EP2811989A1

EP2811989A1 - Combination of muscarinic receptor antagonists and beta- 3 adrenoceptor agonists for treating overactive bladder

Info

Publication number: EP2811989A1
Application number: EP13704702.3A
Authority: EP
Inventors: Stephen Caltabiano; Eliot Ohlstein; Stewart Mccallum
Original assignee: AltheRx Inc
Current assignee: Velicept Therapeutics Inc
Priority date: 2012-02-09
Filing date: 2013-02-08
Publication date: 2014-12-17
Also published as: KR20150020160A; IL234033A0; AR089957A1; AU2013216864A1; PH12014501814A1; HK1204966A1; TW201338772A; JP2015509931A; CA2864173A1; SG11201404776PA; CN104684549A; WO2013119910A1

Abstract

Pharmaceutical combinations comprising a beta-3 adrenergic receptor agonist and a muscarinic receptor antagonist, and methods for their use are disclosed. Methods of using the pharmaceutical combinations for the treatment of one or more symptoms associated with overactive bladder, for example, frequency of urgency, nocturia, and urinary incontinence, are also disclosed.

Description

COMBINATION OF MUSCARINIC RECEPTOR ANTAGONISTS AND BETA- 3 ADRENOCEPTOR AGONISTS

FOR TREATING OVERACTIVE BLADDER

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority of US Provisional Application

5 No, 61/596,893, filed on February 9, 2012. The present application also c!aims

priority to U.S. Application 13/196,068 filed on August 2, 2011 , which claims the benefit of priority of US Provisional Application 81/370,171 filed on August 3, 2010, The entire disclosures of all of the above applications are incorporated herein by reference.

10

FIELD OF THE INVENTION

The present invention relates to pharmaceutical combinations and methods for thei use. In particular, the invention relates to pharmaceutical combinations comprising a beta-3 adrenergic receptor agonist and a muscarinic acetylcholine receptor 15 antagonist (hereinafter referred to as "muscarinic receptor antagonist" or

"antimuscarinic"), and to methods of using such combinations in the treatment of one or more symptoms associated with overactive bladder, for example, frequency of urgency, frequency of mictruitions, nocturia, and urinary incontinence.

20 BACKGROUND OF THE INVENTION

The Internationa! Continence Society (ICS) has defined overactive bladder {OAB} as a symptom complex of urgency, with or without urge Incontinence, accompanied by frequency and nocturia. The symptoms of overactive bladder are usually associated with involuntary contractions of the detrusor (bladder) muscle thus creating a state of

25 bladder hyperactivity. GAB is commonly classified into subtypes including

neurogenic, idiopathic, and outlet obstruction. Neurogenic OAB is attributed to coexisting neurological conditions such as Parkinson's disease, multiple sclerosis, spinal cord injury or stroke. The underlying pathophysiology is the interruption of the otherwise orderly controi of micturition, resulting in the symptom complex described

30 above. The cause of idiopathic OAS is not as well defined; alterations in signalling

within the bladder have been implicated. Finally, OAB may be associated with anatomical changes in the lower urinary tract, for example, in patients with bladder outiet obstruction, which may be the result of an enlarged prostate gland.

Overall, the incidence of OAB increases with age. The ratio of men to women

35 affected depends on the age group, but in general women tend to be more affected

than men, OAB represents a significant quality of life burden to patients. t Muscarinic receptor antagonists {also known as antimuscarinics or anticholinergics) such as Detroi® LA (tolterodine), Ditropan XL® (oxybuiynin), and Vesicare® {solifen- acin succinate) currently represent the major pharmaco!ogica! options approved and marketed for the treatment of OA8, Antimuscarinics are believed to reduce bladder overactivity by inhibiting bladder smooth musc!e contractility. Physicians and patients remain unsatisfied with the current therapies and desire medicines with improved efficacy and toSerability, In particular there is an unaeceptabiy high incidence of side effects, including dry mouth and constipation associated with these medications. Also, current medications do not adequately treat urgency, one of the most bothersome symptoms of OAB.

Accordingly, there remains a need for new medicines and methods of treatment that offer improved efficacy and tolerabiSit in the treatment of symptoms associated with overactive bladder, above and beyond the currently available therapies, SUMMARY OF THE INVENTION

A method of treating one or more symptoms associated with overactive bladder using a new synergistic treatment combination has no been discovered. The treatment combination according to the invention comprises a beta-3 adrenergic receptor agonist and a muscarinic receptor antagonist. The inventors have shown that this combination has unexpectedly increased potency and efficacy, and is useful fo the treatment of one or more symptoms associated with OAS.

Accordingly, the invention encompasses treatment combinations comprising (i) a therapeutically effective amount of a beta~3 adrenergic receptor agonist, and (ii) a therapeutically effective amount, or a sub-therapeutica!iy effective amount, of a muscarinic receptor antagonist, the combination being useful for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components {i) and (ii). The symptoms associated with overactive bladder are selected from the group consisting of frequency of urgency, frequency of mictruitions, nocturia, and urinary incontinence. The invention also encompasses methods of treating one or more symptoms associated with overactive bladder in a mammal using (i) and (ii), either in a single dosage form or separately. Use of the combinations for the treatment of one or more symptoms associated with overactive bladder, use of the combinations in medical therapy, and use of the combinations in the preparation of a medicament fo the treatment of one or more symptoms associated with overactive bladder are also provided. The beia-3 adrenergic receptor agonist can comprise a compound selected from the group consisting of solabegron, CL-316,243, mirabegron, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceutically acceptable solvents thereof.

The muscarinic receptor antagonist can comprise a compound selected from the group consisting of oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceutically acceptable solvents thereof.

In a preferred embodiment the combination comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with

pharmaceutically acceptable solvent thereof ; and (it) a therapeutically effective amount, or a sub-therapeutica!!y effective amount of tolterodine, or a

pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sa!t solvated with pharmaceutically acceptable solvent thereof, the combination being useful for relieving one or more symptoms associated with overactive biadder (OAB) in a synergistic manner, versus the individual components (t) and (it).

Another aspect of the invention is directed to a method of treating one or more symptoms associated with overactive bladder in a mammal, comprising administering to the mamma! (i) a therapeutically effective amount of a beia-3 adrenergic receptor agonist; and (is) a therapeutically effective amount, or a sub-therapeutica!ly effective amount of a muscarinic receptor antagonist, in one embodiment of the method, the beta-3 adrenergic receptor agonist comprises a compound selected from the group consisting of solabegron, CL-316,243, mirabegron, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with

pharmaceutically acceptable solvents thereof. in a further embodiment of the method, the muscarinic receptor antagonist comprises oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable sails thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceutically acceptable solvents thereof. in a preferred embodiment, the method of treating one or more symptoms associated with overactive biadder in a mammal, comprises administering to the mammal (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptabie salt, or a pharmaceutically acceptabie solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof; and (is) a therapeuticai!y effective amount, or a sub-therapeutiea!!y effective amount of toiterodine, or a pharmaceutically acceptabie saSt, or a pharmaceutically acceptabie solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptabie solvent thereof. The method can comprise co-administration of components (i) and (it), in one embodiment components (i) and (ii) are contained in a single dosage form. In another embodiment, co-administration comprises administering together the separately formulated components (i) and (ii).

Th method can also comprise separate administration of components (i) and (it). When administered separately there can be a time delay between the administration of components (i) and (it). in a preferred embodiment, the salt of soSabegron comprises the hydrochloride salt.

Another embodiment is directed to a pharmaceutical composition comprising the combination of components (i) and (ii), and further comprising one or more pharmaceutically acceptabie carriers, diluents, or excipients.

A further embodiment is directed to a method of treating one or more symptoms associated with overactive bladder in a mammal, comprising the step of administering to a mammai in need thereof, a therapeuticai!y effective amount of the above-identified combination of components (i) and (ii), Another embodiment is directed to a method in which component (i) comprises solab (III)

Formula {III},

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows a graph of the Experimental protocol of Example 3.

Figure 2 shows the effects on EFS-induced contractions {% inhibition from basal) of various antimuscarinics in combination with various beia-3 adrenoceptor agonists.

Figure 3 displays the effects of various antimuscarinics on CL-316,243 inhibition of EFS-induced contractions of rat isolated urinary bladder.

Figure 4 displays the effects of antimuscarinics on CL-316,243 inhibition of EFS- induced contractions of rat isolated urinary bladder, including previous results. Figure 5 displays the effects of various antimuscarinics on solabegron inhibition of EFS-induced contractions of rat isolated urinary bladder.

Figure 6 displays the effects of various antimuscarinics on mirabegron inhibition of EFS-induced contractions of rat isolated urinary bladder.

Figure 7 shows E_ma and p!C_S0 vaiues of various beta-3 adrenoceptor agonists , either alone {vehicle) or in the presence of 1 QnM of various antimuscarinics.

Figure 8 shows E_max and SG₅₀ vaiues of various beta-3 adrenoceptor agonists , either atone (vehicle) or in the presence of iOnivi of various antimuscarinics.

DETAILED DESCRIPTION OF THE INVENTION

Unexpectedly, new synergistic drug combinations have been discovered which are useful in treating one or more symptoms associated with OAB. These combinations comprise (i) a beta-3 adrenergic receptor agonist, and (ii) a muscarinic receptor antagonist. It has been demonstrated that these combinations have surprisingly increased potency and efficacy, and are useful for the treatment of at least one symptom associated with OAB.

Accordingly, one embodiment of the invention encompasses treatment combinations comprising (i) a therapeutically effective amount of a beta-3 adrenergic receptor agonist, and (ii) a therapeutically effective amount, or a sub-therapeutica!iy effective amount, of a muscarinic receptor antagonist. A sub-therapeuticaiiy effective dose of the muscarinic antagonist can be used due to the synerg of the combination, !n particular, one embodiment encompasses a synergistic combination comprising: (!) a therapeutical iy effective amount of a beta-3 adrenergic receptor agonist; and (ii) a therapeutically effective amount, or a sub-therapeuticaiiy effective amount, of a muscarinic receptor antagonist,

the combination being useful for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (i) and (ii).

A further embodiment encompasses a method of treating one or more symptoms associated with OAS in a mammal comprising administering to the mammal:

(i) a therapeutical iy effective amount of a beta-3 adrenergic receptor agonist; and

(it) a therapeutically effective amount, or a sub-therapeuticaiiy effective amount, of a muscarinic receptor antagonist,

wherein the administration of the combination of both (i) and {is) is effective for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (i) and (ii).

Thus, in one embodiment, the combinations of (i) and (ii) can be used for the treatment of one or more symptoms associated with overactive bladder. In another embodiment the combinations of (i) and (ii) can be used in medicai therapy. In a further embodiment the combinations of (i) and (ii) can be used in the preparation of a medicament for the treatment of one or more symptoms associated with OAB. in a further embodiment, the compounds (i) and (ii), or pharmaceutical preparations containing them, can be administered separately, with or without a time delay, for the treatment of one or more symptoms associated with OAB.

As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent, or that amount of a combination of drugs or pharmaceutical agents that will elicit the bio!ogical or medicai response of a tissue, system, animai or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeuticaily effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder, as was known in the art as of the date of the present invention. The term also includes within its scope amounts effective to enhance norma! physiological function, as was known in the art as of the date of the present invention.

Accordingly, the term "sub-therapeuticaly effective amount" indicates any amount of the muscarinic receptor antagonist which is not therapeutically effective or is minimally therapeutically effective alone, as was known in the art as of the date of the present invention, but which in combination with a therapeutically effective amount of the beta-3 adrenergic receptor agonist, demonstrates a synergistic therapeutic effect. In particular embodiments of the presently claimed combinations and methods, a lower dose (sub-therapeutic dose) of the antimuscarinic agent can be used to produce superior efficacy of the combination due to the synergy of the two compounds, while avoiding or minimizing the side effects of the antimuscarinic agent In a further embodiment of the invention, either the beta~3 adrenergic receptor agonist or the muscarinic receptor antagonist, or both, can be combined in sub- therapeutically effective amounts, as defined in the art for the single agents as of the date of the present invention, and still provide a therapeutically useful combination because of the synergistic therapeutic effect of the drug combination. As used herein, the terms "synergy" and "synergistic", or the phrase "in a synergistic manner", refer to the interaction of two or more drugs in vitro or in vivo so that their combined effect when administered together is greater than the sum of the effects observed when eac is administered individually. That is, the effect of administering the combination of (i) and (ii) as defined above, is greater than the sum of the effects of administering (i) alone and (ii) alone at their prescribed doses.

One aspect the invention encompasses a method of treating one or more symptoms associated with OAS, comprising administering:

(j) a therapeutically effective amount of a beia-3 adrenergic receptor agonist of Formuia {!),

Formula (I)

or pharmaceutically acceptable sails (for example, the hydrochloride salt),

pharmaceutically acceptable solvates, or pharmaceutically acceptable salts so!vated with pharmaceutically acceptable solvents thereof; and

(ii) a therapeutically effective amount, or a sub-therapeutically effective amount, of a muscarinic receptor

Formula (ft)

o pharmaceuiicaiiy acceptabie salts, pharmaceutically acceptabie solvates, or pharmaceutically acceptabie salts soivated with pharmaceuiicaiiy acceptable solvents thereof.

The compound of Formula (!) has the chemicai name 3'~[(2-{[(2R)-2-(3-chlorophenyl)- 2-hydroxyethy!]amino}ethyi)-amino3-[1 ,1 ^!-biphenyl|-3-carboxyiic acid, and is known as soiabegron, Soiabegron can be administered as a salt, which can be anhydrous, h yd rated, or soivated with a pharmaceuiicaiiy acceptable solvent such as ethanol. In a particular embodiment, soiabegron is administered as the hydrochloride salt. In a preferred embodiment, soiabegron hydrochloride is the anhydrous hydrochloride salt.

The free base, and pharmaceutically acceptable salts, for example, the hydrochloride salt, of soiabegron (Formula (I)) can be prepared, for example, according to the procedures disclosed in international Patent Appiication No. PCT/EP99/03958, filed June 9, 1999, and published as WO 99/65877 on December 23, 1999; International Patent Application No. PCT/G800/04697, filed December 8, 2000 and published as WO 01/42195 on June 14, 2001 ; and international Patent Application No.

S PCT/US01/49355, filed December 17, 2001 and published as WO2006/113649 on August 29, 2002.

in a further embodiment of the invention, when component (i) is solabegron, if can also comprise the primary active human metabolite of solabegron, shown as Formula (il l):

Formuia (III).

The compound of Formuia (11) has the generic name oxybutynin. The chemicai name of the compound of Formuia (II) is 4 iiethylam!nobut-2-ynyi 2-cyclohexyl-2-hydroxy- 2-phenyl-ethanoate also known as 4-{diethy!amino)-2-butynyk.t-cyclohexyi-a~ hydroxybenzeneacetate, also known as 4-(diethyiamino)-2-butyn-1-y!-cycio-hexy!- (hydroxy)phenylacetate. The compound of Formula (II) may be prepared, for example, according to the procedures provided in UK Patent Specification No. GB940.540, filed July 25, 1961 , and published on October 30, 1963. The (S) enanttomer of oxybutynin may be prepared according to the procedures in EP 0806948 B1. The ( )-enantiomer of oxybutynin may be prepared according to the procedures in US6, 123,961. Oxybutynin has been proven to be safe and effective in treating patients with overactive bladder and is marketed globaily, although side effects are known, vide supra.

In a further embodiment, the invention also encompasses compositions, methods and uses comprising other or additional beta-3 adrenergic receptor agonists, for example, and without limitation, those as taught in international Patent Application No, PCT/EP99/03958, filed June 9, 1999, and published as WO 1999/65877 on December 23, 1999, or for exampie, Amibegron (SR-58611 , Sanofi-Avenfis), ritobegron (KUC-7483, Kisses), KRP 204 (N-5984, Kyorin), GS-332 (Mitsubishi Tanabe), YM-178 (Astellas), or the compounds disc!osed in US 2011/0028481., published February 3, 2011 (Merck), or those disclosed in US 2012/0157432, published June 21 , 2012, now US Patent no. 8, 354,403, published January 15, 2013 (Merck), or those taught in International Patent Publication WO 2009/124167, published October 10, 2009 (Merck), or those disclosed in international Patent Publication WO 201 1/025690, published March 3, 201 1 (Merck). One ciass of other or additional beta-3 adrenergic receptor agonists is represented by the generic structure

as disclosed in the Merck patents and patent publications listed above. One specific compound has the structure

All of the above-mentioned patents and patent applications are incorporated herein by reference in their entireties.

In a further embodiment, suitable muscarinic receptor antagonists other than oxybutynin can also be used according to the present invention. Such anttmuscarinics include but are not limited to toiterodine, soiifenacin, trospium, darifenacin, propiverine, and fesoterodine.

Accordingly, the invention encompasses treatment combinations comprising (t) a therapeutically effective amount of a beta-3 adrenergic receptor agonist, and (ii) a therapeutically effective amount, or a sub-therapeuticaiSy effective amount of a muscarinic receptor antagonist, the combination being useful for relieving one or more symptoms associated with overactive bladder (OAS) in a synergistic manner, versus the individual components (i) and (ii). The symptoms associated with overactive bladder include, without limitation, frequency of urgency, frequency of mictruiiions, nocturia, and urinary incontinence. The combinations of (i) and (ii) of the present invention may be used to treat various combinations of symptoms associated with OAS, Such combinations of OAS symptoms can include, without limitation:

frequency of urgency and nocturia; or

frequency of urgency and urinary incontinence; or

nocturia and urinary incontinence; or

frequency of urgency and nocturia and urinary incontinence; or

frequency of mictruitions and nocturia; or

frequency of mictruitions and frequency of urgency; or

frequency of mictruitions and urinar incontinence; or

frequency of mictruitions and frequency of urgency and nocturia; or

frequency of mictruitions and frequency of urgency and urinary incontinence; or frequency of mictruitions and nocturia and urinary incontinence; or

frequency of mictruitions and nocturia and urinary incontinence and frequency of urgency.

The invention also encompasses methods of treating one or more symptoms associated with overactive bladder in a mamma! using (i) and (it), either in a single dosage form or separately. Use of the combinations for the treatment of one or more symptoms associated with overactive bladder, use of the combinations in medical therapy, and use of the combinations in the preparation of a medicament for the treatment of one or more symptoms associated with overactive bladder are also embodiments of the present invention.

In one embodiment of the invention, the beta-3 adrenergic receptor agonist comprises a compound selected from the group consisting of soiabegron, CL- 316,243, mirabegron, pharmaceutically acceptable sa!is thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts so!vated with pharmaceutically acceptable solvents thereof. In a preferred embodiment, the beta-3 adrenergic receptor agonist comprises soiabegron, in a total daily oral dose of about SO to about 800 mg, preferably about 100 to about 500 mg, more preferably about 200 to about 400 mg. In another preferred embodiment, the beta-3 adrenergic receptor agonist comprises mirabegron, in a total daily oral dose of about 25 to about 200 mg, preferably about 25 to about 100 mg, more preferably about 25 to about 50 mg. In yet another preferred embodiment, the beta-3 adrenergic receptor agonist comprises CL-316,243, in a total daily oral dose of about 0.5 to about 500 mg, preferably about 1 to about 100 mg, more preferably about 5 to about 50 mg. These drugs may be administered bis in die (BID), that is, twice daily.

In one embodiment of the invention, the muscarinic receptor antagonist comprises a compound selected from the group consisting of oxybutynin, tolterodine, sofifenacin, pharmaceutically acceptabie sa!is thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceutically acceptabie solvents thereof, in a preferred embodiment, the muscarinic receptor antagonist comprises oxybutynin, in a total daly oral dose of about 1 to about 40 mg, preferably about 1 to about 20 mg, more preferably about 2.5 to about 10 mg. in another preferred embodiment, the muscarinic receptor antagonist comprises to!terodine, in a total dally oral dose of about 1 to about 10 mg, preferably about 1 to about 8 mg, more preferably about 1 to about 4 mg. In still another preferred embodiment, the muscarinic receptor antagonist comprises solifenacin, in a total daily oral dose of about 1 to about 20 mg, preferably about 2.5 to about 15 mg, more preferably about 2.5 to about 0 mg. These drugs may be administered bis in die, that is, twice daily.

in one preferred embodiment the combination comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, o a pharmaceutically acceptable salt solvated with pharmaceutically acceptabie solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticaliy effective amount of tolterodine, or a

pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptable solvent thereof, the combination being useful for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (t) and (it).

In another preferred embodiment the combination comprises (!) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutical !y acceptable solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticaliy effective amount of oxybutynin. or a

pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptable solvent thereof, the combination being usefui for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (Ϊ) and (ii).

In another preferred embodiment the combination comprises (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptabie solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeutically effective amount of soiifenacin, or a

pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptabie solvent thereof, the combination being useful for relieving one or more symptoms associated with overactive bladder (OAS) in a synergistic manner, versus the individual components (i) and (it).

In one preferred embodiment the combination comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptabie salt, or a pharmaceutically acceptabie solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeutically effective amount of tolterodine, or a

pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptabie solvent thereof, the combination being usefui for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (i) and (ii).

In another preferred embodiment the combination comprises (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof; and (ii) a therapeutically effective amount or a sub-therapeutically effective amount of oxybutynin, or a

pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof, the combination being usefui for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (I) and (ii).

in another preferred embodiment the combinaiion comprises (i) a therapeutically effective amount of miragebron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceuticall acceptabie salt solvated with pharmaceutically acceptable solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeutical!y effective amount of soiifenacin, or a

pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptable solvent thereof, the combination being usefui for relieving one or more symptoms associated with overactive bladder (OAS) in a synergistic manner, versus the indi vidua! components (t) and (it). in one preferred embodiment the combination comprises (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable sait, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sait solvated with pharmaceutically acceptable soivent thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticaliy effective amount of tolterodine, or a

pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptabie solvent thereof, the combination being usefu! for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (i) and (ii).

in another preferred embodiment the combination comprises (i) a therapeutically effective amount of 01-316,243, or a pharmaceutically acceptabie salt, or a pharmaceutically acceptabSe solvate, or a pharmaceutically acceptable sait solvated with pharmaceutically acceptable solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticaliy effective amount of oxybutynin, or a

pharmaceutically acceptabie sait, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie sait solvated with pharmaceutically acceptable solvent thereof, the combination being useful for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (t) and (ii).

In another preferred embodiment the combination comprises (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie sait solvated with pharmaceutically acceptable soivent thereof; and (ii) a therapeutieaiiy effective amount, or a sub-therapeuticaliy effective amount of soiifenacin, or a

pharmaceuticall acceptabie salt, or a pharmaceutically acceptabie soivate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptabie solvent thereof, the combination being usefu! for relieving one or more symptoms associated with overactive bladder (OAB) in a synergistic manner, versus the individual components (i) and (ii). Another aspect of the invention is directed to a method of treating one or more symptoms associated with overactive biadder in a mammal, comprising administering to the mammai (i) a therapeutically effective amount of a beta-3 adrenergic receptor agonist; and (ti) a therapeutically effective amount, or a sub-therapeutieaiiy effective amount of a muscarinic receptor antagonist. in one embodiment of the method, the beta-3 adrenergic receptor agonist comprises a compound selected from the group consisting of solabegron, Cl-316,243, mirabegron, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable saits solvated with

pharmaceutically acceptable solvents thereof, in a preferred embodiment, the beta-3 adrenergic receptor agonist comprises solabegron, in a total daily orai dose of about 50 to about 800 mg, preferably about 100 to about 500 mg, more preferably about 200 to about 400 mg. In another preferred embodiment, the beta-3 adrenergic receptor agonist comprises mirabegron, n a total daily oral dose of about 25 to about 200 mg, preferably about 25 to about 00 mg, more preferably about 25 to about 50 mg, in yet another preferred embodiment, the beta-3 adrenergic receptor agonist comprises CL-316,243, in a total daily oral dose of about 0.5 to about 500 mg, preferably about 1 to about 100 mg, more preferably about 5 to about 50 mg. These drugs may be administered bis in die {BID), that is, twice daily, in a further embodiment of the method, the muscarinic receptor antagonist comprises Qxybutynin, tolterodine, soiifenacin, pharmaceutically acceptable saits thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceutically acceptable solvents thereof, in a preferred embodiment, the muscarinic receptor antagonist comprises oxybutynin, in a total dail oral dose of about 1 to about 40 mg, preferably about 1 to about 20 mg, more preferably about 2.5 to about 10 mg. In another preferred embodiment, the muscarinic receptor antagonist comprises tolterodine, in a total daily oral dose of about 1 to about 10 mg, preferably about 1 to about 8 mg, more preferably about 1 to about 4 mg. In stil! another preferred embodiment, the muscarinic receptor antagonist comprises soiifenacin, in a totai daily orai dose of about 1 to about 20 mg, preferably about 2.5 to about 15 mg, more preferably about 2.5 to about 10 mg. These drugs may be administered bis in die, that is, twice daily.

In a preferred embodiment, the method of treating one or more symptoms associated with overactive biadder in a mammal, comprises administering to the mammai {■} a therapeutically effective amount of solabegron, or a pharmaceuticaily acceptabie sail, or a pharmaceutically acceptabie solvate, or a pharmaceutically acceptable salt soivated with pharmaceuticaily acceptable soiverst thereof; and (ii) a therapeutically effective amount, or a sub-therapeutica!!y effective amount of tolterodine, or a pharmaceutically acceptable sait, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sait soivated with pharmaceuticaily acceptable solvent thereof. in another preferred embodiment, the method of treating one or more symptoms associated with overactive bladder in a mamma!, comprises administering to the mammal (i) a therapeutically effective amount of solabegron, or a pharmaceutically acceptable sait, or a pharmaceuticaily acceptabie solvate, or a pharmaceutically acceptabie sait soivated with pharmaceutical iy acceptabie sol vent thereof; and (it) a therapeutically effective amount, or a sub-therapeuticaiiy effective amount of oxybutynin, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie sait soivated with pharmaceutically acceptabie solvent thereof. in another preferred embodiment, the method of treating one or more symptoms associated with overactive bladder in a mamma!, comprises administering to the mammal (i) a therapeutically effective amount of solabegron, or a pharmaceuticali acceptabie sait, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt soivated with pharmaceutically acceptabie solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticaiiy effective amount of solifenacin, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sait soivated with pharmaceutically acceptabie solvent thereof. in a preferred embodiment, the method of treating one or more symptoms associated with overactive bladder in a mammal, comprises administering to the mammal {i} a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceuticaily acceptabie salt soivated with pharmaceutically acceptable solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticaiiy effective amount of tolterodine, or a pharmaceuticaliy acceptable sait, or a pharmaceuticaily acceptabie solvate, or a pharmaceutically acceptabie salt soivated with pharmaceutically acceptabie solvent thereof, in another preferred embodiment, the method of treating one or more symptoms associated with overactive bladder in a mammal, comprises administering to the mammal (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt, or a pharmaceuticaily acceptable solvate, or a pharmaceutica!iy 5 acceptable salt solvated with pharmaceutically acceptable solvent thereof: and (it) a therapeuticai!y effective amount, or a sub-iherapeutically effective amount of oxybutyria or a pharmaceuticaily acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof.

10 In another preferred embodiment, the method of treating one or more symptoms associated with overactive bladder in a mammal, comprises administering to the mammal (i) a therapeutically effective amount of mirabegron, or a pharmaceutically acceptable salt, or a pharmaceuticaily acceptable solvate, or a pharmaceuticaily acceptable salt solvated with pharmaceuticaliy acceptable solvent thereof; and {«) a

I S therapeutically effective amount, o a sub-therapeutieai!y effective amount of solifenacin, or a pharmaceuticaily acceptable salt, or a pharmaceuticaliy acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceuticail acceptable solvent thereof.

In a preferred embodiment, the method of treating one or more symptoms associated 0 with overactive bladder in a mammal, comprises administering to the mammal (i) a therapeutically effective amount of CL-316,243, or a pharmaceuticaliy acceptable salt, or a pharmaceuticaily acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceuticaily acceptable solvent thereof; and (it) a therapeutically effective amount, or a sub-therapeutically effective amount of tolterodine, or a 5 pharmaceuticaliy acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof.

In another preferred embodiment, the method of treating one or more symptoms associated with overactive bladder in a mammal, comprises administering to the 0 mammal (i) a therapeutically effective amount of CL-316,243, or a pharmaceuticaliy acceptable sa!t, or a pharmaceuticaliy acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceuticaily acceptable solvent thereof; and (it) a therapeutically effective amount, or a sub-therapeuticaliy effective amount of oxybutynin, or a pharmaceuticali acceptable salt, or a pharmaceuticaliy acceptable solvate, or a pharmaceutically acceptabie sa!t solvated with pharmaceutically acceptable solvent thereof.

In another preferred embodiment, the method of treating one or more symptoms associated with overactive b!adder in a mamma!, comprises administering to the mammal (i) a therapeutically effective amount of CL-316,243, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticai!y effective amount of solifenacin, or a pharmaceuticaly acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sa!t solvated with pharmaceutically acceptabl solvent thereof.

The methods can comprise co-administration of components (i) and (ii). In one embodiment, components (!) and (ii) are contained in a single or unitary dosage form, in another embodiment, co-administration comprises administering together the separately formulated components (i) and (ii).

The method can also comprise separate administration of components (i) and (ii). When administered separately there can be a time delay between the administration of components (i) and (ii), in one preferred embodiment, the sa!t of so!abegron comprises the hydrochloride salt.

Another embodiment is directed to a pharmaceutical composition comprising the combination of components (i) and (ii), and further comprising one or more pharmaceutically acceptabie carriers, diluents or excipienis. One preferred pharmaceutical composition comprises {i} so!abegron, or a pharmaceutically acceptabie salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptabie solvent thereof, (ii) to!terodine, or a pharmaceutically acceptable sa!t, or a pharmaceutically acceptabie solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptabie solvent thereof, and (lit) one or more pharmaceutically acceptable carriers, diluents or excipienis. Another preferred pharmaceutical composition comprises (i) miragebron, or a pharmaceutically acceptable salt, o a

pharmaceutically acceptable solvate, or a pharmaceutically acceptabie salt solvated with pharmaceutically acceptable solvent thereof, (ii) tolterodine, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sa!t so!vated with pharmaceutically acceptable solvent thereof, and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Another preferred pharmaceutical composition comprises (i) soiabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof, {») oxybutynin, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with

pharmaceutically acceptable solvent thereof, and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Yet another preferred pharmaceutical composition comprises (i) miragebron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof, (ii) oxybutynin, or a

pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof, and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Another preferred pharmaceutical composition comprises (i) soiabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof, (ii) solifenacin, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with

pharmaceutically acceptable solvent thereof, and (iii) one or more pharmaceutically acceptable carriers, diluents or excipients. Still another preferred pharmaceutical composition comprises ø) miragebron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof, (ii) solifenacin, or a

pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof, and (iii) one or more pharmaceutically acceptable carriers, diluents or exciptents,

A further embodiment is directed to a method of treating one or more symptoms associated with overactive bladder in a mammal, comprising the step of administering to a mammal in need thereof, a therapeutically effective amount of the above-identified combination of components (i) and (it), or a pharmaceutical composition thereof. Another embodiment the method of treatment is directed to a method comprising solabegron, wherein component (i) further comprises the primary in vivo metabolite of sol

Formula (fit). it is understood that certain embodiments of the invention encompass the use of pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable salts so!vated with pharmaceutically acceptable solvents, of components ø} and (ii). As used herein, the term "solvate"^' or "salt solvated", refers to a complex of variable sioichiometry formed by a solute (in this invention, compounds of Formulae (!) o (ii) (or a salt thereof)) and a solvent. For the purpose of the present invention, such solvents may not interfere with the biological activity of the soiute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. In a preferred embodiment, the solvent is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid, in a more preferred embodiment, the solvent is water, providing a "hydrate".

The beia-3 adrenergic receptor agonist and muscarinic receptor antagonist may be employed in combination by administration concomitantly in (1 ) a unitar pharmaceutical composition including both compounds {singie dosage form) or (2) separate pharmaceutical compositions, where each composition includes one of the compounds. Alternatively, the combination may encompass the separate administration of the compounds in a sequential manner where, for example, either the beta-3 adrenergic receptor agonist or the muscarinic receptor antagonist is administered first and the other compound is administered second. Such sequential administration may be close in time or remote in time, thai is, with a time delay.

Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to nontoxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition sa!ts derived from a nitrogen on a subststuent in a compound of the present invention. Representative pharmaceuticaiiy acceptable salts include the following; acetate, benzenesulfonate, benzoate, bicarbonate, bisuifate, bitartrate, borate, bromide, caicium edetate, camsyiate, carbonate, chloride, clavulanate, citrate, dihydroch!oride, edetate, edisy!ate, estoiafe, esyiate, fumarate, giuceptate, gluconate, giutamaie, giyco!iylarsaniiate, hexyl-resorcinate, hydrabamine, hydrabromide, hydrochloride, hydroxy naphthoate, iodide, isetbionate, lactate, iactobionate, iaurate, malate, ma!eate, mande!ate, mesylate, methyibromide, methy!nitrate, methylsuifate, monopotassium mafeate, mucate, napsy!ate, nitrate, N~ methylglucamine, oxalate, pamoate (embonate), paimitate, pantothenate, phosphate/diphosphate, poiygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, fannate, tartrate, teoc!ate, tosyiate, triethiodide, trimethylammonium and valerate. Other salts, which are not pharma-ceuticaiiy acceptable, may also be usefui in the preparation of compounds of this invention, and these form a further aspec of the invention.

While it is possible that, for use in medical therapy, the beta-3 adrenergic receptor agonist, muscarinic receptor antagonist, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, or pharmaceutically acceptable saits soivated with pharmaceutically acceptable solvents thereof, may be administered as the chemicai compound itself, the active ingredient or ingredients may also be administered formulated as a pharmaceutical composition. Accordingly, the invention further provides pharmaceutical compositions, which include therapeutically effective amounts of the beta-3 adrenergic receptor agonist, and therapeuticai!y effective amounts, or sub-therapeutical!y effective amounts, of the muscarinic receptor antagonist, or pharmaceutically acceptable saits, pharmaceuticaii acceptable solvates, or pharmaceutically acceptable saits soivated with pharmaceuticaiiy acceptabie solvents thereof, and one or more pharmaceuticaiiy acceptable carriers, diluents, or exctpients. The carriers), diluent(s) or excipient{s) must be acceptabie in the sense of being compatible with the other ingredients of the formulation, capable of pharmaceutical formulation, and not deleterious to the recipient thereof. The invention aiso provides a process for the preparation of a pharmaceutical formulation including admixing the beta-3 adrenergic receptor agonist, muscarinic receptor antagonist or pharmaceutic-a!ly acceptable salts, solvates, soivated pharmaceuticaiiy acceptable saits thereof, with one or more pharmaceuiicaliy acceptabie carriers, diluents or excipients. Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. As is known to those skilled in the art, the amount of active ingredient per dose vviii depend on the condition being treated, the route of administration and the age, weight and condition of the patient, or the pharmaceutical formuiations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Preferred unit dosage formulations are those containing a daily dose or sub-dose, or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formuiations may be prepared by any of the methods well known in the pharmacy art.

The beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist may be administered by any appropriate route. Suitable routes include oral rectal, nasal, and parenteral (including intravesical, subcutaneous, intramuscular, intraveneous, transdermal, intradermai, intrathecal, and epidural). Administration can also be by means of a bladder pump or sustained release in the bladder.

It will be appreciated that the preferred route may vary with, for example, the condition of the recipient of the combination. It will also be appreciated that each of the agents administered may be administered by the same or different routes and that the beta-3 adrenergic receptor agonist and muscarinic receptor antagonist may be compounded together in a pharmaceutical composition/formulation.

The method of the present invention may aiso be employed with other therapeutic methods of treating one or more symptoms associated with overactive bladder. Combination therapies according to the present invention thus include the administration of the beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist as well as optional use of other therapeutic agents including other beta-3 adrenergic receptor agonists and/or muscarinic receptor antagonists. Such combination of agents may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order, both close and remote in time. The amounts of the compounds of the beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist and the other optional pharmaceutically active agent(s and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.

99 Further, the combinations and methods of the present invention can comprise isotopes of components (i) and/or (is), that is, the beta-3 adrenergic receptor agonists and/or muscarinic receptor antagonists are isotopicai!y labeled, in one embodiment, the isotopicaiiy labeled compound has one or more hydrogen atoms replaced with either deuterium or tritium. In another embodiment, the isotopicaiiy iabeled compound has one or more carbon atoms replaced with ^{, ?}C, ^!SC or ^UC, in one preferred embodiment, the beta-3 adrenergic receptor agonist comprises deuterated solabegron.

Pharmaceutical formulations adapted for orai administration may be presented as discrete units such as capsules or tabiets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edib e foams or whips; or oii-in- water liquid emulsions or water-tn-oi! liquid emuisions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutical acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present. Capsuies are made by preparing a powder mixture as described above, and fii!ing formed geiatin sheaths, Giidants and lubricants such as colloidai silica, taic, magnesium stearate, calcium stearate or solid polyethylene giycof can be added to the powder mixture before the filling operation. A disintegrating or solubiiizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be used in granulating. The powder mixture can be run through a tablet machine, and if the result is imperfectly formed slugs, they can be broken into granuies, and the granuies can be lubricated and incorpo-rated back into the mixture. Suitable binders include starch, geiatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylce!iuiose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets, A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethyl-cei!ulose, an aliginate, geiatin, or polyvinyl pyrro!idone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicaicium phosphate. The powder mixture can be granulated b wetting with a binder such as syrup, starch paste, acadia muciiage or solutions of ce!luiosic or polymeric materials and forcing through a screen. As an alternative to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can a!so be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of sheliac, a coating of sugar or polymeric materia! and a polish coating of wax can be provided, Dyestuffs can be added to these coatings to distinguish different unit dosages. Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous soiution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated b dispersing the compound in a non-toxic vehicle. Sofubitizers and emu!sifiers such as ethoxy!ated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for orai administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example, by coating or embedding particulate material in polymers, waxes or the like.

The agents for use according to the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicies and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylatnine or phosphatidylcholines.

Agents for use according to the present invention may aiso be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds may also be coupled with soluble polymers as targefable drug carriers. Such polymers can include, without limitation, polyvinylpyrrolidone, pyran copolymer, poiyhydroxy propy Imethacryla m ide- phenol , poi hydroxyethy!aspart- amide-phenol, or poiyeihy!eneoxidepo!yiysine substituted with paSmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon capro!actone, poiyhydroxy butyric acid, poiyorthoesters, po!yacetals, pofydihydropyrans, polycyanoacrylates and cross-linked or amphipafhie block copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1988).

Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostais and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which ma include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, fo example, water for injections, immediately prio to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. it should be understood that in addition to the ingredients particuSarSy mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question: for example, those suitable for oral administration may include flavoring agents.

Also contemplated in the present invention is a pharmaceutical combination including the beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist, !n another embodiment, the pharmaceutical combination includes the beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist and optionally at least one additional beia-3 adrenergic receptor agonist or muscarinic receptor antagonist. The beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist and the additional beta-3 adrenergic receptor agonist or muscarinic receptor antagonist are as described hereinabove.

Therapeutically effective amounts of the beta-3 adrenergic receptor agonist, and therapeutically effective amounts, or sub-therapeuticaily effective amounts of the muscarinic receptor antagonist, and optionally additional beta-3 adrenergic receptor agonist or muscarinic receptor antagonist are administered to a mammal. Typically, the therapeutically effective amount of one of the administered agents of the present invention will depend upon a number of factors including, for example, the age and weight of the mammal, the precise condition requiring treatment, the severity of the condition, the nature of the formulation, and the route of administration. Ultimately, the therapeuticaiiy effective amount vvili be at the discretion of the attendant physician or veterinarian. Further, a lower dose (sub-therapeutic dose) of the antimuscarinic agent can be administered to provide superior efficacy of the combination while controlling the side effects of the antimuscarinic agent.

The invention encompasses the treatment of any condition that is susceptible to agonism of the beta-3 adrenergic receptor or antagonism of the muscarinic receptor, or a condition that is susceptible to both agonism of the beta-3 adrenergic receptor and antagonism of the muscarinic receptor.

Although not wishing to be bound by any particular theory, it is believed that befa-3 adrenergic receptor agonists, such as solabegron, exert an effect by binding to beta- 3 adrenergic receptors, resulting in relaxation of bladder smooth muscle. It is believed that muscarinic receptor antagonists, such as oxybutynin, act via blockade of parasympathetic nerve mediated bladder contraction. That drugs affecting these two different mechanisms of action should provide a synergistic effect, was heretofore both unknown and unexpected. Exampies of conditions associated with over-activity of smooth muscle which are suitable for treatment using a combination comprising the beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist of the present invention include OAB, gastrointestinal syndromes such as irritable bowel syndrome (IBS), inflammatory bowel disease (!BD), ulcerative colitis, and the like. The pharmaceutical combination of the present invention may therefore be effective in the treatment of such conditions, Beta-3 adrenergic receptors have also been found in cardiac tissue. The pharmaceutical combination of the present invention may therefore be effective in the treatment of cardiovascular disease. The following exampies are intended to be illustrative of particular embodiments of the invention, and are not intended to limit the scope of the invention in any way.

EXAMPLES

As used herein the symbols and conventions used in these processes, schemes and exampies are consistent with those used in the contemporary scientific literature, for example, the Journal of the Amencan Chemical Society and the Journal of Biotogicai Chemistry. Unless otherwise noted, al! starting materials were obtained from commercial suppliers and used without further purification, Speclfica!ly, the following abbreviations may be used in the exampies and throughout the specification;

BID twice daily

ECG Electrocardiogram

g (grams) mg (milligrams)

iR immediate release

L (liters) mL (milliters)

pi (microliters) moi (moies)

M (molar) mM (miiiimolar)

N (Norma!) Kg (kiiogram)

mmol (miilimoies) RT (room temperature)

min (minutes) h (hours)

QID four times daily

XL extended release

Example 1 , Drug Interaction Study with healthy human subjects

A drug interaction study was conducted in healthy human volunteers, using repeat orai doses of solabegron and oxybutynin administered singly as well as in combination with each other, in order to assess the effects on pharmacokinetic and pharmacodynamic parameters, as measured by post void residua! (PVR) volumes. PVR was measured in subjects treated with each agent alone as well as in combination at steady-state.

The study was a two-cohort randomized, open Iabei, repeat dose, 3-way crossover study in healthy adult subjects. Two marketed formulations of oxybutynin were used in the study: i) Ditropan !R®, which is immediate release OR) oxybutynin; and ii) Ditropan XL® which is extended release (XL) oxybutynin. The total daily dose given was 20 mg. Soiabegron was administered as tablets, Details of the soiabegron tablet composition used are provided in Table 1 (composition A).

The first cohort (n=14 subjects) was given soiabegro 2QQ mg BID {100 mgx2) aione fo 5 days, this was followed in the second period by oxybutynin IR 5 mg QID alone for 5 days, and in the final dosing period a combination of soiabegron 200mg BID {100 mg x 2) with oxybutynin IR 5 mg QID was administered for a period of 5 days.

A second cohort (n=12 subjects) was given soiabegron 200 mg BID (100 mg x 2) alone for 5 days, this was followed in the second period by oxybutynin XL 10 mg 8!D alone for 5 days, and in the final dosing period a combination of soiabegron 200 mg BID (100 mg x 2) with oxybutynin XL 10mg BID was administered for a 5 day period.

Each study session was separated by a washout period of at least 5 days. Safety assessments included vita! signs, ambulatory blood pressure monitoring (ABPW) physical examinations, clinical laboratory safety tests, 12~lead ECGs, PVR volume, to assess the potential for urinary retention, and adverse events. PVR was also utilized as a biomarker of bladder smooth muscle relaxation to determine if soiabegron combined with oxybutynin had a greater effect on relaxation than either compound alone in healthy subjects.

Finally, blood samples were collected for pharmacokinetic analysis of piasma concentrations of, as appropriate;

-soiabegron and its primary active metabolite as shown hereinbelow;

-R-oxybutynin, S-oxybutynin and the metabolites R-desethyl oxybutynin and S- desethyi oxybutynin as shown hereinbelow.

Primary active metabolite of soiabegron, Formula (III):

Formula (III)

Primary active metabolite of oxybutynin is desethy!oxybutynin, Formu!a (SV):

Formula (IV)

So!abegron Tablet Composition A

Composition A was prepared by the blending and wet granulation of ingredients (a) through (e), Table 1 , in a suitable high shear mixer/granuiator. Ingredients f) through (h) were added to the dried granulation, b!ended and compressed. Compressed tablets were covered with an aqueous fiim coat.

Tabie 1. Composition A

100 mg after correction for purity and salt/base conversion. Results of the Drug interaction Study - PVR Voiume

Bladder ultrasound scans to measure PVR volumes were conducted on Day-1 (one day prior to the dosing period) and Day 6 (sixth day of the dosing period) of each study session . Subjects dosed with soiabegron alone or oxybutynin IR aione showed a mean increase from baseline of 4.4 ml and 45.7 mL in PVR volume respectively, while subjects dosed with the combination of soiabegron and oxybuiynin !R unexpectedly showed a mean increase from baseline of 73.8 mL. Subjects dosed with oxybuiynin XL aione showed a mean increase from baseline of 20.2 ml in PVR voiume while subjects dosed with the combination of soiabegron and oxybutynin XL unexpectedly showed a mean increase from baseline of 50.8 ml in PVR volume. These data are summarised in Tabie 2.

Table 2. PVR data

These data indicate that in healthy subjects, soiabegron given alone showed minimal changes in PVR volumes and oxybutynin IR or XL given aione showed modest changes in PVR volume, but soiabegron and either oxybutynin IR or oxybutynin XL given in combination showed greater increases in PVR voiumes in each case than is expected from an additive effect of the two active ingredients. When oxybutynin IR is used as the antimuscarinic, the PVR of the combination treatment is 79.8 mL versus 50.1 mL for the PVR sum of the individually administered drugs. Similarly, when oxybutynin XL is used as the antimuscarinic, the PVR of the combination treatment is 50.8 mL versus 24.8 mL for the PVR sum of the individually administered drugs. The tatter comparison shows an increase of over 100% for the combination treatment versus the individual treatments.

This is interpreted as evidence of pharmacological synergism in the combination treatment, which indicates increased efficacy in treating one or more of the symptoms of OAS, since retaining more fluid in the PVR test indicates that the bladder muscles are more relaxed, thereby increasing bladder capacity.

Example 2. Effects of the Combination of Beta-Adreooceptor Agonists and Antimuscarimcs on Bladder Contractility in Rats

Stimulation of efferent nerves to the urinary bladder results in the release of acetylcholine (ACh) that stimulates postjunctional muscarinic (M3) receptors on urinary bladder smooth muscle, resulting in contraction and subsequent urination. M2 receptors are functionally expressed in human bladder smooth muscle and may also play a role in bladder contractility, however most likely indirectly by enhancing 3 mediated contractions and inhibiting p-adrenoceptor mediated relaxation, Antimuscarinic drugs are believed to work primarily by blocking 3 receptors, thus inhibiting the contractions associated with overactive bladder.

Another approach to treating overactive bladder involves targeting ^-adrenoceptors, which are also located on urinary bladder smooth muscle. The stimulation of postjunctional j33-adrenoceptors results in the generation of cA P and production of direct relaxation of bladder smooth muscle.

In order to investigate a possible pharmacological synergy on the combination of the muscarinic and the beta receptor pathways, the combination of the muscarinic antagonist oxybutynin and the beta-3 adrenoceptor agonist CL-316,243 (a very selective and potent rodent p3-AR agonist) was tested on EFS {electrical field stimulation )-induced responses in urinary bladder strips from rats.

Longitudinal strips of rat detrusor muscle were suspended in organ bath chambers containing oxygenated Krebs solution (pH 7,4, gassed with 95% <¾ and 5% C0₃ at 37*C). Prazosin (1 μίν ) was added to the Krebs solution in order to block a1- adrenoceptors. Bladder responses were measured using isometric transducers and recorded using a data acquisition system. Tissues were allowed to equilibrate under a resting tension of 1.0 g for 60 min. Following the equilibration period, strips were exposed to KCi (80 mM) to measure their viability. Tissues were washed and equilibrated for another 45 min period. Bladder strips were then subjected to EFS using the following parameters; maximal current 800 mA, frequency of 15 Hz, square pulse of 0.1 ms, trains of 4 s every 2 min. After approximately 15 min {when EFS contractions had stabilized), the selective p2~adrenoceptor antagonist ICI-1 18551 (30 n ) was incubated for 15 min. After stabilization of the contractile response, a concentration response curve was obtained for each bladder strip by adding CL~ 316,243 or oxybutynin (1 nM to 10 μΜ) (or corresponding vehicle) in log unit concentration increments. in the first series of experiments it was determined thai oxybutynin at a concentration of 10 nM produced a minima! {approximately 15% inhibition of EFS-induced bladder strip contraction. in a second series of experiments, a single concentration of oxybutynin at 10 M (determined from the first series of experiments} was added to organ bath chambers followed by various doses of CL-316,243 to provide a concentration-response curve for CL-316,243. in the presence of a minimally effective dose of oxybutynin, there was an approximate 3.5-foSd shift to the left of concentration-response curve to CL-316,243. The EC_&) for inhibiting bladder contraction by CL-316,243 was 7.2 nM; however, in the presence of oxybutynin ( 0 nM) the ECjc was 2.1 nM. in addition, maximal inhibition of EFS-induced contractions by CL-316,243 aione was 65%, however in the presence of oxybutynin (10nM) inhibition by CL-316,243 achieved 80% inhibition.

The differences in the EC_M, values and the inhibition of the maximal response were statistically significant (p<0.05). These data indicate there was significant pharmacological synergy of the efficacy of inhibiting bladder contraction with the combination of an antimuscarinic agent with a selective beta-3 adrenoceptor agonist.

Example 3, Effects of the Combinations of Various Beta-Adrenoceptor Agonists and Antimuscarmics on Rat Bladder Contractions induced by EFS (electrical field stimulation)

in this study various combinations of p3-adrenoceptor agonists and antimuscarinics were tested in isolated rat urinary bladder strips.

Urinary bladder smooth muscle strips were obtained from female rats (Sprague- Dawley strain, body weight 240-360 g). Two strips per bladder were prepared and connected to tension transducers in 5 mi organ baths containing Krebs-Henseieit solution (kept at 37°C, pH 7.4, gassed with 95% 02/5% 002), Prazosin {1 μΜ) was added to the Krebs solution in order to block al -adrenoceptors. Strips were equilibrated for at least 60 min at 10 g resting tension, during which tissues were washed every 15 min. Then, each strip was exposed to 80 miVI KCI to verify its viability. After another 45 min wash-out period, strips were subjected to EFS {electrical field stimulation parameters: constant current 800 mA; frequency of 15 Hz; square pulse of 0.1 ms, train of 4 s every 2 min). After stabilization, lCl-1 18,551 (30 nM), a j32~adrenoceptor antagonist, was incubated for 15 min then 10 nM of oxybutyria, toiterodine, solifenactn, or their common solvent (vehicle control) were added to the strips for an additional 15 min. Cumulative concentrations of soiabegron {10 nM-10 μ ). mirabegron {10 nM-10 μ ) and CL-316,243 (1 nM-10 μ ) were then added in haif-!og increments. At the end of CRC's, 10 Μ forskolin (FSK) was added to determine maximal relaxation (Figure 1 }.

Results are displayed in Figures 2-8, and are expressed as % inhibition (mean ± SEM) of basai EFS-induced contractions (EFS values obtained IS min after addition of !CI-1 18,551 ).

Each CRC was fit using non-linear regression (GraphPad Prism® software) to obtain Emax and plC_6i! (-log IC_M) values. Mean CRCs for vehicle and treated strips were fit in parallel and statistically compared. The first fit was used to compare E_!513X values and when these values were not statistically different, a second fit was performed, sharing E_mfiX, in order to obtain piC½ values for each pair of curves. Differences were considered statistically significant when the nu!i hypothesis could be rejected at a risk a of less than 0.05.

As evidenced by th data presented in the Figures, the E_mm values of CL-316,243 were significantly increased in the presence of oxybutynin and toiferodine. Further, the ICso of CL-316,243 was significantly decreased in the presence of oxybutynin.

For soiabegron, the E_ma* values were significantly increased by oxybutynin, toiterodine and so!ifenacin. Further, the ICso values of soiabegron were significantly lower in the presence of oxybutynin and toiterodine.

For mirabegron, the E_max value appeared to be increased in the presence of toiterodine. Further, the IC₆₀ values of mirabegron were significantly lower in the presence of oxybutynin, toiterodine and soiifenacin. Thus, it is clear that antimuscarinics can affect both the potency and efficacy of beta- 3 adrenergic receptor agonists.

Ali references cited herein are incorporated herein in their entireties.

Claims

What is claimed is:

1. A synergistic combination for relieving one or more symptoms associated with overactive bladder (OAS) comprising:

(i) a therapeutically effective amount of a beta-3 adrenergic receptor agonist;

and

(it) a therapeutically effective amount, or a sub-therapeuticalfy effective amount of a muscarinic receptor antagonist.

2. The combination of claim 1 , wherein said one or more symptoms associated with overactive b!adder are selected from the group consisting of frequency of urgency, frequency of mictruitions, nocturia, and urinary incontinence.

3. The combination of ciaim 1 or 2, wherein said beta-3 adrenergic receptor agonist comprises a compound selected from the group consisting of so!abegron, CL-316,243, mirabegron, pharmaceuticaily acceptable salts thereof,

pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceuticaily acceptable solvents thereof.

4. The combination of ciaim 3, wherein said beta-3 adrenergic receptor agonist comprises so!abegron, or a pharmaceuticaily acceptable salt, or a pharmaceuticaily acceptable solvate, or a pharmaceutically acceptable salt solvated with

pharmaceutically acceptable solvent thereof.

5. The combination of ciaim 3, wherein said beta-3 adrenergic receptor agonist comprises mirabegron, or a pharmaceuticaily acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceuticaily acceptable salt solvated with

pharmaceutically acceptable solvent thereof. 6. The combination of any one of claims 1-5, wherein said muscarinic receptor antagonist comprises oxybutynin, tolterodsne, solifenacin, pharmaceutically acceptable salts thereof, pharmaceuticaily acceptabie solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceuticaily acceptable solvents thereof. 7, The combination of ciaim 6, wherein said muscarinic receptor antagonist comprises oxybutynin, or a pharmaceuticaily acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sa!t solvated with

pharmaceutically acceptable solvent thereof.

8. The combination of claim 6, wherein said muscarinic receptor antagonist comprises tolierodine, or a pharmaceuiicaliy acceptab!e salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with

pharmaceutically acceptable solvent thereof.

9. The combination of claim 6, wherein said muscarinic receptor antagonist comprises so!ifenacin, or a pharmaceutically acceptable salt, or a pharmaceuiicaliy acceptable solvate, or a pharmaceuiicaliy acceptable salt solvated with

pharmaceutically acceptable solvent thereof.

10. A synergistic combination for relieving one or more symptoms associated with overactive bladder (OAS) comprising;

{1} a therapeutical iy effective amount of soiabegron, or a pharmaceutically acceptable salt, or a pharmaceuiicaliy acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof;

and

{if) a therapeutically effective amount, or a sub-therapeutica!!y effective amount of tolierodine, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof.

11. A method of treating one or more symptoms associated with overactive bladder in a mammal, comprising administering to said mammal:

(!) a therapeutically effective amount of a beia-3 adrenergic receptor agonist;

and

{ii) a therapeutically effective amount, or a sub-therapeutical!y effective amount of a muscarinic receptor antagonist.

12. The method of claim 11 , wherein said one or more symptoms associated with overactive bladder are selected from the group consisting of frequency of urgency, frequency of mictruitions, nocturia, and urinary incontinence. 13, The method of claim 11 or 12, wherein said beta-3 adrenergic receptor agonist comprises a compound selected from the group consisting of soiabegron, 01-316,243, mirabegron, pharmaceutically acceptable salts thereof,

pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated with pharmaceutically acceptable solvents thereof.

14. The method of claim 13, wherein said beta-3 adrenergic receptor agonist comprises solabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sait solvated with

pharmaceutically acceptable solvent thereof, 5. The method of claim 13, wherein said beta-3 adrenergic receptor agonist comprises mtrabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with

pharmaceutically acceptable solvent thereof,

16. The method of any one of claims 11 -15, wherein said muscarinic receptor antagonist comprises oxybutynin, tolterodine, solifenacin, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, and pharmaceutically acceptable salts solvated wit pharmaceutically acceptable solvents thereof.

17. The method of claim 16, wherein said muscarinic receptor antagonist comprises oxybutynin, or a pharmaceuticall acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sait solvated with

pharmaceutically acceptable solvent thereof,

18. The method of claim 16, wherein said muscarinic receptor antagonist comprises tolterodine, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with

pharmaceutically acceptable solvent thereof, 19, The method of claim 16, wherein said muscarinic receptor antagonist comprises soiifenacin, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable sait solvated with

pharmaceutically acceptable solvent thereof.

20. A method of treating one or more symptoms associated with overactive biadder in a mammal, comprising administering to said mammal: (i) a iherapeuticaliy effective amount of soiabegron, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceuticafiy acceptable solvent thereof;

and {if) a therapeutically effective amount, or a sub-therapeuticaily effective amount of to!terodine, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with pharmaceutically acceptable solvent thereof.

21. The method of any one of claims 11-20, wherein components (!) and (is) are co-administered.

22. The method of any one of claims 1 1 -21 , wherein components (I) and (it) are contained in a single dosage form.

23. The method of any one of claims 1-20. wherein components (i) and (is) are administered separately. 24. The method of any one of claims 1 1 -20 or 23, wherein there is a time delay between the administration of components (i) and (ii).

25. The combination according to claim 4, wherein the salt of soiabegron comprises the hydrochloride salt.

26. The method according to claim 14, wherein the salt of soiabegron comprises the hydrochloride salt.

27. A pharmaceutical composition comprising the combination of any one of claims 1 -10 or 25, further comprising one or more pharmaceutically acceptable carriers, diluents, or excipients.

28. Use of the combination of any one of claims 1-10 or 25, in the preparation of a medicament for the treatment of one or more symptoms associated with overactive bladder.

29. A method of treating one or more symptoms associated with overactive bladder in a mammal, comprising the step of administering to a mammal in need thereof, a therapeutically effective amount of the combination of any one of claims 1^» 10 or 25.

30. A method of treating one or more symptoms associated with overactive bladder in a mammal, comprising the ste of administering to a mamma! in need thereof, a therapeuticaily effective amount of the pharmaceuiica! composition of c!aim

5 31. The method of ciaim 14 or 28, wherein component (i) further comprises the com

Formula (tft).

32. The combination of any one of claims 1 -10 or 25 for the treatment of I.0 overactive bladder (GAB).