CN1558756A - Pharmaceutical composition for treating urinary diseases - Google Patents

Abstract

The present invention relates to the field of urology. The present invention provides a novel pharmaceutical composition, which comprises a pharmaceutically effective combination of the following substances: {i) selected from muscarinic receptor antagonists, 5α-reductase inhibitors, α-adrenergic receptor receptor antagonists, their precursors and pharmaceutically acceptable salts, and (ii) selected from the group consisting of 5-HT _1a receptor agonists and antagonists, their precursors and pharmaceutically acceptable salts The second compound, and optionally their pharmaceutically acceptable carrier or diluent. The present invention also provides a method of treating a urinary disorder in a mammal, including a human, comprising administering to a mammal, including a human in need of such treatment, a therapeutically effective amount of a composition according to the present invention.

Description

Pharmaceutical composition for treating urinary diseases

technical field

The invention belongs to the field of urology. More specifically, it is generally based on the combination of certain agonists and/or antagonists used in the treatment of urological diseases.

Background of the invention

Urinary disorders and symptoms thereof include some or all of the following: urgency, frequency, incontinence, urinary leakage, enuresis, dysuria, hesitancy, and difficulty emptying the bladder. In particular, urinary disorders include, for example, urinary incontinence caused by an unstable or overactive bladder.

The term lower urinary tract symptoms (LUTS) describes a well-known medical condition. LUTS include some or all of the following: obstructive urinary symptoms such as slow urination, leakage at the end of urination, inability to urinate and/or need to strain to urinate at an acceptable rate, or irritative symptoms such as urinary frequency and/or urgency. These irritating symptoms may be the result of detrusor overactivity following bladder outlet obstruction caused by enlarged prostate or proximal urethral smooth muscle overactivity.

A significant proportion (5-10%) of adults suffer from urinary incontinence, especially the prevalence of so-called urge incontinence increases with age. Symptoms of an unstable or overactive bladder include urge incontinence, urgency, and frequency. Urge incontinence with urge incontinence (mixed incontinence) is frequently encountered by clinicians.

An unstable or overactive bladder is postulated to result from uncontrolled contraction of the clusters of smooth muscle fibers that form the outer layer of bladder muscle (detrusor muscle) during the bladder filling phase. These contractions are primarily regulated by cholinergic muscarine receptors, and pharmacological treatment of unstable or overactive bladders has traditionally been based on muscarine receptor antagonists.

The cause of inappropriate contraction of the bladder muscles is unclear in many cases. In some people, it can be caused by a problem with the nerve signals that travel from the brain to the bladder. Sometimes minor nerve damage results from surgery or childbirth. This muscle squeezes or contracts more often than normal and at inappropriate times. Instead of remaining at rest while urine fills the bladder, the detrusor muscle contracts while urine fills the bladder. This causes a person to feel a sudden and sometimes absolute urgency to urinate when the bladder is not full.

Another major urological disorder is interstitial cystitis. Cystitis is an inflammation of the bladder and related structures. There is currently no universally effective treatment procedure. Symptoms of cystitis include urgency to urinate, increased frequency and suprapubic pain that is usually relieved by emptying, arthritis, colon spasms, low-grade fever, and allergies. Mammals with cystitis can be significantly incapacitated and may require surgery. For example, cystitis can result from infection, trauma, allergies, and cancer.

U.S. Patent 5,382,600 discloses 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol, also known as N,N-diisopropyl-3- (2-Hydroxy-5-methylphenyl)-3-phenylpropylamine, commonly known as tolterodine, and other substituted 3,3-diphenylpropylamines used in the treatment of urinary incontinence. H Postlind et al., Drug Metabolism and Disposition, 26(4):289-293 (1998) disclose that tolterodine is a muscarinic receptor antagonist. Active metabolites of tolterodine and substituted 3,3 diphenylpropylamines are disclosed in US Patent No. 5,559,269.

US Patent 4,377,584 discloses the use of finasteride, a 5α-reductase inhibitor, for the treatment of benign prostatic hypertrophy.

US Patent 4,026,894 discloses the use of terazosin, an alpha-adrenergic receptor antagonist, as an antihypertensive drug. Alpha-adrenoceptor antagonists relax smooth muscle.

US Patent 5,990,114 discloses the use of certain 5-HT _la receptor antagonists for the treatment of urinary incontinence.

Despite the aforementioned developments in the art, it is desirable to develop new pharmaceutical compositions that further improve the quality of life of a large number of individuals.

Summary of the invention

For these and other purposes, it is an object of the present invention to provide a new pharmaceutical composition for the treatment of urinary disorders in mammals, including humans, which inhibits or stops unstable bladder contractions and eliminates the symptoms associated with incomplete bladder Questions about emptying.

Another object of the present invention is to provide a new method of treating urinary disorders in mammals, including man, which effectively inhibits or stops erratic bladder contractions and eliminates the problems associated with incomplete bladder emptying.

These and other objects will be apparent from the following, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically effective combination of:

(i) a first compound selected from muscarinic receptor antagonists, 5α-reductase inhibitors, α-adrenergic receptor antagonists, their precursors and pharmaceutically acceptable salts, and

(ii) a second compound selected from 5- _HT1a receptor agonists and antagonists, their precursors and pharmaceutically acceptable salts,

and optionally their pharmaceutically acceptable carrier or diluent.

The present invention is based on the recognition of the combination of at least one compound selected from the group consisting of muscarinic receptor antagonists, 5α-reductase inhibitors and α-adrenergic receptor antagonists with 5-HT _1a receptor agonists and antagonists. The combination produces a favorable stimulating effect on bladder contractility and bladder storage, as will be described more below. For example a 5- _HTla -agonist may be an inverse agonist and a 5- _HTla -antagonist may be a neutral 5- _HTla receptor antagonist.

In a preferred embodiment of the composition according to the present invention, the first compound is a muscarinic receptor antagonist or a precursor or a pharmaceutically acceptable salt thereof.

In a more preferred embodiment of the composition according to the invention, the muscarinic receptor antagonist is a substituted 3,3-diphenylpropylamine. Substituted 3,3-diphenylpropylamines having muscarinic receptor antagonist activity refer to the 3,3-diphenylpropylamines referred to in the Background of the Invention.

In a still more preferred embodiment of the composition according to the invention, the substituted 3,3-diphenylpropylamine is selected from tolterodine and hydroxytolterodine.

Preferably the substituted 3,3-diphenylpropylamine is tolterodine. In a most preferred embodiment of the composition according to the invention, the first compound is tolterodine L-tartrate.

In another preferred embodiment of the composition according to the invention, the muscarinic receptor antagonist is selected from oxybutynin and its active derivatives. Its active derivative is its active metabolite N-desethyloxybutynin. Preferably the muscarinic receptor antagonist is oxybutynin.

In another preferred embodiment of the composition according to the invention, the muscarinic receptor antagonist is selected from darfenacin and its active derivatives. Its active derivative is its active 3'-hydroxy metabolite. Preferably the muscarinic receptor antagonist is darfenacin.

In a preferred embodiment of the composition according to the invention, the first compound is present in an amount from about 0.1 mg to about 100 mg.

In a preferred embodiment of the composition according to the invention, the second compound is a neutral 5-HT _la receptor antagonist.

In a preferred embodiment of the composition according to the invention, the second compound is present in an amount from about 0.1 mg to about 1 g.

In another preferred embodiment of the composition according to the invention, the first compound and the second compound are maintained in the same delivery vehicle.

In another preferred embodiment of the composition according to the invention, the first compound and the second compound are maintained in different delivery vehicles.

In one embodiment of the composition according to the invention, the composition is used for the treatment of urinary disorders in mammals, especially humans, but also animals such as pets such as pigs and cats.

In a more preferred embodiment of the compounds according to the invention, the disease is selected from lower urinary tract symptoms, unstable or overactive bladder, bladder outflow obstruction, urinary incontinence, especially stress urinary incontinence and interstitial cystitis .

In another preferred embodiment of the compounds according to the invention, said composition is for the treatment of depression in said mammal, said depression being associated with said urinary disorder.

Furthermore, the present invention provides the use of the composition according to the present invention for the preparation of a medicament for the treatment of urinary diseases in mammals, including humans. In a preferred embodiment of the use according to the invention, said medicament is used for treating depression in said mammal, said depression being accompanied by said urinary disease.

Furthermore, the present invention provides a method of treating a urinary disorder in a mammal, including a human, said method comprising administering to the mammal, including a human, in need of such treatment a therapeutically effective amount of a composition according to the present invention.

In a preferred embodiment of the method according to the invention, the disease is selected from lower urinary tract symptoms, unstable or overactive bladder, bladder outflow obstruction, urinary incontinence, especially stress urinary incontinence and interstitial cystitis .

In another preferred embodiment of the method according to the invention, the method is also used for the treatment of depression in the mammal, said depression being associated with the urinary disorder.

In a preferred embodiment of the method according to the invention, the composition is administered rectally, intravaginally, topically, orally, sublingually, intranasally, transdermally or parenterally.

In another preferred embodiment of the method according to the invention, the first compound and the second compound in the composition are administered simultaneously.

In another preferred embodiment of the method according to the invention, the first compound and the second compound in the composition are administered concomitantly.

Finally, the present invention provides a pharmaceutical kit for treating urinary diseases in mammals, including humans, said kit comprising

(i) a first container comprising the first compound described above,

(ii) a second container comprising the second compound described above,

and optionally (iii) instructions for use of the kit.

Description of the invention

In describing the preferred embodiments, certain terminology is used for the sake of clarity. These terms are intended to include the described embodiments and all technical equivalents which operate in a similar manner, serve a similar purpose to achieve a similar result. To the extent that any pharmaceutically active compound is disclosed or claimed, it is expressly intended to include all active metabolites produced in vivo, and it is expressly intended to include all enantiomers, isomers or tautomers wherein said compound is capable of It exists as enantiomers, isomers or tautomers.

The present invention provides a novel pharmaceutical composition which is at least one muscarinic receptor antagonist or 5α-reductase inhibitor or α-adrenergic receptor antagonist or norepinephrine and / or combinations of serotonin reuptake inhibitors and 5-HT _1a receptor agonists and antagonists.

The compositions of the present invention are useful in the treatment of urinary disorders.

A particularly preferred composition for the treatment of urinary disorders is a combination of an antimuscarinic agent and a neutral 5- _HTla -antagonist.

According to the present invention, it has now been surprisingly and inventively found that treatment with a combination of an antimuscarinic agent and a neutral 5- _HTla -antagonist has a simultaneous effect on bladder contractility and bladder storage.

Antimuscarinic therapy acts on effector organs by suppressing the response to efferent impulses of the central nervous system. Thus, especially at higher doses, antimuscarinic treatment inhibits unstable bladder contractions during the filling phase, but also inhibits contractions elicited during the expulsion phase, leading to decreased voiding pressure and ultimately the negative consequences of incomplete bladder emptying. This effect limits the possibility of other acceptable doses of this agent. Furthermore, antimuscarinic therapy leads to side effects outside the genitourinary system mainly caused by blockade of muscarinic receptors in other tissues such as salivary glands, gut and CNS, causing side effects such as dry mouth, constipation and confusion, respectively. These side effects can be reduced to some extent by the introduction of newer antimuscarinic agents such as tolterodine that are selective for bladder smooth muscle. However, even bladder-selective antimuscarinic agents have always been limited to the treatment of overactive bladder due to their effect on voiding contractions as described above.

The effects of antimuscarinic agents have been studied in a number of animal models and they consistently appear to reduce the magnitude of voiding or voiding contraction without direct effects on bladder capacity. For these agents, the effect on bladder capacity has been shown to follow a marked decrease in voiding pressure.

Clinically, there is no agent that has a direct effect on the storage function of the bladder. However, it is recognized that 5-HT _1a -agonists or -antagonists, especially neutral 5-HT _1a -antagonists and antimuscarinic agents or 5α-reductase inhibitors or α-adrenergic receptor antagonists Combinations of antimuscarinic agents or norepinephrine and/or serotonin reuptake inhibitors, especially antimuscarinic agents, can increase bladder capacity without negative consequences on bladder contractility.

Importantly, coadministration of a neutral 5-HT-antagonist and an antimuscarinic did not attenuate the effect of the antimuscarinic agent on bladder contractility in a model evaluating the effect of an antimuscarinic agent on bladder contractility.

Furthermore, in a model used to evaluate the effects of neutral 5-HT _1a antagonists on bladder volume and voiding reflex inhibition, simultaneous administration of antimuscarinic agents and neutral 5-HT _1a -antagonists did not attenuate the _1a - The effect of the antagonist on bladder capacity and its effect on the voiding reflex.

Muscarinic receptor antagonists or antimuscarinic agents for use in the pharmaceutical compositions of the invention include, but are not limited to, non-selective agents, bladder selective agents, and muscarinic M3 receptor selective agents.

Examples of muscarinic receptor antagonists include, but are not limited to, tolterodine and its active metabolites, such as hydroxytolterodine, YM905, propiverine, oxybutynin, trospium chloride ), propantheline, darfenacin, timivirine and ipratropium and pharmaceutically acceptable salts thereof. YM905 is succinic acid, compound (1S)-(3R)-1-azabicyclo[2.2.2]oct-3-yl 3,4-dihydro-1-phenyl-2(1H)-isoquinoline Formate (1:1) (9CI). Propiverine is 1-methyl-4-piperidinyl α,α-diphenyl-α-(n-propoxy)acetate and is disclosed in West German Patent 106,643 and CAS82155841S (1975). Oxybutynin is 4-(diethylamino)-2-butynyl alpha-phenylcyclohexane glycolate and is disclosed in UK Patent 940,540. Trospium chloride is 3α-hydroxyspiro[1αH,5αH-nortropine-8,1′-pyrrolidinium] chloride benzylate and is disclosed in US Patent No. 3,480,623. Darfenacin is (S)-2-{1-[2-(2,3-dihydrobenzofuran-5-yl)ethyl]-3-pyrrolidinyl}-2,2-diphenyl -Acetamide and disclosed in US Patent 5,096,890. Timivirine is phenylacetic acid, α-cyclohexyl-α-hydroxy-4-(diethylamino)-1,1-dimethyl-2-butynate and is disclosed in US Patent No. 5,036,098. Ipratropium is 8-isopropylnortropine methobromide and is disclosed in US Patent 3,505,337.

Preferred muscarinic receptor antagonists may be selected from substituted 3,3-diphenylpropylamines having antimuscarinic activity (such as 3,3-diphenylpropylamines disclosed in US Pat. No. 5,382,600), and its pharmaceutically acceptable salt. Preferred muscarinic receptor antagonists include, but are not limited to, tolterodine and hydroxytolterodine, oxybutynin and its active derivatives such as N-desethyloxybutynin and darfenacin and Its active derivatives, such as its 3'-hydroxy metabolites, and its pharmaceutically acceptable salts.

5α-reductase inhibitors useful in the pharmaceutical compositions of the present invention include, but are not limited to, finasteride (U.S. Patent 4,377,584), dutasteride (U.S. Patent 5,565,467), eristide (U.S. Patent 5,017,568) and toro Androurea (US Patent 5,155,107) and pharmaceutically acceptable salts thereof.

Alpha-adrenergic receptor antagonists useful in the pharmaceutical compositions of the present invention include, but are not limited to, terazosin (US Patent 4,026,894), doxazosin (US Patent 4,188,390), prazosin (US Patent 3,511,836) , Bunazosin (US Patent 3,920,636), Indolamin (US Patent 3,527,761), Alfuzosin (US Patent 4,315,007), Abanoquine (US Patent 4,686,228), Naftopidil (US Patent 3,997,666) , phentolamine, tamsulosin (US patent 4,703,063), trazodone, dapiprazole, phenoxybenzamine, imazoxan (US patent 4,818,764), efalaxane (US patent 4,411,908), yohimbine, Dibenzamide, trimazosin, tolazoline, corynthanine, rauwolscine, tamsulosin, and peroxan, and pharmaceutically acceptable salts thereof.

Norepinephrine and/or serotonin reuptake inhibitors for use in the pharmaceutical compositions of the present invention include, but are not limited to, duloxetine (US Patent 4,956,388), reboxetine, [S,S]-reboxetine Succinate and racemate of reboxetine and sertraline (Zoloft).

The selected dose of the first compound is that which provides relief to the patient. Dosage and dosing regimens (i.e., one, two, three or more doses per day) of this compound are known to depend on factors such as the potency of the particular compound chosen, the mode of administration, the age and weight of the patient, the The severity of the symptoms being treated, etc.

This is within the purview of the skilled artisan, and it may take into account the existing literature on the ingredients to determine optimum dosages.

When the first compound is an antimuscarinic agent, preferably the average adult daily dose of the first compound is from about 0.05 mg to about 5 mg/kg body weight, administered in one or more doses, for example each comprising about 0.05 mg to About 250mg.

When the first compound is a 5α-reductase inhibitor, preferably the first compound is present in an amount ranging from about 2 mg to about 20 mg, preferably about 5 mg per dose.

When the first compound is an alpha-adrenergic receptor antagonist, preferably the first compound is present in an amount ranging from about 1 mg to about 25 mg, preferably about 10 mg per dose.

5- _{HT la} receptor agonists and antagonists for use in the pharmaceutical compositions of the present invention include, but are not limited to, compounds that act on the central nervous system by binding to 5-HT receptors of the 5-HT _la subtype. A non-limiting example of a 5-HT _1a receptor antagonist is WAY-100,635, cyclohexanecarboxamide, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl Base]-N-2-pyridyl-, trihydrochloride; robalzotan, namely (3R)-3-(dicyclobutylamino)-8-fluoro-3,4-dihydro-2H-l-benzo pyran-5-carboxamide; and LY426965, which is [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl yl-2-phenyl-1-butanone monohydrochloride]. In general, compounds bind selectively to receptors of the 5-HT _Ia subtype to a much greater extent than they bind to other receptors, such as the _α1 and _D2 receptors. Furthermore, they exhibit activity as 5-HT _1a -agonists or antagonists in pharmacological tests. The 5-HT _1a receptor agonists and antagonists of the present invention can be used to treat CNS diseases such as anxiety in mammals, especially humans. They are also used as antidepressants, hypotensive agents, as agents to regulate sleep/wake cycles, feedback performance and/or sexual function, in the treatment of cognitive disorders, and in the treatment of neuromuscular disorders of the lower urinary tract, especially Neuromuscular disorders of the lower urinary tract that involve voiding (urination), such as dysuria, incontinence, and enuresis.

A neutral antagonist is a compound that binds to a receptor without intrinsic activity at the receptor, but blocks receptor-mediated functional activity elicited by an agonist. In this regard, an agonist is defined as a compound that binds to a receptor and activates a receptor-mediated functional response, such as, but not limited to, 5-HT _1a -mediated inhibition of adenylyl cyclase activity or activation of potassium channels .

It is known that the dose and dosing regimen (ie one, two, three or more doses per day) of the second compound depends on the factors mentioned for the choice of dose of the first compound. The average adult daily dose of the second compound is about 1 [mu]g to about 10 mg/kg body weight, administered in one or more doses, eg, each containing about 50 [mu]g to about 1 g. Pediatric dose can be less.

Examples of pharmaceutically acceptable salts for use in compositions according to the invention include, but are not limited to, acetate, benzoate, hydroxybutyrate, bisulfate, bisulfite, bromide, butyne- 1,4-diacid salt, carpoate, chloride, chlorobenzoate, citrate, dihydrogen phosphate, dinitrobenzoate, fumarate, glycolate, heptanoate, hexanoate Alkyne-1,6-dioate, hydroxybenzoate, iodide, lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzene Formate, methyl benzoate, monohydrogen phosphate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylpropionate, phosphate , phthalates, phenylacetates, propanesulfonates, propiolates, propionates, pyrophosphates, pyrosulfates, sebacates, suberates, succinates, sulfuric acid Salt, sulfite, sulfonate, tartrate, xylene sulfonate, etc.

Compositions of the present invention may conveniently be administered as pharmaceutical compositions containing the active compound in association with a suitable excipient. Such pharmaceutical compositions can be prepared by methods known in the art and contain excipients known in the art. A common compendium of these methods and compositions is Remington's Pharmaceutical Sciences by E.W. Martin (Mark Publ. Co., 15th Ed., 1975). This reference is hereby incorporated by reference in its entirety. The compositions of the present invention may be administered parenterally (e.g., by intravenous, intraperitoneal, subcutaneous or intramuscular injection), topically, orally, sublingually, transdermally, intranasally, intravaginally Drug or rectal administration, particularly preferably orally.

For oral therapy, the compositions of the present invention may be combined with one or more excipients and presented as ingestible tablets, sublingual tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, food etc. to use. These compositions and preparations preferably contain at least 0.1% of active compound. The percentages of compositions and preparations may of course vary and may conveniently be from about 0.1 to about 100% by weight of a given dosage unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.

Tablets, troches, pills, capsules, etc. may also contain the following: binders such as tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; disintegrants such as cornstarch, potato starch, alginic acid etc.; lubricating agents such as magnesium stearate; and sweetening agents such as sucrose, fructose, lactose or aspartame or flavoring agents such as peppermint, oil of wintergreen or cherry flavoring. The above list is representative only, and other binders, excipients, sweeteners, etc. may be envisioned by those skilled in the art. When the unit dosage form is a capsule, it contains, in addition to materials of the above type, a liquid carrier such as vegetable oil or polyethylene glycol. Various other materials may be present as coatings or to modify the physical form of the solid unit dosage form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar or the like. A syrup or elixir may contain the active compound, sucrose or fructose as sweetening agents, methyl and propylparabens as preservatives, a dye and flavoring agents such as cherry or orange flavor. Of course, any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially nontoxic in the amounts employed. Additionally, the active ingredient may be incorporated into sustained release formulations and devices, including but not limited to formulations and devices that are dependent on osmotic pressure to achieve a targeted release profile. In particular, once-daily formulations of each active ingredient are included.

Compositions of the present invention containing two or more active compounds may be administered in the same physical form or concomitantly in dosages as described above, and in delivery vehicles as described above. The dose of each active compound may be determined separately and may be presented as a single combined dose or as doses administered separately. They may be administered at the same time or at different times as long as both are active in the patient within a 24 hour period. Concomitant or simultaneous administration means that the patient takes one drug within about 5 minutes of taking the other drug.

The invention also includes pharmaceutical kits for treating urinary disorders in mammals, including humans. Similar to the composition, the kit comprises a first container containing the above-mentioned first compound, a second container containing the above-mentioned second compound and instructions for use of the kit.

"Pharmaceutically acceptable" means acceptable to the patient from a pharmacological/toxicological point of view and a physical/chemical point of view in terms of composition, formulation, stability, patient acceptance and bioavailability Acceptable properties and/or substances for pharmaceutical chemists.

The composition of the invention is intended for use in the treatment of urinary disorders. In particular, the composition is used for the treatment of any type of LUTS or incontinence, such as stress incontinence, pure stress incontinence and mixed incontinence. Stress urinary incontinence is the involuntary loss of urine during any activity that increases intra-abdominal pressure, such as coughing or sneezing. Stress incontinence is also a clinical condition, which is observed by caregivers when a patient coughs or strains to squirt urine out of the urethra (opening). Pure stress incontinence (urge incontinence) is a pathological diagnosis of incompetence of the urethral sphincter diagnosed by the Urodynamic test. Mixed incontinence is stress incontinence with urge incontinence. The latter is part of the symptom complex of an overactive bladder. Retention may result from outflow obstruction (eg, high urethral pressure), poor detrusor (bladder muscle) contraction, or lack of coordination between detrusor contraction and urethral relaxation. The pharmaceutical combination of the present invention can be used for stress incontinence, urge incontinence or mixed incontinence.

The compositions according to the invention are also useful in the treatment of interstitial cystitis.

When antimuscarinic therapy in urological disorders is affected by increased residual urine, therapy can be augmented by the addition of neutral 5-HT _1a antagonists. This condition is especially likely to occur in patients with overactive bladder secondary to bladder outflow obstruction due to enlarged prostate.

In other cases, antimuscarinic therapy may be limited by intolerable side effects such as dry mouth. In this case, the antimuscarinic dose can be reduced, but efficacy is maintained by adding a neutral 5-HT _1a antagonist. In cases where these agents are preferred, more bladder-selective agents than others, this combination allows the use of anti-muscarinic agents that are not selective for the bladder.

In another instance, treatment with neutral 5- _HTla antagonists may be limited by the lack of any effect on bladder contractility. In this case, the addition of antimuscarinic agents brings additional efficacy. This condition may be in patients with bladder hyperreflexia, a condition known to be associated with bladder reflex contraction.

In another instance, the efficacy of neutral 5- _HTla antagonists may be limited by side effects. In such cases, it may be considered to adjust the dosage and thus the potency of the 5-HT antagonist by adding an antimuscarinic agent.

It is believed that the novel compositions of the present invention provide rapid relief to subjects suffering from the above diseases or conditions with a minimal amount of deleterious side effects.

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

Example

Example 1

A pharmaceutical composition is prepared by combining tolterodine and a neutral 5-HT _la receptor antagonist in a pharmaceutically acceptable carrier. The composition comprises about 0.05 mg to about 4 mg of tolterodine per kilogram of patient body weight (e.g. 3 mg to 240 mg tolterodine for a human weighing 60 kg) and about 0.01 mg to about 1 mg of a neutral 5-HT _1a receptor antagonist dose/kg patient body weight. The compositions are administered to a patient for the treatment of incontinence, particularly stress incontinence, urge incontinence or mixed incontinence.

Example 2

The first pharmaceutical composition is prepared by combining the 5-HT _la receptor antagonist in a pharmaceutically acceptable carrier so that it can deliver about 0.5 mg to about 50 mg per day. The second pharmaceutical composition is prepared by combining tolterodine in a pharmaceutically acceptable carrier such that it can deliver about 0.05 mg to about 4 mg tolterodine per kilogram of patient body weight per day.

A patient suffering from one or more forms of incontinence is administered one, two, three, four or six times a day of the first composition to the patient so that the daily dose is from about 0.5 mg to about 50 mg. administering the second composition once, twice, three times, four times or six times per day to the same patient at the same time as the administration of the first composition or at any time within 24 hours of the administration of the first composition, Such that the daily dose is about 0.05 mg to about 4 mg tolterodine per kilogram of patient body weight.

Alternatively, the second composition may be administered first, followed by administration of the first composition as disclosed simultaneously or within 24 hours of its administration.

Example 3

A pharmaceutical composition is prepared by combining a 5α-reductase inhibitor and a neutral 5-HT _la receptor antagonist in a pharmaceutically acceptable carrier. The composition comprises about 2 mg to about 20 mg of a 5α-reductase inhibitor and about 0.5 mg to about 50 mg of a neutral 5-HT _la receptor antagonist. The composition is administered to a patient to treat a urinary disorder.

Example 4

A pharmaceutical composition is prepared by combining an alpha-adrenergic receptor antagonist and a neutral 5-HT _la receptor antagonist in a pharmaceutically acceptable carrier. The composition comprises from about 1 mg to about 25 mg of an alpha-adrenergic receptor antagonist and from about 0.5 mg to about 50 mg of a neutral 5-HT _la receptor antagonist. The composition is administered to a patient for the treatment of urinary disorders.

The invention has been described in detail with reference to preferred embodiments, but it will be obvious that modifications and variations are possible without departing from the scope of the appended claims.

Claims (43)

1. A pharmaceutical composition comprising a pharmaceutically effective combination of the following substances: (i) a first compound selected from muscarinic receptor antagonists, 5α-reductase inhibitors, α-adrenergic receptor antagonists, their precursors and pharmaceutically acceptable salts, and (ii) a second compound selected from 5- _HT1a receptor agonists and antagonists, their precursors and pharmaceutically acceptable salts, and optionally a pharmaceutically acceptable carrier or diluent therefor. 2. The pharmaceutical composition according to claim 1, wherein the first compound is a muscarinic receptor antagonist, or a precursor or a pharmaceutically acceptable salt thereof. 3. The composition according to claim 2, wherein the muscarinic receptor antagonist is a substituted 3,3-diphenylpropylamine. 4. The composition according to claim 3, wherein the substituted 3,3-diphenylpropylamine is selected from tolterodine and hydroxytolterodine. 5. The composition according to claim 4, wherein the substituted 3,3-diphenylpropylamine is tolterodine. 6. The composition according to claim 5, wherein the first compound is tolterodine L-tartrate. 7. The composition according to claim 2, wherein the muscarinic receptor antagonist is selected from oxybutynin and its active derivatives, such as N-desethyloxybutynin. 8. The composition according to claim 7, wherein the muscarinic receptor antagonist is oxybutynin. 9. The composition according to claim 2, wherein the muscarinic receptor antagonist is selected from darfinacin and its active derivatives, such as its 3'-hydroxy metabolite. 10. The composition according to claim 9, wherein the muscarinic receptor antagonist is darfenacin. 11. The composition according to any one of claims 1-10, wherein the first compound is present in an amount from about 0.1 mg to about 100 mg. 12. The composition according to any one of claims 1-11, wherein the second compound is a neutral 5- _HTla receptor antagonist. 13. The composition according to any one of claims 1-12, wherein the second compound is present in an amount from about 0.1 mg to about 1 g. 14. The composition according to any one of claims 1-13, wherein the first compound and the second compound are maintained in the same delivery vehicle. 15. The composition according to any one of claims 1-13, wherein the first compound and the second compound are maintained in different delivery vehicles. 16. A composition according to any one of claims 1-15 for use in the treatment of urinary disorders in mammals, including humans. 17. The composition according to claim 16, wherein the disorder is lower urinary tract symptoms. 18. The composition according to claim 16, wherein the disorder is unstable or overactive bladder. 19. The composition according to claim 16, wherein the disorder is bladder outflow obstruction. 20. The composition according to claim 16, wherein the disorder is urinary incontinence. 21. Composition according to claim 20, wherein the disorder is stress urinary incontinence. 22. The composition according to claim 16, wherein the disease is interstitial cystitis. 23. A composition according to any one of claims 16-22 for use in the treatment of depression in the mammal, said depression accompanying said urinary disorder. 24. Use of the pharmaceutical composition according to any one of claims 1-15 for the preparation of a medicament for treating urinary diseases in mammals, including humans. 25. Use of the composition according to claim 24, wherein the disease is lower urinary tract symptoms. 26. Use of a pharmaceutical composition according to claim 24, wherein the disease is unstable or overactive bladder. 27. Use of a pharmaceutical composition according to claim 24, wherein the disease is bladder outflow obstruction. 28. Use of a pharmaceutical composition according to claim 24, wherein the disorder is urinary incontinence. 29. Use of the pharmaceutical composition according to claim 28, wherein the disorder is stress urinary incontinence. 30. Use of the pharmaceutical composition according to claim 24, wherein the disease is interstitial cystitis. 31. The use of the pharmaceutical composition according to any one of claims 24-30, wherein the medicament is for the treatment of depression in the mammal, said depression accompanying said urinary disease. 32. A method of treating urinary disorders in mammals, including humans, said method comprising administering a therapeutically effective amount of a composition according to any one of claims 1-15 to said mammals, including humans, in need of such treatment . 33. The method of treatment according to claim 32, wherein the disorder is lower urinary tract symptoms. 34. A method of treatment according to claim 32, wherein the disorder is unstable or overactive bladder. 35. The method of treatment according to claim 32, wherein the disorder is bladder outflow obstruction. 36. The method of treatment according to claim 32, wherein the disorder is urinary incontinence. 37. The method of treatment according to claim 36, wherein the disorder is stress urinary incontinence. 38. The method of treatment according to claim 32, wherein the disease is interstitial cystitis. 39. A method of treatment according to any one of claims 32-38, further for treating depression in the mammal which accompanies said urinary disorder. 40. A method of treatment according to any one of claims 32-39, wherein the composition is administered rectally, intravaginally, topically, orally, sublingually, intranasally, transdermally or parenterally. 41. The method of treatment according to any one of claims 32-40, wherein the first compound and the second compound of the composition are administered simultaneously. 42. A method of treatment according to any one of claims 32-40, wherein the first compound and the second compound of the composition are administered concomitantly. 43. A pharmaceutical kit for treating urinary diseases in mammals, including humans, said kit comprising (i) a first container comprising a first compound according to any one of claims 1-10, (ii) a second container comprising a second compound according to claim 1 or 12, and optionally (iii) Instructions for use of the kit.