US 6,964,962 B2
`(16) Patent N0.:
`(12) United States Patent
`
`Wong et al. Nov. 15, 2005 (45) Date of Patent:
`
`
`USOO6964962B2
`
`(54) COMBINATIONS 0F REBOXETINE AND
`NEUROLEPTIC AGENTS
`Inventors: Erik H0 Fong Wong, Portage, MI
`(US); Christopher C. Gallen,
`Wynnewood, PA (US); Torgny
`Svensson, Lidingé') (SE)
`
`(75)
`
`(73) Assignee: Pharmacia & Upjohn Company,
`Kalamazoo, MI (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or “0115th under 35
`U-S~C~ 154(b) by 0 days.
`
`(21) Appl. No.: 10/035,100
`.
`Flled:
`
`(22)
`(65)
`
`Dec. 28’ 2001
`Prior Publication Data
`
`US 2002/0156067 A1 Oct. 24, 2002
`
`EP
`E11:
`W0
`
`FOREIGN PATENT DOCUMENTS
`0 830 864 A1
`3/1998
`3 :33 (9);; if
`13/133491
`WO 99/61014
`12/1999
`
`OTHER PUBLICATIONS
`Koch et al, Eur. J. Clin. Pharmacol. (56, No. 6—7, A10, 2000)
`(abstract).*
`E. Aragues, et al., “Reboxetine in Negative Symptoms of
`Schizophrenia”, European Psychiatry, 2000, pp 426S,
`Abstract Only.
`G. Schutz, et a1., “Reboxetine Add on Therapy to Haloperi-
`dol
`in The Treatment of Schizophrenia:
`a Preliminary
`Double—blind Randomized Placebo—controlled Study”,
`International Clinical Psychopharmacology,
`2001,
`pp
`275—278, vol. 16, No. 5.
`E. Spina, et al, “No Effect of Reboxetine on Plasma Con-
`ccntrations of Clozapinc, Rispcridonc, and Thcir Activc
`Metabolites”, 2001, pp675—678, vol. 23 No. 6.
`*
`.
`.
`Cited by examiner
`
`(60)
`
`Related US. Application Data
`Provisional application No. 60/259,286, filed on Jan. 2,
`2001
`
`Primary Examiner—Phyllis G. Spivack
`(74) Attorney, Agent, or Firm—Charles W. Ashbrook;
`David R. Kurlandsky
`
`(51)
`
`Int. Cl.7 .................. A61K 31/505; A61K 31/5375;
`A61K 31/5513
`................ 514/239.2; 514/220; 514/259.41
`(52) us. Cl.
`(58) Fleld of Search .............................. 514/239.2, 220,
`514/259.41
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(57)
`
`ABSTRACT
`.
`.
`.
`.
`.
`a)“;Igfigfgfcilfggflgificfive amount of reboxefine. and
`selected from the group consisting of clozapine,
`.
`.
`.
`.
`olanzapme, risperidone and mixtures thereof
`(b) a pharmaceutically effective amount of one or more
`neuroleptic agents or a pharmaceutically effective salt
`thereof is provided.
`
`3,505,451 A
`
`4/1970 Burnings et al.
`
`2 Claims, N0 Drawings
`
`1
`
`Exhibit 2032
`
`Slayback v. Sumitomo
`|PR2020—01053
`
`1
`
`Exhibit 2032
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`US 6,964,962 B2
`
`1
`COMBINATIONS 0F REBOXETINE AND
`NEUROLEPTIC AGENTS
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`
`This application claims the benefit of the following pro-
`visional application: U.S. Ser. No. 60/259,286, filed Jan. 2,
`2001, under 35 USC 119(e)(i), which is incorporated herein
`by reference in its entirety.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`This invention describes new treatments that should pro-
`vide for relief from several nervous system disorders with
`reduced side effects, and it involves the administration of a
`norepinephrine reuptake inhibitor, preferably a selective
`norepinephrine reuptake inhibitor such as the drug
`reboxetine, in combination with a neuroleptic agent (typical
`or atypical antipsychotic agents). In particular, the combi-
`nation is to be used to treat schizophrenia.
`2. Technology Description
`The introduction of tricyclic antidepressants in the early
`1960s has provided a major advance in the treatment of
`neuropsychiatric disorders. Reactive and endogenous
`depressions, diagnoses formerly carrying grave prognostic
`implications, have become, with the introduction of the
`tricyclics, manageable disorders with a much smaller toll on
`the patient and the society as a whole.
`The early tricyclic compounds were reuptake inhibitors of
`all the catecholamines released in the synaptic cleft, thus
`resulting in prolongation and enhancement of the dopamine
`(DA), noradrenaline
`(NA)
`and serotonin
`(5-hydroxytryptamine=5-HT) action. Lack of selectivity
`also causes undesired side effects particularly on the ace-
`tylcholine (especially the muscarinic component), and his-
`tamine mediated neurotransmission.
`
`Because of these unwanted pharmacodynamic activities,
`cognitive impairment, sedation, urinary and gastrointestinal
`tract disturbances, and increased intraocular pressure were
`limiting factors in the clinical use of these compounds and
`often required discontinuation of treatment. Of utmost con-
`cern were also the cardiac toxic effects and the proconvul-
`sant activity of this group of drugs.
`More recently, selective reuptake inhibitors for serotonin
`(SSRI) have been introduced with definite advantages in
`regard to fewer side effects without loss of efficacy. Fluox-
`etine is an example of such an inhibitor that has had a great
`amount of commercial success.
`
`Another class of compounds that has been proposed for
`use in the treatment of depression is selective norepineph-
`rine reuptake inhibitors. Lower-than-normal levels of nore-
`pinephrine are associated with a variety of symptoms includ-
`ing lack of energy, motivation, and interest in life. Thus, a
`normal level of norepinephrine is essential to maintaining
`drive and capacity for reward. These neurotransmitters
`travel from the terminal of a neuron across a small gap (i.e.,
`the synaptic cleft) and bind to receptor molecules on the
`surface of a second neuron. This binding elicits intracellular
`changes that initiate or activate a response or change in the
`postsynaptic neuron. Inactivation occurs primarily by trans-
`port (i.e., reuptake) of the neurotransmitter back into the
`presynaptic neuron. Abnormality in noradrenergic transmis-
`sion results in various types of depression, mental,
`behavioral, and neurological disorders attributed to a variety
`of symptoms including a lack of energy, motivation, and
`
`2
`interest in life. See generally, R. J. Baldessarini, “Drugs and
`the Treatment of Psychiatric Disorders: Depression and
`Mania” in Goodman and Gilman’s The Pharmacological
`Basis ofTherapeulics, McGraw-Hill, NY, N.Y., pp. 432—439
`(1996).
`Examples of norepinephrine reuptake inhibitors (both
`selective and not selective) include, but are not limited to the
`following:
`tandamine (CAS 42408-80-0; US. Pat. Nos.
`3,904,617; 4,118,394), pirandamine (CAS 42408-79-7; US.
`Pat. No. 3,995,052), ciclazindol (CAS 37751-39-6; US. Pat.
`No. 3,891,644; No. 3,957,819; No. 3,976,645), fiuparoxan
`(US. Pat. No. 4,880,801), lortalamine (CAS 70384-91-7;
`US. Pat. No. 4,201,783),
`talsupram (CAS 21489-20-3),
`talopram (CAS 7182-51-6), prindamine, nomifensine (US.
`Pat. No. 3,577,424), viloxazine (US. Pat. No. 3,712,890),
`tomoxetine (US. Pat. No. 4,314,081), duloxetine (US. Pat.
`No. 5,023,269), venlafaxine (US. Pat. No. 4,535,186),
`milnacipran (US. Pat. No. 4,478,836) and reboxetine (US.
`Pat. No. 4,229,449).
`The term schizophrenia was first used in 1911 by Eugen
`Bleuler, a Swiss psychiatrist, to diagnose patients whose
`thought processes and emotional responses seemed to be
`disconnected. The term schizophrenia literally means split
`mind and many people still believe incorrectly that the
`condition causes a split personality (actually an uncommon
`problem involving dissociation). Schizophrenia is now used
`to describe a cluster of symptoms that typically includes
`delusions, hallucinations, disordered thinking, and emo-
`tional unresponsiveness. No clear-cut definition of schizo-
`phrenia exists even at this time and no single cause has been
`found to explain all aspects of this devastating syndrome.
`Most likely, the symptoms are triggered by a number of
`disease processes coupled with genetic factors and environ-
`mental stresses.
`
`Chemical treatment for those suffering from schizophre—
`nia include the use of neuroleptic agents (sometimes referred
`to as antipsychotic agents) of either the typical or atypical
`type.
`Typical neuroleptic agents are those that block receptors
`of the neurotransmitter dopamine. These medications are
`also referred to as neuroleptic drugs, because they can cause
`a number of neurologic side effects. The first drug of this
`type used for treating schizophrenia was chlorpromazine
`(Thorazine; US. Pat. No. 2,645,640). Many other antipsy-
`chotic drugs are now available,
`the most popular being
`haloperidol (Haldol; US. Pat. No. 3,438,991). Others
`include perphenazine (Trilafon; US. Pat. No. 2,766,235),
`thioridazine (Mellaril; dosage of 30-800 mg/day),
`mesoridazine (Serentil; US. Pat. No. 3,084,161), trifluop-
`erazine (Stelazine; US. Pat. No. 2,921,069), and fiuphena-
`zine (Prolixin; US. Pat. No. 3058979). For the very severe
`active phase of schizophrenia, injections of an antipsychotic
`drug are often given every four to eight hours until the
`patient
`is calm. If possible, however, physicians prefer
`administering a drug orally. These drugs may be high- or
`low-potency. Generally, higher doses are used to treat acute
`episodes (e.g., 5 to 10 mg of haloperidol) and lower doses
`are given during periods of remission (e.g., 2 to 5 mg).
`However, new studies suggest starting haloperidol treatment
`with daily doses in the 4 to 5 mg range for two to three
`weeks. The beneficial impact of these drugs is greatest on
`psychotic symptoms, particularly hallucinations and delu-
`sions in the early and midterm stages of the disorder. In
`patients who are being treated for the first time, improve-
`ment in psychotic symptoms may be evident within one or
`two days of treatment, although the full benefit of the drug
`usually evolves over about six to eight weeks. Thought
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`

`

`US 6,964,962 B2
`
`3
`disturbances are reduced more gradually. Some estimates of
`poor responses to these drugs are as high as 40%. Antipsy-
`chotic drugs are also not very successful in reducing nega-
`tive symptoms, although people often show less withdrawal
`and apathy because of the reduction in psychotic episodes.
`The most disturbing common side effects of high-dose or
`high-potency therapy of typical antipsychotic drugs are
`those known as extrapyramidal symptoms, which effect the
`nerves and muscles controlling movement and coordination.
`The most serious long term extrapyramidal effect of antip—
`sychotic therapy is tardive dyskinesia, a condition associated
`with repetitive and involuntary movements, or tics, most
`often in the mouth, lips, and tongue and also in the legs, arms
`and trunk. Symptoms range from mild to severe, and some-
`times interfere with eating and walking. They may not
`appear until the antipsychotic drugs have been taken for
`months or even years. A condition known as acute dystonia
`can occur shortly after taking antipsychotic drugs. This side
`effect causes abnormal muscle spasms, particularly sus-
`tained contortions of the neck, jaw, trunk, and eye muscles.
`High potency drugs (e.g., haloperidol, fluphenazine) cause
`less drowsiness and very low blood pressure but induce
`more extrapyramidal side effects. Low-potency drugs (e.g.,
`chlorpromazine, thioridazine) are more sedating and side
`effects are not as acute. Nearly every neuroleptic drug can
`cause extrapyramidal side effects, however, which occur in
`up to 70% of patients taking these medications. After the
`drug is withdrawn, symptoms can sometimes persist for
`weeks or months. Women face a higher risk for these
`symptoms, and they increase with length of therapy and age.
`These medications can have adverse side effects on many
`organs and systems in the body. Sleepiness and lethargy
`commonly occur in the beginning of therapy, but usually
`decrease over time. Other side effects include dry mouth, eye
`problems, allergic reactions,
`temporary weight gain, and
`menstrual irregularities in women. A much more serious but
`rare side effect is the neuroleptic malignant syndrome, in
`which dangerously high body temperatures occur. Without
`prompt and expert treatment, this side effect can be fatal in
`20% of those who develop it. Sometimes the effects of the
`drugs mimic schizophrenic symptoms, such as agitation,
`slow speech, and retarded movement, and so the physician
`may be tempted to increase the dosage.
`Drugs known as atypical drugs (also referred to in this
`document as atypical neuroleptic or atypical antipsychotic
`agents) are rapidly changing treatment for schizophrenia,
`and many experts are now urging that they be used as the
`primary treatment for certain patients instead of the antip-
`sychotics. Atypical drugs appear to be more effective than
`the neuroleptics, even in reducing negative symptoms and
`preventing relapse. They are rarely associated with the
`extrapyramidal side effects, particularly tardive dyskinesia.
`The most successful atypical drugs are able to simulta-
`neously affect dopamine receptors and other neurotransmit-
`ters responsible for psychotic symptoms. Clozapine (US.
`Pat. No. 3,539,573), olanzapine (US. Pat. No. 5,229,382),
`and risperidone (US. Pat. No. 4,804,663) are currently the
`standard atypical drugs, but new medication that may be
`even more effective are becoming available. Clozapine
`(Clozaril) is the best known of these drugs. Clozapine was
`found to benefit up to half of patients with schizophrenia
`who did not respond to other types of treatments, and there
`is now substantial evidence of its superiority over typical
`drugs. It is particularly useful in younger people, although
`toxic side effects are common. Positive effects may not be
`evident for up to nine months. Clozapine has improved
`negative symptoms in short-term trials;
`longer ones are
`
`10
`
`15
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`needed to see if the benefit is sustained. It may also reduce
`aggressive behavior and suicidal impulses. Although the
`drug does not appear to cause tardive dyskinesia, it does
`have other side effects including nasal congestion, drooling,
`low blood pressure, headache, sleeplessness, and significant
`weight gain. Serious side effects include seizures and, in up
`to 1% of cases, agranulocytosis—a potentially life-
`threatening decrease in the patient’s white blood cells. When
`agranulocytosis develops, it usually does so within three
`months of treatment, peaking in the third month; if it hasn’t
`appeared within six months, it most likely will not develop.
`Older women are at higher risk for this side effect. Agranu-
`locytosis can be reversed if treatment with clozapine is
`stopped at once. It is important that people taking clozapine
`have their serum glucose level count monitored frequently,
`especially those with diabetes or a family history of diabetes.
`Although clozapinc is more expensive than halopcridol, this
`extra expense may be offset by its greater efficacy, which
`results in fewer hospitalizations. Risperidone. Risperidone
`(Risperdal) is a dopamine receptor blocker that has shown
`benefit and even superiority in comparison to antipsychotics.
`It is now used by about 20% of schizophrenia patients. Like
`clozapine, risperidone may have a beneficial effect on nega-
`tive symptoms. Risperidone may also improve verbal work-
`ing memory, a common problem in schizophrenics. It has
`few extrapyramidal effects, although they can occur at
`higher doses. Common side effects include sleepiness,
`weight gain, and dizziness. Olanzapine. Olanzapine
`(Zyprexa) may be more effective in blocking the neurotrans-
`mitters serotonin and dopamine than is clozapine and have
`a much lower risk for seizures and agranulocytosis. Studies
`indicate it is at least as effective for acute symptoms and
`possibly more effective for negative ones than the typical
`neuroleptic drugs and that it has a very low risk for extrapy-
`ramidal symptoms. The drug may also be beneficial for
`patients who do not respond to neuroleptic drugs. A new
`study suggests that olanzapine also may be more effective
`than risperidone, particularly in its effect on negative
`symptoms, but more research is needed to confirm result.
`Like risperidone, olanzapine can cause sleepiness, weight
`gain, and dizziness. Other Atypical Drugs. Ziprasidone (US.
`Pat. No. 4,831,031) and quetiapine (Seroquel; US. Pat. No.
`4,879,288), which has recently been approved by the FDA,
`are other promising new drugs. Ziprasidone affects serotonin
`as well as dopamine may also improve negative symptoms
`with limited extrapyramidal side effects. Sertindole (Serlect;
`US. Pat. No. 4,710,500) is another drug well into develop-
`ment. Although promising, reports of increased risk for
`sudden cardiac death are of some concern. Aripiprazole
`(US. Pat. No. 5,006,528) is another atypical drug in devel-
`opment.
`the treatment of schizophrenia
`Still other drugs for
`include, but are not limited to the following typical and
`atypical neuroleptic agents: blonanserin (US. Pat. No.
`5,021,421), iloperidone (EP 402644), perospirone (U.S. Pat.
`No. 4,745,117), raclopride (US. Pat. No. 4,789,683), sone-
`piprazole (US. Pat. No. 5,877,317), zotepine (US. Pat. No.
`3,704,245), DU-127090, ORG-5222 (GB 1567862),
`SM-13496, amisulpride (US. Pat. No. 4,401,822),
`CP-361428, Lu 35-138, balaperidone (WO 94/00458),
`S-18327 (EP 811622), WAY-135452 (also known as DAB-
`452), eplivanserin (EP 373998), E-5842 (WO96/4287),
`SR-31742 (EP 461986), NE-100 (EP 641766), osanetant
`(EP512901, EP 673928), SR-141716 (EP 658546),
`SR-48692 (EP 477049), BSF-201640 (WO99/09015), BSF-
`190555 (WO95/07274), LAX-101a, sarizotan (EP 707007),
`CX-691 (US. Pat. Nos. 5,783,587, 5,891,876) and
`SB-271046 (WO98/27081).
`
`3
`
`

`

`US 6,964,962 B2
`
`5
`it would be
`Despite the above advances in the art,
`desirable to develop a pharmaceutical composition that
`would have both the therapeutic benefits of the neuroleptic
`agents (typical or atypical) with a reduced side effects.
`
`BRIEF SUMMARY OF THE INVENTION
`
`In accordance with the present invention a novel phar-
`maceutical composition is provided. More specifically, the
`composition combines one or more norepinephrine reuptake
`inhibitors, more preferably one or more selective norepi-
`nephrine reuptake inhibitors with one or more neuroleptic
`agents (typical or atypical antipsychotic agents). The com-
`position is considered to be particularly effective against
`schizophrenia.
`A first embodiment of the present invention provides a
`composition comprising:
`(a) a pharmaceutically effective amount of one or more
`norepinephrine reuptake inhibitors or a pharmaceuti-
`cally effective salt thereof; and
`(b) a pharmaceutically effective amount of one or more
`neuroleptic agents or a pharmaceutically effective salt
`thereof.
`
`10
`
`15
`
`20
`
`In particularly preferred embodiments, component (a)
`comprises reboxetine in either its enantiomeric or racemic
`form.
`
`25
`
`Yet another embodiment of the present invention provides
`a method for treating or preventing diseases or disorders of
`the central nervous system comprising administering a
`therapeutically effective amount of the above composition to
`a mammal. In most instances, the mammal will be a human,
`and the disease or disorder to be treated is schizophrenia.
`Afurther embodiment of the present invention comprises
`the use of the above composition to prepare a medicament
`for treating or preventing diseases or disorders of the central
`nervous system.
`An object of the present invention is to provide novel
`composition having biological activity.
`A further object of the present invention is to provide a
`method for treating or preventing diseases of the central
`nervous system by using the novel compositions of the
`present invention.
`An additional object of the present invention is to provide
`an effective treatment for schizophrenia.
`These, and other objects, will readily be apparent to those
`skilled in the art as reference is made to the detailed
`description of the preferred embodiment.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENT
`
`In describing the preferred embodiment, certain terminol-
`ogy will be utilized for the sake of clarity. Such terminology
`is intended to encompass the recited embodiment, as well as
`all technical equivalents which operate in a similar manner
`for a similar purpose to achieve a similar result.
`The present
`invention provides a novel composition
`which is a combination of different chemical entities, more
`specifically, the first entity being a norepinephrine reuptake
`inhibitor, particularly a selective norepinephrine reuptake
`inhibitor and the second being a neuroleptic agent.
`The first component
`is a norepinephrine reuptake
`inhibitor, with selective norepinephrine reuptake inhibitors
`being particularly preferred. This list of compounds
`includes, but is not limited to the following:
`tandamine,
`pirandamine, ciclazindol,
`fluparoxan,
`lortalamine,
`talsupram, talopram, prindamine, nomifensine, Viloxazine,
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`6
`tomoxetine, duloxetine, venlafaxine, milnacipran and
`reboxetine, with reboxetine being particularly preferred.
`Examples of pharmaceutically effective salts for the nore-
`pinephrine reuptake inhibitor include, but are not limited to
`salts prepared from pharmaceutically acceptable acids or
`bases,
`including organic and inorganic acids and bases.
`When the preferred compound of use is basic (for example
`reboxetine), salts may be prepared from pharmaceutically
`acceptable acids. Suitable pharmaceutically acceptable acids
`include acetic, benzenesulfonic (besylate), benzoic,
`p-bromophenylsulfonic, camphorsulfonic, carbonic, citric,
`ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,
`hydrochloric, hydroiodic, isethionic, lactic, maleic, malic,
`mandelic, methanesulfonic (mesylate), mucic, nitric, oxalic,
`pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,
`p-toluenesulfonic, and the like. Examples of such pharma-
`ceutically acceptable salts include, but are not limited to,
`acetate, benzoate, hydroxybutyrate, bisulfate, bisulfite,
`bromide, butyne-1 ,4-dio ate, carpo ate, chloride,
`chlorobenzo ate, citrate, dihydrogenphosphate,
`dinitrobenzoate, fumarate, glycollate, heptanoate, hexyne-l,
`6-dioate, hydroxybenzoate,
`iodide,
`lactate, maleate,
`malonate, mandelate, metaphosphate, methanesulfonate,
`methoxybenzoate,
`methylbenzoate,
`monohydrogenphosphate , naphthalene- 1 -sulfonate,
`naphthalene -2-sulfonate, oxalate , phenylbutyrate ,
`phenylproionate, phosphate, phthalate, phylacetate,
`propanesulfonate, propiolate, propionate, pyrophosphate,
`pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite,
`sulfonate, tartrate, xylenesulfonate, and the like.
`In particularly preferred embodiments the selective nore-
`pinephrine reuptake inhibitor
`is reboxetine, 2-[ot-((2-
`ethoxyphenoxy)benzyl]-morpholine, and its pharmaceuti-
`cally acceptable salts, in either its enantiomeric (particularly
`the (8,8) enantiomer) or racemic form. Synthesis of racemic
`reboxetine is described in greater detail in US. Pat. No.
`4,229,449. Individual stereoisomers of reboxetine can be
`obtained by resolution of the racemic mixture of enanti-
`omers using conventional methods generally known by
`those skilled in the art. Such methods include, but are not
`limited to, resolution by simple crystallization and chro-
`matographic techniques, for example, as set forth in GB
`2,167,407. Other methods of preparation are described in
`US. Pat. Nos. 5,068,433 and 5,391,735. Reboxetine can be
`a free base form, or it can be in salt form, preferably the
`methanesulfonate salt (also called reboxetine mesylate). To
`the extent necessary for completion, the above patents are
`expressly incorporated by reference.
`The selection of the dosage of the first component is that
`which can provide relief to the patient. As is well known, the
`dosage of this component depends on several factors such as
`the potency of the selected specific compound, the mode of
`administration, the age and weight of the patient, the sever-
`ity of the condition to be treated, and the like. This is
`considered to be within the skill of the artisan and one can
`
`review the existing literature on the components to deter-
`mine optimal dosing. To the extent necessary for
`completion, the synthesis of the components and dosages
`described in the patents or CAS documents referenced in the
`Technology Description portion of this document are
`expressly incorporated by reference Desirably, when rebox-
`etine is selected as the active agent, the daily dose contains
`from about 0.1 mg. to about 10 mg. More preferably, each
`dose of the component contains about 0.5 to about 8 mg of
`the active ingredient, and even more preferably, each dose
`contains from about 0.5 to about 5 mg of the active ingre-
`dient. This dosage form permits the full daily dosage to be
`
`4
`
`

`

`US 6,964,962 B2
`
`7
`administered in one or two oral doses. This will allow for
`
`final formulations containing 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7,
`0.8, 0.9, 1.0, 1.1, 1.2,1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9. 2.0, 2.1,
`2.2, 2.3, 2.4, or 2.5 mg of active. More than once daily or
`twice daily administrations (e.g., 3, 4, 5 or 6 administrations
`per day) are also expressly contemplated herein.
`The average daily adult dosage of the other norepineph-
`rine reuptake inhibitors is as follows. The dosages expressly
`include all numerical values, whole or fractional, within the
`stated range. Pediatric dosages may be less.
`
`Component
`Tandamine
`Pirandamine
`Ciclazindol
`Fluparoxan
`Lortalamine
`Talsupram
`Talopram
`Prindamine
`Nomifensine
`Viloxazine
`Tomoxetine
`Duloxetine
`Venlafaxine
`Milnacipran
`
`Average Daily Dosage (mg/day/patient)
`7.5 to 3750
`7.5 to 3750
`5 to 500
`.75 to 750
`1 to 200
`1 to 3750
`1 to 3750
`1 to 3750
`1 to 80
`1 to 3750
`1 to 200
`5 to 500
`2 to 200
`7.5 to 75
`
`The second component comprises one or more neurolep-
`tic agents. These can include those which are typical antip-
`sychotic agents and those which are atypical antipsychotic
`agents. Examples of such agents include, but are not limited
`to the following: chlorpromazine, haloperidol,
`perphenazine,
`thioridazine, mesoridazine,
`trifluoperazine,
`fluphenazine, clozapine, olanzapine, sonepiprazole,
`risperidone, ziprasidone, quetiapine, sertindole,
`aripiprazole, blonanserin,
`iloperidone, perospirone,
`zotepine, DU-127090, ORG-5222, SM-13496, amisulpride,
`raclopride, sonepiprazole, CP-361428, Lu 35-138,
`balaperidone, S-18327, WAY-135452 (also known as DAB-
`452), eplivanserin, E-5842, SR-31742, NE-100, osanetant,
`SR-141716, SR-48692, BSF-201640, BSF-190555, LAX-
`101a, sarizotan, CX-691 and SB-271046.
`
`As is well known, the dosage and administrative regimen
`(i.e., one, two, three or more administrations per day) of the
`second component depends on the factors referred to in
`connection with the dosage selection of the first component.
`To the extent necessary for completion, the synthesis of the
`components and dosages described in the patents or CAS
`documents referenced in the Technology Description portion
`of this document are expressly incorporated by reference
`The average adult daily dosage of the neurolpetic agent is
`as follows. The dosages expressly include all numerical
`values, whole or fractional, within the stated range. Pediatric
`dosages may be less.
`
`Component
`
`Chlorpromazine
`Haloperidol
`Mesoridazine
`Perphenazine
`Thioridazine
`Trifluoperazine
`Fluphenazine
`Clozapine
`
`Average Daily Dosage (mg/day/patient)
`
`10 to 150
`.5 to 100
`75 to 400
`5 to 100
`30 to 800
`1 to 50
`2.5 to 100
`25 to 500
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`8
`
`-continued
`
`Average Daily Dosage (mg/day/patient)
`
`0.05 o 30
`.25 o 25
`5 o 500
`25 o 800
`1 o 500
`7.5 o 750
`.75 to 3750
`.75 o 3750
`.75 o 7500
`.5 o 1000
`30 o 1000
`.05 o 7500
`.75 o 750
`.05 o 7500
`50 o 750
`1 o 500
`.05 o 7500
`.05 o 7500
`.75 o 7500
`.5 0100
`.05 o 7500
`.1 o 2000
`1 o 2000
`.5 o 4000
`.1 o 100
`.5 o 4000
`.5 o 4000
`1 01000
`1 01000
`1 o 500
`.05 o 7500
`0.2 o 2000
`1 o 400
`0.05 01000
`
`
`
`Component
`
`Olanzapine
`Risperidone
`Ziprasidone
`Quetiapine
`Sertindole
`Aripiprazole
`SonepipraAole
`Blonanserin
`Iloperidone
`Perospirone
`Zotepine
`DU-127090
`ORG-5222
`SM-13496
`Amisulpride
`Raclopride
`CP-361428
`Lu 35-138
`Balaperidone
`S-18327
`WAY-135452
`Eplivanserin
`E-5842
`SR-31742
`NE-100
`Osanetant
`SR-141716
`SR-48692
`BSF-201640
`BSF-190555
`LAX-101a
`Sarizotan
`CX-691
`SB-271046
`
`Compositions of the present invention can conveniently
`be administered in a pharmaceutical composition containing
`the active components in combination with a suitable excipi-
`ent. Such pharmaceutical compositions can be prepared by
`methods and contain excipients which are well known in the
`art. A generally recognized compendium of such methods
`and ingredients is Remington’s Pharmaceutical Sciences by
`E. W. Martin (Mark Publ. Co., 15th Ed., 1975). To the extent
`necessary for completion, this reference is hereby incorpo-
`rated by reference. The compositions of the present inven-
`tion can be administered parenterally (for example, by
`intravenous,
`intraperitoneal or
`intramuscular injection),
`topically, orally, intranasally, intravaginally, or rectally, with
`oral administration being particularly preferred.
`For oral therapeutic administration, the inventive compo-
`sition may be combined with one or more excipients and
`used in the form of ingestible tablets, buccal tablets, troches,
`capsules, elixirs, suspensions, syrups, wafers, chewing
`gums, foods and the like. Such compositions and prepara-
`tions should contain at least 0.1% of active compound. The
`percentage of the compositions and preparations may, of
`course, be varied and may conveniently be between about
`0.1 to about 100% of the weight of a given unit dosage form.
`The amount of active compound in such therapeutically
`useful compositions is such that an effective dosage level
`will be obtained.
`
`The tablets, troches, pills, capsules, and the like may also
`contain the following: binders such as gum tragacanth,
`acacia, corn starch or gelatin; excipients such as dicalcium
`phosphate; a disintegrating agent such as corn starch, potato
`starch, alginic acid and the like; a lubricant such as magne-
`sium stearate; and a sweetening agent such as sucrose,
`fructose, lactose or aspartame or a flavoring agent such as
`peppermint, oil of wintergreen, or cherry flavoring. The
`
`5
`
`

`

`US 6,964,962 B2
`
`9
`above listing is merely representative and one skilled in the
`art could envision other binders, excipients, sweetening
`agents and the like. When the unit dosage form is a capsule,
`it may contain, in addition to materials of the above type, a
`liquid carrier, such as a vegetable oil or a polyethylene
`glycol. Various other materials may be present as coatings or
`to otherwise modify the physical form of the solid unit
`dosage form. For instance, tablets, pills, or capsules may be
`coated with gelatin, wax, shellac or sugar and the like. A
`syrup or elixir may contain the active compound, sucrose or
`fructose as a sweetening agent, methyl and propylparabens
`as preservatives, a dye and flavoring such as cherry or
`orange flavor. Of course, any material used in preparing any
`unit dosage form should be pharmaceutically acceptable and
`substantially non-toxic in the amounts employed.
`In
`addition, the active components may be incorporated into
`sustained-release preparations and devices including, but not
`limited to, those relying on osmotic pressures to obtain a
`desired release profile.
`The inventive composition, containing the two active
`components, may be administered in the same physical form
`or concomitantly according to the above-described dosages
`and in the above-described delivery vehicles. The dosages
`for each active component can be measured separately and
`can be given as a single combined dose or given separately.
`They may be given at the same or at different times as long
`as both actives are in the patient at one time over a 24-hour
`period. Concomitant or concurrent administration means the
`patient takes one drug within about 5 minutes of taking the
`other drug. Because the goal is to provide rapid symptomatic
`relief to the patient, in most cases when treatment is started
`the two drugs would be administered to the patient close in
`time and typically concomitantly; thereafter, the timing of
`each drug’s administration may not be as important.
`The inventive composition is used to treat any of the
`diseases or disorders of the central nervous system. Such
`diseases and disorders are defined in The Diagnostic and
`Statistical Manual of Mental Disorders-IV (DSM-IV)
`(American Psychiatric Association (1995)). To the extent
`necessary for completion, the contents of this reference and
`all of the defined diseases or disorders are expressly incor-
`porated by reference. Representative diseases or disorders
`include, but are not
`limited to the following: obesity,
`depression, schizophrenia, a stress related disease (e.g. gen-
`eral anxiety disorder), panic disorder, a phobia, obsessive
`compulsive disorder, post-traumatic-stress syndrome,
`immune system depression, incontinence, a stress induced
`problem with the urinary, gastrointestinal or cardiovascular
`system (e.g., stress incontinence), neurodegenerative
`disorders, autism, chemotherapy-induced vomiting,
`hypertension, migraine headaches, cluster headaches, sexual
`dysfunction in a mammal (e.g. a human), addictive disorder
`and withdrawal syndrome, an adjustment disorder, an age-
`associated learning and mental disorder, anorexia nervosa,
`a