WO1999033453A2

WO1999033453A2 - R-procyclidine for treating urinary incontinence

Info

Publication number: WO1999033453A2
Application number: PCT/US1998/027704
Authority: WO
Inventors: Vincent L. Fabiano; John R. Mccullough
Original assignee: Sepracor Inc.
Priority date: 1997-12-31
Filing date: 1998-12-29
Publication date: 1999-07-08
Also published as: AU2017999A; EP1043992A2; WO1999033453A3; JP2001527038A; CA2315840A1

Abstract

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

Description

-ff-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 instability, and to pharmaceutical compositions for such treatment.

Background of the Invention Urinary incontinence 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 elderly 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. Resnick, Lancet 346:94 (1995)). Medically, it predisposes persons to urinary tract infections, pressure ulcers, perineal rashes, and urosepsis. Psychosocially, urinary incontinence is associated with embarrassment, social stigmatization, depression, and with the risk of institutionalization (Herzo et al, Ann . Rev. Gerontol. Geriatr., 9:74 (1989)). Economically, the costs are great; in the United States alone, over $10 billion is spent per annum managing incontinence.

Treatments for incontinence include drugs with bladder relaxant properties, i.e., which help to control bladder detrusor muscle overactivity. Such drugs are effective in 80 to 85% of patients with uninhibited bladder contractions, with antichoiinergic medications representing the mainstay of this type of treatment. For example, antichohnergics such as propantheline bromide, and combination smooth muscle relaxant/anticholinergics such as racemic oxybutynin and dicyclomine, have been used to treat urge incontinence. (See, e.g., A.J. Wein, Urol. Clin. N. Am., 22:557-77 (1995).)

No treatment for incontinence, including existing drug therapies, has achieved complete success with all classes of incontinent patients, and without significant side effects. For example, adverse effects, such as drowsiness, dry mouth, constipation, blurred vision, headaches, and cardiac arrhythmia which are related to the antichoiinergic activity of drugs such as racemic oxybutynin. 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 antichoiinergic effects in many patients, and an apparent lack of efficacy in the elderly institutionalized population, racemic oxybutynin nevertheless

-1- SUBST.TUTE SHEET (RULE 26) 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 ( 1 95))

Procyc dine. l-cy ohexyl-l-phenyl-3-(l-p\rrohdιnyl)-l-propanol. a synthetic antispasmotic drug, is descπbed as bemg useful in treatmg parkinsonism. and has been used in muscarmic receptor bindmg 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 antichoiinergic drugs may result with the use of procychdine (cf Physician's Desk Reference. 50th Edition, page 11 12 (1996))

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

One aspect of the present invention relates to methods for treatmg urinary incontmence by administration to a subject in need thereof a therapeutically effective amount of enantiomerically enπched (Λ)-procyclιdme. or a pharmaceutically acceptable salt thereof In a preferred embodiment of this method, the enantiomeπcally enπched (R)- procychdine. or a pharmaceutically acceptable salt thereof, is substantially free of (S)- procychdine

The present mvention also relates to methods for treating bladder detrusor muscle instability comprising administration to a subject in need thereof a therapeutically effective amount of enantiomencally ennched (/?)-procychdιne. or a pharmaceutically acceptable salt thereof Preferably, the enantiomerically enπched (Λ)-procychdιne. or a pharmaceutically acceptable salt thereof, is substantially free of (S)-procychdιne

Another aspect of the present mvention relates to pharmaceutical compositions for the treatment of urinary incontinence comprising enantiomeπcally ennched (-R)-procyclιdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner In a preferred embodiment, the pharmaceutical compositions of the present mvention compπse (Λ)-procychdιne. or a pharmaceutically acceptable salt thereof, substantially free of (S)- procyclidine The present mvention also provides for formulating the pharmaceutical compositions of the present invention, compnsing enanUomeπcally enπched (R)- procyc dine. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner, m pharmaceutical unit dosage forms, including, e g , tablets and soft elastic gelatin capsules

Yet another embodiment of the present mvention relates to a kit for treating uπnary incontmence, such as bladder detrusor muscle instability incontmence, stress incontinence, urge incontmence, overflow incontinence, enuresis, and post-prostectomy incontinence, wherein said kit compπses a pharmaceutical composition compnsing enantiomeπcally ennched (K)-procychdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and instructions for administering the same while reducing or eliminating antichoiinergic adverse effects associated with administration of racemic procychdine. or other incontinence drugs with antichoiinergic action Preferably, the enantiomerically enπched (fi)-procyc dιne. or a pharmaceutically acceptable salt thereof, is substantially free of (S)-procvchdιne

Detailed Descπption of the Invention It is known that urinary incontmence 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 acetvlchohne-induced stimulation of postganglionic muscarmic receptor sites on bladder smooth muscle Consistent with this observation, most pharmacologic treatments for incontinence associated with uninhibited bladder contractions include medications with antichoiinergic and smooth muscle relaxant properties However, as set out above, many of the antichoiinergic agents which have been used for the treatment of incontinence often have adverse effects associated with their antichoiinergic actions. which result in at least periodic discontinuation of use in 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, this invention provides enantiomencally enπched preparations of (Λ)-procychdme and methods for their use m the treatment of uπnary incontmence. including, e g . bladder detrusor muscle instability incontmence. stress incontinence, urge incontinence, overflow incontinence, enuresis. and post-prostectomy mcontinence One feature of the subject non-racemic preparations of (R)- procychdine deπves from the enantiomer^'s pharmacological advantage over the racemate in terms of its pπncipal therapeutic and side effect profile Certain deleteπous local and/or systemic adverse effects of the racemic mixture, e g . drowsiness, xerostomia, mydπasis. constipation, cycloplegia. cardiac arrhythmia and/or epistaxis may be reduced through treatment with enantiomencally enπched (R)-procychdιne

The chemical structure of (-R)-procyc dιne is as set forth in Formula I.

I In one aspect, the present invention provides a method for treatmg urinary incontinence using (i?)-procychdιne. which results in a reduction of the adverse effects associated with administration of racemic procychdine The method compπses administering to a patient m need thereof a pharmaceutically effective amount of (R)- procychdine. or a pharmaceutically acceptable salt thereof, substantially free of (S)- procychdine In a preferred embodiment, the methods of the present invention are used to treat uπnary incontinence due to bladder detrusor muscle instability Such instability may result in. for example, stress incontmence or urge incontinence, or combination thereof, and/or enuresis

In another aspect, the present mvention provides pharmaceutical compositions hich compπse an enantiomerically enπched preparation of (i?)-procychdine. or a pharmaceutically acceptable salt thereof, formulated together with one or more pharmaceutically acceptable earners (additives) and/or diluents As desenbed m detail below, the pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for oral administration, parenteral administration, or topical application

For convenience, certain terms employed in the specification, examples, and appended claims are collected here The term "chiral" refers to molecules which have the property of non-supenmposabi tΛ of the mirror image partner, while the term "achiral" refers to molecules which are supenmposable on their mirror image partner With respect to the nomenclature of a chiral center, the terms "5" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E . Fundamental Stereochemistry, Pure Appl Chem . 45 13-30 ( 1976) The terms racemate and enantiomer will be used in their normal context to descπbe the stereochemistry of procychdine preparations

The terms "enantiomencally enπched" and "non-racemic", as used interchangeably herein with reference to preparations of procychdine, refer to procychdine compositions in which the (-R)-procvc dιne enantiomer is ennched, compared to a control mixture of (R)- procychdine and (S)-procvchdιne enantiomers Unless otherwise specified, such terms refer to procychdine compositions in which the ratio of (-R)-procvchdιne to (S)-procychdιne enantiomers is greater than 1 1 by weight For instance, an enantiomerically enπched preparation of (R)-procychdιne. means a preparation of procychdine having greater than 50% by weight of the (i?)-procychdιne enantiomer relative to the (S)-procychdιne enantiomer. more preferably at least 75% by weight, and even more preferably at least 80% by weight Of course, the ennchment can be much greater than 80% by weight, providing a "substantially enantiomencally enπched" or a "substantially non-racemic" preparation, which refers to preparations of procychdine which have at least 85% by weight of the (R)- procychdine enantiomer relative to the (S)-procychdιne enantiomer. more preferabk at least 90% by weight, and even more preferably at least 95% bv weight The term "substantially free of (S)-procychdιne" will be understood to have similar punty ranges . / e , at least 85% by weight of the (R)-procychdιne enantiomer relative to the (S)-procyclιdme enantiomer. more preferably at least 90% by weight, and even more preferably at least 95% by weight The term "adverse effects" as used herein, refers to effects associated with administration of racemic procychdine. which are not part of the desired therapeutic effect of the drug With respect to the treatment of uπnary incontinence, such adverse effects, include, for illustrative purposes, drowsmess. epistaxis. xerostomia, mydnasis.

unstable cardiovascular status such as arrhythmia (e g . tachycardia or palpitations). increased ocular pressure, nausea, constipation, decreased sweating, impotence, and/or dermal manifestations such as urticaria

The term "epistaxis" refers to nosebleeds, e g . hemorrhage from the nose Epistaxis is a side effect of anticho nergics in children

The term "xerostomia" refers to drvness 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 in 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 diastereometnc salts and fractional crystallization can be used to separate enantiomers For the separation of enantiomers of carboxyhc acids, the diastereometnc salts can be formed bv addition of enantiomencally pure chiral bases such as brucine. quimne. ephedπne. strychnine, and the like Alternatively, diastereometnc esters can be formed with enantiomencally pure chiral alcohols such as menthol, followed by separation of the diastereomeπc 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 camphorsulfonic acid, tartaπc acid, mande c acid, or lactic acid can result in formation of the diastereomeπc 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 using methodology well known to those skilled in the art (See, e g . Sjo et al , Ada Chemica Scandinavia. 47 1019-1024 (1993). Schjekderup et al . Ada Chemica Scandinavia. B41 356-361 (1987)) Chiral synthesis can result in products of high enantiomeπc punty However, in some cases, the enantiomeπc puntv 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 enantiomeπc punty of proc\ c dine obtained by chiral synthesis The optical purity of the (R)-procychdιne can be determined by methods known in the art For example, a sample of the procychdine can be analyzed by high performance liquid chromatography on a chiral chromatographic column Another method of determining optical punty 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, (-R)-procychdιne is substantially free of (S)-procychdme "Substantially free" as used herein, means that at least 85% by weight of the total procychdine present is the (Λ)-procychdine enantiomer. more preferably at least 90% by weight, and still more preferably at least 95% by weight is the (-R)-procychdιne enantiomer In a more preferred embodiment, at least 99 % by weight of the total procychdine present is the (Λ)-procychdιne enantiomer

(Λ)-procychdιne can be used to treat unnary incontmence. including, e g , bladder detrusor muscle instability incontmence, stress mcontinence. urge incontmence, overflow incontmence. enuresis. and post-prostectomy incontinence, 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 preferred route of administration is intravenous administration A particularly preferred route of administration is mtravesical delivery, / e . administration directly to the bladder, e g .

injection or infusion

According to the present invention, (-R)-procychdιne is preferably administered as a pharmaceutical formulation (composition) The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, matenals. compositions, and/or dosage forms which are. within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicit} . lrπtation. allergic response. or other problem or complication, commensurate with a reasonable benefit πsk ratio

As set out above. (7?)-procyclidιne contains an ammo functional group, and thus is capable of forming pharmaceutically acceptable salts The term "pharmaceutically acceptable salts" in this respect, refers to the relativeh non-toxic, inorganic and organic salts of (/?)-procychdιne These salts can be prepared in situ duπng the final isolation and puπfication of the (Λ)-procychdιne Representative salts include the bromide, chlonde. hydrobromide. hydrochlonde. sulfate. bisulfate. phosphate, nitrate, acetate, valerate. oleate. palmitate. stearate. laurate. benxoate. lactate. phosphate, tosylate. citrate, maleate. fumarate. succinate. tartrate. naphthylate. mesylate. glucoheptonate. lactobionate. and laurylsulfonate salts and the like (See e g . Berge et al . "Pharmaceutical Salts". J Pharm Sci . 66 1-19 (1977) )

Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sub ngual). rectal, vaginal and/or parenteral administration The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy The amount of active ingredient which is combmed with a earner mateπal to produce a smgle 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 single dosage form preferably will be that amount of (7?)-procychdιne which produces a therapeutic effect Generally, the amount of the active ingredient 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 prepanng these formulations or compositions include the step of bnnging into association (Λ)-procychdιne with a pharmaceutically acceptable carrier and. optionally, one or more accessory ingredients In general, the formulations are prepared by uniformly and intimately bπngmg into association (Λ)-procychdιne with liquid earners, or finely divided solid earners, or both, and any optional accessory ingredients, and then, if necessary, shapmg the product

The phrase "pharmaceutically acceptable earner" as used herein means a pharmaceutically acceptable matenal. composition or vehicle, such as a liquid or solid filler, diluent, excipient. solvent or encapsulating matenal. involved in carrying or transporting the (Λ)-procychdme from one organ, or portion of the body, to another organ or portion of the body Each earner must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious 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 deπvatives. such as sodium

cellulose, ethyl cellulose and cellulose acetate. (4) powdered tragacanth. (5) malt. (6) gelatin. (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 propvlene glycol, (11) polyols. such as glycerin, sorbitol, mannitol and polyethylene glycol. (12) esters, such as ethyl oleate and ethvl laurate, (13) agar, (14) buffenng agents, such as magnesium hydroxide and aluminum hydroxide, (15) algmic acid, (16) pyrogen-free water. (17) lsotonic salme. (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 may be in the form of capsules, cachets, pills, tablets, lozenges (using 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 (usmg an inert base, such as a gelatin and glycerin, or sucrose and acacia), or as soft elastic gelatin capsules, and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active mgredient (/?)-procvchdιne may also be administered as a bolus, electuary or paste

In solid dosage forms 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 mav 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, polyvinyl pyrrohdone. sucrose and/or acacia, (3) humectants. such as glycerol, (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, algmic 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, cetvl alcohol and ghcerol monostearate. (8) absorbents, such as kaolin and bentonite clay, (9) lubneants. such as talc, calcium stearate. magnesium stearate. solid polyethylene ghcols. sodium lauπ l sulfate. and mixtures thereof, and (10) coloring agents In the case of capsules, tablets and pills, the pharmaceutical compositions ma\ also comprise buffering agents Solid compositions of a similar type mav also be emplo\ ed as fillers m soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like

Release agents, coating agents, sweetening. fla\ oπng and perfuming agents, preservatives and antioxidants can also be present m the compositions of the present invention Examples of pharmaceutically acceptable antioxidants include ( 1 ) water soluble antioxidants. such as ascorbic acid, cysteme hydrochloπde. sodium bisulfate. sodium metabisulfate sodium sulfite and the like, (2) oil-soluble antioxidants. such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated h droxytoluene (BHT), lecithm, propyl gallate. alpha-tocopherol. and the like, and (3) metal chelatmg agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA). sorbitol. tartanc acid, phosphonc acid, and the like

A tablet may be made by compression or molding, optionally with one or more accessory ingredients Compressed tablets may be prepared using binder (for example, gelatm or hvdroxypropylmethyl cellulose), lubncant. inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), and/or surface-active or dispersing agents Molded tablets may be made bv molding m a suitable machine a mixture of the powdered (R)-procychdme moistened with an inert, liquid diluent

The pharmaceutical compositions of the present invention may also 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, gelatm 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 mav 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 m a liquid vehicle or earner, such as vegetable or mmeral oils, glycols such as polyethylene glycol and propylene glycol. tnglycendes. surfactants such as polysorbates. or a combination thereof The tablets, and other dosage forms of the pharmaceutical compositions of the present invention, such as dragees. capsules, pills and granules, mav optionally be scored or prepared ith coatings and shells, such as enteric 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 using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, posomes and/or microspheres Thev mav also be administered by controlled release means and delivery devices such as those 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 pharmaceutical compositions of the present invention may also optionally contain opacifying agents and may be formulated such that they release the active ιngredιent(s) onlv. 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 in micro- encapsulated form, if appropπate. with one or more of the above-descπbed excipients Liquid dosage forms for oral administration of (Λ)-procychdme include pharmaceutically acceptable emulsions, microemulsions. solutions, suspensions, syrups and elixirs In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art. such as. for example, water or other solvents, solubi zing agents and emulsifiers. such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzvl alcohol, benzyl benzoate. propylene glycol. 1.3-butylene glycol. oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), givcerol. 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 include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, colonng. perfuming and preservative agents

Suspensions, in addition to the active (Λ)-procychdιne. may contain suspending agents such as. for example, ethoxv lated lsosteary 1 alcohols, polyoxyethvlene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide. bentonite. agar-agar and tragacanth. and mixtures thereof

Formulations of the pharmaceutical compositions of the present invention for rectal and vaginal administration may be presented as a suppository, which ma\ be prepared b\ mixing one or more compounds of the invention with one or more suitable non-irntatmg excipients or carriers compnsing. for example, cocoa butter, polyethylene glycol. a suppository wax or a sa cylate Such formulations of the present invention are solid at room temperature, but liquid at body temperature and. therefore, will melt m the rectum or \ agmal cavity and release the active (-R)-procychdιne

Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such earners as are known m the art to be appropriate

Dosage forms for the topical or transdermal administration of (-R)-procyc dιne 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 hich mav be required

Formulations of the present mvention in the form of ointments, pastes, creams and gels may contain, in addition to (R)-procychdιne. excipients. such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols. sihcones. bentonites. silicic acid, talc and/or zmc oxide, or mixtures thereof

Powders and sprays may contain, in addition to (R)-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, chlorofluorohydrocarbons, volatile unsubstituted hydrocarbons, hydrocarbon ethers and compressed gases

Transdermal patches have the added advantage of providing controlled delivery of the active (/?)-procychdιne of the present mvention to the body Such dosage forms may be made by dissolving or dispersmg the (Λ)-procychdιne in the proper medium Absorption enhancers may also be used to increase the flux of the (R)-procvchdιne across the skin The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the (Λ)-procychdιne in a polymer matnx or gel

Regardless of the route of administration selected, the pharmaceutical compositions of the present invention are formulated into pharmaceuticalh acceptable dosage forms

conventional methods known to those of skill in the art Where necessary, the pharmaceutical compositions of the present invention are sterile or can be steπhzed before administration to a patient

In a preferred embodiment, the enantiomencally ennched procychdine compositions of the present invention are provided in tablet or capsule form with, as inactive ingredients, dibasic calcium phosphate, lactose, magnesium stearate. providone and sodium starch glycolate The capsules or tablets are preferably formulated with from about 0 25 mg to about 250 mg of (-R)-procychdme. more preferably with from about 0 50 mg to about 100 mg of (Λ)-procychdιne. and even more preferably with from about 1 mg to about 50 mg of (-R)-procychdιne

In another preferred embodiment, the enantiomencally enπched (R)-procychdιne preparations of the present invention are provided in soft elastic gelatm capsule form The soft elastic gelatin capsules are preferably formulated with from about 0 25 mg to about 250 mg of (R)-procychdιne. more preferably with from about 0 50 mg to about 100 mg of (-R)-procyc dιne, and even more preferably with from about 1 mg to about 50 mg of (R)- procychdine Actual dosage levels of

in the pharmaceutical compositions of the present invention may be vaπed 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 admimstration. without being toxic to the patient

The selected dosage level and frequency of administration will depend upon a variety of factors including the route of admimstration. the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or matenals used in combmation with the (Λ)-procvchdιne. the age, sex, weight, condition, general health and pnor 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 prescπbe the effective amount of the pharmaceutical composition required For example, the physician could start doses of the compound empkned in the pharmaceutical composition of the present invention at levels lower than that required m order to achieve the desired therapeutic effect and gradualh increase the dosage until the desired effect is achieved A suitable daily dose

will be that amount of the compound hich 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 (-R)-procychdιne for the conditions descnbed herein 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 (-R)-procychdme may be administered as two. three, four. five, six or more sub-doses administered separately at appropnate intervals throughout the day, optionally, in unit dosage forms

Another embodiment of the present invention relates to a kit for treating urinary incontmence. including, e g , bladder detrusor muscle instability incontinence, stress incontinence, urge incontinence, overflow incontmence. enuresis. and post-prostectomy incontinence, wherein said kit compπses a pharmaceutical composition comprising enantiomencally enriched (R)-procychdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner, and instructions for admmistenng enantiomencally ennched (Λ)-procychdιne for the treatment of urinary incontinence while reducing or elimmating antichoiinergic adverse effects associated with racemic procvchdme or other incontinence drugs with antichoiinergic action

The utility of (Λ)-procychdme may be established by the following studies of antimuscaπnic. spasmolytic, and calcium entry blocking effects in models of receptor bindmg and bladder function Binding to Human M,. M_^ M?. M„and Ms Muscannic Receptor Subtypes

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

Table 1

Following mcubation, the assays are rapidly filtered under vacuum through GF/B glass fiber filters (available, e g , from Whatman) and washed w ith an ice-cold buffer usmg a Brandel Cell Harvester Bound radioactivity is determined with a liquid scintillation counter (e g , LS 6000, Beckman) usmg 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 curves In each experiment, the reference compound for the receptor under investigation is simultaneously tested at 8 concentrations m duplicate to obtain a competition curve m order to validate this expeπment

The specific radiohgand bmdmg of each receptor is defined as the difference between total bmdmg and nonspecific bmdmg determined in the presence of an excess of unlabelled hgand IC<;₀ values (concentrations required to inhibit 50% of specific bindmg) are determined by non linear regression analysis of the competition curves These parameters are obtained by curve fitting using Sigmaplot™ software Bindmg to Calcium Channels

Bindmg assays are performed using the methods set forth in Table 2

Table 2

The expeπment 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 usmg 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 10⁵M In each experiment, the reference compound for the receptor under investigation is simultaneously tested at 8 concentrations in duplicate to obtam a competition curve in 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 gand Mean values are expressed as a percentage of inhibition of specific binding IC_S0 values (concentration required to inhibit 50% of specific binding) are determined by non linear regression analysis of their competition curves These parameters are obtamed by curve fitting using Sigmaplot™ software

Functional Characteπzation of Antimuscaπnic/Antispasmodic Activity

The effects of (R)-procychdιne are studied in 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 muscarmic agonist carbachol or with increasing concentrations of external potassium

Bladder strips Experiments are performed using methods similar to those descnbed 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)) Stnps of tissue (approximately 10 mm long and 1 5 mm wide) are removed from the body of the urinan bladder of male guinea pigs weighing 400-600 g (available, e g . from Elm Hill Breeding Laboratoπes, Chelmsford. MA) The tissues are suspended in an oxygenated buffer of the following composition, in mM NaCl. 133. KC1. 4 7. CaC 2 5, MgS0₄. 0 6. NaH₂P0₄ 1 3. NaHC0₃. 16 3. and glucose. 7 7 The tissues are maintained at 37 5° C Isometric contractions of the tissues are recorded b\ using appropnate transducers and an ink-writing polygraph A resting tension of 0 5 grams is maintained on each tissue at all times

Individual tissues are allowed to equilibrate with the bathing solution for one hour before proceed g with the expenment Carbachol-induced contractions. These senes of experiments focus on antichoiinergic 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 stnp of tissue are recorded initially m response to exposure to a tissue medium m which the NaCl is replaced by KG to yield a concentration of 137 7 mM KC1 m the medium This is followed by return to the standard medium, and then by exposure to progressively increasmg concentrations of carbachol. with separate exposure to each concentration only until the peak response has been recorded

Then, leavmg one stnp untreated and/or one stnp exposed to a vehicle to serve as control tιssue(s). the remaining stnps 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 time Potassium-induced contractions These expenments focus on the spasmolytic action of the substances being studied Contractions are recorded in response to sequentially increasmg the concentration of potassium in the medium

To determine whether test substances decrease the peak response to agonists, the peak tension developed by each stnp dunng 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 vaπance (ANOVA) Smce only one concentration of test substance is studied in each stnp 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 agomst producing a half-maximal response (the EC₅₀) is estimated for each stnp from the second set of concentration-effect data The EC₅₀ is obtained from linear regression lines 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 EC,-, of the treated tissue divided by the EC_<0 of the untreated tissue For each expeπment 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 antagonist to which the stnp had been exposed to produce "Schild plots" A regression analysis relating log(CR-l) to the loganthm of the concentration of the antagonist is employed to estimate the pA2 and the slope of the regression line

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 usmg standard methods For experiments in which only one stnp is exposed to a given test substance, a pKD is calculated as (concentration of antagomst)/(CR-l) and the negative loganthm of the KD is then pooled with the pA2 values to yield an expanded set of pA2 values The embodiments of the present invention descnbed above are intended to be merely exemplary and those skilled in the art will recogmze. or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures descnbed 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 descnbed herein are hereby incorporated by reference.

Other embodiments are within the following claims

Claims

Claims What is claimed is

1 A method for treatmg urinary incontinence, compπsmg administering to a subject in need thereof a therapeutically effective amount of enantiomeπcally ennched (R)- procychdine. or a pharmaceutically acceptable salt thereof

2 The method as recited m Claim 1. wherein the enantiomencally ennched (-R)-procychdme, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition compnsing said enantiomencally ennched (-R)-procychdιne, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner

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

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

5 The method as recited m Claim 3. wherein said pharmaceutical composition is administered by parenteral admimstration

6 The method as recited m Claim 2. wherein said pharmaceuticalcomposition 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 (R)- procychdine administered in the preparation is about 0 25 mg to about 500 mg

9 The method as recited in Claim 8. wherein the daily amount of (R)- procyc dine administered m the preparation is about 0 50 mg to about 250 mg

10 The method as recited m Claim 9. wherein the daily amount of (/?)- procychdine administered in the preparation is about 1 mg to about 100 mg

11 The method as recited in Claim 2. wherein (R)-procychdιne compπses greater than 50 % by weight of the total procychdine in said pharmaceutical composition

12 The method as recited in Claim 11. wherein (R)-procychdιne compnses at least 75 % by weight of the total procvchdme in said pharmaceutical composition

13 The method as recited m Claim 12. wherein (R)-procychdιne compnses at least 80 % by weight of the total procychdine in said pharmaceutical composition 14 The method as recited in Claim 1. wherem (R)-procychdιne is administered as a pharmaceutical composition compπsmg substantially enantiomeπcallv enπched (R)- procvchdine. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner

15 The method as recited m Claim 14, wherem (/.)-procychdιne compnses at least 85 % by weight of the total procychdine in said pharmaceutical composition

16 The method as recited in Claim 15, wherem (Λ)-procychdιne compnses at least 90 % by weight of the total procychdine in said pharmaceutical composition

17 The method as recited in Claim 16, wherem (R)-procychdιne compnses at least 95 % by weight of the total procychdine m said pharmaceutical composition

18 The method as recited in Claim 17 wherein (Λ)-procvchdme compnses at least 99 % by weight of the total procychdine in said pharmaceutical composition

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

20 The method as recited m Claim 1, wherem the subject is treated for urge incontinence

21 The method as recited in Claim 1, wherem the subject is treated for post- prostectomy incontmence

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

23 A method for treating bladder detrusor muscle instability, said method compnsing admmistenng to a subject in need thereof a therapeutically effective amount of enantiomencally ennched (R)-procychdιne, or a pharmaceutically acceptable salt thereof

24 The method as recited in Claim 23, wherem said enantiomencally enπched (-R)-procyclιdme, or a pharmaceutically acceptable salt thereof, is substantially free of (S)- procychdine

25 A pharmaceutical composition, compπsmg enantiomencally ennched (R)- procychdine. or a pharmaceutically acceptable salt thereof, and a pharmaceuticalh acceptable earner

26 The pharmaceutical composition as recited in Claim 25. wherein (R)- procychdine compnses greater than 50 % bv weight of the total procvchdme in said pharmaceutical composition 27 The pharmaceutical composition as recited in Claim 26. wherein (R)- procyc dine compnses at least 75 % by weight of the total procychdine in said pharmaceutical composition

28 The pharmaceutical composition as recited m Claim 27. wherein (R)- procychdine compnses at least 80 % by weight of the total procychdine in said pharmaceutical composition

29 The pharmaceutical composition as recited m 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 administration by injection

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

32 The pharmaceutical composition as recited in Claim 25, wherein the amount of (- )-procychdιne present in 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 (/?)-procychdιne present m said pharmaceutical composition is from about 0 50 mg to about 250 mg

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

35 The pharmaceutical composition as recited in Claim 25, wherein enantiomencally ennched (Λ)-procychdιne compnses from about 1 % to about 99 % of the total pharmaceutical composition

36 The pharmaceutical composition as recited in Claim 35, wherem enantiomeπcally enπched (R)-procvchdιne compnses from about 5 % to about 70 % of the total pharmaceutical composition

37 The pharmaceutical composition as recited in Claim 36. wherein enantiomencally ennched (R)-procvclιdme comprises from about 10 % to about 30 % of the total pharmaceutical composition 38 A pharmaceutical composition, compπsmg (R)-procvchdιne. or a pharmaceutically acceptable salt thereof, substantially free of (S)-procychdme, and a pharmaceutically acceptable earner

39 The pharmaceutical composition as recited in Claim 38, wherem (R)- procychdine compnses at least 85 % by weight of the total procychdine in said pharmaceutical composition

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

41 The pharmaceutical composition as recited in Claim 40, wherem (R)- procychdine compnses at least 95 % by weight of the total procychdine in said pharmaceutical composition

42 The pharmaceutical composition as recited in Claim 41. wherein (R)- procychdine comprises at least 99 % by weight of the total procychdine in said pharmaceutical composition

43 The pharmaceutical composition as recited in Claim 38, wherein said pharmaceutical composition is formulated for oral administration

44 The pharmaceutical composition as recited in Claim 38, wherein 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 mtravesical perfusion

46 The pharmaceutical composition as recited in Claim 38. wherein the amount of (Λ)-procychdιne 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 (-R)-procyclιdιne 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 (Λ)-procychdιne present in said pharmaceutical composition is from about 1 mg to about 100 mg

49 The pharmaceutical composition as recited in Claim 38, wherein substantialh enantiomencally ennched (Λ)-procychdιne comprises from about 1 % to about 99 % of the total pharmaceutical composition

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

51 The pharmaceutical composition as recited in Claim 50. wherein substantially enantiomencally enπched (R)-procychdιne compnses from about 10 % to about 30 % of the total pharmaceutical composition

52 A pharmaceutical unit dosage form, which compnses enantiomencally enπched (K)-procychdιne, 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 m Claim 52. wherein said enantiomencally ennched (-R)-procychdιne is present in an amount of about 0 25 mg to about 250 mg

54 The pharmaceutical unit dosage form as recited m Claim 53. wherein said enantiomencally ennched (-R)-procychdιne is present in an amount of about 0 50 mg to about 100 mg

55 The pharmaceutical unit dosage form as recited in Claim 54. wherem said enantiomencally ennched (-/?)-procychdιne is present in an amount of about 1 mg to about 50 mg

56 A pharmaceutical unit dosage form which compnses substantially enantiomencally enπched (-R)-procyc dιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutical earner, where said pharmaceutical unit dosage form is a tablet

57 A pharmaceutical unit dosage form, which compnses enantiomencally ennched (Λ)-procychdine. or a pharmaceutically acceptable salt thereof, and a pharmaceutical earner, wherein said pharmaceutical umt dosage form is a soft elastic gelatin capsule

58 The pharmaceutical unit dosage form as recited m Claim 57. wherein said enantiomencally ennched

is present in an amount of about 0 25 mg to about 250 mg

59 The pharmaceutical unit dosage for as recited in Claim 58. wherein said enantiomencally ennched (Λ)-proc\ chdine is present in an amount of about 0 50 mg to about 100 mg. 60 The pharmaceutical umt dosage for as recited in Claim 59, wherem said enantiomeπcallv ennched (/?)-procychdιne is present in an amount of about 1 mg to about 50 mg

61 A pharmaceutical umt dosage form which compnses substantially enantiomeπcallv ennched (-R)-procychdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutical earner, wherem said pharmaceutical umt dosage form is a soft elastic gelatm capsule

62 Enantiomencally ennched (Λ)-procychdιne, or a pharmaceutically acceptable salt thereof

63 (Λ)-procychdιne, or a pharmaceutically acceptable salt thereof, substantially free of (S)-procychdιne

64 A kit for treatmg urinary mcontmence, wherem said kit compnses a pharmaceutical composition compπsmg enantiomencally ennched (jR)-procychdιne. or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner, and instructions for admmistenng enantiomencally ennched (/?)-procychdιne for the treatment of urmary incontmence while reducmg or elimmating concomitant liability of adverse effect

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

66 A kit for treatmg urinary mcontmence, wherem said kit compnses a pharmaceutical composition compnsmg substantially enantiomencally ennched (R)- procyc dine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable earner, and instructions for admmistenng substantially enantiomencally enπched (-R)-procychdιne for the treatment of urmary mcontmence while reducmg or eliimnatmg concomitant liability of adverse effects

67 The kit as recited in Claim 65 wherem said adverse effect is one or more of drowsiness, epistaxis. xerostomia, mydnasis, cycloplegia, cardiovascular tachycardia, cardiovascular palpitations, increased ocular pressure, nausea, constipation, decreased sweating, impotence, or unwanted dermal manifestations