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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.- 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 , 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 . 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- 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, tion according to the invention, Said muscarinic receptor urinary incontinence, particularly StreSS incontinence, and antagonist is Selected from and active deriva interstitial cystitis. tives thereof. Among active derivatives thereof is its active 0035) In another preferred embodiment of the method metabolite N-desethyloxybutynin. Preferably, said muscar according to the invention, Said method is also for treating inic receptor antagonist is oxybutynin. depression in Said mammal, which depression is concomi 0024. In yet another preferred embodiment of the com tant with Said urinary disorder. position according to the invention, Said muscarinic receptor antagonist is Selected from and active deriva 0036). In a preferred embodiment of the method according tives thereof. Among active derivatives thereof is its active to the invention, Said composition is administered rectally, 3'-hydroxyl metabolite. Preferably, said muscarinic receptor intravaginally, topically, orally, Sublingually, intranasally, antagonist is darifenacin. transdermally or parenterally. 0.025 In one preferred embodiment of the composition 0037. In another preferred embodiment of the method according to the invention, Said first compound is present in according to the invention, Said first compound and Said an amount of from about 0.1 mg to about 100 mg. Second compound of Said composition are simultaneously administered. 0026. In a preferred embodiment of the composition according to the invention, Said Second compound is a 0038. In yet another preferred embodiment of the method neutral 5-HT, receptor antagonist. according to the invention said first compound and Said 0027. In one preferred embodiment of the composition Second compound of Said composition are concomitantly according to the invention, Said Second compound is present administered. in an amount of from about 0.1 mg to about 1 g. 0039 Finally, the present invention provides a pharma 0028. In another preferred embodiment of the composi ceutical kit for therapeutical treatment of urinary disorder in tion according to the invention, Said first compound and Said a mammal, including man, comprising Second compound are maintained in the same delivery 0040 (i) a first container comprising a first com vehicle. pound as described above 0029. In yet another preferred embodiment of the com position according to the invention, Said first compound and 0041 (ii) a second container comprising a second Said Second compound are maintained in different delivery compound as described above, and vehicles. 0042 (iii) instructions for use of the kit. 0.030. In a preferred embodiment of the composition according to the invention, Said composition is for treating DESCRIPTION OF THE INVENTION urinary disorder in a mammal, including man. In a more 0043. In describing the prefer-red embodiment, certain preferred embodiment of the composition according to the terminology will be utilized for the sake of clarity. Such invention, Said disorder is Selected from the group consisting terminology is intended to encompass the recited embodi of lower urinary tract Symptoms, unstable or overactive ments, as well as all technical equivalents that operate in a urinary bladder, bladder outflow obstruction, urinary incon Similar manner for a similar purpose to achieve a similar tinence, particularly StreSS incontinence, and interstitial cyS result. To the extent that any pharmaceutically active com titis. pound is disclosed or claimed, it is expressly intended to 0031. In another preferred embodiment of the composi include all active metaboliteS produced in Vivo, and, is tion according to the invention, Said composition is for expressly intended to include all enantiomers, isomers or treating depression in Said mammal, which depression is tautomers where the compound is capable of being present concomitant with Said urinary disorder. in its enantiomeric, isomeric or tautomeric form. US 2003/0060513 A1 Mar. 27, 2003

0044) The present invention provides a novel composi inhibition of the micturition refleX, Simultaneous adminis tion, which is a combination of tration of an anti-muscarinic agent with a neutral 5-HT antagonist does not attenuate the effects of the 5-HT 0045 at least one muscarinic receptor antagonist or antagonist on bladder capacity or its effect on the micturition 5C.-reductase inhibitor or C.-adrenergic receptor reflex. antagonist or and/or Serotonin reuptake inhibitor and a 5-HT agonist or antago 0053. The muscarinic receptor antagonists, or antimus nist. The inventive composition is useful for the carinic agents, useful in the pharmaceutical compositions of treatment of urinary disorder. this invention include, but are not limited to, non-Selective agents, bladder-Selective agents and muscarinic M3 recep 0046) A particularly preferred composition for the treat tor-Selective agents. Examples of muscarinic receptor ment of urinary disorder is a combination of an anti antagonists include, but are not limited to, tolterodine and muscarinic agent and a neutral 5-HT-antagonist. active metabolites thereof, Such as hydroxytolterodine, YM905, , oxybutynin, trospium, propantheline, 0047 According to the invention, it has now surprisingly darifenacin, temiverine, and ipratropium, as well as phar and inventively been found that treatment with a combina maceutically acceptable salts thereof. YM905 is butanedioic tion of an anti-muscarinic agent and a neutral 5-HT acid, compd. with (1S)-(3R)-1-azabicyclo2.2.2]oct-3-yl antagonist produces a Simultaneous effect on bladder con 3,4-dihydro-1-phenyl-2(1H)-isoquinolinecarboxylate (1:1) tractility and bladder Storage. (9CI). Propiverine is 1-methyl-4-piperidyl alpha...alpha.- 0.048 Anti-muscarinic treatment acts on the effector diphenyl-alpha.-(n-propoxy)acetate and is disclosed in East organ by inhibiting the response to efferent impulses from German Patent 106,643 and in CAS 82-155841s (1975). the central nervous System. Thus, anti-muscarinic treatment Oxybutynin is 4-(diethylamino)-2-butynylalphaphenylcy inhibits unstable bladder contractions during the filling clohexaneglycolate and is disclosed in UK Patent 940,540. phase but also inhibits the contractions elicited during the Trospium is 3alpha-hydroxyspiro1alphaH,5alphaH-nortro elimination phase, especially at higher doses, thereby result pane-8,1"pyrrolidinium chloride benzilate and is disclosed ing in a decrease in micturition pressure, eventually leading in U.S. Pat. No. 3,480,623. Darifenacin is (S)-2-1-2-(2,3- to the negative consequence of incomplete bladder empty dihydrobenzofuran-5-yl)ethyl-3-pyrrolidinyl-2,2-diphe ing. This effect limits the possibilities of otherwise accept nyl-acetamide, and is disclosed in U.S. Pat. No. 5,096,890. able dosing of these agents. Furthermore, anti-muscarinic Temiverine is benzeneacetic acid, alpha.-cyclohexyl-al treatment leads to Side-effects outside of the urogenital pha.-hydroxy-, 4-(diethylamino)-1,1-dimethyl-2-butynyl Systems, mainly due to blockade of muscarinic receptors in ester and is disclosed in U.S. Pat. No. 5,036,098. Ipratro other tissueS Such as the Salivary glands, the gut, and the pium is 8-isopropylnoratropine methobromide and is dis CNS, leading to Side effects Such as dry mouth, constipation, closed in U.S. Pat. No. 3,505,337. and confusion, respectively. To Some extent, these side 0054 Preferred muscarinic receptor antagonists may be effects have been reduced by the introduction of newer Selected from Substituted 3,3-diphenylpropylamines (Such anti-muscarinic agents Such as tolterodine with Selectivity as those disclosed in U.S. Pat. No. 5,382,600) with anti for bladder Smooth muscle. However, even bladder-selective muscarinic activity, as well as pharmaceutically acceptable anti-muscarinic agents will always be limited as a treatment Salts thereof. Preferred muscarinic receptor antagonists of overactive bladder by their effect on the micturition include, but are not limited to tolterodine and hydroxy contraction described above. tolterodine, Oxybutynin and active derivatives thereof, Such 0049. The effects of anti-muscarinic agents have been as N-desethyloxybutynin, and darifenacin and active deriva Studied in a range of animal models and they have consis tives thereof, such as its 3'-hydroxyl metabolite, as well as tently been shown to reduce the amplitude of voiding or pharmaceutically acceptable Salts thereof. micturition contraction without direct effects on bladder 0055. The 5C.-reductase inhibitors useful in the pharma capacity. For these agents, the effects on bladder capacity ceutical compositions of this invention include, but are not have always been shown to be secondary to a significant limited to, finasteride (U.S. Pat. No. 4,377.584), dutasteride decrease in micturition pressure. (U.S. Pat. No. 5,565,467), epristeride (U.S. Pat. No. 5,017, 0050. No clinically available agents have any direct effect 568), and turosteride (U.S. Pat. No. 5,155,107), as well as on the storage function of the bladder. However, it has now pharmaceutically acceptable Salts thereof. been realized that a combination of 5-HT-agonists or 0056. The O.-adrenergic receptor antagonists useful in the antagonists, particularly neutral 5-HT-antagonists, and pharmaceutical compositions of this invention include, but antimuscarinic agents or 5C.-reductase inhibitors or C.-adr are not limited to, (U.S. Pat. No. 4,026,894), energic receptor antagonists or norepinephrine and/or Sero (U.S. Pat. No. 4,188,390), (U.S. Pat. No. tonin reuptake inhibitors, particularly antimuScarinic agents, 3,511,836), (U.S. Pat. No. 3,920,636), increases bladder capacity without negative consequences (U.S. Pat. No. 3,527,761), (U.S. Pat. No. 4,315, on bladder contractility. 007), abanoquil (U.S. Pat. No. 4,686.228), (U.S. Pat. No. 3,997,666), , (U.S. Pat. 0051) Importantly, in models for the evaluation of the No. 4,703,063), , , , effects of an anti-muscarinic agent on bladder contractility, (U.S. Pat. No. 4,818,764), (U.S. Pat. No. Simultaneous administration of a neutral 5-HT-antagonist 4,411,908), , dibenzamine, , , with an anti-muscarinic does not attenuate the effects of the corynthanine, , tamsulosin, and , as anti-muscarinic agent on bladder contractility. well as pharmaceutically acceptable Salts thereof. 0.052 Furthermore, in models used for evaluation of the 0057 The norepinephrine and/or serotonin reuptake effects of neutral 5-HT, antagonists on bladder capacity and inhibitors useful in the pharmaceutical compositions of this US 2003/0060513 A1 Mar. 27, 2003 invention include, but are not limited to, dulloxetine (U.S. with the dosage Selection of the first compound. The average Pat. No. 4,956,388) and reboxetine. adult daily dosage of the Second compound is from about 1 0.058. The selection of the dosage of the first compound tug to about 10 mg per kilogram of body weight, adminis is that which can provide relief to the patient. As is well tered in one or more doses, e.g. containing from about 50 lug known, the dosage and administrative regimen (i.e., one, to about 1 g each. Pediatric dosages may be less. two, three or more administrations per day) of this com 0065 Examples of pharmaceutically acceptable salts for pound depends on Several factorS Such as the potency of the use in the composition according to the invention include, Selected Specific compound, the mode of administration, the but are not limited to, acetate, benzoate, hydroxybutyrate, age and weight of the patient, the Severity of the condition bisulfate, bisulfite, bromide, butyne-1,4-dioate, carpoate, to be treated, and the like. This is considered to be within the chloride, chlorobenzoate, citrate, dihydrogenphosphate, skill of the artisan, and one can review the existing literature dinitrobenzoate, fumarate, glycolate, heptanoate, heXyne-1, on the components to determine optimal dosing. 6-dioate, hydroxybenzoate, iodide, lactate, maleate, mal 0059 When the first compound is an antimuscarinic onate, mandelate, metaphosphate, methaneSulfonate, meth agent, it is preferred that the average adult daily dosage of oxybenzoate, methylbenzoate, monohydrogenphosphate, the first compound is from about 0.05 mg to about 5 mg per naphthalene-1-Sulfonate, naphthalene-2-Sulfonate, oxalate, kilogram of body weight, administered in one or more doses, phenylbutyrate, phenylproionate, phosphate, phthalate, phy e.g. containing from about 0.05 mg to about 250 mg each. lacetate, propanesulfonate, propiolate, propionate, pyro phosphate, pyroSulfate, Sebacate, Suberate, Succinate, Sul 0060. When the first compound is a 5C-reductase inhibi fate, Sulfite, Sulfonate, tartrate, XyleneSulfonate, and the like. tor, it is preferred that the first compound is present in an amount ranging from about 2 mg to about 20 mg, preferably 0066 Compositions of the present invention can conve about 5 mg per dose. niently be administered in a pharmaceutical composition containing the active compounds in combination with a 0061. When the first compound is an O-adrenergic recep Suitable excipient. Such pharmaceutical compositions can be tor antagonist, it is preferred that the first compound is prepared by methods and contain excipients which are well present in an amount ranging from about 1 mg to about 25 known in the art. A generally recognized compendium of mg, and preferably about 10 mg per dose. Such methods and ingredients is Remington's Pharmaceuti 0062) The 5-HT, receptor agonists and antagonists use cal Sciences by E. W. Martin (Mark Publ. Co., 15th Ed., ful in the pharmaceutical compositions of this invention 1975). To the extent necessary for completion, this reference include, but are not limited to, compounds that act on the is hereby incorporated by reference. The compositions of the central nervous system by binding to 5-HT receptors of the present invention can be administered parenterally (for 5-HT, subtype. Non-limiting examples of 5-HT, receptor example, by intravenous, intraperitoneal, Subcutaneous or antagonists are WAY-100,635, i.e. cyclohexanecarboxam intramuscular injection), topically, orally, Sublingually, ide, N-(2-4-(2-methoxyphenyl)-1-piperazinylethyl-N-2- transdermally, intranasally, intravaginally, or rectally, with pyridinyl-, trihydrochloride, robalZotan, i.e. (3R)-3-(dicy oral administration being particularly preferred. clobutylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5- carboxamide, and LY426965, i.e. (2S)-(+)-1-cyclohexyl-4- 0067 For oral therapeutic administration, the inventive 4-(2-methoxyphenyl)-1-piperazinyl 2-methyl-2-phenyl-1- composition may be combined with one or more excipients butanone monohydrochloride. In general, the compounds and used in the form of ingestible tablets, buccal tablets, selectively bind to receptors of the 5-HT, Subtype to a much troches, capsules, elixirs, Suspensions, Syrups, wafers, chew greater extent than they bind to other receptors, Such as C. ing gums, foods and the like. Such compositions and prepa and D receptors. Moreover, they exhibit activity as 5-HT rations preferably contain at least 0.1% of active com agonists or -antagonists in pharmacological testing. The pounds. The percentage of the compositions and 5-HT, receptor agonists and antagonists of the invention can preparations may, of course, be varied and may conveniently be used for the treatment of CNS disorders, such as anxiety be between about 0.1 to about 100% of the weight of a given in mammals, particularly humans. They may also be used as unit dosage form. The amount of active compounds in Such , hypotensives, as agents for regulating the therapeutically useful compositions is Such that effective Sleep/wake cycle, feeding behavior and/or Sexual function, dosage levels will be obtained. for treating cognition disorders, and for treating neuromus 0068 The tablets, troches, pills, capsules, and the like cular dysfunction of the lower urinary tract, particularly may also contain the following: binderS Such as gum traga those involving micturition (urination), Such as dysuria, canth, acacia, corn Starch or gelatin; excipients Such as incontinence, and enuresis. dicalcium phosphate, a disintegrating agent Such as corn Starch, potato Starch, alginic acid and the like; a lubricant 0.063 A neutral antagonist is a compound that binds to a Such as magnesium Stearate; and a Sweetening agent Such as receptor, is devoid of intrinsic activity at the receptor, but Sucrose, fructose, lactose or aspartame or a flavoring agent blocks the receptor-mediated functional activity elicited by Such as peppermint, oil of wintergreen, or cherry flavoring. an agonist. In this respect, an agonist is defined as a The above listing is merely representative, and one skilled in compound that binds to a receptor and activates a receptor the art could envision other binders, excipients, Sweetening mediated functional response Such as, but not limited to, agents and the like. When the unit dosage form is a capsule, 5-HT-mediated inhibition of adenylyl cyclase activity or it may contain, in addition to materials of the above type, a activation of potassium channels. liquid carrier, Such as a vegetable oil or a polyethylene 0064. The dosage and administrative regimen (i.e., one, glycol. Various other materials may be present as coatings or two, three or more administrations per day) of the Second to otherwise modify the physical form of the solid unit compound depends on the factors referred to in connection dosage form. For instance, tablets, pills, or capsules may be US 2003/0060513 A1 Mar. 27, 2003

coated with gelatin, wax, shellac or Sugar and the like. A treatment can be augmented by the addition of a neutral Syrup or elixir may contain the active compound, Sucrose or 5-HT, antagonist. This situation is especially likely to occur fructose as a Sweetening agent, methyl and propylparabens in patients with overactive bladder secondary to bladder as preservatives, a dye and flavoring Such as cherry or outflow obstruction, e.g. due to prostate enlargement. orange flavor. Of course, any material used in preparing any 0075. In other cases, anti-muscarinic treatment might be unit dosage form should be pharmaceutically acceptable and limited by intolerable side effects, such as dry mouth. In Substantially non-toxic in the amounts employed. In addi Such a case, the anti-muscarinic dose might be reduced but tion, the active components may be incorporated into SuS efficacy maintained by the addition of a neutral 5-HT tained-release preparations and devices including, but not antagonist. This combination allows the use of anti-musca limited to, those relying on OSmotic pressures to obtain a rinic agents that are not Selective for the bladder in a desired release profile. Once daily formulations for each of Situation where these agents are preferred over other, more the active components are Specifically included. bladder Selective, agents. 0069. The inventive composition, containing the two, or more, active compounds, may be administered in the same (0076) In another situation, treatment with a neutral 5-HT, physical form or concomitantly according to the above antagonist might be limited due to absence of an effect on described dosages and in the above-described delivery bladder contractility. In Such a case, addition of an anti vehicles. The dosages for each active compound can be muscarinic agent brings additional efficacy. Such a situation measured Separately and can be given as a Single combined might be patients with bladder hyperreflexia, a condition dose or given Separately. They may be given at the same or known to be associated with increased refleX bladder con at different times as long as both actives are in the patient at tractions. one time over a 24-hour period. Concomitant or concurrent 0077. In yet another situation, the effectiveness of a administration means that the patient takes one drug within neutral 5-HT, antagonist might be limited by side effects. In about 5 minutes of taking the other drug. Such a case, adjustment of the dose of the 5-HT antagonist, 0070 The present invention also provides a pharmaceu and thereby its effectiveness can be compensated for by the tical kit for therapeutical treatment of urinary disorder in a addition of an anti-muscarinic agent. mammal, including man. In analogy with the composition, 0078. The novel composition is considered to provide the kit comprises a first container comprising a first com rapid relief to those Suffering from the above diseases or pound as described above, a Second container comprising a disorders with a minimal amount of deleterious Side effects. Second compound as described above, and instructions for 0079 The invention is described in greater detail by the use of the kit. following non-limiting examples. 0071 "Pharmaceutically acceptable” refers to those properties and/or Substances that are acceptable to the EXAMPLES patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a Example 1 physical/chemical point of View regarding composition, formulation, Stability, patient acceptance and bioavailability. 0080 A pharmaceutical composition is prepared by com 0.072 The inventive composition is to be used in the bining tolterodine with a neutral 5-HT, receptor antagonist treatment of urinary disorders. In particular, the composition in a pharmaceutically acceptable carrier. The composition is useful for treating LUTS or incontinence of any type, e.g. contains between about 0.05 mg to about 4 mg of tolterodine StreSS incontinence, genuine StreSS incontinence, and mixed per kilogram of patient body weight (for example, 3 mg to incontinence. StreSS urinary incontinence is a Symptom 240 mg tolterodine for a person weighing 60 kg) and describing involuntary loSS of urine on carrying out any between about 0.01 mg to about 1 mg of neutral 5-HT activity that raises intra-abdominal pressure Such as cough receptor antagonist per kilogram of patient body weight. The ing or Sneezing. StreSS incontinence is also a clinical sign, composition is administered to a patient for the treatment of that is the observation by a care giver of a jet of urine incontinence, and particularly StreSS incontinence, urge escaping from the urethral meatus (opening) when the incontinence or mixed incontinence. patient coughs or Strains. Genuine Stress Incontinence (urge incontinence) is the pathological diagnosis of an incompe Example 2 tent urethral Sphincter as diagnosed by Urodynamic testing. 0081. A first pharmaceutical composition is prepared by Mixed incontinence is StreSS incontinence in combination combining a neutral 5-HT, receptor antagonist in a phar with urge incontinence. The latter is a part of the Symptom maceutically acceptable carrier Such that it can deliver complex of the Overactive Bladder. Retention may be due to between about 0.5 mg to about 50 mg on a daily basis. A outflow obstruction (e.g., high urethral pressure), poor detru Second pharmaceutical composition is prepared by combin Sor (bladder muscle) contractility or lack of coordination ing tolterodine in a pharmaceutically acceptable carrier Such between detrusor contraction and urethral relaxation. The that it can deliver between about 0.05 mg to about 4 mg of inventive drug combination can be used in connection with tolterodine per kilogram of patient body weight on a daily StreSS incontinence, urge incontinence or mixed inconti basis. CCC. 0082 The first composition is administered to a patient 0073. The composition according to the invention is also Suffering from one or more forms of incontinence once, to be used in the treatment of interstitial cystitis. twice, three times, four times or six times daily Such that the 0.074. In a situation where anti-muscarinic treatment of a daily dosage is between about 0.5 mg to about 50 mg. The urinary disorder is limited by an increase in residual urine, Second composition is administered to the same patient at US 2003/0060513 A1 Mar. 27, 2003

the same time as the administration of the first composition 7. A composition according to claim 2, wherein Said or any time within 24 hours of the administration of the first muscarinic receptor antagonist is Selected from Oxybutynin composition once, twice, three times, four times or Six times and active derivatives thereof, such as N-desethyloxybuty daily such that the daily dosage is between about 0.05 mg to nin. about 4 mg of tolterodine per kilogram of patient body 8. A composition according to claim 7, wherein Said weight. Alternatively, the Second composition could first be muscarinic receptor antagonist is oxybutynin. administered, followed by the administration of the first 9. A composition according to claim 2, wherein Said composition as disclosed at the same time, or within 24 muscarinic receptor antagonist is Selected from darifenacin hours thereof. and active derivatives thereof, such as its 3'-hydroxyl metabolite. Example 3 10. A composition according to claim 9, wherein Said 0.083. A pharmaceutical composition is prepared by com muscarinic receptor antagonist is darifenacin. bining a 5o-reductase inhibitor with a neutral 5-HT, recep 11. A composition according to any one of claims 1-10, tor antagonist in a pharmaceutically acceptable carrier. The wherein Said first compound is present in an amount of from composition contains between about 2 mg to about 20 mg of about 0.1 mg to about 100 mg. 5C.-reductase inhibitor and between about 0.5 mg to about 12. A composition according to any one of claims 1-11, 50 mg of neutral 5-HT, receptor antagonist. The composi wherein Said Second compound is a neutral 5-HT, receptor tion is administered to a patient for the treatment of urinary antagonist. disorder. 13. A composition according to any one of claims 1-12, wherein Said Second compound is present in an amount of Example 4 from about 0.1 mg to about 1 g. 14. A composition according to any one of claims 1-13, 0084. A pharmaceutical composition is prepared by com wherein Said first compound and Said Second compound are bining an O-adrenergic receptor antagonist with a neutral maintained in the same delivery vehicle. 5-HT, receptor antagonist in a pharmaceutically acceptable 15. A composition according to any one of claims 1-13, carrier. The composition contains between about 1 mg to wherein Said first compound and Said Second compound are about 25 mg of C.-adrenergic receptor antagonist and maintained in different delivery vehicles. between about 0.5 mg to about 50 mg of neutral 5-HT 16. A composition according to any one of claims 1-15, receptor antagonist. The composition is administered to a which is for treating urinary disorder in a mammal, includ patient for the treatment of urinary disorder. ing man. 0085 Having described the invention in detail and by 17. A composition according to claim 16, wherein said reference to the preferred embodiments thereof, it will be disorder is lower urinary tract Symptoms. apparent that modifications and variations are possible with 18. A composition according to claim 16, wherein Said out departing from the Scope of the appended claims. disorder is unstable or overactive urinary bladder. 19. A composition according to claim 16, wherein Said 1. A pharmaceutical composition comprising a pharma disorder is bladder outflow obstruction. 20. A composition according to claim 16, wherein Said ceutically effective combination of disorder is urinary incontinence. (i) a first compound Selected from the group consisting of 21. A composition according to claim 20, wherein Said muscarinic receptor antagonists, 5C.-reductase inhibi disorder is StreSS incontinence. tors, and C.-adrenergic receptor antagonists, and pre 22. A composition according to claim 16, wherein Said cursors and pharmaceutically acceptable Salts thereof, disorder is interstitial cystitis. and 23. A composition according to any one of claims 16-22, (ii) a second compound Selected from the group consist which is for treating depression in Said mammal, which ing of 5-HT, receptor agonists and antagonists, and depression is concomitant with Said urinary disorder. precursors and pharmaceutically acceptable Salts 24. Use of a pharmaceutical composition according to any one of claims 1-15 for the manufacture of a medicament for thereof, therapeutical treatment of urinary disorder in a mammal, and optionally a pharmaceutically acceptable carrier or including man. diluent therefor. 25. Use of a pharmaceutical composition according to 2. A pharmaceutical composition according to claim 1, claim 24, wherein Said disorder is lower urinary tract Symp wherein Said first compound is a muscarinic receptor antago tomS. nist, or a precursor or a pharmaceutically acceptable Salt 26. Use of a pharmaceutical composition according to thereof. claim 24, wherein Said disorder is unstable or overactive 3. A composition according to claim 2, wherein Said urinary bladder. muscarinic receptor antagonist is a Substituted 3,3-diphenyl 27. Use of a pharmaceutical composition according to propylamine. claim 24, wherein said disorder is bladder outflow obstruc 4. A composition according to claim 3, wherein Said tion. substituted 3,3-diphenylpropylamine is selected from the 28. Use of a pharmaceutical composition according to group consisting of tolterodine and hydroxytolterodine. claim 24, wherein Said disorder is urinary incontinence. 5. A composition according to claim 4, wherein Said 29. Use of a pharmaceutical composition according to Substituted 3,3-diphenylpropylamine is tolterodine. claim 28, wherein Said disorder is StreSS incontinence. 6. A composition according to claim 5, wherein Said first 30. Use of a pharmaceutical composition according to compound is tolterodine L-tartrate. claim 24, wherein Said disorder is interstitial cystitis. US 2003/0060513 A1 Mar. 27, 2003

31. Use of a pharmaceutical composition according to any 39. A method of therapeutical treatment according to any one of claims 24-30, wherein the medicament is for treat one of claims 32-38, which is also for treatment of depres ment of depression in Said mammal, which depression is Sion in Said mammal, which depression is concomitant with concomitant with Said urinary disorder. Said urinary disorder. 32. A method of therapeutical treatment of urinary disor 40. A method of therapeutical treatment according to any der in a mammal, including man, comprising one of claims 32-39, wherein said composition is adminis tered rectally, intravaginally, topically, orally, Sublingually, administering to Said mammal, including man, in need of intranasally, transdermally or parenterally. Such treatment, a therapeutically effective amount of a 41. A method of therapeutical treatment according to any composition according to any one of claims 1-15. one of claims 32-40, wherein said first compound and said 33. A method of therapeutical treatment according to Second compound of Said composition are simultaneously claim 32, wherein Said disorder is lower urinary tract Symp administered. tomS. 42. A method of therapeutical treatment according to any 34. A method of therapeutical treatment according to one of claims 32-40, wherein said first compound and said claim 32, wherein Said disorder is unstable or overactive Second compound of Said composition are concomitantly urinary bladder. administered. 35. A method of therapeutical treatment according to 43. A pharmaceutical kit for therapeutical treatment of claim 32, wherein said disorder is bladder outflow obstruc urinary disorder in a mammal, including man, comprising tion. (i) a first container comprising a first compound according 36. A method of therapeutical treatment according to to any one of claims 1-10, claim 32, wherein Said disorder is urinary in continence. (ii) a Second container comprising a Second compound 37. A method of therapeutical treatment according to according to claim 1 or 12, and optionally claim 36, wherein Said disorder is StreSS incontinence. 38. A method of therapeutical treatment according to (iii) instructions for use of the kit. claim 32, wherein Said disorder is interstitial cystitis. k k k k k