MXPA00005215A - Therapeutic formulation for administering tolterodine with controlled release - Google Patents

Abstract

A method and formulation for treating unstable or overactive urinary bladder, wherein tolterodine or a tolterodine-related compound, or a pharmaceutically acceptable salt thereof, is administered to a patient in a pharmaceutically effective amount thereof through a controlled release formulation that administers tolterodine or said tolterodine-related compound, or salt thereof, at a controlled rate for at least 24 hours.

Description

THERAPEUTIC FORMULA FOR ADMINISTERING CONTROLLED RELEASE TOLTERODINE Field of the Invention The present invention relates to an improved method for treating unstable or high activity bladder, as well as its formula.

Antecedents of the Invention A large part of the adult population (5-10%) suffers from urinary incontinence, and in particular, the predominance of so-called urge incontinence increases with age. The symptoms of an unstable bladder or of high activity include the urge incontinence and the frequency when urinating or having urgency to urinate. It is believed that the unstable bladder or high activity is caused by uncontrollable contractions of the bundle of soft muscle fibers that form the covering of the urinary bladder (the detrusor muscle) during the filling phase of the bladder. These contractions are often controlled by cholinergic muscarinic receptors, and pharmacological treatment of the unstable bladder or high activity has been based on muscarinic receptor antagonists. The chosen medication has been oxybutynin for a long time. Oxybutynin, whose chemical formula of 4-diethylamino-2-butynyl-penylcyclohexylglycolate is DL-racemic, is taken orally, usually in tablets or syrup. Oxybutynin, generally administered as salt chloride, is metabolized into an active metabolite, N-desethylobutinine. The drug is rapidly absorbed in the gastrointestinal tract immediately after administration and lasts three to six hours. Although the effectiveness of oxybutynin has been proven right, its usefulness is limited by secondary antimuscarinic reactions, particularly by dry mouth, which often causes treatment to be interrupted. WO 96/12477 describes a controlled release delivery system for oxybutynin, where said delivery system is said to be not only convenient for the patient by reducing its administration to a daily regimen of one intake, but also reduces the Adverse side reactions by limiting the initial maximum concentrations of oxybutinin and the active metabolite in the patient's blood. However, the intended alleviation of side reactions by reducing or eliminating maximum concentrations through the administration of the controlled release delivery system is contradicted in a clinical report published later by Nilsson, CG, et al., Neurology and Urodynamics 16 (1997) 533-542, where it describes clinical trials performed with the controlled release delivery system described in WO 96/12477 mentioned above. In the clinical trials reported, a 10 mg controlled-release oxybutinin tablet was compared with the administration of a conventional tablet (immediate release) of 5 mg administered twice a day to urge patients with incontinence. Although the maximum levels of the drug were obviously eliminated with the controlled release oxybutinin tablet, no differences were observed in the side reactions between the controlled release tablet and the conventional tablet. Therefore, the advantage of the controlled release tablet was only in improving compliance with the treatment by means of a daily dose, instead of also reducing the side reactions as stated in WO 96/12477. Recently at the market, an improved antlergic muscarinic receptor, tolterodine, (R) -N, N-diisopropyl-3- (2-hydroxy-5-methyl penyl) -3-penylpropanamine, for the treatment of urge incontinence and other symptoms of unstable bladder or high activity. Both tolterodine and its main active metabolite, the 5-hydroxymethyl derivative of tolterodine, which contributes significantly to the therapeutic effect, has considerably less side effects than oxybutynin, especially with regard to the propensity to have dry mouth While tolterodine is as potent as oxybutinin in the bladder, its affinity for the muscarinic receptors of the salivary gland is eight times smaller than oxybutinin, see, for example, Nilvebrant, L., et. AL, European Journal of Pharmacology 327 (1997) 195-207. The selective effect of tolterodine in humans is described in Stahl, M. M. S., et. al., Neurology and Urodynamics 14 (1995) 647-655, and Bryne, N., International Journal of Pharmacology and Therapy, Vol. 35, No. 7 (1995) 287-295. The administration of tolterodine that is currently on the market comes in the form of tablets covered with a layer containing 1 mg or 2 mg of tolterodine L-tartrate for immediate release in the gastrointestinal tract, the recommended dose is usually 2 mg twice perday. Although, as already mentioned, secondary reactions, such as dry mouth, are much lower than with oxybutinin, these still exist, especially at higher doses. According to the present invention, it has recently been discovered surprisingly that, contrary to the case of oxybutynin, the substantial elimination of the maximum levels of tolterodine serum and its active metabolite, through the controlled release of tolterodine for a period of time. of extensive time, such as in the once-a-day administration form, while maintaining the desired effect on the bladder, actually significantly reduce the side reactions (which are already mild), especially dry mouth, compared with those obtained with the same total dose of immediate-release tablets during the same period of time. In other words, by eliminating the maximum serum levels of the active portion, the adverse effects and, in particular, the dry mouth, are more affected than the desired effect on the detrusor activity, while the evaporation of the serum concentration does not lead to the loss of activity or to the increase in the incidence of urinary retention or other safety interests. Therefore, in addition to the convenient advantages of controlled release administration, one can, either (i) for a total dose of tolterodine, reduce side reactions, such as dry mouth, or (ii) for a given level of Acceptable secondary reactions, increase the dose of tolterodine to obtain a greater effect on the bladder, if desired.

SUMMARY OF THE INVENTION Therefore, in one aspect the present invention provides a method for treating unstable or high activity bladder, which method comprises administering to a patient (mammal) in need of a tolterodine-based treatment or of a compound related to tolterodine, or a pharmaceutically acceptable salt thereof, through a controlled release formula that administers tolterodine or said compound related to tolterodine or salt thereof, through a controlled release formula that administer tolterodine or said compound related to tolterodine, or salt thereof, in a controlled amount for at least 24 hours. It is preferable that the dosage form of the formulation has the ability to maintain a constant level of serum in substantial form of the active portion or portions, for at least said 24 hours. The bladder of high activity includes detrusor instability, detrusor hyperflexia, urge incontinence, and urination frequency or urgency to urinate. As mentioned above, the chemical name of tolterodine is (R) -N, N-diisopropyl-3- (2-hydroxy-5-methyl penyl) -3-phenylepropanamine. The term "tolterodine-related compound" means that it encompasses the most important active metabolite of tolterodine, ie (R) -N, N-diisopropyl-3- (2-hydroxy-5-methyl penyl) -3-penylpropanamine; the (S) -entantiomer corresponding to tolterodine, that is, (S) -N, N-diisopropyl-3- (2-hydroxy-5-methyl penyl) -3-penylpropanamine; the 5-hydroxymethylmethyl metabolite of (S) -enantiomer, that is, (S) -N, N-diisopropyl-3- (2-hydroxy-5-methyl penyl) -3-penylpropanamine; as well as the corresponding equivalent to tolterodine, ie (R, S) -N, N-diisopropyl-3- (2-hydroxy-5-methyl penyl) -3-penylpropanamine; and the forms of prodroga of the same. The term "active portion or portions" refers to the sum of the free or independent concentrations (i.e., not bound to the proteins) of (i) tolterodine and the active metabolite thereof, when tolterodine is administered ( or prodigal form); or (ii) tolterodine and the active metabolite and / or tolterodine (S) -enantiomer and the active metabolite thereof, when the corresponding equivalent (or the prodrug form) is administered; or (iii) the active metabolite, when the (R) -5-hydroxymethyl metabolite of tolterodine (or the prodrug form) is administered; or (iv) to tolterodine (S) -enantiomer and the active metabolite thereof, when the (S) -enantiomer (or prodrug) is administered; or (v) the (S) -metabolite active, when the metabolite (S) -5-hydroxymethyl is administered. The term "constant in substantial form" with respect to the serum level of the active portion or portions means that the release profile of the controlled release formula should not exhibit essentially any maximum value. This can, in a more sophisticated way, also be expressed in reference to the "fluctuation index" (F1) for the serum concentration of the active portion (independent) (or the sum of the active portions when they are relevant), where the index of fluctuation F1 is calculated as F1 = (Cmax - Cmin) / AUCt / t where Cmax and Cmin are the maximum and minimum concentrations, respectively, of the active portion, AUCt is the area under the serum concentration profile (concentration against the curve of time) for an interval t between the doses and t is the length of the interval between the doses. Therefore, according to the present invention, the controlled release formula should provide a significant fluctuation index (so that n is at least 30) which is generally not greater than about 2.0, but preferably should not be greater than about 1.5, particularly not greater than about 1.0, for example, not greater than about 0.8. For tolterodine and its metabolite 5-hydroxymethyl, the 24-hour exposure, expressed as the independent active portion AUC (tolterodine plus metabolite) is, in general, within a range of 5 to about 150 nM * h, preferably about 10 to about 120 nM * h, depending on the dose that a particular patient needs. The indicated limits are based on the calculation of the independent concentrations of the active portion assuming an independent fraction of 3.7% for tolterodine and 36% for the metabolite 5-hydroxymethyl (Nilvebrant, L., et al., Life Sciences, Vol. 60, Nos. 13/14 (1997) 1129-1136). Correspondingly, for tolterodine and its 5-hydroxymethyl metabolite, the percentage of serum (blood) or plasma levels are, generally, within a range of about 0.2 to about 6.3 nM, preferably within a range of about 0.4 to about 0.5 nM.

Tolterodine, its (S) -enantiomer and its corresponding equivalent and the preparation thereof are described in example WO 89/06644. For a description of the active (R) -5-hydroxymethyl metabolite of tolterodine (as well as the metabolite (S) -d-hydroxymethyl), see WO 94/1 1337. The (S) -enantiomer and its uses for the Treatment of urinary and gastrointestinal disorders is described in WO 98/03067.

In another aspect, the present invention provides a pharmaceutical formula containing tolterodine or a compound related to tolterodine, or a pharmaceutically acceptable salt thereof, which formula, when administered to the patient, provides controlled release of tolterodine or said compound related to tolterodine, or salt thereof, of at least 24 hours, preferably such that the substantial constant serum level of the active portion or portions is maintained at least, say, for 24 hours. However, another aspect of the present invention provides the use of tolterodine or a compound related to tolterodine, or a pharmaceutically accepted salt thereof, for the manufacture of a therapeutic formula for treating unstable or high activity bladder. , whose formula provides a controlled release of tolterodine or said compound related to tolterodine or salt thereof at a controlled rate of at least 24 hours, preferably such that the substantial constant serum level of the active portion (s) is Keep for at least 24 hours.

It is preferable that the controlled release formula be an oral delivery system or a transdermal preparation, such as a transdermal patch, but also other forms of controlled release can, of course, be contemplated, such as oral tablets, rectal suppositories, subcutaneous implants , formulas for intramuscular administration. An example of the type of oral controlled release formula, a specific mixture which is described in Example 1 below, is a multi-unit formula comprising controlled release granules. Each granule includes (i) a unit of a core of an inert water soluble material, inflatable in water or insoluble in water (having a size of about 0.05 to about 2 mm), such as, for example, a sphere of sucrose; (ii) a first layer in the core of a polymer (often hydrophilic) substantially insoluble in water (this layer can be omitted in the case of an insoluble core, such as, for example, silicon dioxide), (iii) a second layer of a water soluble polymer containing an active ingredient dissolved or dispersed therein, and (iv) a third polymer layer effective for controlled release of the active ingredient (eg, a water insoluble polymer in combination with a water soluble polymer). In the case of an oral controlled release formula for once-a-day administration, the dose of tolterodine (or the compound related to tolterodine) is, for example, 4 mg to 6 mg.

A transdermal patch for tolterodine or for a compound related to tolterodine is described in our pending international application "Tolterodine administered transdermally as an antimuscarinic agent for the treatment of high activity bladder" (based on the Swedish patent application No 9802864-0, filed on August 27, 1998), whose full statement is attached to this document as a reference. The formulas of the patches are described in illustrative form in Example 2 described below. With the guidance of the appended statement, the person skilled in the art can either adapt the controlled release administration forms, such as tablets, capsules, patches, etc., to obtain the objectives of the present invention, or design modified or new controlled release administration forms.

DETAILED DESCRIPTION OF THE INVENTION The present invention is illustrated by means of the following examples, without, however, limiting the scope of the present invention in any way. Percentages are by weight, unless otherwise specified. Reference will be made to accompany the drawings, in which: Figure 1 is a diagram showing the variation of serum concentration (nmol / L) of the active (independent) portion with time (hours) for 24 hours when administer a predetermined total dose of tolterodine (4 mg) through (i) an immediate release tablet (2 mg) twice daily as in the previous procedure and (ii) a controlled release capsule (4 mg) once per day according to the present invention; Figure 2 is a diagram showing the variation of fundamental salivation (g / min) with time (hours) for 4 hours after the administration of (i) a controlled release tolterodine capsule according to the present invention, (ii) an immediate release tolterodine tablet as in the previous procedure and (iii) a placebo; and Figure 3 is a bar chart diagram showing the estimates of each individual patient who had experienced the secondary reaction of dry mouth (nothing, mild, moderate or severe dry mouth sensation) after administration of tolterodine to the patient. through (i) a conventional 2 mg immediate release tablet, (ii) controlled release capsules of 4, 6 and 8 mg respectively, according to the present invention and (iii) a placebo. Example 1 Capsule CR and oral Tolterodine IR Tablet Preparation of tolterodine CR capsules of 2 mg and 4 mg A controlled release capsule (CR) containing non-pareil granules (have no equivalent) covered by (i) ) a layer of ethylcellulose, (ii) a layer of tolterodine / HPMC and (iii) a continuous release layer of ethylcellulose / HPMC was prepared as follows: 1200 g of sugar spheres (containing starch), 20-25 mesh, were placed in a Wurster fluid bed and subsequently covered with the following three coating solutions: - (1) a Surelease ® sealer coating solution prepared by mixing 788 g of Surelease ® with 563 g of purified water (Surelease ® is a dispersion Aqueous for coating with a layer, with approximately 25% solids, consisting basically of ethylcellulose plasticized with fractionated coconut oil, manufactured by Colorcon, Inc., West Point, PA, USA ); - (2) a suspension prepared by first dissolving 35.0 g of toterodine L-tartrate in 2190 g of purified water and subsequently mixing the solution with 6.6 g of Hypromellose, 5cP (hydroxypropylmethyl cellulose) (HPMC)); and (3) a constant release coating solution prepared by mixing 29 g of Hypromellose, 5cP with 375 g of purified water and then mixing it with 695 g of Surelease ®. After drying, the coated spheres were placed in hard gelatin capsules (size 3, white / white) to obtain capsules of 2 mg and 4 mg respectively, of the compound (filling mass for a 2 mg capsule, 169-297 mg / capsule): 2 mg capsule 4 mg capsule Tolterodine L-tartrate 2.0 mg 4.0 mg Sugar spheres, 20-25 mesh 69 mg 137 mg Surelease ® 21 mg 42 mg Hypromellose 5cP 2.0 mg 4.1 mg IR Tolterodine Tablets L- 2 mg tartrate Immediately released L-tartrate (IR) tolterodine tablets of 2 mg (Detrusitol®, Pharmacia &Upjohn AB, Sweden) were commercially available. The tablets had the following composition: Core Tolterodine L-tartrate 2.0 mg Cellulose, microcrystalline 53.4 mg Calcium phosphate dihydrate and hydrogen 18.0 mg Sodium starch glycolate 6.0 mg Magnesium stearate 0.4 mg Colloidal anhydrous silica 0.2 mg Coating Methylhydroxypropyl cellulose 1.5 mg Cellulose, microcrystalline 0.3 mg Stearic acid 0.6 mg Titanium dioxide E 171 0.6 mg Pharmacodynamic and pharmacokinetic studies A clinical experiment was carried out with patients who had bladder with high activity to determine the pharmacodynamic and pharmacokinetic effects of daily doses different from ( i) the tolterodine controlled release capsule described above (hereinafter called TOD), compared to (ii) the tolterodine immediate release tablet described previously (hereinafter called TID), and (iii) a placebo capsule (containing only sugar spheres). The experiment was carried out in 60 patients, which were divided into two groups of 30, giving one group the treatment and the other a placebo for three periods of one week and six treatments (2, 4, 6 and 8 mg TOD). once a day, 2 mg TIR twice a day and placebo). All patients were randomly chosen to take three of the six treatments, meaning that 30 patients were subjected to each of the treatments. Pharmacodynamic and pharmacokinetic measures were taken on the seventh day of each treatment period. The determinations included measurements of (i) the serum concentrations of tolterodine and its principal metabolite 5-hydroxymethyl (hereafter called 5-HM) in time, (ii) salivation (dry mouth) and (iii) the residual volumes in the urine. Serum concentrations of tolterodine and its main metabolite Blood samples were taken immediately before the doses were applied and after 0.5, 1, 2, 3, 6, 9, 12, 24 and 25 hours and the concentrations of tolterodine serum were measured. and its main metabolite 5-HM free (independent) by gas chromatography / mass spectrometry. The independent concentrations were calculated by taking an independent fraction of 3.7% for tolterodine and 36% for 5-HM, as was obtained in studies of the binding of proteins in human serum (Nilvebrant, L., et al. , Life Sciences, Vol. 60, Nos. 13/14 (1997) 1129-1 136). Figure 1 shows the variation obtained over time of the sum of the independent concentrations of tolterodine and 5-HM (to which sum is referred to as "active portion") on the one hand, for the administration of a TOD capsule. mg once a day and, on the other, for the administration of a 2 mg TIR tablet twice daily (ie, equivalent doses every 24 hours of the capsule and tablet). As shown in the Figure, the maximums obtained with the TIR tablet are eliminated with the TOD capsule, the latter providing, therefore, a constant constant serum concentration of the active portion during the 24 hours illustrated. The difference in the fluctuation of serum concentrations between the TIR tablet and the TOD capsule can also be demonstrated by calculating the "fluctuation index". The fluctuation index, F1, is calculated as F1 = (Cmax - Cmin) / AUCt / t, where t is the time interval between the doses and AUCt is the area below the profile of the serum concentration during a time interval between dose. Therefore, the calculated average fluctuation index was 2.40 (95% CI 1.95-2.63) for the TIR tablet (based on n = 28), and 0.68 (95% Cl 0.59-0.78) for the TOD capsule). Salivation (dry mouth) Salivation was measured using cotton wool rolls applied in the mouth for 3 x 2 minutes. The measurements were carried out before breakfast and, thereafter, after each blood sample on the seventh day in each treatment period. Based on all measurements after dosing, intermediate salivation was calculated for 12 hours. Basic salivation in a steady state was measured after treatment with (i) a 4 mg TOD capsule, (ii) a 2 mg TIR tablet and (iii) a placebo. The results are presented in Figure 2. As can be seen in the Figure, salivation is constant in substantial form during the period shown with the TOD capsule, while a significant reduction in salivation (ie, drier mouth) is obtained with the TIR tablet. While Figure 2 shows the total salivation while measuring, the degree of salivation, or dry mouth, was also determined, based on the calculation of the patient according to the intensity experienced of the phenomenon. The results for a tablet b.i.d. 2 mg TIR, a TOD capsule of 4 mg, a TOD capsule of 6 mg and a TOD capsule of 8 mg are presented in the form of a bar graph in Figure 3. The four bars for each dose represent, from left to right in the figure , nothing, mild, moderate and severe dry mouth sensation respectively. Apparently, according to Figure 2, the dry mouth intensity for the tablet b.i.d. IRR of 2 mg is clearly higher than that of the TOD capsule of 4 mg, and about twice that dose, that is, a TOD of 8 mg is required to equalize the adverse effects of dry mouth of the b.i.d. TIR of 2 mg. The results of the salivation determinations, therefore, show that the decrease in the maximum concentrations of the "active portion" (ie, tolterodine plus 5-HM) leads to a substantial reduction of the undesirable effect of dry mouth. Residual volume of urine Residual volume is the volume of urine left in the bladder immediately after emptying it. Measuring residual volume offers a method to determine the effect of antimuscarinic treatment on the bladder. In fact, it offers a measure of effectiveness (changes in residual volume) as well as safety (urinary retention, that is, inability to pass urine). Therefore, the effectiveness can be measured as the average residual volume per unit of time and safety, as in any case, where the residual urine exceeds a fixed level. The average residual volume per micturition was measured by means of a non-invasive method (ultrasound) for the placebo, the b.i.d. TIR of 2 mg, and for the capsules TOD of 2 mg, TOD of 4 mg, TOD of 6 mg, and TOD of 8 mg. The results are presented in Tables 1 and 2 below. Table 1 shows the average residual volume per urination and Table 2 shows the maximum residual volume for 12 hours. The results presented clearly demonstrate that the doses of the TOD capsule are as effective as the doses b.i.d. Corresponding IRRs, and also that the TOD dose can be increased up to 8 mg daily and still be safe with respect to urinary retention. Table 1 Average Residual Volume by micturition (ml) Table 2 Maximum Residual Volume for 12 hours The results of the clinical experiment described above demonstrate that a reduced serum concentration of the active portion (tolterodine plus 5-HM) not only does not lead to a loss of efficacy or to unfavorable side reactions, mainly urinary retention, but, importantly, It also helps to have a reduced dry mouth effect (an unaffected or less reduced salivation). EXAMPLE 2 TRANSDERMAL TOLTERODINE PATCH FORMULA The patches that release tolterodine were prepared as follows: System 1 (adhesive with medicament, acrylate) 5 g of tolterodine base were dissolved in 11 g of ethanol and added to 20 g of Durotak 387-2287 (Chemicals and National Starch, USA) The gel with the drug was covered in a support membrane (Scotchpak 1012; Company 3M, USA) using a coating equipment (Instruments for Printing Coatings RK, SA de CV, Type coating control KCC 202). The thickness of the wet layer was 400 ®m. The laminate was dried for 20 min. RT and then for 30 min. at 40 ° C. A polyester release liner (S 2016; Rexam Separator) was laminated to the gel with the drug already dry. The leaf was cut into patches and stored at 2-8 ° C until use (packed in Barex bags). The tolterodine concentration base in the patches was 2.5 mg / cm2. System 2 (multi-laminate, acrylate) 5 g of tolterodine base were dissolved in 10 ml of ethanol. A mixture of 6.4 g of Eudragit RL 100 (Rohm GmbH Chemical Factory, Germany) and 6.4 g of ethanol and a mixture of 2.6 g of Polyvidone 90 (BASF, Germany) and 10.2 g of ethanol was added. to the solution of tolterodine base in ethanol. Finally, 4 g of propylene glycol was added. The gel with the drug was coated on a support membrane (Scotchpak 1 109; Company 3M, U.S.A.) using the aforementioned equipment. The thickness of the wet layer was 400 μm. The laminate was then dried at 40 ° C for 2 hours. An adhesive layer consisting of Plastoid E35H was coated on a polyester membrane (S 2016, Rexam Separator) and dried at 80 ° C for 10 min. After this the two layers were laminated. The leaf was cut into patches and stored at 2-8 ° C until use (packed in Barex bags). The concentration of tolterodine base in the patches was 1.0 mg / cm2. System 3 (multi-laminate, water-based acrylate) 1 g of tolterodine base was mixed with Tween 80 (Merck) by heating at 60-70 ° C. 1.8 g of triethylacetate and 1.3 g of water dem. To the mix. The final mixture was added to 25 g of Eudragit RL 30 D (Rohm GmbH Chemical Factory, Germany). Finally, 180 mg of 1 N NaOH was added. The gel with the drug was coated on a support membrane (Scotchpak 1109; Company 3M, U.S.A.), using the coating equipment. The thickness of the wet layer was 400 ®m. An adhesive layer consisting of Plastoid E35H was coated on a polyester membrane (S 2016, Rexam Separator) and dried at 80 ° C for 10 min. After this the two layers were laminated. The leaf was cut into patches and stored at 2-8 ° C until use (packed in Barex bags). The concentration of tolterodine base in the patches was 0.5 mg / cm2.

Claims (17)

R E I V I N D I C A C I O N S Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property.

1. A method for treating unstable or high activity urinary bladder, wherein the method comprises administering to a patient in need of this treatment tolterodine or a compound related to tolterodine, or a pharmaceutically accepted salt thereof, in an amount of the same pharmaceutically effective through a controlled release formula having the ability to maintain a substantially constant serum level of the active portion or portions for at least 24 hours.

2. The method as described in Claim 1, further characterized in that the controlled release formula provides an average fluctuation index of the active portion (s) that is not greater than about 2.0, preferably not greater than about 1.0, having been defined said fluctuation index F1, such as F1 = (Cmax - Cmin) / AUCt / t, where Cmax and Cmin are the maximum and minimum concentrations, respectively, of the active portion or portions, AUCt is the area according to the profile of serum concentration and t is the period of time between each interval between doses.

3. The method as described in Claims 1 or 2, further characterized by administering tolterodine, its 5-hydroxymethyl metabolite or the corresponding equivalent to tolterodine and the 24-hour serum profile, expressed as the tolterodine AUC. and its 5-hydroxymethyl metabolite, is from about 5 to about 150 nM * h, preferably from about 10 nM * h to about 120 nM * h.

4. The method as described in Claims 1, 2 or 3, further characterized by the administration of tolterodine, its 5-hydroxymethyl metabolite or the corresponding equivalent to tolterodine and the serum level of the independent tolterodine and its 5-hydroxymethyl metabolite are within a range of from about 0.2 to about 6.3 nM , preferably within a range of from about 0.4 to about 5.0 nM.

5. The method as described in any of the Claims 1 through 4, further characterized in that the controlled release formula is a capsule or tablet for oral administration once a day.

6. The method as described in any of the Claims 1 through 4, further characterized in that the controlled release formula is a transdermal preparation, preferably a transdermal patch.

7. The method as described in any of Claims 1 to 6, further characterized in that tolterodine is administered.

8. The method as described in any one of claims 1 to 6, further characterized in that urinary incontinence is treated.

9. A pharmaceutical formulation containing tolterodine or a compound related to tolterodine, or a pharmaceutically acceptable salt thereof, which formula when administered to a patient provides controlled release of tolterodine or a compound related to tolterodine, or a salt thereof , so that a substantially constant serum level of the active portion or portions is maintained at least, say, for 24 hours.

10. The formula as described in Claim 9, further characterized in that it provides an average fluctuation index of the active portion (s) which is not greater than about 2.0, preferably not greater than about 1.0, said fluctuation index being defined, F1, as F1 = (Cmax -Cmin) / AUCt / t, where Cmax and Cmin are the maximum and minimum concentrations, respectively, of active portion or portions, AUCt is the area according to the serum concentration profile and t is the length of the dose interval.

The formula as described in claims 9 or 10, further characterized in that tolterodine, its metabolite 5-hydroxymethyl or the corresponding equivalent to tolterodine and the serum profile of 24 hours, expressed as the AUC of the independent tolterodine and its 5-hydroxymethyl metabolite is from about 5 to about 150 nM * h, preferably from about 10 nM * h to about 120 nM * h.

12. The formula as described in Claims 9 or 10, further characterized in that tolterodine, its 5-hydroxymethyl metabolite or the corresponding equivalent to tolterodine, and the serum level of the independent tolterodine and its 5-hydroxymethyl metabolite are administered. it is within a range of from about 0.2 to about 6.3 nM, preferably within a range of from about 0.4 to about 5.0 nM.

13. The formula as described in any of Claims 9 to 12, further characterized in that it is a capsule or tablet for oral administration once a day.

14. The formula as described in any of the Claims 1 to 12, further characterized in that it is a transdermal preparation, preferably, a transdermal patch.

15. The formula as described in any of the Claims 9 through 14, further characterized in that it provides controlled release of tolterodine.

16. The use of tolterodine or a compound related to tolterodine, or a pharmaceutically accepted salt thereof, for the manufacture of a therapeutic formula for treating unstable or high activity bladder, whose formula provides controlled release of tolterodine or a compound related to tolterodine, or a salt thereof, so that a substantially constant serum level of the active portion or portions is maintained at least, say, for 24 hours.

17. The use as described in Claim 16, further characterized in that a formula is made according to any one of Claims 10 to 15. SUMMARY A method and formulation for the treatment of unstable or high activity bladder, wherein tolterodine or a compound related to tolterodine or a pharmaceutically acceptable salt thereof is administered to a patient in a pharmaceutically effective amount thereof through a controlled release formulation which administers tolterodine or said compound related to tolterodine, or a salt thereof, in a controlled amount for at least 24 hours.