WO1999033454A2 - S-procyclidine for treating urinary incontinence - Google Patents

Abstract

A method for treating urinary incontinence, such as incontinence resulting from bladder detrusor muscle instability, using enantiomerically enriched (S)-procyclidine. The method comprises administering a therapeutically effective amount of enantiomerically enriched (S)-procyclidine, or a pharmaceutically acceptable salt thereof, substantially free of the (R)-procyclidine enantiomer. Pharmaceutical compositions for the treatment of urinary incontinence comprising enantiomerically enriched (S)-procyclidine, or a pharmaceutically acceptable salt thereof, and an acceptable carrier are also disclosed.

Description

S-PROCYCLIDINE FOR TREATING URINARY INCONTINENCE

Field of the Invention The present invention relates to methods for treating urinary incontinence such as incontinence caused by bladder detrusor muscle instabilitλ . and to pharmaceutical compositions for such treatment

Background of the Invention Urmar> mcontmence is a prevalent problem that affects people of all ages and levels of physical health, both in healthcare settings and in the community at large At present, urinary incontinence afflicts 15-30% of elderlv people living at home, one-third of those living in acute-care settings, and at least one-half of those in long-term care institutions (R M Resmck. Lancet 346 94 ( 1995)) Medicalh . it predisposes persons to uπnarv tract infections, pressure ulcers, peπneal rashes, and urosepsis Psychosocial . urinary incontinence is associated with embarrassment, social stιgmatι.zatιon. depression. and with the risk of lnstitutiona zation (Herzo et a I , Annu Rev Gerontol Genatr . 9 74 (1989)) Economically, the costs are great, in the United States alone, over $10 billion is spent per annum managing mcontmence

Treatments for mcontmence mclude drugs with bladder relaxant properties. / e . which help to control bladder detrusor muscle overactrvrty Such drugs are effective in 80 to 85% of patients with uninhibited bladder contractions, with anticholmergic medications representmg the mamstay of this type of treatment For example, anticholmergics such as propantheline bromide, mά combmation smooth muscle relaxant/anticholinergics such as racemic oxybutymn and dicyclomine, have been used to treat urge mcontmence (See, e g , A J Wein, Urol Chn N Am , 22.557-77 (1995) )

No treatment for mcontmence, including existing drug therapies, has achieved complete success with all classes of mcontment patients, and without sigmficant side effects For example, adverse effects, such as drowsiness, dry mouth,

blurred vision headaches, .and cardiac -urhythmia which are related to the anticholmergic activitv of drugs such as racemic oxybutymn, occur frequently and can be sufficiently troublesome to necessitate discontinuing treatment in up to 25% of patients, depending on the dosage Yet. despite the occurrence of unwanted anticholmergic effects m many patients, and an apparent lack of efficacy m the elderly institutionalized population, racemic oxybutymn nevertheless is considered the drug of first choice in patients with bladder detrusor muscle hyperactivity when pharmacological therapy is indicated (cf Yarllur et al . Drugs Aging. 6 243 (1995))

Procyc dine, l-cyclohe\yl-l-phen\l-3-(l-pyrrolιdιnyl)-l-propanol. a synthetic antispasmotic drug, is described as being useful in treatmg parkmsomsm. and has been used in muscaπmc receptor binding studies (Lambrecht et al , Eur J Pharmacol . 155_ 167-170 (1988). Waelbroeck et al . Brit J Pharmacol , .109 360-370 (1993)) Similar adverse effects to those for anticholmergic drugs may result with the use of procychdine (cf Physician's Desk Reference. 50th Edition, page 1112 (1996))

Summary of the Invention The present invention provides methods and compositions for treatment of urinary incontinence, including, e g , bladder detrusor muscle instability incontinence, stress mcontmence, urge mcontmence, overflow incontinence, enuresis, and post-prostectomy incontinence, with (5)-procychdιne The methods of the present invention provide for treatment of incontinence with fewer adverse effects than occur upon administration of racemic procychdine

One aspect of the present invention relates to methods for treating urinary mcontmence by admimstration to a subject m need thereof a therapeutically effective amount of enantiomerically ennched (S)-procychdme. or a pharmaceutically acceptable salt thereof In a preferred embodiment of this method, the enantiomerically enriched (5)-procychdιne, or a pharmaceutically acceptable salt thereof, is substantially free of (Λ)-procychdme

The present invention also relates to methods for treating bladder detrusor muscle instability compnsmg administration to a subject in need thereof a therapeutically effective amount of enantiomencally ennched (Sj-procychdine, or a pharmaceutically acceptable salt thereof Preferably, the enantiomencally enriched (£)-procyclιdιne. or a pharmaceutically acceptable salt thereof, is substantially free of (R)-procyclιdιne

.Another aspect of the present invention relates to pharmaceutical compositions for the treatment of urinary incontinence compnsmg enantiomencally enriched (S)-procychdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner In a prefened embodiment, the phannaceutical compositions of the present invention comprise (,Sj-procychdιne, or a pharmaceutically acceptable salt thereof, substantially free of (J.)-procyclιdιne

The present mvention also provides for formulating the pharmaceutical compositions of the present invention, compnsmg enantiomencally enriched

or a pharmaceuticalh acceptable salt thereof, and a pharmaceutically acceptable carrier, m phaimaceutical unit dosage foims. including, e g , tablets and soft elastic gelatin capsules Yet another embodiment of the present invention relates to a kit for treating uπnaπ, incontinence, such as bladder detrusor muscle instability incontinence, stress mcontmence. urge incontinence, overflow incontinence, enuresis, and post-prostectomy mcontmence, wherein said kit compnses a pharmaceutical composition comprising enantiomencally enriched (S)-procychdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner, and instructions for administenng the same while reducmg or eliminating anticholmergic adverse effects associated with administration of racemic procychdine, or other mcontmence drugs with anticholmergic action Preferably, the enantiomencally enriched (S)-procychdιne. or a pharmaceutically acceptable salt thereof, is substantially free of (/?)-procychdme Detailed Descnption of the Invention

It is .known that urinary mcontmence can be caused by uncontrolled or unstable bladder contractions, particularly of the bladder detrusor muscle which serves to force fluids out of the bladder The major proportion of the neurohumeral stimulus for physiologic bladder contraction is acetylcholine-induced stimulation of postganghonic muscannic receptor sites on bladder smooth muscle Consistent with this obseiΥation. most pharmacologic treatments for mcontmence associated with uninhibited bladder contractions mclude medications with anticholmergic and smooth muscle relaxant properties However, as set out above, many of the anticholmergic agents which have been used for the treatment of mcontmence often have adverse effects associated with their anticholmergic actions, which result m at least penodic discontinuation of use m a significant portion of the treated population

The present invention relates to compositions and methods for the treatment of bladder instability in mammals, such as humans More specifically, tins mvention provides enantiomencally ennched preparations of (S)-procychdιne and methods for their use m the treatment of urinary incontinence, including, e g . bladder detrusor muscle instability mcontmence, stress mcontmence, urge mcontmence, overflow mcontmence. enuresis, and post-prostectomy mcontmence One feature of the subject non-racemic preparations of (S)-procyclιdιne denves from the enantiomer^" s pharmacological advantage o\ er the racemate m terms of its pnncipal therapeutic and side effect profile Certain deleterious local and/or systemic adverse effects of the racemic mixture, e g . drowsmess. xerostomia, mydπasis. constipation, cycloplegia, cardiac arrhythmia and/or epistaxis mav be reduced through treatment with enantiomencally enriched (S)-procyclιdιne

The chemical structure of (5)-procychdιne is as set forth m Formula I

I

In one aspect, the present invention provides a method for treatmg urinary incontinence using (S)-procychdme, which results in a reduction of the adverse effects associated with admimstration of racemic procychdine The method compnses administering to a patient in need thereof a pharmaceutically effective amount of (<S)-procychdιne, or a pharmaceutically acceptable salt thereof, substantially free of (Λ)-procychdme In a prefened embodiment, the methods of the present invention are used to treat urinary mcontmence due to bladder detrusor muscle instability Such instability may result in, for example, stress incontinence or urge incontinence, or combination thereof, and/or enuresis

In another aspect, the present invention provides pharmaceutical compositions which compnse an enantiomencally enriched preparation of (S)-procychdme. or a pharmaceutically acceptable salt thereof, formulated together with one or more pharmaceutically acceptable earners (additives) and/or diluents As desenbed in detail below, the pharmaceutical compositions of the present invention may be specially formulated for admimstration in solid or liquid form, including those adapted for oral administration, parenteral administration, or topical application For convenience, certain terms employed m the specification, examples, and appended claims are collected here

The term "chiral" refers to molecules which have the property of non-supeπmposabilitΛ of the mirror image partner, while the term "achiral" refers to molecules which are supenmposable on their minor image partner With respect to the nomenclature of a chiral center, the terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E , Fundamental Stereochemistry. Pure Appl Chem , 45 13-30 ( 1976) The teims racemate and enantiomer will be used m their normal context to descnbe the stereochemistry of procychdine preparations

The terms "enantiomencally enriched" and "non-racemic". as used interchangeably herein with reference to preparations of procychdine, refer to procychdine compositions in which the (5)-procvchdme enantiomer is enriched, compared to a control mixture of (S)-procychdιne and (Λ)-procychdιne enantiomers Unless othei-wise specified, such terms refer to procychdine compositions in which the ratio of (S)-procychdme to (/.)-procyclιdιne enantiomers is greater than 1 1 by weight For instance, an enantiomencally ennched preparation of (S)-procychdιne, means a preparation of procychdine having greater than 50%) by weight of the (S)-procychdme enantiomer relative to the ( .)-procychdιne enantiomer, more preferably at least 75% by weight, and even more preferably at least 80%> by weight Of course, the enrichment can be much greater than 80% by weight, providing a "substantially enantiomencally ennched" or a "substantially non-racemic" preparation, which refers to preparations of procychdine which have at least 85% by weight of the (5)-procychdme enantiomer relative to the (K)-procychdme enantiomer. more preferably at least 90% by weight, and even more preferably at least 95% by weight The teim

"substantially free of (/.)-procychdme" will be understood to have similar purity ranges . i e , at least 85% by weight of the (S)-procychdιne enantiomer relative to the (Λ)-procychdιne enantiomer, more preferably at least 90% by weight, and even more preferably at least 95% by weight The term "adverse effects" as used herem, refers to effects associated with admimstration of racemic procychdine, which are not part of the desired therapeutic effect of the drug With respect to the treatment of unnary mcontmence, such adverse effects, include, for illustrative purposes, drowsmess, epistaxis, xerostomia, mydnasis. cycloplegia. unstable cardiovascular status such as anhythnua (e g , tachycardia or palpitations), increased ocular pressure, nausea, constipation, decreased sweating, impotence, and/or dermal mamfestations such as urticana

The teim "epistaxis" refers to nosebleeds, e g , hemorrhage from the nose Epistaxis is a side effect of anticholmergics in children

The term "xerostomia" refers to dryness of the mouth due to lack of normal secretion The term "mydnasis" refers to dilation of the pupil, and often results in blurred vision The term "cycloplegia" refers to paralysis of the ciliary muscle, paralysis of accommodation

The term "enuresis" refers to the involuntary discharge of urine, and "nocturnal enuresis" refers to involuntary discharge of unne during sleep at night

Separation of enantiomers can be accomplished m several ways known in the art (See, e g , Hermanssen et al , J Chromat . 694 57-69 (1995)) For example, a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (see, e g , "Chiral Liquid Chromatography". W J Lough, Ed Chapman and Hall. New York (1989)) Enantiomers can also be separated by classical resolution techniques For example, formation of diastereometπc salts and fractional crystallization can be used to separate enantiomers For the separation of enantiomers of carboxyhc acids, the diastereometπc salts can be formed by addition of enantiomencally pure chiral bases such as brucme, quinine, ephedrme, strychnine, and the like Alternatively, diastereometπc esters can be formed with enantiomencally pure chiral alcohols such as menthol, followed by separation of the diastereomenc esters and hydrolysis to yield the free, enantiomencally enriched carboxyhc acid For separation of the optical isomers of ammo compounds, addition of chiral carboxyhc or sulfonic acids, such as camphorsulfomc acid, tartanc acid, mandelic acid, or lactic acid can result m foimation of the diastereomenc salts

In addition to separation techniques such as those described above, the active enantiomer of procychdine can be synthesized by stereospecific synthesis to produce only the desired optical isomer usmg methodology well .known to those skilled in the art (See, e g., Sjo et al , Ada Chemica Scandinavia. 47 1019-1024 (1993), Schjekdenip et al . Ada Chemica Scandinavia, B41 356-361 (1987)) Chiral synthesis can result in products of high enantiomeπc punty However, in some cases, the enantiomeric purity of the product is not sufficiently high The skilled artisan will appreciate that the separation methods descnbed above can be used to further enhance the enantiomenc punty of procychdine obtained by chiral synthesis

The optical punty of the (S)-procychdιne can be deteimined by methods known in the art For example, a sample of the procychdine can be analyzed by high perfoimance liquid chromatography on a chiral chromatographic column Another method of determining optical purity involves making a chiral ester, such as a Mosher ester of a procychdine sample, and analyzing the NMR spectrum for the presence of the undesired enantiomer

In preferred embodiments, (S)-procychdιne is substantially free of (Λ)-procvchdιne "Substantially free" as used herein, means that at least 85% by weight of the total procychdine present is the (.Sj-procychdine enantiomer, more preferably at least 90% by weight, and still more preferably at least 95% by weight is the (5)-procvchdιne enantiomer In a more preferred embodiment, at least 99 % by weight of the total proc\ chdine present is the (S)-procychdme enantiomer (5)-procyclιdιne can be used to treat urinary incontinence, including, e g , bladder detrusor muscle instability incontinence, stress mcontmence, urge incontinence, overflow incontinence, enuresis, and post-prostectomy mcontmence, by administration to a patient according to any suitable route of administration (See. Remington The Science and Practice of Pharmacy. Nineteenth Edition, Chapters 83-95 (1995) ) For example, a preferred method of administration is oral administration .Another prefened route of administration is intravenous admimstration A particularly preferred route of admimstration is mtravesical delivery, i e , admimstration directly to the bladder, e g , by injection or infusion

According to the present invention, (S)-procychdme is preferably administered as a pharmaceutical foπnulation (composition) The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms winch are, within the scope of sound medical judgment, suitable for use m contact with the tissues of human bemgs and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/nsk ratio As set out above,

contains an ammo functional group, and thus is capable of forming pharmaceutically acceptable salts The term "pharmaceutically acceptable salts" m this respect, refers to the relatively non-toxic, inorganic and organic salts of («S)-procychdιne These salts can be prepared in s tu during the final isolation and punfication of the (S)-procyclιdme Representative salts include the bromide, chlonde, hydrobromide, hydrochlonde. sulfate. bisulfate, phosphate, mtrate, acetate, valerate, oleate, palmitate, stearate, laurate. benxoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succmate, tartrate, naphthylate, mesylate, glucoheptonate. lactobionate, and lauiylsulfonate salts and the like (See, e g . Berge et al . "Pharmaceutical Salts" J Pharm

Formulations of the present mvention include those suitable for oral, nasal, topical (including buccal and sub ngual). rectal, vaginal and or parenteral administration The formulations may convemently be presented in unit dosage form and may be prepared by any methods well known m the art of pharmacy The amount of active ingredient which is combmed with a earner material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration The amount of active ingredient which may be combined with a earner material to produce a smgle dosage form preferably will be that amount of (S)-procyclιdιne which produces a therapeutic effect

Generally, the amount of the active mgredient will range from about 1 % to about 99 % of the total formulation, preferably from about 5 % to about 70 %, and most preferably from about 10 % to about 30 %

Methods of preparing these formulations or compositions include the step of bringing into association (5)-procychdme with a phaimaceutically acceptable earner and, optionally, one or more accessory mgredients In general, the foimulations are prepared by unifoπnly and intimately bnngmg into association (»S)-procychdιne with liquid earners, or finely divided solid carriers, or both, and any optional accessory ingredients, and then, if necessary, shaping the product The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the (S)-procychdme from one organ, or portion of the body, to another organ or portion of the body Each earner must be "acceptable" m the sense of being compatible with the other mgredients of the formulation and not injunous to the patient

Some examples of materials which can serve as pharmaceutically acceptable earners include ( 1 ) sugars, such as lactose, glucose and sucrose, (2) starches, such as corn starch and potato starch, (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, (4) powdered tragacanth, (5) malt. (6) gelatm, (7) talc, (8) excipients, such as cocoa butter and suppository waxes, (9) oils, such as peanut oil. cottonseed oil. safflower oil, sesame oil. olive oil, corn oil and soybean oil, (10) glycols. such as propylene glycol, (11) polyols. such as glycenn. sorbitol. manmtol and polyethylene glycol. (12) esters, such as ethyl oleate and ethyl laurate. (13) agar. (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide, (15) algimc acid. (16) pyrogen-free water, (17) lsotomc saline. (18) Ringer^'s solution, (19) ethyl alcohol (20) phosphate buffer solutions, and (21) other non-toxic compatible substances employed in pharmaceutical formulations (see. Remington The Science and Practice of Pharmacy, Nineteenth Edition, Chapter 80 (1995) )

Formulations of the present invention suitable for oral administration mav be in the form of capsules, cachets, pills, tablets, lozenges (usmg a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as a gelatm and glycerm, or sucrose and acacia), or as soft elastic gelatm capsules, and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient (5)-procychdιne may also be administered as a bolus, electuary or paste In solid dosage foims of the present invention for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable earners, such as sodium citrate or dicalcium phosphate, and/or may also be mixed with one or more of any of the following (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid, (2) bmders, such as, for example, carboxymethylcellulose, algmates, gelatin, polyvmyl pyrro done, sucrose and/or acacia, (3) humectants, such as glycerol, (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, algimc acid, certain silicates, and sodium carbonate, (5) solution retarding agents, such as paraffin, (6) absorption accelerators, such as quaternary ammonium compounds, (7) wetting agents. such as, for example, cetyl alcohol and glycerol monostearate, (8) absorbents, such as kaolin and bentomte clay, (9) lubricants, such as talc, calcium stearate. magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof, and (10) coloring agents In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents Solid compositions of a similar type may also be employed as fillers m soft and hard-filled gelatm capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like

Release agents, coating agents, sweetenmg, flavoring and peifuming agents, preservatives and antioxidants can also be present in the compositions of the present invention Examples of pharmaceutically acceptable antioxidants include (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochlonde. sodium bisulfate. sodium metabisulfate sodium sulfite and the like, (2) oil-soluble antioxidants. such as ascort l palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecitlun. propyl gallate, alpha-tocopherol, and the like, and (3) metal chelating agents, such as citnc acid, ethylenediamme tetraacetic acid (EDTA). sorbitol. tartanc acid, phosphoric acid, and the luce

A tablet may be made by compression or molding, optionally with one or more accessory mgredients Compressed tablets may be prepared usmg binder (for example, gelatm or hydroxypropylmethyl cellulose), lubncant, inert diluent, preservative, dismtegrant (for example, sodium starch glycolate or cross-linked sodium carboxymeth} 1 cellulose), and/or surface-active or dispersing agents Molded tablets may be made by molding in a suitable machine a mixture of the powdered (Sj-procychdine moistened with an inert, liquid diluent

The pharmaceutical compositions of the present invention may also be formulated m a soft elastic gelatin capsule unit dosage form by using conventional methods. well-.known m 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 th-an that of hard gelatin capsules, wherein a gelatm is plasticized by the addition of glycenn, sorbitol, or a similar polyol The hardness of the capsule shell may be changed by varying the type of gelatm 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 earner, such as vegetable or mineral oils, glycols such as polyethylene glycol and propylene glycol. tπglycendes, surfactants such as polysorbates, or a combination thereof

The tablets, and other dosage forms of the pharmaceutical compositions of the present mvention, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as entenc coatings and other coatings well .known in the pharmaceutical formulating art

The pharmaceutical compositions of the present invention may also be formulated so as to provide slow or controlled release of the active ingredient therein usmg. for example.

cellulose in varying proportions to provide the desired release profile, other polymer matrices, hposomes and/or microspheres They may also be administered by controlled release means and delivery devices such as those described in U S Patent Nos 3,845,770, 3.916,899. 3.536.809, 3.598,123. and 4.008.796. and PCT published application WO 92/20377

The phaimaceutical compositions of the present invention may also optionally contain opacifying agents and may be formulated such that they release the active mgredιent(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally in a delayed manner Examples of embedding compositions which can be used include polymeric substances and waxes The active ingredient can also be m micro- encapsulated form, if appropnate. with one or more of the above-described excipients

Liquid dosage forms for oral administration of (5)-procychdme mclude pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs In addition to the active mgredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizmg agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (esp , cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol. tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof Besides inert diluents, the oral compositions of the present invention can also mclude adjuvants such as wetting agents, emulsifying and suspending agents, sweetening. flavoring, coloring, perfuming and preservative agents

Suspensions, in addition to the active (5j-procychdme, may contain suspendmg agents such as, for example, ethoxylated isosteaiyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystallme cellulose, aluminum metahydroxide, bentomte, agar-agar and tragacanth, and mixtures thereof

Formulations of the pharmaceutical compositions of the present mvention for rectal and vagmal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the mvention with one or more suitable non-imtating excipients or earners compnsmg. for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate Such formulations of the present mvention are solid at room temperature, but liquid at body temperature and, therefore, will melt m the rectum or vaginal cavity and release the active (S)-procychdιne

Formulations of the present invention which are suitable for vaginal administration also include pessanes. tampons, creams, gels, pastes, foams or

foimulations containing such earners as are known in the art to be appropnate Dosage forms for the topical or transdermal administration of (Sj-procychdine include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants The active compound may be mixed under sterile conditions with a pharmaceutically acceptable earner, and with any preservatives, buffers, or propellants which may be required Formulations of the present invention in the form of ointments, pastes, creams and gels may contain, in addition to (S)-procychdιne, excipients. such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth. cellulose derivatives, polyethylene glycols, sihcones, bentomtes, silicic acid, talc and/or zinc oxide, or mixtures thereof

Powders and sprays may contain, m addition to (S)-procychdιne. excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances Sprays may additionally contain customary propellants, such as, for example, chlorofiuorohydrocarbons, volatile unsubstituted hydrocarbons, hydrocarbon ethers and compressed gases

Transdermal patches have the added advantage of providmg controlled delivery of the active (S)-procyclιdιne of the present mvention to the body Such dosage foims may be made by dissolving or dispersing the (5)-procychdιne m the proper medium Absorption enhancers may also be used to mcrease the flux of the (S)-procychdme across the skin The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the (S)-procychdιne in a polymer matrix or gel Regardless of the route of admimstration selected, the pharmaceutical compositions of the present mvention are formulated mto pharmaceutically acceptable dosage forms by conventional methods .known to those of skill m the art Where necessary, the pharmaceutical compositions of the present invention are sterile or can be sterilized before admimstration to a patient In a prefened embodiment, the enantiomencally enriched procychdine compositions of the present invention are provided in tablet or capsule foim with, as inactive mgredients, dibasic calcium phosphate, lactose, magnesium stearate. providone and sodium starch glycolate The capsules or tablets are preferably foimulated with from about 0 25 mg to about 250 mg of (.Sj-procychdine, more preferably with from about 0 50 mg to about 100 mg of (S)-procychdιne, and even more preferably with from about 1 mg to about 50 mg of (Sj-procychdine In another prefened embodiment, the enantiomencally enriched

preparations of the present invention are provided m soft elastic gelatin capsule fonn The soft elastic gelatin capsules are preferably formulated with from about 0 25 mg to about 250 mg of (5)-procychdme, more preferably with from about 0 50 mg to about 100 mg of (S)-procyclιdιne. and even more preferably with from about 1 mg to about 50 mg of (5)-procyclιdme

Actual dosage levels of (S)-procychdme in the pharmaceutical compositions of the present invention may be vaned so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition and mode of administration, without being toxic to the patient The selected dosage level and frequency of administration will depend upon a vanety of factors including the route of admimstration, the time of admimstration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used m combination with the (5)-procychdιne, the age. sex, weight, condition, general health and prior medical history of the patient being treated. and like factors well known in the medical arts For example, the dosage regimen is likely to vary with pregnant women, nursing mothers and children relative to healthy adults

A physician having ordinary skill in the art can readily determine and prescribe the effective amount of the phaπnaceutical composition required For example, the physician could start doses of the compound employed in the pharmaceutical composition of the present invention at levels lower than that required m order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved

A suitable daily dose of

will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect Such an effective dose will generally depend upon the factors descnbed above Generally, the total daily dose of (5)-procychdιne for the conditions descnbed herem may be from about 0 25 mg to about 500 mg, more preferably from about 0 50 mg to about 250 mg, and more preferably from about 1 mg to about 100 mg If desired, the effective daily dose of the active (Sj-procyclidine may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.

.Another embodiment of the present invention relates to a kit for treating urinary incontinence, including, e.g., bladder detrusor muscle instability incontinence, stress incontinence, urge incontinence, overflow incontinence, enuresis, and post-prostectomy incontinence, wherein said kit comprises a pharmaceutical composition comprising enantiomerically enriched (S)-procyclidine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and instructions for administering enantiomerically enriched (S)-procyclidine for the treatment of urinary incontinence while reducing or eliminating anticholmergic adverse effects associated with racemic procyclidine or other incontinence drugs with anticholmergic action.

The utility of (S)-procyclidine may be established by the following studies of antimuscarinic, spasmolytic, and calcium entry blocking effects in models of receptor binding and bladder function.

Binding to Human Mi. M-,. M.. M_d and M_^ Muscarinic Receptor Subtypes

These experiments are canied out on membranes prepared from SF9 cells infected with baculovirus to express the human recombinant M M₂, M₃, M₄, and M₅ muscarinic receptor subtypes. The binding assays are performed as set forth in Table 1.

Table 1

Following incubation, the assays are rapidly filtered under vacuum through GF/B glass fiber filters (available, e.g., from Whatman) and washed with an ice-cold buffer using a Brandel Cell Harvester. Bound radioactivity is determined with a liquid scintillation counter (e.g., LS 6000, Beckman) using a liquid scintillation cocktail (e.g.. Formula 99. DuPont NEN). The compounds are tested on each receptor at 10 concentrations in duplicate to obtain competition cui-ves. In each experiment, the reference compound for the receptor under investigation is simultaneously tested at 8 concentrations in duplicate to obtain a competition curve in order to validate this experiment.

The specific radioligand binding of each receptor is defined as the difference between total binding and nonspecific binding determined in the presence of an excess of unlabelled ligand. IC₅₀ values (concentrations required to inhibit 50% of specific binding) are determined by non linear regression analysis of the competition curves. These parameters are obtained by curve fitting using Sigmaplot™ software. Binding to Calcium Channels

Binding assays are performed using the methods set forth in Table 2.

Table 2

The experiment conditions are set forth in Table 3.

Table 3

Following incubation, the assays are rapidly filtered under vacuum through GF/B or GF/C glass fiber filters (available, e.g., from Whatman) and washed with an ice-cold buffer using a Brandel Cell Harvester. Bound radio-activity is determined with a liquid scintillation counter (e.g., LS 6000, Beckman) using a liquid scintillation cocktail (e.g., Formula 989, DuPont NEN). The compounds are tested in duplicate on each receptor at a concentration of 10 ³M In each experiment, the reference compound for the receptor under investigation is simultaneously tested at 8 concentrations in duplicate to obtain a competition cun e m order to validate this experiment The specific radiohgand bindmg of each receptor is defined as the difference between total binding and nonspecific binding determined in the presence of an excess of unlabelled ligand Mean values are expressed as a percentage of inhibition of specific binding IC₅₀ values (concentration required to inhibit 50% of specific binding) are determined by non lmear regression analysis of their competition curves These parameters are obtained by curve fitting usmg Sigmaplot™ software

Functional Charactenzation of Antimuscarmic/Antispasmodic Activity

The effects of (S)-procychdme are studied m an in vitro model of bladder function For example, isolated stnps of guinea pig bladder smooth muscle are mounted in a tissue bath and contracted either with the muscarinic agonist carbachol or with increasing concentrations of external potassium

Bladder strips Experiments are performed using methods similar to those described by Kachur et al (J Pharmacol Exp Ther , 247 867-872 (1988)) and Noronha-Blob and Kachur (J Pharmacol Exp Ther , 256 562-567 (1991)) Strips of tissue (approximately 10 mm long and 1 5 mm wide) are removed from the body of the urinary bladder of male guinea pigs weighing 400-600 g (available, e g , from Elm Hill Breeding Laboratories Chelmsford, MA) The tissues are suspended m an oxygenated buffer of the following composition, in mM NaCl, 133, KC1, 4 7, CaCl₂, 2 5, MgS0₄, 0 6, NaH₂P0₄, 1 3, NaHC0₃, 16 3. and glucose, 7 7 The tissues are mamtamed at 37 5° C Isometric contractions of the tissues are recorded by using appropnate transducers and an ink- wntmg polygraph A restmg tension of 0 5 grams is mamtamed on each tissue at all times

Individual tissues are allowed to equilibrate with the bathing solution for one hour before proceedmg with the experiment

Carbachol-induced contractions. These series of experiments focus on anticholmergic actions .In these experiments, m order to assess the viability of each tissue and to serve as a frame of reference, the contractions of each strip of tissue are recorded initially m response to exposure to a tissue medium m which the NaCl is replaced by KC1 to yield a concentration of 137 7 mM KC1 in the medium This is followed by return to the standard medium, and then by exposure to progressively increasing concentrations of carbachol. with separate exposure to each concentration only until the peak response has been recorded

Then, leaving one strip untreated and/or one strip exposed to a vehicle to serve as control tιssue(s), the remaining strips each are exposed for one hour to one concentration of an antagonist The vehicle controls are used when, because of poor solubility, stock solutions of test substances are prepared in a vehicle, e g . ethanol Finally, the responses to increasmg concentrations of carbachol followed by exposure to 137 7 mM KC1 are recorded a second tune Potassium-induced contractions These expenments focus on the spasmolytic action of the substances being studied Contractions are recorded in response to sequentially increasing the concentration of potassium in the medium

To determine whether test substances decrease the peak response to agonists, the peak tension developed by each strip during the second set of determinations is expressed as a percent of the peak tension developed dunng the first concentration-effect determination Then, for each test substance the resultant data are analyzed for treatment-related differences by one-way analysis of vanance (ANONA) Since only one concentration of test substance is studied m each strip of bladder, the procedures of Arunlakshana and Schild (1959) are used in modified form to estimate the pA2 and slope of the Schild regression First, the concentrations of agonist producmg a half-maximal response (the EC₅₀) is estimated for each strip from the second set of concentration-effect data The EC₅₀ is obtained from linear regression lmes fit to the loganthm of the concentration of drug and the responses bracketing the half maximum level of response For each drug-treated stnp, a "concentration ratio" (CR) is calculated as the ratio of the EC₅₀ of the treated tissue divided by the EC₅₀ ofthe untreated tissue For each expenment where two or more stnps are exposed to the same test substance but at different concentrations, the loganthm of this ratio minus one [/ e , log (CR-1)] is plotted against the loganthm of the concentration of antagomst to which the stnp had been exposed to produce "Schild plots" A regression analysis relatmg log(CR-l) to the loganthm of the concentration of the antagomst is employed to estimate the p.A2 and the slope of the regression lme

Finally, expenments are grouped by test substance and the mean + S E of the pA2 and slope are calculated The 95% confidence limits (CL) for the slope are estimated from its S.E. using standard methods. For experiments in which only one strip is exposed to a given test substance, a pKD is calculated as (concentration of antagonist)/(CR-l) and the negative logarithm of the KD is then pooled with the pA2 values to yield an expanded set of pA2 values. 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. The contents of all references described herein are hereby incorporated by reference.

Other embodiments are within the following claims.

J8-

Claims

Claims What is claimed is

1 A method for treating urinary incontinence, compnsmg administering to a subject in need thereof a therapeutically effective amount of enantiomencally enriched (S)- procychdme, or a pharmaceutically acceptable salt thereof

2 The method as recited in Claim 1, wherem the enantiomencally ennched (£)-procychdιne, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition compnsmg said enantiomencally enriched (5)-procychdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner

3 The method as recited m Claim 2, wherein said pharmaceutical composition is administered by oral, parenteral, transdermal, rectal, or vaginal administration

4 The method as recited in Claim 3, wherein said pharmaceutical composition is administered by oral admimstration

5 The method as recited in Claim 3, wherein said pharmaceutical composition is administered by parenteral administration

6 The method as recited m Claim 2, wherem said pharmaceutical composition is administered by injection

7 The method as recited in Claim 2, wherein said pharmaceutical composition is administered by mtravesical perfusion

8 The method as recited in Claim 1, wherein a daily amount of (^-procychdme administered m the preparation is about 0 25 mg to about 500 mg

9 The method as recited in Claim 8, wherem the daily amount of (S)-procychd╬╣ne administered m the preparation is about 0 50 mg to about 250 mg

10 The method as recited in Claim 9, wherem the daily amount of (S)-procychdme administered m the preparation is about 1 mg to about 100 mg

11 The method as recited in Claim 2, wherem (S)-procychd╬╣ne compnses greater than 50 % by weight of the total procychd e in said pharmaceutical composition

12 The method as recited m Claim 11, wherem (S)-procychd╬╣ne compnses at least 75 % by weight of the total procychdme m said pharmaceutical composition

13 The method as recited in Claim 12, wherein (S)-procycl╬╣d╬╣ne compnses at least 80 % by weight of the total procychdme m said pharmaceutical composition

14. The method as recited in Claim 1, wherein (5)-procyclidine is administered as a pharmaceutical composition comprising substantially enantiomerically enriched (5)-procyclidine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. The method as recited in Claim 14, wherein (5)-procyclidine comprises at least 85 % by weight of the total procychdine in said pharmaceutical composition.

16. The method as recited in Claim 15, wherein (S)-procyclidine comprises at least 90 % by weight of the total procychdine in said pharmaceutical composition.

17. The method as recited in Claim 16, wherein (S)-procyclidine comprises at least 95 % by weight of the total procychdine in said pharmaceutical composition.

18. The method as recited in Claim 17, wherein (S)-procyclidine comprises at least 99 % by weight of the total procychdine in said pharmaceutical composition.

19. The method as recited in Claim 1, wherein the subject is treated for stress incontinence.

20. The method as recited in Claim 1 , wherein the subject is treated for urge incontinence.

21. The method as recited in Claim 1, wherein the subject is treated for post- prostectomy incontinence.

22. The method as recited in Claim 1, wherein the subject is treated for enuresis.

23. A method for treating bladder detrusor muscle instability, said method comprising administering to a subject in need thereof a therapeutically effective amount of enantiomerically enriched (^-procychdine, or a pharmaceutically acceptable salt thereof.

24. The method as recited in Claim 23, wherein said enantiomerically enriched

or a pharmaceutically acceptable salt thereof, is substantially free of (/-)-procyclidine.

25. A pharmaceutical composition, comprising enantiomerically enriched (5)-procyclidine, or a pharmaceutically acceptable salt thereof, and a phaimaceutically acceptable carrier.

26. The pharmaceutical composition as recited in Claim 25, wherein (5 -procyclidine comprises greater than 50 % by weight of the total procychdine in said pharmaceutical composition. 27 The phaimaceutical composition as recited in Claim 26. wherein (S)-proc> chdine compnses at least 75 % b\ weight of the total procychdine in said pharmaceutical composition

28 The pharmaceutical composition as recited in Claim 27, wherein (5)-procychd╬╣ne comprises at least 80 % by weight of the total procychdine m said pharmaceutical composition

29 The pharmaceutical composition as recited in Claim 25, wherein said pharmaceutical composition is formulated for oral administration

30 The pharmaceutical composition as recited in Claim 25, wherein said pharmaceutical composition is formulated for admimstration by injection

31 The pharmaceutical composition as recited m Claim 25, wherein said pharmaceutical composition is formulated for administration by mtravesical perfusion

32 The pharmaceutical composition as recited m Claim 25, wherein the amount of (5)-procychdme present m said pharmaceutical composition is about 0 25 mg to about 500 mg

33 The pharmaceutical composition as recited in Claim 32, wherein the amount of (5)-procychd╬╣ne present m said pharmaceutical composition is from about 0 50 mg to about 250 mg

34 The pharmaceutical composition as recited m Claim 33, wherein the amount of (.Sj-procychdine present in said pharmaceutical composition is from about 1 mg to about 100 mg

35 The pharmaceutical composition as recited in Claim 25, wherem enantiomencally ennched (┬╗S)-procychd╬╣ne comprises from about 1 % to about 99 % of the total pharmaceutical composition

36 The pharmaceutical composition as recited in Claim 35, wherem enantiomencally ennched (S)-procychd╬╣ne comprises from about 5 % to about 70 % of the total pharmaceutical composition

37 The pharmaceutical composition as recited m Claim 36, wherem enantiomencally enriched (S)-procychdme comprises from about 10 % to about 30 % of the total pharmaceutical composition 38 A pharmaceutical composition, compnsmg (S)-procychd╬╣ne. or a pharmaceutically acceptable salt thereof, substantially free of (R)-procychd╬╣ne. and a pharmaceutically acceptable earner

39 The pharmaceutical composition as recited in Claim 38, wherein (S)-procychd╬╣ne compnses at least 85 % by weight of the total procychdine m said pharmaceutical composition

40 The pharmaceutical composition as recited in Claim 39. wherem (^-procychdme compnses at least 90 % by weight of the total procychdme in said pharmaceutical composition

41 The pharmaceutical composition as recited in Claim 40. wherem (S)-procychdme comprises at least 95 % by weight of the total procychdine in said pharmaceutical composition

42 The pharmaceutical composition as recited in Claim 41 , wherem (5)-procychdme compnses at least 99 % by weight of the total procychdme m said pharmaceutical composition

43 The phaπnaceutical composition as recited m Claim 38, wherem said pharmaceutical composition is formulated for oral administration

44 The pharmaceutical composition as recited in Claim 38, wherem said pharmaceutical composition is formulated for administration by injection

45 The pharmaceutical composition as recited in Claim 38, wherein said pharmaceutical composition is formulated for administration by intravesical perfusion

46 The pharmaceutical composition as recited in Claim 38, wherem the amount of (.Sj-procychdine present in said pharmaceutical composition is about 0 25 mg to about 500 mg

47 The pharmaceutical composition as recited in Claim 46. wherem the amount of (^-procychdme present in said pharmaceutical composition is from about 0 50 mg to about 250 mg

48 The pharmaceutical composition as recited in Claim 47, wherein the amount of (5)-procychdιne present m said phaπnaceutical composition is from about 1 mg to about 100 mg 49 The pharmaceutical composition as recited in Claim 38. wherein substantially enantiomencally enriched (S)-procychdιne compnses from about 1 % to about 99 % of the total pharmaceutical composition

50 The pharmaceutical composition as recited in Claim 49. wherein substantially enantiomencally ennched (5)-procychdme comprises from about 5 % to about 70 % of the total pharmaceutical composition

51 The pharmaceutical composition as recited in Claim 50. wherem substantially enantiomencally ennched (5)-procychdme comprises from about 10 % to about 30 % of the total pharmaceutical composition

52 A pharmaceutical unit dosage form, which compnses enantiomencally enriched (S)-procychd╬╣ne, or a pharmaceutically acceptable salt thereof, and a pharmaceutical earner, wherem said pharmaceutical unit dosage form is a tablet

53 The pharmaceutical unit dosage form as recited in Claim 52. wherein said enantiomencally ennched (<S)-procychdme is present in an amount of about 0 25 mg to about 250 mg

54 The pharmaceutical unit dosage form as recited in Claim 53. wherein said enantiomencally enriched (5)-procychd╬╣ne is present in an amount of about 0 50 mg to about 100 mg

55 The pharmaceutical unit dosage form as recited m Claim 54. wherem said enantiomencally enriched (5)-procychdme is present m an amount of about 1 mg to about 50 mg

56 A pharmaceutical umt dosage form which compnses substantially enantiomencally ennched (5)-procychd╬╣ne, or a pharmaceutically acceptable salt thereof, and a pharmaceutical earner, wherem said pharmaceutical unit dosage form is a tablet

57 A pharmaceutical u t dosage foπn, which compnses enantiomencally enriched (5)-procychdme, or a pharmaceutically acceptable salt thereof, and a pharmaceutical earner, wherem said phaπnaceutical unit dosage foπn is a soft elastic gelatm capsule

58 The pharmaceutical unit dosage foim as recited in Claim 57. wherein said enantiomencally enriched (S)-procychd╬╣ne is present m an amount of about 0 25 mg to about 250 mg

59 The pharmaceutical unit dosage for as recited m Claim 58. wherein said enantiomencalh ennched (S)-procychd╬╣ne is present in an amount of about 0 50 mg to about 100 mg

60 The pharmaceutical unit dosage for as recited in Claim 59. wherein said enantiomencally ennched (S)-procychdme is present m an amount of about 1 mg to about 50 mg

61 A pharmaceutical unit dosage form which compnses substantially enantiomencally ennched (S)-procychdme, or a pharmaceutically acceptable salt thereof, and a pharmaceutical earner, wherein said pharmaceutical unit dosage form is a soft elastic gelatin capsule

62 Enantiomencally enriched (5)-procychdme, or a pharmaceutically acceptable salt thereof

63 (5)-procyclιdιne. or a pharmaceutically acceptable salt thereof, substantially free of (Λ)-procychdme

64 A kit for treatmg urinary mcontmence, wherem said kit compnses a phaπnaceutical composition comprising enantiomencally ennched (S)-procyclιdιne, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and instructions for administering enantiomencally ennched (.Sj-procychdine for the treatment of unnary mcontmence while reducing or eliminating concomitant liability of adverse effect

65 The kit as recited m Claim 64, wherein said adverse effect is one or more of drowsiness, epistaxis, xerostomia, mydπasis, cycloplegia, cardiovascular tachycardia, cardiovascular palpitations, increased ocular pressure, nausea, constipation, decreased sweatmg, impotence, or unwanted dermal manifestations

66 A kit for treatmg unnary mcontmence, wherem said kit compnses a pharmaceutical composition compnsmg substantially enantiomencally ennched (S)- procychdine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner, and mstructions for administenng substantially enantiomencally ennched (S)-procychd╬╣ne for the treatment of unnary mcontmence while reducing or eliminating concomitant liability of adverse effects

67 The lot as recited m Claim 65 wherein said adverse effect is one or more of drowsmess, epistaxis, xerostomia, mydnasis, cycloplegia, cardiovascular tachycardia, cardiovascular palpitations, increased ocular pressure, nausea, constipation, decreased sweatmg, impotence, or unwanted dermal manifestations