CA2266070A1 - Method of treating urinary incontinence - Google Patents
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- CA2266070A1 CA2266070A1 CA002266070A CA2266070A CA2266070A1 CA 2266070 A1 CA2266070 A1 CA 2266070A1 CA 002266070 A CA002266070 A CA 002266070A CA 2266070 A CA2266070 A CA 2266070A CA 2266070 A1 CA2266070 A1 CA 2266070A1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/221—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/275—Nitriles; Isonitriles
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
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Abstract
This invention provides a method of treating urinary incontinence in a female mammal which comprises administering to said mammal an effective amount of an anti-incontinent agent intravaginally or rectally.
Description
WO 98/11888 PCT~US97/16509 l~lETHOD OF TREAT~N(~J UR~I~ARY INCONTINENCE
BACKG~OUND OF THE INVENTION
s Urinary incontinence is an involuntary leaking of urine which primarily affects women and older men. There are three major categories of urinary incontinence which are classified according to etiology; these are urinary stress incont~n:~nce (SI), urge incontinence (UI), and mixed incontinence. SI is the involuntary loss of urine as a 10 result of increasing intra-abdominal pressure, typically occurring after coughing, straining, sneezing, lifting or any other activity which suddenly increases intra-abdominal pressure. In women, SI is the most common cause of involuntary loss ofurine, and may be caused by the shortening of the urethra and loss of the normalurethrovesical angle resulting from pelvic relaxation that characteristically occurs with 15 aging or multiparity.
UI is characterized by an urgent desire to void followed by the involuntary lossof urine. It is most often unassociated with any specific disease or disorder, but is increasingly common in older men and women. Among the causes of UI that are 20 known, diabetes, multiple sclerosis, spinal cord injury, and other primarily neurologic disorders are among the most common. Anatomic and traumatic etiologies may also cause UI. Urge incontinence is also referred to as detrusor incontinence or instability, as it is associated with involunt~uy contractions of the detrusor muscle. Mixed incontinence is seen in patients having both Sl and UI.
Although, Sl is usually treated surgically, there are a number of drugs currently used use to treat Ul and mixed incontinence. Since the urinary bladder is thought to contract primarily as a result of parasympathetic activity, drugs with anticholinergic properties have been the most common to be used to treat the unstable bladder. A30 number of other preparations have been used as well. Among these are antispasmodics, tricyclic antidepressants, calcium channel blockers, prostaglandin synthetase inhibitors, - and other agents having an effect on smooth muscle contractility, such as potassium channel modulators. Agents typically used include oxybutynin, propantheline, ~ imipramine, terodiline, dicyclomine, and flurbiprofen These drugs are usually 35 a-lmini~tered orally and are associated with a number of side effects which limit their usefulness.
O98/11888 PCTrUS97/16509 l'he most widely prescribed drug for the treatment of incontinence is oxybutynin. Currently it must be given orally two to four times per day. Although oxybutynin has shown to be effective in a number of clinical trials, side effects prevent more widespread usage. Reported side effects include dry mouth, blurred vision, nausea, and constipation. Alternatives to oral administration have been attempted with oxybutynin; it has been successfully instilled directly into the bladder showingtherapeutic activity with reduced side effects [Weese, D.L., Urolo~y 41:527-530,(1993); Prasad, K.V., Brit J Urology 72:719-722, (1993); Mizunaga, M., Paraplegia 32:25-29, (1994)].
DESCRIPTION OF THE INVENTION
This invention provides a method of treating urinary incontinence which comprises administering an anti-incontinent agent intravaginal3y or rectally. An anti-incontinent is defined an agent which is useful in treating urinary incontinence. Such agents have typically been administered orally or parenterally.
In particular, this invention provides a method of treating urinary incontinencewhich comprises intravaginally or rectally administering an anticholinergic agent, antispasmodic agent, tricyclic antidepressant, calcium channel blocker, prostaglandin synthetase inhibitor, potassium channel modulator, estrogen agonist, tissue selective estrogen (selective estrogen receptor modulator), or oc-agonist. Preferred anticholinergics include agents such as scopolamine, atropine, ipratropium bromide, poldine, glycopyrrolate, propantheline, isopropamide, trihexylphenidyl, benztropine, procyclidine, biperiden, ethopropazine, meth~ncholine, emepronium, fentonium darifenacin, and tolterodine. Preferred antispasmodics include agents such as hyoscyamine, oxybutynin, flavoxate, and dicyclomine. Preferred tricyclic antidepressants include agents such as amitriptyline, nortriptyline, imipramine,desipramine, doxepin, trimipramine, clomipramine, and protriptyline. Preferred calcium blockers include agents such as diltiazem, nifedipine, nicardipine, nimodipine, isradipine, nitrendipine, felodipine, and terodiline. Preferred prostaglandin synthetase inhibitors include agents such as flurbiprofen, indomethacin, and mefanatnic acid.
Preferred potassium channel modulators include agents such as (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (see U.S.
Patent 5,506,252, which is hereby incorporated by reference), 4-[(2-tert-butylamino-3,4-dioxo-cyclobut-1-enylamino)-methyl]-3-chloro-benzonitrile (see Example 5), and 3-(2,3-dichloro-6-methyl-benzylamino)-4-( 1, I -dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (see Example 6). Preferred estrogen agonists include 17,~-estradiol and Wo 98/11888 PCT/USg7/16509 estrogen. Preferred tissue selective estrogens include roloxafine and teremofine.
Preferred oc-agonists include phenyl propanolamine.
More preferred anti-incontinent agents include, but are not limited to, oxybutynin, propantheline, imipramine, terodiline, dicyclomine, flurbiprofen, darifenacin, tolterodine, (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile, 4-[(2-tert-butylamino-3,4-dioxo-cyclobut-1-enyl-amino)-methyl]-3-chloro-benzonitrile, and 3-(2,3-dichloro-6-methyl-benzylamino)-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene- 1 ,2-dione.
Treating covers treatment of an existing condition, inhibiting the progress or development of the condition, ameliorating the condition, and providing palliation of the condition. It is preferred that the anti-incontinent agents of this invention are employed in the treatment of urge or mixed incontinence.
Because of the proximity of the vagina and rectum to the bladder, the intravaginal or rectal administration of anti-incontinent agents provides several advantages over conventional treatments for urinary incontenance, which include all or some of the following (I) site specific delivery of the anti-incontinent agent very near the site of action, (2) locally high concentrations of the anti-incontenent agent in the bladder, (3) a reduction of side effects due to decreased serum concentration and/or reduced ~lrst pass metabolism, (4) a lower effective circulating concentration (systemic load) of the anti-incontenent agent, and (5) ability to control the rate of delivery of the agent with imrnediate release or longer duration of action based on controlled release from the vehicle. This invention, therefore, provides a useful and advantageous method of treating urinary incontinence.
When adrninistered intravaginally or rectally, anti-incontenent agents can be form~ tcd neat or using a variety of phartnaceutical carriers which are amenable for intravaginal or rectal administration including creams, gels, foams, tablets, suppositories, and pessaries containing a number of synthetic or natural materials including but not limited to silicone, si}astic, polycarbophil, polyethylene glycol, and hydrogel. Such carriers may be non-therapeutic or therapeutic, in and of themselves.
Therapeutic carriers with beneficial medicinal properties can be used, for example, to control vaginal pH, treat or inhibit sexually transmitted diseases, or provide vaginal hydration. When adn inistered intravaginally or rectally, it is projected that the preferred dosage for oxybutynin would be 1-20 mg administered 1-4 times per day, the preferred dosage for propantheline would be 1-12() mg administered 1-4 times per day, the preferred dosage for imipramine would be 1-400 mg administered 1-4 times per day, the ~ Ç~I-ed dosage for terodiline would be 1-100 mg administered 1-4 times per day, the preferred dosage for dicyclomine would be 1-40 mg administered 1-4 times per day, and the preferred dosage for flurbiprofen would be 1-100 mg ~1mini~tered 1-4 times per day.
s The following provides representative example of intravaginal or rectal formulations and their preparation.
EXAMPLE l Propantheline Bromide Va~inal or Rectal Suppository Amount per Sg Suppository Propantheline bromide ().()3 g Glycerin 3.5 g Gelatin (TypeA) I o g PurifiedWater 0.47 g Propantheline bromide is dissolved in the Purified Water, gelatin is added and 20 the rnixture is heated nearly to boiling. Glycerin is heated to nearly 100~C and added to the gelatin-water mixture. The resulting mixture is heated in a water bath until the gelatin is dissolved. Water is slowly added to achieve the correct weight and stirred until uniform. The mass is poured into molds, allowed to solidify and packaged.
I~XAMPLE 2 Oxybutynin Hydrochloride Vaginal Cream Amount per 5g dose Oxybutynin Hydrochloride 0 05 g PolyethyleneGlycol 1000 0.09 g Monocetyl Ether Cetostearyl Alcohol 0.3 g Mineral Oil 0.3 g White Petrolatum 0.75 g Propylparaben 0.004 g Methyl paraben 0.0075 g Benzyl Alcohol 0.075 g Puri~ied Water, freshly 3.4085 g boiled and cooled W O 98tll888 PCT~US97/16509 Oxybutynin hydrochloride, methyl and propyl paraben and benzyl alcohol are dissolved in the water with the aid of gentle heat. On a hot water bath, the polyethylene glycol 1000 monocetyl ether, cetostearyl alcohol, mineral oil and white petrolatum are 5 melted together. The aqueous solution is added to the molten oils and stirred until cold.
The cream is packed into tubes and dispensed with a vaginal applicator to provide a 5 g dose.
Dic~/clomineHydrochlorideVa inalGel Amount per 5~ dose Dicyclomine Hydrochloride ().01 g Carbopol 934 ().038 g Triethanolamine 0.056 g 15 Propyl paraben ().004 g Methyl paraben 0.0075 g Purified Water, freshly 4.885 g boiled and cooled 20 Dicyclomine hydrochloride, methyl and propyl paraben are dissolved in the water with the aid of gentle heat. The solution is cooled and carbopol 934 is dispersed in the solution with gentle agitation. Triethanol.mline is added gently to avoid air entrapment until the gel is formed. The gel is packed into tubes and dispensed with a vaginal applicator to provide a 5g dose.
Imipramine Hydrochloride Slow Release Va~inal Tablets Amount per 1~ tablet Imipramine hydrochloride 0.05 g 30 Polycarbophil 0 5 g Lactose 0.4425 g Polyvinylpyrrolidone 0.005 g Magnesium Stearate 0.0025 g Polyvinylpyrrolidone and imipramine hydrochloride ~re dissolved in a suitable quantity of purified water ~nd used to make a wet granule m~ss of the polycarbophil.
. . .
The wet mass is screened through a suitable mesh screen and the resulting granules dried. Lactose is blended with the polycarbophil granules. ~ gnesillm stearate is added and blended just sufficiently to disperse the lubricant. The mixture is compressed into diamond shaped tablets, packed in foil strips and dispense with a vaginal applicator.
The following provide preparations of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile, 4-[(2-tert-butylamino-3,4-10 dioxo-cyclobut-1-enylamino)-methyll-3-chloro-benzonitrile, and 3-(2,3-dichloro-6-methyl-benzylamino)-4-(1,1 -dimethyl-propylamino)-cyclobut-3-ene- 1,2-dione.
4-r~2-tert-BIltvlamino-~4-dioxo-cvclobut-l-envlamino)-methvll-3-chloro-ben~onitrile A. 2-Chloro-4-cyanobenzy1 bromide A mixture of 3-chloro-4-methylbenzonitrile (22.74 g, 150 mmol), N-bromosuccinimide (32.04 g, 18() mmol) and 2,2'-azobis-2-methylpropionitrile (2.46 g, 15 mmol) in carbon tetrachloride (120 mL) was carefullY wa;med to reflux temperature whereupon a moderate exothern- occurred and refluxing proceeded for approximately 10 minutes without external heating. Heating was then resumed and refluxing continued for 26 hours. The hot reaction mixture was suction filtered and the insolubles were rinsed with carbon tetrachloride (3 x 25 mL). The combined carbon tetrachloride fractions were washed with water ànd dried (anhydrous Na2SO4).
Removal of solvent gave a yellow mush which was crystallized from hexane (charcoal).
The product again was recrystallized from hexane to yield 20.44 g (59%) of the white bromide: mp 8().5 - 83.5~C (softens 71.5~C) (lit. mp 85-85.5~C (B. Gogolimska, Acta Pol. Pharm., 25 (4), 391 (1968) [C.A., 70, 87493e (1969)].)); IH NMR (DMSO-d6) ~ 8.10 (d, lH), 7.82 (m, 2H), 4.69 (s, 2H) ppm. IR (KBr): 2220 cm-h B. N-(2-ch]oro-4-cvanobenzYl)phthalimide A mixn~re of product from Example 5, Step A (20.29 g, 88.0 rnmol) and potassium phthalimide (17.92 g, 96.8 mmol) in N,N-dimethylformamide (200 mL) WO 98/11888 PCT/US97l16509 was stirred as the reaction temperature rose to approximately 36~C during approximately S minutes with formation of a tan suspensiol1. The temperature then receded and stirring was continued for 2 hours. After removal of solvent, the residue was triturated thoroughly with water and dried.
The buff solid product was treated with approxilnately 500 mL boiling ethyl acetate, gravity filtered to remove a small amount of white insoluble material, heated to boiling, treated with charcoal and filtered. Concentration and cooling of the filtrate afforded (after drying) 20.26 g (78%) of the title compound ph~h~limide as a white solid: mp 172.5- 173.0~C (softens 170.5~C); lH NMR (DMSO-d6) ~ 8.10 (d, lH), 7.90 (m, 4H), 7.75 (dd, lH), 7.52 (d, IH), 4.88 (s, 2H) ppm. IR (KBr): 2220, 1770, 1715 cm-h C. 2-chloro-4-cyanobenzylamine A mechanically stirred suspension of product from Example 5, Step B (18.99 g, 64 mmol) in absolute ethanol (15() mL) was treated with hydrazine hydrate (6.41 g, 128 mmol) and the mixture was stirred and refluxed for 1 hour and then was allowed to stand at room temperature for approximately 16.5 hours. With stirring 2N HCI (90mL) was added slowly, and after 10 minutes of further stirfing the mixture was filtered.
The insolubles were triturated thorou~hly with ethanol and then with water. The combined filtrate and triturates were freed of solvent and the residue in approximately 250 mL ice-H~O was basified with 2.5 N NaOH (90 mL). The mass was extracted thoroughly with chlorofom1 and the extracts were washed with water, with brine and dried (anhydrous Na~SO4). Removal of solvent gave a cream-colored solid which was recrystallized from hexane to provide 6.85 g (64%) of a white amine- mp 85.0 - 87.0~C
(soften82.5~C); IHNMR(DMSO-d6) â7.96(d, IH), 7.82 (dd, IH), 7.77 (m, lH), 3.82 (s, 2H), 2.12 (br m, 2H) ppm. IR (KBr3: 338(), 332(), 223() cm-~.
D. 4-~(2-tert-Butvlamino-3,4-dic)xo-cyclob-lt- 1-enylamino)-methy]1-3-chloro-benzonitrile Tetrahydrofuran (5() mL), 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (6.76 g, 30 mmol, Example 1) and the product of Example 2, Step 3 (5.00 g, 30 mmol) were refluxed for 6 hours and allowed to stand at room temperature for 16 hours.Following removal of solvent from the reaction mixture, the residue was triturated thoroughly with diethyl ether and dried to give a buff solid. This material in approximately 1.4 L of boiling acetone, was filtered to remove a small amount of white W O 98/11888 PCTrUS97/16509 solid. The hot filtrate was treated with charcoal, filtered, concentrated and cooled to afford 6.521 g of a cream-colored solid. Two additiona} recrystallizations of this material from acetone gave 4.779 g (50%) of the title compound as a white solid: mp 243.5-245.~C (softens 241.0~C); IH NMR (DMSO-d6) o 8.10 (d, lH), 7.88 (dd, lH), 7.82 (m, lH), 7.66 (s, br, lH), 7.61 (d, lH), 4.88 (d, 2H), 1.34 (s, 9H) ppm.
IR (KBr): 3320, 3230, 2240, 1780, 1665 cm-]; MS (m/z) 317/319 (M+). HPLC
indicates a major component (99.6%).
Elemental analysis for C,6H~6ClN3O2 Calc'd:C, 60.48; N, 5.08; N, 13.22; Cl, 11.16.
Found:Ct 60.08; H, 4.97; N, 13.06; Cl, 10.82, 10.71.
3-(2~4-Dichloro-6-methyl-ben7vl~mino)-4-fl.l-dimethyl-propyl~mino)-cvclobut-3-ene-1 ~2-dione A. 3-Butoxy-4~ dimethyl-propylamino)-cyclobut-3-ene- ] ,2-dione A solution of 3,4-dibutoxy-3-cyclobutene-1,2-dione (4.53 g, 20 mmol) and 1,1-dimethylpropylamine (1.74 g, 20 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for approximately 19.5 hours. The solvent was removed and the residue was chromatographed (gravity, chloroform/hexane) on neutral, activity III silica (150 g).
The white solid isolated from the appropriate eluates was recrystallized from hexane to give 4.105 g (86%) of a white product: mp 56.5-57.5~C (softens 55.5~C).
One grarn of this material was recrystallized twice from hexane to provide 0.794g of the title compound as a white solid: mp 56-57~C (softens 55~C); 1H NMR (DMSO-d6): ~ 8.63 and 8.48 (two br s, lH, rotamers), 4.67 (m, br, 2H), 1.67 (m, br, 4H), 1.39 (m, 2H), 1.26 (m, br, 6H), ().91 (t, 3H), 0.78 (t, 3H) ppm. IR (KBr): 3170, 1790, 1700cm~l; MS (m/z): 239 (M+).
Elemental Analysis for C13H21NO3 Calcd: C, 65.24; H, 8.85; N, 5.85 Found: C, 65.12; H, 8.90; N, 5.77 B. 3-(2~4-Diehloro-6-methyl-benzvlamino)-4-(l~l-dimethyl-propylamino)-eyelobut-3-ene- 1 ~2-dione A solution of 3-ethoxy-4-(1,1-dimethyl-propylamino)-eyelobut-3-ene-1,2-dione (16.67 g, 79.0 mmol~ and 2,4-dichloro-6-methylbenzylamine (15.02 g, 79.0 mmol) in absolute ethanol (395 mL) were allowed to stand for 4 days at room le~ ue-dture. The title eompound formed as a white solid, which was filtered, washed with diethyl ether/hexane and dried in vacuo. This yielded 25.7 g (92%) of the title compound as a white solid: mp 247.1-248.3~C; lH NMR (DMSO-d6) ~ 7.54 (d, lH), 7.44 (br t, lH), 7.39 (d, lH), 7.31 (s, lH), 4.9() (d, 2H), 2.40 (s, 3H), 1.66 (q, 2H), 1.28 (s, 6H), 0.80 (t, 3H) ppm. IR (KBr): 32()0, 298(), 1800, 1650 em -1; MS (m/z) 354/356/358 (M+). Analytical HPLC indicates a major component (99.9%).
Elemental analysis for C17H20C12N2~2 Calc'd: C, 57.47; H, 5.67; N, 7.89.
Found: C, 57.31; H, 5.5(); N, 7.X().
BACKG~OUND OF THE INVENTION
s Urinary incontinence is an involuntary leaking of urine which primarily affects women and older men. There are three major categories of urinary incontinence which are classified according to etiology; these are urinary stress incont~n:~nce (SI), urge incontinence (UI), and mixed incontinence. SI is the involuntary loss of urine as a 10 result of increasing intra-abdominal pressure, typically occurring after coughing, straining, sneezing, lifting or any other activity which suddenly increases intra-abdominal pressure. In women, SI is the most common cause of involuntary loss ofurine, and may be caused by the shortening of the urethra and loss of the normalurethrovesical angle resulting from pelvic relaxation that characteristically occurs with 15 aging or multiparity.
UI is characterized by an urgent desire to void followed by the involuntary lossof urine. It is most often unassociated with any specific disease or disorder, but is increasingly common in older men and women. Among the causes of UI that are 20 known, diabetes, multiple sclerosis, spinal cord injury, and other primarily neurologic disorders are among the most common. Anatomic and traumatic etiologies may also cause UI. Urge incontinence is also referred to as detrusor incontinence or instability, as it is associated with involunt~uy contractions of the detrusor muscle. Mixed incontinence is seen in patients having both Sl and UI.
Although, Sl is usually treated surgically, there are a number of drugs currently used use to treat Ul and mixed incontinence. Since the urinary bladder is thought to contract primarily as a result of parasympathetic activity, drugs with anticholinergic properties have been the most common to be used to treat the unstable bladder. A30 number of other preparations have been used as well. Among these are antispasmodics, tricyclic antidepressants, calcium channel blockers, prostaglandin synthetase inhibitors, - and other agents having an effect on smooth muscle contractility, such as potassium channel modulators. Agents typically used include oxybutynin, propantheline, ~ imipramine, terodiline, dicyclomine, and flurbiprofen These drugs are usually 35 a-lmini~tered orally and are associated with a number of side effects which limit their usefulness.
O98/11888 PCTrUS97/16509 l'he most widely prescribed drug for the treatment of incontinence is oxybutynin. Currently it must be given orally two to four times per day. Although oxybutynin has shown to be effective in a number of clinical trials, side effects prevent more widespread usage. Reported side effects include dry mouth, blurred vision, nausea, and constipation. Alternatives to oral administration have been attempted with oxybutynin; it has been successfully instilled directly into the bladder showingtherapeutic activity with reduced side effects [Weese, D.L., Urolo~y 41:527-530,(1993); Prasad, K.V., Brit J Urology 72:719-722, (1993); Mizunaga, M., Paraplegia 32:25-29, (1994)].
DESCRIPTION OF THE INVENTION
This invention provides a method of treating urinary incontinence which comprises administering an anti-incontinent agent intravaginal3y or rectally. An anti-incontinent is defined an agent which is useful in treating urinary incontinence. Such agents have typically been administered orally or parenterally.
In particular, this invention provides a method of treating urinary incontinencewhich comprises intravaginally or rectally administering an anticholinergic agent, antispasmodic agent, tricyclic antidepressant, calcium channel blocker, prostaglandin synthetase inhibitor, potassium channel modulator, estrogen agonist, tissue selective estrogen (selective estrogen receptor modulator), or oc-agonist. Preferred anticholinergics include agents such as scopolamine, atropine, ipratropium bromide, poldine, glycopyrrolate, propantheline, isopropamide, trihexylphenidyl, benztropine, procyclidine, biperiden, ethopropazine, meth~ncholine, emepronium, fentonium darifenacin, and tolterodine. Preferred antispasmodics include agents such as hyoscyamine, oxybutynin, flavoxate, and dicyclomine. Preferred tricyclic antidepressants include agents such as amitriptyline, nortriptyline, imipramine,desipramine, doxepin, trimipramine, clomipramine, and protriptyline. Preferred calcium blockers include agents such as diltiazem, nifedipine, nicardipine, nimodipine, isradipine, nitrendipine, felodipine, and terodiline. Preferred prostaglandin synthetase inhibitors include agents such as flurbiprofen, indomethacin, and mefanatnic acid.
Preferred potassium channel modulators include agents such as (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile (see U.S.
Patent 5,506,252, which is hereby incorporated by reference), 4-[(2-tert-butylamino-3,4-dioxo-cyclobut-1-enylamino)-methyl]-3-chloro-benzonitrile (see Example 5), and 3-(2,3-dichloro-6-methyl-benzylamino)-4-( 1, I -dimethyl-propylamino)-cyclobut-3-ene-1,2-dione (see Example 6). Preferred estrogen agonists include 17,~-estradiol and Wo 98/11888 PCT/USg7/16509 estrogen. Preferred tissue selective estrogens include roloxafine and teremofine.
Preferred oc-agonists include phenyl propanolamine.
More preferred anti-incontinent agents include, but are not limited to, oxybutynin, propantheline, imipramine, terodiline, dicyclomine, flurbiprofen, darifenacin, tolterodine, (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile, 4-[(2-tert-butylamino-3,4-dioxo-cyclobut-1-enyl-amino)-methyl]-3-chloro-benzonitrile, and 3-(2,3-dichloro-6-methyl-benzylamino)-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene- 1 ,2-dione.
Treating covers treatment of an existing condition, inhibiting the progress or development of the condition, ameliorating the condition, and providing palliation of the condition. It is preferred that the anti-incontinent agents of this invention are employed in the treatment of urge or mixed incontinence.
Because of the proximity of the vagina and rectum to the bladder, the intravaginal or rectal administration of anti-incontinent agents provides several advantages over conventional treatments for urinary incontenance, which include all or some of the following (I) site specific delivery of the anti-incontinent agent very near the site of action, (2) locally high concentrations of the anti-incontenent agent in the bladder, (3) a reduction of side effects due to decreased serum concentration and/or reduced ~lrst pass metabolism, (4) a lower effective circulating concentration (systemic load) of the anti-incontenent agent, and (5) ability to control the rate of delivery of the agent with imrnediate release or longer duration of action based on controlled release from the vehicle. This invention, therefore, provides a useful and advantageous method of treating urinary incontinence.
When adrninistered intravaginally or rectally, anti-incontenent agents can be form~ tcd neat or using a variety of phartnaceutical carriers which are amenable for intravaginal or rectal administration including creams, gels, foams, tablets, suppositories, and pessaries containing a number of synthetic or natural materials including but not limited to silicone, si}astic, polycarbophil, polyethylene glycol, and hydrogel. Such carriers may be non-therapeutic or therapeutic, in and of themselves.
Therapeutic carriers with beneficial medicinal properties can be used, for example, to control vaginal pH, treat or inhibit sexually transmitted diseases, or provide vaginal hydration. When adn inistered intravaginally or rectally, it is projected that the preferred dosage for oxybutynin would be 1-20 mg administered 1-4 times per day, the preferred dosage for propantheline would be 1-12() mg administered 1-4 times per day, the preferred dosage for imipramine would be 1-400 mg administered 1-4 times per day, the ~ Ç~I-ed dosage for terodiline would be 1-100 mg administered 1-4 times per day, the preferred dosage for dicyclomine would be 1-40 mg administered 1-4 times per day, and the preferred dosage for flurbiprofen would be 1-100 mg ~1mini~tered 1-4 times per day.
s The following provides representative example of intravaginal or rectal formulations and their preparation.
EXAMPLE l Propantheline Bromide Va~inal or Rectal Suppository Amount per Sg Suppository Propantheline bromide ().()3 g Glycerin 3.5 g Gelatin (TypeA) I o g PurifiedWater 0.47 g Propantheline bromide is dissolved in the Purified Water, gelatin is added and 20 the rnixture is heated nearly to boiling. Glycerin is heated to nearly 100~C and added to the gelatin-water mixture. The resulting mixture is heated in a water bath until the gelatin is dissolved. Water is slowly added to achieve the correct weight and stirred until uniform. The mass is poured into molds, allowed to solidify and packaged.
I~XAMPLE 2 Oxybutynin Hydrochloride Vaginal Cream Amount per 5g dose Oxybutynin Hydrochloride 0 05 g PolyethyleneGlycol 1000 0.09 g Monocetyl Ether Cetostearyl Alcohol 0.3 g Mineral Oil 0.3 g White Petrolatum 0.75 g Propylparaben 0.004 g Methyl paraben 0.0075 g Benzyl Alcohol 0.075 g Puri~ied Water, freshly 3.4085 g boiled and cooled W O 98tll888 PCT~US97/16509 Oxybutynin hydrochloride, methyl and propyl paraben and benzyl alcohol are dissolved in the water with the aid of gentle heat. On a hot water bath, the polyethylene glycol 1000 monocetyl ether, cetostearyl alcohol, mineral oil and white petrolatum are 5 melted together. The aqueous solution is added to the molten oils and stirred until cold.
The cream is packed into tubes and dispensed with a vaginal applicator to provide a 5 g dose.
Dic~/clomineHydrochlorideVa inalGel Amount per 5~ dose Dicyclomine Hydrochloride ().01 g Carbopol 934 ().038 g Triethanolamine 0.056 g 15 Propyl paraben ().004 g Methyl paraben 0.0075 g Purified Water, freshly 4.885 g boiled and cooled 20 Dicyclomine hydrochloride, methyl and propyl paraben are dissolved in the water with the aid of gentle heat. The solution is cooled and carbopol 934 is dispersed in the solution with gentle agitation. Triethanol.mline is added gently to avoid air entrapment until the gel is formed. The gel is packed into tubes and dispensed with a vaginal applicator to provide a 5g dose.
Imipramine Hydrochloride Slow Release Va~inal Tablets Amount per 1~ tablet Imipramine hydrochloride 0.05 g 30 Polycarbophil 0 5 g Lactose 0.4425 g Polyvinylpyrrolidone 0.005 g Magnesium Stearate 0.0025 g Polyvinylpyrrolidone and imipramine hydrochloride ~re dissolved in a suitable quantity of purified water ~nd used to make a wet granule m~ss of the polycarbophil.
. . .
The wet mass is screened through a suitable mesh screen and the resulting granules dried. Lactose is blended with the polycarbophil granules. ~ gnesillm stearate is added and blended just sufficiently to disperse the lubricant. The mixture is compressed into diamond shaped tablets, packed in foil strips and dispense with a vaginal applicator.
The following provide preparations of (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobut-1-enylamino]-3-ethyl-benzonitrile, 4-[(2-tert-butylamino-3,4-10 dioxo-cyclobut-1-enylamino)-methyll-3-chloro-benzonitrile, and 3-(2,3-dichloro-6-methyl-benzylamino)-4-(1,1 -dimethyl-propylamino)-cyclobut-3-ene- 1,2-dione.
4-r~2-tert-BIltvlamino-~4-dioxo-cvclobut-l-envlamino)-methvll-3-chloro-ben~onitrile A. 2-Chloro-4-cyanobenzy1 bromide A mixture of 3-chloro-4-methylbenzonitrile (22.74 g, 150 mmol), N-bromosuccinimide (32.04 g, 18() mmol) and 2,2'-azobis-2-methylpropionitrile (2.46 g, 15 mmol) in carbon tetrachloride (120 mL) was carefullY wa;med to reflux temperature whereupon a moderate exothern- occurred and refluxing proceeded for approximately 10 minutes without external heating. Heating was then resumed and refluxing continued for 26 hours. The hot reaction mixture was suction filtered and the insolubles were rinsed with carbon tetrachloride (3 x 25 mL). The combined carbon tetrachloride fractions were washed with water ànd dried (anhydrous Na2SO4).
Removal of solvent gave a yellow mush which was crystallized from hexane (charcoal).
The product again was recrystallized from hexane to yield 20.44 g (59%) of the white bromide: mp 8().5 - 83.5~C (softens 71.5~C) (lit. mp 85-85.5~C (B. Gogolimska, Acta Pol. Pharm., 25 (4), 391 (1968) [C.A., 70, 87493e (1969)].)); IH NMR (DMSO-d6) ~ 8.10 (d, lH), 7.82 (m, 2H), 4.69 (s, 2H) ppm. IR (KBr): 2220 cm-h B. N-(2-ch]oro-4-cvanobenzYl)phthalimide A mixn~re of product from Example 5, Step A (20.29 g, 88.0 rnmol) and potassium phthalimide (17.92 g, 96.8 mmol) in N,N-dimethylformamide (200 mL) WO 98/11888 PCT/US97l16509 was stirred as the reaction temperature rose to approximately 36~C during approximately S minutes with formation of a tan suspensiol1. The temperature then receded and stirring was continued for 2 hours. After removal of solvent, the residue was triturated thoroughly with water and dried.
The buff solid product was treated with approxilnately 500 mL boiling ethyl acetate, gravity filtered to remove a small amount of white insoluble material, heated to boiling, treated with charcoal and filtered. Concentration and cooling of the filtrate afforded (after drying) 20.26 g (78%) of the title compound ph~h~limide as a white solid: mp 172.5- 173.0~C (softens 170.5~C); lH NMR (DMSO-d6) ~ 8.10 (d, lH), 7.90 (m, 4H), 7.75 (dd, lH), 7.52 (d, IH), 4.88 (s, 2H) ppm. IR (KBr): 2220, 1770, 1715 cm-h C. 2-chloro-4-cyanobenzylamine A mechanically stirred suspension of product from Example 5, Step B (18.99 g, 64 mmol) in absolute ethanol (15() mL) was treated with hydrazine hydrate (6.41 g, 128 mmol) and the mixture was stirred and refluxed for 1 hour and then was allowed to stand at room temperature for approximately 16.5 hours. With stirring 2N HCI (90mL) was added slowly, and after 10 minutes of further stirfing the mixture was filtered.
The insolubles were triturated thorou~hly with ethanol and then with water. The combined filtrate and triturates were freed of solvent and the residue in approximately 250 mL ice-H~O was basified with 2.5 N NaOH (90 mL). The mass was extracted thoroughly with chlorofom1 and the extracts were washed with water, with brine and dried (anhydrous Na~SO4). Removal of solvent gave a cream-colored solid which was recrystallized from hexane to provide 6.85 g (64%) of a white amine- mp 85.0 - 87.0~C
(soften82.5~C); IHNMR(DMSO-d6) â7.96(d, IH), 7.82 (dd, IH), 7.77 (m, lH), 3.82 (s, 2H), 2.12 (br m, 2H) ppm. IR (KBr3: 338(), 332(), 223() cm-~.
D. 4-~(2-tert-Butvlamino-3,4-dic)xo-cyclob-lt- 1-enylamino)-methy]1-3-chloro-benzonitrile Tetrahydrofuran (5() mL), 3-butoxy-4-tert-butylamino-cyclobut-3-ene-1,2-dione (6.76 g, 30 mmol, Example 1) and the product of Example 2, Step 3 (5.00 g, 30 mmol) were refluxed for 6 hours and allowed to stand at room temperature for 16 hours.Following removal of solvent from the reaction mixture, the residue was triturated thoroughly with diethyl ether and dried to give a buff solid. This material in approximately 1.4 L of boiling acetone, was filtered to remove a small amount of white W O 98/11888 PCTrUS97/16509 solid. The hot filtrate was treated with charcoal, filtered, concentrated and cooled to afford 6.521 g of a cream-colored solid. Two additiona} recrystallizations of this material from acetone gave 4.779 g (50%) of the title compound as a white solid: mp 243.5-245.~C (softens 241.0~C); IH NMR (DMSO-d6) o 8.10 (d, lH), 7.88 (dd, lH), 7.82 (m, lH), 7.66 (s, br, lH), 7.61 (d, lH), 4.88 (d, 2H), 1.34 (s, 9H) ppm.
IR (KBr): 3320, 3230, 2240, 1780, 1665 cm-]; MS (m/z) 317/319 (M+). HPLC
indicates a major component (99.6%).
Elemental analysis for C,6H~6ClN3O2 Calc'd:C, 60.48; N, 5.08; N, 13.22; Cl, 11.16.
Found:Ct 60.08; H, 4.97; N, 13.06; Cl, 10.82, 10.71.
3-(2~4-Dichloro-6-methyl-ben7vl~mino)-4-fl.l-dimethyl-propyl~mino)-cvclobut-3-ene-1 ~2-dione A. 3-Butoxy-4~ dimethyl-propylamino)-cyclobut-3-ene- ] ,2-dione A solution of 3,4-dibutoxy-3-cyclobutene-1,2-dione (4.53 g, 20 mmol) and 1,1-dimethylpropylamine (1.74 g, 20 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for approximately 19.5 hours. The solvent was removed and the residue was chromatographed (gravity, chloroform/hexane) on neutral, activity III silica (150 g).
The white solid isolated from the appropriate eluates was recrystallized from hexane to give 4.105 g (86%) of a white product: mp 56.5-57.5~C (softens 55.5~C).
One grarn of this material was recrystallized twice from hexane to provide 0.794g of the title compound as a white solid: mp 56-57~C (softens 55~C); 1H NMR (DMSO-d6): ~ 8.63 and 8.48 (two br s, lH, rotamers), 4.67 (m, br, 2H), 1.67 (m, br, 4H), 1.39 (m, 2H), 1.26 (m, br, 6H), ().91 (t, 3H), 0.78 (t, 3H) ppm. IR (KBr): 3170, 1790, 1700cm~l; MS (m/z): 239 (M+).
Elemental Analysis for C13H21NO3 Calcd: C, 65.24; H, 8.85; N, 5.85 Found: C, 65.12; H, 8.90; N, 5.77 B. 3-(2~4-Diehloro-6-methyl-benzvlamino)-4-(l~l-dimethyl-propylamino)-eyelobut-3-ene- 1 ~2-dione A solution of 3-ethoxy-4-(1,1-dimethyl-propylamino)-eyelobut-3-ene-1,2-dione (16.67 g, 79.0 mmol~ and 2,4-dichloro-6-methylbenzylamine (15.02 g, 79.0 mmol) in absolute ethanol (395 mL) were allowed to stand for 4 days at room le~ ue-dture. The title eompound formed as a white solid, which was filtered, washed with diethyl ether/hexane and dried in vacuo. This yielded 25.7 g (92%) of the title compound as a white solid: mp 247.1-248.3~C; lH NMR (DMSO-d6) ~ 7.54 (d, lH), 7.44 (br t, lH), 7.39 (d, lH), 7.31 (s, lH), 4.9() (d, 2H), 2.40 (s, 3H), 1.66 (q, 2H), 1.28 (s, 6H), 0.80 (t, 3H) ppm. IR (KBr): 32()0, 298(), 1800, 1650 em -1; MS (m/z) 354/356/358 (M+). Analytical HPLC indicates a major component (99.9%).
Elemental analysis for C17H20C12N2~2 Calc'd: C, 57.47; H, 5.67; N, 7.89.
Found: C, 57.31; H, 5.5(); N, 7.X().
Claims (4)
1. A method of treating urinary incontinence in a mammal which comprises administering to said mammal an effective amount of an anti-incontinent agent intravaginally or rectally.
2. The method according to claim 1 wherein the anti-incontinent agent is an anticholinergic agent, antispasmodic agent, tricyclic antidepressant, calcium channel blocker, prostaglandin synthetase inhibitor, potassium channel modulator, tissueselective estrogen, estrogen agonist, or .alpha.-agonist.
3. The method according to claim 1 wherein the anti-incontinent agent is selected from the group consisting of oxybutynin, propantheline, imipramine, terodiline, dicyclomine, flurbiprofen, darifenacin, tolterodine, (R)-4-[3,4-dioxo-2-(1,2,2-trimethyl-propylamino)-cyclobllt-1-enylamino]-3-etthyl-benzonitrile, 4-[(2-tert-butyl-amino-3,4-dioxo-cyclobut-1-enylamino)-methyl]-3-chloro-benzonitrile, and 3-(2,3-dichloro-6-methyl-benzylamino)-4-(1,1-dimethyl-propylamino)-cyclobut-3-ene-1,2-dione.
4. An intravaginal or rectal composition which comprises an anti-incontinent agent and a pharmaceutically acceptable carrier.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US72426396A | 1996-09-19 | 1996-09-19 | |
| US08/724,263 | 1996-09-19 | ||
| PCT/US1997/016509 WO1998011888A1 (en) | 1996-09-19 | 1997-09-17 | Method of treating urinary incontinence |
Publications (1)
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| CA2266070A1 true CA2266070A1 (en) | 1998-03-26 |
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| Application Number | Title | Priority Date | Filing Date |
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| CA002266070A Abandoned CA2266070A1 (en) | 1996-09-19 | 1997-09-17 | Method of treating urinary incontinence |
Country Status (7)
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|---|---|
| EP (1) | EP0927034A1 (en) |
| JP (1) | JP2001502302A (en) |
| KR (1) | KR20010029519A (en) |
| AU (1) | AU4421697A (en) |
| CA (1) | CA2266070A1 (en) |
| WO (1) | WO1998011888A1 (en) |
| ZA (1) | ZA978427B (en) |
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| DE69942928D1 (en) | 1998-08-27 | 2010-12-23 | Pfizer Health Ab | THERAPEUTIC FORMULATION FOR THE ADMINISTRATION OF TOLTERODIN WITH CONTROLLED RELEASE |
| CA2387973C (en) | 1999-11-11 | 2009-12-22 | Pharmacia Ab | Pharmaceutical formulation containing tolterodine and its use |
| US6436428B1 (en) * | 2000-03-21 | 2002-08-20 | Enhance Pharmaceuticals, Inc. | Device and method for treating urinary incontinence in females |
| GB0029903D0 (en) * | 2000-12-07 | 2001-01-24 | Arakis Ltd | Use of anti-muscarinic agents |
| GB0030580D0 (en) * | 2000-12-15 | 2001-01-31 | Medicare Man Consultancy Ltd | Composition and method |
| DE10103262A1 (en) * | 2001-01-25 | 2002-08-01 | Axel Schmidt-Dossi | Suppository containing oxybutynin, useful for treatment of incontinence, avoids side effects and allows an increase in dose |
| AU2002336472B2 (en) * | 2001-10-02 | 2007-08-23 | Kimberly-Clark Worldwide, Inc. | Inhibition of exoprotein production using aromatic compositions |
| US6773421B2 (en) | 2001-12-14 | 2004-08-10 | Kimberly-Clark Worlwide, Inc. | Combination for managing the involuntary loss of bladder control |
| WO2003053292A1 (en) * | 2001-12-20 | 2003-07-03 | Femmepharma, Inc. | Vaginal delivery of drugs |
| US7005138B2 (en) * | 2001-12-21 | 2006-02-28 | Duramed Pharmaceuticals, Inc. | Method of systematically delivering SSRIs |
| GB0207104D0 (en) * | 2002-03-26 | 2002-05-08 | Pfizer Ltd | Stable hydrate of a muscarinic receptor antagonist |
| FR2843303B1 (en) * | 2002-08-07 | 2006-01-21 | R & D Pharma | NOVEL PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF URINARY INCONTINENCE |
| AU2003287248A1 (en) * | 2002-11-12 | 2004-06-03 | Pharmacia And Upjohn Company | Combination therapy for postmenopausal female sexual dysfunction comprising an androgen, an estrogen and an antimuscarinic |
| MXPA05007266A (en) | 2003-01-02 | 2006-01-17 | Femmepharma Holding Co Inc | Pharmaceutical preparations for treatments of diseases and disorders of the breast. |
| US9173836B2 (en) | 2003-01-02 | 2015-11-03 | FemmeParma Holding Company, Inc. | Pharmaceutical preparations for treatments of diseases and disorders of the breast |
| US20040248989A1 (en) * | 2003-06-05 | 2004-12-09 | Risto Santti | Method for the treatment or prevention of lower urinary tract symptoms |
| DE10356112A1 (en) * | 2003-11-27 | 2005-06-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | A pharmaceutical composition of a beta-3 adrenoceptor agonist and a progglandin metabolite |
| CN101448490A (en) | 2006-05-22 | 2009-06-03 | 霍尔莫斯医疗有限公司 | Method of treatment of chronic nonbacterial prostatitis with selective estrogen receptor modulators or aromatase inhibitors |
| US20110003000A1 (en) | 2009-07-06 | 2011-01-06 | Femmepharma Holding Company, Inc. | Transvaginal Delivery of Drugs |
| US10010514B2 (en) | 2010-07-08 | 2018-07-03 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for reducing frequency of urination and method of use thereof |
| US9532959B2 (en) | 2010-07-08 | 2017-01-03 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for reducing frequency of urination and method of use thereof |
| US10105328B2 (en) | 2014-06-06 | 2018-10-23 | Wellesley Pharmaceuticals, Llc | Composition for reducing frequency of urination, method of making and use thereof |
| JP2017516832A (en) * | 2014-06-06 | 2017-06-22 | ウェルズリー ファーマスーティカルズ、エルエルシー | Pharmaceutical formulations for reducing urination frequency and methods of use thereof |
| GB201601855D0 (en) * | 2016-02-02 | 2016-03-16 | Inura Medical Ag | Urethral devices for treatment of pathological urological conditions |
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| DE69120699T2 (en) * | 1990-03-08 | 1997-01-09 | Fujisawa Pharmaceutical Co | N-Monosubstituted cyclopentenylamines, a process for their preparation, and their use as a medicament |
| US5281624A (en) * | 1991-09-27 | 1994-01-25 | Eli Lilly And Company | N-alkyl-3-phenyl-3-(2-substituted phenoxy) propylamines and pharmaceutical use thereof |
| US5234947A (en) * | 1991-11-07 | 1993-08-10 | New York University | Potassium channel activating compounds and methods of use thereof |
| JP2549480B2 (en) * | 1991-12-10 | 1996-10-30 | ヘキストジャパン株式会社 | Urinary disorder improving agent |
| GB9305295D0 (en) * | 1993-03-15 | 1993-05-05 | Zeneca Ltd | Therapeutic compounds |
| GB2278054A (en) * | 1993-05-18 | 1994-11-23 | Zeneca Ltd | Compounds for the treatment of urinary incontinence |
| US5441950A (en) * | 1994-06-09 | 1995-08-15 | G. D. Searle & Co. | Substituted dibenzoxazepine and dibenzthiazepine carbamate compounds, pharmaceutical compositions and methods of use |
| GB9417135D0 (en) * | 1994-08-23 | 1994-10-12 | Medinnova S F | Method |
| US5677346A (en) * | 1995-01-31 | 1997-10-14 | Sepracor, Inc. | Treating urinary incontinence using (S)-desethyloxybutynin |
| GB9518953D0 (en) * | 1995-09-15 | 1995-11-15 | Pfizer Ltd | Pharmaceutical formulations |
-
1997
- 1997-09-17 JP JP10514847A patent/JP2001502302A/en active Pending
- 1997-09-17 WO PCT/US1997/016509 patent/WO1998011888A1/en not_active Application Discontinuation
- 1997-09-17 AU AU44216/97A patent/AU4421697A/en not_active Abandoned
- 1997-09-17 CA CA002266070A patent/CA2266070A1/en not_active Abandoned
- 1997-09-17 EP EP97942538A patent/EP0927034A1/en not_active Withdrawn
- 1997-09-17 KR KR1019997002314A patent/KR20010029519A/en not_active Application Discontinuation
- 1997-09-18 ZA ZA978427A patent/ZA978427B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0927034A1 (en) | 1999-07-07 |
| ZA978427B (en) | 1999-06-18 |
| KR20010029519A (en) | 2001-04-06 |
| AU4421697A (en) | 1998-04-14 |
| WO1998011888A1 (en) | 1998-03-26 |
| JP2001502302A (en) | 2001-02-20 |
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