EP2811989A1 - Kombination von muscarinrezeptorantagonisten und 3-beta-adrenozeptoragonisten zur behandlung von blasenhyperaktivität - Google Patents
Kombination von muscarinrezeptorantagonisten und 3-beta-adrenozeptoragonisten zur behandlung von blasenhyperaktivitätInfo
- Publication number
- EP2811989A1 EP2811989A1 EP13704702.3A EP13704702A EP2811989A1 EP 2811989 A1 EP2811989 A1 EP 2811989A1 EP 13704702 A EP13704702 A EP 13704702A EP 2811989 A1 EP2811989 A1 EP 2811989A1
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- EP
- European Patent Office
- Prior art keywords
- pharmaceutically acceptable
- effective amount
- solvated
- combination
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/10—Drugs for disorders of the urinary system of the bladder
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to pharmaceutical combinations and methods for thei use.
- 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.
- overactive bladder ⁇ OAB ⁇ 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
- GAB is commonly classified into subtypes including
- 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
- 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.
- Muscarinic receptor antagonists also known as antimuscarinics or anticholinergics
- Detroi® LA tolterodine
- Ditropan XL® oxybuiynin
- Vesicare® ⁇ solifen- acin succinate
- 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.
- 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 criza-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.
- 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
- 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
- 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.
- 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).
- the salt of soSabegron comprises the hydrochloride salt.
- Another embodiment is directed to a pharmaceutical composition
- 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)
- 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 SG 50 vaiues of various beta-3 adrenoceptor agonists , either atone (vehicle) or in the presence of iOnivi of various antimuscarinics.
- 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 combinations of (i) and (ii) can be used for the treatment of one or more symptoms associated with overactive bladder.
- the combinations of (i) and (ii) can be used in medicai therapy.
- 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.
- 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.
- 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.
- therapeutically 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.
- 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.
- 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
- 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.
- 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:
- 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
- Soiabegron can be administered as a salt, which can be anhydrous, h yd rated, or soivated with a pharmaceuiicaiiy acceptable solvent such as ethanol.
- soiabegron is administered as the hydrochloride salt.
- soiabegron hydrochloride is the anhydrous hydrochloride salt.
- the free base, and pharmaceutically acceptable salts, for example, the hydrochloride salt, of soiabegron 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.
- component (i) when component (i) is solabegron, if can also comprise the primary active human metabolite of solabegron, shown as Formula (il l):
- 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.
- 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.
- 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.
- 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
- suitable muscarinic receptor antagonists other than oxybutynin can also be used according to the present invention.
- anttmuscarinics include but are not limited to toiterodine, soiifenacin, trospium, darifenacin, propiverine, and fesoterodine.
- 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:
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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 selle thereof; and (ii) a therapeutically effective amount, or a sub-therapeuticaliy effective amount of tolterodine, or a
- 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
- 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 selle thereof; and (ii) a therapeutieaiiy effective amount, or a sub-therapeuticaliy effective amount of soiifenacin, or a
- 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.
- 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
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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
- 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
- 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.
- 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.
- 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).
- 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).
- the sa!t of so!abegron comprises the hydrochloride salt.
- Another embodiment is directed to a pharmaceutical composition
- 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
- 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
- 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, (ii) solifenacin, or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate, or a pharmaceutically acceptable salt solvated with
- Still another preferred pharmaceutical composition comprises ⁇ ) 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.
- the method of treatment is directed to a method comprising solabegron, wherein component (i) further comprises the primary in vivo metabolite of sol
- solvate 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.
- solvents may not interfere with the biological activity of the soiute.
- suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
- the solvent is a pharmaceutically acceptable solvent.
- 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.
- 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.
- 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, methyls
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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, !S C or U C, in one preferred embodiment, the beta-3 adrenergic receptor agonist comprises deuterated solabegron.
- compositions 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.
- the active drug component can be combined with an oral, non-toxic pharmaceutical acceptable inert carrier such as ethanol, glycerol, water and the like.
- 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.
- suitable binders 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.
- 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
- an absorption agent such as bentonit
- 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.
- a binder such as syrup, starch paste, acadia muciiage or solutions of ce!luiosic or polymeric materials and forcing through a screen.
- 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!
- 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.
- 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.
- 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.
- 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.
- compositions 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.
- the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1988).
- compositions adapted for rectal administration may be presented as suppositories or as enemas.
- compositions 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.
- 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.
- a pharmaceutical combination including the beta-3 adrenergic receptor agonist and the muscarinic receptor antagonist
- 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.
- 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.
- the therapeuticaiiy effective amount vvili be at the discretion of the attendant physician or veterinarian.
- 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.
- befa-3 adrenergic receptor agonists such as solabegron
- beta- 3 adrenergic receptors resulting in relaxation of bladder smooth muscle.
- muscarinic receptor antagonists such as oxybutynin
- 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.
- Example 1 Drug Interaction Study with healthy human subjects
- PVR post void residua!
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- ⁇ -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.
- 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 ⁇ ) (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!
- Example 3 Effects of the Combinations of Various Beta-Adrenoceptor Agonists and Antimuscarmics on Rat Bladder Contractions induced by EFS (electrical field stimulation)
- 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 ⁇ ) 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.
- 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).
- 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.
- lCl-1 18,551 (30 nM) a j32 ⁇ adrenoceptor antagonist
- 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 ⁇ ).
- 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 piC1 ⁇ 2 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.
- soiabegron 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.
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US20100113469A1 (en) * | 2007-03-29 | 2010-05-06 | Merck & Co., Inc. | Combination therapy for the treatment-of lower urinary tract symptoms |
PE20091825A1 (es) | 2008-04-04 | 2009-12-04 | Merck & Co Inc | Hidroximetil pirrolidinas como agonistas del receptor adrenergico beta 3 |
EP2470021B1 (de) | 2009-08-27 | 2014-10-22 | Merck Sharp & Dohme Corp. | Neue aus einem pyrrolidin abgeleitete beta-3-adrenerge rezeptoragonisten |
EP2485595A4 (de) * | 2009-10-07 | 2014-03-12 | Merck Sharp & Dohme | Kombinationstherapie mit einem adrenergischen beta-3-rezeptoragonist und einem antimuskarinikum |
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2013
- 2013-02-08 AR ARP130100415A patent/AR089957A1/es unknown
- 2013-02-08 CA CA2864173A patent/CA2864173A1/en not_active Abandoned
- 2013-02-08 EP EP13704702.3A patent/EP2811989A1/de not_active Withdrawn
- 2013-02-08 CN CN201380019041.9A patent/CN104684549A/zh active Pending
- 2013-02-08 WO PCT/US2013/025285 patent/WO2013119910A1/en active Application Filing
- 2013-02-08 KR KR20147023969A patent/KR20150020160A/ko not_active Application Discontinuation
- 2013-02-08 SG SG11201404776PA patent/SG11201404776PA/en unknown
- 2013-02-08 AU AU2013216864A patent/AU2013216864A1/en not_active Abandoned
- 2013-02-08 JP JP2014556709A patent/JP2015509931A/ja active Pending
- 2013-02-08 TW TW102105243A patent/TW201338772A/zh unknown
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2014
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2015
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Non-Patent Citations (2)
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See also references of WO2013119910A1 * |
Also Published As
Publication number | Publication date |
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SG11201404776PA (en) | 2014-09-26 |
CN104684549A (zh) | 2015-06-03 |
WO2013119910A1 (en) | 2013-08-15 |
IL234033A0 (en) | 2014-09-30 |
HK1204966A1 (en) | 2015-12-11 |
JP2015509931A (ja) | 2015-04-02 |
PH12014501814A1 (en) | 2014-11-24 |
CA2864173A1 (en) | 2013-08-15 |
KR20150020160A (ko) | 2015-02-25 |
AR089957A1 (es) | 2014-10-01 |
AU2013216864A1 (en) | 2014-09-11 |
TW201338772A (zh) | 2013-10-01 |
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