition of claim 49, having an enantiomeric purity of the (R)(-) bupropion of 95% enantiomeric excess (ee) or greater after a stability period of at least two weeks after isolation and crystallization of the (R)(-) bupropion.
56. The pharmaceutical composition of claim 49, having having an enantiomeric purity of the (R)(-) bupropion of 75% enantiomeric excess (ee) or greater after a stability period of four-six weeks.
57. The pharmaceutical composition of claim 49, having an enantiomeric purity of the (R)(-) bupropion of 85% enantiomeric excess (ee) or greater after an extended stability period of four-six months.
58. The pharmaceutical composition of claim 49, having an enantiomeric purity of the (R)(-) bupropion of 85% enantiomeric excess (ee) or greater after an extended stability period of at least six months.
59. The pharmaceutical composition of claim 49, having an enantiomeric purity of the (R)(-) bupropion of 85% enantiomeric excess (ee) or greater after an extended stability period of at least six months under a constant elevated storage temperature of at least 40 degrees centigrade.
60. The pharmaceutical composition of claim 49, wherein the (R)(-) bupropion is provided in a sustained release formulation or delivery device.
61. The pharmaceutical composition of claim 60, wherein the sustained release formulation or device provides therapeutically effective plasma levels of (R)(-) bupropion over a sustained delivery period of approximately 8 hours or longer.
62. The pharmaceutical composition of claim 49, wherein the (R)(-) bupropion is provided in a therapeutically effective dose of between about 100 mg to about 900 mg.
63. The pharmaceutical composition of claim 49, wherein the (R)(-) bupropion is provided in a therapeutically effective dose selected from a 50 mg dose, a 100 mg dose, a 150 mg dose, a 200 mg dose, and a 400 mg dose.
64. A pharmaceutical composition comprising enantiomerically purified (R)(-) bupropion in a formulation having a water content of less than about 1.0% by weight.
65. A pharmaceutical composition comprising enantiomerically purified (R)(-) bupropion in a formulation that is essentially anhydrous, having a water content that is less than about 0.1% by weight.
66. A pharmaceutical composition comprising enantiomerically purified (R)(-) bupropion in a formulation including a pH stabilizing buffer or carrier effective to maintain a stable pH of the formulation at or below approximately pH 2.5.
67. The pharmaceutical composition according to claim 66, wherein the pH stabilizing buffer or carrier is effective to maintain a stable pH of the formulation at or below approximately pH 2.0 for a stability period of at least two weeks, sufficient to maintain an enantiomeric purity of the (R)(-) bupropion in the formulation at or above 85% ee for a full duration of the stability period.
68. The pharmaceutical composition according to claim 66, wherein the pH stabilizing buffer or carrier is effective to maintain a stable pH of the formulation at or below approximately pH 2.0 for a stability period of at least two months, sufficient to maintain an enantiomeric purity of the (R)(-) bupropion in the formulation at or above 85% ee for a full duration of the stability period.
69. The pharmaceutical composition according to claim 66, wherein the pH stabilizing buffer or carrier is effective to maintain a stable pH of the formulation at or below approximately pH 2.0 for a stability period of six months or longer, and wherein an enantiomeric purity of the (R)(-) bupropion in the formulation at least 85% ee for a full duration of the stability period at an elevated storage temperature above room temperature.
70. The pharmaceutical composition according to claim 66, wherein the pH stabilizing buffer or carrier is selected from citric acid, salicylic acid, tartaric acid, succinic acid, and fumaric acid, glycopyrrolate, sorbitol, and tween 80.
71. The pharmaceutical composition according to claim 66, wherein the pH stabilizing buffer or carrier is citric acid.
72. A pharmaceutical kit comprising enantiomerically purified (R)(-) bupropion in a sealed container wherein an environment of a sealed drug-containing compartment of the container is is essentially anhydrous, having a water content that is less than about 0.1% by weight.
73. A pharmaceutical kit according to claim 72, wherein the(R)(-) bupropion in said sealed container has an enantiomeric purity of the (R)(-) bupropion of 95% enantiomeric excess (ee) or greater after a stability period of at least two weeks.
74. A pharmaceutical kit according to claim 72, further comprising a dessicant.
75. A pharmaceutical kit according to claim 72, wherein the sealed container is made of a polyethylene plastic.
76. A pharmaceutical kit according to claim 72, wherein the container is sealed under heat and after sealing has a partial vacuum within a drug-containing compartment of the container.
77. A method of treating a central nervous system (CNS) disorder in a
mammalian subject comprising administering a composition comprising an effective amount of a substantially pure (R)(-) bupropion agent to the subject sufficient to treat the CNS disorder, which treatment is attended by reduced side effects compared to side effects elicited by administration of an equal or lesser amount of racemic bupropion or (S)(+) bupropion to a suitable control subject.
78. The method of claim 77, wherein a selected therapeutic dose of (R)(-) bupropion administered to a patient presenting with a targeted CNS disorder elicits reduced side effects characterized by least a 10%-20% reduction in measurable side effects associated with the targeted CNS disorder in the patient after an effective treatment period compared to a side effect profile observed in a suitable control subject after a comparable treatment period following administration of a same dose of racemic bupropion or (S)(+) bupropion.
79. The method of claim 78, wherein the (R)(-)bupropion-treated patient ehibits at least a 25%-50% reduction in side effects compared to a side effect incidence or level determined for a suitable racemic bupropion- or (S)(+) bupropion-treated control subject
80. The method of claim 78, wherein the (R)(-)bupropion-treated patient ehibits at least a 50%-75% reduction in side effects compared to a side effect incidence or level determined for a suitable racemic bupropion- or (S)(+) bupropion-treated control subject
81. The method of claim 78, wherein the (R)(-)bupropion-treated patient ehibits more than a 75% reduction in side effects compared to a side effect incidence or level determined for a suitable racemic bupropion- or (S)(+) bupropion-treated control subject 82. A method of treating a central nervous system (CNS) disorder in a
mammalian subject comprising administering a composition comprising an effective amount of a substantially pure (R)(-) bupropion agent to the subject sufficient to treat the CNS disorder, which treatment is more therapeutically effective at a same or lesser dosage than treatment efficacy determined for racemic bupropion or (S)(+) bupropion administered to a suitable control subject.
83. The method of claim 82, wherein a selected therapeutic dose of (R)(-) bupropion administered to a patient presenting with a targeted CNS disorder elicits increased therapeutic effects characterized by least a 10%-20% comparative reduction in measurable symptoms of targeted CNS disorder or other index of therapeutic efficacy for treating the targeted CNS condition in the patient after an effective treatment period compared to treatment efficacy determined by measuring the same symptoms or indices in a suitable control subject after a comparable treatment period following administration of an equal or greater dose of racemic bupropion or (S)(+) bupropion.
84. The method of claim 83, wherein (R)(-)bupropion-treated patients ehibit at least a 25%-50% comparative reduction in measurable symptoms of the targeted CNS disorder compared to symptom reduction or other therapeutic efficacy value determined for racemic bupropion- or (S)(+) bupropion administered at an equal dosage and comparable treatment period to control subjects.
85. The method of claim 83, wherein (R)(-)bupropion-treated patients ehibit at least a 50%-75% comparative reduction in measurable symptoms of the targeted CNS disorder compared to symptom reduction or other therapeutic efficacy value determined for racemic bupropion- or (S)(+) bupropion administered at an equal dosage and comparable treatment period to control subjects.
86. A method for reducing side effects of drug treatment for a central nervous system (CNS) disorder in a mammalian subject comprising administering a composition comprising an effective amount of a substantially pure (R)(-) bupropion agent to the subject sufficient to treat the CNS disorder, which treatment is attended by reducing an incidence and/or level of 2(R)(-) hydroxybupropion in a plasma or CNS compartment of the subject.
87. The method of claim 86, wherein the drug treatment is bupropion drug treatement and the reduced incidence and/or level of 2(R)(-) hydroxybupropion in a plasma or CNS compartment of the subject is determined in comparison to 2(R)(-)
hydroxybupropion incidence or level in a plasma or CNS compartment of a racemic bupropion-treated positive control subject.
88. A method of treating a central nervous system (CNS) disorder in a
mammalian subject comprising administering a composition comprising an effective amount of a substantially pure (R)(-) bupropion agent to the subject sufficient to treat the CNS disorder, which treatment is attended by an (R)(-)-bupropion-mediated therapeutic increase in an incidence or level of 2(S)(+) hydroxybupropion in a plasma or CNS compartment of the subject.
89. The method according to claim 88, which yields an incidence or level of 2(S)(+) hydroxybupropion in a blood or CNS sample of the subject that is increased by at least 25%-60% compared to an incidence or level of 2(S)(+) hydroxybupropion observed in a comparable sample from a test subject administered the same amount, or an equivalent therapeutic amount, of racemic bupropion or (S)(+)bupropion.
90. A method of treating a central nervous system (CNS) disorder in a
mammalian subject comprising administering a composition comprising an effective amount of a substantially pure (R)(-) bupropion agent to the subject sufficient to treat the CNS disorder, which treatment is attended by an (R)(-)-bupropion-mediated therapeutic increase in an incidence or level of dopamine and/or norepinephrine a blood or CNS sample of the subject.
91. A method of treating a central nervous system (CNS) disorder in a
mammalian subject comprising administering a composition comprising an effective amount of a substantially pure (R)(-) bupropion agent to the subject sufficient to treat the CNS disorder, which treatment is attended by an (R)(-)-bupropion-mediated therapeutic inhibition of dopamine and/or norepinephrine transport activity in the subject
92. A method according to claim 90 or 91 , wherein both dopamine and norepinephrine levels are increased in the blood or CNS of the subject.
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