WO1998011888A1 - Method of treating urinary incontinence - Google Patents

Method of treating urinary incontinence Download PDF

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Publication number
WO1998011888A1
WO1998011888A1 PCT/US1997/016509 US9716509W WO9811888A1 WO 1998011888 A1 WO1998011888 A1 WO 1998011888A1 US 9716509 W US9716509 W US 9716509W WO 9811888 A1 WO9811888 A1 WO 9811888A1
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WO
WIPO (PCT)
Prior art keywords
agent
incontinent
cyclobut
methyl
propylamino
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Application number
PCT/US1997/016509
Other languages
French (fr)
Inventor
Michael Jay Gast
Theodore Richard Koziol
Original Assignee
American Home Products Corporation
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Family has litigation
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Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to JP10514847A priority Critical patent/JP2001502302A/en
Priority to CA002266070A priority patent/CA2266070A1/en
Priority to EP97942538A priority patent/EP0927034A1/en
Priority to AU44216/97A priority patent/AU4421697A/en
Publication of WO1998011888A1 publication Critical patent/WO1998011888A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/275Nitriles; Isonitriles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/192Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/221Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having an amino group, e.g. acetylcholine, acetylcarnitine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/275Nitriles; Isonitriles
    • A61K31/277Nitriles; Isonitriles having a ring, e.g. verapamil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0034Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system

Definitions

  • Urinary incontinence is an involuntary leaking of urine which primarily affects women and older men.
  • SI is the involuntary loss of urine as a result of increasing intra-abdominal pressure, typically occurring after coughing, straining, sneezing, lifting or any other activity which suddenly increases intra- abdominal pressure.
  • SI is the most common cause of involuntary loss of urine, and may be caused by the shortening of the urethra and loss of the normal urethrovesical angle resulting from pelvic relaxation that characteristically occurs with aging or multiparity.
  • UI is characterized by an urgent desire to void followed by the involuntary loss of 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 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 involuntary contractions of the detrusor muscle. Mixed incontinence is seen in patients having both SI and UI.
  • SI is usually treated surgically
  • drugs with anticholinergic properties have been the most common to be used to treat the unstable bladder.
  • 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, dicyclo ine, and flurbiprofen These drugs are usually administered orally and are associated with a number of side effects which limit their usefulness.
  • the most widely prescribed drug for the treatment of incontinence is oxybutynin.
  • oxybutynin Currently it must be given orally two to four times per day.
  • 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.
  • This invention provides a method of treating urinary incontinence which comprises administering an anti-incontinent agent intravaginally 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.
  • this invention provides a method of treating urinary incontinence which 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 ⁇ -agonist.
  • Preferred anticholinergics include agents such as scopolamine, atropine, ipratropium bromide, poldine, glycopyrrolate, propantheline, isopropamide, trihexylphenidyl, benztropine, procyclidine, biperiden, ethopropazine, methancholine, 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- (l,2,2-trimethyl-propylamino)-cyclobut-l -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-l-enylamino)-methyl]-3-chloro-benzonitrile see Example 5
  • 3-(2,3-dichloro-6-methyl-benzylamino)-4-( 1 , 1 -dimethyl-propylamino)-cyclobut-3-ene- 1,2-dione see Example 6
  • Preferred estrogen agonists include 17 ⁇ -estradiol and estrogen.
  • Preferred tissue selective estrogens include roloxafine and teremofine.
  • Preferred ⁇ -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-(l,2,2-trimethyl-propylamino)-cyclobut-l- 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- (l,l-dimethyl-propylamino)-cyclobut-3-ene- l,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.
  • the intravaginal or rectal administration of anti-incontinent agents provides several advantages over conventional treatments for urinary in repeatedlyce, which include all or some of the following (1 ) 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 first 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 immediate release or longer duration of action based on controlled release from the vehicle.
  • This invention therefore, provides a useful and advantageous method of treating urinarv incontinence.
  • anti-incontenent agents When administered intravaginally or rectally, anti-incontenent agents can be formulated neat or using a variety of pharmaceutical 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, silastic, 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.
  • the preferred dosage for oxybutynin would be 1-20 mg administered 1-4 times per day
  • the preferred dosage for propantheline would be 1-120 mg administered 1-4 times per day
  • the preferred dosage for imipramine would be l -400 mg administered 1-4 times per day
  • the preferred 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
  • the preferred dosage for flurbiprofen would be 1-100 mg administered 1-4 times per day.
  • Propantheline bromide is dissolved in the Purified Water, gelatin is added and the mixture 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.
  • Purified Water freshly 3.4085 g boiled and cooled Oxybutynin hydrochloride, methyl and propyl paraben and benzyl alcohol are dissolved in the water with the aid of gentle heat.
  • the polyethylene glycol 1000 monocetyl ether, cetostearyl alcohol, mineral oil and white petrolatum are 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.
  • 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.
  • Triethanolamine 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.
  • Polyvinylpyrrolidone and imipramine hydrochloride are dissolved in a suitable quantity of purified water and used to make a wet granule mass 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.
  • Magnesium 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.
  • Example 1 (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 solid. The hot filtrate was treated with charcoal, filtered, concentrated and cooled to afford 6.521 g of a cream-colored solid.

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

METHOD OF TREATING URINARY INCONTINENCE
BACKGROUND OF THE INVENTION
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 incontenance (SI), urge incontinence (UI), and mixed incontinence. SI is the involuntary loss of urine as a 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 of urine, and may be caused by the shortening of the urethra and loss of the normal urethrovesical angle resulting from pelvic relaxation that characteristically occurs with aging or multiparity.
UI is characterized by an urgent desire to void followed by the involuntary loss of 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 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 involuntary contractions of the detrusor muscle. Mixed incontinence is seen in patients having both SI and UI.
Although, SI is usually treated surgically, there are a number of drugs currently used use to treat UI 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. A 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, dicyclo ine, and flurbiprofen These drugs are usually administered orally and are associated with a number of side effects which limit their usefulness. The 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 showing therapeutic activity with reduced side effects [Weese, D.L., Urology 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 intravaginally 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 incontinence which 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 α-agonist. Preferred anticholinergics include agents such as scopolamine, atropine, ipratropium bromide, poldine, glycopyrrolate, propantheline, isopropamide, trihexylphenidyl, benztropine, procyclidine, biperiden, ethopropazine, methancholine, 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- (l,2,2-trimethyl-propylamino)-cyclobut-l -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-l-enylamino)-methyl]-3-chloro-benzonitrile (see Example 5), and 3-(2,3-dichloro-6-methyl-benzylamino)-4-( 1 , 1 -dimethyl-propylamino)-cyclobut-3-ene- 1,2-dione (see Example 6). Preferred estrogen agonists include 17β-estradiol and estrogen. Preferred tissue selective estrogens include roloxafine and teremofine. Preferred α-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-(l,2,2-trimethyl-propylamino)-cyclobut-l- 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- (l,l-dimethyl-propylamino)-cyclobut-3-ene- l,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 (1 ) 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 first 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 immediate release or longer duration of action based on controlled release from the vehicle. This invention, therefore, provides a useful and advantageous method of treating urinarv incontinence.
When administered intravaginally or rectally, anti-incontenent agents can be formulated neat or using a variety of pharmaceutical 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, silastic, 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 administered 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 1-120 mg administered 1-4 times per day, the preferred dosage for imipramine would be l -400 mg administered 1-4 times per day, the preferred 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 administered 1-4 times per day.
The following provides representative example of intravaginal or rectal formulations and their preparation.
EXAMPLE 1 Propantheline Bromide Vaginal or Rectal Suppository
Amount per 5g Suppository
Propantheline bromide 0.03 g Glycerin 3.5 g
Gelatin (Type A) 1.0 g
Purified Water 0.47 g
Propantheline bromide is dissolved in the Purified Water, gelatin is added and the mixture 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.
EXAMPLE 2
Oxybutynin Hvdrochloride Vauinal Cream
Amount per 5g dose
Oxybutynin Hydrochloride 0.05 g
Polyethylene Glycol 1000 0.09 g Monocetyl Ether
Cetostearyl Alcohol 0.3 g
Mineral Oil 0.3 g
White Petrolatum 0.75 g
Propyl paraben 0.004 g Methyl paraben 0.0075 g
Benzyl Alcohol 0.075 g
Purified Water, freshly 3.4085 g boiled and cooled 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 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.
EXAMPLE 3 Dicyclomine Hydrochloride Vaginal Gel
Amount per 5g dose
Dicyclomine Hydrochloride 0.01 g
Carbopol 934 0.038 g
Triethanolamine 0.056 g Propyl paraben 0.004 g
Methyl paraben 0.0075 g
Purified Water, freshly 4.885 g boiled and cooled
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. Triethanolamine 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.
EXAMPLE 4 Imipramine Hydrochloride Slow Release Vaginal Tablets
Amount per 1 g tablet
Imipramine hydrochloride 0.05 g Polycarbophil 0.5 g
Lactose 0.4425 g
Polyvinylpyrrolidone 0.005 g
Magnesium Stearate 0.0025 g
Polyvinylpyrrolidone and imipramine hydrochloride are dissolved in a suitable quantity of purified water and used to make a wet granule mass 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. Magnesium 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-(l,2,2-trimethyl- propylamino)-cyclobut-l-enylamino]-3-ethyl-benzonitrile, 4-[(2-tert-butylamino-3,4- dioxo-cyclobut-l-enylamino)-methyl]-3-chloro-benzonitrile, and 3-(2,3-dichloro-6- methyl-benzylamino)-4-( 1 , 1 -dimethyl-propylamino)-cyclobut-3-ene- 1 ,2-dione.
EXAMPLE 5 4-r(2-tert-Btιtvlamino-3.4-dioxo-cvclohut- l -envlamino - meth yll-3-chloro-benzonitrile
A. 2-Chloro-4-cvanobenzyl bromide
A mixture of 3-chloro-4-methylbenzonitrile (22.74 g, 150 mmol), N- bromosuccinimide (32.04 g, 180 mmol) and 2,2'-azobis-2-methylpropionitrile (2.46 g, 15 mmol) in carbon tetrachloride ( 120 L) was carefully warmed to reflux temperature whereupon a moderate exotherm 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 and 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 80.5 - 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)].)); 'H NMR (DMSO-d6) δ 8.10 (d, 1H), 7.82 (m, 2H), 4.69 (s, 2H) ppm. IR (KBr): 2220 cm 1.
B . N-(2-chloro-4-cvanobenzyl)phthalimide
A mixture of product from Example 5, Step A (20.29 g, 88.0 mmol) and potassium phthalimide (17.92 g, 96.8 mmol) in N,N-dimethylformamide (200 mL) was stirred as the reaction temperature rose to approximately 36°C during approximately 5 minutes with formation of a tan suspension. T e 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 approximately 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 phthalimide as a white solid: mp 172.5 - 173.0°C (softens 170.5°C); >H NMR (DMSO-d6) δ 8.10 (d, IH), 7.90 (m, 4H), 7.75 (dd, IH), 7.52 (d, IH), 4.88 (s, 2H) ppm. IR (KBr): 2220, 1770, 1715 cm-'.
C. 2-chloro-4-cvanobenzylamine
A mechanically stirred suspension of product from Example 5, Step B (18.99 g, 64 mmol) in absolute ethanol (150 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 HC1 (90 mL) was added slowly, and after 10 minutes of further stirring the mixture was filtered. The insolubles were triturated thoroughly with ethanol and then with water. The combined filtrate and triturates were freed of solvent and the residue in approximately 250 mL ice-H2O was basified with 2.5 N NaOH (90 mL). The mass was extracted thoroughly with chloroform and the extracts were washed with water, with brine and dried (anhydrous Na2S04). 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 (soften 82.5°C); -H NMR (DMSO-d6) δ 7.96 (d, I H), 7.82 (dd, IH), 7.77 (m, IH),
3.82 (s, 2H), 2.12 (br m, 2H) ppm. IR (KBr): 3380, 3320, 2230 cm-'.
D. 4-f(2-tert-Butylamino-3.4-dioxo-cyclobut- l-enylamino)-methyll-3-chloro- benzonitrile
Tetrahydrofuran (50 mL), 3-butoxy-4-tert-butylamino-cyclobut-3-ene-l,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 solid. The hot filtrate was treated with charcoal, filtered, concentrated and cooled to afford 6.521 g of a cream-colored solid. Two additional 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); »H NMR (DMSO-d6) δ 8.10 (d, IH), 7.88 (dd, IH), 7.82 (m, IH), 7.66 (s, br, IH), 7.61 (d, IH), 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 C16H16ClN3O2 Calc'd: C, 60.48; N, 5.08; N, 13.22; Cl, 1 1.16.
Found: C, 60.08; H, 4.97; N, 13.06; Cl, 10.82, 10.71.
EXAMPLE 6 3-(2.4-Dichloro-6-methyl-benzylπmino)-4-(U -dimethyl- propylamino)-cvclobυt-3-ene-1.2-dione
A. 3-Butoxy-4-( 1.1 -dimethyl-propylamino)-cyclobut-3-ene- 1.2-dione
A solution of 3,4-dibutoxy-3-cyclobutene-l,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 gram of this material was recrystallized twice from hexane to provide 0.794 g of the title compound as a white solid: mp 56-57°C (softens 55°C); 1H NMR (DMSO- d6): δ 8.63 and 8.48 (two br s, I H, rotamers), 4.67 (m, br, 2H), 1.67 (m, br, 4H),
1.39 (m, 211), 1.26 (m, br, 6H), 0.91 (t, 3H), 0.78 (t, 3H) ppm. IR (KBr): 3170, 1790, 1700 cm- 1 ; MS (m/z): 239 (M+).
Elemental Analysis for C13H21NO
Calcd: C, 65.24; H, 8.85; N, 5.85 Found: C, 65.12; H, 8.90; N, 5.77 B . 3-(2.4-Dichloro-6-methyl-benzylamino)-4-(l ,l -dimethyl-propylamino)- cvclobut-3-ene- 1.2-dione
A solution of 3-ethoxy-4-(l ,l-dimethyl-propylamino)-cyclobut-3-ene-l,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 temperature. The title compound 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 tide compound as a white solid: mp 247.1 -248.3°C; lH NMR (DMSO-d6) δ 7.54 (d, IH), 7.44 (br t, IH), 7.39 (d, IH), 7.31 (s, IH), 4.90 (d, 2H), 2.40 (s, 3H), 1.66 (q, 2H), 1.28 (s, 6H), 0.80 (t, 3H) ppm. IR (KBr): 3200, 2980, 1800, 1650 cm -1 ; MS (m/z) 354/356/358 (M+). Analytical HPLC indicates a major component (99.9%).
Elemental analysis for C]yH2QCl2N2θ Calc'd: C, 57.47; H, 5.67; N, 7.89.
Found: C, 57.31 ; H, 5.50; N, 7.80.

Claims

WHAT IS CLAIMED IS:
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, tissue selective estrogen, estrogen agonist, or α-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-l3,4-dioxo-2-(l,2,2- trimethyl-propylamino)-cyclobut- 1 -enylamino]-3-ethyl-benzonitrile, 4-[(2-tert-butyl- amino-3,4-dioxo-cyclobut-l -enylamino)-methyl]-3-chloro-benzonitrile, and 3-(2,3- dichloro-6-methyl-benzylamino)-4-( l ,l -dimethyl-propylamino)-cyclobut-3-ene-l,2- dione.
4. An intravaginal or rectal composition which comprises an anti-incontinent agent and a pharmaceutically acceptable carrier.
PCT/US1997/016509 1996-09-19 1997-09-17 Method of treating urinary incontinence WO1998011888A1 (en)

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US6436428B1 (en) 2000-03-21 2002-08-20 Enhance Pharmaceuticals, Inc. Device and method for treating urinary incontinence in females
US6630162B1 (en) 1999-11-11 2003-10-07 Pharmacia Ab Pharmaceutical formulation and its use
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WO2004043429A1 (en) * 2002-11-12 2004-05-27 Pharmacia & Upjohn Company Combination therapy for postmenopausal female sexual dysfunction comprising an androgen, and at least one agent selected from an estrogen and an anti-muscarinic
US6773421B2 (en) 2001-12-14 2004-08-10 Kimberly-Clark Worlwide, Inc. Combination for managing the involuntary loss of bladder control
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