Specification PHARMACEUTICAL COMPOSITION FOR THERAPY OF INTERSTITIAL CYSTITIS TECHNICAL The present invention disorder drug of the relates of interstitial lower to a urinary depressant of a specifically nerve, sensory capsaicin-sensitive therapeutic FIELD cystitis, tract, hypersensitive and/ or abacterial prostatitis. BACKGROUND Interstitial primarily as is sterile cystitis in women and is a disease exhibiting severe nocturia, cystitis ART pain and urinary frequency, that occurs symptoms urinary and a sense of suprapubic pressure urgency, or pain when the bladder is filled, which is alleviated after urination Opinion on Invest Drug, The abacterial prostatitis is sterile prostatitis on the basis of white quantitative determination of bacteria (1978), to the and interstitial is blood cell in urine counts classification of Drach, thought as of a variant (Expert Opinion 1 and et al. condition on Invest that specimens disease cystitis (Expert 10: p.521). is diagnosed according such Drug, of 10: p.521). Hypersensitive referred to herein hypersensitivity occurs even disorder means of the lower urinary the state of exhibiting in anyone in the absence of the bladder wall and urethra. a pain by or urethra of infectious urinary tract or apparent pathological tract as diseases and in the changes in the bladder During the infusion period of cytometrogram, there is no increase in the intravesical 15 cm H20): nonetheless, pressure the physiological (lower than bladder volume is small, and these finding are characteristics for this disorder (Diagnostic Disorders Criteria of the Hypersensitive by NJR George in Sensory Disorders of the Bladder and Urethra, edited by NJR George and JA Gosling, Springer-Verlag, Berilin, 1986, pp.17-29). With respect the intravesical is approved States, to drugs to treat interstitial administration of dimethyl sulfoxide by Food and Drug Administration and its mechanism desensitization of of cystitis, action is in the United considered capsaicin-sensitive (DMSO) sensory to be nerves (Expert Opinion on Invest Drug, 10: p.521 and J. Urol., 158: pp.1989-1995). instillation Also, , it is reported of capsaicin or resiniferatoxin, same pharmacological of interstitial Suppl: p.254 that the intravesical that is wi th the action, improves pain or other symptoms cystitis in clinical testing (J. Urol., 157, (1997) and J. Urol., 163, Suppl: p.60 2 (2000)). In addition, effective against bladder pain, urinary tract it is suggested that resiniferatoxin symptoms, as such due to hypersensitive that is not accompanied Accordingly, having a depressant nerves are effective interstitial urinary action tract, and/or improving pain hypersensitive abacterial of improving cystitis, hypersensitive and abacterial extensive a result, line-2-carboxylate or a salt the lower urinary the in of the lower in interstitial present inventors on a compound sensory made having nerves. OF THE INVENT'ION present inventjLon has (hereinafter abbreviated a has sensory therapy of interstitial the symptoms found that I-phenyl-l,2,3,4-tetrahydroisoquino- thereof capsaicin-sensitive sensory a novel therapeutic on capsaicin-sensit:Lve quinuclidin-3'-yl that drugs prostatitis. investigations DISCLOSURE As and disorder pain and symptoms prostatitis, action (J. Urol., 164: disorder of the lower urinary tract, and intensive a depressant interstitial it is considered Thus, for the purpose of creating drug capable with change and of the lower on capsaicin-sensitive for cystitis, urgency disorder cystitis nor the typical pathological pp. 676 -679 (2000». urinary is nerves as "Compound A") depressant and is useful cystitis, hypersensitive tract, and/or 3 effect abacterial for on the disorder of prostatitis, leading to accomplishment Compound International A or a Patent of the invention. salt thereof Publication disclosed to have binding action receptors and contraction inhibitory and indicated for urogenital diseases pollakiuria/urinary pain of urogenital neither indicated diseases such disorder of prostatitis the such diseases it anticholinergic has on exhibiting painful resul ts of excreted giving Test Compound symptoms cystitis, of is tract, hypersensitive and abacterial been considered have only of intersti tia.l cystitis sensory 2. and at all. and more. Example drug and the therapy of specific A is calculated (Primary later, Compound A, a depressant nerve at concentration to be about 10 mg per day orally and about 3.6 ~ 4 a minor action urinary On the other hand, from the the mg per day orally. that 2: pp.181-187). instilled, exhibited of 1 ~ M3 bladder the improvement urinary capsaicin-sensitive concentrations rhythmic However, As shown in Test Example 1 described when intravesically is incontinence & Gyneco~ogy, Care Update Obstetrics and as urinary (antimuscarinics) role in the drug therapy in for muscarine on rat hitherto drugs 96/20194 selective interstitial is not disclosed Also, described to be useful as a therapeutic frequency. lower No. effects nor disclosed, as is of urinary 1 .. 9 ~ when when giving 20 Accordingly, thereof it is considered have an inhibitory that Compound A or salts activity on capsaicin-sensitive sensory nerves within the bladder by oral administration and are effective for improving pain and symptoms such as urinary urgency in interstitial the lower urinary cystitis, hypersensitive tract, and/or Specifically, abacterial disorder of prostatitis. the invention relates to a pharmaceutical composition for inhibition nerve, containing of capsaicin-sensitive sensory quinuclidin-3'-yl I-phen- yl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate pharmaceutically ingredient, acceptable salt and specifically thereof or as to a pharmaceutical an a active composition for therapy of a urogenital disease selected from interstitial cysti tis, hypersensitive and abacterial disorder of the :Lowerurinary tract, prostatitis. Also, the invention relates to use of quinuclidin- 3' -yl I-phenyl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate pharmaceutically of a depressant invention acceptable salt thereof for the production of capsaicin-sensitive relates to use of sensory pharmaceutically acceptable of a therapeutic drug of a urogenital urinary cystitis, tract, nerve. qUinuclidin-3'-yl yl-l,2,3,4-tetrahydroisoquinoline-2-carboxylate interstitial or a The I-phenor a salt thereof for the production hypersensitive and abacterial disease disorder prostatitis. 5 selected from of the lower Also. the invention capsaicin-sensitive a patient with a abacterial incJ.uding administering therapeutically or a The invention disease hypersensitive of depressing effective amount pharmaceutically relates selected disorder prostatitis. wi th a therapeutically acceptable to a method from of' the including effective of therapy interstitial lower salt urinary of a cystitis. tract. administering pharmaceutically acceptable The invention amount of quinuclidin- 3' -yl quinuclidin-3'-yl Publication of the drug of the invention {compound salt thereof. described below in more detail. is 1-phenyl-1.2.3.4-tetrahydroisoquino- line-2-carboxylate salts or a salt thereof. will be described The active ingredient and a patient 1-phenyl-1.2.3.4-tetrahydroisoquinoline-2-carboxylate acceptable of 1-phenyl-1.2.3.4-tetrahydroisoquino- line-2-carboxylate urogenital to a method sensory nerves. quinuclidin-3'-yl thereof. relates in A} or pharmaceutically As such salts. are enumerated the· foregoing No. 96/20194. a Specific International examples the Patent acid addition salts of inorganic acid such as hydrochlor:ic acid. hydrobromic acid. hydroiodic phosphoric acid. sulfuric acid. nitric acid. and acid. or organic acids such as formic acid. acetic acid. propionic acid. oxalic acid. malonic acid. succinic acid. fumaric acid. maleic acid. lactic acid. malic acid. tartaric acid. citric acid. methanesulfonic 6 acid. ethanesulfonic acid. aspartic acid, and glutamic acid; and quaternary salts with halogen atom ions, triflates, etc. Above all, succinic acid ammonium tosylates, mesylates, salts are particularly preferable. Also, since aSYmmetric carbon the active atoms, ingredient an optically active existed, and hence the active ingredient diastereomers or enantiomers Also, the active ingredient hydrates and solvates polymorphisms. as a succinic thereof. and crystal acid salt of 1-phenyl-1,2,3,4-tetra- hydroisoquinoline-2-carboxylate particularly is includes all of ethanol quinuclidin-3'-yl has substance isomers of the invention such A) includes mixtures of and isolated In the invention, (+)-(lS,3'R)- (Compound (solifenacin) is preferable. These compounds are readily available by the production process as described Publication No. in the foregoing 96/20194 International or according to that Patent production process. The drug of the invention can be prepared as oral solid preparations, organic or oral liquid preparations inorganic carrier, suitable for according to customary ingredient of the drug of the invention absorbing property, or excipient, additives the oral an or injections using an parenteral manner. and other administration Since the active has excellent oral the drug of the invention is sui table for 7 oral preparations. easily take conveyance Oral solid preparations themselves and are convenient of oral powders. fine sustained release solid preparations granules. least one active granules. products. substance cellulose. such starch. corn additives as (HPMC); polyethylene capsules. tablets. pills. polyvinylpyrrol.idone. The composition other than inert diluents cel.lulose lubricants calcium at such and glycolate and may such as binders hydroxypropylmethyl as magnesium stearate. glycol. starch. and talc; disintegrating such as cellulose and glucose. microcrystalline aluminate. hydroxypropyl cellulose and is mixed with at least one inert starch. metasilicate include In such solid compositions. diluent such as lactose. mannitol. contain in storage are the most preferable. Examples magnesium that patients can and carmellose agents calcium; stabilizers such as lactose; dissolution aids such as glutamic acid and aspartic glycol; yellow coloring iron desired. coating acid; agents oxide plasticizers such as titanium according the tablets or pills may or intestinal emulsJ..ons. solutions. 8 manner. with If a sugar cellulose phthalate. soluble The oral liquid preparations acceptable be coated talc. and agar. pectin. hydroxypropyl and hydroxypropylmethyl gastric-soluble oxide. to the customary such as sugar. gelatin. cellulose, such as polyethylene or a f~lm. include pharmaceutically suspensions. syrups and elixirs and contain a generally as purified water and ethanol. an auxiliary agent such employed inert diluent This composition as wetting agents agents, a sweetener, a flavor, an aromatic, in addition The may contain and suspending or an antiseptic, to the inert diluent. injections such injections, intramuscular as intravenous and and emulsions. injections, subcutaneous include sterile aqueous or non-aqueous injections solutions, suspensions Examples of diluents for aqueous solutions or suspensions include distilled water and physiological Examples of diluents for non-aqueous glycol, vegetable oils such as olive oil, alcohols such as ethanol, such Such a composition as an antiseptic, dispersant, aid (such a stabilizer as composi tions through a glutamic are a wetting agent, agents an emulsifier, a (such as lactose), and a dissolution acid sterilized and aspartic by, for filter, agent, or irradiation. used by producing and Polysolvate may further contain auxiliary bacteria-holding anti-bacterial saline. solutions or suspensions include propylene glycol, polyethylene 80. such acid). example, filtration compounding Further, a sterile solid composition These with an these can be and dissolving it in sterile water or a sterile solvent for injection before use. The invention dose of the active is properly determined 9 ingredient depending compound of the on the individual case while taking into symptom of a patient, account the ingredient can be usually administered 1 to 100 mg/day, and preferably once or dividedly with urogenital the active in a dose of from about from 5 to 50 mg/day per adult twice. Incidentally, combination route, age of the subject to be administered, In the case of oral administration, sex, etc. while. administration the drug of the invention other diseases drugs that simultaneously are used can be used in for therapy or after elapsing Examples of drugs that can be used .incombination the drug of the invention injections for a with include oral drugs such as pentosan sulfate, anti-inflammatory intravesical of steroids, and antihistamines; such as Baci~~us and and Ca~mette-Guerin doxorubicin. BRIEF EXPLANATIONB Fig. 1 shows capsaicin-induced OF THE DRAWING inhibitory extravasation effects of Compound 1 on of Evans blue in the mouse bladder. BEST MODE FOR CARRYING OUT THE INVENTION The invention will be hereunder described in detail wi th reference to the following Examples and Test Examples, but it should not be construed that the invention. is limited to these Examples. Incidentally, Compound 10 1 as used in the following Examples and so on means a succinic acid salt of (+) - (IS, 3'R)1-phenyl-1,2,3,4-tetrahydroisoquino- quinuclidin-3'-yl line-2-carboxylate (solifenacin). Example preparation Table 1: Capsule 1 -- Compound 1 Lactose Total Components a capsule 10-mg Caps ule 10.0 mg 190.0 m 9 200.0 m 9 . 1-mg Capsule 1.0 mg 199.0 mg 200.0 mg J g loo.-m capSUl~ 100.0 mg 100.0 mg 200.0 mg as shown in Table 1 were mixed and filled in to produce capsule preparations. Test Example 1: Inhibitory action of Compound 1 aga.inst plasma protein induced extravasation by capsaicin in the mouse bladder (Method) (l) Used animal: In the experiment, four or five female Balb/c mice (Japan SLC, Inc.) per group were used. (2) Measurement A catheter anesthetized of plasma protein was inserted with urethane extravasation: into the bladder (intraperitoneally with 0.15 ml of a 20 % solution administered per mouse) via the urethra, and after emptying the bladder, a physiological solution was injected. of a mouse saline or drug This catheter was prepared by blunting 11 the tip of a 24-guage hypodermic needle and making a side hole at 2 romfrom the newly prepared instillation plasma into proteins stimulation the due of tip. bladder, to the About one hour after extrava.scular inflammatory capsaicin-sensitive according to the method of Maggi, et al. Arch. Pharmaco~. (30 mg/kg) killed by cervical After removing urine dye was extracted of !lL from the bladder overnight, determined by measuring 620 nm of 100 ilL supernatant addition, the content wet tissue was calculated. instilled with administered light by nerve 5 Evans blue (300 vein, and the mouse.was then the bladder wa.sremoved. and blood remaining formamide caused and capsaicin the administration, dye in the organs was quantitatively 150 That is to the mouse from the tail dislocation, of (Nauny-Schmiedeberg' a dye bound by plasma proteins five minutes after leakage sensory pp. 546- 555 (1987)).. , 336: 1l9/kg) were administered precisely reaction the in the tissue, determined. by placing and ,~as absorbance the Evans blue the tissue quantitatively at a wavelength in a 96-well in of microplate. of Evans blue dye ln one milligram In of Moreover, the mouse intravesically physiological saline with a capsaicin-free and intravenously Evans blue solut.ion served as a normal control. (3) Test drug and other reagents: Compound1 was dissolved saline, and then administered and diluted in physiological into the bladder 12 at a volume of 100 !lLper mouse. Wako Pure Capsaicin and formamide were purchased from Chemical Industries, purchased from Aldrich. blue, physiological Ltd., and Evans blue was As the vehicle for capsaicin and Evans saline containin9 0.1 % dimethyl sulfoxide and 0.1 % Tween 80 was used in a volume of 10 mL/kg. (4) Statistic processing: Results were shown as [(mean values) ± (standard errors of the mean) ]. The Student's t -test was used to determine the significance of difference between the group of mice receiving intravesicla saline and stimulated group of normal control mice. with capsaicin With respect effects of Compound 1 in the mice administered a significance comparison with physiological variance. judged was determined the saline in the case where wi th capsaicin, intravesically folloeing In these tests, to inhibitory using the Dunnett's group the t-test by injected one-way the statistical e and the with analysis of significance was the p value was less than 5 %. (Results) The experimental value by comparison physiological 0.0027; the (The p between the normal control group and the p value of the analysis groups was 0.0033; by the Dunnett's physiological are shown in Fig. 1. saline group according to the Student t-test was capsaicin-treated determined results of variance and in the p value, t-test when comparing the as with the saline group, for 1, 10 and 100 !lM groups of 13 Compound 1 when was 0.043, 0.0053 and 0.0023. respect~vely.) Capsa~c~n mouse bladder control ~ncreased by about group. concentrat~ons ~ncreases ~n respect~vely. s~gn~f~cant the Evans blue dye content 5 t~mes as compa.red w~ th the normal Compound 1 dye content These changes d~fference. ~ntraves~cally extravascular ~njected of 1, 10 and 100 ~ the ~ntraves~cally 52 brought ~~, 76 Compound of 1 ~ capsa~c~n-sens~t~ve sensory and 80 %, ~nduced 1 as ~nfused or more ~nh~b~ted the of plasma prote~ns react~on % about a stat~st~cally Therefore, to the ~nflammatory at reducE~d capsa~c~n-~nduced by at concentrat~ons leakage ~n the ~n the bladder due by st~mulat~on of the nerve. Test Example 2: Amount (of compound 1) excreted to ur~ne after oral adm~nistration to humans (Method) For Compound of, the purpose of evaluat~ng 1 for the pharmacok~net~cs, healthy Compound sUbjects were orally adm~n~stered tolerab~l~ ty and safety repeatedlyadmin~stered w~th 1 at a dose of 10 mg or 20 mg per day for 15 days. To determine the amount compound 1 excreted ~nto ur~ne as the non-metabolized substance, the~r ur~ne was collected hours after the f~nal admin~strat~on. added a sodium b~carbonate substance, for 24 To the ur~ne sample were solut~on and an ~nternal standard then, the m~xture was extracted 14 w~th tert-butyl methyl ether. and the organic residue was dissolved methanol, layer wa.s evaporated. in a mixed solution and Compound 1 was separated liquid chromatog+aphy. Detection The of acet~c acid and by high-performance of Compound 1 was carried out by mass spectrometry. (Results) The results are shown in Table 2. Table 2 Dose of Compound 1 Male Female Male -Female 10 mg/day 20 mg/day Assuming (Review that the daily urine volume is about one liter of Medica~ concentration was calculated Excret ion amount in urine (mg/day) 0.911 0.907 1. 844 1.690 Sex 13th Edition, p.643), the mean Physio~ogy, in urine of Compound 1 (mo:Lecular weight: 480) to be about 1.9 ""Mfor oral administration 10 mg per day and about 3.6 !-tM for oral administration of of 20 mg per day. From the results of Test Example it is considered inflammation that, since in the bladder capsaicin-sensitive sensory 1 and Test Example 2, Compound induced nerve 1 can by stimulation when orally adult at doses from 10 to 20 mg per day, Compound 15 inhibit given the of the to an 1 is useful for the therapy interstitial urinary of a cystitis, urogenital disease hypersensitive tract, and abacterial selected disorder from of the lower prostatitis. Also, the effect of the invention can also be confirmed by clinical tests to a patient hypersensitive abacterial pathology disorder prostatitis of and According oral lower animal urinary tests cystitis, tract reflecting or the APPLICABILITY to the invention, therapeutic hypersensitive abacterial the interstitial of such a disease. INDUSTRIAL an with disorder drug of it is possible to provide interstitial cystitis, of the lower urinary prostatitis. 16 tract, and/or WE CLAIM: 1, A process for preparing a pharmaceutical composition for depression of capsaicin-sensitive sensory nerve, which comprises mixing qUinuclidin-3'-yt 1-phenyl-1,2,3,4-tetrahydroisoquinolin.2-carboxytate or a salt thereof with a pharmaceutically acceptable excipient. 2. A process for preparing a pharmaceutical composition for therapy of interstitial cystitis, 'ltlhlch comprises mixing quinu(:lldln-3'-y11-phenyl1,2,3,4-tetrahydroisoquinolin.2-carboxylate or a salt thereof' with a pharmaceutically acceptable excipient. 3. A process for preparing a pharmaceutical composition for therapy of hypersensitive disorder of the 10'N8rurinary tract, 'ltlhich comprises mixing quinuclidin-3'-y1 1-phenyl-1,2,3,4-tetrahydroisoquinolin.2- carboxylate or a salt thereof with a pharmaceutically acceptable excipient. •. A pmtl888 for prepal1ng a pharmaceutical composition for therapy of abacterial prostatitis, which comprises mixing qUinuclidin-3'-y11·- - It .- phenyl-1 ,2,3,4-tetrahydroisoquinoline-2-carboxylate \Nith a pharmaceutically acceptable or a salt thereof excipient. Dated this 29ltl DAY OF DECEMBER, 2003. f=R~ OF L,S. DAVAR & CO, APPLICANTS' AGENT - I~ Abstract ,. ITLE OF A : PHARMA<:.EUT "INTERSTITIAL depressant containing of I CA\. interstitial urinary tract, and/or or specifically cystitis, ~OR -T\-\£ R A P't a a hypersensitive abacterial 18 sensory nerve, 1-phenyl-1,2,3,4-tetra- quinuclidin-3'-yl ingredient, T ION capsaicin- sensi tive hydroisoquinoline-2-carboxylate active COMPO~1 c'f~TITIS: salt thereof therapeutic disorder prostatitis. as drug an of of the lower , _113SI 01677 lKOL.w1 2003 CI611/KOLNf!0'3 '1Af1ANOlJC~1 Figure o~ 2,.'l.I2..o"3 PHAI<MAc-EUTI<:AL co. LTD. 1 35 30+-' c 25 Q)+-'Q) C ::J o () 00 00 Q):.t=:' 20 ::JO) .ClE 00-roO) 15 UJ 10 c-S > 5 compound 1 (~) capsaicin injected ~~-~M .I.BANER.~E~ OF L..S .1)A\lAR A~~l;.,-a--t-) 1/1 A~- '-~ C.O.