MX2008002907A - Therapy for the treatment of disease - Google Patents

Abstract

Disclosed herein are pharmaceutical compositions comprising various combinations of an antimuscarinic or an anticholinergic agent, a compound that causes stimulation of salivary glands, and a compound that relieves constipation. Also disclosed are methods of treating a patient suffering from overactive bladder comprising administering to the patient the above pharmaceutical composition.

Description

THERAPY FOR DISEASE TREATMENT So L ci ucl k < t 1? _L_i ouaaa Esta ^ ciiciiu? "Proclamation of the Provisional Application of US Patent Number Series 60 / 714,150, filed on September 2, 2005, by Mehdi Paborj, and entitled" THERAPY FOR THE TREATMENT OF DISEASE ", which is hereby incorporated by reference in its whole. Background of the Invention Field of the Invention The present invention is in the field of composing pharmaceutical clones and methods for using them for the treatment of overactive ve iga and reduction of its side effects. Description of the Related Art Overactive bladder (OAB = Overactive B) adder) is characterized by involuntary contractions of the detrusor muscle during bladder filling These contractions may be asymptomatic or they may cause the three common symptoms that clinically define OAB: frequency of urine; urgency; and urgency or reflex incontinence. The frequency is an increase in the number of urinations to as many as 8 or more per day. Urgency is the strong and sudden desire to urinate. The urgency incontinence, or reflex incontinence, is the situation in which Hnnicia can not be controlled by PL mar Noctupa, or nocturnal urinary frequency that disturbs sleep (more than twice per night), is often included as a fourth symptom The symptoms of OAB can appear individually or together, and it is not known if they have a pathological or neurogenic cause. Incontinence is present in more than half of the female patients with OAB. This condition affects more than 33 million Americans and imposes considerable economic, social and psychological burdens. Although continuing research into the pharmacological administration of lower urinary tract disorders has led to alternative treatment options, OAB symptoms are generally under-reported by patients and sub-treated by health care professionals. Several classes of medications have been used to treat and manage OAB, including calcium channel blockers, tricyclic antidepressants, alpha-adrenergic antagonists, estrogen, and anti-cholelgic agents. Anticholmergic agents that exert their effects on muscarinic receptors and suppress the intensity of involuntary detmsor muscle contractions, are the pharmacotherapy of first choice for OAB, and may be the only available therapy of which there is no doubt in the efficacy Oxybutynin chloride and tolterodm tartrate are the most extensively studied and widely used anticolmergic agents A systematic review based on recent evidence from controlled clinical trials of several agents, concludes that anticholinergic therapies significantly improve several indices of lower urinary tract function, including frequency of emission and number of episodes of incontinence. A major limitation of these agents is that they lack specificity for bladder tissue with resulting bothersome side effects such as dry mouth and constipation. Tolterodine has generally been associated with less dry mouth than oxybutynin. This property is considered to be due to the decreased selectivity of the tolterodm by any of the 5 muscarinic receptor subtypes (M1-M5), such as the M3 receptor that predominates in the parotid tissue. Oxybutynin, more than tolterodine, has high affinity for this receptor, which also mediates bladder contraction. It has been argued based on data in animals, that the tolterodm has greater selectivity than the oxybutinium bladder than for parotid muscarinic receptors, but this mechanism remains to be elucidated Effects on M2 receptors that populate the smooth muscle of the bladder although it is not glandular tissue, and for which tolterodine shows greater affinity than oxybutynin, has also been invoked to explain the slightly lower degree of relative dry mouth that is associated with the therapeutic effect of tolterodma. Additional reports that the superior extent or proportion of dry mouth with oxybutynin are attributed to the formation of the major metabolite, desethyloxybutynin, which appears to have a higher affinity for M3 subtype receptors, also expressed in the salivary glands However, the most recent prolonged release formulations of oxybutynin and tolterodine, provide improved efficacy and tolerability and comparable or slightly better efficacy, in comparison with immediate release formulations. More recently approved agents including trospium chloride, solfenacma succmate (Vesicare) and dapfenacin (Enablex) appear to have a better side effect profile, ie slightly less mouth However, the dry mouth and constipation continue to be problematic and the patients were to take the medication after a short period of therapy. Thus, there is a need in the art for a drug that provides sufficient efficacy for the treatment of OAB, with a very low level of side effects in order to increase compliance comfort and effectiveness with patients. COMPENDIUM OF THE INVENTION Here pharmaceutical compositions are described 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 agent or an anticolmeric agent and the second compound causes stimulation of the salivary glands. Also described herein are pharmaceutical compositions comprising a therapeutically effective amount of a first compound and a therapeutically effective amount of a second compound. where, the first compound is an antimuscarinic agent or an anticolmergic agent and the second compound alleviates constipation. describe pharmaceutical compositions comprising a therapeutically effective amount of a first compound, a therapeutically effective amount of a second compound and a therapeutically effective amount of a third compound, wherein the first compound is an antimuscarolytic agent or an anticolmergic agent, the second compound causes stimulation of the salivary glands and the third compound alleviates constipation Here methods for treating a patient, 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, are described. wherein the first compound is an antimuscarinic agent or an anticolmergic agent and the second compound causes stimulation of the salivary glands. Also described herein are methods for treating a patient that comprise 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 and the second compound causes stimulation of the glands In addition, methods for treating a patient comprising administering to a patient in need thereof, a therapeutically effective amount of a first compound, a therapeutically effective amount of a second compound and a therapeutically effective amount of a third compound, are described herein. where the first compound is an antimuscarinic agent or an anticholinergic, the second compound causes stimulation of the salivary glands and the third compound relieves constipation BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the amount of saliva flow collected in a human subject, subsequent to the administration of oxybutynin (, diamond), pilocarpine (, square), both (•, circle), and none (, triangle). Figure 2 is a graph showing the percent of saliva flow with reference to time zero. Figure 3 is a graph showing the effect of time delay for the administration of pilocarpine with oxybutmma which is administered at t = 0 for all experiments, except for placebo (, triangle) where there is no oxybutynin and pilocarpma is administered at - 0 (, square), t = 30 min (•, circle), and t = 60 min (, diamond) Figure 4 is a graph showing the effect of different dose proportions between oxybutynin and pilocarpma in the saliva flow Figure 5 is a graph showing the comparison of stimulated saliva output, after oral administration of oxybutynin 5 mg (•, circle), cevimelma 30 mg (, diamond), placebo (, triangle), and combination of oxybutyn and cevimelm (THVD-102) (, square) Figure 6 is a graph showing the comparison of stimulated saliva output, after oral administration of 2 mg of tolterodm tartrate, with various combinations of (2 mg of tolterodm / 5 mg of pilocarpine and 2 mg of tolterodm / 10 mg of pilocarpm, with pilocarp which is administered at different times), and placebo . Figure 7 is a graph showing the administration rate in time of 10 mg of pilocarpm in saliva output stimulated after oral administration of 2 mg of tolterodine tartrate. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES The main limitations of treatment of overactive bladder (OAB) are the side effects of dry mouth and constipation The current approach to resolve dry mouth is the development of sustained release of the active portion, such as oxybutynin or tolterodine patients taking OAB drugs still suffer from these side effects and in this way their quality of life is affected significantly in the proportion that most patients discontinue medications after approximately 4 or 6 months. Thus, in the 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 agent or an anticolmergic agent. and the second compound causes stimulation of the salivary glands. The first compound of the pharmaceutical compositions described herein is a compound useful in the treatment of overactive bladder. In some embodiments, the first compound is an M2 or M3 muscarinic receptor agonist. In additional embodiments, the first compound can be selected of the group consisting of oxybutynin, tolterodine, solifenacin, darifenacin, trospium, fesoterodine or its pharmaceutically acceptable salt or prodrug. Other compounds now known or further developed for the treatment of OAB are within the scope of the present disclosure. In some embodiments, the first compound is a compound of Formula I or its pharmaceutically acceptable salt or prodrug, wherein: R-L-R9 each independently is selected from the group consisting of hydrogen, alkyl, nitro, amino, cyano, hydroxy, alkoxy, carboxylate, and amide; and m and n, each independently are chosen from 1, 2, 3, 4, and 5. In some embodiments, each of Rx and R2 is independently chosen from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy In certain embodiments, each R and R2 is hydrogen. In some embodiments, R is selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R3 is hydroxy. In some embodiments, R4 and R5 each independently are selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R, and R5 each independently are an alkyl. In further embodiments, R4 and R5 each independently is selected from the group consisting of methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl. In other embodiments, R4 and R5 each are independently ethyl. In some embodiments, R6-R9 each independently are selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R6-R9 each independently is a hydrogen. In some embodiments, the first compound is oxybutynin, or its pharmaceutically acceptable salt or prodrug. Oxybutynin is the active ingredient found in drugs such as Ditropan®; Ditropan XL®; and Oxytrol®. The Oxybutynin is an anticolmergic drug, which in this way suppresses involuntary contractions of the smooth muscle of the bladder. Oxybutynin is also considered to have a muscarinic receptor activity, which further improves its effectiveness for OAB, but may also be the reason behind its more predominant, which is dry mouth In some embodiments, the first compound is tolterodine, or its pharmaceutically acceptable salt or prodrug Tolterodine, which has the chemical name acid (R) -2- [3- [bis (1-methylethyl-amino ] -1-phenylpropyl] -4-methy1fenol [R- (R *, R *)] -2,3-dihydroxybutandionic, is a muscarinic receptor antagonist and is the active ingredient found in drugs such as Detrol® ( as tolterodine tartrate.) In another embodiment, the first compound is the 5-h? drox? met? l derivative of tolterodine The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to a organism to which it is administered and does not abrogate the biological activities and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succinic acid, tartaric acid, methanesulfonic acid, eiansulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. 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, an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt such as calcium or magnesium salt, a salt of organic bases such dicyclohexylamine , N-methyl-D-glucamine, tris (hydroxymethyl) methylamma, and its salts with amino acids such as argimna, lysine and the like. Through the present disclosure, when a particular compound is named, it is understood that the name refers to both the free base or free acid, of the compound and its pharmaceutically acceptable salts. In this way, for example, the scope of the term "tolterodm" covers both the toterodm free base, ie, acid (R) -2- [3- [bis (1-methyl-ethyl-aryl] -1-phenylpropyl] - 4-methylphenol [R- (R *, R *)] -2,3-dihydroxybutadiene, and its various pharmaceutically acceptable salts, for example tolterodine tartrate.

A "piodroga" refers to an agent that becomes a prsor drug 111 vi Pro-drugs are often useful because in some situations, they may be easier to administer than the prsor drug. They may, for example, be bioavailable by administration. oral, while the prsor does not. The prodrug may also have improved solubility in pharmaceutical compositions against the prsor drug, or may demonstrate increased taste on the palate or be easier to formulate. An example, without limitation, of a prodioga shall be a compound of the present invention which is administered as an ester (the "prodrug") to facilitate transmission through a cell membrane wherein the solubility in water is harmful to mobility but which is then hydrolyzed metabolically to the carboxylic acid, the active entity, once Within the cell where water solubility is beneficial An additional example of a prodrug may be a short peptide gone (polyammo acid) linked to an acid group where the peptide is metabolized to deliver the active portion In some embodiments, the second compound is a cholinergic agonist In certain embodiments, the second compound is selected from the group consisting of pilocaipma, cevimelin and amifostma (the latter agent is chemically known as dihiclrogen phosphate (ester) of 2 - [(3-aminopropyl) to mo] ethantiol), or its salt or prodrug pharmaceutically acceptable In additional embodiments, the second compound is pilocarp, or its pharmaceutically acceptable salt or prodrug. In other embodiments, the second compound is cevimelm, or its pharmaceutically acceptable salt or prodrug. In some embodiments, the second compound is a compound of Formula II R, or its pharmaceutically acceptable salt or prodrug, wherein R x - R g each is independently selected from the group consisting of hydrogen, alkyl, nitro, amino, cyano, hydroxy, alkoxy, carboxylate, and amide.

In some embodiments, R x and R 2 each is independently selected from the group consisting of hydrogen, alkyl, hydroxyl, and alkoxy. In certain embodiments, R and R2 each independently are an alkyl. In further embodiments, R and R2 are each independently selected from the group consisting of methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl. In other embodiments, R and R2 each are independently methyl. In some embodiments, R, -R9 each is independently selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R3-R9 each independently is a hydrogen. In another 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, as described above. and the second compound relieves constipation. In certain embodiments, the second compound is selected from the group consisting of a laxative, emollient, a fiber treatment, and a partial agonist 5HT4 receptor. In some embodiments, the second compound is selected from the group consisting of bisacodyl, carboxymethylcellulose, casanthranol, cascara sagrada, castor oil, dantrón, dehydrocholic acid, docusate calcium, docusate sodium, glycerin, lactulose, magnesium citrate, magnesium hydroxide, magnesium oxide, magnesium sulfate, malt soup extract, methylcellulose, milk of magnesia, mineral oil, muciloid, polycarbofil, polyethylene glycol 3350, poloxamer 188, psilium, hydrophilic psilium, sen, sennosides, and sodium phosphate. In certain embodiments, the second compound is a compound of Formula III or its pharmaceutically acceptable salt or prodrug, where R3 - R0 each is independently selected from the group consisting of hydrogen, alkyl, nitro, arrimo, cyano, hydroxy, alkoxy, carboxylate, and amide, and m is chosen from 1, 2, and 3. In some embodiments, Rx is selected of the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R x is a hydroxy or an alkoxy. In further embodiments, R 1 is selected from the group consisting of hydroxy, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, and ter-butoxy. In other embodiments, R is methoxy. In some embodiments, each R2 and R3-R9 are independently selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, each R2 and R3-R9 are independently hydrogen. In some embodiments, R9 is selected from the group consisting of hydrogen, alkyl, hydroxy, and alkoxy. In certain embodiments, R9 is an alkyl. In further embodiments, R9 is selected from the group consisting of methyl, ethyl, propyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, and octyl. In other embodiments, R9 is n-pentyl.

In certain embodiments, the second compound is tegaserod, or its pharmaceutically acceptable salt or prodrug. In some of these embodiments, the pharmaceutically acceptable salt of tegaserod is selected from the group consisting of nitrate, lactate, succinate, sulfate, mesylate, esylate, and hydrogen sulfate. However, other salts of tegaserod are also within the scope of the present invention. Through the present description, when a particular compound is mentioned by name, for example oxybutynin, tolterodm, pilocarp, cevimelm, or tegaserod, it is understood that the scope of the present disclosure encompasses pharmaceutically acceptable salts, esters, amides or prodrugs of named compound. Also, if the named compound comprises a chiral center, the scope of the present composition also includes compositions comprising the racemic mixture of the two enantiomers, as well as comprising each enantiomer individually, substantially free of the other enantiomer. Thus, for example, a composition comprising the S enantiomer substantially free of the R enantiomer, or a composition comprising the R-enantiomer substantially free of the S-enantiomer By "substantially free" is meant that the composition comprises less than 10% or less than 8%, or less than 5%, or less than 3%, or less than 1% of the minor enantiomer If the The named compound comprises more than one chiral center, the scope of the present disclosure also includes compositions comprising a mixture of the various diastereomers, as well as compositions comprising each diastereomer substantially free of the other diastereomers. Thus, for example, commercially available oxybutomer is a racemic mixture comprising two separate enantiomers. The mention of "oxybutynin" throughout this disclosure includes compositions comprising the racemic mixture of oxybutynin, compositions comprising the (+) enantiomer substantially free of (-) enantiomer, and compositions comprising the substantially free (-) enantiomer of the (+) enantiomer. In addition, for example, commercially available pilocarpma, which is an alkaloid of natural origin, comprises two stereocenters. The scope of the present invention includes pharmaceutical compositions comprising all four diastereomers, compositions Pharmaceuticals comprising the racemic mixture of R, R and S, S isomers, pharmaceutical compositions comprising the racemic mixture of R, S and S, R isomers, pharmaceutical compositions comprising the R5R enantiomer substantially free of the other diastereomers, pharmaceutical compositions which comprise the S, S enantiomer substantially free of the other diastereomers, pharmaceutical compositions comprising the R, S enantiomer substantially free of the other diastereomers, and pharmaceutical compositions comprising the S, R enantiomer substantially free of the other diastereomers. In yet another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a first compound, a therapeutically effective amount of a second compound, and a therapeutically effective amount of a third compound, wherein the first compound is an antimuscarimic agent or an anticholinergic agent, as described above, the second compound causes stimulation of salivary glands, as described above, and the third compound relieves constipation, as described above.

In certain embodiments, the present invention is directed to a pharmaceutical composition comprising ov? But? N? Na v pilocaipma. In other embodiments, the present invention relates to a pharmaceutical composition comprising tolterodm and pilocarpine. In still other embodiments, the present invention relates to to a pharmaceutical composition comprising trospium and pilocarp In some embodiments, the present invention relates to a pharmaceutical composition comprising solifenacma and pilocarpine In further embodiments, the present invention relates to a pharmaceutical composition comprising dapfenacma and pilocarpine. Still in other embodiments, The present invention relates to a pharmaceutical composition comprising fesoterodm and pilocarpine In other embodiments, the present invention relates to a pharmaceutical composition comprising oxybutum and cevmielin In other embodiments, the present invention relates to a pharmaceutical composition eutica comprising tolterodma and cevimelma In certain embodiments described herein, an individual is given a pharmaceutical composition comprising a combination of two more compounds to treat hyperactive ve iga In some of these modalities, each compound is a separate chemical entity. However, in other embodiments, the two compounds are joined together by a chemical bond, such as a covalent bond, such that the two compounds different ones form separate parts of the same molecule The chemical bond is chosen such that after entering the body, the bond is broken, such as by enzymatic action, acid hydrolysis, base hydrolysis or the like and the two separate compounds are then formed other embodiments, the chemical bond is chosen such that it does not rupture under physiological conditions and is impermeable to enzymatic attack. In these embodiments, the two parts of the compound remain intact in the patient's body. By "not broken" and "waterproof" it is meant that the half-life of the chemical reaction leading to the breaking of the bond between the two parts of the molecule is longer than the pharmacological half-life of the binding compound, ie the compound Binding is excreted or etabolized faster than the junction between the two parts is broken In this way, in another aspect, the present invention relates to synthetic routes for novel compounds wherein oxybutynin, tolterod to trospium solifenacma, and dapfenac a is linked by a flexible linker to a pilocarpine or other salivary gland stimulants. The compounds useful for the compositions and methods described herein can be used in various formulations. Certain formulations affect the speed at which the compound enters the patient's bloodstream. In this way some formulations are immediate release formulations, while other formulations are delayed release, sustained release or prolonged release formulations. Thus, in some embodiments, the first compound is of immediate formulation, while in other embodiments, the first compound is in a delayed release formulation and still in other embodiments, the first compound is in sustained release formulation, and in additional embodiments the first compound is in an extended release formulation. 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 still in other embodiments, the second compound is in a sustained release formulation, and in additional embodiments, the second compound is in an extended release formulation. In some embodiments, the third compound is in immediate release formulation, while in other embodiments, the third compound is in a delayed release formulation and still in other embodiments, the third compound is in a sustained release formulation, and in In addition, the third compound is in prolonged release formulation. The compositions described herein are particularly useful for alleviating the main side effects in the treatment of OAB, ie dry mouth and / or constipation, improving tolerability and improving patient compliance while increasing the quality of life of the patient. In another aspect, the present invention relates to a method for treating a patient comprising administering to the 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 agent or an anticolmer, as described above, and the second compound causes stimulation of the salivary glands, as described above. A patient or a patient who requires Treatment methods described herein may be a patient suffering from overactive bladder. The patient may also be the one who finds the current therapies for overactive bladder and / or the side effects of the therapy uncomfortable, such as dry mouth or constipation, sufficiently intolerable in order to require auxiliary therapy to relieve side effects. The patient may also be the one who considers interrupting the therapy for overactive ve iga due to the side effects of the therapy. In some embodiments, a patient who was recently diagnosed with overactive bladder but has not yet been treated, is therefore a patient that requires the treatment methods and compositions described herein. In these modalities, the patient begins the therapy using the methods and combinations described herein in such a way that the patient does not experience any Side effects or experience side effects to a lesser degree In some modalities the patient may suffer from overactive, urge, tension and mixed incontinence. In some modalities, the first compound and the second compound are administered more or less simultaneously. the first compound is administered before the second compound. Still in other embodiments, the first compound is administered subsequent to the second compound. In another aspect, the present invention relates to a method of treating a patient, comprising identifying a patient suffering from bladders. over reactive, and administering to the patient a therapeutically effective amount of a first compound and a therapeutically effective amount of a second compound, wherein the first compound is an antimuscarinic agent or an anticholinergic agent, as described above, and with second compound alleviates constipation , as described above iormente In some modalities, the patient may suffer from bladder over reactive, urge incontinence, tension and mixed. Still in another aspect, the present invention relates to a method for treating a patient, comprising administering to the patient in need, a therapeutically effective amount of a first compound, a therapeutically effective amount of a second compound, and a therapeutically effective amount of a third compound, wherein the first compound is an antimuscarinic agent or an anticholinergic agent, as described above, the second compound causes stimulation of salivary glands, as described above and the third compound alleviates constipation, as described above In some embodiments, the patient may suffer bladder over reactive, urgency, tension and mixed incontinence In some embodiments of the above methods, the first compound and the second compound they are administered more or less simultaneously. In other embodiments, the first compound is administered before the second compound. In still other embodiments, the first compound is administered subsequent to the second compound. In certain embodiments of the above methods, the first compound and the second compound are administered individually. modalities, the first compound and the second compound can be covalently linked together, so that they form a single chemical entity. The single chemical entity is then digested and metabolized into two separate physiologically active chemical entities, one of which is the first compound and the other is the second compound Both chemical entities, once metabolized, exert their therapeutic effect independently or smergística In additional modalities, the bond between the two parts of the compound is not broken and each part of the binding molecule exerts its therapeutic effect independently, with no need for the rupture of the linker between the two parts. It should be noted that simply taking pilocarpme HCl commercially available, eg, Salagen® tablets, or any other salivary gland stimulant, in conjunction with an OAB drug is not effective in relieving the dry mouth side effect. Certain effective treatments couple the ethical pharmacocological profile of each salivary gland stimulant such as pilocarp, cevimeline HCl and amifostm, with the pharmaco-ethical profiles of the OAB agents, for example, oxybutynin, tolterodine, solifenacin, darifenacma, trospium and other agents approved or under development. Therefore, in certain embodiments of the above methods, the first and second compounds are administered in such a way that the plasma peak concentration for the first compound occurs almost at the same time after administration as the peak plasma concentration for the second compound. Thus, the two compounds can be administered simultaneously, but formulating such a delay in their release causes the two peak concentrations to occur at about the same time. in plasma. In other embodiments, a compound is administered at a time interval after another compound, in order to ensure peak plasma concentrations occur at about the same time. In other embodiments in the above methods, the first and second compounds are administered in such a way that the point in time at which the lowest flow of saliva occurs due to the action of the first compound almost corresponds to the point in time at which the highest flow of saliva occurs due to the action of the second In this way, the two compounds can be administered simultaneously, but formulating such a delay in their release causes the point in peak flow time of saliva for the second compound, to occur almost at the same time as the point in time of the lower saliva flow for the first compound In other embodiments, one compound is administered at a time interval after the other compound in order to ensure that the points in time of peak and channel saliva flow correspond In some embodiments of the above methods, the first and second compounds are administered in such a way that the proportion of their plasma concentrations at a given point following their administration is a predetermined value. Those of ordinary skill in the art will recognize that the proportion of Plasma concentrations are not necessarily the same as the proportion of the amount of compound administered Compounds are digested differently in the intestine, pass the intestinal wall differently, and have a different rate of first pass metabolism in the liver. , the rate of release by the kidney is different for various compounds In this way, for example Even if two compounds are administered in equivalent molar amounts their plasma concentrations at one point in time after administration can be significantly different. The methods described here take into account the pharmacokinetics of drug intake and metabolism, so that the proportion of the two compounds at the time of administration is adjusted so that the two compounds have a proportion in predetermined concentration in the plasma. Still in other modalities of the previous methods, the first and second compounds are administered in such a way that the point in time for maximum therapeutic effect of the compound that stimulates the flow of saliva corresponds to the point in time for the maximum side effect of the therapeutic compound OAB. In this way, the two compounds can being administered simultaneously, but formulated such that the delay in its release causes the maximum therapeutic effect of the second compound to occur at about the same time as the maximum side effect of the first compound. In other embodiments, a compound is administered at a time interval after of the other compound in order to ensure that the maximum therapeutic effect ofSecond compound occurs at almost the same time as the maximum secondary effect of the first compound. In some embodiments, the dosage form is designed as a sustained derivation of a combined agent with either sustained release or immediate release of the second agent to ensure that concentrations occur. Plasma peak at almost the same time In addition, the dosage form can be designed based on pharmacokinetic profiles wherein the peak plasma concentration of a compound, for example the salivary gland stimulating agent, eg pilocarp, corresponds to the amount maximum dry mouth caused by the drug OAB, for example oxybutmma. Thus, some of the pharmaceutical compositions contemplated for use in the methods described herein, include but are not limited to immediate release of oxybutmma, tolterod a, solifenacma, dapfenacma , trospium or fesoterodma in combination with pilocarpma and tegaserod, liber delayed (either sustained or prolonged) oxybutus and pilocarpic delayed release (either sustained or prolonged), oxybutynin delayed release iva sustained or prolonged) and delayed release pilocarpma (either sustained or extended) and tegaserod sustained release, immediate release of oxybutynin, tolterodine, solifenacin, darifenacma, trospium or fesoterodm and delayed formulation (either sustained or prolonged) of pilocarprna and tegaserod; delayed release (either sustained or prolonged) of oxybutmma, tolterodm, solifenacin, dapfenacin, trospium or fesoterodine and delayed (sustained or prolonged) release of prlocarp and sustained release tegaserod; delayed release (either sustained or prolonged) of oxybutyme, tolterod a, solifenacin, dapfenacma, trospium or fesoterodm and delayed (either sustained or prolonged) formulation of pilocarp and immediate release formulation of tegaserod. Unlimited by any particular theory, the improved treatment described here of OAB for resolving dry mouth and constipation, is based on a mechanistic approach that works at the receptor level, ie the adverse effect of these M2 / M3 muscarinic antagonists are counteracted or denied with cholinergic agents that work in the opposite direction but in concert with the intended therapy. In addition to reducing the adverse side effects experienced by those treated by bladder over reactive, the methods and compositions described herein have additional advantages. Currently, the drug dose of treatment such as oxybutynin, is limited due to side effects. Some patients suffering from reactive bladders can not tolerate doses that provide adequate therapy due to adverse side effects, for example dry mouth. These patients continue to suffer bladder over reactive even when they take their medications, only because the medication is not given at an effective dose. By reducing side effects using the methods and compositions described herein, the patient may be prescribed to take higher doses of treatment drugs such as oxybutidine. You are with higher doses results in having a less active bladder and also results in an increased inability of intrinsic bladder.

Thus, in another aspect, the present invention relates to a method for increasing the intrinsic capacity of the vein, which comprises administering to a patient in need, a therapeutically effective amount of a first compound and a therapeutically effective amount of a second compound, wherein the first compound is an antimuscarinic agent or an anticolmeric agent, as described above and the second compound causes stimulation of salivary glands, as described above. In another aspect, the present invention relates to a method for increasing the Intrinsic capacity of bladder, which comprises 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 agent or an anticholinergic agent, as described above and the Second compound relieves constipation, as described above. In another aspect, the present invention relates to a method for increasing intrinsic bladder capacity, which comprises administering to a patient who requires it, an amount Therapeutically effective of a first compound, a therapeutically effective amount of a second compound, and a therapeutically effective amount of a third compound, wherein the first compound is an antimuscarinic agent or an anticholinergic, as described above, the second compound causes stimulation of salivary glands, as described above and the third compound alleviates constipation, as described above. In another aspect, the invention relates to a pharmaceutical composition comprising a combination of an antimuscarolytic agent or an anticholinergic agent, as described herein, and a compound that causes stimulation of salivary glands, as described here; an antimuscarinic agent or an anticholinergic agent, as described herein, and a compound that relieves constipation, as described herein; or an antimuscarinic or anticholmergic agent as described herein, a compound that elicits salivary gland stimulation, as described herein and a constipation relieving compound, as described herein; Y a physiologically acceptable carrier, diluent or excipient or a combination thereof The term "pharmaceutical composition" refers to a mixture of a compound of the invention with other chemical components, such as diluents, lubricants, thickening agents, disintegrants or carriers. Pharmaceutical facilitates the administration of the compound to an organism. Multiple techniques of administration of a compound exist in the art including but not limited to oral, injection, inhalation, aerosol, parenteral and topical Pharmaceutical compositions can also be obtained by reacting compounds with organic and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid , nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly used carrier since it facilitates the intake of many organic compounds in the cells or tissues of an organism.

The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Dissolved salts in buffered solutions are used as diluents in the art. A buffered solution is commonly used in phosphate buffered saline. because it mimics the salt conditions of human blood Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound. In certain modalities, the same substance can act as a carrier, diluent or excipient or have either of two functions, or have all three functions. In this way, a single additive of the pharmaceutical composition can have multiple functions. The term "physiologically acceptable" defines a diluent carrier that does not abrogate the activity and biological properties of the compound. The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients as in Combination therapy, or suitable technical carriers or excipients for formulation and administration of the compounds of the present application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co, Easton, PA, 18th edition, 1990 Convenient administration routes, for example may include oral, transdermal, rectal, transmucosal or intestinal, parenteral delivery, including intramuscular, subcutaneous, intravenous, tramedullary injections as well as inhalation, tratacal, direct ventricular, mtraperitoneal, mtranasal or intraocular injections alternately, the compound can be administered in a local rather than systemic form, for example by injection of the compound directly into the renal or cardiac area, often in a depot or sustained release, prolonged or delayed formulation. In addition, the composition by a transdermal approach The pharmaceutical compositions of the present invention can be manufactured in a manner that is known per se, for example by conventional mixing, dissolving, granulating, preparation of dragees, levigation, emulsification, encapsulation, entrapment or processes tabletting Pharmaceutical compositions for use in accordance with the present invention, can thus be formulated in a conventional manner using one or more physiologically acceptable bidders comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically. The proper formulation depends on the selected administration route and the desired pharmaco-ethical profiles of each component of the combination therapy. Any of the well known carrier and excipient techniques can be used as convenient and as understood in the art, for example in Remmgton's Phar aceutical Sciences, above. Injection, the agents of the invention can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological salmo buffer. For transmucosal administration, appropriate penetrants to the barrier to permeate are used in the formulation. These penetrants are generally known in the Technique For oral administration, the compounds can be easily formulated by combining the active compounds with pharmaceutically acceptable carriers well known in the art. These carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slimes, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipients with the pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or cores from dragees Suitable excipients, in particular, are fillers such as sugars, including lactose, sucrose, mamtol or sorbitol; cellulose preparations such as, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methyl cellulose, hydroxypropylmethyl cellulose, carboxy ethyl cellulose sodium and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents, such as polyvinyl pyrrolidone, can be added. interlaced, agar, or alginic acid or a salt thereof such as sodium algite Dragee cores are provided with suitable coatings For this purpose, solutions of concentrated sugar, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, may be employed. , carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments can be added to tablets or dragee coatings for identification or to characterize different combinations of active compound doses. Pharmaceutical preparations that can be used orally include pressure setting capsules made of gelatin, as well as soft sealed capsules, made of gelatin and a plasticizer, such as glycerol or sorbitol. The pressure adjustment capsules may contain the active ingredients in admixture with 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 convenient liquids, such as Fatty agents, liquid paraffin, or liquid polyethylene glycols In addition, stabilizers can be added. All formulations for oral administration should be in suitable doses for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. The compounds can also be formulated in rectal compositions such as suppositories or retention enemas. Many of the compounds employed in the pharmaceutical combinations of the invention can be provided as counter-pharmaceutically compatible salts. Pharmaceutically compatible salts can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic and the like. The salts tend to be more soluble in aqueous or other protonic solvents which are the corresponding free base or acid forms. Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intd purpose More specifically, a therapeutically effective amount means an amount of effective compound to avoid, alleviate or ameliorate symptoms of the disease or prolong the survival of the subject being treated. Typically, the dose range of the 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 or a series of two or more supplied in the course of one or more days, as required by the patient. It should be noted that for almost all specific compounds mentioned in the present description, doses have been established for human treatment of at least some condition For example, for oxybutynin, tolterod a, solifenac a, dapfenacma, trospium, fesoterodm the preferred dose is between 0.1 mg to 50 mg, and the most preferred dose is between 1 mg to 30 mg. Other dose ranges include between 10 to 50 mg, between 20 to 50 mg, between 30 to 50 mg, between 40 to 50 mg, between 20 to 40 mg, between 10 to 20 mg, between 10 to 30 mg, between 20 to 30 mg and between 30 to 40 mg. The dose can also be in 10 mg, 20 mg, 30 mg, 40 mg or 50 mg For pilocarpma, the preferred dose it is between 0.1 mg to 50 mg, and the most preferred dose is between 1 mg to 30 mg. Other dose ranges include between 10 to 50 mg, between 20 to 50 mg, between 30 to 50 mg, between 40 to 50 mg, between 20 to 40 mg and between 30 to 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 to 50 mg, and the most preferred dose is between 0.5 mg to 2 mg. Other dose ranges include between 10 to 50 mg, between 20 to 50 mg, between 30 to 50 mg, between 40 to 50 mg, between 20 to 40 mg, between 30 to 40 mg, between 0.5 to 1 mg, and between 1 to 2 mg. The dose can also be 0.5 mg, 1 mg, 1.5 mg, and 2 mg. Although the exact dose can be determined on a drug-by-drug basis, in most cases, some generalizations can be made about the dose. The daily dose regimen for a human adult patient, for example, can be an oral dose of between 0.001 mg and 1000 mg of each ingredient, preferably between 0.01 mg and 500 mg, for example 1 to 200 mg or each ingredient in the compositions of the present invention or its pharmaceutically acceptable salt calculated as the free acid or free base, the composition is administered 1 to 4 times per day or per week. In Alternatively, the compositions of the invention may be administered by sustained release such as sustained, delayed or prolonged, preferably at a dose of each ingredient up to 500 mg per day. Thus, the total daily dose per oral administration of each ingredient, typically it will be in the range of 0 1 mg to 2000 mg. Conveniently the compounds will be administered for a period of continuous therapy, for example for a day, a week or more, or for months or years In cases of local administration or selective absorption, the effective local concentration of the drug may not be related to plasma concentration The amount of composition administered will, of course, depon the subject to be treated, the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. It will be understood by those skilled in the art that numerous and various modifications can be made to depart from the spirit of the present invention. Therefore, it will be clearly understood that the forms of the present invention are illustrative only and are not intd to limit the scope of the present invention.

EXAMPLES The following examples are not limiting and are only representative of various aspects of the invention. Example 1. Combination of a Drug for OAB and a Salivary Gland Stimulant for the Treatment of Individual with Peractive Bladder An individual with overactive bladder is identified. The individual is given 5 mg of oxybutynin two to four times a day in addition to 5 mg of pilocarpine two or three times a day. If the individual continues to complain of dry mouth, the dose of pilocarpma is increased to 10 mg two or three times a day. The dose can be increased up to 20 mg or 50 mg, if required. Each dose of oxybut may be increased to 10, 15, 20 or 30 mg Example 2: Combination of a Drug for OAB and a Tegaserod for the Treatment of Individual with Hyperactive Bladder An individual with overactive bladder is identified. The individual is given 5 mg of oxybutynin two to four times a day plus 2 mg of tegaserod twice a day. If the individual continues to complain of constipation, the dose of tegaserod is increased to 6 mg twice a day. The Dosage can be increased to 12 mg, 20 mg or 50 mg, if required The dose of oxybutm a can be increased to 10, 15, 20 or 30 mg Example 3 Synopsis of Protocol for Clinical Study A study is done to evaluate the effect of oxybutmma and pilocarpine, alone and in combination with placebo in salivary output in healthy comments The objectives of the study are to determine the salivary flow and the degree of dry mouth after oral administration of oxybutynin and pilocarpma, alone and in combination with placebo, and to determine the effect of oxybutynin and pilocarpma, alone and in combination, or vital signs and hollow / volume of urine. In each treatment period, following a nocturnal fast, the subjects enter the clinic and after measuring from baseline, they are randomized with one of four medications • Oxibutmma (5 mg) followed 30 minutes later by placebo • Pilocarpma ( 5 mg) followed by 30 minutes with placebo • Placebo followed 30 minutes later by placebo • Oxibut ma (5 mg) followed 30 minutes by pilocarpma (5 mg) The following measurements are made just before and at frequent intervals for up to 6 hours post dose: • Salivary flow is determined by chewing Parafilm for 2 minutes • Dry mouth is determined by VAS • Urine volume / void and frequency for 6 hours post doses are measured • Blood samples are taken for pre-dose pharmacokinetics, and 0.5, 1, 2, 3, 4 and 6 hours, post dose • Food intake and water are normalized during the 6 hour period The study is a randomized double blind, placebo controlled, with 4 sequences (4 doses for 4 weeks) with drugs that are administered orally as a single dose. There is a pharmacological rest or medication depuration between the study days. The study population is chosen as follows: • Healthy volunteers • 12 subjects • 18-year-old men or non-pregnant women • Weight 18-28 BMI ° No known allergy to anti-muscarmic agents ° No previous history of glaucoma, urinary retention, cardiac arrhythmias • Without OTC drugs, nutraceuticals or vitamins within 10 days of study participation and through the study Evaluations (except for urinary output) are performed at: 0.5 hr and within 10 minutes pre-dose, 0 5, 1, 1.5, 2, 2 5, 3, 3 5, 4, 4 5, 5 and 6 hours post dose The following is estimated. 1) Stimulated salivary flow 2) Dry mouth (VAS) 3) Hollow / urinary volume for 6 hours post dose 4) Pharmacokinetics of oxybutyn and pilocarpine Standard safety precautions, such as physical examination, medical history, complementary medications, ECG, hematology , clinical chemistry, performed analysis, supervision and completion of study, monitoring of alcohol / drugs in the urine pre-dose for each period, vital signs (HR and BP) to: pre-dose, and at intervals 30 min for 6 hours, and to be aware of adverse events through and between study periods, are taken. Example 4 Case Study for a Combination of Oxybutynin and Pilocarpma In this study, the effect of oxybutynin, pilocarp, the combination of two, and placebo, was measured in six separate studies, however identical in a single individual. Effect of Oxybutynin - A healthy human subject is given a dose of 5 mg oxybutynin HCl and the amount of salivation is measured over time over a period of 8 hours. As illustrated in Figure 1 (, diamond), the amount of saliva flow collected during periods of 2 minutes decreased after dose of oxybutmma and the flow of saliva remained low after 3 hours. The amount of saliva flow began to increase after 3 hours and the continuous increase reached the pre-dose level after 8 hours post-dose. The data generated in this study are consistent with the data in the literature. Effect of Pilocarpma - In a separate study in humans, the effect of pilocarpma HCl is evaluated in a healthy human subject to ensure that without eluda the pilocarprna increases the flow of salivary gland This was demonstrated as illustrated in tiguia 1 (, square) The amount of saliva collected during a 2-minute period increased markedly after dosing and the flow of saliva began to decrease after the peak observed at half an hour. The decrease in saliva flow continues until it reaches approximately the flow of saliva normal and pre-dose level after approximately 5 hours Effect of Placebo - In the third tranche of the study in humans, the placebo effect was evaluated Since this was a non-blinded test, the salivary flow was measured by not taking medication some or a real placebo but the same protocol was followed as in the other studies As illustrated in Figure 1 (, triangle), the variation in salivary flow with time is minimal and the average salivary flow? s approximately 2 g / 2 min, consistent with published literature Combination Effect of Oxibutmma and Pilocarpma - In a separate study in humans, the combination of oxybutyl and pilocarpma is administered to a human subject not healthy The subject was given 5 mg of oxybut ma followed by 5 mg of pilocarpma after 30 minutes of dose The flow of saliva was measured as before Results are illustrated in Figure 1 (ß, circle) As illustrated in Figure 1, the decrease in saliva flow caused by oxybutynin was well compensated by the increase in salivary flow induced by pilocarpma As a result, the amount of salivary flow remained approximately the same as the pre-dose level. Figure 1 further shows that the amount of salivary flow measured for the combination study was similar to that of the placebo study. therefore, the administration of 5 mg of pilocarpm to half an hour after the administration of 5 mg of oxybutynin, completely neutralized the adverse side effect of oxybutmma The percent of deviation of saliva flow from the baseline after administration of pilocarpma, oxybutmma, combination of pilocarpma and oxybutma (with pilocarpma administered 30 minutes after oxybutynin) and placebo, was plotted against time and is illustrated in Figure 2 The percent deviation for the combination study, where pilocarpma is administered 30 minutes after oxybut a, (•, circle), is minimal and is not significantly different from baseline or place (, triangle) suggesting that the combination approach eliminates the major side effect of OAB therapy. Synchronization effect of the Administration of Pilocarp a with Respect to the Administration of Oxybutynin - In two additional studies in humans, the synchronization effect of pilocarpma administration was measured. In one study, the combination of oxybutyn and pilocarp was administered to a healthy human subject. To the subject, 5 mg of oxybutyl a and 5 mg of pilocarp were administered simultaneously. The flow of saliva was measured as before. The results are illustrated in Figure 3 (, square). In the last study, the combination of oxybutynin and pilocarp was administered to a healthy human subject. To the subject, 5 mg of oxybutyn followed by 5 mg of pilocarp were administered after 60 minutes of dose. The flow of saliva was measured as before. The results are illustrated in Figure 3 (, diamond). Figure 3 shows the effect of the time delay for administration of pilocarpma. All studies are compared with placebo (, triangle). When oxybutynin and pilocarpma are administered at same time (, square), there is a large initial increase in the flow of saliva, which reaches a maximum at approximately t = 30 minutes to less than approximately t = 60 minutes, but then falls to normal levels (placebo) at approximately t = 1 hour and stay at this level When pilocarp is given at 60 minutes after oxybutyn (diamond), there is a precipitous drop in salivary flow, which lasts until about t = 1 hour, after which there is a large increase in the flow of saliva, with a maximum occurring at approximately t = 3 hours The flow of saliva returns to normal (placebo) at approximately t = 5 hours However, when pilocarpm is administered 30 minutes after oxybutynin (•, circle), there is a small fall in the flow of saliva, with a minimum approximately at = 30 minutes, but returns to (placebo) within one hour Effect of Dose Ratio Between Oxybutynin and Pilocarpma- - In this experiment, the results of two p Separate dose roportions between oxybutynin and pilocarpma were compared with placebo results and administration of oxybutynin alone. In one experiment, 5 mg of oxybutyn was administered to a healthy individual and the flow of saliva was measured for 8 hours The results are illustrated in Figure 4 (, diamond) Using a similar protocol, 5 mg of oxibut myrrh is administered to a healthy individual at t = 0, followed by 5 mg of pilocarp aat = 30 minutes. illustrated in Figure 4 (•, circle). Similarly, 10 mg of oxybutmma are administered to a healthy individual at t = 0, followed by 5 mg of pilocarp a at t = 30 minutes. The results are illustrated in Figure 4 (-, script) Finally, the results were compared with the administration of placebo (Figure 4 (, triangle)). The results shown in Figure 4 suggest that increasing oxybutyn from 5 to 10 mg leads to a decrease in salivation. The increase in the ratio of 1: 1 to 2: 1 disturbs the balance between salivation decreased by oxybutmma and increased salivation by pilocarpma, respectively. It is noted that the flow of saliva for the 2: 1 oxybutmma-pilocarpine ratio is similar to that of 5 mg oxybutyn alone, suggesting that the amount of pilocarpma 5 mg in this experiment is not sufficient to compensate for the decrease in saliva flow caused by the increase in oxybutmma amount of 5 to 10 mg. Therefore, an effective dose ratio for the combination oxybutyn and pilocarpma is when 5 mq of each is administered to a patient Oxybutynin Plasma Concentration - In a separate study, the plasma concentration of oxybutynin is measured in two groups of subjects one group received 5 mg oxybutynin alone and another group received 5 mg of oxybutynin followed by 5 mg of pilocarpine after 30 minutes Plasma concentrations were measured before administration of oxybutyl and at hours 1, 2, 3, 4, and 6 after administration The results were illustrated in Tables 1 and 2 below Table 1 shows plasma levels of oxybutyme after administration of 5 mg of oxybutynin alone in a blind placebo-controlled, four-way crossed clinical trial in 12 male subjects Table 2 presents plasma levels of oxybutyme after administration of 5 mg of oxybutmma followed by the administration of 5 mg of pilocaprm 30 minutes after administration of oxybutum. n a blind, placebo-controlled, four-way crossover clinical trial in 12 male subjects Table 1 Average 0.012 6.693 3.269 STD 0.034597 4.861029 2.289476 Table 1 (Cont.) 2 Average 1,711 1,263 0.724 STD 0.969634 1.29161! 0.58554Í Table 2 Average 0.00153! 6.228462 3.109231 STD 5.967714 2.92391 Table 2 Average 2.25153! 1.998231 1.277692 STD 1.961773 1.67978 0.948956 As can be seen from the tables in both groups, the plasma concentration of oxybutynin reaches a maximum at about one hour, followed by a gradual decrease. Furthermore, the plasma concentration of oxybutynin follows the same curve for both groups. Therefore, the addition of 5 mg of pilocarpine does not in fact affect the plasma concentration of oxybutynin. Two conclusions are obtained from this observation. First, pilocarpine does not affect the absorption of Oxybutynin in the intestine also does not affect the first-pass metabolism of pilocarpma in the liver. Secondly, pilocarp does not affect the ability to bind oxybutyn to, since the concentration of free oxybutynin in the plasma remains the same between the two groups. the presence of pilocarpma in the combination does not interfere with the pharmacokinetics of oxybutyme. Thus, the oxybutymal activity of oxybut ma responsible for the therapeutic effect of oxybut ma in OAB remains unaffected. Example 5 Case Study for a Combination of Oxybutynin and Cevimelma In this study, the effect of oxybutmma, cevimelma, the combination of the two and placebo, was measured in separate studies in a single individual. Oxibutmin effect- A healthy human subject is given a dose of 5 mg oxybut ma HCl and the amount of salivation is measured by time over a period of 8 hours. As illustrated in Figure 5 (•, circle), the amount of saliva flow will collected over the 2 minute period decreases after dose and the saliva flow remains after 3 hours The amount of saliva flow begins to increase after 3 hours and continues to increase, reaching the level of pre-dose after 8 hours after dosing. The data generated in this study are consistent with the data from the literature. Effect of Cevimelma - In a separate study in humans, the effect of administering 30 mg of cevimelm is evaluated in a healthy human subject to ensure that the cevimelm certainly increases salivary gland flow. This was demonstrated as illustrated in Figure 5 (, diamond). The amount of saliva collected over the 2-minute period increases markedly after dosing and the flow of saliva begins to decrease after the observed peak close to two hours. The decrease in saliva flow continues until it reaches approximately normal saliva flow and pre-dose levels after approximately 6 hours. Effect of Placebo - In the third branch of the study in humans, the placebo effect was evaluated. Since this was a non-mowing test the salivary flow was measured by not taking any medication or a real placebo, but the same protocol was followed as in the other studies. As illustrated in Figure 5 (, triangle), the variation in saliva flow with time is minimal and the flow of average saliva is approximately 2.5 g / 2 minutes, consistent with published literature Oxybutynin Combination Effect and Cevimelma- In a separate human study, the combination of oxybutynin and cevimeline is administered to a healthy human subject. mg of oxybutmma followed simultaneously by 30 mg of cevimelm, without time delay The saliva flow is measured as before The results are illustrated in Figure 5 (, square), where the combination is referred to as THVD-102 The results of the previous experiments are also illustrated in Table 3, below the data for the evaluation of the combination of oxybutmmna and cevimelm in flow of stimulated saliva are shown. Figure 5 is a graphic illustration of the data set forth in Table 3. Table 3 *: Not determined As illustrated in Figure 5, the decrease in saliva flow caused by oxybutynin was well compensated by the increase in saliva flow induced by cevimeline. As a result, the amount of saliva flow remained approximately equal at the pre-dose level. Figure 5 further shows that the amount of saliva flow The measure for the combination study was similar to that of the placebo study. Therefore, the administration of 30 mg of cevimelm, simultaneously with the administration of 5 mg of oxybutyn completely neutralized the adverse side effects of oxybutyn. Example 6: Case Study for a Combination of Tolterodma and Pilocarpine. In this study, the effect of tolterodm, pilocarp, the combination of the two and placebo, was measured in separate yet identical studies, in a single individual. Effect of Tolterodma - A A healthy human subject is given a dose of tolterodm and the amount of salivation measured by time over a period of 8 hours As illustrated in Figures 6 and 7 (, diamond), the amount of saliva flow collected during the 2 minute period decreases after dose and saliva flow remains low after 3 hours The amount of saliva flow begins to increase after approximately 4 hours and continues to increase but does not fully reach the pre-dose levels even after 8 hours post-dose Effect of Pilocarpine - The effect of the Administration of pilocarpma individually has been studied and the data illustrated above. Effect of Placebo - In another section of the study in humans, the placebo effect was evaluated. Since this was a non-blinded study, salivary flow is measured by not taking any medication or a real placebo but the same protocol was followed as in the other studies. As illustrated in Figures 6 and 7 (•, closed circle), the variation in saliva flow over time is minimal and the average saliva flow is approximately 2.5 g / 2 minutes, consistent with the published literature. Dosage Between Tolterodma and Pilocarp a- - In this experiment the results of two separate dose ratios between tolterodm and pilocarpma were compared with the results of placebo and administration of tolterodm alone. In one experiment, 2 mg of tolterodm was administered to a healthy individual and the flow of saliva was measured for 8 hours. The results are illustrated in Figure 6 (, diamond). Using a similar protocol, 2 mg of tolterod a are administered to a healthy individual at t = 0, followed by 5 mg of pilocarp a at t = 30 minutes. The results are illustrated in Figure 6 (, closed triangle).

Similarly, 2 mg of tolterod a is administered to a healthy individual at 0, followed by 10 mg of pilocarpine at t = 30 minutes The results are illustrated in Figure 6 (», open circle) Finally, the results were compared with the administration of placebo (Figure 6 (•, closed circle)) The results shown in Figure 6 suggest that increasing pilocarpine from 5 to 10 mg leads to an increase in salivation. The decrease in proportion from 2: 5 to 2:10 (tolterod to: pilocarpine) restores the balance between reduced salivation by tolterodm and increased salivation by pilocarp, respectively. It is noted that the flow of saliva for the 2: 5 ratio of tolterodine ipilocarpma is similar to that of 2 mg tolteradma alone, suggesting that the amount of pilocarpma 5 mg in this experiment is not sufficient to compensate for the decrease in saliva flow caused by the increase in the amount of 2 mg tolterodm. Therefore, an effective dose ratio for the combination of oxybutynin and pilocarp is when 2 mg of tolteradm are combined with 10 mg of pilocarp. Effect of Combination of Tolterad a and Pilocarpine - In a human study, separately, the combination of tolteradm and pilocarpm is administered to a healthy human subject To the subject 2 mg of tolterodm followed by 10 mg of pilocarp a is administered with various delays in the administration of pilocarpma The flow of saliva is measured as before The results are illustrated in Figure 7 In one study, 10 mg of pilocarp a is administered to the subject, 15 minutes after administration of 2 mg of tolterodm. The flow of saliva is measured as before. The results are illustrated in Figure 7 (, open triangle). Another study, 10 mg of p locarp a is administered to the subject 22 minutes after administration of 2 mg tolterod to Saliva flow is measured as before The results are illustrated in Figure 7 (B, open square) In this last study , 10 mg of pilocarp a is administered to the subject 30 minutes after administration of 2 mg of tolterodm Saliva flow is measured as before The results are illustrated in Figure 7 (•, c) open circle) As illustrated in Figure 7, the decrease in saliva flow caused by tolterod a is well compensated by the increase in flow of saliva induced by pilocarpma As a result, the amount of saliva flow remains approximately the same as the pre-dose level, when pilocarpma is administered 22 minutes after the administration of tolterodine Figure 7 further shows that the amount of saliva flow measured by the combination study, with a 22-minute delay of pilocarpma was similar to that of the placebo study. Therefore, administration of 10 mg ] or pilocarpine after administration of 2 mg of tolterodm completely neutralizes the adverse side effect of oxybutyn whereas high doses are not tolerated due to the severity of the dry mouth, the The described approach allows administration of higher doses of oxybutmma, tolterodine, solifenacin, dapfenacin, trospium, fesoterodine, and other approved or developing compounds thus leading to a more tolerable and effective treatment. economic.

Claims (31)

1. CLAIMS 1 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 agent or an anticolmergic agent and the second compound causes stimulation of the salivary glands. The composition according to claim 1, characterized in that the first compound is selected from the group consisting of oxybut ma, tolterodm, solifenacma, darifenac a, trospium, fesoterodm, a free base thereof, and a pharmaceutically acceptable salt or prodrug. thereof . 3. The composition according to claim 1, characterized in that the first compound is oxybutmma, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof. 4. The composition according to claim 1, characterized in that the first compound is oxybutyn, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof. The composition according to claim 1, characterized in that the second compound is selected from the group consisting of pilocarpine, cevimelm and ainiphosyl a, a free base thereof, and a pharmaceutically acceptable salt or pro-drug thereof. with claim 1, characterized in that the second compound is pilocarp, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof. The composition according to claim 1, characterized in that the second compound is cevimelm, a base free thereof, or a pharmaceutically acceptable salt or prodrug thereof 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 agent or an anticolmergic agent and the second compound relieves constipation 9 The composition according to claim 8, characterized in that the first The compound is the group consisting of oxybutynin, tolterodine, solifenacin, dapfenacma, trospium, fesoterodine, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof 10. The composition according to claim 8, characterized because the second compound is selected from the group consisting of a laxative, emollient, fiber treatment, and a partial 5HT4 receptor agonist. The composition according to claim 8, characterized in that the second compound is selected from the group consisting of tegaserod, bisacodyl, carboxymethylcellulose, casanthranol, cascara sagrada, castor oil, dantron, dehydrocholic acid, docusate calcium, docusate sodium, glycerin , lactulose, magnesium citrate, magnesium hydroxide, magnesium oxide, magnesium sulfate, malt soup extract, methylcellulose, milk of magnesia, mineral oil, muciloid, polycarbonate, polyethylene glycol 3350, poloxamer 188, psyllium, hydrophilic psyllium , senna, sennosides, and sodium phosphate, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. A pharmaceutical composition comprising a therapeutically effective amount of a first compound, a therapeutically effective loss of a second compound, and a therapeutically effective amount of a third compound, wherein the first compound is an antimuscarinic agent or an anticolmer, the second compound causes stimulation of the salivary glands, and a third compound relieves constipation. The composition according to claim 12, characterized in that the first compound is selected from the group consisting of oxybutynin, tolterodm, solifenacma, dapfenacma, trospium, fesoterodm, a free base thereof, and a pharmaceutically acceptable salt or prodrug of the 14. The composition according to claim 12, characterized in that the second compound is selected from the group consisting of pilocarp, cevimelm and amifostm, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. 15. The composition according to claim 12, characterized in that the third compound is the group consisting of tegaserod, bisacocil, caLboxi ethylcellulose, casantra cascara sagrada, castor castor, dantrone, dehydrocholic acid, docusate calcium, docusate sodium, glycerin, lactulose, magnesium citrate, magnesium hydroxide, magnesium, magnesium sulfate, malt soup extract, methylcellulose, milk of magnesia, mineral oil, mucilloid, polycarbonate, polyethylene glycol 3350, poloxamer 188, psyllium, hydrophilic psyllium, senna, sennosides, and sodium phosphate, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof 16 A method for treating a patient, characterized in that it comprises 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 agent or an anticholinergic and the second compound causes stimulation of salivary glands 17 The method according to claim 16, characterized in that the first compound is selected from the group consisting of oxybutynin, tolterodine, solifenacin, darifenacma, trospium, fesoterodine a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof 18 The method according to claim 16, characterized in that the first compound is oxybutynin, a free base of the same, or a pharmaceutically acceptable salt or prodrug thereof 19 The method according to claim 16, characterized in that the first compound is tolterodm, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof 20 The method according to claim 16, characterized in that the second compound is selected from the group consisting of pilocarp, cevimeline, and amifostine, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. claim 16, characterized in that the second compound is pilocarp, a free base thereof, or a salt or pharmaceutically acceptable prodrug thereof The method according to claim 1G, characterized in that the second compound is cevimelm, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof. A pharmaceutical composition characterized in that it comprises a therapeutically effective amount of a first compound. , a therapeutically effective amount of a second compound, and a pharmaceutically acceptable carrier, diluent or excipient, wherein the first compound is selected from the group consisting of oxybutyn, tolterodm, solifenac, darifenacma, trospium, fesoterodm, a free base of the and a pharmaceutically acceptable salt or prodrug thereof, and wherein the second compound is selected from the group consisting of pilocarp, cevimelm and amifostm, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. 24. The composition according to claim 23, characterized in that the first compound is oxybutyn, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof. 25. Composition in accordance with claim 23, characterized in that the first compound is tol Lerodma, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof 26 The composition according to claim 23, characterized in that the second compound is pilocarpine, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof The composition according to claim 23, characterized in that the second compound is cevimel a, a free base thereof, or a pharmaceutically acceptable salt or prodrug thereof A method for treating a patient, characterized in that it comprises 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 agent or an anticolmergic agent and the second compound relieves constipation 29 The method of compliance with n claim 28, characterized in that the first compound is selected from the group consisting of oxybutynin, tolterod a, solifenacma, darifenacma, trospium, fesoterodm, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. 30. The method according to claim 28, characterized in that the second compound is selected from the group consisting of tegaserod, bisacodyl, carboxymethylcellulose, casanthranol, cascara sagrada, castor oil, dantron, dehydrocholic acid, docusate calcium, docusate sodium , glycerin, lactulose, magnesium citrate, magnesium hydroxide, magnesium oxide, magnesium sulfate, malt soup extract, methylcellulose, milk of magnesia, mineral oil, muciloid, polycarbonate, polyethylene glycol 3350, poloxamer 188, psyllium , psyllium drofilic, senna, sennosides, and sodium phosphate, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. 31. A method for treating a patient, characterized in that it comprises: administering to a patient in need, a therapeutically effective amount of a first compound, a therapeutically effective amount of a second compound, and a therapeutically effective amount of a third compound, wherein the first compound is an antimuscarinic agent or an anticholinergic, the second compound causes stimulation of the salivary glands, and the third compound alleviates constipation 32 The method according to claim 31, characterized in that the first compound is selected from the group consisting of oxybutynin, tolterodine, solifenacma, dapfenacin, trospium, fesoterod a, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. The method according to claim 31, characterized in that the The second compound is selected from the group consisting of pilocarp, cevimel, and amifostine, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof. The method according to claim 31, characterized in that the third compound is choose from the group consisting of tegaserod, bisacodyl, carboxymethylcellulose, casantranol, cascara sagrada, olive Castor, dantron, dehydrocholic acid, docusate calcium, docusate sodium, glycerin, lactulose, citrate magnesium, magnesium hydroxide, magnesium oxide, magnesium sulfate, malt soup extract, methylcellulose, milk of magnesia, mineral oil, muciloid, polycarbonate, polyethylene glycol 3350, poloxamer 188, psyllium, hydrophilic psyllium, senna, sennósidos, and sodium phosphate, a free base thereof, and a pharmaceutically acceptable salt or prodrug thereof.