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(12) Patent Application Publication (10) Pub. No.: US 2003/0060513 A1 Arneric Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0060513 A1 Arneric Et Al US 20030060513A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0060513 A1 Arneric et al. (43) Pub. Date: Mar. 27, 2003 (54) PHARMACEUTICAL COMPOSITION (57) ABSTRACT (76) Inventors: Stephen P. Arneric, Portage, MI (US); Per-Olof Andersson, Whitehouse The present invention concerns the field of urology. The Station, NJ (US) invention provides a novel pharmaceutical composition, comprising a pharmaceutically effective combination of (i) Correspondence Address: a first compound Selected from the group consisting of DINSMORE & SHOHL, LLP muscarinic receptor antagonists, 5C-reductase inhibitors, 1900 CHEMED CENTER and C.-adrenergic receptor antagonists, and precursors and 255 EAST FIFTH STREET pharmaceutically acceptable Salts thereof, and (ii) a second CINCINNATI, OH 45202 (US) compound Selected from the group consisting of 5-HT receptor agonists and antagonists, and precursors and phar (21) Appl. No.: 09/965,556 maceutically acceptable Salts thereof, and optionally a phar maceutically acceptable carrier or diluent therefor. (22) Filed: Sep. 27, 2001 There is also provided a method of therapeutical treatment Publication Classification of urinary disorder in a mammal, including man, comprising administering to Said mammal, including man, in need of (51) Int. Cl. ............................................. A61K 31/137 Such treatment, a therapeutically effective amount of a (52) U.S. Cl. .............................................................. 514/648 composition according to the invention. US 2003/0060513 A1 Mar. 27, 2003 PHARMACEUTICAL COMPOSITION 0008 U.S. Pat. No. 5,382,600 discloses 2-(1R)-3-(diiso propylamino)-1-phenylpropyl)-4-methylphenol, also known TECHNICAL FIELD as N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phe 0001. The present invention is within the field of urology. nylpropylamine, with the generic name of tolterodine, as More Specifically, it is generally based on the use of a well as other Substituted 3,3-diphenylpropylamines, as being combination of certain agonists and/or antagonists for thera useful to treat urinary incontinence. H Postlind et al, Drug peutical treatment of urinary disorder. Metabolism and Disposition, 26(4): 289-293 (1998) dis closes that tolterodine is a muscarinic receptor antagonist. BACKGROUND OF THE INVENTION The active metabolites of tolterodine, as well as other 0002 Urinary disorders and symptoms thereof include Substituted 3,3-diphenylpropylamines, are disclosed in U.S. Some or all of the following: urgency, frequency, inconti Pat. No. 5,559,269. nence, urine leakage, enuresis, dySuria, hesitancy, and dif 0009 U.S. Pat. No. 4,377.584 discloses the use of finas ficulty of emptying bladder. In particular, urinary disorders teride, a 5C-reductase inhibitor, or the treatment of benign include urinary incontinence, caused by e.g. unstable or prostatic hypertrophy. overactive urinary bladder. 0010 U.S. Pat. No. 4,026,894 discloses the use of tera 0003) The term Lower Urinary Tract Symptoms (LUTS) Zosin, an O-adrenergic receptor antagonist, as an anti-hy describes a well-recognized medical condition. LUTS pertensive agent. C.-adrenergic receptor antagonists relax include some or all of the following: obstructive urinary Smooth muscle. Symptoms, Such as slow urination, dribbling at the end of a urination, inability to urinate and/or the need to Strain to 0011 U.S. Pat. No. 5,990,114 discloses the use of certain urinate at an acceptable rate, or irritative Symptoms, Such as 5-HT, receptor antagonists for the treatment of urinary frequency and/or urgency. These irritative Symptoms may incontinence. result from detrusor overactivity secondary to bladder outlet 0012 Despite the above advances in the art, it is desirable obstruction resulting from prostatic enlargement or proximal to develop novel pharmaceutical compositions that further urethral Smooth muscle hyperreactivity. improve the quality of life for a large number of individuals. 0004. A substantial part (5-10%) of the adult population Suffers from urinary incontinence, and the prevalence, par SUMMARY OF THE INVENTION ticularly of So-called urge incontinence, increases with age. 0013 For these and other purposes, it is an object of the The symptoms of an unstable or overactive bladder com present invention to provide a novel pharmaceutical com prise urge incontinence, urgency and urinary frequency. position for treating urinary disorder in a mammal, including Urge incontinence in combination with StreSS incontinence man, which composition inhibits, or Suppresses, unstable (mixed incontinence) is frequently encountered by clini bladder contractions and diminishes problems associated CS. with incomplete bladder emptying. 0005. It is assumed that unstable or overactive bladder is 0014. It is also an object of the present invention to caused by uncontrolled contractions of the bundles of provide a novel method of treating urinary disorder in a Smooth muscle fibers forming the muscular coat of the mammal, including man, which method effectively inhibits, urinary bladder (the detrusor muscle) during the filling phase or Suppresses, unstable bladder contractions and diminishes of the bladder. These contractions are mainly controlled by problems associated with incomplete bladder emptying. cholinergic muscarinic receptors, and the pharmacological treatment of unstable or overactive bladder has traditionally 0.015 For these and other objects that will be evident been based on muscarinic receptor antagonists. from the following disclosure, the present invention pro vides a novel pharmaceutical composition, comprising a 0006 The reason why the bladder muscle contracts inap pharmaceutically effective combination of propriately is unclear in many cases. For Some people it may be due to a problem with the nerve signals that run from the 0016 (i) a first compound selected from the group brain to the bladder. Sometimes minor nerve damage is consisting of muscarinic receptor antagonists, 5C-re caused by Surgery or childbearing. This muscle Squeezes or ductase inhibitors, and C.-adrenergic receptor antago contracts more often than normal and at inappropriate times. nists, and precursors and pharmaceutically accept Instead of Staying at rest as urine fills the bladder, the able Salts thereof, and detrusor contracts while the bladder is filling with urine. 0017 (ii) a second compound selected from the This causes a person to feel a Sudden and Sometimes group consisting of 5-HT, receptor agonists and overwhelming urge to urinate even when the bladder is not antagonists, and precursors and pharmaceutically full. acceptable Salts thereof, 0007 Another major urinary disorder is interstitial cys 0018 and optionally a pharmaceutically acceptable titis. Cystitis is an inflammation of the urinary bladder and carrier or diluent therefor. asSociated Structures. There is currently no universal effec tive treatment program. Symptoms from cystitis include 0019. The invention is based on the insight that a com urgency for urination, increased frequency of urination and bination of at least one compound Selected from the group Suprapubic pain, usually relieved by Voiding, arthritis, Spas consisting of muscarinic receptor antagonists, 5C-reductase tic colon, low grade fever and irritability. Mammals with inhibitors, and C.-adrenergic receptor antagonists, with a cystitis can be Significantly disabled and may require Sur 5-HT-agonist or -antagonist produces a favorable Simul gery. CyStitis can result from e.g. infection, trauma, allergy taneous effect on bladder contractility and bladder Storage, and malignancy. as will be described more below. US 2003/0060513 A1 Mar. 27, 2003 0020. In a preferred embodiment of the composition 0032. Furthermore, the present invention provides use of according to the invention, Said first compound is a musca the composition according to the invention for the manu rinic receptor antagonist, or a precursor or a pharmaceuti facture of a medicament for therapeutical treatment of cally acceptable Salt thereof. urinary disorder in a mammal, including man. In a preferred 0021. In a more preferred embodiment of the composi embodiment of the use according to the invention, the tion according to the invention, Said muscarinic receptor medicament is for treatment of depression in Said mammal, antagonist is a Substituted 3,3-diphenylpropylamine. Among which depression is concomitant with Said urinary disorder. Substituted 3,3-diphenylpropylamines with muscarinic receptor antagonist activity are those referred to in the 0033. Furthermore, the present invention provides a method of therapeutical treatment of urinary disorder in a background of the invention. mammal, including man, comprising administering to Said 0022. In an even more preferred embodiment of the mammal, including man, in need of Such treatment, a composition according to the invention, Said Substituted therapeutically effective amount of a composition according 3,3-diphenylpropylamine is Selected from the group consist to the invention. ing of tolterodine and hydroxytolterodine. Preferably, said substituted 3,3-diphenylpropylamine is tolterodine. In the 0034. In a preferred embodiment of the method according most preferred embodiment of the composition according to to the invention, Said disorder is Selected from the group the invention, Said first compound is tolterodine L-tartrate. consisting of lower urinary tract symptoms, unstable or 0023. In another preferred embodiment of the composi overactive urinary bladder, bladder outflow obstruction,
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