Methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation

Abstract

To provide methods and compositions for treatment of disorders ameliorated by muscarinic receptor activation.SOLUTION: This invention relates to a method for treating central nervous system disease using a combination of a muscarine activator and a muscarine inhibitor, and an agent comprising the muscarine activator and the muscarine inhibitor.SELECTED DRAWING: None

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to: 1) methods of using a combination of one or more muscarinic agonists and one or more muscarinic antagonists for the treatment of diseases ameliorated by activation of muscarinic receptors (e.g., schizophrenia and related disorders); and 2) pharmaceutical agents comprising one or more muscarinic agonists and one or more muscarinic antagonists. [Background technology]

[0002] 2. Background of the Invention The acetylcholine neurotransmitter system plays an important role in various central nervous system (CNS) and peripheral functions. Acetylcholine signaling is carried out by two different types of receptors: nicotinic and muscarinic receptors. Muscarinic cholinergic receptors are G protein-coupled receptors with five different receptor subtypes (M1-M5) (Raedler et al. American Journal of Psychiatry. 160:118. 2003), each of which is found in the CNS but has a different tissue distribution. Activation of the muscarinic system by using muscarinic agonists has been suggested to have the potential to treat several diseases, including Alzheimer's disease, Parkinson's disease, movement disorders and drug addiction (U.S. Patent Application Publication No. 2005 / 0085463; Langmead et al. Pharmacology & Experimental Therapeutics. 117:232:2008). Genetic evidence suggests a direct link between the muscarinic system and both alcohol addiction (Luo X. Et al. Hum Mol Genet. 14:2421. 2005) and nicotine addiction (Mobascher A et al. Am J Med Genet B Neuropsychiatr Genet.5:684.2010). The M1 and M4 subtypes have been of particular interest as therapeutic targets for various diseases. For example, lithium and valproic acid, mood stabilizers used to treat bipolar depression, can exert their effects via the muscarinic system, particularly through the M4 subtype of receptors (Bymaster & Felder. Mol Psychiatry. 7 Suppl 1:S57. 2002).

[0003] Among the most relevant to the muscarinic system is schizophrenia, a serious psychiatric disorder that affects about 0.5-1% of the population (Arehart-Treichel. Psych News. 40:9. 2005). The disease is characterized by a set of symptoms that are generally classified into three categories: 1) positive symptoms (e.g., hallucinations, delusions, etc.); 2) negative symptoms (e.g., social isolation, anhedonia, etc.); and 3) cognitive symptoms (e.g., loss of information processing ability, reduced working memory, etc.) (Schultz. Am Fam Physician. 75:1821. 2007). Patients with schizophrenia have a significantly reduced quality of life and a high risk of death from several factors, including an increased suicide rate (Brown et al. British Journal of Psychiatry. 177:212. 2000). Schizophrenia also has a high cost to society, as people with schizophrenia are much more likely to be incarcerated, homeless, or unemployed.

[0004] Currently, antipsychotic drugs are the mainstay of treatment for schizophrenia. First generation antipsychotics are commonly known as "typical antipsychotics," whereas newer antipsychotics are commonly referred to as "atypical antipsychotics." Both typical and atypical antipsychotics have limited efficacy and severe side effects. There is little to no difference in efficacy between typical and atypical antipsychotics, likely because both classes of drugs exert their therapeutic effects through the same pharmacological mechanism (e.g., acting as dopamine receptor antagonists) (Nikam et al. Curr Opin Investig Drugs. 9:37. 2008). Side effects of typical antipsychotics include abnormal movements (e.g., rigidity), whereas atypical antipsychotics have different but equally severe side effects (e.g., significant weight gain, cardiovascular effects, etc.). The side effect profile of current antipsychotic drugs further reduces compliance in an often already non-compliant patient population, and thus there is a clear need for new therapies for treating schizophrenia and related disorders (e.g., schizoaffective disorder).

[0005] Clozapine is an example of an antipsychotic with severe side effects including sialorrhea (hypersalivation) which occurs in up to 54% of patients (Davydov and Botts, Ann Pharmacother. 34:662. 2000). The exact mechanism of hypersalivation is still unknown (Rogers and Shramko. Pharmacotherapy. 20:109. 2000). Clozapine has a complex pharmacology with considerable activity at various receptors including dopamine receptors, serotonin receptors, adrenergic receptors, muscarinic receptors and possibly other receptors (Coward. Br J Psychiatry Suppl. 17:5. 1992). Researchers have tried various pharmacological approaches to prevent sialorrhea, including the antipsychotics amisulpride (Croissant et al. Pharmacopsychiatry. 38:38. 2005) and sulpiride (Kreinin et al. Isr J Psychiatry Relat Sci. 42:61. 2005), as well as botulinum toxin (Kahl et al. Nervenarzt. 76:205. 2005). Efforts have focused primarily on alpha2 adrenergic agonists as well as anticholinergics, since clozapine is known to interact with these receptors. Antimuscarinic drugs such as pirenzepine have shown efficacy in small trials (Schneider et al. Pharmacopsychiatry. 37:43. 2004), but other studies of the same drugs have not confirmed this effect (Liu et al. J Clin Psychopharmacol. 21.:608. 2001). Alpha-2 adrenergic agonists such as clonidine (Singh et al., J Psychopharmacol. 19:426. 2005) have also shown efficacy in reducing sialorrhea in small trials. However, in a 2008 review, Syed et al. reported that there were insufficient data to guide clinical practice (Syed et al. Cochrane Database Syst Rev. 16:3. 2008).

[0006] Another approach for the treatment of schizophrenia has been the use of muscarinic agonists. Muscarinic receptors are G protein-coupled receptors that bind the neurotransmitter acetylcholine (Eglen RM. Auton Autacoid Pharmacol 26:219. 2006). To date, five subtypes of muscarinic receptors have been identified, generally designated M1, M2, M3, M4, and M5, respectively (Caulfield MP et al. Pharmacol. Rev. 50:279. 1998). These muscarinic subtypes vary with respect to the affinity of various agonists and antagonists for the receptor. Several lines of evidence suggest that the muscarinic system plays a major role in the pathology of schizophrenia. In particular, a reduced expression of M1 and M4 receptor subtypes was noted in postmortem studies of deceased schizophrenic patients (Dean et al. Mol Psych. 1:54. 1996). Similarly, SPECT imaging has demonstrated reduced muscarinic availability in schizophrenia (Raedler et al. Am J Psych.160:118. 2003).

[0007] There is also pharmacological evidence suggesting activation of muscarinic receptors as a potential therapeutic approach for schizophrenia. For example, the muscarinic antagonist scopolamine, used to treat motion sickness, causes the type of cognitive impairment and delusions seen in schizophrenia (Ellis et al. Int. J. Neuropsychopharmacol. 9:175. 2006). It has been suggested that more selective M1 agonists promote glutamatergic signaling that may help exert therapeutic effects (Jones et al. J. Neurosci. 28:10422. 2008). In a double-blind placebo-controlled study of schizophrenic patients with xanomeline, which has selective activity at M1 and M4 receptors, relief of schizophrenia was observed (Shekhar et al. Am. J. Psych. 165:1033. 2008). However, because xanomeline also binds to receptor subtypes other than M1, several different severe side effects have been observed, including hypersalivation, gastrointestinal (GI) side effects, cardiac side effects and disorders.

[0008] No one has been able to take advantage of muscarinic agonist approaches before because of the side effects associated with muscarinic agonist binding to certain muscarinic receptor subtypes. There is a need for methods of using muscarinic agonists and medicaments using such muscarinic agonists that can enable the therapeutic effects associated with activation of muscarinic receptors with fewer side effects. Summary of the Invention [Means for solving the problem]

[0009] Summary of the Invention In one embodiment, the invention relates to a method of treating a disease or condition ameliorated by activation of the muscarinic system by administering one or more muscarinic "activators" (e.g., agonists, partial agonists, co-agonists, physiological agonists, potentiators, stimulants, allosteric potentiators, positive allosteric modulators, or allosteric agonists) and one or more muscarinic "inhibitors" (e.g., antagonists, partial antagonists, competitive antagonists, non-competitive antagonists, uncompetitive antagonists, silent antagonists, inverse agonists, reversible antagonists, physiological antagonists, irreversible antagonists, inhibitors, reversible inhibitors, irreversible inhibitors, negative allosteric modulators, or allosteric antagonists). In a preferred embodiment, such diseases include schizophrenia and related disorders. In a preferred embodiment, one muscarinic activator and one muscarinic inhibitor are used. In a preferred embodiment, the combination of Activator and Inhibitor has a score ("Theta score") of greater than 230 as determined by in silico testing using the proprietary algorithms described herein. In another embodiment, two or more muscarinic Activators and / or two or more muscarinic Inhibitors are used.

[0010] In another embodiment of the invention, the method of treatment may be administered to a mammal. In the present invention, the mammal is a human.

[0011] In one embodiment of the invention, the use of the inhibitor reduces the side effects associated with the use of the activator, hi another embodiment, the use of the inhibitor allows for a higher maximum tolerated dose of the activator.

[0012] In one embodiment, the muscarinic Activator may be taken sequentially with the Inhibitor. In another embodiment of the invention, the muscarinic Activator may be taken simultaneously with the Inhibitor. In a preferred embodiment of the invention, the Activator and Inhibitor are formulated to be contained in the same dosage form or dosage vehicle. In another embodiment of the invention, the muscarinic Activator and the muscarinic Inhibitor are formulated in separate dosage forms or dosage vehicles. In one embodiment, the Activator and the Inhibitor are formulated in an immediate release dosage form. In another embodiment, the Activator and the Inhibitor are formulated in a sustained release dosage form. In another embodiment, either the Activator or the Inhibitor is formulated in an immediate release dosage form while the other is formulated in a sustained release dosage form.

[0013] In another embodiment of the present invention, the muscarinic Activators and Inhibitors can be taken orally. The Activators and Inhibitors can be administered orally in tablets, lozenges, liquids, drops, capsules, caplets, and gel caps, or other such formulations known to those skilled in the art. Other routes of administration can include, but are not limited to, parenteral, topical, transdermal, ocular, rectal, sublingual, and vaginal.

[0014] In another embodiment of the present invention, the muscarinic activator and muscarinic inhibitor are administered simultaneously or consecutively with other treatments for schizophrenia.In one embodiment of the present invention, the muscarinic activator and muscarinic inhibitor are administered simultaneously or consecutively with psychotherapy.In another embodiment of the present invention, the muscarinic activator and muscarinic inhibitor are administered simultaneously or consecutively with other drug therapy.Drug therapy may include, but is not limited to, antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers and other pharmacological interventions known to those skilled in the art.

[0015] Another embodiment of the present invention is a medicament that includes both a muscarinic Activator and a muscarinic Inhibitor. In a preferred embodiment, the combination of Activator and Inhibitor has a theta score of greater than 230 as determined by in silico testing using the proprietary algorithm described herein.

[0016] In another embodiment of the present invention, the drug can be taken orally.The drug can be administered orally in tablets, lozenges, liquids, drops, capsules, caplets and gel capsules or other such formulations known to those skilled in the art.Other routes of administration can include, but are not limited to, parenteral, topical, transdermal, intraocular, rectal, sublingual and intravaginal.

[0017] In another embodiment of the present invention, the drug can be administered in combination with other therapies.In one embodiment of the present invention, the drug is administered simultaneously or consecutively with psychotherapy.In another embodiment of the present invention, the drug is administered simultaneously or consecutively with other medications.Such medications may include, but are not limited to, antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers and other pharmacological interventions known to those skilled in the art.

[0018] These and other embodiments of the present invention, and their features and characteristics, are described in further detail in the specification and claims that follow. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] Detailed Description of the Invention definition For convenience, before further description of the present invention, some terms used in this specification, examples and the appended claims are summarized here.These definitions should be read in light of the remaining parts of this disclosure and understood as understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those that can be understood by those skilled in the art.

[0020] As used herein, the articles "a" and "an" are used to refer to one or to more than one (i.e. to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0021] The terms "comprise" and "comprising" are used in their inclusive, open sense, meaning that additional elements may be included.

[0022] The term "consisting of" is used to limit the elements to those specified, excluding impurities ordinarily accompanying them.

[0023] The term "consisting essentially of" is used to limit the elements to those specified and that do not materially affect the basic and novel characteristics of the material or process.

[0024] As used herein, unless otherwise specified, the term "controlled release" is defined as a prolonged release pattern of one or more drugs, such that the drug is released over a period of time. A controlled release formulation is a formulation that has a release rate that provides a measurable blood concentration of the drug for a period of time that is longer than that which may occur after intravenous injection or administration of an immediate release oral dosage form. Controlled release, slow release, sustained release, extended release, prolonged release, and delayed release have the same definition for the present invention.

[0025] As used herein, the term "including" is used to mean "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0026] The term "mammal" is known in the art, and exemplary mammals include humans, primates, cows, pigs, dogs, cats, and rodents (eg, mice and rats).

[0027] The terms "parenteral administration" and "administered parenterally" are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intraspinal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0028] A "patient," "subject," or "host" treated by the method of the present invention may mean either a human or non-human mammal.

[0029] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharma- ceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that is involved in carrying or transporting any of the compositions of the invention or its components from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the compositions of the invention and their components, and not injurious to the patient. Some examples of materials which can serve as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and derivatives of cellulose such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations.

[0030] The term "pharmaceutical acceptable salts", which is used synonymously with "salts", is recognized in the art and refers to salts prepared from relatively non-toxic acids or bases, including inorganic and organic acids and bases, including those contained in the compositions of the present invention.Suitable non-toxic acids include inorganic and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid.

[0031] The term "treatment" is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disease.

[0032] The term "therapeutic agent" is recognized in the art and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of therapeutic agents, also called "drugs", are described in well-known references such as the Merck Index (14th Edition), the Physicians' Desk Reference (64th Edition), and The Pharmacological Basis of Therapeutics (12th Edition), and include, but are not limited to, pharmaceutical agents; vitamins; mineral supplements; substances used in the treatment, prevention, diagnosis, cure, or mitigation of disease or illness; substances that affect the structure or function of the body, or prodrugs that become biologically active or more active after being placed in a physiological environment.

[0033] The term "psychotherapy" refers to the use of non-pharmacological therapy, where practitioners use a variety of techniques, including verbal and other interactions with patients to affect positive therapeutic outcomes. Such techniques include, but are not limited to, behavioral therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, occupational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also called person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavior therapy, reality therapy, response-based therapy, sandplay therapy, status dynamics therapy, hypnosis and confirmation therapy. It is further understood that psychotherapy can include combining two or more techniques and that the therapeutic professional can select and adjust techniques based on the needs and responses of individual patients.

[0034] The term "muscarinic disorder" refers to any disease or condition that is ameliorated by activation of the muscarinic system. Such diseases include diseases in which direct activation of the muscarinic receptors themselves or inhibition of the cholinesterase enzyme produces a therapeutic effect.

[0035] The terms "schizophrenia-related illness" and "schizophrenia-related disease" include, but are not limited to, schizoaffective disorder, psychosis, delusional disorder, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, manic-depressive illness with psychosis, or any other illness with psychotic features.

[0036] The term "movement disorder" includes, but is not limited to, Gilles de la Tourette syndrome, Friedreich's ataxia, Huntington's chorea, restless legs syndrome and other diseases or disorders whose symptoms include excessive movements, tics and convulsions.

[0037] The term "mood disorder" includes major depressive disorder, dysthymia, recurrent mild depression, minor depression disorder, bipolar disorder, mania and anxiety disorders.

[0038] The term "cognitive disorder" refers to a disease or disorder characterized by cognitive impairment (e.g., having abnormal working memory, problem-solving abilities, etc.). These diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, dementia (including but not limited to AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy body disease, and idiopathic dementia), Pick's disease, confusion, cognitive impairment associated with fatigue, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, and Cushing's disease, cognitive impairment associated with autoimmune diseases.

[0039] The term "attention disorder" refers to diseases or conditions characterized by abnormal or shortened attention span, including, but not limited to, attention deficit hyperactivity disorder, attention deficit disorder, Dubowitz syndrome, FG syndrome, Down syndrome, growth retardation due to insulin-like growth factor I deficiency, hepatic encephalopathy syndrome, and Strauss syndrome.

[0040] The term "addictive disorder" refers to a disease or condition characterized by addiction or substance dependence as defined by the Diagnostic & Statistical Manual IV. Such diseases are characterized by physical dependence, withdrawal symptoms and tolerance to a particular substance. Such substances include, but are not limited to, alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine and cannabis. Addictive disorders can also encompass behaviors that patients continue to perform compulsively despite obvious negative consequences. For example, problem gambling is recognized by those skilled in the art as an addictive behavior that often has destructive consequences.

[0041] The term "activator" refers to a molecule that may be described as an agonist, partial agonist, coagonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator, allosteric agonist, or that increases muscarinic receptor activity or signaling by direct or indirect means.

[0042] The term "inhibitor" refers to a molecule that can be described as an antagonist, partial antagonist, competitive antagonist, noncompetitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist, or a molecule that reduces muscarinic receptor activity or signaling by direct or indirect means.

[0043] The term "maximum tolerated dose" refers to the highest dose of a drug or therapeutic agent that a patient can take without experiencing intolerable side effects. The maximum tolerated dose is usually determined empirically in clinical trials.

[0044] The term "muscarinic receptor" refers to a G protein-coupled receptor that binds the neurotransmitter acetylcholine, and five subtypes of muscarinic receptors have been identified to date. "M1" refers to subtype 1 muscarinic receptors. "M2" refers to subtype 2 muscarinic receptors. "M3" refers to subtype 3 muscarinic receptors. "M4" refers to subtype 4 muscarinic receptors. "M5" refers to subtype 5 muscarinic receptors.

[0045] The term "antipsychotic" refers to a drug that relieves psychosis, hallucinations or delusions.Antipsychotics can include, but are not limited to, haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, pericyazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupentixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetrabenazine.

[0046] The term "anti-anxiety drug" refers to a drug that reduces anxiety, fear, panic or related feelings. Such drugs include, but are not limited to, benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital) and hydroxyzine.

[0047] The term "antidepressant" refers to drugs that relieve depression and related disorders (e.g., dysthymia), and includes selective serotonin reuptake inhibitors (e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), mianserin, mirtazapine, norepinephrine reuptake inhibitors ( For example, atomoxetine, mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline), monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine).

[0048] The term "sedative" or "tranquilizer" refers to a drug that induces drowsiness, promotes lethargy or a desire to sleep, or promotes a state of unconsciousness. Such drugs include, but are not limited to, benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), eszopiclone, zaleplon, zolpidem, and zopiclone.

[0049] The term "theta score" is defined as a numerical value assigned by the in silico algorithm described herein used to predict the overall efficacy and side effects of any given combination of a muscarinic Activator and an Inhibitor.

[0050] Introduction The present invention relates to a method of combining one or more activators and inhibitors of muscarinic receptors in the treatment of various diseases that can be improved by the activation of the muscarinic system. The present invention also describes a drug comprising one or more activators and one or more inhibitors of muscarinic receptors. It has already been hypothesized that the use of muscarinic activators is useful for various central nervous system-related diseases. In particular, the activation of M1 and M4 receptor subtypes may prove to be therapeutic. However, due to unacceptable side effects, no one has been able to advance M1 and M4 muscarinic activators through clinical development to the point of receiving regulatory approval for CNS indications. For example, activators of M1 and M4 muscarinic receptors have been suggested to be effective treatments for schizophrenia (Shekhar et al. Am J Psychiatry. 165:1033. 2008; Shirey et el. Nature Chem Biol. 4:41. 2007), but binding by these activators to muscarinic receptor subtypes, not just M1 and M4, results in side effects that have hindered the use of muscarinic activators in the clinic (Shekhar et al. Am. J. Psych. 165:1033.2008). For example, in both Phase I and subsequent studies, the muscarinic agonist xanomeline had unacceptable gastrointestinal (GI) side effects as well as other side effects primarily related to binding of muscarinic receptors, not just M1 and M4 (Sramek et al. The Journal of Clinical Pharmacology. 35:800. 1995), (Cutler & Sramek. Eur. J. Clin. Pharmacol. 48:421-428. 1995), (Bodick et al. Arch Neuro 54:465-473. 1997). By combining a muscarinic activator with an inhibitor, it is possible to obtain the desired therapeutic effect while reducing or eliminating the side effects associated with binding of undesirable subtypes.

[0051] Muscarinic inhibitors are used to treat overactive bladder and pulmonary diseases and have been proposed for the treatment of other diseases (Witte LP et al. Curr. Opin. Urol. 1:13. 2009). Several groups have outlined the use of muscarinic inhibitors in combination with other classes of drugs to achieve better disease treatment. For example, WO 2008 / 121268 suggests a combination of a beta-3 adrenergic agonist (itself being studied for the treatment of LUTS) with a muscarinic antagonist for the treatment of lower urinary tract symptoms (LUTS). Other publications suggest combining certain muscarinic activators or inhibitors with other certain therapeutic agents other than muscarinic agonists to provide additional therapeutic benefit (e.g., WO 2009 / 037503, WO 2009 / 036243, WO 2008 / 104776, WO 2008 / 096136, WO 2008 / 096126, WO 2008 / 096137, WO 2008 / 096140, WO 2008 / 096150, WO 2008 / 096162, WO 2008 / 096170, WO 2008 / 096182, WO 2008 / 096190, WO 2008 / 096192, WO 2008 / 096194, WO 2008 / 096196, WO 2008 / 096198 ... (see, for example, WO 96121, WO 2008 / 096111, WO 2007 / 127196, WO 2007 / 125293, EP 2002843, EP 2002844, U.S. Pat. No. 5,744,476, U.S. Pat. No. 7,524,965, U.S. Pat. Appl. Pub. No. 2005 / 0267078, U.S. Pat. Appl. Pub. No. 2006 / 0189651, and U.S. Pat. Appl. Pub. No. 2008 / 0045565). U.S. Pat. Appl. Pub. No. 2006 / 0287294 A1 reviews the use of aspartyl protease inhibitors in combination with either M1 agonists or M2 antagonists for the treatment of a variety of diseases, including the amelioration of cognitive impairment. Both M1 activators and M2 inhibitors have been suggested by themselves (Carey et al. Eur J Pharmacol 431:198. 2001) to be useful in the treatment of cognitive disorders, and the reason for the combination with the aspartyl protease inhibitor was to enhance the effect of the aspartyl protease inhibitor. There has been no suggestion of combining an M1 activator with an M2 inhibitor, and both compounds are capable of reaching the central nervous system and would be active in the central nervous system.US Patent No. 5,480,651 discloses that after using an agent that increases acetylcholine in synapses or activates nicotinic acetylcholine receptors, an acetylcholine receptor antagonist is administered to reduce the craving associated with nicotine addiction. A preferred composition uses physostigmine, an inhibitor of acetylcholinesterase, as opposed to a muscarinic activator that would not activate nicotinic acetylcholine receptors. WO 03 / 092580 discloses compounds that can act as muscarinic activators at certain receptor subtypes and at the same time as antagonists at other receptor subtypes. Several groups have combined various muscarinic activators and muscarinic inhibitors in the context of trying to distinguish the role of various muscarinic subtypes in drug pharmacology or normal physiology without suggesting the therapeutic use of the combination. Such studies include the use of cellular assays starting from animal material (e.g., Iwanaga K. et al. J. Pharmacol. Sci. 110:306. 2009). In US Patent Application Publication No. 2009 / 0318522, Paborji discloses the use of peripherally acting muscarinic antagonists targeting M2 and M3 receptors for the treatment of overactive bladder. Paborji's publication also discloses the use of peripherally acting muscarinic M2 / M3 agonists to prevent the dry mouth associated with peripherally acting M2 / M3 muscarinic antagonists. However, Paborji's approach does not relate to the activity at muscarinic receptors in the CNS, which is crucial to the research described herein, nor to the activity at either M1 or M4 receptors. Paborji's approach is very limited to specific muscarinic inhibitors, and does not provide any selection criteria for identifying preferred or defined combinations of muscarinic activators and muscarinic antagonists, despite the large number of possible combinations that can be experimentally tested.

[0052] Methods of Using Muscarinic Activators in Combination with Muscarinic Inhibitors In one embodiment of the present invention, one or more muscarinic activators are combined with one or more muscarinic inhibitors to treat muscarinic disorders. In a preferred embodiment, such disorders or diseases include schizophrenia and disorders related to schizophrenia. In another embodiment, one or more muscarinic activators are combined with one or more muscarinic inhibitors to treat mood disorders. In another embodiment, one or more muscarinic activators are combined with one or more muscarinic inhibitors to treat movement disorders. In another embodiment, one or more muscarinic activators are combined with one or more muscarinic inhibitors to treat cognitive disorders, including using the combination to enhance cognitive function not associated with a specific pathology. For example, improved cognition can be important in performing complex tasks. In another embodiment, one or more muscarinic activators are combined with one or more muscarinic inhibitors to treat attention disorders. In addition to disease treatment, enhancing attention can improve learning and reduce symptoms related to fatigue due to both sleep deprivation and circadian rhythm disruptions such as jet lag. In another embodiment, to treat an addictive disorder, one or more of muscarinic Activators are used in combination with one or more muscarinic Inhibitors.

[0053] In another embodiment, a combination of one or more muscarinic Activators and one or more muscarinic Inhibitors can be used to treat muscarinic diseases characterized by symptomatic improvement in response to an inhibitor of the cholinesterase enzyme. Cholinesterase inhibitors have been shown to be therapeutically effective against certain diseases (e.g., Alzheimer's disease), but the use of such inhibitors is limited due to toxicity. Indeed, potent chemical weapons such as Sarin gas exert their toxic effects by inhibiting acetylcholinesterase (Material Safety Data Sheet for Sarin Gas 103d Congress, 2d Session. United States Senate. May 25, 1994. http: / / www.gulfweb.org / bigdoc / report / appgb.html). A combination of one or more muscarinic Activators and one or more muscarinic Inhibitors is not only a safer method of treating diseases that have been shown to respond to cholinesterase inhibitors, but also a more effective method given the current limitations on cholinesterase inhibitors.

[0054] In one embodiment, the combination of one or more muscarinic activators and one or more muscarinic inhibitors is used to treat animals. In a further embodiment, the animal is a mammal. In a preferred embodiment, the mammal is a human. In one embodiment, one muscarinic activator and one muscarinic inhibitor are used. In another embodiment, two or more muscarinic activators and / or two or more muscarinic inhibitors are used.

[0055] In one embodiment, the use of the inhibitor reduces the side effects associated with the use of the active agent. Such side effects include, but are not limited to, gastrointestinal (GI) side effects, cardiac side effects, excessive sweating and excessive salivation. The combination of one or more inhibitors with one or more active agents allows the active agent to be used clinically when its side effects would otherwise prevent it from being used clinically. In another embodiment, the combination of the inhibitors with the active agent allows the active agent to achieve a higher maximum tolerated dose than it would otherwise achieve.

[0056] To demonstrate the efficacy of both the activator and inhibitor combinations of the above-mentioned embodiments, various methods may be used that are time-consuming and resource-intensive. To demonstrate the efficacy of new treatments for schizophrenia, animal models are used, including both pharmacological models (e.g., ketamine model) and genetic models (e.g., DISCI mice) (Dawe GS et al. Ann Acad Med Singapore. 38:425. 2009; Desbonnet L. Biochem Soc Trans. 37:308. 2009; Geyer MA. Neurotox Res. 14:71. 2008). Similarly, animal models, including rodents, dogs and non-human primates, may be used to demonstrate the side effect profile of drugs. Although animal models serve as experimental surrogates for humans, they may have deficiencies related to physiological differences between humans and animals, and therefore may have limited predictive power for transition to clinical trials, especially for central nervous system diseases. Alternatively, the combination may be tested in human comparative clinical trials. Various side effects, such as gastrointestinal (GI) discomfort, can be assessed by one skilled in the art using standard scales based on patient self-report. As another example, one skilled in the art may use objective physiological scales (e.g., EKG). A series of standard scales have also been developed to assess symptoms of schizophrenia, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Symptoms Scale (PANSS), and the Clinical Global Impression (CGI) (Mortimer AM. Br J Psychiatry Suppl. 50:s7. 2007). Clinical trials are usually conducted in a double-blind fashion, with one group of patients receiving a placebo and the other group receiving the active intervention.

[0057] In one embodiment of the invention, the muscarinic Activator is administered simultaneously with the muscarinic Inhibitor. In another embodiment, the muscarinic inhibitor is administered sequentially with the Activator. In a further embodiment, the muscarinic Activator is administered prior to administration of the muscarinic inhibitor. In another embodiment, the muscarinic inhibitor is administered prior to administration of the muscarinic Activator. In one embodiment, the muscarinic inhibitor is administered within 1 hour of administration of the muscarinic Activator. In another embodiment, the muscarinic inhibitor is administered within 30 minutes of administration of the muscarinic Activator. In another embodiment, the muscarinic inhibitor is administered within 10 minutes of administration of the muscarinic Activator. In another embodiment, the muscarinic inhibitor is administered within 1 minute of administration of the muscarinic Activator. In another embodiment, the muscarinic inhibitor is administered within 30 seconds of administration of the muscarinic Activator. Prior to the initiation of the dosing regimen of the type outlined above, there may be a lead-in period lasting from 1 day to 14 days. During this lead-in period, the muscarinic inhibitor may be given alone prior to initiating administration of the combination.

[0058] In one embodiment, 10 micrograms to 10 grams of active agent are used in combination with the inhibitor. In another embodiment, 1 milligram to 1 gram of active agent are used in combination with the inhibitor. In a preferred embodiment, 5 to 500 milligrams of active agent are used. In one embodiment, 10 micrograms to 10 grams of inhibitor are used in combination with the active agent. In another embodiment, 1 milligram to 1 gram of inhibitor are used in combination with the active agent. In a preferred embodiment, 2.5 milligrams to 200 milligrams of inhibitor are used.

[0059] In one embodiment, the muscarinic Activator and Inhibitor are administered to the patient six times per 24 hours. In another embodiment, the muscarinic Activator and Inhibitor are administered to the patient five times per 24 hours. In another embodiment, the muscarinic Activator and Inhibitor are administered to the patient four times per 24 hours. In a preferred embodiment, the muscarinic Activator and Inhibitor are administered to the patient three times per 24 hours. In another preferred embodiment, the muscarinic Activator and Inhibitor are administered to the patient two times per 24 hours. In another preferred embodiment, the muscarinic Activator and Inhibitor are administered to the patient once per 24 hours.

[0060] In silico testing of muscarinic combinations There are currently 65 unique muscarinic Activators and 114 unique muscarinic Inhibitors known (Adis R&D Insight™, Pubmed, Web of Science, US FDA Orange Book, U.S. Patent No. 5,852,029). Thus, there are 7,410 possible combinations in which one muscarinic Activator can be combined with one muscarinic Inhibitor. If two or more muscarinic Activators are combined with one or more muscarinic Inhibitors, the number of combinations would be even greater. Although several animal models exist for related diseases such as schizophrenia (Dawe GS et al. Ann Acad Med Singapore. 38:425. 2009; Desbonnet L. Biochem Soc Trans. 37:308. 2009; Geyer MA. Neurotox Res. 14:71. 2008), animal models of complex diseases such as schizophrenia are incomplete, so the ability to predict efficacy and side effect burden in humans based on animal data may be limited. Similarly, it is possible to test combinations in humans suffering from a particular disease such as schizophrenia when standard metrics exist for both efficacy and side effects of treating the disease (Mortimer AM. Br J Psychiatry Suppl. 50:s7. 2007). However, testing such a large number of combinations in either animal models of the disease or, more importantly, in human clinical trials is practically impossible as it would be very costly and may take decades due to constraints on the number of skilled investigators present and the time required for patient recruitment.

[0061] Without a way to test and predict the efficacy of a given combination, it is extremely difficult to predict in advance whether such a combination will be effective. For example, Medina et al. administered the muscarinic agonist xanomeline and the muscarinic antagonist methscopolamine to see if the syncope observed as a side effect of xanomeline could be modulated by a muscarinic antagonist (Medina et al. Hypertension. 29:828. 1997). The group observed no effect on syncope. This may reflect that the muscarinic system is not involved in syncope or may reflect an inappropriate choice of muscarinic combination. Similarly, Maral et al. demonstrated the combination of the muscarinic agonist RS-86 with the anticholinergic glycopyrrolate for the treatment of Alzheimer's disease (Maral et al. Neurology. 38:606. 1988). This approach did not result in any improvement in cognition, despite the use of increasing doses of RS-86. US Patent Application Publication No. 2006 / 0194831 discloses the use of clozapine derivatives to activate muscarinic receptors. US Patent Application Publication No. 2006 / 0194831 discloses that the use of clozapine derivatives can be combined with another treatment selected from a wide list of treatments including the use of muscarinic antagonists, but this publication does not provide guidance or rationale for, for example, why a particular agent should be selected from a wide list of combinations with clozapine derivatives, or why such combinations would be useful. US Patent No. 5,852,029, which discloses certain muscarinic agonists, describes the possibility of combining muscarinic antagonists with certain agonists, which helps to eliminate side effects, but does not provide any criteria for selecting suitable antagonists.

[0062] The failure of groups such as Maral et al. indicates that combinations of muscarinic activators and inhibitors must be carefully selected and ideally tested. Given the impractical nature of physically testing such a large number of combinations, the inventors have created an algorithm for in silico testing to perform the extremely difficult task of predicting in advance whether a given combination will be effective and safe without in vivo testing. To perform in silico testing based on this algorithm, the inventors have created an extensive database of known information about muscarinic activators and inhibitors. The way in which the inventors created this unique algorithm and database of muscarinic agonists and their properties was multi-step and resource intensive. First, the inventors created a list of all known muscarinic activators and inhibitors. Then, the inventors selected the properties of muscarinic agonists that are useful for predicting effective and safe combinations and determined the relative importance of each property. Next, the inventors undertook an extensive data collection process to collect as much data as possible related to each characteristic of each muscarinic activator and muscarinic inhibitor. After obtaining this data, the inventors created a computer-based algorithm that calculates a score for each characteristic and each combination, and then uses these scores to generate an overall score for each combination. A rating system was created such that a higher total score ("θ score") is applied to combinations that are more likely to be effective with tolerable side effects. Thus, by testing each combination using this algorithm, the inventors create a prioritized list of combinations, whereby combinations with higher scores are more attractive candidates for clinical trials. Given the impracticality of testing every possible combination in vivo, prioritization is important for selecting combinations to test in humans.

[0063] To evaluate various combinations of muscarinic Activators and Inhibitors, the inventors created a proprietary database of all known muscarinic Activators and Inhibitors (see Tables 2 and 3). This database was created by systematically searching various resources for all current and past programs related to muscarinic Activators and Inhibitors. The inventors' search included academic literature databases such as Pubmed and Web of Science, patent databases such as Delphion, and pharmaceutical research and development databases such as Adis R&D Insight™. The inventors also searched drug package inserts, newspaper databases, company websites, and conference abstracts. In total, the inventors searched thousands of journal publications, patents, Adis records, and other literature to create a comprehensive database of 65 muscarinic Activators and 114 muscarinic Inhibitors.

[0064] Next, the inventors selected properties that are useful for predicting whether a given combination will be effective with acceptable side effects. In other words, the inventors determined criteria by which each combination can be evaluated to perform a quantitative predictive evaluation. This method of selecting relevant properties was driven by rigorous internal analysis, and identified several properties that are not usually considered and / or are usually considered unfavorable, but that the inventors considered favorable. The combination therapy approach in this application is quite different from the usual combination therapy approach, which requires looking for synergistic efficacy of two agents. In this invention, the inventors look for one agent that counteracts the effect of the other agent, which results in unconventional drug selection criteria. For example, the inventors evaluated each muscarinic inhibitor based on efficacy data, so that in some cases, low or weak efficacy data was rewarded. Also, in contrast to the usual approach, the inventors reviewed the muscarinic inhibitors in some cases for side effects that were exhibited during clinical development. Most muscarinic inhibitors have been tested for unrelated indications, such as overactive bladder, so their efficacy for these unrelated indications may be undesirable and may predict combinations that may have unacceptable side effects.For example, polyuria is not a commonly reported side effect of muscarinic activators.Therefore, giving the inhibitor with the greatest ability to reduce urination may be the greatest risk of causing urinary retention without providing the benefits of combination.

[0065] The inventors have reviewed certain side effects, particularly those known to be associated with peripheral anticholinergic effects, because peripheral anticholinergic effects may eliminate or reduce the impact of the side effects of muscarinic activators. This combination of reviewed side effects with reviewed weak efficacy leads to the selection of muscarinic inhibitors with physiological effects over the periphery that are desirable for eliminating the side effects of muscarinic activators. For example, if a compound shows efficacy in treating overactive bladder without any side effects, this would suggest that the compound inhibits muscarinic receptors in the bladder but not so much in the gastrointestinal tract or salivary glands. Such a compound would be ideal for a drug whose intended purpose is the treatment of overactive bladder, but such a compound would not be preferred for the uses described herein. A more preferred inhibitor for the envisioned combination would show a pharmacological effect (i.e., the side effects observed when treating overactive bladder) in the same organ (e.g., gastrointestinal tract) in which the activator causes undesirable side effects. The review of side effects and adverse efficacy ratings contrast with the usual methods for selecting medicines.

[0066] Our exhaustive selection process resulted in 95 relevant properties based on which each of the 7,410 combinations of known muscarinic activators and inhibitors can be evaluated. These properties are classified into three categories: properties associated only with muscarinic activators; properties associated only with muscarinic inhibitors; and properties that combine attributes of both activators and inhibitors. These classifications are explained in detail below.

[0067] To collect data for each muscarinic activator and muscarinic inhibitor based on each property, we engaged in a rigorous data collection process using many of the same resources used to create a database of all known muscarinic activators and muscarinic inhibitors. Our research also spanned academic literature databases such as Pubmed and Web of Science, patent databases such as Delphion, pharmaceutical research and development databases such as Adis R&D Insight™ and the US FDA Orange Book, as well as drug package inserts and other resources. However, this process differed in the detailed and often quantitative nature of the information extracted. For example, we collected and classified all known efficacy and side effect data for each muscarinic activator and muscarinic inhibitor. We also collected all known data on pharmacokinetics and pharmacodynamics. When new data is entered for compounds currently in our database, or when information is entered about the prospect of a new entry in our database, an update of the database can be performed, which will result in a new θ score. For example, MCD 386 is a muscarinic Activator where the addition of data could increase the theta scores for combinations of muscarinic Activators and Inhibitors that include MCD 386.

[0068] The inventors then used these data to create a computer-based algorithm to quantify the relative probability that each muscarinic Activator and Inhibitor combination would be effective with acceptable side effects. The scoring system worked by applying a score to each combination based on each characteristic, which the inventors call a p-score. Each p-score contributed to an overall calculation, with higher p-scores indicating that the combination was more likely to be effective with acceptable side effects based on the given characteristics. The algorithm tested all 7,410 possible combinations, each of which was scored based on a p-score of 95, so that the algorithm compiled a total of 703,950 p-scores when it calculated a unique overall score ("θ-score") for each combination (see Table 1).

[0069] Given the varying nature of the data for each attribute, different assessment methods were used to generate p-scores. In each case, the assessment methods were consistent within the range of a given attribute, resulting in a maximum value of 10, which was further multiplied by a "weight factor." The weight factor was used to reflect the importance of each attribute in predicting the probability that a combination would be effective with acceptable side effects. Some attributes, such as those related to the demonstration of agonist efficacy, were weighted more heavily because they have a stronger influence in assessing favorable combinations. The baseline weight factor for all attributes was 1, and the maximum weight factor used was 2.

[0070] The main methods used to generate p-scores were rank-based scoring, binary scoring, and value cut-off scoring. The mechanics of each of these methods are detailed below: · A ranking-based p-score was generated using quantitative data such as efficacy measures, with the highest value (e.g., a score of 10) given to the most favorable data point and the lowest value (e.g., a score of 0) given to the least favorable data point. The remaining values ​​were then distributed linearly such that less favorable data points were given proportionally lower scores. Finally, a weighting factor was applied to each value by multiplying each score by a predefined weight reflecting the importance of a given attribute. Take for example the case where three muscarinic inhibitors (Inhibitor A, Inhibitor B, and Inhibitor C) are evaluated based on their demonstrated reduction in urinary frequency (number of urinations per 24 hours), such that the smallest reduction, or lowest efficacy, is required. In this case, Inhibitor A shows a reduction of one urination per 24 hours, while Inhibitors B and C show values ​​of two and four, respectively. To calculate each p-score, we must first give inhibitor A a proportionally higher value than B or C because inhibitor A showed the most favorable results (e.g., inhibitors A, B, and C are given values ​​of 1, ½, and ¼, respectively). We then linearly distribute these values ​​such that inhibitor A receives a score of 10, inhibitor B receives a score of 5, and inhibitor C receives a score of 2.5. Finally, we multiply these scores by a weighting factor (which in this case could be 1) to obtain final p-scores of 10, 5, and 2.5. · Binary p-scores were generated by assigning one of two values ​​associated with the binary trait. Take the case of two muscarinic activators, A and B, which are evaluated based on whether they have shown efficacy in clinical trials. Muscarinic activator A, which has shown efficacy, is given a value of 10, while B, which has not shown efficacy, receives a score of 0. As this important trait has a weighting factor of 2, muscarinic activators A and B receive a final p-score of 20 and 0, respectively. A p-score with cut-off values ​​was applied based on the group into which a given value falls. This method was used in non-binary cases where a ranking method was not preferred or possible (e.g., scoring qualitative data or scoring quantitative data where a cut-off is relevant). In these cases, the muscarinic activator or inhibitor whose value falls into the most desirable category was given a value of 10 (before multiplying by the corresponding weighting factor).

[0071] The p-scores applied to each combination were summed to generate three unique subscores: Activator Independent Subscore, Inhibitor Independent Subscore, and Combination Subscore. The Activator Independent Subscore represents an assessment of each agonist based on its properties independent of the antagonist with which it is combined (e.g., demonstration of efficacy in clinical trials). Similarly, the Inhibitor Independent Subscore represents an assessment of each antagonist based on its properties independent of the agonist with which it is combined (e.g., level of CNS penetration). In contrast, the Combination Subscore represents an assessment of each antagonist based on its properties independent of the agonist with which it is combined (e.g., T-test based on pharmacokinetic studies). max The p-scores represent ratings based on the similarity of the p-scores (similarity of the p-scores between the activator and inhibitor independent subscores). For both the activator independent and inhibitor independent subscores, values ​​were calculated by summing the individual p-scores and then normalizing each score such that the highest ranked entry was given a score of 100, with each lower ranked entry being proportionally increased or decreased by the same factor as the highest ranked entry. When calculating combination subscores, the same principles were applied; however, the maximum score awarded was 50.

[0072] Finally, the algorithm generated a final "θ score" for each combination such that as the θ score increases, so does the probability that the combination will achieve efficacy with tolerable side effects. The θ score was calculated by summing the three subscores.

[0073] [Table 1]

[0074] [Table 2]

[0075] [Table 3]

[0076] The algorithm was constructed using the input data listed in the following three tables. The Attribute, Scoring Method, Criteria for High Score, and Weight columns in each table represent the basic input data and mechanisms used in calculating each subscore.

[0077] [Table 4]

[0078] [Table 5]

[0079] [Table 6]

[0080] [Table 7]

[0081] [Table 8]

[0082] [Table 9]

[0083] In a preferred embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 230 or greater as determined by in silico testing using the above algorithm is used. In another embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 200 or greater as determined by in silico testing using the above algorithm is used. In another embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 150 or greater as determined by in silico testing using the above algorithm is used. In a further embodiment of the invention, a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 149 or less as determined by in silico testing using the above algorithm is used.

[0084] In one embodiment, xanomeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, xanomeline is administered to the patient 1 to 5 times per 24 hours. In a preferred embodiment, xanomeline is administered 1 to 3 times per 24 hours. In another embodiment, 25 milligrams to 700 milligrams of xanomeline are used in a 24 hour period. In a preferred embodiment, 75 milligrams to 300 milligrams of xanomeline are used in a 24 hour period.

[0085] In one embodiment, sabcomeline is used in combination with a muscarinic inhibitor as a muscarinic activator. In another embodiment, sabcomeline is administered to a patient 1 to 5 times per 24 hours. In a preferred embodiment, sabcomeline is administered 1 to 3 times per 24 hours. In another embodiment, 50 micrograms to 5 milligrams of sabcomeline are used in a 24 hour period. In a preferred embodiment, 150 micrograms to 450 micrograms of sabcomeline are used in a 24 hour period.

[0086] In one embodiment, miramelin is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, miramelin is administered to the patient 1-5 times per 24 hours. In a preferred embodiment, miramelin is administered 1-3 times per 24 hours. In another embodiment, 0.5 milligrams to 50 milligrams of miramelin are used in a 24 hour period. In a preferred embodiment, 4 milligrams to 16 milligrams of miramelin are used in a 24 hour period.

[0087] In one embodiment, talsaclidine is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, talsaclidine is administered to the patient 1 to 5 times per 24 hours. In a preferred embodiment, talsaclidine is administered 1 to 3 times per 24 hours. In another embodiment, 5 milligrams to 1 gram of talsaclidine is used in a 24 hour period. In a preferred embodiment, 120 milligrams to 480 milligrams of talsaclidine is used in a 24 hour period.

[0088] In one embodiment, cevimeline is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, cevimeline is administered to a patient 1 to 5 times per 24 hours. In a preferred embodiment, cevimeline is administered 1 to 3 times per 24 hours. In another embodiment, 45 milligrams to 750 milligrams of cevimeline are used in a 24 hour period. In a preferred embodiment, 90 milligrams to 360 milligrams of cevimeline are used in a 24 hour period.

[0089] In one embodiment, pilocarpine is used as the muscarinic Activator in combination with the muscarinic Inhibitor. In another embodiment, pilocarpine is administered to the patient 1 to 5 times per 24 hours. In a preferred embodiment, pilocarpine is administered 1 to 3 times per 24 hours. In another embodiment, 7.5 milligrams to 500 milligrams of pilocarpine are used in a 24 hour period. In a preferred embodiment, 30 milligrams to 200 milligrams of pilocarpine are used in a 24 hour period.

[0090] In one embodiment, trospium chloride is used in combination with the muscarinic Activator as a muscarinic Inhibitor. In another embodiment, trospium chloride is administered to the patient 1 to 5 times per 24 hours. In a preferred embodiment, trospium chloride is administered 1 to 3 times per 24 hours. In another embodiment, 5 milligrams to 400 milligrams of trospium chloride are used in a 24 hour period. In a preferred embodiment, 20 milligrams to 200 milligrams of trospium chloride are used in a 24 hour period.

[0091] In one embodiment, sustained release trospium chloride is used in combination with the muscarinic Activator as a muscarinic Inhibitor. In another embodiment, sustained release trospium chloride is administered to the patient 1-5 times per 24 hours. In a preferred embodiment, sustained release trospium chloride is administered 1-3 times per 24 hours. In another embodiment, 5 milligrams to 400 milligrams of sustained release trospium chloride are used in a 24 hour period. In a preferred embodiment, 20 milligrams to 200 milligrams of sustained release trospium chloride are used in a 24 hour period.

[0092] In one embodiment, solifenacin is used in combination with the muscarinic activator as a muscarinic inhibitor. In another embodiment, solifenacin is administered to the patient 1 to 5 times per 24 hours. In a preferred embodiment, solifenacin is administered 1 to 3 times per 24 hours. In another embodiment, 0.25 milligrams to 100 milligrams of solifenacin are used in a 24 hour period. In a preferred embodiment, 1 milligram to 30 milligrams of solifenacin are used in a 24 hour period.

[0093] In one embodiment, tolterodine is used in combination with the muscarinic Activator as a muscarinic Inhibitor. In another embodiment, tolterodine is administered to the patient 1 to 5 times per 24 hours. In a preferred embodiment, tolterodine is administered 1 to 3 times per 24 hours. In another embodiment, 1 milligram to 16 milligrams of tolterodine are used in a 24 hour period. In a preferred embodiment, 2 milligrams to 8 milligrams of tolterodine are used in a 24 hour period.

[0094] In one embodiment, fesoterodine is used as a muscarinic Inhibitor in combination with a muscarinic Activator. In another embodiment, fesoterodine is administered to a patient 1 to 5 times per 24 hours. In a preferred embodiment, fesoterodine is administered 1 to 3 times per 24 hours. In another embodiment, 2 milligrams to 56 milligrams of fesoterodine are used in a 24 hour period. In a preferred embodiment, 4 milligrams to 28 milligrams of fesoterodine are used in a 24 hour period.

[0095] In one embodiment, darifenacin is used in combination with the muscarinic activator as a muscarinic inhibitor. In another embodiment, darifenacin is administered to a patient 1 to 5 times per 24 hours. In a preferred embodiment, darifenacin is administered 1 to 3 times per 24 hours. In another embodiment, 3.75 milligrams to 150 milligrams of darifenacin are used in a 24 hour period. In a preferred embodiment, 7.5 milligrams to 30 milligrams of darifenacin are used in a 24 hour period.

[0096] While the subject is being treated, the patient's health can be monitored by measuring one or more of the relevant indicators at a given time during the treatment period.The treatment, including the composition, amount, and frequency of administration and formulation, can be optimized according to the results of such monitoring.The patient can be periodically reevaluated to determine the degree of improvement by measuring the same parameters.Adjustments can be made to the amount of the composition of the present invention administered and, optionally, the frequency of administration, based on these reevaluations.

[0097] Treatment may be initiated with smaller doses that are less than the optimum amount of the compound, and the dose may then be increased by small increments until an optimal balance between therapeutic effect and side effects is obtained.

[0098] Combination dosage form In one embodiment, the muscarinic Activator and the muscarinic Inhibitor are different in dosage form or administration vehicle. In a preferred embodiment, the muscarinic Activator and the muscarinic Inhibitor are the same in dosage form or administration vehicle. The dosage form may include one or more pharma- ceutically acceptable carriers. The dosage form may also include one or more pharma- ceutically acceptable salts. The dosage form may be administered orally. The Activator and the Inhibitor may be delivered orally using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, caplets, or gel capsules, and other oral administration methods known to those skilled in the art. The muscarinic Activator and the muscarinic Inhibitor may also be administered parenterally. Other routes of administration include, but are not limited to, topical, transdermal, nasal, intraocular, rectal, sublingual, inhalation, and vaginal. For topical and transdermal administration, the Activator and the Inhibitor may be delivered in creams, gels, ointments, sprays, suspensions, emulsions, foams, or patches, or by other methods known to those skilled in the art. For nasal administration, the active agent and the inhibitor can be delivered by spray, drops, emulsion, foam, cream, ointment or other methods known to those skilled in the art. For nasal administration, the formulation for inhalation can be prepared as either a solution aerosol where the active agent is solubilized in a carrier such as a propellant, or a dispersion aerosol where the active agent is suspended or dispersed throughout a carrier and optional solvent. For intraocular administration, the active agent and the inhibitor can be delivered by drops, spray, injection, solution, emulsion, suspension, or ointment, or other methods known to those skilled in the art. For rectal administration, the active agent and the inhibitor can be delivered using a suppository, an enema, cream, foam, gel, or ointment, or other methods known to those skilled in the art. For sublingual administration, the active agent and the inhibitor can be delivered by tablet, troche, liquid, emulsion, suspension, drops, capsule, caplet or gel capsule, and other oral administration methods known to those skilled in the art. For administration by inhalation, the Activator and Inhibitor may be delivered in vapor, spray, powder, aerosol, or atomized form, or by other methods known to those of skill in the art. For intravaginal administration, the Activator and Inhibitor may be delivered in a solution, emulsion, suspension, ointment, gel, foam, or vaginal ring, or by other methods known to those of skill in the art.

[0099] The muscarinic activator and muscarinic inhibitor can be in a dosage form that releases the drug immediately. In an alternative embodiment, the muscarinic activator and muscarinic inhibitor are in a sustained release dosage form. In one embodiment of a sustained release dosage form, the activator and inhibitor have similar release rates. In another embodiment, the inhibitor is released before the activator is released. In another embodiment, a three-stage release profile is used, such that the inhibitor is released immediately, followed by a sustained release of the activator, and then a sustained release of the inhibitor. In one embodiment, the muscarinic activator and muscarinic inhibitor are placed in a liposome. In a further embodiment, the liposome comprises phospholipids. In further embodiments, the phospholipids in the liposomes are phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg phosphatidylethanolamine (EPE), egg phosphatidic acid (EPA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy phosphatidylinositol (SPI), soy phosphatidylethanolamine (SPE), soy phosphatidyl Hydrogenated egg phosphatidylcholine (HEPC), Hydrogenated soy phosphatidylcholine (HSPC), Dipalmitoyl phosphatidylcholine (DPPC), Dioleoyl phosphatidylcholine (DOPC), Dimyristoyl phosphatidylcholine (DMPC), Dimyristoyl phosphatidylglycerol (DMPG), Dipalmitoyl phosphatidylglycerol (DPPG), Distearoyl phosphatidylcholine (DSPQ), Distearoyl phosphatidylglycerol (DSPG), Dioleoyl phosphatidylethanolamine (DOPE), Palmitoyl stearoyl phosphatidylcholine (PSPC), Palmitoyl stearoyl phosphatidylglycerol (PSPG), Monooleoyl phosphatidylethanolamine (MOPE),The phosphocholine is selected from dilauroylethylphosphocholine (DLEP), dimyristoylethylphosphocholine (DMEP), dipalmitoylethylphosphocholine (DPEP), distearoylethylphosphocholine (DSEP), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA), dimyristoylphosphatidylinositol (DMPI), dipalmitoylphosphatidylinositol (DPPI), distearoylphosphatidylinositol (DSPI), dimyristoylphosphatidylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), distearoylphosphatidylserine (DSPS), N-acylated phosphorylethanolamine (NAPE), and combinations thereof.

[0100] In a further embodiment, the sustained release formulation comprises a semipermeable membrane. The muscarinic Activator and the muscarinic Inhibitor may be in different membranes in the same formulation. In another embodiment, the muscarinic Activator and the muscarinic Inhibitor may be in different membranes in different formulations or administration vehicles. In a further embodiment, the semipermeable membrane comprises a polymer. In a further embodiment, the sustained release formulation comprises a matrix that suspends the muscarinic Activator and the muscarinic Inhibitor. The muscarinic Activator and the muscarinic Inhibitor may be in different matrices in the same formulation. In a further embodiment, the matrix comprises a polymer. In a further embodiment, the polymer comprises a water-soluble polymer. In a further embodiment, the water-soluble polymer is selected from Eudragit RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof. In a further embodiment, the polymer comprises a water-insoluble polymer. In further embodiments, the water insoluble polymer is selected from Eudragit RS, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), low density poly(ethylene), high density poly(ethylene), poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and mixtures thereof. In further embodiments, the matrix comprises an aliphatic compound. In a further embodiment, the fatty compound is a wax or glyceryl tristearate.In a further embodiment, the polymer comprises a water soluble polymer and a water insoluble polymer, hi a further embodiment, the matrix further comprises a lipid compound.

[0101] The muscarinic Activators and Inhibitors may be formulated using other methods of sustained release formulations known to those skilled in the art (e.g., Dixit & Puthli. J. Control Release. 2:94. 2009; Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. 2008; Forqueri & Singh. Recent Pat Drug Deliv Formul. 3:40. 2009; Kalantzi et al. Recent Pat Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv Formul. 2:94. 2008; Panos et al. Curr Drug Discov Technol. 5:333. 2008; 2008. Wan et al. Nanomed. 2:483. 2007. Wang et al. Drug Delivery: Principles & Applications. Wiley 2005).

[0102] In another embodiment, the combination of muscarinic activator and muscarinic inhibitor is combined with one or more therapeutic agents, which may include both psychotherapy and drugs.The therapeutic agents include, but are not limited to, antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers and other pharmacological interventions known to those skilled in the art.The therapeutic agent may be classified into two or more drug categories.For example, benzodiazepines may be considered as anxiolytics, sedatives and tranquilizers.

[0103] Drugs containing one or more muscarinic activators and muscarinic inhibitors One embodiment of the present invention is a medicament comprising one or more muscarinic Activators and one or more muscarinic Inhibitors.

[0104] In one embodiment, 10 micrograms to 10 grams of active agent are combined with the inhibitor in the medicament. In another embodiment, 1 milligram to 1 gram of active agent are combined with the inhibitor. In another embodiment, 10 micrograms to 10 grams of inhibitor are combined with the active agent. In another embodiment, 1 milligram to 1 gram of inhibitor are combined with the active agent.

[0105] In one embodiment, the agent is administered to the patient six times per 24 hours. In another embodiment, the agent is administered to the patient five times per 24 hours. In another embodiment, the agent is administered to the patient four times per 24 hours. In another embodiment, the agent is administered to the patient three times per 24 hours. In another embodiment, the agent is administered to the patient two times per 24 hours. In another embodiment, the agent is administered to the patient once per 24 hours. In a preferred embodiment, the agent is administered one to three times per 24 hours.

[0106] In one embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 230 or greater as determined by in silico testing using the above algorithm. In another embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 200 or greater as determined by in silico testing using the above algorithm. In another embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 150 or greater as determined by in silico testing using the above algorithm. In a further embodiment of the invention, the medicament contains a combination of a muscarinic Activator and a muscarinic Inhibitor having a theta score of 149 or less as determined by in silico testing using the above algorithm. In a further embodiment, xanomeline is used as the muscarinic Activator in the medicament. In another embodiment, the medicament contains 5 milligrams to 700 milligrams of xanomeline. In a preferred embodiment, the medicament contains 25 milligrams to 300 milligrams of xanomeline.

[0107] In one embodiment, sabcomeline is used as the muscarinic activator in the medicament. In another embodiment, the medicament contains 10 micrograms to 5 milligrams of sabcomeline. In a preferred embodiment, the medicament contains 50 micrograms to 450 micrograms of sabcomeline.

[0108] In one embodiment, miramelin is used as the muscarinic active agent in the medicament. In another embodiment, the medicament contains 0.1 milligrams to 50 milligrams of miramelin. In a preferred embodiment, the medicament contains 1 milligram to 16 milligrams of miramelin.

[0109] In one embodiment, talsaclidine is used as the muscarinic active agent in the medicament. In another embodiment, the medicament contains 1 milligram to 1 gram of talsaclidine. In a preferred embodiment, the medicament contains 40 milligrams to 480 milligrams of talsaclidine.

[0110] In one embodiment, cevimeline is used as the muscarinic active agent in the medicament. In another embodiment, the medicament contains 9 milligrams to 750 milligrams of cevimeline. In a preferred embodiment, the medicament contains 30 milligrams to 360 milligrams of cevimeline.

[0111] In one embodiment, pilocarpine is used as the muscarinic activator in the medicament. In another embodiment, the medicament contains 1.5 milligrams to 500 milligrams of pilocarpine. In a preferred embodiment, the medicament contains 10 milligrams to 200 milligrams of pilocarpine.

[0112] In one embodiment, trospium chloride is used as the muscarinic inhibitor in the medicament. In another embodiment, the medicament contains 1 milligram to 400 milligrams of trospium chloride. In a preferred embodiment, the medicament contains 6.5 milligrams to 200 milligrams of trospium chloride.

[0113] In one embodiment, sustained release trospium chloride is used as the muscarinic inhibitor in the medicament. In another embodiment, the medicament contains 1 milligram to 400 milligrams of sustained release trospium chloride. In a preferred embodiment, the medicament contains 6.5 milligrams to 200 milligrams of sustained release trospium chloride.

[0114] In one embodiment, solifenacin is used as the muscarinic inhibitor in the medicament. In another embodiment, the medicament contains 0.25 milligrams to 100 milligrams of solifenacin. In a preferred embodiment, the medicament contains 1 milligram to 30 milligrams of solifenacin.

[0115] In one embodiment, tolterodine is used as the muscarinic inhibitor in the medicament. In another embodiment, the medicament contains 0.2 milligrams to 16 milligrams of tolterodine. In a preferred embodiment, the medicament contains 0.7 milligrams to 8 milligrams of tolterodine.

[0116] In one embodiment, fesoterodine is used as the muscarinic inhibitor in the medicament. In another embodiment, the medicament contains 0.4 milligrams to 56 milligrams of fesoterodine. In a preferred embodiment, the medicament contains 1 milligram to 28 milligrams of fesoterodine.

[0117] In one embodiment, darifenacin is used as the muscarinic inhibitor in the medicament. In another embodiment, the medicament contains 0.8 milligrams to 150 milligrams of darifenacin. In a preferred embodiment, the medicament contains 2.5 milligrams to 30 milligrams of darifenacin.

[0118] While the subject is being treated, the patient's health can be monitored by measuring one or more of the relevant indicators at a given time during the treatment period.The treatment, including the composition, amount, and frequency of administration and formulation, can be optimized according to the results of such monitoring.The patient can be periodically reevaluated to determine the degree of improvement by measuring the same parameters.Adjustments can be made to the amount of the composition of the present invention administered and, optionally, the frequency of administration, based on these reevaluations.

[0119] Treatment can be started with a lower dose that is less than the optimal amount of the compound.Then, the dose can be increased by small increments until the optimal balance between therapeutic effect and side effects is obtained.This principle of drug titration is well understood by those skilled in the art.

[0120] The agent may also include one or more pharma- ceutically acceptable salts. The agent may include one or more pharma- ceutically acceptable carriers. The agent may be administered orally. The agent may be delivered orally using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, caplets, or gel capsules, and other oral administration methods known to those skilled in the art. The agent may also be administered parenterally. Other routes of administration include, but are not limited to, topical, transdermal, nasal, rectal, ocular, sublingual, inhalation, and vaginal. For topical and transdermal administration, the agent may be delivered in creams, gels, ointments, sprays, suspensions, emulsions, foams, or patches, or by other methods known to those skilled in the art. For nasal administration, the agent may be delivered in sprays, drops, emulsions, foams, creams, or ointments, or by other methods known to those skilled in the art. For nasal administration, the formulation for inhalation can be prepared as either a solution aerosol, in which the active agent is solubilized in a carrier such as a propellant, or a dispersion aerosol, in which the active agent is suspended or dispersed throughout a carrier and optional solvent. For rectal administration, the drug can be delivered using a suppository, an enema, a cream, a foam, a gel, or an ointment, or by other methods known to those skilled in the art. For intraocular administration, the drug can be delivered in drops, sprays, injections, solutions, emulsions, suspensions, or ointments, or by other methods known to those skilled in the art. For sublingual administration, the drug can be delivered in tablets, lozenges, solutions, emulsions, suspensions, drops, capsules, caplets, or gel capsules, and by other oral administration methods known to those skilled in the art. For administration by inhalation, the drug can be delivered in steam, spray, powder, aerosol, or atomized form, or by other methods known to those skilled in the art. For vaginal administration, the agent may be delivered in a solution, emulsion, suspension, ointment, gel, foam, or vaginal ring, or by other methods known to those of skill in the art.

[0121] The agent may be in a dosage form that immediately releases the drug. In an alternative embodiment, the agent may have a sustained release dosage form. In one embodiment, the agent is encased in a liposome. In a further embodiment, the liposome comprises a phospholipid. In a further embodiment, the phospholipid in the liposome is phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid (PA), egg phosphatidylcholine (EPC), egg phosphatidylglycerol (EPG), egg phosphatidylinositol (EPI), egg phosphatidylserine (EPS), egg phosphatidylethanolamine (EP E), egg phosphatidic acid (EPA), soy phosphatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy phosphatidylserine (SPS), soy phosphatidylinositol (SPI), soy phosphatidylethanolamine (SPE), soy phosphatidic acid (SPA), hydrogenated egg phosphatidylcholine (HEPC), hydrogenated soy phosphatidylcholine (HSPC), dipalmitoylphosphatidylcholine (DPPC), dioleoylphosphatidylcholine ( DOPC), dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylcholine (DSPQ), distearoyl phosphatidylglycerol (DSPG), dioleoyl phosphatidylethanolamine (DOPE), palmitoyl stearoyl phosphatidylcholine (PSPC), palmitoyl stearoyl phosphatidylglycerol ( PSPG), monooleoylphosphatidylethanolamine (MOPE), dilauroylethylphosphocholine (DLEP), dimyristoylethylphosphocholine (DMEP), dipalmitoylethylphosphocholine (DPEP), distearoylethylphosphocholine (DSEP), dimyristoylphosphatidic acid (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoylphosphatidic acid (DSPA), dimyristoylphosphatidylinositol (DMPI),The phosphatidyl ester is selected from dipalmitoyl phosphatidylinositol (DPPI), distearoyl phosphatidylinositol (DSPI), dimyristoyl phosphatidylserine (DMPS), dipalmitoyl phosphatidylserine (DPPS), distearoyl phosphatidylserine (DSPS), N-acylated phosphorylethanolamine (NAPE), and combinations thereof.

[0122] In a further embodiment, the sustained release formulation comprises a semipermeable membrane. The muscarinic Activator and the muscarinic Inhibitor may be in different membranes in the same formulation. In another embodiment, the muscarinic Activator and the muscarinic Inhibitor may be in different membranes in different formulations or administration vehicles. In a further embodiment, the semipermeable membrane comprises a polymer. In a further embodiment, the sustained release formulation comprises a matrix that suspends the muscarinic Activator and the muscarinic Inhibitor. The muscarinic Activator and the muscarinic Inhibitor may be in different matrices in the same formulation. In a further embodiment, the matrix comprises a polymer. In a further embodiment, the polymer comprises a water-soluble polymer. In a further embodiment, the water-soluble polymer is selected from Eudragit RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof. In a further embodiment, the polymer comprises a water-insoluble polymer. In further embodiments, the water insoluble polymer is selected from Eudragit RS, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), low density poly(ethylene), high density poly(ethylene), poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and mixtures thereof. In further embodiments, the matrix comprises an aliphatic compound. In a further embodiment, the fatty compound is a wax or glyceryl tristearate.In a further embodiment, the polymer comprises a water soluble polymer and a water insoluble polymer, hi a further embodiment, the matrix further comprises a lipid compound.

[0123] The drug may be in a dosage form using other methods of sustained release formulations known to those skilled in the art (e.g., Dixit & Puthli. J. Control Release. 2:94. 2009; Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. 2008; Forqueri & Singh. Recent Pat Drug Deliv Formul. 3:40. 2009; Kalantzi et al. Recent Pat Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv Formul. 2:94. 2008; Panos et al. Curr Drug Discov Technol. 5:333. 2008; Wan et al. Nanomed. 2:483. 2007. Wang et al. Drug Delivery: Principles & Applications. Wiley 2005).

[0124] In another embodiment, the drug is combined with one or more therapeutic methods, which may include both psychotherapy and drugs.Therapeutic agents include, but are not limited to, antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers, and other pharmacological interventions known to those skilled in the art.Therapeutic agents may be classified into two or more drug categories.For example, benzodiazepines may be considered as anxiolytics, sedatives, and tranquilizers.

[0125] The above-described advantages of the novel methods and compositions of the present invention are illustrated by the following non-limiting examples. EXAMPLES

[0126] Example 1 In one embodiment, the invention is a single capsule formulation containing 75 milligrams of xanomeline and 20 milligrams of trospium chloride. The capsule comprises a gelatin shell surrounding a fill material comprised of the active compound, a vehicle, a surfactant, and a modifier. The vehicle is a polyethylene glycol having a molecular weight in the range of 500-10,000 Daltons and is 10% by weight of the fill material. The surfactant is polysorbate 80 and represents 0.1% by weight of the fill material. The modifier is fumed silica present at 0.25% by weight of the fill material. The total fill material represents 50% of the total weight of the capsule and the gelatin shell is 50% of the total weight of the capsule.

[0127] Example 2 The second formulation is the capsule of Example 1 with the addition of an outer sustained release layer comprising an enteric material (a material that is relatively insoluble in the acidic environment of the stomach). There are a variety of enteric materials known to those skilled in the art. For this particular formulation, we use hydroxyethylcellulose, which may comprise 20% of the total weight of the capsule.

[0128] Example 3 The third example is a formulation prepared as in Example 2, in which the capsule contains 225 mg of xanomeline and 60 milligrams of trospium chloride.

[0129] Example 4 In one embodiment, the present invention is a single capsule formulation containing 75 milligrams of xanomeline and 5 milligrams of solifenacin. The capsule comprises a gelatin shell surrounding a fill material comprised of the active compound, a vehicle, a surfactant, and a modifier. The vehicle is a polyethylene glycol having a molecular weight in the range of 500-10,000 Daltons and is 10% by weight of the fill material. The surfactant is polysorbate 80 and represents 0.1% by weight of the fill material. The modifier is fumed silica present at 0.25% by weight of the fill material. The total fill material represents 50% of the total weight of the capsule and the gelatin shell is 50% of the total weight of the capsule.

[0130] Example 5 The second formulation is the capsule of Example 4 with the addition of an outer sustained release layer comprising an enteric material (a material that is relatively insoluble in the acidic environment of the stomach). There are a variety of enteric materials known to those skilled in the art. For this particular formulation, we use hydroxyethylcellulose, which may comprise 20% of the total weight of the capsule.

[0131] Example 6 The third example is a formulation prepared as in Example 5, where the capsule contains 225 mg of xanomeline and 10 milligrams of solifenacin.

[0132] References All publications and patents mentioned herein are incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the case of conflict, the present application, including definitions set forth herein, will control.

[0133] Equivalent While specific embodiments of the invention have been described, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.

[0134] Unless otherwise indicated, all numerical values ​​expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention.

Claims

1. A single capsule formulation containing xanthomerin or a salt thereof and tropisetron hydrochloride, wherein the formulation (a) contains 5 milligrams to 700 milligrams of xanthomerin, and (b) contains 6.5 milligrams to 200 milligrams of tropisetron hydrochloride and the amount of tropisetron hydrochloride reduces one or more side effects associated with xanthomerin or a salt thereof, a single capsule formulation.

2. The single capsule formulation according to claim 1, wherein one or more side effects associated with xanthomerin or a salt thereof include nausea, vomiting, diarrhea, sweating, excessive salivation, or a combination thereof.

3. The single capsule formulation according to claim 1, wherein xanthomerin or a salt thereof is xanthomerin tartrate.

4. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 25 milligrams to 300 milligrams of xanthomerin.

5. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 25 milligrams to 225 milligrams of xanthomerin.

6. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 25 milligrams of xanthomerin.

7. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 75 milligrams of xanthomerin.

8. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 20 milligrams to 200 milligrams of tropisetron hydrochloride.

9. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 20 milligrams to 60 milligrams of tropisetron hydrochloride.

10. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 6.5 milligrams of tropisetron hydrochloride.

11. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 20 milligrams of tropisetron hydrochloride.

12. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 75 milligrams of xanthomerin and 20 milligrams of tropisetron hydrochloride.

13. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation contains 225 milligrams of xanthomerin and 60 milligrams of tropisetron hydrochloride.

14. The single capsule formulation according to any one of claims 1 to 3, wherein the formulation further contains a pharmaceutically acceptable carrier.

15. The single capsule formulation of claim 14, wherein the pharmaceutically acceptable carrier is selected from cellulose, lactose, talc, and combinations thereof. **Claim 16** The single capsule formulation according to any one of claims 1 to 3, wherein the formulation is for oral administration.

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