CN101340946A - Pharmaceutical combination for the treatment of luts - Google Patents

Abstract

This invention relates to the combined use of a PDE5 inhibitor and a muscarinic antagonist in the treatment of lower urinary tract symptoms (LUTS), such as urgency, frequency, nocturia and urge incontinence.

Description

The drug regimen that comprises PDE5 inhibitor and muscarine antagonist that is used for the treatment of LUTS

The present invention relates to PDE5 inhibitor and the muscarine antagonist combined use in treatment lower urinary tract spmptom (LUTS).

LUTS comprises three groups of urinary symptoms, and it may be defined as storage urine (zest) symptom, (obstructive) symptom of urinating and the back symptom of urinating.Storage urine symptom comprises urgent micturition, frequent micturition, nocturia, urge incontinence and stress incontinence, this this a little relevant with overactive bladder (OAB) and benign prostatic hyperplasia (BPH).The symptom of urinating comprises urine unable (hesitancy), urinating has some setbacks (poor flow), urinates intermittent (intermittency), firmly urinates (straining) and dysuria (dysuria).The back symptom of urinating comprises terminal dribbling (terminal dribbling), dribbling after urination (post-void dribbling) and residual urine sense (sense of incomplete emptying).

Overactive bladder (OAB) is defined as urgent micturition (containing or do not contain urge incontinence), can be attended by usually frequent micturition and nocturia [Abrams etc., Neurourology and Urodynamics 21:167-178 (2002)].The popularity degree of OAB in male and women is similar, and U.S. population has about 16% to suffer from this symptom [Stewart etc., Prevalence of Overactive Bladder in the United States:Results from the NOBLE Program; Abstract Presented at the 2nd InternationalConsultation on Incontinence, July 2001, Paris, France].

Term " moist OAB (OBD Wet) " reaches " dry OAB (OBD Dry) " and describes out the OAB patient who suffers from or do not suffer from urinary incontinence respectively.Up to date, the cardinal symptom of OAB is considered to urinary incontinence.Yet along with the appearance of new terminology, this obviously is insignificant to a large amount of not patients of incontinence (being dry OAB patient).Therefore, from [' Health Related Quality ofLife Among Adults with Symptoms of Overactive Bladder:Results From A USCommunity-Based Survey ' such as Liberman; Urology 57 (6), 1044-1050,2001] nearest research checked all OAB symptoms to impact based on the quality of the life of the U.S. population sample of community.This research is illustrated, and when comparing, suffers from OAB and has impaired quality of the life without any the obvious individuality of leakage of urine.

BPH is a kind of chronic progressive disease, and it can cause the complication of for example acute urinary retention, recidivity urinary tract infection, vesical calculus and kidney malfunction.In the male, the popularity degree of the LUTS relevant with BPH and average seriousness can increase and increase along with the age.

BPH causes prostate volume to increase, cause urethra and bladder outlet to block and the secondary of bladder function changes.This effect can be by storage urine (zest) and the two performance of (obstructive) symptom of urinating.

[' Phosphodiesterase inhibition by sildenafil citrate attenuates thelearning impairment induced by blockade of cholinergic muscarinic receptors inrats ' such as Devan, Pharmacology, Biochemistry and Behaviour, vol 79, No 4, December2004, pages 691-699] the study Study on Damage whether check sldenafil citrate (a kind of PDE5 inhibitor) can reverse and be caused by eastern gelsemium henbane element (a kind of muscarinic receptor antagonists) disclosed.Yet, as from the paragraph of striding the 694th page and the 695th page as can be known, two kinds of chemical compounds can independently be applied in the injection, and be not present in the identical prescription.

WO 99/02161 discloses the purposes of selective depressant in the treatment prostatosis of PDE1, PDE4 and PDE5.

EP 1020190 discloses the purposes of PDE5 inhibitor in treatment BPH, and with regard to this purpose with the combination of alpha antagonist.

WO 01/27112 and WO 01/27113 respectively disclose a series of pyrazolo [4,3-d] pyrimidin-7-ones class, and it is the PDE5 inhibitor.Inter alia, pointed out that this chemical compound can be treated BPH, the bladder outlet is blocked and urinary incontinence.

WO 99/58478 and priority document EP 0957073 thereof disclose 3, the derivant of 3-diphenyl propylamine, comprise and fly Suo Tairuoding (fesoterodine) [R-(+)-isopropylformic acid. 2-(3-diisopropyl amido-1-phenylpropyl)-4-hydroxymethyl phenylester, capable] referring to the 62nd page of 15-16 of WO 99/58478.Inter alia, pointed out that this chemical compound can treat urinary incontinence.

US 2001/0044438 discloses alpha-adrenergic aceptor antagonist and the combined use of muscarine antagonist in the treatment LUTS relevant with BPH.

US 2004/0180958 (and corresponding WO 2004/054560) discloses the purposes of alpha-2-delta ligand in the treatment LUTS (except that urinary incontinence) relevant with OAB and/or BPH.The combined use of they and PDE5 inhibitor is also disclosed in the treatment LUTS relevant with OAB and/or BPH.

WO 89/06644 and coordinate EP 325571 thereof disclose one group 3, and 3-diphenyl propylamine class comprises tolterodine (tolterodine) [(+)-N, N-diisopropyl-3-(2-hydroxy-5-methyl base phenyl)-3-amfetamine is referring to embodiment 22].Pointed out that this chemical compound can treat urinary incontinence.

WO 94/11337 discloses one group 3, and 3-diphenyl propylamine class comprises (+)-N, N-diisopropyl-3-(2-hydroxyl-5-hydroxymethyl phenyl)-3-amfetamine (referring to embodiment 1), and it also forms by the metabolism of tolterodine.Pointed out that this chemical compound can treat urinary incontinence.

The purposes of muscarine antagonist in treatment of overactive blad-der then is described in meeting report ' the Directions in urological research and drug therapies ' of Gopalakrishnan etc., Drug Newsand Perspectives, vol 9, No 14, among November 2001 (2001-11) the pages 544-550.

US 6,642, and 274 disclose the method for treatment prostatic disorder, and described method comprises the mucosa that multiple medicine is applied directly to lower urinary tract.Advised that seven classes can be used for the treatment chemical compound in this method, comprised phosphodiesterase inhibitor and anticholinergic (this term often and term " muscarine antagonist " be used alternatingly).Advise that also this compounds can be used alone or in combination in disclosed method, but clearly do not mention the combination of PDE5 inhibitor and anticholinergic.

WO 99/65228 relates to the treatment that male's testosterone lacks, yet it can protect prostate simultaneously.This combination contains natural or synthetic androgen; Be selected from the multiple chemical compound chemical compound of (comprising testosterone 5-alpha reductase inhibitor and phosphodiesterase inhibitor).

WO 01/17480 discloses the treatment of mammal urological disorders, and it comprises the mucosa that the treatment chemical compound is applied directly to lower urinary tract.Preferred chemical compound group is described to endocrine (autocoids), cytokines class, chemotherapeutant, alpha-receptor antagonist, prostaglandin dehydrogenase inhibitor, phosphodiesterase inhibitor, anticholinergic and convulsion relieving agent.

Have been found that when PDE5 inhibitor and muscarine antagonist be used for the treatment of LUTS together particularly useful now.

Therefore, according to an aspect of the present invention, provide a kind of pharmaceutical formulation, it comprises:

The PDE5 inhibitor; With

Muscarine antagonist.

According to a second aspect of the invention, provide PDE5 inhibitor and muscarine antagonist to be used for the treatment of purposes in the medicine of LUTS in manufacturing.

According to a third aspect of the invention we, provide the method for treatment LUTS, described method comprises bestows the patient who needs this treatment simultaneously, respectively or one after the other with PDE5 inhibitor and muscarine antagonist.

According to a forth aspect of the invention, provide the drug products that comprises PDE5 inhibitor and muscarine antagonist, with as simultaneously, be used for the treatment of the combination preparation of LUTS respectively or in succession.

Multiple aspect of the present invention is known as " combination of the present invention " in this article together.

Most interested lower urinary tract spmptom is urgent micturition, frequent micturition, nocturia and urge incontinence, particularly urgent micturition.

Though the LUTS relevant with BPH only find in the male, combination of the present invention be applicable to treatment male and women the two.

Suffering from the two male of LUTS and male erectile dysfunction (MED) also can be by accepting the alleviation that combination of the present invention obtains the MED symptom.

Be applicable to that PDE5 inhibitor of the present invention comprises, but be not limited to:

(i) International Patent Application WO 03/000691; WO 02/64590; WO 02/28865; WO02/28859; WO 02/38563; WO 02/36593; WO 02/28858; WO 02/00657; WO 02/00656; WO 02/10166; WO 02/00658; WO 01/94347; WO01/94345; The PDE5 inhibitor of mentioning among WO 00/15639 and the WO 00/15228;

(ii) United States Patent (USP) 6,143, and 746; The PDE5 inhibitor of mentioning in 6,143,747 and 6,043,252;

(iii) be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the EP 0463756; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the EP0526004; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the WO 93/06104; Be disclosed in isomery pyrazolo [3,4-d] the pyrimidin-4-one class among the WO 93/07149; Be disclosed in the quinazoline-4-one class among the WO 93/12095; Be disclosed in pyrido [3,2-d] the pyrimidin-4-one class among the WO 94/05661; Be disclosed in the purine-6-one class among the WO 94/00453; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the WO 98/49166; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the WO 99/54333; Be disclosed in pyrazolo [4,3-d] the pyrimidin-4-one class among the EP 0995751; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the WO 00/24745; Be disclosed in pyrazolo [4,3-d] the pyrimidin-4-one class among the EP0995750; Be disclosed in hexahydropyrazine [2 ', 1 ': 6,1] pyrido [3, the 4-b] indole-1 also among the WO 95/19978,4-two ketones; Be disclosed in pyrazolo [4,3-d] the pyrimidin-4-one class among the WO 00/27848; Be disclosed in imidazo [5,1-f] [1,2, the 4] triazine-ketone among EP 1092719 and the WO 99/24433; Be disclosed in the dicyclic compound among the WO 93/07124; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the WO 01/27112; Be disclosed in pyrazolo [4,3-d] the pyrimidin-7-ones class among the WO 01/27113; Be disclosed in the chemical compound among the EP 1092718; Be disclosed in the chemical compound among the EP1092719; Be disclosed in the tricyclic compound among the EP 1241170; Be disclosed in the alkyl sulphone compound among the WO02/074774; Be disclosed in the chemical compound among the WO 02/072586; Be disclosed in the chemical compound among the WO 02/079203; With the chemical compound that is disclosed among the WO 02/074312;

(iv) 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazine sulfuryl) phenyl]-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil), also be known as 1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d] pyrimidine-5-yl)-and the 4-ethoxyl phenenyl] sulfuryl]-4-methyl piperazine (referring to EP 0463756); 5-(2-ethyoxyl-5-morpholino acetylphenyl)-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to EP 0526004); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfuryl)-2-positive propoxy phenyl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 98/49166); 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfuryl)-2-(2-methoxy ethoxy) pyridin-3-yl]-2-(pyridine-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 99/54333); (+)-3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfuryl)-2-(2-methoxyl group-1 (R)-methyl ethoxy) pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones, also be known as 3-ethyl-5-{5-[4-ethyl piperazidine-1-base sulfuryl]-2-([(1R)-and 2-methoxyl group-1-Methylethyl] the oxygen base) pyridin-3-yl }-2-methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 99/54333); 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones, also be known as 1-{6-ethyoxyl-5-[3-ethyl-6,7-dihydro-2-(2-methoxy ethyl)-7-oxo-2H-pyrazolo [4,3-d] pyrimidine-5-yl]-3-pyridine radicals sulfuryl }-4-ethyl piperazidine (referring to WO 01/27113, embodiment 8) [interested especially] in free alkali and benzene sulfonate; 5-[2-is different-butoxy-5-(4-ethyl piperazidine-1-base sulfuryl) pyridin-3-yl]-3-ethyl-2-(1-methyl piperidine-4-yl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO01/27113, embodiment 15); 5-[2-ethyoxyl-5-(4-ethyl piperazidine-1-base sulfuryl) pyridin-3-yl]-3-ethyl-2-phenyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27113, example 66); 5-(5-acetyl group-2-propoxyl group-3-pyridine radicals)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27112, example 124); 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (referring to WO 01/27112, example 132); (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base) pyrazine is [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1 also, and (tower draws non-(tadalafil) greatly to the 4-diketone, IC-351, sharp scholar (Cialis) ), that is, and the embodiment 78 of WO 95/19978 and 95 chemical compound, and the chemical compound of embodiment 1,3,7 and 8; 2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfuryl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil (vardenafil), upright prestige mistake (Levitra)

), also be known as 1-[[3-(3,4-dihydro-5-methyl-4-oxo-7-propyl imidazole is [5,1-f]-as-triazine-2-yl also)-4-ethoxyl phenenyl] sulfuryl]-the 4-ethyl piperazidine, that is, and the embodiment 20,19,337 of WO 99/24433 and 336 chemical compound; The chemical compound of the embodiment 11 of WO 93/07124 (Ai Sai (EISAI)); From Rotella D P, J.Med.Chem., 2000,43,1257 chemical compound 3 and 14; 4-(4-benzyl chloride base) amino-6,7,8-trimethoxy quinazoline; N-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl group-1H-pyrazolo [4,3-d]-pyrimidine-5-yl)-4-propoxyl group phenyl] sulfuryl]-1-methyl-2-pyrrolidine propionic acid amide. [" DA-8159 " (embodiment 68 of WO 00/27848)]; With 7,8-dihydro-8-oxo-6-[2-propoxyl group phenyl]-1H-imidazo [4,5-g] quinazoline and 1-[3-[1-[(4-fluorophenyl) methyl]-7,8-dihydro-8-oxo-1H-imidazo [4,5-g] quinazoline-6-yl]-4-propoxyl group phenyl] Methanamide;

(v) 4-bromo-5-(pyridylmethyl amino)-6-[3-(4-chlorphenyl)-propoxyl group]-3 (2H) 2H-Pyridazin-3-one; 1-[4-[(1,3-benzo dioxolanes-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-4-piperidines-carboxylic acid, a sodium salt; (+)-suitable-5,6a, 7,9,9,9a-six hydrogen-2-[4-(trifluoromethyl)-phenyl methyl-5-methyl-ring penta-4,5] imidazo [2,1-b] purine-4 (3H) ketone; XiLin, husband Lip river (furazlocillin); Suitable-2-hexyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydro ring penta [4,5]-imidazo [2,1-b] purine-4-ketone; 3-acetyl group-1-(2-benzyl chloride base)-2-propyl indole-6-carboxylate; 3-acetyl group-1-(2-benzyl chloride base)-2-propyl indole-6-carboxylate; 4-bromo-5-(3-pyridylmethyl amido)-6-(3-(4-chlorphenyl) propoxyl group)-3-(2H) 2H-Pyridazin-3-one; I-methyl-5 (5-morpholino acetyl group-2-positive propoxy phenyl)-3-n-pro-pyl-1, and 6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-ones; 1-[4-[(1,3-benzo dioxolanes-5-ylmethyl) amino]-6-chloro-2-quinazolyl]-4-piperidine carboxylic acid one sodium salt; Drug development (Pharmaprojects) No.4516 (Glaxo Wellcome); Drug development No.5051 (Bayer); Drug development No.5064 (Kyowa Hakko; Referring to WO96/26940); Drug development No.5069 (Schering Plough); GF-196960 (GlaxoWellcome); E-8010 and E-4010 (Eisai); Bay-38-3045 ﹠amp; 38-9456 (Bayer); FR229934 and FR226807 (Fujisawa); And Sch-51866;

And officinal salt.

Preferred PDE5 inhibitor comprises: 5-[2-ethyoxyl-5-(4-methyl isophthalic acid-piperazine sulfuryl) phenyl]-1-methyl-3-n-pro-pyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (sldenafil), particularly sldenafil citrate; (6R, 12aR)-2,3,6,7,12,12a-six hydrogen-2-methyl-6-(3,4-methylenedioxyphenyl base)-pyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indole-1,4-diketone (IC-351 or tower draw non-greatly); 2-[2-ethyoxyl-5-(4-ethyl-piperazine-1-base-1-sulfuryl)-phenyl]-5-methyl-7-propyl group-3H-imidazo [5,1-f] [1,2,4] triazine-4-ketone (Vardenafil); 5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; 5-(5-acetyl group-2-propoxyl group-3-pyridine radicals)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones; 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones; 4-[(3-chloro-4-methoxy-benzyl) amino]-2-[(2S)-2-(methylol) pyrrolidine-1-yl]-N-(pyrimidine-2-base methyl) pyrimidine-5-Methanamide (TA-1790); 3-(1-methyl-7-oxo-3-propyl group-6,7-dihydro-1 h-pyrazole be [4,3-d] pyrimidine-5-yl also)-N-[2-(1-methylpyrrolidin-2-yl) ethyl]-4-propoxyl group benzsulfamide (DA 8159); And officinal salt.

More preferably, this PDE5 inhibitor is selected from sldenafil, tower and draws non-, Vardenafil, DA-8159 and 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl greatly]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones, and officinal salt.

Most preferably, this PDE5 inhibitor is selected from sldenafil, 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones and officinal salt thereof.The sldenafil citrate is preferred sldenafil salt.Benzene sulfonate is preferred 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones salt.

Be applicable to that muscarine antagonist of the present invention can be to M ₃Receptor is optionally, or they can be nonselective, to M ₁, M ₂And M ₃Has antagonism.Preferably to M ₃The receptor tool is antagonist optionally.

Specific muscarine antagonist comprises:

Atropine (atropine);

Fu Lufo writes spy (fluvoxate);

Scopolamine (hyoscine);

Oxibutynin (oxybutynin);

Darifenacin (darifenacin);

Tolterodine and other are disclosed in the chemical compound in the International Patent Application WO 89/06644;

(+)-N, N-diisopropyl-3-(2-hydroxyl-5-hydroxymethyl phenyl)-3-amfetamine and other are disclosed in the chemical compound among the WO 94/11337;

Propantheline (propantheline);

Propiverine (propiverine);

A wrong department grace (trospium);

Saliphen is hot (solifenacin) how;

Fly Suo Tairuoding (festerodine) and other and be disclosed in chemical compound among the WO 99/58478;

Be disclosed in the chemical compound among the WO 98/05641;

And officinal salt.

Particularly preferably be:

Darifenacin;

Oxibutynin;

Tolterodine;

(+)-N, N-diisopropyl-3-(2-hydroxyl-5-hydroxymethyl phenyl)-3-amfetamine;

How hot Saliphen is;

Fly Suo Tairuoding;

And officinal salt.

Interestedly especially be tolterodine (particularly its tartrate form) and fly Suo Tairuoding (or its officinal salt, as difumarate).

According to another aspect of the invention, provide a kind of pharmaceutical formulation, it comprises:

The PDE5 inhibitor; With

Muscarine antagonist;

As long as when described muscarine antagonist was eastern gelsemium henbane element or its salt, described PDE5 inhibitor was not sldenafil or its salt.

Combination of the present invention can have following advantage: two kinds of component synergism, self compare unexpected effective function and/or unexpected favourable side effect level to produce one of these components with corresponding accumulated dose.In addition, combination of the present invention can have more useful properties of the selectivity of compared with prior art longer action period, improvement or other.

Can use the method for well known to a person skilled in the art to prepare the component composition of combination of the present invention.Especially, above-mentioned patent, patent application and open (all by with reference to incorporating this paper into) have been enumerated chemical compound, pharmaceutical composition, method and test kit according to use capable of being combined of the present invention, and relate to the method for preparing these chemical compounds.

The officinal salt that is applicable to chemical compound of the present invention comprises sour addition and alkali salt thereof.

The summary of acceptable acid addition salts is referring to " Handbook of Pharmaceutical Salts:Properties, Selection, and Use " by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Can suitably mix with acid or the alkali wanted by solution, easily prepare the officinal salt that is applicable to chemical compound of the present invention chemical compound.Can be from solution deposited salt and collect by filtering, maybe can reclaim by evaporating solvent.Degree of ionization in the salt can be to be changed to almost unionization from complete ionizing.

The chemical compound that is applicable to combination of the present invention comprises chemical compound and polymorphs body, prodrug and the isomer (comprising optics, geometry and compounds tautomeric) that defines as hereinbefore.

Usually, the chemical compound that use in the present invention will be as being applied with the bonded prescription of one or more pharmaceutically acceptable excipient.The selection of described excipient depends on following factor largely, as specific mode of administration, excipient to dissolubility and the effect of stability and the character of dosage form.These chemical compounds may reside in the dosage form identical with a first aspect of the present invention, or they may reside in independently in the dosage form, for example the dosage form that a fourth aspect of the present invention comprised.

Be applicable to carry and be applicable to that the pharmaceutically acceptable composition and method of making the same of the chemical compound that the present invention makes up is that those skilled in the art are conspicuous.This based composition and preparation method thereof for example is found in ' Remington ' s Pharmaceutical Sciences ', among the 19th Edition (Mack PublishingCompany, 1995).

Preferably, be applicable to chemical compound that the present invention makes up by Orally administered, therefore prescription of the present invention, purposes, method and product should be applicable to or relate to Orally administered.Swallow Orally administered comprising, so that this chemical compound enters gastrointestinal tract; Maybe can use cheek or sublingual administration, this chemical compound can tap into the blood flow from outspoken by this.

Be applicable to that Orally administered prescription comprises solid for mulation, as tablet, comprise the capsule of microgranule, liquid or powder, lozenge (liquid that comprises filling), masticatory, multiple microgranule and nanoparticle, gel, solid solution, liposome, thin film (comprising mucoadhesive), ovulum (ovules), spraying and liquid formulations.Preferred tablet and capsule.

Liquid formulations comprises suspension, solution, syrup and elixir.This class prescription can be used as the filler agent of soft capsule or hard capsule, and it typically comprises carrier (for example, water, ethanol, Polyethylene Glycol, propylene glycol, methylcellulose or suitable oil) and one or more emulsifying agents and/or suspending agent.Liquid formulations also can prepare by solid reconstruct (for example from capsule).

Be applicable to that the chemical compound of the present invention in making up can use with quick dissolving, the dosage form of decomposing fast, Expert Opinion in Therapeutic Patents for example, 11 (6), the dosage form described in the 981-986by Liang andChen (2001).

For Tabules, based on dosage, the 1wt% (weight %) that described medicine can constitute dosage form is to 80wt%, more typically from the 5wt% of dosage form to 60wt%.Except medicine, tablet contains disintegrating agent usually.The hydroxypropyl cellulose that examples of disintegrants comprises sodium starch glycolate, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, croscarmellose (croscarmellose) sodium, crospovidone (crospovidone), polyvinylpyrrolidone, methylcellulose, microcrystalline Cellulose, replace through the lower alkanols alkyl, starch, through pregelatinized starch and sodium alginate.Generally speaking, disintegrating agent accounts for the 1wt% of this dosage form to 25wt%, and preferred 5wt% is to 20wt%.

The common cohesion character of using binding agent to give tablet formulation.Suitable bonding comprises microcrystalline Cellulose, gelatin, saccharide, Polyethylene Glycol, natural and synthetic glue class, polyvinylpyrrolidone, through pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl emthylcellulose.Tablet also can contain diluent, for example lactose (monohydrate, spray-dired monohydrate, anhydride etc.), mannitol, xylitol, glucose, sucrose, Sorbitol, microcrystalline Cellulose, starch and dicalcium phosphate dihydrate.

Tablet also can randomly comprise: surfactant, for example sodium lauryl sulfate and polyoxyethylene sorbitan monoleate; And fluidizer, as silicon dioxide and Talcum.When having surfactant, its 0.2wt% that can account for tablet is to 5wt%, and fluidizer can account for the 0.2wt% of tablet to 1wt%.

Tablet also contains lubricant, for example mixture of magnesium stearate, calcium stearate, zinc stearate, stearyl fumarate and magnesium stearate and sodium lauryl sulfate usually.Lubricant accounts for the 0.25wt% of tablet usually to 10wt%, and preferred 0.5wt% is to 3wt%.

Other possible composition comprises antioxidant, coloring agent, flavoring agent, antiseptic and mask agent.

Exemplary tablet contains the highest about 80% medicine, the binding agent from about 10wt% to about 90wt%, the diluent from about 0wt% to about 85wt%, the disintegrating agent from about 2wt% to about 10wt% and the lubricant from about 0.25wt% to about 10wt%.

Tablet mixture can be suppressed directly or by cylinder forms tablet.Perhaps can be before film-making to the part of tablet mixture or mixture carry out wet granulation, dry type granulation or fusion granulation, melt freezes or extrude.Final prescription can comprise one layer or more, and can be through the bag quilt or without the bag quilt; Itself in addition can be loaded into capsule.

Being formed on of tablet " Pharmaceutical Dosage Forms:Tablets, Vol.1 ", by H.Lieberman and L.Lachman, Marcel Dekker, N.Y. discusses among the N.Y., 1980 (ISBN 0-8247-6918-X).

Be used for that Orally administered solid for mulation can be configured to immediately and/or modified release type.Modified release formulation comprises delay, that continue, pulse, controlled, directed and release sequencing.

When described muscarine antagonist was darifenacin, the suitable modified prescription that is used for the object of the invention was described in U.S. Patent No. 6,106, in 864.The suitable modified release formulation of tolterodine is described among WO 00/12069, WO 00/27364 and the WO 01/34139.These prescriptions can be modified to second active component that comprises according to combination of the present invention.It is preferred being used for the Orally administered modified release capsule of this class.

The details of the suitable release tech of this class (for example high energy dispersion liquid and permeability and coated granule) is found in Verma etc., Pharmaceutical Technology On-line, 25 (2), 1-14 (2001).Using chewing gum to reach controlled release then is described among the WO 00/35298.

Be applicable to that chemical compound in the combination of the present invention can directly be used and enter blood flow, enter muscle or enter in the internal organs.The appropriate means that is applicable to parenteral administration comprises in intravenous, intra-arterial, intraperitoneal, the canalis spinalis, in the ventricle, in the urethra, in the breastbone, intracranial, intramuscular and subcutaneous.The device that is used for parenteral administration comprises needle-like (comprising the micropin head) syringe, needleless injector and infusion techn.

The parenteral prescription typically is aqueous solution, and it can contain excipient (for example salt, carbohydrate) and buffer agent (preferably to from 3 to 9 pH); But concerning some was used, they can more suitably be formulated into aseptic non-aqueous solution, or are formulated into the dried forms that will be used in combination with suitable supporting agent (for example aseptic, apirogen water).

Can use the standard pharmaceutical technology of well known to a person skilled in the art easily to reach this parenteral prescription of preparation (for example, passing through freeze-drying) under aseptic condition.

The dissolubility that is used for the chemical compound of parenteral solution preparation can improve by using suitable preparation technique (for example, mixing solubilizing agent).

The prescription that is used for parenteral administration can be configured to immediately and/or modified release type.Modified release formulation comprises delay, that continue, pulse, controlled, directed and release sequencing.Therefore, chemical compound of the present invention can be formulated into solid, semisolid or thixotropic liquid, is used for accumulating (depot) as implantation and uses, and the modified release of reactive compound is provided.The example of this class prescription comprises the support and the PGLA microsphere of pharmaceutical pack quilt.

Be applicable to that the chemical compound that uses in combination of the present invention also can be by local application to skin or mucosa, promptly skin is used or applied dermally.The representative formula that is used for this purpose comprises gel, hydrogel, lotion, solution, cream, ointment, loose powder, dressing, foam, thin film, transdermal patches, wafer (wafer), implant, sponge, fiber, binder and microemulsion.Also can use liposome.Typical delivery agent comprises alcohol, water, mineral oil, liquid paraffin, paraffinum molle alba, glycerol, Polyethylene Glycol and propylene glycol.Can mix penetration enhancer, referring to for example, J Pharm Sci, 88 (10), 955-958 byFinnin and Morgan (October 1999).

Other local application means comprise by electroporation, iontophoresis, ultrasonic method (phonophoresis), phonophoresis method (sonophoresis) and micropin head or the needleless (Powderject for example that penetrates ^TM, Bioject ^TM, or the like) inject and transmit.

The prescription that is used for local application can be formulated into immediately and/or modified release.Modified release formulation comprises delay, that continue, pulse, controlled, directed and release sequencing.

Be applicable to that the chemical compound that uses also can intranasal or be applied by suction in the present invention combination, typically (separately with dry powder; Or as mixture, for example with the drying composite of lactose in; Or, for example mix with phospholipid such as phosphatidylcholine as blended composition granule) form use from Diskus, or (use or do not use suitable propellant from pressurizing vessel, pump, sprinkler, nebulizer (preferably using electrohydrodynamics to produce the nebulizer of meticulous fog) or aerosol apparatus as aerosol spray, for example 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3, the 3-heptafluoro-propane) use.Intranasal is used, and described powder can comprise bioadhesive agents, for example, and chitosan or cyclodextrin.

Described pressurizing vessel, pump, sprinkler, nebulizer or aerosol apparatus contain the solution or the suspension of The compounds of this invention, it comprises for example ethanol, ethanol water, or be applicable to dispersion, solubilising or prolong the suitable alternative reagent that discharges this active substance, propellant such as solvent and optional surfactant are as three oleic acid sorbitan esters, oleic acid or lactic acid oligomer.

Before using in dry powder or suspension formulation, this drug products can be micronized into and be applicable to the size (typically less than 5 microns) of sending by suction.This can reach for example spiral spray grinding, thermopnore jet grinding, the supercritical fluid that can be processed to form nano-particle, high pressure homogenizing or spray drying by any suitable method of grinding into powder.

Capsule (for example making from gelatin or HPMC), cover bubble (blister) and the cartridge case that is used for inhaler or insufflator can be mixed with and contain The compounds of this invention, the suitable basic thing (for example lactose or starch) of powder and the mixture of powders of modifier (for example 1-leucine, mannitol or magnesium stearate).Described lactose can be the form of anhydrous or monohydrate, the preferred latter.Other suitable excipient comprises glucosan, glucose, maltose, Sorbitol, xylitol, fructose, sucrose and trehalose.

The appropriate solution prescription that is used for nebulizer (it uses Electrofluid Mechanics to produce meticulous fog) can contain the The compounds of this invention of each driving 1 μ g to 20mg, drives volume and can be changed to 100 μ l from 1 μ l.Typical prescription can comprise chemical compound of the present invention, propylene glycol, sterilized water, ethanol and sodium chloride.Can be used for replacing the alternative solvent of propylene glycol to comprise glycerol and Polyethylene Glycol.

Suitable flavoring agent (for example Mentholum and levomenthol) or sweetener (for example glucide or saccharin sodium) can be added the purpose of the present invention is to be used in to suck/those prescriptions of intranasal administration in.

Be used to suck/prescription of intranasal administration for example can use poly (DL-lactic acid-glycolic) altogether (PGLA) to be formulated as immediately and/or modified release.This modified release formulation comprises delay, that continue, pulse, controlled, directed and release sequencing.

Be applicable to that the chemical compound that uses can for example come rectum or vaginal application with the form of suppository, vaginal suppository or enema in combination of the present invention.Cocoa butter is traditional suppository base, but suitable words can be used multiple standby.

The prescription that is used for rectum/vaginal application can be formulated into immediately and/or modified release.Modified release formulation comprises delay, that continue, pulse, controlled, directed and release sequencing.

Be applicable to that the chemical compound that uses can combine with soluble macromole entity (for example cyclodextrin and suitable derivant thereof or contain the polymer of Polyethylene Glycol) in combination of the present invention, but cover to improve its dissolubility, rate of dissolution, taste, biology availability and/or the stability in any aforementioned mode of administration, used.

For example, find that the drug-cyclodextrin complex is applicable to most dosage form and route of administration usually.Can use envelope and non-envelope complex the two.Except direct and medicine complexation, described cyclodextrin can be used as auxiliary additive, promptly as carrier, diluent or lytic agent.Be most commonly used to these purposes have α-, β-and gamma-cyclodextrin, its example is found among international patent application No.WO91/11172, WO 94/02518 and the WO 98/55148.

According to a forth aspect of the invention, can make up two or more pharmaceutical compositions with the form that is applicable to the test kit of using compositions jointly expediently.

Therefore, the test kit of the present invention means (for example container, the bottle that separates or the paper tinsel parcel that separates) that comprise two or more independently medical compositions (wherein at least a contain mentioned above according to chemical compound of the present invention) and be used for keeping independently described compositions.The example of such test kit is the cover blister package of knowing that are used for package troche, capsule or the like.

Test kit of the present invention is specially adapted to use different dosage form (for example, oral and parenteral), is applicable to the various dose interval and uses independently compositions, or is applicable at the compositions independently of titration each other.In order to promote compliance (compliance), this test kit typically comprises uses description, and so-called memory aid can be provided.

For fear of query, " treatment " mentioned in this article comprises healing property, retentivity and prophylactic treatment.

The suitable dose that is applicable to the chemical compound of using in combination of the present invention will depend on related chemical compound, symptom to be treated and patient's body weight.Yet suitable muscarine antagonist dosage every day is in the scope of 0.1-100mg: for example, tolterodine tartrate is 0.1-4mg usually; For flying Suo Tairuoding or its officinal salt is 0.2-8mg.Generally speaking, suitable PDE5 inhibitor dosage every day is in the 0.1-120mg scope: for example, the sldenafil citrate is 2.5-100mg; To 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones or its officinal salt are 0.5-200mg; Draw non-greatly and officinal salt is 0.5-20mg for Vardenafil, tower.

Certain preferred being combined as of the present invention:

Sldenafil or its officinal salt+tolterodine or its officinal salt;

Sldenafil or its officinal salt+fly Suo Tairuoding or its officinal salt;

5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones or its officinal salt+tolterodine or its officinal salt; And

5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones or its officinal salt+fly Suo Tairuoding or its officinal salt.

In these specific preferred compositions, the typical weight ratio of active component [PDE5 inhibitor: muscarine antagonist] can be changed to 10: 1 from 1: 10, for example, and 1: 4 to 4: 1,1: 3 to 3: 1,1: 2 to 2: 1, and comprise 1: 1.

Example 1

The tablet of release type immediately that comprises tolterodine and sldenafil

The tablet that uses the conventional method preparation to have following compositions:

Core

Tolterodine L-tartrate 2.0mg

Sldenafil citrate 25.0mg

Cellulose, crystallite 53.4mg

Dicalcium phosphate dihydrate 18.0mg

Explotab 6.0mg

Magnesium stearate 0.4mg

Colloid anhydride silica 0.2mg

Coating

Methylhydroxypropylcellulose 1.5mg

Cellulose, crystallite 0.3mg

Stearic acid 0.6mg

Titanium dioxide E 171 0.6mg

Embodiment 2

Comprise tolterodine and 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2, the tablet that the tablet of release type immediately of 6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones uses the conventional method preparation to have following compositions:

Core

Tolterodine L tartrate 2.0mg

5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-the 3-ethyl-

5.0mg

2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones

Cellulose, crystallite 53.4mg

Dicalcium phosphate dihydrate 18.0mg

Explotab 6.0mg

Magnesium stearate 0.4mg

Colloid anhydride silica 0.2mg

Coating

Methylhydroxypropylcellulose 1.5mg

Cellulose, crystallite 0.3mg

Stearic acid 0.6mg

Titanium dioxide E 171 0.6mg

Embodiment 3

Comprise and fly Suo Tairuoding and 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2, the tablet of release type immediately of 6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones

The tablet that uses the conventional method preparation to have following compositions:

Core

Fly Suo Tairuoding difumarate 2.0mg

5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-the 3-ethyl-

2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones benzene 5.0mg

Sulfonate

Cellulose, crystallite 53.4mg

Dicalcium phosphate dihydrate 18.0mg

Explotab 6.0mg

Magnesium stearate 0.4mg

Colloid anhydride silica 0.2mg

Coating

Methylhydroxypropylcellulose 1.5mg

Cellulose, crystallite 0.3mg

Stearic acid 0.6mg

Titanium dioxide E 171 0.6mg

Embodiment 4

The controlled release type capsule that contains tolterodine and sldenafil

According to the example 1 of WO 00/27364, the controlled release type globule that contains tolterodine tartrate can be manufactured and have following array structure:

Core: the starch-containing sugared ball of about 0.8 mm dia (can commerce buy) accounts for the 73%w/w into final globule;

Purpose: coated substrate;

Ground floor: Surelease ^TM" sealing coating " (Surelease ^TMBe aqueous thin film bag by dispersion liquid, it contains about 25% solid, mainly by forming with the plastifying ethyl cellulose of fractionated Oleum Cocois, and by Colorcon, Inc, USA makes); It comprises about 12%w/w of final globule;

Purpose: for more uniform core surfaces is provided; Maximization medicine saturated time in globule during the drug release stage, and minimum permeation effect; With the 3rd layer of control drug release speed;

The second layer: tolterodine L-tartrate/hydroxypropyl emthylcellulose (HPMC); It accounts for about 3%w/w of final globule; The ratio of tolterodine: HPMC is 5: 1;

Purpose: supply medicine;

The 3rd layer: Surelease ^TM/ HPMC; It accounts for about 12%w/w of final globule; Surelease ^TM: the ratio of HPMC is 6: 1;

Purpose: control release rate of drugs.

Be prepared as follows and have three layers of globule with coating of above-mentioned feature:

1200g 20-25 purpose sugar ball is charged in the Wurster fluid bed, under 36 to 40 ℃ specified product temperature, wraps subsequently by following three kinds of coating buffer bodies:

-(1) is by the Surelease with 788 grams ^TMMix with the purified water of 563 grams and to prepare Surelease ^TMSealed packet is by liquid;

-(2) are mixed this solution then and are prepared the solution that contains medicine by at first the tolterodine L-tartrate of 35.0g being dissolved in the purified water of 2190 grams with HYDROXY PROPYL METHYLCELLULOSE (HPMC) 5cP of 6.6g; And

Mix by the water that HPMC 5cP and the 375g of 29 grams is purified-(3), then with 695 Surelease that restrain ^TMMix and prepare sustained releasing type coating buffer body.

Prepare the controlled release type globule that contains the sldenafil citrate with similar means, but replace the tolterodine tartrate of 35 grams in the coating buffer body (2) with the sldenafil tartrate of 70mg.

, coated ball is inserted in the hard gelatin capsule of size #4 or size #3 after 3 hours 70 ℃ of following tray dried, acquisition contains the capsule of the compositions of 2mg tolterodine L-tartrate and 4mg sldenafil citrate:

Tolterodine L-tartrate 2.0mg

Sldenafil citrate 4.0mg

The sugar ball, 20-25 order 137.2mg

Surelease ^TM 42.4mg

HPMC 5cP 4.0mg

Alternatively, can before being dried, apply the 4th layer of coating to globule by the Wurster bag.

The 4th layer: HPMC; It accounts for about 1%w/w of final globule;

Purpose: reduce the adhesiveness that is used for the globule of post-treatment (sclerosis and capsule are filled).

Under the situation of above-mentioned globule, can make bag be applied the 4th layer by solution, described bag is dissolved in 234 water that restrain by the HPMC with 16.4 grams by solution and prepares.

Biology embodiment A

In a large amount of animal species, developed and related to the BPH experimental model that bladder outlet blocks.The prostate obturation of these models (it relates to around urethra placement rope band or disc) imitation urethra, and cause do not urinate apparent, or the instability of bladder is shunk [Levin et al (2000) In:Prostatic Diseases (eds Lepor and Oesterling), WB Saunders ﹠amp in the assessment of Bladder Volume pressure; Co.].In addition, these models have reproduced the relevant LUT symptom of OBD many and multiple form, comprise increasing urinating frequency and reducing the function capacity of urinating.

The useful effect of combination of the present invention can be illustrated in the following LUTS mouse model relevant with BPH.

The mouse model of short-term urethral obstruction characterized and be proved shown the frequency and have non-urinating property contraction of urinating that improves, this bladder capacity with minimizing be associated (Schroder et al. (2003) J.Urol.170,1017-1021).The advantage of this model is that it has critically imitated observed bladder function obstacle in BPH patient and the LUTS relevant with other overactive bladder symptom.

Material and method

Animal: (it can derive from Charles River Laboratories, UK) is used for research to use the DBA/1LacJ mice.Arrive at the back under identical condition, down mice was lived for 6 weeks, food and water arbitrarily are provided in 12 little time/dark light circulation.

Mice is divided into 3 groups at random.1/3rd accept following bladder outlet blocks (BOO), and 1/3rd accept sham-operation.Remaining mice is as the not contrast of operation.

Operating procedure: with ketamine (Ketalar

, Parke Davis, Barcelona, Spain; 100mg/kg IP) and xylazine (Rompun

, Bayer, Leverkusen, Germany, 15mg/kg IP) and the mice of anesthesia BOO group.By 2003 J.Urol 170 such as Schroder, the standardized method described in the 1017-1021 causes obstruction.The sham-operation animals received is similarly performed the operation, but not ligation is blocked.

Blocked the back the 5th day, (PE, ID 0.38mm OD0.61mm) insert the bladder top, and it are fixing to sew up (7-0 silk) with bundling type will to have the polyethylene catheter of little cuff.Stop band keeps in position.Subcutaneous break-through catheter is also drawn it on nape, fix in the surgery mode.Preceding 2 days of cystometry makes the control animal winding be subjected to the bladder catheter.

Cystometry: behind the insertion catheter two days (cause and blocked back 7 days), carry out cystometry research without any anesthesia or inhibition ground.Mice is placed in the metabolic cage (Gazzada, Buguggiatade, Italy).The bladder catheter is connected with pressure converter, described pressure converter subsequently with Grass

7E Polygraph logging machine connects.At room temperature,, fill bladder continuously with saline with the filling speed of 25 μ l/min by means of micro syringe pump (CMA 100, CarnegieMedicine, Solna, Sweden).

By means of with power displacement transducer (FT 03D; Grass instrument Co., MA, USA) fluid collector of Lian Jieing is measured voided volume.After 60-80 minute stable period (bladder is filled continuously), reached the reproducible pattern and it is being carried out record surpassing in 30 minutes cycle of urinating therebetween.Measure following parameter: the interval of urinating (2 times urinate between time), baseline pressure (2 times urinate between minimum pressure), face pressure limiting power (before the beginning of urinating at once pressure), the pressure of urinating (voiding peak pressure power) and the volume of urinating.When cystometry finished, remaining urine manually emptied 3 times and measures.The salt water yield of injecting bladder between bladder capacity is calculated as and urinates for twice time adds the average magnitude of residual urine.

Observe animal continuously, thereby between mobile illusion (moving artifacts) and non-urinating property bladder contraction, distinguish.Spray the polysiloxane thin layer on the collection funnel surface under the metabolic cage net grid.

Biology Embodiment B

The useful effect of combination of the present invention can be illustrated in following experimental model, and described experimental model has been estimated according to test substances in the guinea pig of (Eur J Pharmacol.383:137-303,1999) such as Doe the effect of lower urinary tract function.

Material and method

Animal: female Hartley guinea pig (body weight 300-350 gram).

Operating procedure: with urethane (intraperitoneal 1.5g/kg) anesthetized animal, described urethane gives with 20% broken dose after initial 80% and 15 minute.Body temperature maintains 37 ± 2 ℃ in whole experiment.Expose bladder by following abdominal incision, and will have the polyethylene catheter insertion bladder top of little cuff, and with the bundling type sutured.Ligation ureter then.Bladder is placed under the stomach wall and conduit is connected with pressure transducer by the T-pipe, thus the measurement intravesical pressure.Carry out the organ intubate.To the jugular vein intubate allowing to use test compounds, thereby and femoral arteriography collected plasma sample.

Cystometry: during whole experiment measuring week, carry out a series of filling cystometry circulation, to set up baseline parameter and to measure drug effect.Before each cystometry circulation, manually empty bladder.With the flow velocity of 600 μ L/min the saline continuous infusion under the room temperature is entered bladder by conduit then, up to urinating.Measure the following parameter of urinating in each cystometry cycle period :-pressure of urinating (MP, the pressure during the drainage in the bladder) and critical size (ThV, the volume when urinating generation, mL).

Estimate drug effect: after the establishment of base line parameter (3 circulation averages of urinating), with test substances or supporting agent continuous administration 60 minutes.When the infusion of drug end cycle, measure the effect of medicine to the cystometry parameter by the average of taking the measured value of generation in two circulations of urinating.For combination research, measure baseline parameter after, in 60 minutes cycle with the dosage separately of test compounds infusion together.

The result:

Muscarine antagonist oxibutynin (3.18mg/kg) has produced in the pressure of urinating in a small amount and has improved, and PDE5 inhibitor 3-ethyl-5-[5-(4-ethyl piperazidine-1-base sulfuryl)-2-positive propoxy phenyl]-1-(pyridine-2-yl) methyl isophthalic acid, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones (is called " compd A " herein, consult WO 98/49166 embodiment 2,0.11mg/kg, 0.32mg/kg) in the pressure of urinating, produced reduction in a small amount.Oxibutynin (3.18mg/kg) adds that being combined in of compd A (0.32mg/kg) produced in the pressure of urinating than the observed separately bigger pressure reduction of urinating of compd A (0.32mg/kg).Therefore, these data suggest the oxibutynin of test and more the compd A of high dose to the synergism of the pressure of urinating.

(0.11mg/kg, 0.32mg/kg) effect to critical size is shown in the table 1 for independent and oxibutynin (3.18mg/kg) combination and compd A.

Table 1: oxibutynin and compd A are to the effect of cystometry parameter in the dopey guinea pig

Treatment	The pressure of urinating changes %	Critical size changes %
			Oxibutynin (3.18mg/kg)	+3.2	+18.9
Compd A (0.11mg/kg)	-6.7	-2.7
			Compd A (0.32mg/kg)	-6	+11.4
Oxibutynin (3.18mg/kg)+compd A (0.11mg/kg)	+1.5	+10.4
			Oxibutynin (3.18mg/kg)+compd A (0.32mg/kg)	-13.3	-4

Claims (15)

1. pharmaceutical formulation, it comprises PDE5 inhibitor and muscarine antagonist.

2. the described prescription of claim 1, wherein said PDE5 inhibitor is selected from:

Sldenafil;

Tower draws non-greatly;

Vardenafil;

5-(5-acetyl group-2-butoxy-3-pyridine radicals)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;

5-(5-acetyl group-2-propoxyl group-3-pyridine radicals)-3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-ones;

5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones;

4-[(3-chloro-4-methoxy-benzyl) amido]-2-[(2S)-2-(methylol) pyrrolidine-1-yl]-N-(pyrimidine-2-base methyl) pyrimidine-5-Methanamide (TA-1790);

3-(1-methyl-7-oxo-3-propyl group-6,7-dihydro-1 h-pyrazole be [4,3-d] pyrimidine-5-yl also)-N-[2-(1-methylpyrrolidin-2-yl) ethyl]-4-propoxyl group benzsulfamide (DA 8159);

And officinal salt.

3. claim 1 or 2 described prescriptions, wherein said PDE5 inhibitor is selected from:

Sldenafil;

Tower draws non-greatly;

Vardenafil;

DA-8159; With

5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones;

And officinal salt.

4. each described prescription in the aforementioned claim, wherein said PDE5 inhibitor is selected from:

Sldenafil;

5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones;

And officinal salt.

5. each described prescription in the aforementioned claim, wherein said muscarine antagonist is selected from:

Atropine;

Fu Lufo writes the spy;

Scopolamine;

Oxibutynin;

Darifenacin;

Tolterodine;

(+)-N, N-diisopropyl-3-(2-hydroxyl-5-hydroxymethyl phenyl)-3-amfetamine;

Propantheline;

Propiverine;

A wrong department grace;

How hot Saliphen is;

Fly Suo Tairuoding;

And officinal salt.

6. each described prescription in the aforementioned claim, wherein said muscarine antagonist is selected from:

Darifenacin;

Oxibutynin;

Tolterodine;

(+)-N, N-diisopropyl-3-(2-hydroxyl-5-hydroxymethyl phenyl)-3-amfetamine;

How hot Saliphen is;

Fly Suo Tairuoding;

And officinal salt.

7. each described prescription in the aforementioned claim, wherein said muscarine antagonist are selected from tolterodine, fly Suo Tairuoding and officinal salt thereof.

8. each defined PDE5 inhibitor and muscarine antagonist are used to make the purposes of the medicament of treatment LUTS in the claim 1 to 7.

9. method for the treatment of LUTS, it comprises simultaneously, respectively or one after the other each defined PDE5 inhibitor and muscarine antagonist in the claim 1 to 7 is bestowed the patient who needs this treatment.

10. drug products, it comprises each defined PDE5 inhibitor and muscarine antagonist among the claim 1-7, and it can be used as the combination preparation that can be used for the treatment of LUTS simultaneously, respectively or one after the other.

11. each described purposes, method or product in the claim 8 to 10, wherein said LUTS is urgent micturition, frequent micturition, nocturia or urge incontinence.

12. each described prescription, purposes, method or product in the aforementioned claim, wherein said PDE5 inhibitor are sldenafil or its officinal salt, described muscarine antagonist is tolterodine or its officinal salt.

13. each described prescription, purposes, method or product in the claim 1 to 12, wherein said PDE5 inhibitor are sldenafil or its officinal salt, described muscarine antagonist is for flying Suo Tairuoding or its officinal salt.

14. each described prescription, purposes, method or product in the claim 1 to 12, wherein said PDE5 inhibitor is 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones or its officinal salt, described muscarine antagonist is tolterodine or its officinal salt.

15. each described prescription, purposes, method or product in the claim 1 to 12, wherein said PDE5 inhibitor is 5-[2-ethyoxyl-5-(4-ethyl-piperazine-1-sulfuryl)-pyridin-3-yl]-3-ethyl-2-[2-methoxyl group-ethyl]-2,6-dihydro-pyrazolo [4,3-d] pyrimidin-7-ones or its officinal salt, described muscarine antagonist is for flying Suo Tairuoding or its officinal salt.