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Home , Ciclazindol, Lortalamine, Nomifensine, Pirandamine, Sonepiprazole, Talsupram

US 2006OOO3992A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0003992 A1 Wong et al. (43) Pub. Date: Jan. 5, 2006

(54) NEW COMBINATIONS (60) Provisional application No. 60/259,286, filed on Jan. 2, 2001. (75) Inventors: Erik Ho Fong Wong, Ann Arbor, MI (US); Christopher C. Gallen, Publication Classification Wynnewood, PA (US); Torgny Svensson, Lidingo (SE) (51) Int. Cl. A6IK 3I/551 (2006.01) A6IK 3.1/5415 (2006.01) Correspondence Address: A6IK 3I/519 (2006.01) WARNER-LAMBERT COMPANY A6IK 31/496 (2006.01) 2800 PLYMOUTH RD A6IK 3III.37 (2006.01) ANN ARBOR, MI 48105 (US) (52) U.S. Cl...... 514/220; 514/259.41; 514/649; 514/225.8 (73) Assignee: Pharmacia & Upjohn Company, LLC (57) ABSTRACT (21) Appl. No.: 11/219,901 A composition comprising: (a) a pharmaceutically effective amount of one or more reuptake inhibitors or (22) Filed: Sep. 6, 2005 a pharmaceutically effective Salt thereof, and (b) a pharma ceutically effective amount of one or more neuroleptic Related U.S. Application Data agents or a pharmaceutically effective Salt thereof is pro Vided. The composition is useful in treating disorders or (62) Division of application No. 10/035,100, filed on Dec. diseases of the central , and particularly 28, 2001, now Pat. No. 6,964,962. useful in treating . US 2006/0003992 A1 Jan. 5, 2006

NEW DRUG COMBINATIONS rotransmitter back into the presynaptic neuron. Abnormality in noradrenergic transmission results in various types of CROSS-REFERENCE TO RELATED depression, mental, behavioral, and neurological disorders APPLICATION attributed to a variety of Symptoms including a lack of energy, motivation, and interest in life. See generally, R. J. 0001. This application claims the benefit of the following Baldessarini, “ and the Treatment of Psychiatric Dis provisional application: U.S. Ser. No. 60/259,286, filed Jan. orders: Depression and Mania” in Goodman and Gilman's 2, 2001, under 35 USC 119(e)(i), which is incorporated The Pharmacological Basis of Therapeutics, McGraw-Hill, herein by reference in its entirety. NY, N.Y., pp.432-439 (1996). BACKGROUND OF THE INVENTION 0010 Examples of norepinephrine reuptake inhibitors (both selective and not selective) include, but are not limited 0002) 1. Field of the Invention to the following: (CAS 42408-80–0; U.S. Pat. No. 0003. This invention describes new treatments that 3,904,617; U.S. Pat. No. 4,118,394), (CAS should provide for relief from several nervous system dis 42408-79-7; U.S. Pat. No. 3,995,052), (CAS orders with reduced side effects, and it involves the admin 37751-39-6; U.S. Pat. No. 3,891,644; U.S. Pat. No. 3,957, istration of a norepinephrine , preferably a 819; US 3976645), (U.S. Pat. No. 4,880,801), Selective norepinephrine reuptake inhibitor Such as the drug (CAS 70384-91-7; U.S. Pat. No. 4,201,783), , in combination with a neuroleptic agent (typical (CAS 21489-20-3), (CAS 7182-51-6), or atypical agents). In particular, the combi prindamine, (U.S. Pat. No. 3,577,424), vilox nation is to be used to treat Schizophrenia. azine (U.S. Pat. No. 3,712.890), tomoxetine (U.S. Pat. No. 4,314,081), (U.S. Pat. No. 5,023,269), venlafax 0004 2. Technology Description ine (U.S. Pat. No. 4,535,186), (U.S. Pat. No. 0005 The introduction of in the 4,478,836) and reboxetine (U.S. Pat. No. 4,229,449). The early 1960s has provided a major advance in the treatment term schizophrenia was first used in 1911 by Eugen Bleuler, of neuropsychiatric disorders. Reactive and endogenous a Swiss psychiatrist, to diagnose patients whose thought depressions, diagnoses formerly carrying grave prognostic processes and emotional responses Seemed to be discon implications, have become, with the introduction of the nected. The term Schizophrenia literally means split mind , manageable disorders with a much Smaller toll on and many people still believe incorrectly that the condition the patient and the society as a whole. causes a Split personality (actually an uncommon problem involving dissociation). Schizophrenia is now used to 0006 The early tricyclic compounds were reuptake describe a cluster of Symptoms that typically includes delu inhibitors of all the catecholamines released in the Synaptic Sions, hallucinations, disordered thinking, and emotional cleft, thus resulting in prolongation and enhancement of the unresponsiveness. No clear-cut definition of Schizophrenia (DA), noradrenaline (NA) and Serotonin (5-hy exists even at this time and no single cause has been found droxytryptamine=5-HT) action. Lack of selectivity also to explain all aspects of this devastating Syndrome. Most causes undesired Side effects particularly on the acetylcho likely, the Symptoms are triggered by a number of disease line (especially the muscarinic component), and histamine processes coupled with genetic factors and environmental mediated neurotransmission. StreSSeS. 0007 Because of these unwanted pharmacodynamic 0011 Chemical treatment for those suffering from activities, cognitive impairment, Sedation, urinary and gas Schizophrenia include the use of neuroleptic agents (Some trointestinal tract disturbances, and increased intraocular times referred to as antipsychotic agents) of either the preSSure were limiting factors in the clinical use of these typical or atypical type. compounds and often required discontinuation of treatment. Of utmost concern were also the cardiac toxic effects and the 0012 Typical neuroleptic agents are those that block proconvulsant activity of this group of drugs. receptors of the neurotransmitter dopamine. These medica tions are also referred to as neuroleptic drugs, because they 0008 More recently, selective reuptake inhibitors for can cause a number of neurologic side effects. The first drug serotonin (SSRI) have been introduced with definite advan of this type used for treating Schizophrenia was chlorprom tages in regard to fewer Side effects without loSS of efficacy. azine (Thorazine; U.S. Pat. No. 2645640). Many other is an example of Such an inhibitor that has had a antipsychotic drugs are now available, the most popular great amount of commercial Success. being (Haldol; U.S. Pat. No. 3,438,991). Others 0009. Another class of compounds that has been pro include (Trilafon; U.S. Pat. No. 2,766,235), posed for use in the treatment of depression is Selective (Mellaril; dosage of 30-800 mg/day), norepinephrine reuptake inhibitors. Lower-than-normal lev (Serentil; U.S. Pat. No. 3,084.161), trifluop els of norepinephrine are associated with a variety of Symp erazine (Stelazine; U.S. Pat. No. 2,921,069), and fluphena toms including lack of energy, motivation, and interest in zine (Prolixin; U.S. Pat. No. 3,058,979). For the very severe life. Thus, a normal level of norepinephrine is essential to active phase of Schizophrenia, injections of an antipsychotic maintaining drive and capacity for reward. These neu drug are often given every four to eight hours until the rotransmitters travel from the terminal of a neuron acroSS a patient is calm. If possible, however, physicians prefer Small gap (i.e., the Synaptic cleft) and bind to receptor administering a drug orally. These drugs may be high- or molecules on the Surface of a Second neuron. This binding low-. Generally, higher doses are used to treat acute elicits intracellular changes that initiate or activate a episodes (e.g., 5 to 10 mg of haloperidol) and lower doses response or change in the postsynaptic neuron. Inactivation are given during periods of remission (e.g., 2 to 5 mg). occurs primarily by transport (i.e., reuptake) of the neu However, new Studies Suggest starting haloperidol treatment US 2006/0003992 A1 Jan. 5, 2006 with daily doses in the 4 to 5 mg range for two to three and (U.S. Pat. No. 4,804,663) are currently the weeks. The beneficial impact of these drugs is greatest on Standard atypical drugs, but new that may be psychotic Symptoms, particularly hallucinations and delu even more effective are becoming available. Sions in the early and midterm Stages of the disorder. In (Clozaril) is the best known of these drugs. Clozapine was patients who are being treated for the first time, improve found to benefit up to half of patients with schizophrenia ment in psychotic Symptoms may be evident within one or who did not respond to other types of treatments, and there two days of treatment, although the full benefit of the drug is now Substantial evidence of its Superiority over typical usually evolves over about Six to eight weeks. Thought drugs. It is particularly useful in younger people, although disturbances are reduced more gradually. Some estimates of toxic side effects are common. Positive effects may not be poor responses to these drugs are as high as 40%. Antipsy evident for up to nine months. Clozapine has improved chotic drugs are also not very Successful in reducing nega negative Symptoms in short-term trials, longer ones are tive Symptoms, although people often show leSS withdrawal needed to See if the benefit is Sustained. It may also reduce and apathy because of the reduction in psychotic episodes. aggressive behavior and Suicidal impulses. Although the The most disturbing common side effects of high-dose or drug does not appear to cause tardive dyskinesia, it does high-potency therapy of drugs are have other Side effects including nasal congestion, drooling, those known as , which effect the low blood preSSure, headache, SleepleSSneSS, and Significant nerves and muscles controlling movement and coordination. weight gain. Serious Side effects include Seizures and, in up The most Serious long term extrapyramidal effect of antip to 1% of cases, agranulocytosis-a potentially life-threat Sychotic therapy is tardive dyskinesia, a condition associated ening decrease in the patients white blood cells. When with repetitive and involuntary movements, or tics, most agranulocytosis develops, it usually does So within three often in the mouth, lips, and tongue and also in the legs, arms months of treatment, peaking in the third month; if it hasn’t and trunk. Symptoms range from mild to Severe, and Some appeared within Six months, it most likely will not develop. times interfere with eating and walking. They may not Older women are at higher risk for this Side effect. Agranu appear until the antipsychotic drugs have been taken for locytosis can be reversed if treatment with clozapine is months or even years. A condition known as acute dystonia Stopped at once. It is important that people taking clozapine can occur Shortly after taking antipsychotic drugs. This side have their Serum glucose level count monitored frequently, effect causes abnormal muscle Spasms, particularly SuS especially those with diabetes or a family history of diabetes. tained contortions of the neck, jaw, trunk, and eye muscles. Although clozapine is more expensive than haloperidol, this High potency drugs (e.g., haloperidol, ) cause extra expense may be offset by its greater efficacy, which leSS drowsineSS and very low blood pressure but induce results in fewer hospitalizations. Risperidone. Risperidone more extrapyramidal side effects. Low-potency drugs (e.g., (Risperdal) is a blocker that has shown , thioridazine) are more Sedating and Side benefit and even Superiority in comparison to . effects are not as acute. Nearly every neuroleptic drug can It is now used by about 20% of schizophrenia patients. Like cause extrapyramidal side effects, however, which occur in clozapine, risperidone may have a beneficial effect on nega up to 70% of patients taking these . After the tive Symptoms. Risperidone may also improve Verbal work drug is withdrawn, Symptoms can Sometimes persist for ing memory, a common problem in Schizophrenics. It has weeks or months. Women face a higher risk for these few extrapyramidal effects, although they can occur at Symptoms, and they increase with length of therapy and age. higher doses. Common Side effects include Sleepiness, These medications can have adverse side effects on many weight gain, and dizzineSS. . Olanzapine organs and Systems in the body. SleepineSS and lethargy (Zyprexa) may be more effective in blocking the neurotrans commonly occur in the beginning of therapy, but usually mitterS Serotonin and dopamine than is clozapine and have decrease over time. Other Side effects include dry mouth, eye a much lower risk for Seizures and agranulocytosis. Studies problems, allergic reactions, temporary weight gain, and indicate it is at least as effective for acute Symptoms and menstrual irregularities in Women. A much more Serious but possibly more effective for negative ones than the typical rare Side effect is the neuroleptic malignant Syndrome, in neuroleptic drugs and that it has a very low risk for extrapy which dangerously high body temperatures occur. Without ramidal Symptoms. The drug may also be beneficial for prompt and expert treatment, this side effect can be fatal in patients who do not respond to neuroleptic drugs. A new 20% of those who develop it. Sometimes the effects of the Study Suggests that olanzapine also may be more effective drugs mimic Schizophrenic Symptoms, Such as agitation, than risperidone, particularly in its effect on negative Symp Slow speech, and retarded movement, and So the physician toms, but more research is needed to confirm result. Like may be tempted to increase the dosage. risperidone, Olanzapine can cause sleepiness, Weight gain, and dizziness. Other Atypical Drugs. (U.S. Pat. 0013 Drugs known as atypical drugs (also referred to in No. 4,831,031) and (Seroquel; U.S. Pat. No. this document as atypical neuroleptic or atypical antipsy 4,879,288), which has recently been approved by the FDA, chotic agents) are rapidly changing treatment for Schizo are other promising new drugs. Ziprasidone affects Serotonin phrenia, and many experts are now urging that they be used as well as dopamine may also improve negative Symptoms as the primary treatment for certain patients instead of the with limited extrapyramidal side effects. (Serlect; antipsychotics. Atypical drugs appear to be more effective U.S. Pat. No. 4,710,500) is another drug well into develop than the neuroleptics, even in reducing negative Symptoms ment. Although promising, reports of increased risk for and preventing relapse. They are rarely associated with the Sudden cardiac death are of Some concern. extrapyramidal Side effects, particularly tardive dyskinesia. (U.S. Pat. No. 5,006,528) is another atypical drug in devel The most Successful atypical drugs are able to Simulta opment. neously affect dopamine receptors and other neurotransmit ters responsible for psychotic Symptoms. Clozapine (U.S. 0014 Still other drugs for the treatment of schizophrenia Pat. No. 3,539,573), olanzapine (U.S. Pat. No. 5,229,382), include, but are not limited to the following typical and US 2006/0003992 A1 Jan. 5, 2006 atypical neuroleptic agents: (U.S. Pat. No. 0026. These, and other objects, will readily be apparent to 5,021,421), (EP402644), (U.S. Pat. those skilled in the art as reference is made to the detailed No. 4,745,117), (U.S. Pat. No. 4,789,683), Sone description of the preferred embodiment. piprazole (U.S. Pat. No. 5,877,317), (U.S. Pat. No. 3,704.245), DU-127090, ORG-5222 (GB 1567862), DETAILED DESCRIPTION OF THE SM-13496, (U.S. Pat. No. 4,401,822), PREFERRED EMBODIMENT CP-361428, Lu 35-138, balaperidone (WO 94/00458), S-18327 (EP811622), WAY-135452 (also known as DAB 0027. In describing the preferred embodiment, certain 452), eplivanserin (EP 373998), E-5842 (WO96/4287), terminology will be utilized for the sake of clarity. Such SR-31742 (EP 461986), NE-100 (EP 641766), osanetant terminology is intended to encompass the recited embodi (EP512901, EP 673928), SR-141716 (EP 658546), ment, as well as all technical equivalents which operate in a SR-48692 (EP 477049), BSF-201640 (WO99/09015), BSF Similar manner for a similar purpose to achieve a similar 190555 (WO95/07274), LAX-101a, (EP 707007), result. CX-691 (U.S. Pat. No. 5,783.587, U.S. Pat. No. 5,891,876) 0028. The present invention provides a novel composi and SB-271046 (W098/27081). tion which is a combination of different chemical entities, 0.015 Despite the above advances in the art, it would be more specifically, the first entity being a norepinephrine desirable to develop a pharmaceutical composition that reuptake inhibitor, particularly a Selective norepinephrine would have both the therapeutic benefits of the neuroleptic reuptake inhibitor and the Second being a neuroleptic agent. agents (typical or atypical) with a reduced side effects. 0029. The first component is a norepinephrine reuptake inhibitor, with Selective norepinephrine reuptake inhibitors BRIEF SUMMARY OF THE INVENTION being particularly preferred. This list of compounds 0016. In accordance with the present invention a novel includes, but is not limited to the following: tandamine, pharmaceutical composition is provided. More Specifically, pirandamine, ciclazindol, fluparoxan, lortalamine, talsu the composition combines one or more norepinephrine pram, talopram, prindamine, nomifensine, , reuptake inhibitors, more preferably one or more Selective tomoxetine, duloxetine, , milnacipran and rebox norepinephrine reuptake inhibitors with one or more neuro etine, with reboxetine being particularly preferred. leptic agents (typical or agents). The 0030 Examples of pharmaceutically effective salts for composition is considered to be particularly effective against the norepinephrine reuptake inhibitor include, but are not Schizophrenia. limited to Salts prepared from pharmaceutically acceptable acids or bases, including organic and inorganic acids and 0.017. A first embodiment of the present invention pro bases. When the preferred compound of use is basic (for vides a composition comprising: example reboxetine), Salts may be prepared from pharma 0018 (a) a pharmaceutically effective amount of one or ceutically acceptable acids. Suitable pharmaceutically more norepinephrine reuptake inhibitors or a pharmaceuti acceptable acids include acetic, benzenesulfonic (beSylate), cally effective salt thereof; and benzoic, p-bromophenylsulfonic, camphorSulfonic, car bonic, citric, ethaneSulfonic, fumaric, gluconic, glutamic, 0019 (b) a pharmaceutically effective amount of one or hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, more neuroleptic agents or a pharmaceutically effective Salt maleic, malic, mandelic, methaneSulfonic (meSylate), thereof. mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, Suc 0020. In particularly preferred embodiments, component cinic, Sulfuric, tartaric, p-toluenesulfonic, and the like. (a) comprises reboxetine in either its enantiomeric or race Examples of Such pharmaceutically acceptable Salts include, mic form. but are not limited to, acetate, benzoate, hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1,4-dioate, carpoate, 0021. Yet another embodiment of the present invention chloride, chlorobenzoate, citrate, dihydrogenphosphate, provides a method for treating or preventing diseases or dinitrobenzoate, fumarate, glycolate, heptanoate, heXyne-1, disorders of the central nervous System comprising admin 6-dioate, hydroxybenzoate, iodide, lactate, maleate, mal istering a therapeutically effective amount of the above onate, mandelate, metaphosphate, methaneSulfonate, meth composition to a mammal. In most instances, the mammal oxybenzoate, methylbenzoate, monohydrogenphosphate, will be a human, and the disease or disorder to be treated is naphthalene-1-Sulfonate, naphthalene-2-Sulfonate, oxalate, Schizophrenia. phenylbutyrate, phenylproionate, phosphate, phthalate, phy 0022. A further embodiment of the present invention lacetate, propanesulfonate, propiolate, propionate, pyro comprises the use of the above composition to prepare a phosphate, pyroSulfate, Sebacate, Suberate, Succinate, Sul medicament for treating or preventing diseases or disorders fate, Sulfite, Sulfonate, tartrate, XyleneSulfonate, and the like. of the central nervous System. 0031. In particularly preferred embodiments the selective 0023. An object of the present invention is to provide norepinephrine reuptake inhibitor is reboxetine, 2-O-((2- novel composition having biological activity. ethoxyphenoxy)benzyl-morpholine, and its pharmaceuti cally acceptable salts, in either its enantiomeric (particularly 0024. A further object of the present invention is to the (S,S) enantiomer) or racemic form. Synthesis of racemic provide a method for treating or preventing diseases of the reboxetine is described in greater detail in U.S. Pat. No. central nervous System by using the novel compositions of 4,229,449. Individual stereoisomers of reboxetine can be the present invention. obtained by resolution of the racemic mixture of enanti 0.025. An additional object of the present invention is to omers using conventional methods generally known by provide an effective treatment for Schizophrenia. those skilled in the art. Such methods include, but are not US 2006/0003992 A1 Jan. 5, 2006 limited to, resolution by Simple crystallization and chro done, Ziprasidone, quetiapine, Sertindole, aripiprazole, blo matographic techniques, for example, as Set forth in GB nanserin, illoperidone, peroSpirone, Zotepine, DU-127090, 2,167,407. Other methods of preparation are described in ORG-5222, SM-13496, amisulpride, raclopride, Sonepipra U.S. Pat. No. 5,068,433 and U.S. Pat. No. 5,391,735. zole, CP-361428, Lu 35-138, balaperidone, S-18327, WAY Reboxetine can be a free base form, or it can be in Salt form, 135452 (also known as DAB-452), eplivanserin, E-5842, preferably the methaneSulfonate Salt (also called reboxetine SR-31742, NE-100, osanetant, SR-141716, SR-48692, BSF meSylate). To the extent necessary for completion, the above 201640, BSF-190555, LAX-101a, Sarizotan, CX-691 and patents are expressly incorporated by reference. SB-271046. 0.032 The selection of the dosage of the first component 0036 AS is well known, the dosage and administrative is that which can provide relief to the patient. As is well regimen (i.e., one, two, three or more administrations per known, the dosage of this component depends on Several day) of the Second component depends on the factors factorS Such as the potency of the Selected Specific com referred to in connection with the dosage Selection of the pound, the mode of administration, the age and weight of the first component. To the extent necessary for completion, the patient, the Severity of the condition to be treated, and the Synthesis of the components and dosages described in the like. This is considered to be within the skill of the artisan patents or CAS documents referenced in the Technology and one can review the existing literature on the components Description portion of this document are expressly incorpo to determine optimal dosing. To the extent necessary for rated by reference. completion, the Synthesis of the components and dosages 0037. The average adult daily dosage of the neurolpetic described in the patents or CAS documents referenced in the agent is as follows. The dosages expressly include all Technology DeScription portion of this document are numerical values, whole or fractional, within the Stated expressly incorporated by reference range. Pediatric dosages may be leSS. 0033. Desirably, when reboxetine 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 con Component Average Daily Dosage (mg/day/patient) tains about 0.5 to about 8 mg of the active ingredient, and Chlorpromazine 10 to 150 even more preferably, each dose contains from about 0.5 to Haloperidol .5 to 100 about 5 mg of the active ingredient. This dosage form Mesoridazine 75 to 400 permits the full daily dosage to be administered in one or Perphenazine 5 to 100 two oral doses. This will allow for final formulations con Thioridazine 30 to 800 1 to 50 taining 0.1, 0.2,0.3, 0.4,0.5,0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, Fluphenazine 2.5 to 100 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 Clozapine 25 to SOO mg of active. More than once daily or twice daily admin Olanzapine O.O5 to 30 istrations (e.g., 3, 4, 5 or 6 administrations per day) are also Risperidone 25 to 25 Ziprasidone 5 to SOO expressly contemplated herein. Quetiapine 25 to 800 Sertindole 1 to SOO 0034. The average daily adult dosage of the other nore Aripiprazole 7.5 to 750 pinephrine reuptake inhibitorS is as follows. The dosages Sonepiprazole .75 to 3750 expressly include all numerical values, whole or fractional, Blomanserin .75 to 3750 within the Stated range. Pediatric dosages may be leSS. Iloperidone .75 to 7500 Perospirone .5 to 1000 Zotepine 30 to 1000 DU-127090 O5 to 7SOO ORG-5222 .75 to 750 Component Average Daily Dosage (mg/day/patient) SM-13496 O5 to 7SOO Amisulpride 50 to 750 Tandamine 7.5 to 3750 Raclopride 1 to SOO Pirandamine 7.5 to 3750 CP-361428 O5 to 7SOO Ciclazindol 5 to SOO Lu 35-138 O5 to 7SOO Fluparoxan .75 to 750 Balaperidone .75 to 7500 Lortalamine 1 to 200 S-18327 .5 to 100 Talsupram 1 to 37SO WAY-1354.52 O5 to 7SOO Tallopram 1 to 37SO Eplivanserin 1 to 2000 Prindamine 1 to 37SO E-5842 1 to 2000 Nomifensine 1 to 8O SR-31742 .5 to 4000 Viloxazine 1 to 37SO NE-1OO 1 to 100 Tomoxetine 1 to 200 Osanetant .5 to 4000 Duloxetine 5 to SOO SR-141716 .5 to 4000 Venlafaxine 2 to 200 SR-48692 1 to 1OOO Milnacipran 7.5 to 75 BSF-2O1640 1 to 1OOO BSF-190555 1 to SOO LAX-101a O5 to 7SOO Sarizotan O.2 to 2000 0035. The second component comprises one or more CX-691 1 to 400 neuroleptic agents. These can include those which are typi SB-271046 O.O5 to 1 OOO cal antipsychotic agents and those which are atypical antip Sychotic agents. Examples of Such agents include, but are not limited to the following: chlorpromazine, haloperidol, 0038 Compositions of the present invention can conve perphenazine, thioridazine, mesoridazine, trifluoperazine, niently be administered in a pharmaceutical composition fluphenazine, clozapine, olanzapine, Sonepiprazole, risperi containing the active components in combination with a US 2006/0003992 A1 Jan. 5, 2006

Suitable excipient. Such pharmaceutical compositions can be when treatment is started the two drugs would be adminis prepared by methods and contain excipients which are well tered to the patient close in time and typically concomi known in the art. A generally recognized compendium of tantly; thereafter, the timing of each drug's administration Such methods and ingredients is Remington's Pharmaceuti may not be as important. cal Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., 0042. The inventive composition is used to treat any of 1975). To the extent necessary for completion, this reference the diseases or disorders of the central nervous System. Such is hereby incorporated by reference. The compositions of the diseases and disorders are defined in The Diagnostic and present invention can be administered parenterally (for Statistical Manual of Mental Disorders-IV (DSM-IV) example, by intravenous, intraperitoneal or intramuscular (American Psychiatric Association (1995)). To the extent injection), topically, orally, intranasally, intravaginally, or necessary for completion, the contents of this reference and rectally, with oral administration being particularly pre all of the defined diseases or disorders are expressly incor ferred. porated by reference. Representative diseases or disorders 0.039 For oral therapeutic administration, the inventive include, but are not limited to the following: obesity, depres composition may be combined with one or more excipients Sion, Schizophrenia, a stress related disease (e.g. general and used in the form of ingestible tablets, buccal tablets, anxiety disorder), panic disorder, a phobia, obsessive com troches, capsules, elixirs, Suspensions, Syrups, wafers, chew pulsive disorder, post-traumatic-streSS Syndrome, immune ing gums, foods and the like. Such compositions and prepa System depression, incontinence, a StreSS induced problem rations should contain at least 0.1% of active compound. The with the urinary, gastrointestinal or cardiovascular System percentage of the compositions and preparations may, of (e.g., stress incontinence), neurodegenerative disorders, course, be varied and may conveniently be between about autism, chemotherapy-induced vomiting, hypertension, 0.1 to about 100% of the weight of a given unit dosage form. migraine headaches, cluster headaches, Sexual dysfunction The amount of active compound in Such therapeutically in a mammal (e.g. a human), addictive disorder and with useful compositions is Such that an effective dosage level drawal Syndrome, an adjustment disorder, an age-associated will be obtained. learning and mental disorder, anorexia nervosa, apathy, an 0040. The tablets, troches, pills, capsules, and the like attention-deficit disorder due to general medical conditions, may also contain the following: binderS Such as gum traga attention-deficit hyperactivity disorder, bipolar disorder, canth, acacia, corn Starch or gelatin; excipients Such as bulimia nervosa, chronic fatigue Syndrome, conduct disor dicalcium phosphate, a disintegrating agent Such as corn der, cyclothymic disorder, dysthymic disorder, fibromyalgia Starch, potato Starch, alginic acid and the like; a lubricant and other Somatoform disorders, generalized anxiety disor Such as Stearate; and a Sweetening agent Such as der, an inhalation disorder, an intoxication disorder, a move Sucrose, fructose, lactose or aspartame or a flavoring agent ment disorder (e.g., Tourette's Syndrome), oppositional defi Such as peppermint, oil of wintergreen, or cherry flavoring. ant disorder, a pain disorder, peripheral neuropathy, post The above listing is merely representative and one skilled in traumatic StreSS disorder, premenstrual dysphoric disorder, a the art could envision other binders, excipients, Sweetening psychotic disorder, Seasonal affective disorder, a Sleep dis agents and the like. When the unit dosage form is a capsule, order, a specific developmental disorder, and Selective Sero it may contain, in addition to materials of the above type, a tonin reuptake inhibition (SSRI) “poop out” syndrome. liquid carrier, Such as a vegetable oil or a polyethylene Treatment of the above diseases or disorderS is accom glycol. Various other materials may be present as coatings or plished by delivering a therapeutically effective amount of to otherwise modify the physical form of the solid unit the inventive composition to a mammal. In most cases this dosage form. For instance, tablets, pills, or capsules may be will be a human being, but treatment of food animals (e.g., coated with gelatin, wax, shellac or Sugar and the like. A livestock and poultry) and companion animals (e.g., dogs, Syrup or elixir may contain the active compound, Sucrose or cats and horses) is expressly covered herein. fructose as a Sweetening agent, methyl and propylparabens 0043. In particular, the inventive composition is to be as preservatives, a dye and flavoring Such as cherry or used in the treatment of schizophrenia. While not wishing to orange flavor. Of course, any material used in preparing any be bound to any specific scientific theory, it is believed that unit dosage form should be pharmaceutically acceptable and the addition of the norepinephrine reuptake inhibitor can Substantially non-toxic in the amounts employed. In addi Significantly reduce the Side effects associated with the tion, the active components may be incorporated into SuS neuroleptic treatments for Schizophrenia. tained-release preparations and devices including, but not 0044) The novel composition is expected to provide rapid limited to, those relying on OSmotic pressures to obtain a relief to those suffering from the above diseases or disorders desired release profile. with a minimal amount of deleterious side effects. More 0041. The inventive composition, containing the two Specifically, the incidence of weight gain typically associ active components, may be administered in the same physi ated with the administration of atypical neuroleptic agents is cal form or concomitantly according to the above-described minimized by the administration of the norepinephrine dosages and in the above-described delivery vehicles. The reuptake inhibitor. dosages for each active component can be measured Sepa 004.5 The invention is described in greater detail by the rately and can be given as a single combined dose or given following non-limiting example. Separately. They may be given at the same or at different times as long as both actives are in the patient at one time EXAMPLE 1. over a 24-hour period. Concomitant or concurrent adminis tration means the patient takes one drug within about 5 0046) A pharmaceutical composition is prepared by com minutes of taking the other drug. Because the goal is to bining reboxetine in either its racemic or +(S,S) entantio provide rapid symptomatic relief to the patient, in most cases meric form with a neuroleptic agent which is either: (a) US 2006/0003992 A1 Jan. 5, 2006 clozapine, (b) olanzapine or (c) risperidone in a pharmaceu 1. A composition comprising: tically acceptable carrier. The composition contains respec (a) a pharmaceutically effective amount of one or more tive amounts of reboxetine and clozapine, olanzapine or norepinephrine reuptake inhibitors or a pharmaceuti risperidone to deliver on a daily basis between about 0.1 mg cally effective salt thereof; and to about 10 mg reboxetine and between about (a): 25 to 500 (b) a pharmaceutically effective amount of one or more mg clozapine; or (b) 0.05 to 30 mg olanzapine; or (c) 0.25 neuroleptic agents or a pharmaceutically effective Salt to 25 mg risperidone. The composition is administered to a thereof. patient for the treatment of Schizophrenia on a daily, twice 2. The composition according to claim 1 wherein com daily, three times daily, four times daily or six times daily ponent (a) is selected from the group consisting of tan basis. damine, pirandamine, ciclaZindol, fluparoXan, lortalamine, talsupram, talopram, prindamine, nomifensine, Viloxazine, EXAMPLE 2 tomoxetine, duloxetine, Venlafaxine, milnacipran and rebox etine and mixtures thereof. 0047 A first pharmaceutical composition is prepared by 3. The composition according to claim 2 wherein com combining reboxetine in either its racemic or +(S,S) enan ponent (a) is reboxetine in either its racemic or +(S,S) tiomeric form in a pharmaceutically acceptable carrier Such enantiomeric form. that it can deliver between about 0.1 mg to about 10 mg 4. The composition according to claim 3 containing reboxetine on a daily basis. A Second pharmaceutical com between about 0.1 mg to about 10 mg reboxetine. position is prepared by combining either (a) clozapine, (b) 5. The composition according to claim 1 wherein com olanzapine or (c) risperidone in a pharmaceutically accept ponent (b) is selected from the group consisting of chlor able carrier such that it can deliver between about (a): 25 to , haloperidol, perphenazine, thioridazine, 500 mg clozapine; or (b) 0.05 to 30 mg olanzapine; or (c) meSoridazine, trifluoperazine, fluphenazine, clozapine, olan 0.25 to 25 mg risperidone on a daily basis. The first Zapine, risperidone, Ziprasidone, quetiapine, Sertindole, arip composition is administered to a patient Suffering from iprazole, Sonepiprazole, blonanserin, illoperidone, per Schizophrenia once, twice, three times, four times or Six ospirone, raclopride, Zotepine, DU-127090, ORG-5222, times daily Such that the daily dosage is between about 0.1 SM-13496, amisulpride, CP-361428, Lu 35-138, balaperi to about 10 mg. The Second composition is administered to done, S-18327, WAY-135452, eplivanserin, E-5842, the same patient at the same time as the administration of the SR-31742, NE-100, osanetant, SR-141716, SR-48692, BSF first composition or any time within 24 hours of the admin 201640, BSF-190555, LAX-101a, Sarizotan, CX-691 and istration of the first composition once, twice, three times, SB-271046 and mixtures thereof. 6. The composition according to claim 5 wherein com four times or six times daily Such that the daily dosage is ponent (b) is selected from the group consisting of clozap between about (a): 25 to 500 mg clozapine; or (b) 0.05 to 30 ine, olanzapine, risperidone and mixtures thereof. mg olanzapine; or (c) 0.25 to 25 mg risperidone. Alterna 7. The composition according to claim 1 wherein com tively, the Second composition could first be administered, ponent (a) and component (b) are maintained in the same followed by the administration of the first composition as delivery vehicle. disclosed at the same time, or within 24 hours thereof. 8. The composition according to claim 1 wherein com ponent (a) and component (b) are maintained in different EXAMPLE 3 delivery vehicles. 9. A method for treating a disease or disorder of the central 0.048 Eleven mice per sample group are tested using a nervous System in a mammal comprising administering to conditioned avoidance response assay, which can be used to Said mammal a pharmaceutically effective amount of a predict the likelihood of possible detrimental side effects composition comprising: asSociated with the administration of a neuroleptic agent. The regimen included a pre-treatment with either Saline or (a) a pharmaceutically effective amount of one or more reboxetine (at a dosage of 6 mg/kg, i.p.) followed thirty Selective norepinephrine reuptake inhibitors or a phar minutes afterwards by treatment with either Saline or raclo maceutically effective Salt thereof, and pride (0.05 mg/kg or 0.10 mg/kg, s.c.). The mice are tested (b) a pharmaceutically effective amount of one or more in the assay twenty minutes after administration of the Saline neuroleptic agents or a pharmaceutically effective Salt or raclopride. The mean average avoidance as measured by thereof. the assay for the Six different Sample groups are as follows: 10. The method according to claim 9 wherein said disease or disorder is Selected from the group consisting of obesity, depression, Schizophrenia, a StreSS related disease, panic disorder, a phobia, obsessive compulsive disorder, post SAMPLE saline 0.05 raclopride 0.10 raclopride traumatic-streSS Syndrome, immune System depression, a saline 1OO 90 70 StreSS induced problem with the urinary, gastrointestinal or reboxetine (6 mg/kg) 1OO 70 2O cardiovascular System, neurodegenerative disorders, autism, chemotherapy-induced vomiting, hypertension, migraine headaches, cluster headaches, incontinence, Sexual dysfunc 0049 Having described the invention in detail and by tion, addictive disorder and withdrawal Syndrome, an adjust reference to the preferred embodiments thereof, it will be ment disorder, an age-associated learning and mental disor apparent that modifications and variations are possible with der, anorexia nervosa, apathy, an attention-deficit disorder out departing from the Scope of the appended claims. due to general medical conditions, attention-deficit hyper US 2006/0003992 A1 Jan. 5, 2006 activity disorder, bipolar disorder, bulimia nervosa, chronic (b) a pharmaceutically effective amount of one or more fatigue Syndrome, conduct disorder, cyclothymic disorder, neuroleptic agents Selected from the group consisting dysthymic disorder, fibromyalgia and other Somatoform of clozapine, olanzapine, risperidone and mixtures disorders, generalized anxiety disorder, an inhalation disor thereof or a pharmaceutically effective Salt thereof; der, an intoxication disorder, a movement disorder, opposi tional defiant disorder, a pain disorder, peripheral neuropa wherein components (a) and (b) are maintained in the thy, post-traumatic StreSS disorder, premenstrual dysphoric same or in different delivery vehicles. disorder, a psychotic disorder, Seasonal affective disorder, a 19. The use of a composition comprising: Sleep disorder, a Specific developmental disorder, and Selec tive serotonin reuptake inhibition (SSRI) “poop out” syn (a) a pharmaceutically effective amount of one or more drome. norepinephrine reuptake inhibitors or a pharmaceuti 11. The method of claim 9 wherein said composition is cally effective salt thereof; and administered rectally, topically, orally, Sublingually, intrana (b) a pharmaceutically effective amount of one or more Sally, transdermally or parenterally. neuroleptic agents or a pharmaceutically effective Salt 12. The method according to claim 9 wherein component thereof to prepare a medicament for treating or pre (a) and component (b) of Said composition are simulta venting diseases or disorders of the central nervous neously administered. System. 13. The method according to claim 9 wherein component (a) and component (b) of Said composition are concomi 20. The use according to claim 19 wherein component (a) tantly administered. comprises reboxetine in its racemic or enantiomeric form. 14. The method according to claim 9 wherein said disease 21. The use according to claim 19 wherein component (b) or disorder comprises Schizophrenia. is Selected from the group consisting of clozapine, olanza 15. The method according to claim 9 wherein component pine, risperidone and mixtures thereof or a pharmaceutically (a) of Said composition comprises reboxetine in its racemic effective Salt thereof. or enantiomeric form. 22. A composition comprising: 16. The method according to claim 15 wherein between about 0.1 mg to about 10 mg reboxetine is administered to (a) a pharmaceutically effective amount of one or more the patient on a daily basis. norepinephrine reuptake inhibitors or a pharmaceuti 17. The method according to claim 9 wherein said neu cally effective salt thereof; and roleptic agent is Selected from the group consisting of (b) a pharmaceutically effective amount of one or more clozapine, olanzapine, risperidone and mixtures thereof. neuroleptic agents or a pharmaceutically effective Salt 18. A composition consisting essentially of thereof for use as a medicament. (a) a pharmaceutically effective amount of reboxetine in its racemic or enantiomeric form; and