WO2000076490A2 - Methodes de traitement de la frequence exageree des mictions ainsi que les mictions imperieuses a l'aide de oxybutynine-(s) optiquement pure et compositions a cet effet - Google Patents

Methodes de traitement de la frequence exageree des mictions ainsi que les mictions imperieuses a l'aide de oxybutynine-(s) optiquement pure et compositions a cet effet Download PDF

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Publication number
WO2000076490A2
WO2000076490A2 PCT/US2000/040183 US0040183W WO0076490A2 WO 2000076490 A2 WO2000076490 A2 WO 2000076490A2 US 0040183 W US0040183 W US 0040183W WO 0076490 A2 WO0076490 A2 WO 0076490A2
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WO
WIPO (PCT)
Prior art keywords
oxybutynin
pharmaceutically acceptable
acceptable salt
urgency
frequency
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PCT/US2000/040183
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English (en)
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WO2000076490A3 (fr
Inventor
Paul D. Rubin
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Sepracor Inc.
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Priority to AU64036/00A priority Critical patent/AU6403600A/en
Publication of WO2000076490A2 publication Critical patent/WO2000076490A2/fr
Publication of WO2000076490A3 publication Critical patent/WO2000076490A3/fr

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    • A—HUMAN NECESSITIES
    • 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
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder

Definitions

  • the invention relates to methods for treating urinary frequency and urgency using optically pure (S)-oxybutynin.
  • Urinary urgency is the sudden compelling urge to urinate accompanied by discomfort in the bladder.
  • Urinary frequency is a change in the regular voiding pattern, commonly an increase in the frequency of urination.
  • a number of normal and abnormal occurrences can give rise to urinary urgency and increased urinary frequency.
  • An increase in urinary frequency can result from an increase in urinary output or diminished bladder capacity.
  • Increased fluid intake, for example, will increase the volume of urine produced and lead to an increased frequency of urination.
  • diabetics often experience a change in urinary frequency when the levels of sugar in the blood are elevated.
  • Racemic oxybutynin is currently used therapeuticaUy in the treatment of intestinal hypermotility and in the treatment of urinary incontinence. Racemic oxybutynin exerts a direct antispasmodic effect on smooth muscle and inhibits the action of acetylcholine on smooth muscle. It exhibits only one-fifth of the anticholinergic activity of atropine on the rabbit detrusor muscle, but four to ten times the antispasmodic activity. It is quite selective for muscarinic receptors in the presence of nicotinic receptors and as a result, blocking effects are seldom observed at skeletal neuromuscular junctions or autonomic ganglia.
  • racemic oxybutynin is contraindicated in many situations such as patients with untreated angle closure glaucoma, patients with untreated narrow anterior chamber angles, patients with partial or complete obstruction of the gastrointestinal tract, paralytic ileus, intestinal atony in elderly or debilitated patients, megacolon, toxic megacolon complicating ulcerative colitis , severe colitis, and myasthenia gravis, patients with obstructive uropathy and patients with unstable cardiovascular status in acute hemorrhage.
  • racemic oxybutynin may exacerbate the symptoms of hyperthyroidism, coronary heart disease, congestive heart failure, cardiac arrhythmias, hiatal hernia, tachycardia, hypertension, and prostatic hypertrophy.
  • Additional adverse side affects of racemic oxybutynin include palpitations tachycardia, vasodilatation, decreased perspiration, rash, constipation, decreased gastrointestinal motility, nausea, urinary hesitance and retention, asthenia, dizziness, drowsiness, hallucinations, insomnia, restlessness, amblyopia, cycloplegia, decreased lacrimal function, impotence, suppression of lactation.
  • the high incidence of side effects (40 to 80%) associated with the administration of racemic oxybutynin often results in dosage reduction or discontinuation of therapy.
  • the substantially optically pure S enantiomer provides a superior therapy for the treatment of urinary urgency and frequency.
  • Optically pure (S)-oxybutynin provides this treatment while substantially reducing the adverse effects that are associated with the administration of racemic oxybutynin. These include, but are not limited to, xerostomia, mydriasis, drowsiness, nausea, constipation, palpitations and tachycardia.
  • the amelioration of cardiovascular side effects of racemic oxybutynin, such as tachycardia and palpitations, by the administration of (S)-oxybutynin is of particular therapeutic value.
  • the active compound of these compositions and methods is an optical isomer of oxybutynin, namely, the S enantiomer of 4-(diethylamino)-2-butynyl ⁇ -cyclohexyl- ⁇ - hydroxybenzeneacetate, also known as 4-(diethylamino)-2-butynyl phenylcyclohexylglycolate, and hereinafter referred to as oxybutynin.
  • the generic name given to the hydrochloride salt of racemic oxybutynin by the USAN Council is oxybutynin chloride; it is sold under the trade name of Ditropan®.
  • the isomer of oxybutynin having the S absolute stereochemistry (Registry Number 1 19618-22-3) is dextrorotatory, and is shown in Formula I:
  • the invention relates to a method for treating urinary urgency and frequency while avoiding concomitant liability of adverse effects, which comprises administering to a human in need of such treatment a therapeuticaUy effective amount of (S)-oxybutynin or a pharmaceutically acceptable salt thereof, substantially free of its R enantiomer.
  • the present invention provides pharmaceutical compositions which comprise (S)-oxybutynin, or a pharmaceutically acceptable salt thereof, substantially free of (R)-oxybutynin, an additional therapeutic agent, for example, an antibiotic, and a pharmaceutically acceptable carrier.
  • compositions contain at least 90% by weight of (S)-oxybutynin and 10%) by weight or less of (R)-oxybutynin. In a more preferred embodiment, the composition contains at least 98% by weight of (S)-oxybutynin and less than 2% (R)-oxybutynin. In a most preferred embodiment, the composition contains at least 99% by weight of (S)-oxybutynin and less than 1%) of (R)-oxybutynin.
  • the substantially optically pure (S)-oxybutynin may be administered parenterally, rectally, intravesically, transdermally, orally or by aerosol, orally and transdermally being preferred, at a rate of about 250 mg to about 1 gram per day, depending on age, body weight and response of the individual patient.
  • the invention relates to the administration of a pharmaceutical unit dosage form comprising (S)-oxybutynin, or a pharmaceutically acceptable salt thereof, substantially free of its (R) stereoisomer, a second therapeutic agent such as an antibiotic, and a pharmaceutically acceptable carrier in the form of a tablet, soft elastic gelatin capsule, or transdermal delivery device.
  • (S)-oxybutynin preferably is present in an amount of about 25 mg to 500 mg, and more preferably in an amount of about 50 mg to 250 mg, and even more preferably in an amount of about 75mg to 200 mg, and are prepared by conventional methods, well-known in the art.
  • the transdermal administration is improved by the inclusion of a permeation enhancer in the transdermal delivery device, for example as described in PCT application WO 92/20377.
  • (S)-oxybutynin for the treatment of urinary frequency and urgency may be desirable where the increased urge and frequency is due not to increased urine volume but rather the cause of the urinary frequency and urgency is unknown or is caused by an underlying medical condition which would not be worsened by treating the urinary frequency and urgency.
  • Antibiotics for this use include but are not limited to cephalosporins, such as cephalexin; penicillins such as amoxicillin; sulfonamides, such as sulfa ethoxazole in combination with trimethoprim; and nitrofurantoin.
  • cephalosporins such as cephalexin
  • penicillins such as amoxicillin
  • sulfonamides such as sulfa ethoxazole in combination with trimethoprim
  • nitrofurantoin The S enantiomer of oxybutynin may be obtained by resolution of the intermediate mandelic acid followed by esterification as described by Kachur et al. [L Pharmacol. Exp. Ther., 247:867-872 (1988)]. Improved syntheses are described in copending U.S. patent applications serial nos.09/187,832, 09/21 1 ,646, and 09/050,825.
  • the mixed anhydride I is coupled with the propargyl alcohol derivative 4-N,N- diethylamino butynol (4-N,N-DEB)( III where R 1 is -CH 2 R 2 ; R 2 is - ⁇ R 3 R 4 ; and R 3 and R 4 are each ethyl.) Reaction of the optically active mixed anhydride with 4-NN-DEB produces a single enantiomer of oxybutynin, in this case, (S)-4-diethylamino-2- butynylphenylcyclohexylglycolate.
  • a single diastereomer of the product ester is separated from the reaction mixture, and hydrolyzed to provide S- ⁇ - cyclohexylphenylglycolic acid (S-CHPGA).
  • S-CHPGA S- ⁇ - cyclohexylphenylglycolic acid
  • the second (09/050,832) discloses an alternate stereoselective process for preparing CHPGA.
  • a substituted acetaldehyde is condensed with mandelic acid to provide a 5-phenyl-l,3-dioxolan-4-one, which is subsequently reacted with cyclohexanone to provide a 5-(l-hydroxy cyclohexyl)-5- phenyl-l,3-dioxolan-4-one.
  • the product is dehydrated to a 5-(l-cyclohexenyl)-5-phenyl- l,3-dioxolan-4-one, hydrolyzed and reduced to CHPGA.
  • a third method, as described in U.S. application serial no. 09/187,832 proceeds via a 5-phenyl-l ,3-dioxolan-4-one.
  • the S enantiomer may be obtained by the resolution of racemic oxybutynin using conventional means such as fractional crystallization of diastereomeric salts with chiral acids.
  • the magnitude of a prophylactic or therapeutic dose of (S)-oxybutynin in the acute or chronic management of disease will vary with the severity and nature of the condition to be treated and the route of administration. The dose and perhaps the dose frequency will also vary according to the age, body weight and response of the individual patient.
  • the total daily dose range for (S)-oxybutynin for the conditions described herein is from about 50 mg to about 1 gram, preferably from about 100 mg to about 750 mg, more preferably from about 150 mg to about 600 mg, and even more preferably from about 200 mg to 500 mg, in single or divided doses, preferably in divided doses.
  • the therapy should be initiated at a lower dose, perhaps at about 150 mg to about 300 mg, and increased depending on the patient's global response, e.g., up to about lg. It is further recommended that patients over 65 years and those with impaired renal or hepatic function initially receive low doses and that they be titrated based on individual response(s) and blood level(s). It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art. Further, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response.
  • the terms "a therapeuticaUy effective amount” and “an amount sufficient to treat urgency/frequency but insufficient to cause adverse effects” are encompassed by the above-described dosage amounts and dose frequency schedule.
  • any suitable route of administration may be employed for providing the patient with an effective dosage of (S)-oxybutynin.
  • oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, aerosol and similar forms of administration may be employed.
  • the drug may be administered directly into the bladder through the urethra, as described for racemic oxybutynin by Massad et al. rj. Urol.. 148:595-597 (1992)].
  • compositions administered in accordance with the method of the present invention include suspensions, solutions, dispersions, elixirs, or solid dosage forms, with oral solid preparations being preferred over the oral liquid preparations.
  • Pharmaceutical compositions suitable for oral administration in accordance with the method of the present invention may be presented as discrete units such as capsules, cachets, troches or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules. Because of their ease of administration, tablets and capsules represent one of the more advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed.
  • compositions may be prepared by any of the methods of pharmacy well known to those skilled in the art, and general methods for preparing them are found in most standard pharmacy school textbooks.
  • An exemplary source is Remington: The Science and Practice of Pharmacy. Generally, all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like are suitable in the case of oral solid preparations (such as, powders, capsules, and tablets). If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the pharmaceutical compositions administered in accordance with the method of the present invention comprise (S)-oxybutynin as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • pharmaceutically acceptable salts or "a pharmaceutically acceptable salt thereof refer to salts prepared from pharmaceutically acceptable non-toxic acids.
  • suitable pharmaceutically acceptable acid addition salts for the compound of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and the like.
  • the compounds of the present invention may also be administered by controlled release means and delivery devices.
  • Controlled release of a therapeutic agent makes it possible to further reduce any side effects due to peak plasma concentrations of the drug.
  • Such methods include controlled release delivery of a drug to the oral mucosa or transdermally, for example, using a bandage-type strip which has been impregnated with the medicament to be administered.
  • a systemically active drug, e.g. (S)-oxybutynin, in a therapeuticaUy effective amount is encapsulated in a suitable material, the microcapsules are then distributed throughout the adhesive used to affix the device to the patient's skin or mucosa.
  • the pharmaceutical compositions administered in accordance with the method of the present invention may be formulated in a soft elastic gelatin capsule unit dosage form by using conventional methods, well-known in the art (see, e.g., Ebert, Pharm. Tech.. 1(5):44-50(1977)).
  • Soft elastic gelatin capsules have a soft, globular, gelatin shell somewhat thicker than that of hard gelatin capsules, wherein a gelatin is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the hardness of the capsule shell may be changed by varying the type of gelatin and the amounts of plasticizer and water.
  • the soft gelatin shells may contain a preservative to prevent the growth of fungi, such as methyl- and propylparabens and sorbic acid.
  • the active ingredient may be dissolved or suspended in a liquid vehicle or carrier, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol, triglycerides, surfactants such as polysorbates, or a combination thereof.
  • (S)- oxybutynin is preferably present in an amount of about 10 mg to about 500 mg, more preferably in an amount of about 50 mg to about 250 mg, and even more preferably in an amount of about 70 mg to about 200 mg.
  • the primary endpoint was an improvement, that is, a decrease in urinary frequency associated with voluntary voiding.
  • the study was conducted over a three week period of time, the first week being a lead-in, in which all groups received placebo. Baseline voiding patterns were established during week 1. Subsequently, during weeks 2 and 3, patients received the dosages of (S)-oxybutynin indicated above.
  • S-oxybutynin has therapeutic effects on voluntary micturition frequency, which is generally accepted as a surrogate marker for urinary urgency, while this isomer has very little effect on the normal voiding mechanism and also has decreased side effects as compared with the racemate.

Abstract

Cette méthode permet de traiter la fréquence exagérée des mictions ainsi que les mictions impérieuses tout en évitant le risque concomitant lié aux réactions indésirables associées à l'oxybutynine racémique. La méthode consiste à administrer une quantité efficace du point de vue thérapeutique d'oxybutynine-(S) ou un sel de celle-ci, admissible du point de vue thérapeutique, quasiment exempt de son énantiomère R. L'invention a également trait à des compositions à usage pharmaceutique renfermant de l'oxybutynine-(S) ou un sel de celle-ci, admissible du point de vue thérapeutique, quasiment exempt de son énantiomère R, à un antibiotique ainsi qu'à un excipient admissible du point de vue pharmaceutique.
PCT/US2000/040183 1999-06-10 2000-06-09 Methodes de traitement de la frequence exageree des mictions ainsi que les mictions imperieuses a l'aide de oxybutynine-(s) optiquement pure et compositions a cet effet WO2000076490A2 (fr)

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US32969699A 1999-06-10 1999-06-10
US09/329,696 1999-06-10

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011109403A1 (fr) * 2010-03-01 2011-09-09 Xenoport, Inc. Utilisation d'acide (3r)-4-{[(1s)-2-méthyl-1-(2-méthylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophényl) butanoïque pour le traitement de l'incontinence urinaire

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5532278A (en) * 1995-01-31 1996-07-02 Sepracor, Inc. Methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin
WO1996033678A1 (fr) * 1995-04-26 1996-10-31 Theratech, Inc. Utilisation de la triacetine comme stimulation de penetration transdermique
WO1996037202A1 (fr) * 1995-05-22 1996-11-28 Alza Corporation Forme galenique contenant de l'oxybutynine
WO1998000126A1 (fr) * 1996-06-28 1998-01-08 Sepracor, Inc. Utilisation de (s)-oxybutynine et de (s)-desethyloxybutynine pour traiter l'incontinence urinaire
WO1999024106A1 (fr) * 1997-11-06 1999-05-20 Situs Corporation Infuseur intravesical
WO1999048494A1 (fr) * 1998-03-26 1999-09-30 Alza Corporation Composition d'oxybutine a liberation continue et effet de xerostomie reduit

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JPH04273818A (ja) * 1991-02-28 1992-09-30 Kissei Pharmaceut Co Ltd 経皮投与製剤
JP2665858B2 (ja) * 1992-05-30 1997-10-22 日本ヘキスト・マリオン・ルセル株式会社 持効性塩酸オキシブチニン製剤

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5532278A (en) * 1995-01-31 1996-07-02 Sepracor, Inc. Methods and compositions for treating urinary incontinence using optically pure (S)-oxybutynin
WO1996033678A1 (fr) * 1995-04-26 1996-10-31 Theratech, Inc. Utilisation de la triacetine comme stimulation de penetration transdermique
WO1996037202A1 (fr) * 1995-05-22 1996-11-28 Alza Corporation Forme galenique contenant de l'oxybutynine
WO1998000126A1 (fr) * 1996-06-28 1998-01-08 Sepracor, Inc. Utilisation de (s)-oxybutynine et de (s)-desethyloxybutynine pour traiter l'incontinence urinaire
WO1999024106A1 (fr) * 1997-11-06 1999-05-20 Situs Corporation Infuseur intravesical
WO1999048494A1 (fr) * 1998-03-26 1999-09-30 Alza Corporation Composition d'oxybutine a liberation continue et effet de xerostomie reduit

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Title
DATABASE WPI Week 199404 Derwent Publications Ltd., London, GB; AN 1994-031722 XP002183937 & JP 05 339151 A (KODAMA KK), 21 December 1993 (1993-12-21) *
PATENT ABSTRACTS OF JAPAN vol. 0, no. 0 & JP 04 273818 A (KISSEI PHARMACEUTICAL CO LTD), 30 September 1992 (1992-09-30) *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011109403A1 (fr) * 2010-03-01 2011-09-09 Xenoport, Inc. Utilisation d'acide (3r)-4-{[(1s)-2-méthyl-1-(2-méthylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophényl) butanoïque pour le traitement de l'incontinence urinaire
US8377956B2 (en) 2010-03-01 2013-02-19 Xenoport, Inc. Use of (3R)-4-{[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino}-3-(4-chlorophenyl) butanoic acid for treating urinary incontinence

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AU6403600A (en) 2001-01-02

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