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US 20050222165A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0222165 A1 Wylie (43) Pub. Date: Oct. 6, 2005

(54) PHARMACEUTICAL COMBINATIONS (60) Provisional application No. 60/181,310, filed on Feb. 9, 2000. (76) Inventor: Michael G. Wyllie, Herne Kent (GB) Publication Classification Correspondence Address: NOVARTS (51) Int. Cl...... A61K 31/517 CORPORATE INTELLECTUAL PROPERTY (52) U.S. Cl...... 514/252.17; 514/266.21 ONE HEALTH PLAZA 104/3 EAST HANOVER, NJ 07936-1080 (US) (57) ABSTRACT (21) Appl. No.: 11/140,723 Pharmaceutical combinations Suitable for treating the lower urinary tract Symptoms (LUTS) associated with benign (22) Filed: May 31, 2005 prostatic hyperplasia (BPH) in men are described herein. The combinations contain an alpha-adrenoceptor antagonist Related U.S. Application Data and a that may be administered Simul taneously, Separately or Sequentially. The methods of treat (63) Continuation of application No. 09/778,290, filed on ment using the combinations are particularly Suitable for Feb. 7, 2001. treating moderate or severe LUTS. US 2005/0222165 A1 Oct. 6, 2005

PHARMACEUTICAL COMBINATIONS body. Neurotransmitters, Such as noradrenaline, control many physiological processes via an action on these recep 0001) This application claims the benefit of U.S. Provi tors and thereby transmit information between cells or sional Patent Application No. 60/181,310 filed Feb. 9, 2000, influence cells or influence biochemical processes within the incorporated herein by reference in its entirety. cell. Many agents capable of modifying noradrenaline activ ity on alpha-adrenoceptorS have been developed over the FIELD OF THE INVENTION last 40 years. Drugs active at alpha-adrenoceptors can be 0002 This invention relates to pharmaceutical combina broken down into two major classes, agonists and antago tions Suitable for treating the lower urinary tract Symptoms nists. Agonists, of which and (LUTS) associated with benign prostatic hyperplasia (BPH) are examples, activate the receptor System in the same way in men, which combinations contain an alpha-adrenoceptor as the endogenous neurotransmitters, and nora antagonist and a muscarinic antagonist. The combinations of drenaline. Antagonists, of which and the invention are particularly Suitable for treating moderate are examples, do not activate the receptor, but or Severe LUTS. block the actions of the endogenous neurotransmitters. 0007 Different alpha-adrenoceptor types have been dis BACKGROUND covered over the years including alpha-adrenoceptorS and alpha-adrenoceptors. These receptor types are now consid 0.003 BPH is a progressive, nearly universal condition in aging men characterized by a nodular enlargement of pro ered to be subdivided further into subtypes including alpha Static tissue resulting, through obstruction of the urethra, in 1A, 1B, 1D, 1H, 1L and N. variable degrees of bladder outlet obstruction. The disorder 0008 Alpha-adrenoceptors are known to mediate the is not a major cause of death, but it is a leading cause of contraction of vascular (arterial and venous) and prostatic morbidity in elderly men and is associated with a variety of Smooth muscle. Alpha-adrenoceptor antagonists have been lower urinary tract Symptoms. LUTS in males include, inter widely used as first line therapy for the treatment of hyper alia, increased frequency of urination, nocturia, a poor urine tension and, more recently, for the Symptomatic relief of Stream and hesitancy or delay in Starting the urine flow. BPH (see Kenny et al., Expert Opin in Invest Drugs, 1995, Chronic consequences of BPH can include hypertrophy of 4,915-923). bladder Smooth muscle, a decompensated bladder and an 0009 Alpha-adrenoceptor antagonists are known to increased incidence of urinary tract infection. The specific relieve the obstruction by causing relaxation of the prostate biochemical, histological and pharmacological properties of Smooth muscle, a decrease in urethral resistance and the prostate adenoma leading to the bladder outlet obstruc increased uroflow. As a result of these changes, male patients tion are not yet known. However, the development of BPH with the clinical symptoms of mild-moderate BPH experi is considered to be an ineScapable phenomenon for the aging ence a moderate improvement in Symptoms. The magnitude male population. BPH is commonly seen in men over the age of 50 and is observed in approximately 70% of males of the effect is considerably less than that achieved after over the age of 70. Currently, in the United States, the Surgery. method of choice for treating BPH is the administration of 0010 LUTS, although traditionally associated with BPH, alpha-adrenoceptor antagonists and, to a lesser extent, can be found in both men and women. It is noted that Surgery, usually involving transurethral resection of the Women, although they of course do not develop morpho prostate (TURP). The limitations of surgery for treating logical BPH, also suffer due to unstable bladder contrac BPH include the morbidity associated with an operative tions. The clinical Symptoms, particularly frequency and procedure in elderly men, persistence or recurrence of urgency, are similar in women and men. obstructive and irritative Symptoms, as well as the Signifi 0011 Bladder excitability is under control of the para cant cost of Surgery. In general, alpha-adrenoceptor antago Sympathetic nervous System that releases the neurotransmit nists are used only in the treatment of patients with mild or ter acetylcholine. Acetylcholine acts on protein recognition moderate LUTS. Sites in the bladder called antimuscarinic receptors, produc 0004 LUTS are recognized as arising from changes in ing an increase in electrical excitability of the bladder and urethral resistance induced by the enlarging prostate; the concentration of bladder muscle. Unstable bladder is known outflow of urine is restricted and Secondary changes are to arise due to abnormal excitability or contractility. induced in the bladder. A characteristic pattern of unstable 0012 Drugs active at muscarinic receptors can be broken bladder contractions, also known as irritable bladder, is often into two major classes, agonists and antagonists. Agonists observed in men with morphological BPH. activate the receptor System in the same way as the endog 0005 Although LUTS can arise from many causes, enous neurotransmitter acetylcholine. Muscarinic antago abnormally high activity in the Sympathetic nervous System nists (herein referred to as “antimuscarinics', of which is considered a prime determinant. Noradrenaline, a neu atropine and hyoscine are examples) do not activate the rotransmitter released from Sympathetic nerve terminals, receptor, but block the actions of the endogenous transmitter. contracts the prostatic Smooth muscle that Surrounds the Different muscarinic receptor types have been discovered urethra, increases urethral resistance and thereby reduces over the years including M1, M2 and Ms. uroflow. 0013 Antimuscarinic-agents are known to relieve many 0006 Alpha- receptors (herein also referred to of the symptoms arising from unstable or irritable bladder in as “alpha-adrenoceptors' or as “alpha-receptors') are spe Women experiencing urinary urge incontinence. The com cific protein recognition sites loaded in the peripheral and bination of Hyoscyamine and has also been central nervous Systems and other tissues throughout the found to be efficacious in treating these Symptoms in women

US 2005/0222165 A1 Oct. 6, 2005

0029. The muscarinic antagonist activity of a compound, contemplated that Separate administration of each com and therefore its Suitability for use in the present invention, pound, at different times and by different routes, will Some can be determined using a number of conventional assays in times be recommended. Thus the two components need not vitro (see, Wallis and Napier, LifeSci, 64,395-401, (1997)). necessarily be administered at essentially the same time. In the preferred embodiment the alpha-adrenoceptor antagonist 0030) A suitable combination is a muscarinic antagonist will be given Several days prior to initiation of the musca and a non-Selective alpha-adrenoceptor antagonist. rinic antagonist either daily or "on demand”. In another 0.031 Preferred combinations are a muscarinicantagonist preferred embodiment, administration is timed So that the with a selective alpha-adrenoceptor antagonist and a non peak pharmacokinetic effect of the alpha-adrenoceptor Selective alpha-antagonist with a muscarinic antagonist that antagonist precedes the peak pharmacokinetic effect of the is selective for the M receptor. muscarinic antagonist. If co-administered Separately, it is 0032. A more preferred combination is a selective alpha also preferred that both components be administered in an adrenoceptor antagonist and a muscarinic antagonist that is oral dosage form. selective for the M receptor subtype. The most preferred is 0039 The product may comprise a kit. The kit may the combination of any alpha-adrenoceptor antagonist with comprise a container for containing the Separate composi . tions Such as a divided bottle or a divided foil packet, 0.033 Preferred specific combinations include doxazosin wherein each compartment contains a plurality of dosage with darifenacin, 4-amino-6,7-dimethoxy-2-(5-methane forms (e.g., tablets) comprising either the alpha-adrenocep Sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-py tor antagonist or the muscarinic antagonist. ridyl)guinazoline and darifenacin; and pharmaceutically 0040 Alternatively, rather than separating the active acceptable Salts thereof. ingredient-containing dosage forms, the kit may contain 0034 Administering both therapeutic agents produces an Separate compartments each of which contains a whole effect that is greater than that of the alpha-adrenoceptor dosage which comprises Separate compositions. An example antagonist administered alone. This is advantageous in that of this type of kit is a blister pack wherein each individual it allows for a Smaller amount of the alpha-adrenoceptor blister contains two tablets, one tablet comprising the alpha antagonist to be administered to provide a therapeutic effect. adrenoceptor antagonist, the other comprising the muscar A further advantage is that therapy can be effected for inic antagonist. patients who, for example, do not respond adequately to the 0041 Typically the kit comprises directions for the use of the alpha-adrenoceptor antagonist at what would be administration of the Separate components. Such instruc considered a maximal Strength dose. tions would cover Situations Such as: 0035. According to one aspect of the present invention, 0042 i) the dosage form in which the components are there is provided a product (medicament) comprising a first administered (e.g. oral and parenteral), pharmaceutically acceptable composition containing an alpha-adrenoceptor antagonist and a Second pharmaceuti 0043 ii) when the component parts of the product are cally acceptable composition containing a muscarinic administered at different dosage intervals, or antagonist for use as a combined preparation for Simulta 0044) iii) when titration of the individual components of neous, Separate or Sequential use in treating the lower the combination is desired by the prescribing physician. The urinary tract Symptoms associated with benign hyperplasia container may have deposited thereon a label that describes in mammals. the contents therein and any appropriate warnings. 0036). In one embodiment, the alpha-adrenoceptor 0045 An example of Such a kit is a so-called blister pack. antagonist in the first composition is non-Selective. Prefer Blister packs are well known in the packaging industry and ably the alpha-adrenoceptor antagonist in the first compo are widely used for the packaging of pharmaceutical unit Sition is Selective for C. receptors. More preferably the dosage forms Such as tablets, capsules, and the like. Blister alpha-adrenoceptor antagonist in the first composition is packs generally consist of a sheet of relatively Stiff material selected from 4-amino-6,7-dimethoxy-2-(5-methane covered with a foil of a preferably transparent plastic mate Sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-py rial. During the packaging proceSS recesses are formed in the ridyl)guinalZoline, doxazosin, tetrazosin, abanoquil, pra plastic foil. The receSSes have the size and shape of the ZoSin and and pharmaceutically acceptable Salts tablets or capsules to be packed. Next, the tablets or capsules thereof. are placed in the recesses and the sheet of relatively Stiff 0037. The muscarinic antagonist in the second composi material is Sealed against the plastic foil at the face of the foil tion may be non-Selective. Preferably the muscarinic antago which is opposite from the direction in which the recesses nist in the Second composition is Selected from darifenacin, between the plastic foil and the sheet. Preferably, the and and pharmaceutically acceptable Strength of the sheet is Such that the tablets or capsules can Salts thereof. More preferably the muscarinic antagonist in be removed from the blister pack by manually applying the Second composition is selective for M receptors. Most preSSure on the recesses whereby an opening is formed in the preferably the muscarinic antagonist in the Second compo sheet at the place of the recess. Tablet(s) or capsule(s) can Sition is darifenacin and pharmaceutically acceptable Salts then be removed by means of the opening. thereof. 0046. It may be desirable to provide a memory aid on the 0.038. The present invention provides for the administer kit, e.g., in the form of numbers next to the tablets or ing of each of the antagonists Separately but as part of the capsules whereby the numbers correspond with the days of Same therapeutic treatment program or regimen, and it is the regimen during which the tablets or capsules So Specified US 2005/0222165 A1 Oct. 6, 2005 should be ingested. Another example of Such a memory aid cium carbonate, dibasic calcium phosphate and glycine, is a calendar printed on the card, e.g. as follows "First Week, disintegrants Such as Starch (preferably corn, potato or Monday, Tuesday, . . . etc . . . . Second Week, Monday, tapioca Starch), Sodium starch glycollate, croScarmellose Tuesday, ... ', etc. Other variations of memory aids will be Sodium and certain complex Silicates, and granulation bind readily apparent. A "daily dose” can be a Single tablet or erS Such as polyvinylpyrrolidone, hydroxypropylmethylcel capsule or Several pills or capsules to be taken on a given lulose (HPMC), hydroxypropylcellulose (HPC), sucrose, day. Also a daily dose of the first compound can consist of gelatin and acacia. Additionally, lubricating agents Such as one tablet or capsule while a daily dose of the Second magnesium Stearate, Stearic acid, glyceryl behenate and talc compound can consist of Several tablets or capsules and Vice may be included. Tablets may be manufactured by any versa. The memory aid should reflect this. Standard tablet-making proceSS, for example, direct com 0047. It is also within the scope of the present invention pression or a wet or dry granulation process. The tablet cores that both the alpha-adrenoceptor antagonist and the musca may also be coated with one or more appropriate overcoats. rinic antagonist may be present in a single composition. 0055 Solid compositions of a similar type are also Thus according to a further aspect of the invention, there is employed as fillers in gelatin capsules. Preferred excipients provided a pharmaceutical composition containing an alpha in this regard include lactose, milk Sugar, cellulose, Starch or adrenoceptor antagonist, a muscarinic antagonist and a phar high molecular weight polyethylene glycols. For aqueous maceutically acceptable carrier. Suspensions and/or elixirs, the compounds of this invention can be combined with various Sweetening agents, flavoring 0.048 Suitable alpha-adrenoceptor antagonists include agents, coloring agents or dyes, emulsifying agents and/or those that are non-selective. Preferably the alpha-adreno Suspending agents, diluents (e.g., Water, ethanol, propylene ceptor antagonist is selective for the C. receptor. More preferably the alpha-adrenoceptor antagonist is Selected glycol, glycerin and mixtures thereof and combinations from 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1, thereof. 2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)cquinazoline, 0056. The compounds of the invention can also be doxazosin, tetraZosin, abanoquil, praZOsin and indoramin administered parenterally, for example, intravenously, intra and pharmaceutically acceptable Salts thereof. arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly 0049 Suitable muscarinic antagonists include those that or Subcutaneously, or they may be administered by infusion are non-Selective. Preferably the muscarinic antagonist is techniques. For Such parenteral administration they are best Selected from darifenacin, tolterodine and oxybutynin and used in the form of a sterile aqueous Solution which may pharmaceutically acceptable Salts thereof. More preferably contain other Substances, for example, enough Salts or the muscarinic antagonist is Selective for M receptors. Most glucose to make the Solution isotonic with blood. If neces preferably the muscarinic antagonist in the Second compo Sary, the aqueous Solutions should be Suitably buffered Sition is darifenacin and pharmaceutically acceptable Salts (preferably to a pH from 3 to 9). The preparation of suitable thereof. parenteral formulations under Sterile conditions is readily 0050 Most preferred is a composition containing a com accomplished by Standard pharmaceutical techniques well bination of any alpha-adrenoceptor antagonist with darifena known to those skilled in the art. cin. Preferred specific combinations include: doxazosin and 0057 For application topically to the skin, the com darifenacin; and 4-amino-6,7-dimethoxy-2-(5-methane pounds of the invention can be formulated as a Suitable Sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-py ointment containing the active compound Suspended or ridyl)guinazoline and darifenacin; and pharmaceutically dissolved in, for example, a mixture with one or more of the acceptable Salts thereof. following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene or polyoxypropylene 0051. The compositions of the present invention, both compound, emulsifying wax and water. Alternatively, they those that contain only one component and those that can be formulated as a Suitable lotion or cream, Suspended contain both, may be Suitable for topical, oral, parenteral or or dissolved in, for example, a mixture of one or more of the rectal administration. The compositions may be formulated following: mineral oil, Sorbitan monoStearate, a polyethyl to provide immediate or Sustained release of the therapeutic ene glycol, liquid paraffin, polySorbate 60, cetyl esters wax, agent. Particularly Suitable delayed or Sustained release cetearyl alcohol, 2-oxtyldodecanol, benzyl alcohol and formulations are those disclosed in WO 97/09980. Water. 0.052 The compounds of the invention can be adminis 0058. The alpha-adrenoceptor antagonist and/or the mus tered alone but will generally be administered as an admix carinic antagonist may also be used in combination with a ture with a Suitable pharmaceutical excipient, diluent or cyclodextrin. Cyclodextrins are known to form inclusion carrier Selected with regard to the intended route of admin and non-inclusion complexes with drug molecules. Forma istration and Standard pharmaceutical practice. tion of a drug-cyclodextrin complex may modify the Solu 0.053 For example, the compounds of the invention can bility, dissolution rate, bioavailability and/or stability prop be administered orally, buccally or Sublingually in the form erty of a drug molecule. Drug-cyclodextrin complexes are of tablets, capsules, ovules, elixirs, Solutions or Suspensions, generally useful for most dosage forms and administration which may contain flavoring or coloring agents, for imme routes. As an alternative to direct complexation with the diate-, delayed-, modified-, Sustained-, pulsed- or con drug the cyclodextrin may be used as an auxiliary additive, e.g., as a carrier, diluent or Solubilizer. Alpha-, beta- and trolled-release applications. gamma-cyclodextrins are most commonly used and Suitable 0.054 Generally, tablets contain various excipients such examples are described in WO91/11172, WO 94/02518 and as microcrystalline cellulose, lactose, Sodium citrate, cal WO 98/55148. US 2005/0222165 A1 Oct. 6, 2005

0059) Other pharmaceutical components may also be Example 2 optionally included as part of the combinations useful in this invention So long as they do not interfere or adversely affect 0066. Immediate Release Darifenacin Tablet: the effects of the alpha-adrenoceptor antagonist/muscarinic antagonist combination. 0060. The exact dose of each component administered Ingredient % w/w will, of course, differ depending on the Specific components Darifenacin hydrobromide 2.976 prescribed, on the Subject being treated, on the Severity of Microcrystalline Cellulose 131.024 the LUTS, on the manner of administration and on the Calcium phosphate dibasic 6O.OOO judgement of the prescribing physician. Thus, because of Croscarmellose sodium 4.OOO patient-to-patient variability, the dosages given below are a Magnesium stearate 2.OOO guideline and the physician may adjust doses of the com Total weight 2OOOOO pounds to achieve the treatment that the physician considers appropriate for the patient, male or female. In considering the degree of treatment desired, the physician must balance 0067. The darifenacin hydrobromide, microcrystalline a variety of factorS Such as the age of the patient and the cellulose, lactose and Sodium Starch glycollate were blended presence of other diseases or conditions (e.g. cardiovascular together, passed through a Screen, then blended again. The disease). In general, the muscarinic antagonist will be blend was lubricated with magnesium Stearate and com administered in a range of from 0.5 to 200 mg per day, pressed using a tablet preSS. The resulting tablet was then preferably 10 to 125 mg per day, more preferably 25 mg to given a film coating. 100 mg per day. The alpha-adrenoceptor antagonist will generally be administered in an amount of from 0.01 mg to Example 3 50 mg per day, preferably from 0.5 to 10 mg per day. 0068 Combination Immediate Release Darifenacin/Dox 0061 Doxazosin, when in combination, will be admin azosin Tablet: istered in the range 0.25 mg to 16 mg per day, preferably 2 mg to 4 mg per day. Tolterodine will be administered twice a day in the range 0.2 mg to 2 mg per day, preferably from 0.5 mg to 1 mg per day and darifenacin will be administered Ingredient % w/w in the range 0.5 mg to 5 mg twice a day, preferably 1 mg or Doxazosin Mesylate 4.05 2 mg. All weights quoted above refer to the weight of the Darifenacin hydrobromide 2.976 compounds as the free base. Microcrystalline Cellulose 125.28 Lactose 63.694 0.062 Methods of preparing various pharmaceutical com Sodium Starch Glycolate 2.OO positions with a certain amount of active ingredient are Magnesium stearate 2.OO known, or will be apparent in light of this disclosure, to Total weight 2OOOO those skilled in this art. For examples of methods of pre paring pharmaceutical compositions, See, Remington's Pharmaceutical Sciences, Mack Publishing Company, Eas 0069. The doxazosin mesylate, darifenacin hydrobro ter, Pa., 15th Edition (1975). mide, microcrystalline cellulose, lactose and Sodium Starch 0063) The invention is further illustrated by the follow glycollate were blended together, passed through a Screen, ing, non-limiting examples. then blended again. The blend was lubricated with magne sium Stearate and compressed using a tablet press. The EXAMPLES resulting tablet was then given a film coating. Example 1 Example 4 0064. Immediate Release Doxazosin Tablet: 0070 Combination Immediate Release Doxazosin/Con trolled Release Darifenacin Tablet:

Ingredient % w/w Doxazosin Mesylate 4.05 Ingredient % w/w Microcrystalline Cellulose 125.28 Lactose 66.67 Doxazosin Mesylate 4.05 Sodium Starch Glycolate 2.OO Microcrystalline Cellulose 125.28 Magnesium stearate 2.OO Lactose 66.67 Sodium Starch Glycolate 2.OO Total weight 2OO.OO Magnesium stearate 4.OO Darifenacin hydrobromide 17.857 Methylhydroxypropyl cellulose 114.400 0065. The doxazosin mesylate, microcrystalline cellu Calcium phosphate dibasic 65.743 lose, lactose and Sodium Starch glycolate were blended Total weight 4OOOOO together, passed through a Screen, then blended again. The blend was lubricated with magnesium Stearate and com pressed using a tablet preSS. The resulting tablet was then 0071. The doxazosin mesylate, microcrystalline cellu given a film coating. lose, lactose and Sodium Starch glycolate were blended US 2005/0222165 A1 Oct. 6, 2005 together, passed through a Screen, then blended again. The a manner Such that both components co-operate pharmaco blend was then lubricated with magnesium Stearate. kinetically, preferably Such that fully effective drug plasma levels of both agents will be obtained. Co-administration is 0.072 The darifenacin hydrobromide, methylhydrox evaluated according to IPSS questionnaires mentioned ypropyl cellulose and calcium phosphate dibasic were above, thereby providing a basis for comparison of the blended together, passed through a Screen, then blended effects of co-administration with that for each Single admin again. The blend was then lubricated with magnesium istration. The efficacy of the present invention is demon Stearate. strated by the results of the IPSS questionnaire. 0073. The individual blends were then compressed on a bi-layer tablet press. The resulting tablet was then given a 1-28. (canceled) film coating. 29. A method for treating the lower urinary tract symp toms associated with benign prostate hyperplasia in mam mals comprising administering to a mammal Suffering from Example 5 benign prostate hyperplasia an effective amount of an alpha 0074 Controlled Release Darifenacin Tablet: adrenoreceptor antagonist in combination with a muscarinic antagonist. 30. The method of claim 29 wherein said alpha-adreno ceptor antagonist and Said muscarinic antagonist are admin Ingredient % w/w istered simultaneously. Darifenacin hydrobromide 17.857 31. The method of claim 29 wherein said alpha-adreno Methylhydroxypropyl cellulose 114.400 ceptor antagonist and Said muscarinic antagonist are admin Calcium phosphate dibasic 65.743 istered Separately. Magnesium stearate 2.OOO 32. The method of claim 29 wherein said alpha-adreno ceptor antagonist and Said muscarinic antagonist are admin Total weight 2OOOOO istered Sequentially. 33. The method of claim 29 wherein the alpha-adreno 0075) The darifenacin hydrobromide, methylhydrox ceptor antagonist is non-Selective or Selective for C.1 recep ypropyl cellulose and calcium phosphate dibasic were torS. blended together, passed through a Screen, then blended 34. The method of claim 29 wherein said alpha-adreno again. The blend was lubricated with magnesium Stearate ceptor antagonist is selected from the group consisting of and compressed using a tablet press. The resulting tablet was 4-amino-6,7-dimethoxy-2-(5-methaneSulfonamido-1,2,3,4- then given a film coating. tetrahydroisoquinol-2-yl)-5-(2-pyridyl)guinazoline, dox aZosin, tetraZoSin, abanoquil, prazosin, and indoramin or 0.076 The individual components of a combination of an pharmaceutically acceptable Salts thereof. alpha-adrenoceptor antagonist and a muscarinic antagonist 35. The method of claim 29 wherein said muscarinic can be tested in Vivo in an anaesthetized beagle dog model antagonist is non-Selective or Selective for M receptors. (see, Kenny, et al., Urol. 44, 52-57 (1994) in which urethral 36. The method of claim 29 wherein said muscarinic preSSure and/or bladder function are measured. However, antagonist is Selected from the group consisting of darifena the unexpected advantage of the combination can only be cin, tolterodine and oxybutynin or pharmaceutically accept determined, and thus becomes apparent, on evaluation of able salts thereof. Symptoms, an assessment that can only be carried out in 37. The method of claim 29 wherein said muscarinic a. antagonist is darifenacin, or a pharmaceutically acceptable 0077. The combination of an alpha-adrenoceptor antago Salt thereof. nist and a muscarinic antagonist can be tested clinically, 38. The method of claim 29 wherein said alpha-adreno typically orally, in humans. Each component is administered is doxazosin and Said muscarinic antago Singly at different times to a population of male patients, nist is darifenacin, or pharmaceutically acceptable Salts of each component being administered in conjunction with the either thereof. International Prostate Symptom Score (IPSS) questionnaire 39. The method of claim 29 wherein said alpha-adreno (see, Barry, et al., J. Urol., 148, 1549-1563 (1992)) which ceptor antagonist is 4-amino-6,7-dimethoxy-2-(5-methane evaluated patient Satisfaction. By administering each com Sulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-py ponent Singly, it is meant that one component is adminis ridyl)guinazoline and said muscarinic antagonist is tered, followed at a later time by the Second component after darifenacin, or pharmaceutically acceptable Salts of either having allowed an appropriate time for washout of the first thereof. component. After the washout period for each component administered singly, the components are co-administered in