Therapy for the treatment of overactive bladder

[0001] The present invention belongs to the field of pharmaceutical compositions and methods of their use for the treatment of overactive bladder and reduction of its various side effects.

Description of the Related Art [0002] Overactive bladder (OAB) is characterized by involuntary contractions of the displacement muscle during bladder filling. These contractions can be asymptomatic or cause three common symptoms that clinically define OAB: frequency of urination; sudden pressure on the bladder; and urinary incontinence due to urgent or neurogenic pressure. Frequency is the increase in the number of voids to even eight or more during the day. Sudden pressure on the bladder is a strong and unexpected need to urinate. Urinary incontinence due to urgency or neurogenic urinary incontinence is a situation where the urge to urinate cannot be controlled. Urination at night or frequency of urination at night that disturbs sleep (more than twice a night) is often included as the fourth symptom. Symptoms of OAB may appear separately or together, and it is not known if they have a pathological or neurogenic cause.

[0003] Urinary incontinence occurs in more than half of female patients suffering from OAB. This condition affects over 33 million Americans and imposes significant economic, social and psychological burdens. Although ongoing pharmacovigilance studies of lower urinary tract disorders have led to alternative treatment options, OAB symptoms are generally under-reported by patients and under-treated by healthcare professionals.

[0004] Several classes of drugs have been used to treat and control OAB, including calcium channel blockers, tricyclic antidepressants, alpha-adrenoreceptor antagonists, estrogen and anticholinergic agents. Anticholinergic agents that exert their effects on muscarinic receptors and suppress or reduce the intensity of involuntary contraction muscle contraction

Bladder bladders are the first-line pharmacotherapy for OAB and perhaps the only therapy available whose efficacy is not questioned. Oxybutynin chloride and tolterodine tartrate are the most widely studied and most widely used among anticholinergics. A recent systematic, fact-based review of clinical trials of several agents showed that anticholinergic therapies significantly improved several urinary function indicators, including mix frequency and the number of episodes of urinary incontinence. An important limitation of these agents is their lack of specificity for bladder tissue and the resulting onerous side effects such as dry mouth and constipation.

[0005] Tolterodine has generally been associated with less dry mouth than oxybutynin. This property is thought to be due to the reduced specificity of tolterodine for any of the 5 muscarinic receptor (M1M5) subtypes, such as the M3 receptor, which predominates in tissue around the ears. Oxybutynin has a greater affinity for this receptor than tolterodine, which also mediates bladder contractions. Based on animal data, it was argued that tolterodine has greater bladder selectivity than oxybutynin than parotin muscarinic receptors, but this mechanism still needs to be clarified. In order to explain a relatively slightly dry mouth than that associated with the therapeutic effect of tolterodine, action was also invoked on M2 receptors that are found in smooth muscle but not in glandular tissue, and which tolterodine has a higher affinity than oxybutynin.

[0006] Additional reports that a greater degree of dry mouth with oxybutynin are attributed to the formation of the major metabolite, desethyloxybutynin, which appears to have greater affinity for M3 subtype receptors, which are also expressed in the salivary glands. However, newer oxsybutynin and tolterodine extended release formulations provide comparable or slightly better performance and increased tolerability compared to immediate release formulations. Recently approved agents, including trospium chloride, solifenacin succinate (Vesicare) and darifenacin (Enablex) appear to have a better side effect profile, i.e. slightly less dry mouth. However, dry mouth and constipation are still problematic and patients stop taking the medicine after a short period of treatment. Salah et al. [Am J Psychiatry 153: 4, 579 (1996)] discusses the use of pilocarpine for

EP 1 933 833 B1 to treat xerostomy associated with the treatment of depressive disorders using desipramine. Masters [Am J Psychiatry 162: 5, 1023 (2005)] discusses the use of pilocarpine for the treatment of xerostomia induced by psychoactive drugs having antimuscarinic and anticholinergic side effects. Oki et al. [British Journal of Pharmacology 145, 219-227 (2005)] discusses the comparison of the binding of several muscarinic receptor antagonists, including oxybutynin and solifenation, in a mouse model, by measuring the reduction of salivary secretion caused by pilocarpine in mice due to oral administration of an antimuscarinic compound.

[0007] There is therefore a need in the art for a drug that would provide sufficient efficacy for OAB treatment and with a significantly reduced level of side effects to increase patient compliance, comfort and efficacy.

Summary of the Invention [0008] Disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of a first compound and a therapeutically effective amount of a second compound, wherein the first compound is an antimuscarinic or anticholinergic agent, and the second compound causes stimulation of salivary glands, wherein the first compound is oxybutynin or tolterodine, and the second compound is pilocarpine for use in the treatment of overactive bladder.

Brief Description of the Drawings [0009] Fig. 1 is a graph showing the amount of saliva flowing from a human individual following administration of oxybutynin (♦, rhombus), pilocarpine (, square), both (•, circle) or none (A, triangle) .

[0010] Fig. 2 is a graph showing the percentage of saliva flowing out relative to zero time.

[0011] Fig. 3 is a graph showing the effect of time delay for pilocarpine administration when oxybutynin was given at t = 0 in all experiments except placebo (A, triangle), in which case oxybutynin was not given and pilocarpine was given in t = 0 (, square), t = 30 min (•, circle) and t = 60 min (♦, rhombus).

[0012] Fig. 4 is a graph showing the effect of different dose ratios of oxybutynin and pilocarpine on saliva flow.

[0013] Fig. 5 is a graph showing a comparison of stimulated salivation after oral administration of 5 mg oxybutynin (·, circle), 30 mg cevimeline (♦, rhombus), placebo (▲, triangle) and a combination of oxybutynin and cevimeline (THVD-102) (, square).

[0014] Fig. 6 is a graph showing a comparison of stimulated salivation after oral administration of 2 mg tolterodine tartrate with different combinations (2 mg tolterodine / 5mg pilocarpine and 2 mg tolterodine / 10 mg pilocarpine, with pilocarpine given at different times) and placebo.

[0015] Fig. 7 is a graph showing the relationship between the time of administration of 10 mg of pilocarpine on stimulated salivation after oral administration of 2 mg tolterodine tartrate.

Detailed Description of Preferred Embodiments [0016] The main limitations of treatment of overactive bladder (OAB) are the side effects of dry mouth and constipation. The current approach to dry mouth is the continuous release of an active particle such as oxybutynin or tolterodine. Patients taking OAB drugs continue to suffer from these side effects and thus their quality of life deteriorates significantly, to the extent that most patients stop taking medication after about 4-6 months.

[0017] Thus, in a first aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a first compound and a therapeutically effective amount of a second compound, wherein the first compound is an antimuscarinic or anticholinergic agent and the second compound causes the stimulation of the salivary glands the compound is oxybutynin or tolterodine, and the second compound is pilocarpine for use in the treatment of overactive bladder (OAB).

[0018] In some embodiments, the first compound is oxybutynin or a pharmaceutically acceptable salt or prodrug thereof. Oxybutynin is an active ingredient found in drugs such as Ditropan®; Ditropan XL®; and Oxytrol®. Oxybutynin is an anticholinergic drug, thereby tolerating involuntary contractions of bladder smooth muscle. Oxybutynin is also thought to have muscarinic receptor activity that further enhances it

OAB performance, but may also be the cause of its most common side effect, dry mouth.

[0019] In certain embodiments, the first compound is tolterodine or a pharmaceutically acceptable salt or prodrug thereof. Tolterodine, having the chemical name (R) -2- [3- [bis (1-methylethylamino] -1-phenylpropyl] -4-methylphenol [R- (R *, R *)] - 2,3-dihydroxybutanedioic acid , is a muscarinic receptor antagonist and is the active ingredient found in drugs such as Detrol® (as tolterodine tartrate).

[0020] The term "pharmaceutically acceptable salt" refers to the formulation of a compound that does not cause significant irritation to the organism to which it is administered, and does not inhibit the biological activity and properties of the compound. Pharmaceutical salts can be prepared by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and like them. Pharmaceutical salts can also be obtained by reacting a compound of the invention with a base to form a salt such as an ammonium salt, a metal salt from the alkali group such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium or magnesium salt, an organic base salt, such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine and their salts with amino acids such as arginine, lysine and the like.

[0021] Throughout this disclosure, when a specific compound is mentioned, it is understood that the name refers to both the free base, the free acid of this compound, and its pharmaceutically acceptable salts. Thus, for example, the scope of the term "tolterodine" includes both tolterodine free base, i.e. (R) -2- [3- [bis (1-methylethylamino] -1-phenylpropyl] -4-methylphenol- [R- (R *, R *)] -2; 3-dihydroxybutanedioic acid and its various pharmaceutically acceptable salts , for example, tolterodine tartrate.

[0022] "Prodrug" refers to an agent that is converted in vivo to the parent drug. Prodrugs are often useful because they may be easier to administer than parent drugs in some situations. They may for example be bioavailable by oral administration, while the parent drug is not. A prodrug may also have increased solubility in pharmaceutical compositions than

The parent drug or may be more appetizing or easier to prepare. A non-limiting example of a prodrug would be a compound of the present invention that is administered as an ester ("prodrug") to facilitate transfer across a cell membrane in which water solubility inhibits motility, but which then hydrolyzes to the carboxylic acid, the active unit when found inside the cell, where water solubility is preferred. A further example of a prodrug could be a short peptide (polyamino acid) bound to an acid group in which the peptide is metabolized to release the active particle.

[0023] Throughout the present disclosure, when a specific compound is mentioned by name, for example oxybutynin, tolterodine or pilocarpine, it is understood that the scope of the present disclosure includes the pharmaceutically acceptable salts of the named compound. Also, if said compound contains a center of chirality, the scope of the present disclosure includes compositions comprising a racemic mixture of two enantiomers, as well as compositions individually containing each enantiomer, substantially free of the other enantiomer. Thus, for example, a composition comprising the S enantiomer substantially free of R enantiomer, or a composition comprising the R enantiomer substantially free of the S enantiomer is thus contemplated herein. By "substantially free" is meant that the composition contains less than 10% or less than 8%, or less than 5%, or less than 3%, or less than 1% of the minor enantiomer. If said compound contains more than one chiral center, the scope of the present disclosure also includes compositions containing a mixture of different diastereomers, as well as compositions containing each diastereomer, substantially free of other diastereomers. Thus, for example, commercially available oxybutynin is a racemic mixture containing two different enantiomers. "Oxybutynin", as mentioned throughout the present disclosure, includes compositions that comprise a racemic mixture of oxybutynin, compositions containing the (+) enantiomer substantially free of the (-) enantiomer, and compositions (-) enantiomer, substantially free of the (+) enantiomer. In addition, for example, commercially available pilocarpine, which is a naturally occurring alkaloid, contains two stereocenters. The scope of the present invention includes pharmaceutical compositions containing all four diastereomers, pharmaceutical compositions containing a racemic mixture of R, R and S, S isomers, pharmaceutical compositions

EP 1 933 833 B1 containing a racemic mixture of R, S and S, R isomers, pharmaceutical compositions containing the R, R enantiomer substantially free of other diastereomers, pharmaceutical compositions containing the R, R enantiomer substantially free of other diastereomers, pharmaceutical compositions containing the S, S enantiomer essentially free of other diastereomers, pharmaceutical compositions containing the R, S enantiomer substantially free of other diastereomers and pharmaceutical compositions containing the S, R enantiomer substantially free of other diastereomers.

[0024] In some embodiments, the present invention relates to a pharmaceutical composition comprising oxybutynin and pilocarpine for use in the treatment of overactive bladder. In other embodiments, the present invention relates to a pharmaceutical composition comprising tolterodine and pilocarpine for use in the treatment of overactive bladder.

[0025] Compounds useful for the compositions and methods described herein can be used in a variety of formulations. Certain formulations affect the rate at which the compound enters the patient's bloodstream. Thus, some formulations are immediate release formulations, while other formulations are delayed release, sustained release, or sustained release formulations.

[0026] Thus, in some embodiments, the first compound is in an immediate formulation, while in other embodiments, the first compound is in a delayed release formulation, and in still other embodiments, the first compound is in a sustained release formulation, and in further embodiments the first compound is in an extended release formulation. Thus, in some embodiments, the second compound is in an immediate release formulation, while in other embodiments, the second compound is in a delayed release formulation, and in still other embodiments, the second compound is in a sustained release formulation, and in further embodiments, the second the compound is in a sustained release formulation. In some embodiments, the third compound is in an immediate release formulation, while in other embodiments, the third compound is in a delayed release formulation, and in still other embodiments, the third compound is in a sustained formulation.

In a further embodiment, the third compound is in an extended release formulation.

[0027] The compositions described herein are particularly useful in alleviating the main side effects in the treatment of OAB, namely dry mouth and / or constipation, increasing tolerance and improving patient compliance while increasing the patient's quality of life.

[0028] A patient in need of the treatment disclosed herein is a patient who suffers from overactive bladder. The patient may also be a person who considers current overactive bladder therapies as unpleasant and / or side effects of therapy, such as dry mouth or constipation, to be unbearable enough to require adjuvant therapy to alleviate side effects. The patient may also be a person who is considering discontinuing overactive bladder therapy due to side effects of the therapy. In some embodiments, a patient who has recently been diagnosed with overactive bladder but has not yet received treatment is therefore a patient in need of the treatment methods and compositions disclosed herein. In these embodiments, the patient initiates therapy using the methods and combinations disclosed herein, such that the patient experiences no side effects or experiences less side effects.

[0029] In some embodiments, the patient may suffer from overactive bladder, bladder pressure, stress, and mixed incontinence.

[0030] It should be noted that taking simply commercially available pilocarpine HCl, e.g. Salagen® tablets or any other salivary gland stimulants in combination with OAB is not effective in alleviating the side effect - dry mouth. Some effective therapies correspond to the pharmacokinetic profile of pilocarpine with the pharmacokinetic profile of OAB agents, i.e. oxybutynin and tolterodine.

[0031] Thus, in some embodiments in the above methods, the first and second compounds are administered such that the peak plasma concentration of the first compound occurs almost at the same time after administration as the peak plasma concentration of the second compound. Thus, both compounds can be administered simultaneously, but they must be prepared in such a way that a delay in them

Release results in peak plasma concentrations occurring almost at the same time. In other embodiments, one compound is administered after a second compound to ensure that peak plasma concentrations occur at almost the same time.

[0032] In other embodiments of the above methods, the first and second compounds are administered in such a way that the time at which the smallest saliva flow occurs due to the first compound almost corresponds to the time when the greatest saliva flow occurs due to the second relationship. Thus, both compounds can be administered simultaneously, but they must be prepared in such a way that a delay in their release causes the peak moment of saliva flow for the second compound at almost the same time as the moment of the lowest saliva flow for the first compound. In other embodiments, one compound is administered at an interval after the other compound to ensure that the peak and lowest moments of saliva flow are consistent.

[0033] In some embodiments of the above methods, the first and second compounds are administered so that the ratio of their plasma concentrations at a given point in time after their administration has a predetermined value. The expert will recognize that the plasma concentration ratio need not necessarily be equivalent to the ratio of the amount of compound administered. The compounds undergo different digestion in the intestine, pass through the intestinal wall differently, and have a different rate of first pass metabolism through the liver. In addition, the renal clearance index is different for different compounds. Thus, for example, even if two compounds are administered in equivalent molar amounts, their plasma concentrations at some point in time after administration may be significantly different. The methods disclosed herein take into account the pharmacokinetics of drug intake and metabolism, such that the ratio of the two compounds at the time of administration is selected such that both compounds have a predefined ratio of plasma concentrations.

[0034] In yet other embodiments in the above methods, the first and second compounds are administered such that the moment of the maximum therapeutic effect of the compound that stimulates saliva flow corresponds to the moment of the maximum side effect of the therapeutic compound against OAB. Thus, both compounds can be administered simultaneously, but they must be prepared in such a way that the delay in

Their release causes the moment of maximum therapeutic effect of the second compound to occur at almost the same time as the maximum side effect of the first compound. In other embodiments, one of the compounds is administered after a second compound to ensure that the maximum therapeutic effect of the second compound occurs at almost the same time as the maximum side effect of the first compound.

[0035] In some embodiments, the dosage form is designed as such with sustained release of one agent with sustained release or immediate release of the other agent to ensure that peak plasma concentrations occur at almost the same time. Further dosage forms can be designed based on pharmacokinetic profiles in which the peak plasma concentration of one compound, e.g. salivary gland stimulant, e.g. pilocarpine, corresponds to the maximum amount of dry mouth caused by OAB, for example oxybutynin.

[0036] Thus, certain pharmaceutical compositions contemplated for use as disclosed herein include, but are not limited to:

immediate-release oxybutynin or tolterodine in combination with pilocarpine and tegaserod;

delayed (sustained or prolonged) release oxybutynin and delayed (sustained or prolonged) release pilocarpine;

delayed (sustained or sustained) release oxybutynin and delayed (sustained or sustained release) pilocarpine and sustained release teserodium;

immediate release (sustained or prolonged) oxybutynin or tolterodine and delayed (sustained or prolonged) release pilocarpine and tenserod;

delayed (sustained or prolonged) release oxybutynin or tolterodine and delayed (sustained or extended) release pilocarpine and sustained release tegaserod;

Delayed (sustained or sustained) release oxybutynin or tolterodine and delayed (sustained or sustained) release pilocarpine and immediate release tegaserod formulation.

[0037] Without being limited to a particular theory, the improved OAB treatment for dry mouth and constipation disclosed herein is based on consideration of individual phenomena and processes at the receptor level, i.e. counteract or abolish the negative effects of these muscarinic M2 / M3 antagonists with cholinergic agents that work in the opposite direction, but according to the intended therapy.

[0038] In addition to reducing the adverse side effects experienced by subjects treated from overactive bladder, the methods and compositions disclosed herein have additional advantages. Currently, the dose of therapeutic drugs such as oxybutynin is limited due to side effects. Some patients who suffer from overactive bladder cannot tolerate doses that provide adequate therapy because of negative side effects, such as dry mouth. These patients continue to suffer from overactive bladder even despite taking medication, only because the drug is not given in an effective dose. By reducing side effects using the methods and compositions disclosed herein, the patient may be prescribed to take drugs such as oxybutynin at higher doses. These higher doses result in less active bladder and also result in increased own bladder efficiency.

[0039] Thus, in another aspect, there is disclosed herein the use of a composition for increasing the intrinsic bladder capacity, comprising administering to a patient in need thereof a therapeutically effective amount of a first compound and a therapeutically effective amount of a second compound, wherein the first compound is an antimuscarinic or anticholinergic agent as described above and the second compound causes the stimulation of salivary glands as described above.

[0040] In another aspect, a pharmaceutical composition is disclosed comprising a combination of:

An antimuscarinic or anticholinergic agent as described herein and a compound that causes the stimulation of salivary glands as described herein;

an antimuscarinic or anticholinergic agent as described herein and a compound that alleviates constipation as described herein;

an antimuscarinic or anticholinergic agent, as described herein, a compound that causes stimulation of the salivary glands as described herein; and a compound that alleviates constipation as described herein; and a physiologically acceptable carrier, diluent or excipient or combination thereof.

[0041] The term "pharmaceutical composition" refers to a mixture of a compound of the invention with other chemical components, such as diluents, lubricants, caking agents, dispersants or carriers. The pharmaceutical composition facilitates the administration of the compound into the body. There are numerous techniques in the art for administering a compound, including but not limited to oral administration, injections, inhalations, aerosols, parenteral and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid and the like.

[0042] The term "carrier" defines a chemical compound that facilitates the introduction of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier because it facilitates the uptake of many organic compounds into the body's cells or tissues.

[0043] The term "diluent" defines chemical compounds diluted in water that will dissolve a given compound as well as stabilize the biologically active form of the compound. In the prior art, salts dissolved in buffer solutions are used as diluents. One commonly used buffer solution is phosphate buffered saline because it mimics the salt conditions of human blood. Because buffer salts can regulate

In low pH solutions, a buffered diluent rarely changes the biological activity of a compound.

[0044] In some embodiments, the same substance may act as a carrier, diluent or excipient, or may perform either of two roles or all of three roles. Thus, a single additive to a pharmaceutical composition can perform many functions.

[0045] The term "physiologically acceptable" defines a diluent that does not affect the biological activity and properties of the compound.

[0046] The pharmaceutical compositions described herein may be administered to a human patient alone or in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or with appropriate carriers or excipient (s). Techniques for preparing and administering compounds of the present application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th Edition, 1990.

[0047] Suitable routes of administration may, for example, include oral, transdermal, rectal, transmucosal or enteral administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as inhalations, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections.

[0048] Alternatively, the compound may be administered locally rather than systemically, for example by injecting the compound directly into the kidney or heart region, often in a delayed or sustained, sustained or delayed release formulation. In addition, the composition can be administered transdermally.

[0049] The pharmaceutical compositions of the present invention can be prepared in a manner known per se, e.g. by means of conventional mixing, dissolving, granulating, dragee-making, wet-milling, emulsifying, encapsulating, encapsulating or tableting processes.

[0050] Pharmaceutical compositions for use in the present invention can thus be manufactured in a conventional manner using one or more physiologically acceptable carriers including excipients and adjuvants that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The correct formulation depends on

EP 1 933 833 B1 selected the mode of administration and desired pharmacokinetic profiles of each component of the combination therapy. Any well known techniques, carriers and excipients may be used as appropriate and as known in the art; e.g. in Remington's Pharmaceutical Sciences, above.

[0051] For injection, the agents of the invention may be prepared in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer solution. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0052] For oral administration, the compounds can be easily prepared by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be prepared in the form of tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by the patient being treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with the pharmaceutical combination according to the invention, optionally by crushing the resulting mixture and processing the mixture into granules after adding suitable auxiliaries, if necessary, to obtain tablet or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, dispersing agents such as crosslinked polyvinylpyrrolidone, agar or alginic acid or their salts such as sodium alginate may be added.

[0053] Dragee cores have suitable coatings. To this end, concentrated sugar solutions may be added, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or tablet coatings

Dragees to identify or characterize different combinations of active compound doses.

[0054] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Capsules of pressed portions may contain active ingredients admixed with a filler such as lactose, binders such as starches and / or lubricants such as talc or magnesium stearate and optionally stabilizers. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids such as oils, liquid paraffin or liquid polyethylene glycols. In addition, stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.

[0055] For buccal administration, the compositions may take the form of tablets or lozenges prepared in conventional manner.

[0056] The compounds may also be prepared in rectal compositions such as suppositories or retention enemas.

[0057] Many of the compounds used in the pharmaceutical combinations of the invention can be provided in the form of salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be prepared from many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic and the like. Salts tend to dissolve more easily in aqueous or other protic solvents than the corresponding free acid or base forms.

[0058] Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount of the compound effective to prevent, alleviate or reduce the symptoms of the disease or extend the life of the subject being treated.

[0059] Typically, the dose range of the composition administered to the patient may be from about 0.5 to 1000 mg / kg of the patient's body weight. The dose may be a single dose or a series of two or more administered for one or several days as is

EP 1 933 833 B1 required by the patient. It is noted that for most of the specific compounds mentioned in the present disclosure, dosages for treatment in humans of at least some conditions have been established. For example, for oxybutynin and tolterodine, the preferred dose is between 0.1 mg and 50 mg, and the more preferred dose is between 1 mg and 30 mg. Other dose ranges include between 10 and 50 mg, between 20 and 50 mg, between 30 and 50 mg, between 40 and 50 mg, between 20 and 40 mg, between 10 and 20 mg, between 10 and 30 mg, between 20 and 30 mg and between 30 and 40 mg. The dose may also be 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. The preferred dose for pilocarpine is between 0.1 mg and 50 mg, and a more preferred dose is between 1 mg and 30 mg. Other dose ranges include between 10 and 50 mg, between 20 and 50 mg, between 30 and 50 mg, between 40 and 50 mg, between 20 and 40 mg and between 30 and 40 mg. The dose may also be 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. For tegaserod, the preferred dose is between 0.05 mg and 50 mg, and the more preferred dose is between 0.5 mg and 2 mg. Other dose ranges include between 10 and 50 mg, between 20 and 50 mg, between 30 and 50 mg, between 40 and 50 mg, between 20 and 40 mg, between 30 and 40 mg, between 0.5 and 1 mg and between 1 and and 2 mg. The dose may also be 0.5 mg, 1 mg, 1.5 mg and 2 mg.

[0060] Although the exact doses can be determined from the confrontation of the drugs, in most cases some generalizations regarding the dosage can be made. The daily adult dose may be, for example, an oral dose of between 0.001 mg and 1000 mg of each ingredient, preferably between 0.01 mg and 500 mg, for example from 1 to 200 mg, or each component of the pharmaceutical compositions of the present invention or a pharmaceutically-active acceptable salt, calculated as the free base or free acid, the composition being administered 1 to 4 times a day or weekly. Alternatively, the compositions of the invention may be administered on a continuous basis, such as via sustained, delayed or sustained release, preferably at a dose of each ingredient of up to 500 mg per day. Thus, the total daily oral dose of each component will typically be in the range of 0.1 mg to 200 mg. Suitable compounds will be administered over a period of continuous therapy, for example, for a day, a week or more, or for months or years.

[0061] In cases of local administration or selective uptake, effective local drug concentration may not be related to plasma concentration.

[0062] The amount of composition administered will, of course, depend on the subject being treated, the weight of the subject, the severity of the suffering, the method of administration and the evaluation of the prescribing physician.

Examples [0063] The following examples are non-limiting and are given only to illustrate the various aspects of the invention. The scope of the invention should therefore be determined by the appended claims.

Example 1: Combination of OAB and Salivary Gland Stimulant for

Treating a Subject with Overactive Bladder [0064] A subject with an overactive bladder is recognized. The subject is given 5 mg of oxybutynin two to four times a day, along with 5 mg of pilocarpine two to three times a day. If the individual continues to complain of dry mouth, the dose of pilocarpine is increased to 10 mg two to three times a day. The dose can be increased to 20 mg or 50 mg, if necessary. Each oxybutynin dose can be increased to 10, 15, 20 or 30 mg.

Comparative Example 2: Combination of OAB and Tegaserod for treatment

Subjects with Overactive Bladder [0065] Subjects with overactive bladder are recognized. The subject is given 5 mg of oxybutynin two to four times a day, along with 2 mg of tegaserod two to three times a day. If the subject continues to complain of dry mouth, the dose of tegaserod is increased to 6 mg twice a day. The dose can be increased to 12 mg, 20 mg or 50 mg as needed. The dose of oxybutynin can be increased to 10, 15, 20 or 30 mg.

Example 3: Summary of the Clinical Study Protocol [0066] A study is being conducted to evaluate the effect of oxybutynin and pilocarpine, alone and in combination, relative to placebo, on salivation in healthy volunteers. The aim of the study was to determine saliva flow and the degree of dry mouth after oral administration of oxybutynin and pilocarpine, alone and in combination compared with placebo, and to determine the effect of oxybutynin and pilocarpine, alone and in combination, on volume / lack of urine and signs of life.

EP 1 933 833 B1 [0067] After each treatment period, after overnight fasting, subjects reported to the clinic and after initial tests were randomly assigned to one of four drugs • Oxybutynin (5 mg) and then after 30 minutes of placebo • Pilocarpine (5 mg) and then after 30 minutes of placebo • Placebo and then after 30 minutes of placebo • Oxybutynin (5 mg) followed by pilocarpine (5 mg) after 30 minutes [0068] The following measurements were taken immediately after and at regular intervals up to 6 hours after dosing:

o Saliva flow was determined by chewing Parafilm foil for 2 minutes. o Mouth dryness was determined by VAS. Volume / lack of urine was measured every 6 hours after dosing. Blood samples were taken for pharmacokinetics before dosing and 0.5, 1, 2, 3, 4 and 6 hours after dosing o Food and water intake were standardized after a period of 6 hours [0069] The study is a double-blind, randomized, placebo-controlled trial with 4 sequences (4 doses every 4 weeks), and the drug is administered orally as a single dose. There was a one-week recovery period between study days. The study population was selected as follows:

• Healthy volunteers • 12 individuals • men or women who are not pregnant> 18 • Weight 18-28 BMI • No known allergy to antimuscarinic drugs • No previous history of glaucoma, urinary retention, cardiac arrhythmias • No treatment with OTC, nutraceuticals or vitamins during 10 days before the examination and during the examination

[0070] Assessments (except for urine production) are carried out: 0.5 h and 10 minutes before dose, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 and 6 hours after dose . The following are assessed:

1) Stimulated saliva flow

2) Dry mouth (VAS)

3) Volume / lack of urine within 6 hours after dosing

4) Pharmacokinetics of oxybutynin and pilocarpine [0071] Standard precautions are taken such as physical examination, medical history, concurrent medications, ECG, hematology, clinical chemistry, urinalysis performed as monitoring and at the end of the study, monitoring of drug / alcohol content in urine before giving the dose in each period, signs of life (pulse and blood pressure) before dosing and at 30-minute intervals for 6 hours, and disclosure of adverse events throughout the period and between the study period.

Example 4: Case Study Combination of Oxybutynin and Pilocarpine [0072] In this study, the effects of oxybutynin, pilocarpine, a combination of both and placebo were measured in six separate but identical studies in a single individual.

[0073] Effect of Oxybutynin - A healthy human subject was given a 5 mg dose of oxybutynin HCl and the amount of saliva was measured over a period of 8 hours. As shown in Figure 1 (♦, rhombus), the amount of saliva flow collected over a 2-minute period decreased after oxybutynin dosing and saliva flow remained low after 3 hours. The amount of saliva flow began to increase after 3 hours and continued to approach the pre-dose level after 8 hours after dosing. The data obtained in this study are consistent with the literature data.

[0074] Effect of Pilocarpine - A separate human study evaluated the effect of pilocarpine HCl on a healthy human individual to make sure that pilocarpine actually increases salivary gland discharge. This was shown as shown in Fig. 1 (, square). The amount of saliva collected over a 2-minute period increased rapidly after dosing, and saliva flow began to decrease after the peak observed after

EP 1 933 833 B1 half an hour. The decrease in saliva flow continued until it reached normal pre-dosing saliva level after about 5 hours.

[0075] Effect of Placebo - in the third branch of the human study, the effect of placebo was estimated. Because this was not a blank test, saliva flow was measured not by using any drug or real placebo, but according to the same protocol as in other studies. As shown in Figure 1 (A, triangle), the change in saliva flow over time is minimal and the average saliva flow is about 2g / 2 min, according to published literature.

[0076] Effect of Combination of Oxybutynin and Pilocarpine - In a separate human study a combination of oxybutynin and pilocarpine was administered to a healthy human individual. The subject was given 5 mg of oxybutynin followed by 5 mg of pilocarpine 30 minutes after dosing. Saliva flow was measured as before. The results are shown in Figure 1 (•, circle).

[0077] As shown in Figure 1, the decrease in salivary flow caused by oxybutynin was well compensated by the increase in salivary flow caused by pilocarpine. As a result, the amount of saliva flow remained approximately the same as the pre-dosing level. Figure 1 further shows that the amount of salivary flow measured for the combination studies was similar to the placebo studies. Thus, administration of 5 mg pilocarpine half an hour after administration of 5 mg oxybutynin completely neutralized the harmful side effect of oxybutynin.

[0078] The percent change in salivary flow from baseline after administration of pilocarpine, oxybutynin, a combination of pilocarpine and oxybutynin (where pilocarpine was administered 30 min after oxybutynin) and placebo were plotted versus time and is shown in Figure 2. The percentage change for combination studies in which pilocarpine was given 30 min after oxybutynin (•, circle) is minimal and does not differ significantly from baseline or placebo (A, triangle), suggesting that the combined approach eliminates the main side effect of OAB therapy .

[0079] Effect of Pilocarpine Administration Time Relative to Oxybutynin Administration - In two additional human studies, the effect of the duration of pilocarpine administration was measured. In one study, a combination of oxybutynin and pilocarpine was administered to a healthy human subject. The patient was administered 5 mg of oxybutynin and 5 mg of pilocarpine simultaneously. Saliva flow was measured as before. Results

EP 1 933 833 B1 is shown in Fig. 3 (, square). In a recent study, a combination of oxybutynin and pilocarpine was administered to a healthy human individual. The subject was given 5 mg of oxybutynin followed by 5 mg of pilocarpine 60 minutes after dosing. Saliva flow was measured as before. The results are shown in Figure 3 (♦, diamond).

[0080] Fig. 3 shows the effect of time delay in pilocarpine administration. All studies were compared with placebo (▲, triangle). When oxybutynin and pilocarpine were administered at the same time (, square), there is then an initial large increase in saliva flow, which reaches a maximum in time from about t = 30 min to less than t = 60 min, but then the normal level (placebo) decreases more for t = 1 h and remains at this level. When pilocarpine is given 60 minutes after oxybutynin (♦, rhombus), there is a sudden decrease in saliva flow, which occurs to about t = 1 h, followed by a significant increase in saliva flow, with a maximum for t = about 3 h. Saliva flow returned to normal (placebo) for t = about 5 h. However, when pilocarpine was given 30 minutes after oxybutynin (•, circle), there is a slight decrease in saliva flow with a minimum for t = about 30 min, but it returns to normal in an hour ( placebo).

[0081] Effect of Dose Ratio Between Oxybutynin and Pilocarpine - In this experiment, the results of two separate dose ratios between oxybutynin and pilocarpine were compared with those of placebo and oxybutynin alone. In one experiment, a healthy individual was given 5 mg of oxybutynin and saliva flow was measured after 8 hours. The results are shown in Figure 4 (♦, diamond). Using a similar protocol, 5 mg oxybutynin was administered to a healthy individual at t = 0, followed by 5 mg pilocarpine for t = 30 min. The results are shown in Figure 4 (•, circle). Similarly, 10 mg oxybutynin was administered to a healthy individual at t = 0, followed by 5 mg pilocarpine for t = 30 min. The results are shown in Figure 4 (-, line). Finally, the results were compared with the administration of placebo (Fig. 4 (A, triangle)).

[0082] The results shown in Figure 4 suggest that increasing oxybutynin from 5 to 10 mg leads to an increase in salivation. An increase in the ratio from 1: 1 to 2: 1 disturbs the balance between reducing saliva secretion by oxybutynin and increasing saliva secretion by pilocarpine, respectively. It is noted that saliva flow for an oxybutynin: pilocarpine ratio of 2: 1 is similar to that of single 5 mg oxybutynin, suggesting that 5 mg of pilocarpine in

In this experiment, it is not sufficient to compensate for the decrease in salivary flow caused by increasing the amount of oxybutynin from 5 to 10 mg. Thus, an effective dose ratio for a combination of oxybutynin and pilocarpine occurs when a patient is given 5 mg of each.

[0083] Oxybutynin Plasma Concentration - In a separate study, oxybutynin plasma concentration was measured in two groups of individuals: one group received only 5 mg oxybutynin and the other group received 5 mg oxybutynin followed by 5 mg pilocarpine after 30 minutes. Plasma levels were measured before oxybutynin and 1, 2, 3, 4 and 6 hours after administration. The results are shown in Tables 1 and 2 below. Table 1 shows plasma oxybutynin levels after administration of only 5 mg oxybutynin in a placebo-controlled, blind, four-stage resultant clinical trial on 12 male subjects. Table 2 shows plasma oxybutynin levels after administration of 5 mg oxybutynin, followed by administration of 5 mg pilocarpine 30 minutes after administration of oxybutynin in a placebo-controlled, blind, four-stage resultant clinical trial on 12 male subjects.

Table 1

<td rowspan="2"></td><td colspan="6">Oxybutynin Plasma Level (ng / mL)</td>

<td colspan="6">Time (in Hours) after Oxybutynin administration</td>

<td>Individual Number</td><td> 0</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td> 1</td><td> 0,000</td><td> 0,980</td><td> 1,760</td><td> 1,620</td><td> 0,869</td><td> 0,786</td>

<td> 2</td><td> 0,000</td><td> 5,380</td><td> 2,910</td><td> 2,410</td><td> 1,490</td><td> 1,150</td>

<td> 3</td><td> 0,000</td><td> 9,840</td><td> 3,870</td><td> 2,320</td><td> 1,840</td><td> 1,150</td>

<td> 4</td><td> 0,120</td><td> 3,250</td><td> 1,990</td><td> 1,270</td><td> 1,070</td><td> 0,783</td>

<td> 5</td><td> 0,020</td><td> 16,000</td><td> 9,260</td><td> 3,920</td><td> 4,690</td><td> 1,900</td>

<td> 6</td><td> 0,000</td><td> 2,600</td><td> 1,400</td><td> 1,230</td><td> 1,140</td><td> 1,330</td>

<td> 7</td><td> 0,000</td><td> 15,420</td><td> 6,110</td><td> 2,700</td><td> 2,390</td><td> 0,650</td>

<td> 8</td><td> 0,000</td><td> 7,600</td><td> 2,890</td><td> 1,530</td><td> 0,010</td><td> 0,000</td>

<td> 9</td><td> 0,000</td><td> 3,910</td><td> 2,580</td><td> 0,440</td><td> 0,210</td><td> 0,190</td>

<td> 10</td><td> 0,000</td><td> 7,230</td><td> 3,120</td><td> 1,330</td><td> 0,880</td><td> 0,190</td>

<td> 11</td><td> 0,000</td><td> 4,900</td><td> 1,820</td><td> 0,970</td><td> 0,340</td><td> 0,560</td>

<td> 12</td><td> 0,000</td><td> 3,200</td><td> 1,520</td><td> 0,790</td><td> 0,230</td><td> 0,000</td>

EP 1 933 833 B1

<td rowspan="2"></td><td colspan="6">Oxybutynin Plasma Level (ng / mL)</td>

<td colspan="6">Time (in Hours) after Oxybutynin administration</td>

<td>Individual Number</td><td> 0</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td>Average</td><td> 0,012</td><td> 6,693</td><td> 3,269</td><td> 1,711</td><td> 1,263</td><td> 0,724</td>

<td>Standard deviation</td><td> 0,034597</td><td> 4,861029</td><td> 2,289476</td><td> 0,969634</td><td> 1,291618</td><td> 0,585548</td>

Table 2

<td rowspan="2"></td><td colspan="6">Oxybutynin Plasma Level (ng / mL)</td>

<td colspan="2">Time in</td><td colspan="4">Hours) after administration of Oxybutynin</td>

<td>Individual Number</td><td> 0</td><td> 1</td><td> 2</td><td> 3</td><td> 4</td><td> 6</td>

<td> 1</td><td> 0,000</td><td> 1,830</td><td> 1,380</td><td> 0,980</td><td> 0,977</td><td> 0,740</td>

<td> 2</td><td> 0,000</td><td> 5,260</td><td> 2,490</td><td> 1,220</td><td> 1,820</td><td> 1,100</td>

<td> 3</td><td> 0,000</td><td> 1,720</td><td> 2,120</td><td> 6,920</td><td> 5,150</td><td> 3,100</td>

<td> 4</td><td> 0,020</td><td> 3,080</td><td> 2,790</td><td> 2,230</td><td> 1,460</td><td> 0,150</td>

<td> 5</td><td> 0,000</td><td> 14,600</td><td> 6,580</td><td> 2,550</td><td> 5,010</td><td> 1,580</td>

<td> 6</td><td> 0,000</td><td> 2,750</td><td> 1,690</td><td> 1,280</td><td> 1,020</td><td> 0,000</td>

<td> 7</td><td> 0,000</td><td> 20,800</td><td> 11,100</td><td> 5,310</td><td> 3,060</td><td> 2,110</td>

<td> 8</td><td> 0,000</td><td> 1,180</td><td> 0,470</td><td> 0,230</td><td> 0,270</td><td> 0,000</td>

<td> 9</td><td> 0,000</td><td> 8,580</td><td> 2,920</td><td> 1,410</td><td> 0,940</td><td> 0,550</td>

<td> 10</td><td> 0,000</td><td> 9,200</td><td> 3,650</td><td> 1,870</td><td> 1,110</td><td> 0,340</td>

<td> 11</td><td> 0,000</td><td> 7,490</td><td> 1,710</td><td> 1,340</td><td> 0,600</td><td> 0,680</td>

<td> 12</td><td> 0,000</td><td> 3,480</td><td> 1,520</td><td> 0,930</td><td> 0,560</td><td> 0,260</td>

<td>Average</td><td> 0,001538</td><td> 6,228462</td><td> 3,109231</td><td> 2,251538</td><td> 1,998231</td><td> 1,277692</td>

<td>Standard deviation</td><td> 0</td><td> 5,967714</td><td> 2,92391</td><td> 1,961773</td><td> 1,67978</td><td> 0,948956</td>

[0084] As can be seen from the tables, in both groups, oxybutynin plasma concentrations reach a maximum after about an hour, followed by a gradual decrease. In addition, plasma oxybutynin concentration has the same curve for both groups. Thus, the addition of 5 mg pilocarpine does not affect the plasma oxybutynin concentration at all. There are two conclusions from these observations. First, pilocarpine does not affect the absorption of oxybutynin in the intestine, nor does it affect the first pass metabolism of pilocarpine in the liver. Secondly, pilocarpine does not affect

The ability to bind oxybutynin because the concentration of free oxybutynin in the eye os is the same between the two groups. In addition, the presence of pilocarpine in combination does not interfere with the pharmacokinetics of oxybutynin. Thus, the anti-muscarinic activity of oxybutynin responsible for the therapeutic effect of oxybutynin on OAB remains unaffected.

Example 5: Case Study for a Combination of Oxybutynin and Cevimeline (Example

Comparative) [0085] In this study, the effects of oxybutynin, cevimeline, their combination and placebo were measured in separate individual studies.

[0086] Effect of Oxybutynin - A healthy subject was given a 5 mg dose of oxybutynin HCl and the amount of saliva secreted was measured over a period of 8 hours. As shown in Figure 5 (•, circle), the amount of saliva secreted in 2-minute periods decreased to dosing and saliva flow remained low for 3 hours. The amount of saliva started to increase after 3 hours. and continued to rise to pre-dose levels after 8 hours. after dosing. The data obtained in this study are consistent with the literature data.

[0087] Effects of Cevimeline - In a separate human study, the effect of administering 30 mg of cevimeline on a healthy individual was assessed to see if cevimeline actually increases the outflow of salivary glands. The results are shown in Figure 5 (♦, diamond). The amount of saliva collected in 2-minute periods increased rapidly after dosing and saliva flow began to decrease after the peak observed after about two hours. The decrease in saliva flow continued until about the normal level of pre-dosing saliva was reached after about 6 hours.

[0088] Impact of Placebo - in the third branch of the human study, the effect of placebo was estimated. Because this was not a blank test, saliva flow was measured not by using any drug or real placebo, but according to the same protocol as in other studies. As shown in Figure 5 (A, triangle), the change in saliva flow over time is minimal and the average saliva flow is about 2.5 g / 2 min, according to published literature.

[0089] Effect of the Combination of Oxybutynin and Cevimeline - In a separate human study a combination of oxybutynin and

Cevimeline EP 1 933 833 B1. The subject was given 5 mg of oxybutynin followed by 30 mg of cevimeline simultaneously without any time delay. Saliva flow was measured as before. The results are shown in Figure 5 (square) in which no combination was specified as THVD-102.

[0090] The results of the above experiments are also presented in Table 3 below, which presents data estimating the effect of the combination of oxybutynin and cevimeline on stimulated saliva flow. Fig. 5 is a graphic illustration of the data shown in Table 3.

Table 3

<td>Center</td><td>cevimeline</td><td>Cev + Oxy</td><td>oxybutynin</td><td>Placebo</td>

<td>Oxybutynin, mg</td><td> 0</td><td> 5</td><td> 5</td><td> 0</td>

<td>Cevimeline, mg</td><td> 30</td><td> 30</td><td> 0</td><td> 0</td>

<td>Time (hours)</td><td colspan="2">Amount of Saliva Collected for 2 min</td><td colspan="2">Amount of Saliva Collected for 2 min</td>

<td> -0,17</td><td> 2,4808</td><td> 2,862</td><td> 2,2208</td><td> 1,7143</td>

<td> 0</td><td> 2,6273</td><td> 2,9442</td><td> 2,4536</td><td> 1,4786</td>

<td> 0,5</td><td> 2,7791</td><td> 2,3742</td><td> 1,8558</td><td> 1,959</td>

<td> 1</td><td> 4,1213</td><td> 2,4091</td><td> 1,2308</td><td> 2,0143</td>

<td> 1,5</td><td> 4,6029</td><td> 3,0437</td><td> 1,2326</td><td> 1,9861</td>

<td> 2</td><td> 3,7314</td><td> 2,2793</td><td> 1,3548</td><td> 2,0671</td>

<td> 2,5</td><td> 3,7641</td><td> 2,4445</td><td>Well*</td><td>Well</td>

<td> 3</td><td> 3,5888</td><td> 2,0601</td><td> 1,1829</td><td> 1,6538</td>

<td> 3,5</td><td> 3,9316</td><td> 2,5827</td><td>Well</td><td>Well</td>

<td> 4</td><td> 3,5914</td><td> 2,4358</td><td> 1,5868</td><td> 1,9866</td>

<td> 5</td><td> 2,6099</td><td> 2,312</td><td> 2,1475</td><td> 1,8417</td>

<td> 6</td><td> 2,205</td><td> 2,4915</td><td> 2,0096</td><td> 2,3332</td>

<td> 8</td><td> 1,7973</td><td> 2,4158</td><td> 2,3028</td><td> 2,0182</td>

<td colspan="5">*: Not marked</td>

[0091] As shown in Figure 5, the decrease in salivary flow caused by oxybutynin was well compensated by the increase in salivary flow caused by cevimeline. As a result, the amount of saliva flow remained approximately the same as the pre-dosing level. Fig. 5 further shows that the amount of saliva flow measured for the combination study was similar to the study

Placebo. Thus, administration of 30 mg cevimeline simultaneously with 5 mg oxybutynin completely neutralized the harmful side effect of oxybutynin.

Example 6: Case Study for Combination of Tolterodine and Pilocarpine [0092] In this study, the effects of tolterodine, pilocarpine, their combination and placebo were measured in separate but identical studies in a single individual.

[0093] Effect of Tolterodine - A healthy individual was given a 2 mg dose of tolterodine tartrate and the amount of saliva secreted was measured over a period of 8 hours. As shown in Figures 6 and 7 (♦, rhombus), the amount of saliva secreted in 2-minute periods decreased to dosing and saliva flow remained low for 3 hours. The amount of saliva secreted began to increase after about 4 hours. and continued to increase, but did not fully reach pre-dose levels even after 8 hours. after dosing.

[0094] Effect of Pilocarpine - The effect of administering pilocarpine individually has been studied and the data are presented above.

[0095] Impact of Placebo - in another branch of the human study the effect of placebo was estimated. Because this was not a blank test, saliva flow was measured not by using any drug or real placebo, but according to the same protocol as in other studies. As shown in Figures 6 and 7 (•, closed circle), the change in saliva flow over time is minimal and the average saliva flow is about 2.5 g / 2 min, according to published literature.

[0096] Effect of Dose Ratio Between Tolterodine and Pilocarpine - In this experiment, the results of two separate dose ratios between tolterodine and pilocarpine were compared with the results of placebo and single dose administration of tolterodine. In one experiment, 2 mg tolterodine was administered to a healthy individual and saliva flow was measured after 8 hours. The results are shown in Figure 6 (♦, diamond). Using a similar protocol, a healthy individual was given 2 mg of tolterodine at t = 0, followed by 5 mg of pilocarpine for t = 30 min. The results are shown in Figure 6 (A, closed triangle). Similarly, 2 mg tolterodine was administered to a healthy individual at t = 0, followed by 10 mg pilocarpine for t = 30 min. The results are shown in Figure 6 (s, open circle). Finally, the results were compared with the administration of placebo (Fig. 6 (•, closed circle)). The results shown in Figure 6 suggest that increase

Pilocarpine from 5 to 10 mg leads to a decrease in salivation. Decreasing the ratio from 2: 5 to 2: 1 (tolterodine: pilocarpine) restores the balance between reducing salivation by tolterodine and increasing salivation by pilocarpine, respectively. It is noted that saliva flow for tolterodine: pilocarpine ratio of 2: 5 is similar to that of single 2 mg tolterodine, suggesting that the 5 mg amount of pilocarpine in this experiment is not sufficient to compensate for the decrease in saliva flow caused by 2 mg tolterodine. Thus, an effective dose ratio for a combination of oxybutynin and pilocarpine occurs when 2 mg tolterodine is combined with 10 mg pilocarpine.

[0097] Effect of Combination of Tolterodine and Pilocarpine - In a separate study in a human subject a combination of tolterodine and pilocarpine was administered to a healthy individual. The subject was given 2 mg of tolterodine followed by 10 mg of pilocarpine with various time delays in the administration of pilocarpine. Saliva flow was measured as before. The results are shown in Figure 7.

[0098] In one study, 10 mg pilocarpine was administered to a subject 15 minutes after administration of 2 mg tolterodine. Saliva flow was measured as before. The results are shown in Figure 7 (Δ, open triangle). In the second study, 10 mg pilocarpine was administered to the subject 22 minutes after administration of 2 mg tolterodine. Saliva flow was measured as before. The results are shown in Figure 7 (□, open square). In a recent study, 10 mg pilocarpine was administered to the subject 30 minutes after administration of 2 mg tolterodine. Saliva flow was measured as before. The results are shown in Figure 7 (o, open circle).

[0099] As shown in Fig. 7, the decrease in salivary flow caused by tolterodine was well compensated by the increase in salivary flow caused by pilocarpine. As a result, the amount of saliva flow remained approximately the same as before dosing when pilocarpine was administered 22 minutes after administration of tolterodine. Figure 7 further shows that the amount of saliva flow measured for the combination study with 22 minutes delay for pilocarpine was similar to the placebo study. Thus, administration of 10 mg pilocarpine 22 minutes after administration of 2 mg tolterodine completely neutralized the harmful side effect of oxybutynin.

[0100] Given that the highest doses are not tolerated due to the severity of dry mouth, the disclosed approach allows the administration of larger

Doses of oxybutynin or tolterodine, which results in better tolerated, effective and cost-effective treatment.

EP 1 933 833 B1