HK1051814A - New drug combinations - Google Patents

Description

Novel pharmaceutical combination

Background

1. Field of the invention

The present invention describes novel therapeutic methods for providing rapid relief from a variety of neurological disorders comprising the administration of a norepinephrine reuptake inhibitor, preferably a selective norepinephrine reuptake inhibitor, most preferably reboxetine, in combination with an antimuscarinic agent, preferably tolterodine. In particular, the combination is used for the treatment of incontinence.

2. Description of the technology

Tricyclic antidepressants appearing in the early 60 s of the 20 th century provided a significant improvement in the treatment of neuropsychiatric diseases. With the advent of tricyclic drugs, reactive and endogenous depression, previously diagnosed as having poor prognosis, has become a manageable disease and has greatly reduced costs to both the patient and the community at large.

Early tricyclic compounds were reuptake inhibitors of all catecholamines released in the synaptic cleft, thus leading to prolonged and enhanced action of Dopamine (DA), Norepinephrine (NA) and serotonin (5-hydroxytryptamine ═ 5-HT). Lack of selectivity can also cause adverse side effects, particularly on acetylcholine (especially muscarinic components) and histamine mediated neurotransmission.

Because of these undesirable pharmacodynamic activities, cognitive impairment, sedation, urinary and gastrointestinal tract disorders, and increased intraocular pressure are limiting factors in the clinical use of these compounds, and treatment discontinuation is often required. Of greatest concern are the cardiotoxicity and convulsive activity of this group of drugs.

Recently, Selective Serotonin Reuptake Inhibitors (SSRIs) have emerged, which have the advantage of less side effects without loss of efficacy.

Fluoxetine is an example of such an inhibitor, which has enjoyed great commercial success.

Another proposed compound for the treatment of depression is a selective norepinephrine reuptake inhibitor. Sub-normal levels of norepinephrine have been associated with a variety of symptoms, including a lack of vitality, motivation, and interest in life. Thus, normal norepinephrine levels are necessary to maintain motivation and reward capacity. These neurotransmitters migrate from the end of a neuron through a small gap (i.e., the synaptic cleft) and then bind to receptor molecules on the surface of a second neuron. This binding causes an alteration within the cell, thereby initiating or activating a response or alteration of the postsynaptic neuron. Inactivation occurs primarily by transport of neurotransmitters back to the postsynaptic neurons (i.e., reuptake). Abnormalities in noradrenergic neurotransmission result in various types of depression, mental, behavioral and neurological disorders caused by various symptoms, including lack of vitality, motivation and interest in life. See, r.j. baldesarini, psychiatric disorders: depression and mania medications and treatments ", Goodman and Gilman's The Pharmacological basis of Therapeutics, McGraw-Hill, NY, NY, 432-.

Examples of norepinephrine reuptake inhibitors (selective and non-selective) include, but are not limited to: tandamine (CAS 42408-80-0; US 3904617: US 4118394), pirandamine (CAS 42408-79-7; US 3995052), benpyriminoindole (CAS 37751-39-6; US 3891644; US 3957819; US 3976645), fluloxan (US 4880801), loratadine (CAS 70384-91-7; US 4201783), talopram (CAS 21489-203), talopram (CAS 7182-51-6), prindamine, nomifensine (US 3577424), viloxazium (US 3712890), tomoxetine (US 4314081), duloxetine (US5023269), venlafaxine (US 4535186), milnacipran (US 4478836) and reboxetine (US 4229449).

Tomoxetine, (R) - (-) -N-methyl-3- (2-methylphenoxy) -3-phenylpropylamine is disclosed in U.S. Pat. No. 4,314,081. Reboxetine, 2- [ α - (2-ethoxy) phenoxybenzyl ] morpholine, is disclosed in U.S. Pat. No. 4,229,449. Reboxetine includes the racemate as well as the (-) (R, R) and (+) (S, S) enantiomers. The product may also be identified by the following trademarks: VESTRA, PROLIFT, NOREBOX and ERDONAX. Duloxetine, N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) propylamine, is disclosed in U.S. Pat. No. 4,956,388. It is usually administered as the hydrochloride salt and the (+) enantiomer. Venlafaxine is equivalent to compound a in us patent No. 4,761,501. Milnacipran, N-diethyl-2-aminomethyl-1-phenylcyclopropanecarboxamide is disclosed in U.S. patent No. 4,478,836. These documents are incorporated herein by reference for the sake of completeness.

Antimuscarinic agents are useful in the treatment of urinary incontinence. Examples of antimuscarinic agents include, but are not limited to: tolterodine, propiverine, oxybutynin, trospium chloride, darifenacin, temiverine, ipratropium bromide.

Tolterodine, (R) -2- [3- [ bis (1-methylethyl) amino]-1-phenylpropyl]-4-methyl-phenol, an antimuscarinic agent with high bladder selectivity, produced by Pharmacia&Developed by Upjohn and sold under the trademark DETROL^For the treatment of incontinence associated with overactive bladder. This product is disclosed in U.S. Pat. No. 5,382,600. Active metabolites of tolterodine are disclosed in U.S. Pat. No. 5,559,269, with a preferred metabolite being 2- [ (1R) -3- (diisopropylamino) -1-phenylpropyl]-4- (hydroxymethyl)) Phenol or its hydroxy (phenyl) acetate salt.

Propiverine is 1-methyl-4-piperidinyl α, α -diphenyl- α - (n-propoxy) acetate, which is disclosed in east de patent No. 106643 and CAS 82-155841s (1975). Oxybutynin is 4- (diethylamino) -2-butynyl α -phenylcyclohexane glycolate and is disclosed in UK patent No. 940540. Trospium chloride is 3 α -hydroxy spiro [1 α H, 5 α H-nortropane-8, 1' -pyrrolidinium ] chloride diphenyiglycolate, which is disclosed in U.S. patent No. 3480623. Darifenacin, 1- [2- (2, 3-dihydro-5-benzofuranyl) ethyl ] - α, α -diphenyl-3-pyrrolidineacetamide, is disclosed in U.S. Pat. No. 5,096,890. Temiverine is phenylacetic acid, α -cyclohexyl- α -hydroxy-, 4- (diethylamino) -1, 1-dimethyl-2-butynyl ester, which is disclosed in U.S. Pat. No. 5036098. Ipratropium bromide is 8-isopropylnoratropine methyl bromide, which is disclosed in U.S. patent No. 3505337.

Despite the advances in the art, there remains a need to develop pharmaceutical compositions that have the benefits of both norepinephrine reuptake inhibitors and antimuscarinic agents.

Summary of The Invention

According to the present invention, a novel pharmaceutical composition is provided. More specifically, the compositions combine one or more selective norepinephrine reuptake inhibitors with one or more antimuscarinic agents, preferably tolterodine. The composition is believed to be particularly effective in the broad sense of incontinence, particularly stress incontinence.

In a first embodiment of the invention, there is provided a composition comprising: (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more antimuscarinic agents or a pharmaceutically effective salt thereof.

In a particularly preferred embodiment, component (a) comprises reboxetine in enantiomeric or racemic form and component (b) comprises tolterodine, including its active metabolites.

In another embodiment of the invention, there is provided a method of treating or preventing incontinence or a central nervous system disease or disorder, the method comprising administering to a mammal a therapeutically effective amount of the above-described composition. In most cases, the mammal is a human and the disease or condition being treated is incontinence.

Another embodiment of the present invention encompasses the use of the above-described composition in the manufacture of a medicament for the treatment or prevention of incontinence or a disease or disorder of the central nervous system.

It is an object of the present invention to provide novel compositions having biological activity.

It is another object of the present invention to provide methods of treating or preventing incontinence or central nervous system diseases or disorders using the novel compositions of the present invention.

It is another object of the present invention to provide an effective treatment for incontinence.

These and other objects will be apparent to those skilled in the art by reference to the detailed description of the preferred embodiments.

Description of The Preferred Embodiment

For purposes of clarity, certain terms will be used in describing the preferred embodiments. These terms are intended to include the recited embodiments as well as all technical equivalents which operate in a similar manner to accomplish a similar result. With respect to any pharmaceutically active compound disclosed or claimed, it is intended to include all active metabolites produced in vivo, and to include all enantiomers, isomers or tautomers in which the compound is capable of existing in its enantiomeric, isomeric or tautomeric form.

The present invention provides novel compositions which are combinations of different chemical substances, more particularly a first substance which is a norepinephrine reuptake inhibitor and a second substance which is an antimuscarinic agent.

The first component is a norepinephrine reuptake inhibitor, more preferably a selective norepinephrine reuptake inhibitor. Such compounds include, but are not limited to: tamdamine, piradamine, benzazolol, fluloxacin, clotalamine, talsupram, talopram, prindamine, nomifensine, viloxazine, tomoxetine, duloxetine, venlafaxine, milnacipran and reboxetine, with reboxetine being particularly preferred.

Pharmaceutically effective salts of selective norepinephrine reuptake inhibitors include, but are not limited to, salts prepared from pharmaceutically acceptable acids or bases, including organic or inorganic acids and bases. When the preferred compound used is basic (e.g. reboxetine), salts may be prepared with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acids include acetic, benzenesulfonic, benzoic, p-bromophenylsulfonic, camphorsulfonic, carbonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, hydroiodic, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Examples of such pharmaceutically acceptable salts include, but are not limited to, acetate, benzoate, hydroxybutyrate, bisulfate, bisulfite, bromide, butyne-1, 4-dioate, hexanoate, chloride, chlorobenzoate, citrate, dihydrogen phosphate, dinitrobenzoate, fumarate, glycolate, heptanoate, hexyne-1, 6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylpropionate, phosphate, phthalate, phenylacetate, propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate, heptasulfate, Sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylene sulfonate, and the like.

In a particularly preferred embodiment, the selective norepinephrine reuptake inhibitor is reboxetine, 2- [ (α - ((2-ethoxyphenoxy) benzyl ] -morpholine and its pharmaceutically acceptable salts, its enantiomers (particularly the (S, S) enantiomer), or racemic forms, the synthesis of racemic reboxetine is described in detail in U.S. Pat. No. 4,229,449, the individual stereoisomers of reboxetine can be resolved by conventional methods known to those skilled in the art, including but not limited to, for example, resolution by simple crystallization and chromatographic techniques as described in GB 2,167,407. other methods of preparation are described in US5,068,433 and US5,391,735, reboxetine can be in the form of the free base or can be in the form of a salt, preferably the mesylate salt (also known as reboxetine mesylate), the above patents are incorporated herein by reference.

The dosage of the first component is selected to provide relief from the condition of the patient. It is well known that the dosage of such ingredients will depend on a variety of factors such as the potency of the particular compound selected, the mode of administration, the age and weight of the patient, the severity of the condition being treated, and the like. This is well known to those skilled in the art and the optimum dosage for administration can be determined by those skilled in the art by reference to the available literature for such ingredients. For completeness, the synthesis and dosage of these ingredients described in the patents or CAS documents cited in the "technical description" section herein are incorporated by reference.

Preferably, when reboxetine is selected as the active ingredient, the daily dose contains from about 0.1mg to about 10 mg. More preferably, each dose of the ingredient contains from about 0.5 to about 8mg of the active ingredient, and still more preferably from about 0.5 to about 5mg of the active ingredient per dose. The dosage form allows the administration of a complete daily dose in one or two oral doses. This allows the final formulation to contain 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 2.5mg of active ingredient. The invention also encompasses administration once or more than twice daily (e.g., 3, 4, 5, or 6 times daily).

The average daily adult dose of other norepinephrine reuptake inhibitors is as follows. Dosages include all numbers within the stated range, including whole or fractional numbers. Pediatric dosages may be smaller.

Composition (I)	Average daily dose (mg/day/patient)
		Tandamine	7.5 to 3750
Pyrndamine	7.5 to 3750
		Phenylpyrimidineindoles	5 to 500
Fluoroxan	75 to 750
		Chlortalamine	1 to 200
Tashupulan	1 to 3750
		Talopram	1 to 3750
Prindamine	1 to 3750
		Nomifensin	1 to 80
Viloxazin	1 to 3750
		Tomoxetine	1 to 200
Duloxetine	5 to 500
		Venlafaxine	2 to 200
Milnacipran	7.5 to 75

The second component includes one or more antimuscarinic agents. Examples of such agents include tolterodine, propiverine, oxybutynin, trospium chloride, darifenacin, temiverine, and ipratropium bromide. Tolterodine is particularly preferred.

Tolterodine has the chemical name (R) -2- [3- [ bis (1-methylethyl) amino ] -1-phenylpropyl ] -4-methyl-phenol, including pharmaceutically active salts thereof (such as those described above with respect to the first active ingredient) and active metabolites thereof produced in vivo. The synthesis of tolterodine is disclosed in U.S. Pat. No. 5,382,600. This patent is incorporated herein by reference for the sake of completeness. The compounds are particularly suitable as anticholinergics, especially for the treatment of incontinence.

It is well known that the dosage and dosing regimen (i.e., once, twice, three times or more daily administration) of the second component depends on those factors mentioned in the selection of the dosage with respect to the first component. For completeness, the synthesis and dosage of these ingredients described in the patents or CAS documents cited in the "technical description" section herein are incorporated by reference. The average adult daily dose of the second component is from about 0.05mg to about 5mg per kg of body weight, administered in one or more doses, e.g., containing from about 0.05 to about 250mg per dose. Dosages include all numbers within the stated range, including whole or fractional numbers. Pediatric dosages may be smaller.

The compositions of the invention may conveniently be administered in the form of a pharmaceutical composition comprising the active ingredient and suitable excipients. The pharmaceutical compositions may be prepared by methods known in the art and may contain excipients known in the art. A well-established compendium for this process and composition is the Remington's Pharmaceutical Sciences, ed.w. martin (Mark publication, co., 15 th edition, 1975). This document is incorporated herein by reference for the sake of completeness. The compositions of the invention may be administered parenterally (e.g., by intravenous, intraperitoneal, subcutaneous or intramuscular injection), topically, orally, intranasally, intravaginally or rectally, with oral administration being particularly preferred.

For oral therapeutic administration, the compositions of the present invention may be combined with one or more excipients and administered in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums, foodstuffs. These compositions and preparations should contain at least 0.1% of active compound. Of course, the percentage of the compositions and preparations can vary and can be between about 0.1 to about 100 weight percent of a given unit dosage form. The amount of active compound in the therapeutic composition is such that an effective dosage level is achieved.

The tablets, troches, pills, capsules and the like also contain the following ingredients: binders such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; disintegrating agents such as corn starch, potato starch, alginic acid, and the like; lubricants such as magnesium stearate; and sweetening agents such as sucrose, fructose, lactose or aspartyl or flavouring agents such as peppermint, oil of wintergreen or cherry flavouring. The above list is merely representative and other binders, excipients, sweeteners, etc. may be envisaged by the skilled person. 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 polyethylene glycol. Various other materials may also be present as coatings or to improve the morphology of the material in the solid unit dosage form. For example, 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, a sweetening agent such as sucrose or fructose, preservatives such as methyl and propylparabens, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing unit dosage forms should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, the active ingredients may be incorporated into sustained release formulations and devices, including but not limited to those that rely on osmotic pressure to achieve the desired release profile. Specifically, the preparation comprises once-daily preparations of each active ingredient.

The compositions of the invention containing both active ingredients can be administered in the same physical form or co-administered in the above excipients in the above dosages. The dosages of the individual active ingredients can be determined separately and can be administered as a single combined dose or separately. They may be administered simultaneously or at different times, provided that the two active ingredients are simultaneously in the patient over a 24 hour period. Co-administration refers to a patient taking one drug within 5 minutes of taking the other. Because the goal is to provide rapid relief from the patient's symptoms, in most cases, the two drugs should be administered within close time proximity, typically co-administration, when treatment is initiated; thereafter, the timing of administration of each drug is not critical.

The compositions of the present invention are useful for treating incontinence or various diseases or disorders of the central nervous system. These diseases and conditions are defined in The Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) (United states psychiatric Association (1995)). For the sake of completeness, the content of this document and all defined diseases or conditions are incorporated by reference. It can also be used for treating various types of incontinence. Representative diseases or conditions include, but are not limited to: obesity, depression, schizophrenia, stress-related disorders (e.g., generalized anxiety disorder), panic disorder, phobias, obsessive-compulsive disorder, post-traumatic stress syndrome, immune system suppression, incontinence, stress-induced urological, gastrointestinal or cardiovascular problems (e.g., stress incontinence), neurodegenerative disorders, autism, chemotherapy-induced emesis, hypertension, migraine, cluster headache, sexual dysfunction in mammals (e.g., humans), addictive disorders and withdrawal syndromes, adaptation disorders, age-related learning and mental disorders, anorexia nervosa, affective flattening, attention deficit due to general medical conditions, attention deficit hyperactivity disorder, bipolar disorders, bulimia nervosa, chronic fatigue syndrome, behavioral disorders, cyclothymic disorders, dysthymic disorders, mental retardation, obsessive compulsive disorders, mental retardation, stress disorders, stress, Fibromyalgia and other somatic disorders, generalized anxiety disorder, inhalation disorder, intoxication, movement disorders (e.g., Tourette's syndrome), oppositional defiant disorder, pain, peripheral neuropathy, post-traumatic stress state, premenstrual dysphoric disorder, psychosis, seasonal affective disorder, sleep disorders, specific developmental disorders, and Selective Serotonin Reuptake Inhibition (SSRI) "popout" syndrome. Treatment of the above diseases or conditions can be accomplished by delivering to the mammal a therapeutically effective amount of a composition of the present invention. In most cases, these mammals are humans, but the present invention also encompasses the treatment of food animals (e.g., livestock and poultry) as well as pets (e.g., dogs, cats and horses).

In particular, the compositions of the present invention are useful for treating incontinence (i.e., stress incontinence, genuine stress incontinence, and mixed incontinence). Stress incontinence is a symptom of involuntary urination upon completion of an action that increases intra-abdominal pressure, such as coughing or sneezing. Stress incontinence is also a clinical sign, observed by caregivers, of the ejection of urine from the urethral meatus when a patient coughs or stresses. Genuine stress incontinence (urge incontinence) is a pathological diagnosis of urethral sphincter insufficiency diagnosed by urodynamic testing. Mixed incontinence is a combination of stress incontinence and urge incontinence. The latter is part of the overactive bladder syndrome. Retention may be due to outflow obstruction (e.g., high urethral pressure), poor detrusor (bladder muscle) contraction, or an incompatibility between detrusor contraction and urethral relaxation. The pharmaceutical combination of the invention may be due to stress incontinence, urge incontinence or mixed incontinence.

It is expected that the novel compositions will provide rapid relief and minimize the amount of deleterious side effects in those patients suffering from the above-mentioned diseases or conditions.

The invention is described in more detail by the following non-limiting examples.

Example 1

A pharmaceutical composition is prepared by combining reboxetine in either its racemic or (S, S) enantiomeric form with tolterodine in a pharmaceutically acceptable carrier vehicle. The composition contains reboxetine and tolterodine in respective amounts that can deliver (on a daily basis) about 0.1mg to about 10mg reboxetine and about 0.05mg to about 4mg tolterodine per kilogram patient body weight (e.g., 3mg to 240mg tolterodine for a patient weighing 60 kg). The composition is administered to a patient to treat incontinence, particularly stress incontinence, urge incontinence or mixed incontinence.

Example 2

A first pharmaceutical composition is prepared by mixing reboxetine in either its racemic or + (S, S) enantiomeric form in a pharmaceutically acceptable carrier, which can deliver from about 0.1mg to about 10mg reboxetine (on a daily basis). A second pharmaceutical composition is prepared by mixing tolterodine in a pharmaceutically acceptable carrier, which can deliver from about 0.05mg to about 4mg of tolterodine per kg of patient body weight (on a daily basis). The first composition is administered once, twice, three times, four times or six times daily to a patient suffering from one or more forms of incontinence in a daily dose of about 0.1 to about 10 mg. The second composition is administered to the same patient either simultaneously with administration of the first composition or at any time within 24 hours of administration of the first composition, once, twice, three times, four times or six times daily, at a daily dose of about 0.05mg to about 4mg of tolterodine per kg of patient body weight. Alternatively, the second composition may be administered first, followed by administration of the first composition simultaneously or within 24 hours as described above.

Having described the invention in detail and by reference to preferred embodiments thereof, it will be apparent that modifications and variations are possible without departing from the scope of the appended claims.

Claims (34)

1. A composition comprising: (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more antimuscarinic agents or a pharmaceutically effective salt thereof.

2. The composition of claim 1 wherein component (a) is selected from the group consisting of tandamine, pirandamine, benzimidoline, fluxofenadine, lortalamine, talsupram, talopram, prindamine, nomifensine, viloxazine, tomoxetine, duloxetine, venlafaxine, milnacipran and reboxetine and mixtures thereof and wherein component (b) is selected from the group consisting of tolterodine, propiverine, oxybutynin, trospium, darifenacin, temiverine and ipratropium bromide and mixtures thereof.

3. The composition of claim 2 wherein component (a) is reboxetine in either its racemic or + (S, S) enantiomeric form and component (b) is tolterodine, an active metabolite thereof, or a mixture thereof.

4. The composition of claim 3 comprising from about 0.1mg to about 10mg reboxetine and from about 0.05mg to about 4mg tolterodine per kilogram patient body weight.

5. The composition of claim 1, wherein component (a) and component (b) are in the same delivery vehicle.

6. The composition of claim 1, wherein component (a) and component (b) are in different delivery vehicles.

7. A method of treating incontinence or a central nervous system disease or disorder in a mammal, the method comprising administering to the mammal a pharmaceutically effective amount of a composition comprising: (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more antimuscarinic agents or a pharmaceutically effective salt thereof.

8. The method of claim 7, wherein the disease or condition is selected from the group consisting of obesity, depression, schizophrenia, stress-related disorders (e.g., generalized anxiety disorder), panic disorders, phobias, obsessive-compulsive disorders, post-traumatic stress syndrome, immune system suppression, incontinence, stress-induced urinary, gastrointestinal or cardiovascular problems, neurodegenerative disorders, autism, chemotherapy-induced emesis, hypertension, migraine, cluster headache, mammalian sexual dysfunction, addictive disorders and withdrawal syndrome, accommodation disorders, age-related learning and mental disorders, anorexia nervosa, affective anergy, attention deficit due to general medical conditions, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, chronic fatigue syndrome, behavioral disorders, cyclothymic disorder, affective disorder, Dysthymic disorder, fibromyalgia and other somatic diseases, generalized anxiety disorder, inhalation disorder, intoxication, movement disorder, oppositional defiant disorder, pain, peripheral neuropathy, post-traumatic stress state, premenstrual dysphoric disorder, psychosis, seasonal affective disorder, sleep disorder, specific developmental disorder, and Selective Serotonin Reuptake Inhibition (SSRI) "poop out" syndrome.

9. The method of claim 7, wherein said composition is administered rectally, topically, orally, sublingually, intranasally, transdermally, or parenterally.

10. The method of claim 7, wherein component (a) and component (b) of the composition are administered simultaneously.

11. The method of claim 7, wherein component (a) and component (b) of the composition are co-administered.

12. The method of claim 7, wherein the disease or disorder comprises incontinence.

13. The method of claim 12, wherein the incontinence is stress incontinence, genuine stress incontinence or mixed incontinence.

14. The method of claim 13 wherein component (a) of the composition comprises reboxetine in its racemic or enantiomeric form and component (b) of the composition comprises tolterodine, its active metabolites, or mixtures thereof.

15. The method of claim 12 wherein said composition comprises from about 0.1mg to about 10mg reboxetine and from about 0.05mg to about 4mg tolterodine per kilogram of patient body weight.

16. A pharmaceutical composition consisting essentially of: (a) a pharmaceutically effective amount of reboxetine in its racemic or enantiomeric form or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of tolterodine, an active metabolite thereof, or a combination thereof, or a pharmaceutically effective salt thereof; wherein components (a) and (b) are in the same or different delivery vehicles.

17. Use of a composition comprising: (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors or a pharmaceutically effective salt thereof; and (b) a pharmaceutically effective amount of one or more antimuscarinic agents or a pharmaceutically effective salt thereof.

18. The use according to claim 17 wherein component (a) comprises reboxetine in its racemic or enantiomeric form and component (b) comprises tolterodine, an active metabolite thereof, or a mixture thereof.

19. A composition comprising (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors or pharmaceutically effective salts thereof and (b) a pharmaceutically effective amount of one or more antimuscarinic agents or pharmaceutically effective salts thereof for use as a medicament.

20. A composition comprising: (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors selected from the group consisting of tandamine, pirandamine, benzazole, fluloxan, loratadine, talsupram, talopram, prindamine, nomifensine, viloxazine, tomoxetine, duloxetine, venlafaxine, milnacipran and reboxetine, and mixtures or pharmaceutically effective salts thereof; and (b) a pharmaceutically effective amount of one or more antimuscarinic agents selected from tolterodine, propiverine, oxybutynin, trospium chloride, darifenacin, temiverine, and ipratropium bromide, and mixtures or pharmaceutically effective salts thereof.

21. The composition of claim 20 wherein component (a) is reboxetine in either its racemic or + (S, S) enantiomeric form and component (b) is darifenacin.

22. The composition of claim 20 wherein component (a) is reboxetine in either its racemic or + (S, S) enantiomeric form and component (b) is trospium chloride.

23. The composition of claim 20 wherein component (a) is reboxetine in its racemic or + (S, S) enantiomeric form and component (b) is ipratropium bromide.

24. The composition of claim 20, wherein ingredient (a) is duloxetine.

25. The composition of claim 23 wherein component (b) is selected from the group consisting of tolterodine, darifenacin, trospium chloride, ipratropium bromide, and mixtures thereof.

26. The composition of claim 25, comprising from about 1mg to about 200mg duloxetine and from about 0.05mg to about 5mg of ingredient (b) per kg body weight of the patient.

27. The composition of claim 20, wherein component (a) and component (b) are in the same delivery vehicle.

28. The composition of claim 20, wherein component (a) and component (b) are in different delivery vehicles.

29. A method of treating incontinence or a central nervous system disease or disorder in a mammal, the method comprising administering to the mammal a pharmaceutically effective amount of a composition comprising: (a) a pharmaceutically effective amount of one or more norepinephrine reuptake inhibitors tamdamine, pirandamine, benzimidoline, flulopran, loratadine, talsupram, talopram, prindamine, nomifensine, viloxazine, tomoxetine, duloxetine, venlafaxine, milnacipran, and reboxetine, and mixtures or pharmaceutically effective salts thereof; and (b) a pharmaceutically effective amount of one or more antimuscarinic agents selected from tolterodine, propiverine, oxybutynin, trospium chloride, darifenacin, temiverine, and ipratropium bromide, and mixtures or pharmaceutically effective salts thereof.

30. The method of claim 29, wherein the disease or condition is selected from the group consisting of obesity, depression, schizophrenia, stress-related disorders (e.g., generalized anxiety disorder), panic disorders, phobias, obsessive-compulsive disorders, post-traumatic stress syndrome, immune system suppression, incontinence, stress-induced urinary, gastrointestinal or cardiovascular problems, neurodegenerative disorders, autism, chemotherapy-induced emesis, hypertension, migraine, cluster headache, mammalian sexual dysfunction, addictive disorders and withdrawal syndrome, accommodation disorders, age-related learning and mental disorders, anorexia nervosa, affective anergy, attention deficit due to general medical conditions, attention deficit hyperactivity disorder, bipolar disorder, bulimia nervosa, chronic fatigue syndrome, behavioral disorders, cyclothymic disorder, affective disorder, Dysthymic disorder, fibromyalgia and other somatic diseases, generalized anxiety disorder, inhalation disorder, intoxication, movement disorder, oppositional defiant disorder, pain, peripheral neuropathy, post-traumatic stress state, premenstrual dysphoric disorder, psychosis, seasonal affective disorder, sleep disorder, specific developmental disorder, and Selective Serotonin Reuptake Inhibition (SSRI) "poop out" syndrome.

31. The method of claim 30, wherein component (a) and component (b) of the composition are administered simultaneously.

32. The method of claim 30, wherein component (a) and component (b) of the composition are co-administered.

33. The method of claim 30, wherein the disease or disorder comprises incontinence.

34. The method of claim 33, wherein the incontinence is stress incontinence, genuine stress incontinence or mixed incontinence.