BACKGROUND OF THE INVENTION 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. These symptoms, singly or in combination, can have a profound impact on lifestyle because daily routines and activities are disrupted.

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. Similarly, diabetics often experience a change in urinary frequency when the levels of sugar in the blood are elevated.

Diminished bladder capacity due to disease and other medical conditions such as urinary tract infection, prostatitis, and pregnancy can also lead to urinary urgency and frequency of urination. In other cases, the cause of urgency/frequency is unknown. In some situations, however, it may be desirable to suppress the urge and reduce the frequency of urination.

Racemic oxybutynin is currently used therapeutically 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.

Treatment with racemic oxybutynin, however, has certain disadvantages.

Xerostomia (dry mouth) and mydriasis (dilated pupils), for example, are very common side effects of racemic oxybutynin therapy. Additionally, 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.

Furthermore, 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. Ultimately, 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.

Pharmacological studies of the individual enantiomers have suggested that the R- enantiomer is the efficacious enantiomer. Noronha-Blob et al. LL Pharmacol. Exp Ther., 256: 562-567 (1991)] concluded that the cholinergic antagonism of racemic oxybutynin (measured in vitro by its affinity for M,, M2 and M3 receptors subtypes and in vivo for diverse physiological responses) could be attributed mainly to the activity of the R- enantiomer. For all responses they found the rank order of potency of racemic

oxybutynin and its enantiomers to be the same, namely, (R)-oxybutynin greater than or equal to racemic oxybutynin, which was much greater than (S)-oxybutynin, with (S)-oxybutynin being I to 2 orders of magnitude less potent than (R)-oxybutynin.

More recently, the (S)-enantiomers of oxybutynin and desethyloxybutynin have been shown to provide a superior therapy in treating urinary incontinence, as disclosed in U. S. Patent Nos. 5,532,278,5,677,346, and 5,736,577.

SUMMARY OF THE INVENTION It has now been unexpectedly found that 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 a-cyclohexyl-a- 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 119618-22-3) is dextrorotatory, and is shown in Formula I:

The synthesis of (S)-oxybutynin has been described, but (S)-oxybutynin itself is not presently commercially available.

In one aspect 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 therapeutically effective amount of (S)-oxybutynin or a pharmaceutically acceptable salt thereof, substantially free of its R enantiomer. In another aspect, 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.

The term"substantially free of its R enantiomer"as used herein means that the 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.

In another aspect, 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. For the tablet and soft elastic gelatin capsule forms, (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.

DETAILED DESCRIPTION OF THE INVENTION Use of (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.

Where the increased frequency and urgency is due, for example, to diminished bladder capacity resulting from a medical condition, administration of (S)-oxybutynin with an additional therapeutic agent, one that is appropriate for the underlying medical condition, may be warranted. For example, in patients with urinary tract infection, temporary relief of the discomfort associated with the frequency and urgency may be effected by administering a dose of (S)-oxybutynin alone or in combination with an additional therapeutic agent, an antibiotic appropriate for treatment of urinary tract infection. Antibiotics for this use include but are not limited to cephalosporins, such as cephalexin; penicillins such as amoxicillin; sulfonamides, such as sulfamethoxazole in combination with trimethoprim; and 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. LL Pharmacol. Exp. Ther., 247: 867-872 (1988)]. Improved syntheses are described in copending U. S. patent applications serial nos. 09/187,832,09/211,646, and 09/050,825.

The synthesis of the (S)-enantiomer of oxybutynin described in serial no. 09/211,646 is as follows: an activated derivative of cyclohexylphenylglycolic acid (CHPGA), the mixed anhydride I, is prepared. H isobutylchloroformate Oh oh ! The mixed anhydride I is coupled with the propargyl alcohol derivative 4-N, N diethylamino butynol (4-N, N DEB) ( III where R'is-CHR';; is-NR'R'; and R3 and R4 are each ethyl.) Reaction of the optically active mixed anhydride with 4-N, N-DEB produces a single enantiomer of oxybutynin, in this case, (S)-4-diethylamino-2- butynylphenylcyclohexylglycolate.

Improved syntheses of starting material CHPGA have been described in two copending U. S. Patent Applications, Serial Numbers 09/050,825 and 09/050,832. In the first (09/050,825), phenylglyoxylic acid or cyclohexylglyoxylic acid is condensed with a single enantiomer of a cyclic vicinal aminoalcohol to form an ester of the phenylglyoxylic

acid or the cyclohexylglyoxylic acid. The ester is reacted with an appropriate Grignard reagent to provide an a-cyclohexylphenylglycolate ester. A single diastereomer of the product ester is separated from the reaction mixture, and hydrolyzed to provide S-a- cyclohexylphenylglycolic acid (S-CHPGA). 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-1,3-dioxolan-4-one, which is subsequently reacted with cyclohexanone to provide a 5- (l-hydroxy cyclohexyl)-5- phenyl-1, 3-dioxolan-4-one. The product is dehydrated to a 5- (1-cyclohexenyl)-5-phenyl- 1,3-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-1, 3-dioxolan-4-one.

Alternatively, 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. In general, the total daily dose range for (S)-oxybutynin for the conditions described herein is from about 50 mg to about I 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. In managing the patient, 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 therapeutically 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. For example, oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, aerosol and similar forms of administration may be employed. Additionally, the drug may be administered directly into the bladder through the urethra, as described for racemic oxybutynin by Massad et al.

[J. Urol., 148: 595-597 (1992)].

The 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.

Such 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.

The terms"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.

Specific methods for the preparation of oral syrups, as well as other oral liquid formulations, can be found in Chapter 86 of the 19th edition of Remington entitled "Solutions, Emulsions, Suspensions and Extracts". It describes in complete detail the preparation of syrups (pages 1503-1505) and other oral liquids. Similarly, sustained release formulation is well known in the art, and Chapter 94 of the same reference, entitled"Sustained-Release Drug Delivery Systems,"describes the more common types of oral and parenteral sustained-release dosage forms (pages 1660-1675.) The relevant disclosure, Chapters 86 and 94, is incorporated herein by reference.

In addition to the common dosage forms set out above, in a preferred embodiment, 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 therapeutically 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. Materials used to encapsulate the drug or drug solution are

permeable to the drug to permit passage of the drug, by diffusion, through the walls of the microcapsules at a relatively low rate. Other examples of controlled release devices are described in U. S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,399,359; 5,840,754, and PCT application WO 92/20377.

In another preferred embodiment, 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 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. In the soft elastic gelatin capsule pharmaceutical unit dosage form of the present invention, (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 following examples will serve to illustrate the invention without in any way being limiting thereon.

The unexpected advantages of the S enantiomer for urgency and frequency has been established by the following studies.

A Phase II clinical study was conducted to evaluate the effectiveness of (S)- oxybutynin in treating urinary frequency and urgency. One hundred seventy-eight patients suffering from urinary incontinence were entered in the study and randomly assigned to three groups. Patients in two groups each received three dosages of (S)-

oxybutynin per day. Those patients receiving the lower-dosage regimen were given 80mg, 80mg, and 160mg (S)-oxybutynin, while their higher-dosage counterparts received 160mg, 160mg, and 160mg. The third group received placebo.

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.

Improvement was indicated by the decrease in frequency as measured by the decrease in urinary episodes per day. By the end of the first week of treatment, the group on the lower dose of (S)-oxybutynin showed a decrease in frequency, on average, of 1.6 episodes per day. Similarly, the higher dose of (S)-oxybutynin decreased urinary frequency by 2.4 episodes per day. At the end of two weeks of treatment, both groups had reduced the number of urinary episodes per day by at least two and almost three for the group taking the higher dose of (S)-oxybutynin.

The presence of side effects, for example, dry mouth, was evaluated three times a day. Less than 15% of the patients receiving the lower dose of (S)-oxybutynin and approximately 16% of the high dosage group experienced moderate to severe dry mouth.

The data from the clinical study described above allows one to conclude that 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.

The embodiments of the present invention described above are intended to be merely exemplary and those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. All such equivalents are considered to be within the scope of the present invention and are covered by the following claims.

All patents, publications, or other references that are listed herein are hereby incorporated by reference.