KR100476550B1 - Urinary incontinence treatment with (S) -oxybutynin and (S) -desethyloxybutynin - Google Patents

Abstract

Urinary incontinence therapies are disclosed that have no potential side effects associated with racemic oxybutynin. This method administers 100 mg to 1000 mg / day of (S) -oxybutynin, (S) -desethyloxybutynin or a pharmaceutically acceptable salt thereof, substantially free of the corresponding R enantiomer. It involves doing. Also disclosed are pharmaceutical compositions in the form of tablets, soft elastic gelatin capsules and transdermal devices comprising an acceptable carrier and 500 mg of (S) -oxybutynin or (S) -desethyloxybutynin.

Description

Urinary incontinence treatment with (S) -oxybutynin and (S) -desethyloxybutynin

The present invention is a method for treating urinary incontinence using optically pure (S) -oxybutynin (S-OXY) and (S) -desethyloxybutynin (S-DEO) And formulations.

Racemic oxybutynin (OXY) is used therapeutically in the treatment of urinary incontinence due to detrusor instability and in the treatment of enteromotor hyperactivity. Racemic oxybutynin has a direct nervous effect on smooth muscle and inhibits the action of acetylcholine on smooth muscle. Only one fifth of the anticholinergic activity of atropine on rabbit detrusor muscles, and 4 to 10 times anticonvulsant activity. It is completely selective for the muscarinic receptors in the presence of nicotine receptors and as a result no blocking effect is observed at skeletal neuromuscular junctions or autonomic ganglia.

Racemic oxybutynin relaxes bladder smooth muscle, and in patients with conditions characterized by involuntary bladder contractions, bladder studies have shown that racemic oxybutynin increases the volume of vesicles and the frequency of involuntary contractions of the detrusor muscle It has been shown to reduce the number of people and slow down the initial desire to urinate. Thus, it is useful for treating and preventing both incontinence and frequent spontaneous urination. The efficacy of racemic oxybutynin in the bladder has been thought to be due to a combination of antimuscarinic effects, direct antifungal and local anesthetic effects on smooth urination muscles. Because of the antimuscarinic activity of racemic drugs, xerostomia and mydriasis associated with muscarinic cholinergic receptors are very common side effects. In fact, at least one investigator cited inevitable symptoms such as mydriasis, xerostomia and tachycardia associated with racemic oxybutynin administration [Lish et al. Arch, Int Pharmacodyn. 156 , 467-488 (1965), 481]. The high incidence of anticholinergic side effects (40 to 80%) sometimes results in decreased dosage or discontinuation of treatment.

Pharmacological studies on each enantiomer have suggested that R-enantiomers are potent enantiomers. Noronha-Blob et al. Are measured by the affinity of racemic oxybutynin for choline antagonism (in vitro, affinity for the M ₁ , M ₂ and M ₃ receptor subtypes, and various physiological in vivo). (Measured by pharmacological response) can be thought to be mainly due to the activity of R-enantiomers [ J. Pharmacol. Exp. Ther, 256 , 562-567 (1991). The degree of efficacy of racemic oxybutynin and its enantiomers for all reactions is the same, that is, (R) -oxybutynin is greater or equal in efficacy than racemic oxybutynin, and racemic Since oxybutynin is much more potent than (S) -oxybutynin, it has been found that (S) -oxybutynin is 1 to 2 grades less potent than (R) -oxybutynin.

Summary of the Invention

It was surprisingly found that substantially optically pure S enantiomers of oxybutynin and its desethyl metabolite provide excellent treatment for incontinence treatment.

Optically pure (S) -oxybutynin (S-OXY) and (S) -desethyloxybutynin (S-DEO) primarily result from anticholinergic activity and have side effects associated with the administration of racemic oxybutynin. This treatment is provided while substantially reducing. Such side effects include, but are not limited to, dry mouth, dysphagia, drowsiness, vomiting, constipation, palpitations and tachycardia. The reduction of cardiovascular side effects of racemic oxybutynin, such as tachycardia and palpitations, by administration of (S) -oxybutynin or S-DEO is of particular therapeutic value.

The active compounds of these compositions and methods are optical isomers of oxybutynin and desethyloxybutynin. The preparation of racemic oxybutynin is described in British Patent Specification No. 940,540. Chemically, the active compounds are (1) 4- (diethylamino) -2-butynyl α -cyclohexyl- α -hydroxy, also known as 4- (diethylamino) -2-butynyl phenylcyclohexyl glycolate S enantiomers of benzeneacetate (hereinafter referred to as oxybutynin); And (2) S enantiomer of 4- (ethylamino) -2-butynyl α -cyclohexyl- α -hydroxybenzeneacetate (hereinafter referred to as desethyloxybutynin). The generic name given to the hydrochloride salt of racemic oxybutynin by the USAN Commission is oxybutynin chloride; It is sold under the trade name of a Detroit plate ^ⓡ (Ditropan ^ⓡ).

Isomers of oxybutynin with S absolute stereochemistry (Reg. No. 119618-22-3) are preferential and are shown in Formula I.

The S enantiomer of desethyloxybutynin is shown in Formula II.

Synthesis of (S) -oxybutynin (Kachur et al. J. Pharmacol. Exp. Ther. 247 , 867-872 (1988)) is known, but (S) -oxybutynin itself is currently not commercially available. For guinea pigs and letts, the pharmacology of each enantiomer is described by Kachur et al. J Pharmacol. Exp. Ther . 247, 867-872 (1988) and Noronha-Blob et al. J. Pharmacol.Exp. Ther . 256, 562-567 (1991)], all reported clinical results have been obtained with racemic mixtures.The synthesis and pharmacology of (S) -desethyloxybutynin has been published by us in PCT application. No. WO96 / 23492.

In one aspect the present invention provides a therapeutical method for treating (S) -oxybutynin, (S) -desethyloxybutynin, or a pharmaceutically acceptable salt of any of these, substantially free of the corresponding R enantiomer. A method of treating urinary incontinence with no potential for side effects, including administration to an individual in need thereof.

In another aspect the invention provides a pharmaceutical composition comprising (S) -oxybutynin, (S) -desethyloxybutynin, or a pharmaceutically acceptable salt of any one of these, substantially free of the corresponding (R) -enantiomer and A pharmaceutical composition comprising a pharmaceutically acceptable carrier of any of these is provided. As used herein, the phrases "substantially free of its R enantiomers" and "substantially free of corresponding enantiomers" are at least 90% by weight of (S) -oxybutynin or (S) -desethyloxybuty. A composition containing nin and up to 10% by weight of (R) -oxybutynin or (R) -desethyloxybutynin respectively. In a more preferred embodiment, the composition contains at least 99% by weight S enantiomer and up to 1% R enantiomer.

Substantially optically pure (S) -oxybutynin or (S) -desethyloxybutynin can be administered parenterally, rectally, bladder, transdermal, oral or aerosol. Oral and transdermal administration is preferably administered at a rate of about 1 mg to 100 mg per day.

In another aspect, the invention provides (S) -oxybutynin, (S) -desethyloxybutynin, or a pharmaceutically acceptable salt of any one of which is substantially free of the corresponding (R) -enantiomer. And pharmaceutical unit dosage forms in the form of tablets, soft elastic gelatin capsules or transdermal delivery devices containing a therapeutically effective amount of a pharmaceutically acceptable carrier. Tablet and soft elastomeric gelatin capsule forms may be prepared by conventional methods well known in the art and may be (S) -oxybutynin, (S) -desethyloxybutynin, or any of these present in each unit dosage form. The amount of pharmaceutically acceptable salt of is preferably about 0.1 to 500 mg, more preferably about 25 to 250 mg, even more preferably about 100 to 200 mg. Transdermal administration is enhanced by including a permeation enhancer in the transdermal administration device.

S enantiomers of oxybutynin and DEO can be obtained by resolution of intermediate mandelic acid followed by esterification. Esterification can be performed as described by Kachur et al. For oxybutynin or by an improved method described in PCT Application WO-096 / 23492. Alternatively, the S enantiomers of OXY and DEO can be obtained by resolution of racemic oxybutynin or racemic DEO using conventional methods such as fractional recrystallization of diastereomeric salts with chiral acids. Other conventional methods of resolution known to those skilled in the art may also be used, including, but not limited to, simple crystallization and chromatography on chiral substrates.

Schematic representations of racemic, ambiscalemic and scalamic or enantiomerically pure compounds used herein are described in Mayer J. Chem. Ed. 62, 114-120 (1985). Hence, the broken wedge shape (as shown in Formula I) is used to indicate the absolute arrangement of chiral elements; Wedge contours and dashed or broken lines are used to represent pure compounds in an enantiomerically indeterminate absolute configuration.

In the acute or chronic treatment of the disease, the dosage for the prophylactic or therapeutic purpose of (S) -oxybutynin or S-DEO will vary depending on the severity and nature of the disease state to be treated and the route of administration. Dosage and possibly frequency of administration will also vary with each patient's age, weight and response (sensitivity to the drug). In general, the total daily dosage of (S) -oxybutynin or S-DEO for the conditions described herein ranges from about 0.1 mg to about 1 g, preferably from about 0.4 mg to about 600 mg, more preferably Is about 100 mg to about 1 g, even more preferably about 240 mg to 750 mg, most preferably 300 to 600 mg, which is taken at once or preferably in divided portions. When actually administered to treat a patient's disease, it should start at a small dose, perhaps at about 80 mg, and increase to, for example, about 600 mg / day depending on the patient's overall response.

Furthermore, for patients 65 years of age and older and those with impaired renal or hepatic function, we recommend starting with small doses and adjusting the dose according to each patient's response and blood drug levels. However, in some cases it may be necessary to use doses outside these ranges, as will be apparent from the point of view of those skilled in the art. In addition, the clinician or therapist will know how, when, to stop, control or terminate the treatment with respect to each patient's response. The phrases "therapeutically effective amounts" and "sufficient amounts for treating urinary incontinence but insufficient for the occurrence of side effects" can be achieved by the above-described dosages and dosing schedules.

Any dosage route may be applied as long as it is suitable to administer an effective dose of (S) -oxybutynin or S-DEO to the patient. For example, dosage forms such as oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, aerosol and the like can be applied. In addition, as Massard et al. Describe the racemic oxybutynin [ J. Urol. 148 , 595-597 (1992), the drug may be administered directly to the bladder via the urethra. Formulations include tablets, troches, dispersants, suspensions, solutions, capsules, transdermal administration systems, and the like.

The pharmaceutical composition of the present invention comprises (S) -oxybutynin or S-DEO, or a pharmaceutically acceptable salt of any of these, as an active ingredient, and also contains a pharmaceutically acceptable carrier and optionally other therapeutic Ingredients may also be contained.

"Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt of any of these" refers to salts prepared from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid addition salts for the compounds of the invention include acetic, benzenesulphonic (vesylate), benzoic, camphorsulphonic, citric, ethanesulphonic, fumaric, gluconic, glutamic , Hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulphonic, musik, nitrik, phamoic, pantodenic, phosphoric, lean, sulfary, tartaric, p-toluenesulphonic and the like. Hydrochloric acid is particularly useful and is in fact the salt used in the studies described below.

Compositions of the present invention include suspensions, solutions, elixirs or solid dosage forms. Carriers such as starch, sugar and microcrystalline cellulose and excipients, granulating agents, lubricants, binders, disintegrating agents, etc. are suitable for the preparation of oral solids (such as powders, capsules and tablets), and oral solids are oral It is more preferable than a solution. Because of the ease of administration, tablets and capsules are represented in one of the more convenient oral dosage unit forms, in which case solid pharmaceutical carriers are used. If necessary, tablets may be coated by conventional aqueous or non-aqueous coating methods.

In a preferred embodiment, the pharmaceutical compositions of the present invention can be formulated in soft elastic gelatin capsule unit dosage forms using conventional methods known in the art (Ebert, Pharm. Tech., 1 (15): 44-50 (1977). Soft elastomeric gelatin capsules are soft, spherical and have a gelatinous shell that is somewhat thicker than that of hard gelatin capsules, where gelatin is plasticized by the addition of glycerin, sorbitol or similar polyols. Hardness of the capsule hard can be changed by changing the gelatin type and the amount of plasticizer and water. Soft gelatin shells may contain preservatives to prevent the growth of fungi such as methyl- and propylparabens and sorbic acid. Liquid excipients or carriers such as vegetable oils or mineral oils; Glycols such as polyethylene glycol and propylene glycol; Triglycerides; Surfactants such as polysorbates; Alternatively, the active ingredient may be dissolved or suspended in a mixture thereof. In the soft elastic gelatin capsule pharmaceutical unit dosage form of the invention, the (S) -oxybutynin or (S) -desethyloxybutynin is preferably from about 0.1 mg to about 500 mg, more preferably from about 25 mg to It is present in an amount of about 250 mg, even more preferably about 100 mg to about 200 mg.

In addition to the conventional formulations described above, the compounds of the present invention may also be administered by other controlled release means and delivery devices known to those skilled in the art.

Pharmaceutical compositions of the invention suitable for oral administration may be presented in discrete unit forms such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient, as a powder or granules, or as a soft elastic gelatin capsule. Wherein the active ingredient is dissolved or suspended in a liquid carrier, or a solution or suspension in an aqueous solution, in a non-aqueous solution, in an O / W emulsion or in an W / O emulsion. It can be provided as. Such compositions may be prepared by any pharmaceutical preparation but all preparations comprise the step of bringing into association the active ingredient with the carrier consisting of one or more necessary ingredients. Generally, the composition is known, as is known for racemic mixtures, by homogeneously and intimately mixing the active ingredient with the liquid carrier or the finely ground solid carrier or both, and then, if necessary, by making the product into the desired shape. Are manufactured.

The surprising utility of (S) -enantiomers of both OXY and DEO was demonstrated by the following study.

Enantiomer of oxybutynin

Human Muscarinic Receptor Subtype M _One , M ₂ , M ₃  And M ₄  Of (R)-and (S) -oxybutynin to

Protein raw materials

Experiments were performed on membranes prepared from SF9 cells infected with baculovirus to express human recombinant M ₁ , M ₂ , M ₃ and M ₄ muscarinic receptor subtypes.

Binding analysis

TABLE 1

After incubation the analytes were quickly filtered through a GF / B glass fiber filter (Watman) under vacuum and washed with cold buffer using a Brandel Cell Harvester. Labeled radioactivity was measured with a liquid scintillation counter (LS 6000, Beckman) using a liquid scintillation coctail (Formula 99, DuPont NEN).

Experimental protocol

In order to obtain the competition curve of each compound, the concentrations were changed to 10 and the reaction test for each receptor was performed in duplicate. In order to validate the experiments, the competition curves were also obtained by varying the concentration of the reference compounds for the receptors to be investigated in each experiment in 8 kinds and also performing the experiments in duplicate.

Analysis and display of results

Specific radioligand binding of each receptor was defined as the difference between nonspecific binding and total binding measured in the presence of excess unlabeled ligand. IC ₅₀ values (concentrations required to inhibit 50% of specific binding) were determined by nonlinear regression analysis of competition curves. These parameters were obtained by curve fitting using SigmaPlot ^™ software. IC ₅₀ for R- and S-OXY is shown in Table 2.

TABLE 2

Binding of R-oxybutynin and S-oxybutynin to human muscarinic subtype M1-M4

These results indicate that S-OXY is less friendly to the anhydrous carine receptor subtype than R-OXY.

Binding of (R)-and (S) -oxybutynin to calcium channels

Binding analysis

The binding was analyzed in the following manner.

TABLE 3

Experimental conditions are as follows.

TABLE 4

After incubation, the analytes were quickly filtered through a GF / B or GF / C glass fiber filter (Watman) under vacuum and washed with cold buffer using a Brandel Cell Harvester. Labeled radioactivity was measured with a Liquid Scintillation Counter (LS 6000, Beckman) using Liquid Scintillation Cocktail (Formula 989, DuPont NEN).

Experimental protocol

Compounds were run in duplicate for each receptor phase at a concentration of 10 ⁻⁵ M. In order to verify the experiments, the concentrations of the reference compounds for the receptors investigated in each experiment were changed to eight different concentrations, and the experiments were also repeated to obtain a competition curve.

Analysis and display of results

Specific radioligand binding of each receptor was defined as the difference between nonspecific binding and total binding measured in the presence of excess unlabeled ligand. Mean values expressed as percent inhibition of specific binding are shown in Table 5. IC ₅₀ values (concentrations required to inhibit 50% specific binding) were determined by nonlinear regression analysis of the competition curve. These parameters were obtained by curve fitting using SigmaPlot ^TM software.

TABLE 5

Binding of R-oxybutynin and S-oxybutynin to calcium channel [inhibition of binding of diltiazem and verapamil to calcium channel receptor]

These results indicate that S-OXY has a similar calcium influx inhibitory activity to R-OXY.

Enantiomer of desethyloxybutynin

The main metabolite of racemic oxybutynin is RS-desethyloxybutynin (DEO). Prior to our study, the R and S enantiomers of DEO have not been described so far, ie the anticonvulsant activity and calcium influx inhibiting activity of the respective enantiomers R- and S-DEO are unknown. We have synthesized these enantiomers, and have studied their antimuscarinic, antiviral and calcium influx effects in models of receptor binding and bladder function. We found that each enantiomer of the metabolite has a pharmacological profile associated with its "parent" oxybutynin enantiomer.

Binding to Muscarinic Receptor Subtypes

The percent inhibition of specific radioligand binding induced by the three concentrations of each compound (R-, S-, and RS-DEO) was replicated as described for the enantiomers of oxybutynin as replicated human muscarinic receptors. . It was tested on subtypes (M1-M4). The following tables (Tables 6 and 7) show the percent inhibition in each subtype. In addition, IC ₅₀ values were measured for the M ₁ and M ₂ human receptor subtypes and are shown in Table 6.

TABLE 6

TABLE 7

These results indicate that S-DEO is less friendly to muscarinic receptor subtypes than R- or racemic DEO.

Binding to Calcium Channels

Percent inhibition of specific radioligand binding induced by each compound (R-, S-, and RS-DEO) was tested at the diltiazem and verapamil sites of the L-type calcium channel. The results are shown in Table 8.

TABLE 8

These results indicate that S-DEO has a calcium influx inhibitory activity similar to that of R- and racemic DEO.

Functional Features of Antimuscarin / Anticonvulsive Activity

The effects of R-, S- and RS-oxybutynin (OXY) and R-, S-, and RS-DEO were studied in an in vitro model of bladder function. As described below, a separate strip of guinea pig bladder smooth muscle was placed in a tissue bath and shrunk by increasing the muscarinian agonist carbacolo or external potassium concentration.

Bladder strips. Experiments were performed using methods similar to those described by Kachur et al (1988) and Noronha-Blob and Kachur (1991). Strips of tissue (approximately 10 mm long and 1.5 mm wide) were removed from the body of the bladder of a male Hartley guinea pig weighing 400-600 g (Erm Hill Breeding Lab, Kelmsford, MA). The tissues were suspended in an oxygenated buffer with the following composition. mM unit; NaCl, 133; KCl, 4.7; CaCl ₂ , 2.5; MgSO ₄ , 0.6; NaH ₂ PO ₄ , 1.3; NaHCO ₃ , 16.3; And glucose, 7.7. They were kept at 37 5 ° C. Shrinkage was recorded with an isometric transducer (model FT-10) and ink-writing polygraph (model 7) (Astro-Med, Inc., Grass Instrument Div., West Warwick, RI). A resting tension of 0.5 grams was maintained on all tissues for all time.

In each experiment, up to seven strips from a single bladder were removed, suspended in separate tissue chambers, and allowed to equilibrate with the bathing solution for one hour before the experiment was performed.

Carbacol-Induced Contraction A series of experiments focused on the anticholinergic action of oxybutynin. In these experiments, to assess the viability of each tissue and as a control frame, each strip of tissue reacted to exposure to tissue culture (HaCl replaced with KCl so that the concentration of the culture was 137 7 mM KCl). Shrinkage was recorded first. Immediately after returning to the standard medium, the concentration of carbacol was gradually increased and exposure to each concentration of carbacol was made until the peak reaction was recorded at each concentration. Thereafter, one strip untreated and / or one strip exposed to 17 mM ethanol to serve as control tissue was left, and each of the remaining strips was exposed to a specific concentration of antagonist for one hour. Because of poor solubility, an ethanol control was used when a stock solution of the test material had to be prepared in ethanol, and the tissue solution was found to experience 17mM effective concentration of ethanol. Finally, responses to exposure to increased concentrations of carbacol and 137.7 mM KCl were recorded in seconds.

Potassium-induced contraction. The second series of experiments focused on the hardening of the material under study. Contraction was recorded as a response to continuously increasing concentrations of potassium in the culture.

Data analysis. To determine whether the antagonist reduced the peak response to the agonist, the peak tension developed by each strip during the second set of measurements was expressed as a percentage of the peak tension developed during the first concentration-effect measurement. The resulting data for each antagonist was then analyzed for treatment-related differences by one-way ananlysisi of variance (ANOVA). Since only one antagonist concentration was tested for each strip of the bladder, the procedure of Arunlakshana and Schild (1959) was used in a modified form to determine the pA2 and slope of the skilled regression. First, the concentration of agonist exhibiting a half-maximal response (EC ₅₀ ) was evaluated for each strip from the second set of concentration-effect data. EC ₅₀ was obtained from linear regression lines that fit the logarithm of the drug concentration and the response covering the half-high level response. For each drug treated strip, the "concentration ratio" (CR) was calculated as the ratio of EC ₅₀ of treated tissue divided by EC ₅₀ of untreated tissue. For each experiment in which two or more strips were exposed to the same compound at different concentrations, the logarithm of this ratio Peggy 1 (ie log (CR-1)) was plotted against the logarithm of the antagonist concentration exposed to the "skill plot". "Was written. Regression analysis of log (CR-1) against the logarithm of the antagonist concentration was used to evaluate the pA2 and slope of the regression line. Finally, experiments were categorized according to chemicals and the mean values of pA2 and slope ± SE were calculated. The 95% confidence limit (CL) for the slope was evaluated from its SE using standard methods. For experiments exposed to chemicals given only one strip, calculate the pKD as (concentration of antagonist) / (CR-1) and add the negative number of this KD with the pA2 value to expand the set of pA2 The value was calculated.

The effects of racemic oxybutynin and DEO and their respective enantiomers on carbacol-induced contraction are summarized in Table 9 below. The values given are summaries of the skilled analysis that provide the pA2 values [mean value ± SE] and the slope [mean value ± SE].

TABLE 9

These results indicate that both S-OXY and S-DEO have less efficacy as antagonists of bladder muscarinic receptors than R- and racemic OXY and R- and racemic DEO.

The effects of racemic oxybutynin and its enantiomers on potassium-induced contraction are summarized in Table 10 below. (Given values are the amount of shrinkage induced by 137.7 mM K + after 60 minutes of exposure to the compound divided by the amount of shrinkage induced before exposure to the drug.)

TABLE 10

* Significant difference from corresponding value for untreated tissue (p <0.01)

These results indicate that oxybutynin and its enantiomers and desethyloxybutynin and its enantiomers have equal efficacy in bladder smooth muscle menstrual gels.

It is well known that normal urination of the bladder is regulated through choline mechanisms, whereas bladder instability in patients suffering from urinary incontinence appears to be related to the bladder's noncholinergic contraction. Anderson et al [ Neurourol Urodyn 5 , 579-586 (1986)] showed that atropine-resistant compressive muscles are very sensitive to calcium antagonists in animals.

Receptor binding affinity studies of (R)-and (S) -oxybutynin to receptor sites for the calcium channel blockers diltiazem and verapamil described above have been described in terms of S-oxybutynin and (S) -desethyloxybutyin. It is concluded that nin has little therapeutic effect on normal urination mechanisms (unlike R-isomers and racemics) while it has a therapeutic effect on involuntary urination. Both S-OXY and S-DEO also exhibit significantly reduced anticholinergic side effects compared to the corresponding R-isomers and racemics. It is particularly important to avoid cardiovascular side effects arising from the anticholinergic action of racemic oxybutynin. We conclude that S-oxybutynin and S-desethyloxybutynin are effective agents for treating urinary incontinence in humans, with much reduced side effects compared to racemic or pure R-enantiomers.

Example 1

Oral preparations

Capsules:

S-DEO, lactose and corn starch were mixed evenly, magnesium stearate was mixed into the powder obtained, then sieved and filled into a two-piece, hard gelatin capsule of the appropriate size using conventional machines. Other doses may be prepared by varying the fill weight and changing the size of the capsule as appropriate.

Since at least one crystalline form of the compound of the present invention is acicular, it is desirable to use a dry-powder technique to grind or powder the active ingredient to provide a free flowable powder for tableting or encapsulation.

Example 2

Oral preparations

refine:

^* Water evaporates during manufacture.

S-OXY is mixed with lactose until a homogeneous mixture is formed. A small amount of corn starch is mixed with water to obtain a corn starch paste. It is mixed with the homogeneous mixture to form a uniform wet mass. The remaining corn starch is added to the resulting wet mass and mixed until uniform granules are obtained. The granules are filtered through a suitable mill, using a 1/4 inch stainless steel screen. The ground granules are dried in a suitable drying oven until the desired moisture content is obtained. The dried granules are then milled through a suitable mill, the magnesium stearate is mixed and the resulting mixture is compression molded into tablets of the desired form, thickness, hardness and disintegration. Different amounts of tablets may be prepared by varying the ratio of active ingredient to excipient or to the final weight of the tablet.

Claims (8)

A compound selected from the group consisting of (S) -oxybutynin, (S) -desethyl oxybutynin or pharmaceutically acceptable salts of any one thereof containing up to 10% by weight of (R) enantiomer; Urinary incontinence treatment composition comprising. The composition for treating urinary incontinence according to claim 1, which is administered parenterally, percutaneously, rectally, orally or by inhalant. The composition for treating urinary incontinence according to claim 2, which is administered orally or transdermally. (S) -oxybutynin, (S) -desethyloxybutynin, or a pharmaceutically acceptable one, containing a pharmaceutically acceptable carrier and up to 10% by weight of (R) enantiomer A pharmaceutical unit dosage form in the form of a tablet or soft elastic gelatin capsule comprising 0.1 to 500 mg of one of the groups consisting of possible salts. The pharmaceutical unit dosage form of claim 4, wherein the pharmaceutically acceptable salt of (S) -oxybutynin, (S) -desethyloxybutynin, or any one thereof is present in an amount of 25 mg to 250 mg. . The pharmaceutical unit dosage form according to claim 5, wherein the pharmaceutically acceptable salt of (S) -oxybutynin, (S) -desethyloxybutynin, or any one thereof is present in an amount of 100 mg to 200 mg. (S) -oxybutynin, (S) -desethyloxybutynin, or a pharmaceutically acceptable one, containing a pharmaceutically acceptable carrier and up to 10% by weight of (R) enantiomer A pharmaceutical formulation in the form of a transdermal delivery device comprising 100 to 500 mg of a crowd of possible salts. 8. The pharmaceutical formulation of claim 7, wherein the pharmaceutically acceptable carrier comprises a permeation enhancer.