US 201700.95465A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2017/0095465 A1 Elenko et al. (43) Pub. Date: Apr. 6, 2017

(54) METHODS AND COMPOSITIONS FOR application No. 13/592.480, filed on Aug. 23, 2012, TREATMENT OF DISORDERS now abandoned, which is a continuation of applica AMELORATED BY MUSCARNC tion No. 13/348,057, filed on Jan. 11, 2012, now RECEPTOR ACTIVATION abandoned, which is a continuation of application No. 12/840,980, filed on Jul. 21, 2010, now abandoned. (71) Applicant: PureTech Health LLC, Boston, MA (60) Provisional application No. 61/282,658, filed on Mar. (US) 15, 2010, provisional application No. 61/213,853, (72) Inventors: Eric Elenko, Boston, MA (US); filed on Jul. 22, 2009. Andrew C. Miller, East Walpole, MA (US); Philip E. Murray, III, Publication Classification Somerville, MA (US) (51) Int. Cl. A63L/46 (2006.01) (21) Appl. No.: 15/378,796 A69/48 (2006.01) A6II 3/4439 (2006.01) (22) Filed: Dec. 14, 2016 (52) U.S. Cl. Related U.S. Application Data CPC ...... A61K 31/46 (2013.01); A61K 31/4439 (2013.01); A61K 9/48 (2013.01) (63) Continuation-in-part of application No. 15/161,840, filed on May 23, 2016, now abandoned, which is a (57) ABSTRACT continuation of application No. 14/534,698, filed on Nov. 6, 2014, now abandoned, which is a continu Methods for the treatment of CNS disorders using combi ation of application No. 13/858,985, filed on Apr. 9. nations of muscarinic activators and inhibitors, and medi 2013, now abandoned, which is a continuation of caments comprising muscarinic activators and inhibitors. Patent Application Publication Apr. 6, 2017 Sheet 1 of 2 US 2017/009S465 A1

,{(8))ERHOOSWLEIHILauoose?aul Patent Application Publication Apr. 6, 2017 Sheet 2 of 2

US 2017/0095465 A1 Apr. 6, 2017

METHODS AND COMPOSITIONS FOR efficacy and severe side effects. There is little to no differ TREATMENT OF DISORDERS ence in efficacy between typical and atypical antipsychotics, AMELIORATED BY MUSCARINC most likely due to the fact that both classes of drugs achieve RECEPTOR ACTIVATION their therapeutic effect through the same pharmacological mechanisms (e.g., acting as dopamine receptor antagonists). FIELD OF INVENTION (Nikam et al. Curr Opin Investig Drugs. 9:37. 2008). Side effects of typical antipsychotics include abnormal move 0001. The present invention relates to: (1) a method of ment (e.g., rigidity) whereas atypicals have different but using a combination of one or more muscarinic agonists and equally significant side effects (e.g., major weight gain, one or more muscarinic antagonists for treatment of diseases cardiovascular effects, etc.). The side effect profile of current that are ameliorated by activation of muscarinic receptors antipsychotics further decreases compliance in a patient (e.g., Schizophrenia and related disorders); and (2) a medi population that is already frequently non-compliant. Thus, cament comprising one or more muscarinic agonists and one there exists a clear need for new therapeutics to treat or more muscarinic antagonists. Schizophrenia and related disorders (e.g., schizoaffective disorder). BACKGROUND OF THE INVENTION 0005 Clozapine is an example of an antipsychotic that 0002 The acetylcholine neurotransmitter system plays a has major side effects, including sialorrhea (hypersalivation) significant role in a variety of central nervous system (CNS) which occurs in up to 54% of patients. (Davydov and Botts, and peripheral functions. Acetylcholine signaling occurs Ann Pharmacother: 34:662. 2000). The exact mechanism of through two different families of receptors: nicotinic recep hypersalivation remains unknown. (Rogers and Shramko. tors and muscarinic receptors. Muscarinic cholinergic recep Pharmacotherapy. 20:109. 2000). Clozapine has a complex tors are G-protein coupled receptors with five different pharmacological profile with appreciable activity at a variety receptor subtypes (M1-M5) (Raedler et al. American Jour of receptors, including dopamine receptors, serotonin recep nal of Psychiatry. 160: 118. 2003), each of which are found tors, adrenergic receptors, muscarinic receptors and possibly in the CNS but have different tissue distributions. Activation others. (Coward. BrJ Psychiatry Suppl. 17:5. 1992). Inves of the muscarinic system through use of muscarinic agonists tigators have tried a variety of pharmacological approaches has been suggested to have the potential to treat several in an attempt to counteract sialorrhea, including botulinum diseases including Alzheimer's disease, Parkinson's disease, toxin (Kahl et al. Nervenarzt. 76:205. 2005) as well as the movement disorders and drug addiction. (US 2005/0085463: antipsychotics amisulpride (Croissant et al. Pharmacopsy Langmead et al. Pharmacology & Experimental Therapeu chiatry. 38:38. 2005) and sulpiride. (Kreinin et al. Isr J tics. 117: 232:2008). Genetic evidence has suggested a direct Psychiatry Relat Sci. 42:61. 2005). Efforts have focused link between the muscarinic system and both alcohol addic mostly on alpha2 adrenergic agonists as well as anti-cho tion (Luo X. Et al. Hum Mol Genet. 14:2421. 2005) and linergic drugs due to clozapine's known interaction with nicotine addiction (Mobascher A et al. Am J Med Genet B these receptors. Anti-muscarinic drugs such as pirenzepine Neuropsychiatr Genet. 5:684. 2010). M1 and M4 subtypes have shown efficacy in small scale trials (Schneider et al. have been of particular interest as therapeutic targets for Pharmacopsychiatry. 37:43. 2004), but other trials with the various diseases. For instance, the mood stabilizers lithium same agent found no effect. (Liu et at. J. Clin Psychophar and Valproic acid, which are used to treat bipolar depression, macol. 21.608. 2001). Alpha2 adrenergic agonist such as may exert their effects via the muscarinic system particularly clonidine (Singh et al., J Psychopharmacol. 19:426. 2005) through the M4 subtype receptor. (Bymaster & Felder. Mol have also shown efficacy in reducing sialorrhea in small Psychiatry: 7 Suppl 1:S57. 2002). scale trials. However, Syed et al. reported in a 2008 review 0003. Some of the strongest linkages to the muscarinic that there is inadequate data to guide clinical practice. (Syed system have been with schizophrenia, which is a serious et al. Cochrane Database Syst Rev. 16:3. 2008). mental illness affecting approximately 0.5-1% of the popu 0006) Another approach to the treatment of schizophrenia lation. (Arehart-Treichel. Psych News. 40:9. 2005). The has been use of muscarinic agonists. Muscarinic receptors disease is characterized by a set of symptoms that are are G-protein linked receptors that bind the neurotransmitter generally divided into three categories: 1) Positive symp acetylcholine. (Eglen R M. Auton Autacoid Pharmacol 26: toms (e.g., hallucinations, delusional thoughts, etc.); 2) 219. 2006). To date, five subtypes of muscarinic receptor Negative symptoms (e.g., social isolation, anhedonia, etc.); have been identified and are generally labeled M1, M2, M3, and 3) Cognitive symptoms (e.g., inability to process infor M4, and M5, respectively. (Caulfield MP et al. Pharmacol. mation, poor working memory, etc.). (Schultz. Am Fam Rev. 50: 279. 1998). These muscarinic subtypes vary in Physician. 75:1821. 2007). Patients who suffer from schizo terms of the affinity of various agonists and antagonists for phrenia both experience a major decline in quality of life and the receptors. A number of lines of evidence have suggested are at increased risk for mortality due to a number of factors, that the muscarinic system plays a significant role in the such as an increased suicide rate. (Brown et al. British pathology of schizophrenia. In particular, decreased expres Journal of Psychiatry. 177: 212. 2000). The cost of schizo sion of M1 and M4 receptor subtypes has been noted in phrenia to society is also significant as sufferers of schizo post-mortem studies in deceased schizophrenic patients. phrenia are much more likely to be incarcerated, homeless (Dean et al. Mol Psych. 1: 54. 1996). Likewise, SPECT or unemployed. imaging studies have shown decreased muscarinic availabil 0004 Today, antipsychotics are the mainstay of treatment ity in schizophrenia. (Raedler et al. Am J Psych. 160:118. for schizophrenia. The first generation of antipsychotics are 2003). generally known as “typical antipsychotics” while newer 0007. There is also pharmacological evidence implicat antipsychotics are generally called "atypical antipsychot ing activation of muscarinic receptors as a potential thera ics.” Both typical and atypical antipsychotics have limited peutic approach to schizophrenia. For example, the musca US 2017/00954.65 A1 Apr. 6, 2017

rinic antagonist Scopolamine, which is used to treat motion side effects associated with the agents binding certain sickness, produces cognitive impairment and delusions of muscarinic receptor Subtypes. A need exists for a method of the type seen in Schizophrenia. (Ellis et al. Int. J. Neurop using muscarinic agonists and for a medicament employing sychopharmacol. 9:175. 2006). More selective M1 agonists Such muscarinic agonists that would allow for the therapeu have been Suggested to potentiate glutamate signaling which tic effects associated with activation of muscarinic receptors, could help exert a therapeutic effect. (Jones et al. J. Neuro but with fewer side effects. sci. 28:10422. 2008). In a double-blind placebo controlled trial of Schizophrenic patients using Xanomeline, which has SUMMARY OF THE INVENTION preferential activity at the M1 and M4 receptors, alleviation 0011. In one embodiment, the present invention relates to of schizophrenia was observed. (Shekhar et al. Am. J. Psych. a method of treating diseases or conditions ameliorated by 165: 1033. 2008). However, because xanomeline also bound activation of the muscarinic system by administering one or to subtypes of receptors other than M1, a number of various more muscarinic “Activators (e.g., agonist, partial agonist, serious side effects were observed including GI side effects, co-agonist, physiological agonist, potentiator, stimulator, cardiac side effects and problems with hyper-salivation. allosteric potentiator, positive allosteric modulator or allos 0008. During the development of xanomeline, dose-lim teric agonist) and one or more muscarinic "Inhibitors” (e.g., ited adverse events were problematic and led to very high antagonist, partial antagonist, competitive antagonist, non discontinuation rates (including a 56% dropout rate in a competitive antagonist, uncompetitive antagonist, silent 26-week study of Alzheimer's disease) and eventually to antagonist, inverse agonist, reversible antagonist, physi discontinuation of Xanomeline development. Despite the ological antagonist, irreversible antagonist, inhibitor, revers earlier promise of targeting muscarinic acetylcholine recep ible inhibitor, irreversible inhibitor, negative allosteric tors for the treatment of CNS disorders as demonstrated in modulator, or allosteric antagonist). In a preferred embodi part by the clinical efficacy signal observed with Xanome ment, such diseases include Schizophrenia and related dis line, no active pharmaceutical industry development for orders. In a preferred embodiment, a single muscarinic Xanomeline has occurred for more than 15 years due to Activator and a single muscarinic Inhibitor are used. In a adverse events observed in previous studies. Many compa preferred embodiment, the combination of the Activator and nies have attempted to develop muscarinic acetylcholine Inhibitor has a score (“Theta score') above 230 as deter agonists for CNS disorders as is reflected in the collection of mined by in silico testing using a proprietary algorithm as muscarinic activators disclosed herein, but no such agonist described herein. In another embodiment, more than one has reached the market, due to problematic tolerability muscarinic Activator and/or more than one muscarinic profiles. The focus of these past development efforts has Inhibitor are used. been an attempt to use medicinal chemistry to develop a 0012. In another embodiment of the invention, the molecule that would be more tolerable, typically by attempt method of treatment can be applied to a mammal. In another ing to gain selectivity for the M1 and M4 muscarinic embodiment, the mammal is a human being. receptors subtypes over the M2 and M3 subtypes. The M2 0013. In one embodiment of the invention, the use of the and M3 subtypes are believed to be the main cause of the Inhibitor alleviates the side effects associated with use of the problematic adverse events with muscarinic activators, Activator. In another embodiment, use of the Inhibitor although M1 and M4 may play a role as well. allows for a higher maximum tolerated dose of the Activator. 0009. There is a need in the art to improve the tolerability 0014. In one embodiment, the muscarinic Activator may of xanomeline, which could permit the development of be taken sequentially with the Inhibitor. In another embodi Xanomeline as a potential first-in-class, novel-mechanism ment of the invention, the muscarinic Activator may be of-action agent for the treatment of cognitive and psychotic taken concurrently with the Inhibitor. In a preferred embodi symptoms across a number of disorders for which there is a ment of the invention, the Activator and Inhibitor are for significant medical need, including Schizophrenia, Alzheim mulated to be contained in the same dosage form or dosage er's disease, and others. In Schizophrenia, existing treat vehicle. In another embodiment of the invention, the mus ments rely upon activity at the dopamine and serotonin carinic Activator and Inhibitor are formulated to be in receptors, as was the case with the first antipsychotic, separate dosage forms or dosage vehicles. In one embodi chlorpromazine, which was discovered in 1952. For more ment, the Activator and Inhibitor are formulated in an than 60 years, the same fundamental pharmacology has immediate release dosage form. In another embodiment, provided the standard of care in schizophrenia. Current Activator and Inhibitor are formulated in a controlled release antipsychotics only have efficacy for positive symptoms dosage form. In another embodiment, either the Activator or while leaving negative and cognitive symptoms untreated. the Inhibitor is formulated in an immediate release dosage The lack of novel treatments over the last 60 years demon form, while the other is formulated in a controlled release strates the difficulty in developing new medicine in Schizo dosage form. phrenia. Alzheimer's disease is another therapeutic area in 0015. In another embodiment of the invention, the mus which it has proven extremely difficult to develop new carinic Activator and Inhibitor can be taken orally. The therapies, with a reported Success rate for molecules that Activator and Inhibitor may be given orally in tablets, enter clinical development being approved by regulatory troches, liquids, drops, capsules, caplets and gel caps or agencies for use of only 0.4% (Cummings et al., Alzheimers other such formulations known to one skilled in the art. Res. Ther: 2014 Jul. 3: 6(4):37). New treatments are des Other routes of administration can include but are not perately needed by patients in these areas, but development limited to: parenteral, topical, transdermal, ocular, rectal, has proved extremely difficult despite substantial effort from Sublingual, and vaginal. Scientist and drug developers around the world. 0016. In another embodiment of the invention, the mus 0010. To date, no one has been able to harness the carinic Activator and Inhibitor are administered either simul approach of employing muscarinic agonists because of the taneously or consecutively with other therapies for schizo US 2017/00954.65 A1 Apr. 6, 2017

phrenia. In one embodiment of the invention, the muscarinic 0026. The term “consisting is used to limit the elements Activator and Inhibitor are used simultaneously or sequen to those specified except for impurities ordinarily associated tially with psychotherapy. In another embodiment of the therewith. invention, the muscarinic Activator and Inhibitor are admin 0027. The term “consisting essentially of is used to limit istered either simultaneously or consecutively with other the elements to those specified and those that do not mate pharmacological therapies. Pharmacological therapies could rially affect the basic and novel characteristics of the mate include but are not limited to: antipsychotics, anxiolytics, rial or steps. anti-depressants, sedatives, tranquilizers and other pharma 0028. As used herein, unless otherwise specified, the term cological interventions known to one skilled in the art. “controlled release' is defined as a prolonged release pattern 0017. A separate embodiment of the invention is a medi of one or more drugs, such that the drugs are released over cament comprising both a muscarinic Activator and a mus a period of time. A controlled release formation is a formu carinic Inhibitor. In a preferred embodiment, the combina lation with release kinetics that result in measurable serum tion of the Activator and Inhibitor have a theta score above levels of the drug over a period of time longer than what 230 as determined by in silico testing using a proprietary would be possible following intravenous injection or fol algorithm as described herein. lowing administration of an immediate release oral dosage 0.018. In another embodiment of the invention, the medi form. Controlled release, slow release, Sustained release, cament can be taken orally. The medicament may be given extended release, prolonged release, and delayed release orally in tablets, troches, liquids, drops, capsules, caplets have the same definitions for the present invention. and gel caps or other such formulations known to one skilled 0029. The term “including is used herein to mean in the art. Other routes of administration can include but are “including but not limited to.” “Including and “including not limited to: parenteral, topical, transdermal, ocular, rectal, but not limited to are used interchangeably. Sublingual, and vaginal. 0030 The term “mammal’ is known in the art, and 0019. In another embodiment of the invention, the medi exemplary mammals include humans, primates, bovines, cament can be administered in conjunction with other thera porcines, canines, felines, and rodents (e.g., mice and rats). pies. In one embodiment of the invention, the medicament is 0031. The terms “parenteral administration' and “admin used simultaneously or sequentially with psychotherapy. In istered parenterally are art-recognized and refer to modes another embodiment of the invention, the medicament is of administration other than enteral and topical administra administered either simultaneously or consecutively with tion, usually by injection, and includes, without limitation, other pharmacological therapy. Such pharmacological intravenous, intramuscular, intraarterial, intrathecal, intraca therapy could include but is not limited to: antipsychotics, psular, intraorbital, intracardiac, intradermal, intraperito anxiolytics, anti-depressants, sedatives, tranquilizers and neal, transtracheal, Subcutaneous, Subcuticular, intra-articu other pharmacological interventions known to one skilled in lar, Subcapsular, Subarachnoid, intraspinal, and intrasternal the art. injection and infusion. 0020. These and other embodiments of the invention, and 0032. A “patient,” “subject” or “host” to be treated by the their features and characteristics, will be described in further Subject method may mean either a human or non-human detail in the description and claims that follow. mammal. 0033. The term “pharmaceutically-acceptable carrier is BRIEF DESCRIPTION OF THE DRAWINGS art-recognized and refers to a pharmaceutically-acceptable 0021 FIG. 1 illustrates the relationships among p-Scores, material, composition or vehicle, such as a liquid or Solid Subscores, and Theta Scores in accordance with the present filler, diluent, excipient, Solvent or encapsulating material, invention. involved in carrying or transporting any subject composition 0022 FIG. 2 illustrates features of the Study Design of or component thereof from one organ, or portion of the body, Example 7. to another organ, or portion of the body. Each carrier must be “acceptable' in the sense of being compatible with the DETAILED DESCRIPTION OF THE Subject composition and its components and not injurious to INVENTION the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include: Sugars, such as Definitions lactose, glucose and Sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as 0023 For convenience, before further description of the sodium carboxymethyl cellulose, ethyl cellulose and cellu present invention, certain terms employed in the specifica lose acetate; powdered tragacanth; malt, gelatin; talc, excipi tion, examples and appended claims are collected here. ents, such as cocoa butter and Suppository waxes; oils, such These definitions should be read in light of the remainder of as peanut oil, cottonseed oil, Safflower oil, Sesame oil, olive the disclosure and understood as by a person of skill in the oil, corn oil and soybean oil; glycols, such as propylene art. Unless defined otherwise, all technical and scientific glycol; polyols, such as glycerin, Sorbitol, mannitol and terms used herein have the same meaning as would be polyethylene glycol; esters, such as ethyl oleate and ethyl understood by a person of ordinary skill in the art. laurate; agar; buffering agents, such as magnesium hydrox 0024. The articles “a” and “an are used herein to refer to ide and aluminum hydroxide; alginic acid; pyrogen-free one or to more than one (i.e. to at least one) of the water, isotonic saline; Ringer's solution; ethyl alcohol; grammatical object of the article. By way of example, “an phosphate buffer Solutions; and other non-toxic compatible element’ means one element or more than one element. Substances employed in pharmaceutical formulations. 0025. The terms “comprise' and “comprising are used 0034. The term “pharmaceutically-acceptable salts.” in the inclusive, open sense, meaning that additional ele used interchangeably with “salts,' is art-recognized and ments may be included. refers to salts prepared from relatively non-toxic acids or US 2017/00954.65 A1 Apr. 6, 2017

bases including inorganic acids and bases and organic acids diseases or disorders whose symptoms include excessive and bases, including, for example, those contained in com movements, ticks and spasms. positions of the present invention. Suitable non-toxic acids 0041. The term “Mood Disorders” includes major include inorganic and organic acids such as acetic, benze depressive disorder, dysthymia, recurrent brief depression, nesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, minor depression disorder, bipolar disorder, mania and anxi fumaric, gluconic, glutamic, hydrobromic, hydrochloric, ety. isethionic, lactic, maleic, malic, mandelic, methanesulfonic, 0042. The term "Cognitive Disorders' refers to diseases mucic, nitric, pamoic, pantothenic, phosphoric, succinic, or disorders that are marked by cognitive deficit (e.g., having Sulfuric, tartaric acid, p-toluenesulfonic, hydrochloric, hyd abnormal working memory, problem solving abilities, etc.). robromic, phosphoric, and Sulfuric acids and the like. Diseases include but are not limited to Alzheimer's disease, 0035. The term “treating is art-recognized and refers to Parkinson's Disease, dementia (including, but not limited to, curing as well as ameliorating at least one symptom of any AIDS related dementia, Vascular dementia, age-related condition or disorder. dementia, dementia associated with Lewy bodies and idio 0036. The term “therapeutic agent' is art-recognized and pathic dementia), Pick's disease, confusion, cognitive deficit refers to any chemical moiety that is a biologically, physi associated with fatigue, learning disorders, traumatic brain ologically, or pharmacologically active Substance that acts injury, autism, age-related cognitive decline, and Cushings locally or systemically in a subject. Examples of therapeutic Disease, a cognitive impairment associated with auto-im agents, also referred to as “drugs.” are described in well mune diseases. known literature references such as the Merck Index (14" 0043. The term "Attention Disorders’ refers to diseases edition), the Physicians' Desk Reference (64" edition), and or conditions that are marked by having an abnormal or The Pharmacological Basis of Therapeutics (12" edition), decreased attention span. Diseases include but are not lim and they include, without limitation, medicaments; Vita ited to attention hyperactivity deficit disorder, attention mins; mineral Supplements; Substances used for the treat deficit disorder, Dubowitz Syndrome, FG Syndrome, ment, prevention, diagnosis, cure or mitigation of a disease Down's Syndrome, growth delay due to insulin-like growth or illness; substances that affect the structure or function of factor I deficiency, hepatic encephalopathy syndrome, and the body, or pro-drugs, which become biologically active or Strauss Syndrome. more active after they have been placed in a physiological 0044. The term "Addictive Disorders' refers to diseases environment. or conditions marked by addiction or Substance dependence as defined by the Diagnostic & Statistical Manual IV. Such 0037. The term “psychotherapy” refers to use of non disorders are characterized by physical dependence, with pharmacological therapies in which those skilled in the art drawal and tolerance to a particular Substance. Such Sub use a variety of techniques that involve verbal and other stances include but are not limited to alcohol, cocaine, interactions with a patient to affect a positive therapeutic amphetamines, opioids, benzodiazepines, inhalants, nico outcome. Such techniques include, but are not limited to, tine, barbiturates, cocaine and cannabis. Addictive Disorders behavior therapy, cognitive therapy, psychodynamic can also encompass behaviors that a patient does in a therapy, psychoanalytic therapy, group therapy, family coun compulsive, continual manner despite clear negative conse Seling, art therapy, music therapy, vocational therapy, quences. For instance, ludomania is recognized by those humanistic therapy, existential therapy, transpersonal skilled in the art as being an addictive behavior that often has therapy, client-centered therapy (also called person-centered devastating consequences. therapy), Gestalt therapy, biofeedback therapy, rational emo tive behavioral therapy, reality therapy, response based 0045. The term “Activator” means a molecule that can be therapy, Sandplay therapy, status dynamics therapy, hypno described as an agonist, partial agonist, co-agonist, physi sis and validation therapy. It is further understood that ological agonist, potentiator, stimulator, allosteric potentia psychotherapy may involve combining two or more tech tor, positive allosteric modulator, allosteric agonist or a niques and that a therapist can select and adjust the tech molecule that increases the activity or signaling of musca niques based on the needs of the individual patient and the rinic receptors through direct or indirect means. patient's response. 0046. The term "Inhibitor” means a molecule that can be described as an antagonist, partial antagonist, competitive 0038. The term “Muscarinic Disorder” refers to any antagonist, non-competitive antagonist, uncompetitive disease or condition that is ameliorated by activation of the antagonist, silent antagonist, inverse agonist, reversible muscarinic system. Such diseases include ones in which antagonist, physiological antagonist, irreversible antagonist, direct activation of muscarinic receptors themselves or inhi inhibitor, reversible inhibitor, irreversible inhibitor, negative bition of cholinesterase enzymes has produced a therapeutic allosteric modulator, allostericantagonist or a molecule that effect. decreases the activity or signaling of muscarinic receptors 0039. The terms “Diseases Related To Schizophrenia' through direct or indirect means. and “Disorders Related To Schizophrenia' include, but are 0047. The term “maximum tolerated dose” means the not limited to, Schizo-affective disorder, psychosis, delu highest dose of a drug or therapeutic that can be taken by sional disorders, psychosis associated with Alzheimer's dis patients without the patients’ experiencing intolerable side ease, psychosis associated with Parkinson's disease, psy effects. The maximum tolerated dose is typically determined chotic depression, bipolar disorder, bipolar with psychosis, empirically in clinical trials. Huntington's disease, Lewy Body dementia, or any other 0048. The term "Muscarinic receptors’ refers to G-pro disease with psychotic features. tein linked receptors that bind the neurotransmitter acetyl 0040. The term “Movement Disorders' includes, but is choline, and to date, five Subtypes of muscarinic receptor not limited to, Gilles de la Tourette's syndrome, Friederich's have been identified. "M1" means the subtype one musca ataxia, Huntington's chorea, restless leg syndrome and other rinic receptor. “M2” means the subtype two muscarinic US 2017/00954.65 A1 Apr. 6, 2017

receptor. “M3” means the subtype three muscarinic receptor. nia (Shekhar et al. Am J Psychiatry. 165:1033. 2008: Shirey “M4” means the subtype four muscarinic receptor. “M5” et el. Nature Chem Biol. 4:41. 2007), the binding by those means the Subtype five muscarinic receptor. Activators to subtypes of muscarinic receptors besides M1 0049. The term “Antipsychotic' refers to a drug that and M4 results in side effects which have prevented use of diminishes psychosis, hallucinations or delusions. Antipsy muscarinic Activators in the clinic. (Shekhar et al. Am. J. chotics can include, but are not limited to: Haloperidol, Psych. 165: 1033.2008). For instance, in both phase I and droperidol, chlorpromazine, fluiphenazine, perphenazine, Subsequent trials, the muscarinic agonist Xanomeline had prochlorperazine, thioridazine, trifluoperazine, unacceptable GI side effects as well as other side effects mesoridazine, periciazine, promazine, triflupromazine, primarily linked to binding of muscarinic receptors besides levomepromazine, promethazine, pimozide, chlorprothix M1 and M4. (Sramek et al. The Journal of Clinical Phar ene, flupenthixol, thiothixene, Zuclopenthixol, clozapine, macology: 35:800. 1995), (Cutler & Sramek. Eur: J. Clin. olanzapine, risperidone, quetiapine, Ziprasidone, amisul Pharmacol. 48:421-428. 1995), (Bodick et al. Arch Neuro pride, asenapine, paliperidone, Zotepine, aripiprazole, 54:465-473. 1997). By combining a muscarinic Activator bifeprunoX, and tetrabenazine. with an Inhibitor, it is possible to achieve the desired 0050. The term “Anxiolytics' refers to drugs that reduce therapeutic effect while diminishing or eliminating the side anxiety, fear, panic or related feelings. Such drugs include, effects associated with unwanted Subtype binding. but are not limited to: benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, cloraZepate, diazepam, lora 0055 Muscarinic Inhibitors are used for treatment of Zepam), buspirone, barbiturates (e.g., amobarbital, pento overactive bladder and pulmonary disorders and have been barbital, secobarbital, phenobarbitol) and hydroxyzine. suggested for treatment of other disorders. (Witte LP et al. 0051. The term “Anti-depressants' refers to drugs that Curr. Opin. Urol. 1:13. 2009). Groups have outlined use of alleviate depression and related conditions (e.g., dysthymia) muscarinic Inhibitors with drugs in other classes to achieve and include, but are not limited to: Selective serotonin a greater effect for treatment of a disease. For example, WO reuptake inhibitors (e.g., citalopram, escitalopram, fluox 2008/121268 suggests a combination for the treatment of etine, fluvoxamine, paroxetine, Sertraline), serotonin- nor lower urinary tract symptoms (LUTS) consisting of a beta-3 epinephrine reuptake inhibitors (e.g., desvenlafaxine, adrenergic agonist, which on its own has been investigated dulloxetine, milnacipram, Venlafaxine), mianserin, mirtaza for the treatment of LUTS, and a muscarinic antagonist. pin, norepinephrine reuptake inhibitors (e.g., atomoxetine, Others have Suggested combining specific muscarinic Acti mazindol, reboxetine, Viloxazine), bupropion, tianeptine, vators or Inhibitors with other specific therapeutic agents agomelatine, trycyclic antidepressants (e.g., amitriptyline, other than muscarinic agents to further have a therapeutic clomipramine, doxepin, imipramine, trimipramine, desipra effect (e.g., WO 2009/037503, WO 2009/036243, WO 2008/ mine, nortriptyline, protriptyline), monoamine oxidase 104776, WO 2008/096.136, WO 2008/096126, WO 2008/ inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, 096121, WO 2008/096111, WO 2007/127196, WO 2007/ Selegiline, tranylcypromine). 125293, EP2002843, EP2002844, U.S. Pat. No. 5,744,476, 0052. The terms “Sedatives” or “tranquilizers' refer to U.S. Pat. No. 7,524,965, US 2005/0267078, US 2006/ drugs that induce Somnolence, promote a feeling of being 0189651, and US 2008/0045565). US 2006/0287294 A1 tired or desire to sleep or promote a state of unconscious outlines use of aspartyl protease inhibitors with either an M1 ness. Such drugs include but are not limited to benzodiaz agonist or an M2 antagonist for treatment of various dis epines, barbiturates (e.g., amobarbital, pentobarbital, seco eases, including improvement of cognitive deficit. Both M1 barbital, phenobarbitol), esZopiclone, Zaleplon, Zolpidem, Activators and M2 Inhibitors themselves (Carey et al. Eur Zopiclone. Pharmacol 431: 198. 2001.) have been suggested to be useful treatments for cognitive deficit, and the rationale for 0053. The term “Theta Score” is defined as the numerical the combination with the aspartyl protease inhibitor was to value assigned by an in silico algorithm described herein enhance the effects of the aspartyl protease inhibitor. No used to predict the overall efficacy and side effects of any Suggestion was made of combining the M1 Activator with given combination of a Muscarinic Activator and a Musca the M2 Inhibitor, and both compounds would be capable of rinic Inhibitor. reaching and would be active in the central nervous system. U.S. Pat. No. 5,480,651 discloses use of agents that increase Introduction acetylcholine in the synapse or that activate the nicotinic 0054 The present invention relates to the method of use acetylcholine receptors, followed by administration of an of one or more Activators and Inhibitors of muscarinic acetylcholine receptor antagonist to relieve craving associ receptors in combination for treatment of various disorders ated with nicotine addiction. The preferred composition uses that can be ameliorated by activation of the muscarinic physostigmine which is an inhibitor of acetylcholinesterase, system. The present invention also describes a medicament as opposed to a muscarinic Activator which would not comprising one or more Activators and one or more Inhibi activate the nicotinic acetylcholine receptors. WO tors of muscarinic receptors. Use of muscarinic Activators 03/092580 discloses compounds that can act simultaneously has previously been hypothesized to be useful for various as muscarinic Activators at certain receptor Subtypes and central nervous system related conditions. In particular, antagonists at others. Groups have used various muscarinic activation of the M1 and M4 receptor subtypes could prove Activators with muscarinic Inhibitors in the context of trying to be of therapeutic value. However, no one has been able to to differentiate the role of various muscarinic subtypes in advance M1 and M4 muscarinic Activators through clinical drug pharmacology or normal physiology without Suggest development to receive regulatory approval for CNS indi ing a therapeutic use of the combination. Such studies cations because of unacceptable side effects. For instance, include use of cellular assays starting from animal materials. while Activators of M1 and M4 muscarinic receptors have (e.g., Iwanaga K. et al. J. Pharmacol. Sci. 110:306. 2009). been suggested to be efficacious treatments for Schizophre In US 2009/0318522, Paborji discloses use of a peripher US 2017/00954.65 A1 Apr. 6, 2017 ally-acting muscarinic antagonist targeting the M2 and M3 response to inhibitors of cholinesterase enzymes. While receptors for the treatment of overactive bladder. The cholinesterase inhibitors have proven therapeutic for certain Paborji publication also discloses use of a peripherally diseases (e.g., Alzheimer's disease), the use of Such inhibi acting muscarinic M2/M3 agonist to counteract dry mouth tors is limited due to toxicity. In fact, powerful chemical associated with the peripherally-acting M2/M3 muscarinic weapons such as Sarin gas exert their toxic effects by antagonist. Paborji's approach does not, however, relate to inhibiting acetylcholinesterase (sarin gas material safety activity at muscarinic receptors in the CNS, which is of data sheet 103d Congress, 2d Session. United States Senate. critical importance for the work described herein, nor does May 25, 1994. http://www.gulfweb.org/bigdoc/report/ap it pertain to activity at either the M1 or M4 receptor. pgb.html). The combination of one or more muscarinic Paborji's approach is highly limited to a specific muscarinic Activators with one or more Muscarinic Inhibitors repre inhibitor and does not provide any selection criteria to sents not only a safer method of treatment of those diseases identify preferred or specific combinations of muscarinic shown to be response to cholinesterase inhibitors, but also a Activators with the muscarinic antagonist, in spite of the more effective one given the limitations on current cholin prohibitively large number of potential combinations for esterase inhibitors. which experimental testing could be done. 0060. In one embodiment, the combination of one or 0056 We have developed a novel approach to improve more muscarinic Activators with one or more Muscarinic the tolerability of xanomeline, which is a muscarinic Acti Inhibitors is used to treat an animal. In a further embodi vator, by co-administering trospium chloride, which is a ment, the animal is a mammal. In a preferred embodiment, muscarinic antagonist. Our approach is completely different the mammal is a human being. In one embodiment, a single from the medicinal chemistry approaches that have been the muscarinic Activator and a single muscarinic Inhibitor are focus of efforts in the past to develop muscarinic agonist used. In another embodiment more than one muscarinic treatment with improved tolerability. Based on our in silico Activator and/or more than one muscarinic Inhibitor is used. testing, we believe that Xanomeline and troSpium chloride is 0061. In one embodiment, use of the Inhibitor decreases an optimal combination. the side effects associated with use of the Activator. Such 0057 The most common adverse events observed with side effects include, but are not limited to, GI side effects, administration of Xanomeline are nausea, vomiting, diar cardiac side effects, excessive Sweating and excessive Sali rhea, excessive Sweating, and excessive salivation (so-called vation. Use of one or more Inhibitors in combination with cholinergic adverse events) (Boddick et al., Arch Neurol. one or more Activators may allow the Activators to be used 1997 April; 54(4):465-73; Shekhar et al. Am. J. Psych. 165: clinically when the Activators may not otherwise be used 1033. 2008)). A demonstration of reduction in the incidence clinically due to the their side effects. In another embodi rate of these adverse events in humans would provide ment, use of the Inhibitor in conjunction with the Activator compelling evidence of improvement in the tolerability of allows for the Activator to achieve a higher maximum Xanomeline. We describe such a demonstration herein. tolerated dose than the Activator would otherwise achieve. Method of Using Muscarinic Activators in Combination 0062 Various time and resource intensive methods may with Muscarinic Inhibitors be used to demonstrate both the efficacy of combination of 0.058. In one embodiment of the invention, one or more the Activator and Inhibitor for the aforementioned embodi muscarinic Activators are used in combination with one or ments. For example animal models have been used to more Muscarinic Inhibitors for treatment of Muscarinic demonstrate the efficacy of new therapeutics for schizophre Disorders. In a preferred embodiment, such diseases or nia, including both pharmacological models (e.g., ketamine disorders include schizophrenia and Diseases Related to model) and genetic models. (e.g., DISC1 mouse) (Dawe G Schizophrenia. In another embodiment one or more musca Set al. Ann Acad Med Singapore. 38:425. 2009: Desbonnet rinic Activators are used in combination with one or more L. Biochem Soc Trans. 37:308. 2009; Geyer M A. Neurotox Muscarinic Inhibitors for treatment of Mood Disorders. In Res. 14:71. 2008). Likewise, animal models including another embodiment, one or more muscarinic Activators are rodents, dogs and non-human primates can be used to used with one or more muscarinic Inhibitors to treat Move demonstrate the side effect profile of pharmacological ment Disorders. In another embodiment, one or more mus agents. Animal models serve as an experimental proxy for carinic Activators are used with one or more muscarinic humans, but may suffer from deficiencies associated with the Inhibitors to treat Cognitive Disorders, including using the physiological differences between human and animals and combination to enhance cognitive function not associated thus may have limited predictive power for translation to with a specific pathology. For instance, improvement in human experiments, particularly for central nervous system cognition could be important in undertaking complex tasks. disorders. Alternatively, the combination can be tried in In another embodiment, one or more muscarinic Activators controlled clinical trials of people. Standard measures based are used with one or more muscarinic Inhibitors to treat on patient self-report can be used by those skilled in the art Attention Disorders. Outside of disease treatment, enhance to assess various side effects Such as GI discomfort. As ment of attention could improve learning and decrease another example, objective physiological measures (e.g., symptoms associated with fatigue due to both lack of sleep EKGs) may be used by those skilled in the art. A set of and circadian rhythm disturbances such as jet lag. In another standard measures has also been developed to assess Schizo embodiment, one or more muscarinic Activators are used phrenia symptoms including the Brief Psychiatric Rating with one or more muscarinic Inhibitors to treat Addictive Scale (BPRS), the Positive and Negative Syndrome Scale Disorders. (PANSS) and Clinical Global Impression (CGI). (Mortimer 0059. In another embodiment, the combination of one or AM. BrJ Psychiatry Suppl. 50:s7. 2007). Typically, clinical more muscarinic Activators with one or more Muscarinic trials are conducted in a double blinded manner in which one Inhibitors can be used to treat Muscarinic Disorders which group of patients receives an inactive placebo and the other are characterized by an amelioration of symptoms in group the active intervention. US 2017/00954.65 A1 Apr. 6, 2017

0063. In one embodiment of the invention, the muscar ride as a muscarinic Inhibitor. In another embodiment, 225 inic Activator is administered concurrently with the musca mg of Xanomeline as a muscarinic Activator and 40 mg of rinic Inhibitor. In another embodiment, the muscarinic trospium chloride as a muscarinic Inhibitor are administered Inhibitor is administered consecutively with the Activator. In to a patient in a 24 hour period. In a further embodiment, 75 further embodiment, the muscarinic Activator is adminis mg of Xanomeline as a muscarinic Activator is administered tered prior to administration of the muscarinic Inhibitor. In three times a day, and 20 mg of trospium chloride as a another embodiment, the muscarinic Inhibitor is adminis muscarinic Inhibitor is administered twice a day, to a patient tered prior to administration of the muscarinic Activator. In in a 24 hour period. In another embodiment, troSpium one embodiment, the muscarinic Inhibitor is administered chloride is administered for one or more dose periods prior within one hour of administration of the muscarinic Acti to administration of Xanomeline. In another embodiment, vator. In another embodiment, the muscarinic Inhibitor is trospium chloride is administered for one or more days prior administered within 30 minutes of administration of the to administration of Xanomeline. muscarinic Activator. In another embodiment, the muscar inic Inhibitor is administered within 10 minutes of admin In Silico Testing of Muscarinic Combinations istration of the muscarinic Activator. In another embodi ment, the muscarinic Inhibitor is administered within one 0068. There are 65 unique muscarinic Activators and 114 minute of administration of the muscarinic Activator. In unique muscarinic Inhibitors that are currently known (Adis another embodiment, the muscarinic Inhibitor is adminis R&D InsightTM, Pubmed, Web of Science, U.S. FDA Orange tered within 30 seconds of administration of the muscarinic Book, U.S. Pat. No. 5,852,029). Therefore, there exist 7,410 Activator. Prior to the start of a drug regimen of the type potential combinations in which a single muscarinic Acti outlined above, there may be a lead-in period that lasts from vator could be paired with a single muscarinic Inhibitor. If one to fourteen days. During this lead-in period, the mus one were to combine more than one muscarinic Activator carinic Inhibitor may be given by itself prior to the start of with one or more muscarinic Inhibitors, then the number of administration of the combination. combinations would be even greater. While a number of animal models exist for relevant diseases such as Schizo 0064. In one embodiment, from 10 micrograms to 10 phrenia (Dawe G Set al. Ann Acad MedSingapore. 38:425. grams of Activator is used in the combination with the 2009: Desbonnet L. Biochem Soc Trans. 37:308. 2009: Inhibitor. In another embodiment, from 1 milligram to 1 Geyer M A. Neurotox Res. 14:71. 2008), animal models of gram of Activator is used in the combination with the complex diseases such as Schizophrenia are imperfect, and Inhibitor. In a preferred embodiment, from 5 to 500 milli thus the ability to predict human efficacy and side effect grams of Activator is used. In one embodiment from 10 burden based on animal data may be limited. Likewise, it is micrograms to 10 grams of Inhibitor is used in the combi possible to test combinations in humans Suffering from a nation with the Activator. In another embodiment, from 1 particular disease Such as Schizophrenia where there exist milligram to 1 gram of Inhibitor is used in the combination standard measuring scales (Mortimer AM. Br. J Psychiatry with the Activator. In a preferred embodiment, from 2.5 Suppl. 50:s7. 2007) for both efficacy of disease treatment as milligrams and 200 milligrams of Inhibitor is used. well as side effects. However, testing such a large number of 0065. In one embodiment, the muscarinic Activator and combinations in either animal models of disease or more muscarinic Inhibitor are administered to a patient 6 times importantly in human clinical trials is practically impossible during a 24 hour period. In another embodiment, the mus as it would be prohibitively expensive, and could take carinic Activator and muscarinic Inhibitor are administered decades due to limitations in the number of existing skilled to a patient 5 times during a 24 hour period. In another investigators and required time for patient recruitment. embodiment, the muscarinic Activator and muscarinic 0069. Without a method of testing and predicting the Inhibitor are administered to a patient 4 times during a 24 efficacy of a given combination, it is extremely difficult to hour period. In a preferred embodiment, the muscarinic predict a priori if such a combination will be efficacious. For Activator and muscarinic Inhibitor are administered to a instance, Medina et al. gave the muscarinic agonist Xanome patient 3 times during a 24 hour period. In another preferred line and the muscarinic antagonist methScopolamine to embodiment, the muscarinic Activator and muscarinic investigate whether syncope, which is a side effect observed Inhibitor are administered to a patient 2 times during a 24 with Xanomeline, can be mediated by muscarinic antagonists hour period. In another preferred embodiment, the muscar (Medina et al. Hypertension. 29: 828. 1997). The group inic Activator and muscarinic Inhibitor are administered to observed no effect on syncope, which may reflect the lack of a patient one time during a 24 hour period. involvement of the muscarinic system in Syncope or, alter 0.066. In one embodiment, the muscarinic Inhibitor is natively, may reflect the incorrect selection of a muscarinic administered for one or more dose periods prior to admin combination. Likewise, Maral et al. documented use of the istration of the muscarinic Activator to allow for accumu muscarinic agonist RS-86 with the anticholinergic agent lation of the muscarinic Inhibitor in the body, or for the glycopyrrolate for treatment of Alzheimer's Disease (Maral muscarinic Inhibitor to reach or approach steady State expo et al. Neurology: 38:606. 1988). The approach did not result Sure levels. This accumulation, or higher exposure levels of in any improvement in cognition despite use of escalating the muscarinic Inhibitor, could increase the blockade of amounts of RS-86. US 2006/0194831 discloses use of a muscarinic receptors and reduce adverse events upon initia derivative of clozapine to activate muscarinic receptors. tion of dosing of the muscarinic Activator. In another While US 2006/0194831 discloses that the use of the embodiment, the muscarinic Inhibitor is administered for clozapine derivative can be combined with another therapy one or more days prior to administration of the muscarinic selected from a broad list of therapies including use of a Activator. muscarinic antagonist, the publication provides no guidance 0067. In one embodiment, Xanomeline is administered as or reasoning, for example, as to why a particular agent a muscarinic Activator in combination with trospium chlo should be selected from the broad list for combination with US 2017/00954.65 A1 Apr. 6, 2017

the clozapine derivative, or why such a combination would typically thought to be unfavorable, but which we treated as be useful. US 5852029, which discloses a particular mus favorable. The combination therapy approach in this appli carinic agonist, mentions potential use of the particular cation is significantly different from typical combination agonist with muscarinic antagonists to help eliminate side therapy approaches, which entail looking for synergistic effects but does not provide any criteria for selecting an efficacy of two agents. In the present invention, we look for appropriate antagonist. one agent to eliminate the effects of the other agent, which 0070 Lack of success by groups such as Maral et al. leads to unorthodox criteria for drug selection. For example, points to the need to carefully select and ideally test com we evaluated each muscarinic Inhibitor based on efficacy binations of muscarinic Activators and Inhibitors. Given the data Such that, in Some cases, low or poor efficacy data was impractical nature of physically testing such a large number rewarded. Also, contrary to typical approaches, in some of combinations, we created an algorithm for in silico testing cases we rewarded muscarinic Inhibitors for the side effects to perform the extremely difficult task of predicting a priori, they exhibited during clinical development. Since most without in vivo testing, if a given combination will be muscarinic Inhibitors were tested for unrelated indications, efficacious and safe. In order to carry out the in silico testing such as overactive bladder, efficacy for these unrelated based on the algorithm, we created an extensive database indications may be undesirable and may be predictive of a which captured the known information about muscarinic combination with potentially unacceptable side effects. For Activators and Inhibitors. The process by which we created instance, excessive urination is not a commonly reported this unique algorithm, as well as the database of muscarinic side effect of muscarinic Activators. Therefore, having agents and their properties, was both multi-phased and Inhibitors that have the greatestability to decrease micturi resource-intensive. First, we created a list of all known tion may present the greatest risk of causing urinary reten muscarinic Activators and Inhibitors. Next, we selected tion without providing a benefit in the combination. properties of muscarinic agents that are useful in predicting 0073. We rewarded certain side effects, particularly those an efficacious and safe combination and determined the known to be associated with peripheral anticholinergic relative importance of each property. We then embarked on effects, because they may counteract or lessen the impact of an exhaustive data-collection process to, wherever possible, muscarinic Activator side effects. This combination of gather data related to each property for each muscarinic rewarding side effects and rewarding poor efficacy leads to Activator and Inhibitor. With this data on-hand, we then the selection of a muscarinic Inhibitor that will have physi created a computer-based algorithm, whereby a score is ological effects throughout the periphery, which is desired calculated for each property and each combination, such that for the elimination of muscarinic Activator side effects. For these scores are then used to generate an overall score for example, if a compound demonstrated efficacy for the treat each combination. The scoring system was created Such that ment of overactive bladder without any side effects, this higher total scores (“Theta Scores') are applied to combi would suggest that the compound was inhibiting muscarinic nations with a higher probability to be efficacious with receptors in the bladder, but not in the gastrointestinal tract acceptable side effects. Therefore, by testing each combina or in the salivary glands to a significant degree. Although tion with the algorithm, we created a prioritized list of Such as compound would be ideal for a drug whose intended combinations whereby combinations with higher scores are purpose is the treatment of overactive bladder, such a more attractive candidates for clinical testing. Given the compound would be unfavorable for the uses described impracticality of testing every possible combination in Vivo, herein. A more favorable Inhibitor for the envisioned com prioritization to select combinations for testing in humans is bination would demonstrate pharmacological effects (i.e., critical. side effects observed when treating overactive bladder) in 0071. In order to evaluate different combinations of mus the same organs where the Activator causes undesired side carinic Activator and Inhibitors, we created a proprietary effects (e.g., the gastrointestinal tract). The rewarding of side database of all known muscarinic Activators and Inhibitors effects and penalizing of efficacy stands in contrast to the (see Tables 1 and 2). This database was created through typical method for selecting pharmaceutical agents. systematic reviews of a variety of resources in search of all 0074. Our intensive selection process resulted in 95 rel current and past programs related to muscarinic Activators evant properties, on the basis of which each of the 7,410 and Inhibitors. Our reviews included scholarly literature combinations of known muscarinic Activators and Inhibitors databases, such as Pubmed and Web of Science, patent would be evaluated. The properties fell into three general databases, such as Delphion, and pharmaceutical research categories: properties related exclusively to muscarinic Acti and development databases, such as Adis R&D InsightTM. vators; properties related exclusively to muscarinic Inhibi We also reviewed drug package inserts, news databases, tors; and properties that combined attributes of both the company websites, and conference abstracts. In all, we Activator and Inhibitor. These classifications are discussed reviewed several thousand journal publications, patents, below in detail. Adis records, and other documents to generate a compre 0075 To collect data for each muscarinic Activator and hensive database of 65 muscarinic Activators and 114 mus Inhibitor based on each property, we embarked on a rigorous carinic Inhibitors. data collection process using many of the same resources as 0072 We then selected properties useful in predicting those used in generating a database of all known muscarinic whether a given combination will be efficacious with accept Activators and Inhibitors. Again, our review spanned schol able side effects. We determined, in other words, the criteria arly literature databases, such as Pubmed and Web of by which each combination may be evaluated in order to Science, patent databases, such as Delphion, pharmaceutical generate a quantitative, predictive assessment. This process research and development databases, such as Adis R&D of selecting relevant properties was driven by rigorous InsightTM and the U.S. FDA Orange Book, as well as internal analyses and resulted in the identification of several package inserts and other resources. This process differed, properties that are typically not considered, and/or that are however, in the detailed and often quantitative nature of the US 2017/00954.65 A1 Apr. 6, 2017

information extracted. For example, we gathered and cat C (e.g., Inhibitors A, B, and C are given values of 1, /2, egorized all known efficacy and side effect data for each and /4, respectively). We then linearly distribute these muscarinic Activator and Inhibitor. We also gathered all values such that Inhibitor A receives a score of 10, known data related to pharmacokinetics and pharmacody Inhibitor B a score of 5, and Inhibitor C a score of 2.5. namics. As new data becomes available for compounds Finally, these scores are multiplied by a weight factor, currently in our database, or as information regarding poten which in this case would be 1, giving final p-scores of tial new entries for our database becomes available, database 10, 5, and 2.5. updates may be made, which would yield new theta scores. 0080 Binary p-scores were generated by assigning one For example, MCD 386 is a muscarinic Activator for which of two values relating to a binary property. Take, for additional data could result in increased theta scores for example, the case of two muscarinic Activators, A and muscarinic Activator and Inhibitor combinations that B, which are evaluated based on whether they have include MCD 386. shown efficacy in human trials. Muscarinic Activator A, 0076. Using these data, we then created a computer which has shown efficacy, is awarded a value of 10, based algorithm to quantify the relative probability that each while B, which has not, receives a score of 0. Since this muscarinic Activator and Inhibitor combination will be important property has a weight factor of 2, muscarinic efficacious with acceptable side effects. The scoring system Activators A and B receive final p-scores of 20 and 0. functions by applying a score to each combination based on respectively. each property, which we call a p-score. Each p-score con 0081 Value cut-off p-scores were applied based on the tributed to an overall calculation, such that a high p-score group into which a given value fell. This methodology signified that a combination has an increased likelihood of was used for non-binary cases where a ranking meth being efficacious with acceptable side effects based on a odology is not preferred or possible (e.g., scoring given property. Since the algorithm tested a total of 7,410 qualitative data, or scoring quantitative data in which possible combinations, each of which was evaluated based cut-offs are relevant). In these cases, muscarinic Acti on 95 p-scores, the algorithm summed a total of 703.950 vators or Inhibitors whose values fall into the most p-scores in calculating a unique overall score (a "Theta desirable category are awarded values of 10 (prior to Score’) for each combination (see FIG. 1). multiplication by the corresponding weight factor). 0077. Given the varied nature of data from one property I0082. The p-scores applied to each combination were to the next, a variety of Scoring methodologies were used to Summed to generate three unique Subscores: the Activator generate p-scores. In all cases, scoring methodologies were Independent Subscore, the Inhibitor Independent Subscore, consistent within a given property and generated a maxi and the Combination Subscore. The Activator Independent mum value of 10, which was then multiplied by a “weight Subscore represents an evaluation of each agonist based on factor.” Weight factors were used to reflect the importance of properties that are independent of the antagonist with which each property in predicting the probability that a combina it is combined (e.g., the demonstration of efficacy in human tion is efficacious with acceptable side effects. Some prop trials). Similarly, the Inhibitor Independent Subscore repre erties, such as those relating to the demonstration of efficacy sents an evaluation of each antagonist based on properties for an agonist, have a stronger impact in assessing a pre that are independent of the agonist with which it is combined ferred combination and were thus weighted more heavily. (e.g., level of CNS penetrance). The Combination Subscore, The baseline weight factor for all properties was 1, and the in contrast, represents an evaluation based on properties in maximum weight factor used was 2. which characteristics of both the agonist and antagonist are 0078. The primary methodologies used in generating relevant (e.g., similarity of T. based on pharmacokinetic p-scores were ranking-based scoring, binary scoring, and studies). For both the Activator Independent Subscore and scoring by value cut-off. The mechanics of each of these the Inhibitor Independent Subscore, the value was calculated methodologies are detailed below: by Summing each p-score and then normalizing each score 0079 Ranking-based p-scores were generated using Such that the highest ranking entry was given a score of 100. quantitative data, Such as efficacy measurements, and Each lower ranking entry was thus increased or decreased awarding the highest value (e.g., a score of 10) to the proportionally by the same factor as the highest ranking most preferable data point, and the lowest value (e.g., entry. In calculating the Combination Subscore, the same a score of 0) to the least preferable data point. The principle was applied; however, the maximum score given remaining values were then distributed linearly, Such was 50. that less preferable data points were awarded propor I0083 Ultimately, the algorithm generated a final “Theta tionally lower scores. Finally, a weight factor was Score' for each combination such that, as the theta score applied to each value by multiplying each score by a increased, so did the probability that the combination would pre-determined weight that reflected the importance of produce efficacy with acceptable side effects. The Theta the given property. Take, for example, the case where Score was calculated by summing the three Subscores. three muscarinic Inhibitors (Inhibitor A, Inhibitor B, and Inhibitor C) are evaluated based on the demon TABLE 1. strated reduction in urinary frequency (number of mic List of Muscarinic Activators turitions per 24 hours), such that the minimum reduc Muscarinic Activators tion, or lowest efficacy, is desired. In this case, Inhibitor A shows a reduction of 1 micturition per 24 hours, 1 A 720SS while Inhibitors B and C show values of 2 and 4 2 AF 12S 3 AF 150(S) respectively. To calculate each p-score, since Inhibitor 4 AF 18S A demonstrated the most desirable results, we first must 5 Alvameline give Inhibitor A a proportionally higher value than B or US 2017/00954.65 A1 Apr. 6, 2017 10

TABLE 1-continued TABLE 2-continued

List of Muscarinic Activators List of Muscarinic Inhibitors Muscarinic Activators Muscarinic Inhibitors Amifostine AQRA 721 Arecoline transdermal-Cogent Pharmaceuticals AQRA 741 Cevimeline AZD 9164 CI1017 BIBN 99 CMI 1145 CEB 1957 11 CMI936 11 Clozapine extended release-AZur Pharma 12 CS 932 12 Darenzepine 13 DM 71 13 Darifenacin 14 FPL 14995 14 Darotropium bromide 15 GSK 1.034702 15 Dextro-mecquitamium iodide 16 Himbacine 16 Ebeinone 17 Itameline 17 Esoxybutynin 18 KST 2818 18 Espatropate 19 KSIS410 19 Fesoterodine 2O KST S452 2O Glycopyrrolate/indacaterol 21 L 670548 21 Glycopyrronium bromide 22 L 68966O 22 GSK 1160724 23 L 696986 23 GSK2O2405 24 L 705106 24 GSK 573719 25 LY 31 6108 25 GSK 656398 26 MCD 386 26 GSK 96.1081 27 Milameline 27 GYKI46903 28 Muscarinic receptor agonistS-ACADIA Allergan 28 Homatropine methylbromide 29 NC 111585 29 midafenacin 30 Nebracetam 30 inhaled glycopyrrolate-Novartis 31 NGX 267 31 pratropium bromide dry-powder inhalation-Dura Spiros 32 Norclozapine 32 pratropium bromide dry-powder inhalation-ML Laboratories 33 ORG 20091 33 pratropium bromide hydrofluoroalkane inhalatior-Boehringer 34 PD 141606 ngelheim 35 PD 142505 34 pratropium bromide intranasal-Chiesi 36 PD 151832 35 pratropium bromide metered solution inhalation-Sheffield 37 PDC OO8004 36 pratropium bromidefxylometazoline 38 Pilocarpine 37 104129 39 Pilocarpine-Controlled Therapeutics 38 106366 40 PTAC 39 L 696986 41 Anavex Life Sciences preclinical muscarinic activator 40 LAS 352O1 42 Eli Lilly preclinical M1 receptor muscarinic activator 41 Levosalbutamolipratropium inhalation solution 43 Eli Lilly preclinical M4 receptor muscarinic activator Arrow International Limited Sepracor Torry Pines Therapeutics preclinical muscarinic activator 42 Liriodenine 45 Banyu preclinical muscarinic activator 43 LK 12 46 Mithridion preclinical muscarinic activator 44 Mequitamium iodide 47 ACADIA, Sepracor preclinical muscarinic activator 45 Methantheline 48 ACADLA preclinical muscarinic activator 46 Methantheline bromide 49 RU 35963 47 Methscopolamine bromide 50 Sabcomeline 48 N-butylscopolamine 51 SDZ 210086 49 N-methylatropine 52 50 NPC 14695 53 SR 96777A 51 NX303 S4 Stacofylline 52 Otenzepad 55 Talsacidine 53 Oxybutynin-Labopharm 56 Tazomeline S4 Oxybutynin-Penwest Pharmaceuticals 57 Thiopilocarpine 55 Oxybutynin chloride-ALZA 58 Ticalopride 56 Oxybutynin intravesical-Situs 59 U 8O816 57 Oxybutynin transdermal-Schwarz Pharma 58 60 Vedadidine Oxybutynin transdermal-Watson 59 Oxybutynin transdermal gel-Antares 61 WAY 131256 60 OXVbutynin transmucosal-Auxilium 62 WAY 132983 61 Oxybutynin vaginal-Barr Laboratories 63 Xanomeline 62 PG 1000 64 YM 796 63 Pirenzepine ophthalmic 65 YM 954 64 Pirmenol 65 PNU 200577 66 Promethazine/hydrocodone/paracetamol-Charleston Laboratories 67 Propantheline TABLE 2 68 Propantheline bromide 69 Propiverine List of Muscarinic Inhibitors 70 PSD 506 Muscarinic Inhibitors 71 PTAC 72 QAT 370 1 Acidinium bromide 73 Almirall muscarinic Inhibitor 2 Acidinium bromideformoterol 74 Anavex Life Sciences primary muscarinic Inhibitor 3 Acotiamide 75 Anavex Life Sciences secondary muscarinic inhibitor 4 AH 9700 76 FF2-Nuada 5 Alvameline 77 GlaxoSmithKline. Theravance muscarinic Inhibitor US 2017/00954.65 A1 Apr. 6, 2017 11

TABLE 2-continued TABLE 2-continued

List of Muscarinic Inhibitors List of Muscarinic Inhibitors Muscarinic Inhibitors Muscarinic Inhibitors 78 Chiesi FarmaceuticiSALVAT muscarinic inhibitor 100 Telenzepine 79 UCB muscarinic Inhibitor 101 Temiverine 8O Theravance primary muscarinic Inhibitor 102 Tiotropium bromide 81 Theravance secondary muscarinic Inhibitor 103 Tolterodine 82 Novartis muscarinic Inhibitor 104 Tolterodine?tamsulosin 83 ACADIA/Sepracor muscarinic Inhibitor 105 Tropenzilium 84 Safetek muscarinic Inhibitor 106 Trospium chloride 85 Revatropate 107 Trospium chloride controlled release 86 Rispenzepine 108 Trospium chloride inhalation 87 RL 315535 109 V O162 88 RO 465934 110 YM35636 89 SCH 211803 111 YM 46303 90 SCH 57790 112 YM 53705 91 Scopolamine intranasal-Nastech 113 YM 58790 92 Scopolamine transmucosal-Anesta 114 Zamifenacin 93 Secoverine 94 S-ET 126 95 Sintropium bromide I0084. The algorithm was structured with inputs accord 96 Solifenacin 97 Solifenacintamsulosin ing to the following 3 tables. The Property, Scoring Meth 98 SVT 40776 odology, Criteria for a High Score, and Weight columns in 99 TD 6301 each table represent the underlying inputs and mechanics used in calculating each Subscore. TABLE 3

Mechanics of Activator Independent Subscore Activator Subscore Mechanics

Criteria for a Weight Count Property Category Property Scoring Methodology High Score Factor

1 Development Highest Phase Unique value assigned to High stage of 1 each dev. stage evelopment 2 Development Highest Phase CNS Unique value assigned to High stage of 1 each dev. stage evelopment 3 Development Highest Phase US Unique value assigned to High stage of 1 each dev. stage evelopment 4 ROA Route of Unique value assigned to Oral 1 Administration each RDA 5 Pharmakinetics Tmax Ranked by Tmax value High Tmax 1 5 Pharmakinetics T(1/2) Ranked by T(1/2) value HIgh T(1/2) 1 7 Efficacy Demonstrated Efficacy Binary scoring Efficacy Shown 2 8 Efficacy Demonstrated Efficacy Binary scoring Efficacy Shown 2 Cognition 9 Efficacy Demonstrated Efficacy Binary scoring Efficacy Shown 2 Schizophrenia 10 Receptor Selectivity M2 Agonist? Binary scoring Not M2 Agonist 1 11 Recep or Selectivity M3 Agonist? Binary scoring Not M3 Agonist 1 12 Recep or Selectivity M1 M2 ratio Ranked by ratio volume High ratio 1 13 Recep or Selectivity M1M3 ratio Ranked by ratio volume High ratio 1 14 Recep or Selectivity M1 M5 ratio Ranked by ratio volume High ratio 1 15 Recep or Selectivity M4, M2 ratio Ranked by ratio volume High ratio 1 16 Recep or Selectivity M4. M3 ratio Ranked by ratio volume High ratio 1 17 Recep or Selectivity M4, M5 ratio Ranked by ratio volume High ratio 1 18 Recep or Selectivity M2M3 ratio Ranked by ratio volume Close to 1 1 19 Recep or Selectivity MS M2 ratio Ranked by ratio volume Close to 1 1 20 Recep or Selectivity MS M3 ratio Ranked by ratio volume Close to 1 1 US 2017/00954.65 A1 Apr. 6, 2017 12

TABLE 4 Mechanics of Inhibitor Independent Subscore Inhibitor Subscore Mechanics

Criteria for Weight Count Property Category Property Scoring Methodology High Score Factor Development Highest Phase Unique value assigned to High stage of each dev. stage development Development Highest Phase US Unique value assigned to High stage of each dev. stage ROA Route of Administration Unique value assigned to each ROA Pharmacokinetics Tmax Ranked by Tmax value High Tmax Pharmacokinetics T(1/2) Ranked by T(/2) value High T(/2) CNS Penetrance CNS Penetrance Unique va ue assigned based Low penetrance on H, M, L penetrance Receptor Selectivity M2M1 ratio Ranked by ratio value High ratio Receptor Selectivity M2M4 ratio Ranked by ratio value High ratio Receptor Selectivity M3M1 ratio Ranked by ratio value High ratio Receptor Selectivity M3 M4 ratio Ranked by ratio value High ratio Efficacy Urinary Frequency Ranked by efficacy value Low efficacy (# Micturitions per 24 hrs)- Reduction E ficacy Urinary Frequency Ranked by efficacy value Low efficacy (# Micturitions/24 hrs)- % Reduction E ficacy Urinary Frequency Ranked by efficacy value Low efficacy (# Micturitions/24 hrs)- % Reduction over Placebo E ficacy Urinary Frequency Ranked by efficacy value Low efficacy (# Micturitions/24 hrs)- Reduction over Placebo E ficacy Volume Voided micturition Ranked by efficacy value Low efficacy (mL)-Reduction E ficacy Volume Voided micturition Ranked by efficacy value Low efficacy (mL)-96 Reduction E ficacy Volume Voided micturition Ranked by efficacy value Low efficacy (mL)-96 Reduction over Placebo E ficacy Volume Voided micturition Ranked by efficacy value Low efficacy (mL)-Reduction over Placebo E ficacy # of Incontinence Epst Ranked by efficacy value Low efficacy 24 hours-% Reduction E ficacy # of Incontinence Epst Ranked by efficacy value Low efficacy 24 hours-Reduction 21 E ficacy # of Incontinence Epst Ranked by efficacy value Low efficacy week-% Reduction 22 E ficacy # of Incontinence Epst Ranked by efficacy value Low efficacy week-Reduction 23 E ficacy # Urge incontinence epsi Ranked by efficacy value Low efficacy 24 hrs-% Reduction 24 E ficacy # Urge incontinence epsi Ranked by efficacy value Low efficacy 24 hrs-Reduction 25 E ficacy # Urge incontinence epsi Ranked by efficacy value Low efficacy week-% Reduction 26 E ficacy # Urge incontinence epsi Ranked by efficacy value Low efficacy week-Reduction 27 verse Events Dry Mouth-% increase Ranked by AE value LowAE values over placebo 28 verse Even S Constipation-% increase Ranked by AE value Low AEE values over placebo 29 verse Events Dyspepsia-% increase Ranked by AE value Low AEE values over placebo 30 verse Events Abdominal Pain-% Ranked by AE value Low AEE values increase over placebo 31 verse Events Dry Mouth-absolute % Ranked by AE value Low AE values values 32 verse Even S Constipation-absolute % Ranked by AE value Low AE values values 33 verse Events Dyspepsia-absolute % Ranked by AE value Low AE values values 34 verse Events Abdominal Pain Ranked by AE value Low AEE values absolute % values 35 verse Events Constipation aggravated Ranked by AE value Low AE values 36 verse Events Nausea Ranked by AE value Low A 37 verse Events Abdominal Distension Ranked by AE value Low A US 2017/00954.65 A1 Apr. 6, 2017 13

TABLE 4-continued Mechanics of Inhibitor Independent Subscore Inhibitor Subscore Mechanics Criteria for Weight Count Property Category Property Scoring Methodology High Score Factor

38 weSe Even Flatulence Ranked by AE value Low AE values 39 weSe Even Diarrhea Ranked by AE value Low AE values 40 weSe Even Vomiting Ranked by AE value Low AE values 41 weSe Even UTI Ranked by AE value Low AE values 42 weSe Even Upper Respiratory tract Ranked by AE value Low AE values infection 43 weSe Even Influenza Ranked by AE value Low AE values 44 weSe Even Pharyngitis Ranked by AE value Low AE values 45 weSe Even Headache Ranked by AE value Low AE values 46 weSe Even Dizziness Ranked by AE value Low AE values 47 weSe Even Vision Blurred Ranked by AE value Low AE values 48 weSe Even Dry Eyes Ranked by AE value Low AE values 49 weSe Even Urinary Retention Ranked by AE value Low AE values 50 weSe Even Dysuria Ranked by AE value Low AE values 51 weSe Even Edema Lower Limb Ranked by AE value Low AE values 52 weSe Even Edema peripheral Ranked by AE value Low AE values 53 weSe Even Fatigue Ranked by AE value Low AE values S4 weSe Even Depression Ranked by AE value Low AE values 55 weSe Even Insomnia Ranked by AE value Low AE values 56 weSe Even Cough Ranked by AE value Low AE values 57 weSe Even Dry Throat Ranked by AE value Low AE values 58 weSe Even Hypertension Ranked by AE value Low AE values 59 weSe Even Asthenia Ranked by AE value Low AE values 60 weSe Even Nasal dryness Ranked by AE value Low AE values 61 weSe Even Back pain Ranked by AE value Low AE values 62 weSe Even ALT increased Ranked by AE value Low AE values 63 weSe Even GGT increased Ranked by AE value Low AE values 64 weSe Even Rash Ranked by AE value Low AE values

Note: ALT = Alanine transaminase; GGT = Gamma-glutamyltransferase

TABLE 5

Mechanics of Combination Subscore Combination Subscore Mechanics

Property Scorin 9. Criteria for a Weight Count Category Property Methodo Ogy High Score Factor 1 Pharmaco Tmax Unique value given based on Close Tmax values kinetics closeness o Tmax 2 Pharmaco T(1/2) Unique value given based on Close T(/2) values kinetics closeness o T(1/2) Metabolism Drug-drug interaction Unique value assigned based on Low overall risk of drug-drug potential H, M, or L. degree of interaction, interaction specifically regarding CYP450 Receptor (M1 Activa or selectivity/M1 Ranked by ra io value High ratio value (devalue if Selectivity In hibitor selectivity) ratio Inhibitor acts on M1, Activator is weak M1 Activator) Receptor (M4 Activa or selectivity/M4 Ranked by ra io value High ratio value (devalue if Selectivity In hibitor selectivity) ratio Inhibitor acts on M4, Activator is weak M4 Activator) Receptor (M3 Activa or selectivity/M3 Ranked by ra io value Low ratio value (With M3 Selectivity In hibitor selectivity) ratio Ac ivator, M3 Inhibitor is desired) Receptor (M2 Activa or selectivity/M2 Ranked by ra io value Low ratio value (If M2 Selectivity In hibitor selectivity) ratio Ac ivator, M2 Inhibitor is desired) Receptor (M5 Activa or selectivity/M5 Ranked by ra io value High ratio value Selectivity In hibitor selectivity) ratio Receptor M2, M3 ratio comparison Ranked by ra io value Ratio value close to 1 Selectivity 10 Efficacy Rewards pecific cases of Case specific Case specific Inhibitor A Es if “offsetting an Activator AE US 2017/00954.65 A1 Apr. 6, 2017 14

TABLE 5-continued

Mechanics of Combination Subscore Combination Subscore Mechanics Property Scoring Criteria for a Weight Count Category Property Methodology High Score Factor 11 Adverse Events Reward specific cases of Case specific Case specific 1 Inhibitor AEs if “offsetting an Activator AE

Note: In cases where an Activator inhibits a receptor, or where an Inhibitor activates a receptor, receptor selectivity ratios are changed to equal one divided by the ratio for determining the p-score,

TABLE 6 Top 15 Combinations by Theta Score Activator Inhibitor Combination Theta Independent Independent Combination ID Combination Score Subscore Subscore Subscore 6355 Xanomeline & Trospium chloride 250 OO 1OO 50 5003 Sabcomeline & Trospium chloride 245 95 1OO 50 2611 Milameline & Trospium chloride 243 98 1OO 45 634-6 Xanomeline & Tolterodine 241 OO 91 50 26O2 Kililameline & Tolterodine 239 98 91 50 5005 Sabcomeline & Trospium chloride 238 95 93 50 controlled release 6357 Xanomeline & Trospium chloride 238 OO 93 45 controlled release 2613 Milameline & Trospium chloride 236 98 93 45 controlled release 6347 Xanomeline & Darifenacin 235 OO 95 40 6348 Xanomeline & Solifenacin 234 OO 94 40 4996 Sabcomeline & Solifenacin 229 95 94 40 5523 Talsaclidine & Trospium chloride 224 94 1OO 30 635 Cevimeline & Trospium chloride 219 89 1OO 30 5515 Talsacidine & Darifenacin 219 94 95 30 5516 Talsacidine & Solifenacin 218 94 94 30 55.25 Talsaclidine & Trospium chloride 217 94 93 30 controlled release SS1.4 Talsacidine & Tolterodine 215 94 91 30 6349 Xanomeline & Fesoterodine 215 1OO 85 30 627 Cevimeline & Darifenacin 214 89 95 30 637 Cevimeline & Trospium chloride 212 89 93 30 controlled release

TABLE 7 TABLE 7-continued

Further list of Muscarinic Activators Further list of Muscarinic Activators Muscarinic Activators Muscarinic Activators

NSXO527 WUO184670 NSXO559 VUO357017 AF71OB VUO364572 Anavex 141 Brucine HTL9936 HTL18318 PQCA 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2- ML-137 (trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380) ML-169 WUO1521 OO WUO405652 VUO255035 3HPT-1284 LY211962O WUO238429 I0085. In a preferred embodiment of the invention, a Thiochrome combination of a muscarinic Activator and a muscarinic VU152099 Inhibitor with a theta score of 230 or greater as determined LY2O33928 by in silico testing using the above described algorithm is ML173 ML293 used. In another embodiment of the invention, a combina AC-42 tion of a muscarinic Activator and a muscarinic Inhibitor N-desmethylclozapine with a theta score of 200 or greater as determined by in silico 77-LH-28-1 testing using the above described algorithm is used. In another embodiment of the invention, a combination of a US 2017/00954.65 A1 Apr. 6, 2017

muscarinic Activator and a muscarinic Inhibitor with a theta milligrams of pilocarpine is used during a 24 hour period. In score of 150 or greater as determined by in silico testing a preferred embodiment, from 30 milligrams to 200 milli using the above described algorithm is used. In a further grams of pilocarpine is used during a 24 hour period. embodiment of the invention, a combination of a muscarinic 0092. In one embodiment, trospium chloride is used as Activator and a muscarinic Inhibitor with a theta score of the muscarinic Inhibitor in combination with the muscarinic 149 or lower as determined by in silico testing using the Activator. In another embodiment, trospium chloride is above described algorithm is used. administered to a patient from one time to five times during 0.086. In one embodiment, xanomeline is used as the a 24 hour period. In a preferred embodiment, troSpium muscarinic Activator in combination with the muscarinic chloride is administered from one time to three times during Inhibitor. In another embodiment, Xanomeline is adminis a 24 hour period. In another embodiment, from five milli tered to a patient from one time to five times during a 24 grams to 400 milligrams of trospium chloride is used during hour period. In a preferred embodiment, Xanomeline is a 24 hour period. In a preferred embodiment, from 20 administered from one time to three times during a 24 hour milligrams to 200 milligrams of trospium chloride is used period. In another embodiment, from 25 milligrams to 700 during a 24 hour period. milligrams of Xanomeline is used during a 24 hour period. 0093. In one embodiment, trospium chloride extended In a preferred embodiment, from 75 milligrams to 300 release is used as the muscarinic Inhibitor in combination milligrams of Xanomeline is used during a 24 hour period. with the muscarinic Activator. In another embodiment, tro 0087. In one embodiment, sabcomeline is used as the spium chloride extended release is administered to a patient muscarinic Activator in combination with the muscarinic from one time to five times during a 24 hour period. In a Inhibitor. In another embodiment, sabcomeline is adminis preferred embodiment, trospium chloride extended release is tered to a patient from one time to five times during a 24 administered from one to three times during a 24 hour hour period. In a preferred embodiment, sabcomeline is period. In another embodiment, from five milligrams to 400 administered from one to three times during a 24 hour milligrams of trospium chloride extended release is used period. In another embodiment, from 50 micrograms to five during a 24 hour period. In a preferred embodiment, from 20 milligrams of sabcomeline is used during a 24 hour period. milligrams to 200 milligrams of trospium chloride extended In a preferred embodiment, from 150 micrograms to 450 release is used during a 24 hour period. micrograms of sabcomeline is used during a 24 hour period. 0094. In one embodiment, solifenacin is used as the 0088. In one embodiment, milameline is used as the muscarinic Inhibitor in combination with the muscarinic muscarinic Activator in combination with the muscarinic Activator. In another embodiment, solifenacin is adminis Inhibitor. In another embodiment, milameline is adminis tered to a patient from one time to five times during a 24 tered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, solifenacin is hour period. In a preferred embodiment, milameline is administered from one time to three times during a 24 hour administered from one to three times during a 24 hour period. In another embodiment, from 0.25 milligrams to 100 period. In another embodiment, from 0.5 milligrams to 50 milligrams of Solifenacin is used during a 24 hour period. In milligrams of milameline is used during a 24 hour period. In a preferred embodiment, from 1 milligram to 30 milligrams a preferred embodiment, from four milligrams to 16 milli of Solifenacin is used during a 24 hour period. grams of milameline is used during a 24 hour period. 0.095. In one embodiment, tolterodine is used as the 0089. In one embodiment, talsaclidine is used as the muscarinic Inhibitor in combination with the muscarinic muscarinic Activator in combination with the muscarinic Activator. In another embodiment, tolterodine is adminis Inhibitor. In another embodiment, talsaclidine is adminis tered to a patient from one time to five times during a 24 tered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, tolterodine is hour period. In a preferred embodiment, talsaclidine is administered from one to three times during a 24 hour administered from one to three times during a 24 hour period. In another embodiment, from one milligram to 16 period. In another embodiment, from five milligrams to 1 milligrams oftolterodine is used during a 24 hour period. In gram of talsaclidine is used during a 24 hour period. In a a preferred embodiment, from two milligrams to eight preferred embodiment, from 120 milligrams to 480 milli milligrams of tolterodine is used during a 24 hour period. grams of talsaclidine is used during a 24 hour period. 0096. In one embodiment, fesoterodine is used as the 0090. In one embodiment, cevimeline is used as the muscarinic Inhibitor in combination with the muscarinic muscarinic Activator in combination with the muscarinic Activator. In another embodiment, fesoterodine is adminis Inhibitor. In another embodiment, cevimeline is adminis tered to a patient from one time to five times during a 24 tered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, fesoterodine is hour period. In a preferred embodiment, cevimeline is administered from one to three times during a 24 hour administered from one to three times during a 24 hour period. In another embodiment, from two milligrams to 56 period. In another embodiment, from 45 milligrams to 750 milligrams of fesoterodine is used during a 24 hour period. milligrams of cevimeline is used during a 24 hour period. In In a preferred embodiment, from four milligrams to 28 a preferred embodiment, from 90 milligrams to 360 milli milligrams of fesoterodine is used during a 24 hour period. grams of cevimeline is used during a 24 hour period. 0097. In one embodiment, darifenacin is used as the 0091. In one embodiment, pilocarpine is used as the muscarinic Inhibitor in combination with the muscarinic muscarinic Activator in combination with the muscarinic Activator. In another embodiment, darifenacin is adminis Inhibitor. In another embodiment, pilocarpine is adminis tered to a patient from one time to five times during a 24 tered to a patient from one time to five times during a 24 hour period. In a preferred embodiment, darifenacin is hour period. In a preferred embodiment, pilocarpine is administered from one to three times during a 24 hour administered from one to three times during a 24 hour period. In another embodiment, from 3.75 milligrams to 150 period. In another embodiment, from 7.5 milligrams to 500 milligrams of darifenacin is used during a 24 hour period. In US 2017/00954.65 A1 Apr. 6, 2017

a preferred embodiment, from 7.5 milligrams to 30 milli administration, the Activator and Inhibitor may be delivered grams of darifenacin is used during a 24 hour period. in tablets, troches, liquids, emulsions, Suspensions, drops, 0098. In one embodiment, Xanomeline is administered as capsules, caplets or gel caps and by other methods of oral a muscarinic Activator in combination with trospium chlo administration known to one skilled in the art. For admin ride as a muscarinic Inhibitor. In another embodiment, 225 istration by inhalation, the Activator and Inhibitor may be mg of Xanomeline as a muscarinic Activator and 40 mg of delivered in vapor, mist, powder, aerosol, or nebulized form, trospium chloride as a muscarinic Inhibitor are administered or by other methods known to one skilled in the art. For to a patient in a 24 hour period. In a further embodiment, 75 vaginal administration, the Activator and Inhibitor may be mg of Xanomeline as a muscarinic Activator is administered delivered in Solutions, emulsions, Suspensions, ointments, three times a day, and 20 mg of trospium chloride as a gels, foams, or vaginal rings or by other methods known to muscarinic Inhibitor is administered twice a day, to a patient one skilled in the art. in a 24 hour period. 0102 The muscarinic Activator and Inhibitor may be in 0099 While the subject is being treated, the health of the a dosage form that immediately releases the drug. In an patient may be monitored by measuring one or more of the alternative embodiment, the muscarinic Activator and relevant indices at predetermined times during the treatment Inhibitor are in a controlled release dosage form. In one period. Treatment, including composition, amounts, times of embodiment of the controlled release dosage form, the administration and formulation, may be optimized according Activator and Inhibitor have similar release kinetics. In to the results of Such monitoring. The patient may be another embodiment, the Inhibitor is released prior to the periodically reevaluated to determine the extent of improve Activator's being released. In another embodiment, a three ment by measuring the same parameters. Adjustments to the part release profile is used such that the Inhibitor is released amount(s) of Subject composition administered and possibly immediately, followed by the Activator in a controlled to the time of administration may be made based on these release fashion and then by the Inhibitor in a controlled reevaluations. release fashion. In one embodiment, the muscarinic Activa 0100 Treatment may be initiated with smaller dosages tor and Inhibitor are packaged in liposomes. In a further that are less than the optimum dose of the compound. embodiment, the liposome comprises a phospholipid. In a Thereafter, the dosage may be increased by Small increments further embodiment, the phospholipid in the liposome is until the optimum balance between therapeutic effect and selected from phosphatidylcholine (PC), phosphatidylglyc side effects is attained. erol (PG), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE), phosphatidic acid Dosage Forms of the Combination (PA), egg phosphatidylcholine (EPC), egg phosphatidyl 0101. In one embodiment, the muscarinic Activator and glycerol (EPG), egg phosphatidylinositol (EPI), egg phos muscarinic Inhibitor are in different dosage forms or dosage phatidylserine (EPS), egg phosphatidylethanolamine (EPE), vehicles. In a preferred embodiment, the muscarinic Acti egg phosphatidic acid (EPA), soy phosphatidylcholine vator and muscarinic Inhibitor are in the same dosage form (SPC), soy phosphatidylglycerol (SPG), soy phosphatidyl or dosage vehicles. The dosage forms may include one or serine (SPS), soy phosphatidylinositol (SPI), soy phospha more pharmaceutically-acceptable carriers. The dosage tidylethanolamine (SPE), soy phosphatidic acid (SPA), forms may also include one or more pharmaceutically hydrogenated egg phosphatidylcholine (HEPC), hydroge acceptable salts. The dosage forms may be administered nated soy phosphatidylcholine (HSPC), dipalmitoylphos orally. The Activator and Inhibitor may be delivered orally phatidylcholine (DPPC), dioleoylphosphatidylcholine using tablets, troches, liquids, emulsions, Suspensions, (DOPC), dimyristoylphosphatidylcholine (DMPC), drops, capsules, caplets or gel caps and other methods of oral dimyristoylphosphatidylglycerol (DMPG), dipalmitoyl administration known to one skilled in the art. The musca phosphatidylglycerol (DPPG), di Stearoylphosphatidylcho rinic Activator and Inhibitor may also be administered line (DSPQ), di stearoylphosphatidylglycerol (DSPG), dio parentally. Other routes of administration include but are not leoylphosphatidyl-ethanolamine (DOPE), limited to: topical, transdermal, nasal, ocular, rectal, Sublin palmitoylstearoylphosphatidyl-choline (PSPC), palmitoyl gual, inhalation, and vaginal. For topical and transdermal stearolphosphatidylglycerol (PSPG), mono-oleoyl-phospha administration, the Activator and Inhibitor may be delivered tidylethanolamine (MOPE), dilauroyl ethylphosphocholine in a cream, gel, ointment, spray, Suspension, emulsion, foam, (DLEP), dimyristoyl ethylphosphocholine (DMEP), or patch or by other methods known to one skilled in the art. dipalmitoyl ethylphosphocholine (DPEP), distearoyl ethyl For nasal administration, the Activator and Inhibitor may be phosphocholine (DSEP), dimyristoylphosphatidic acid delivered by sprays, drops, emulsions, foams, creams, oint (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoyl ments or other methods known to one skilled in the art. For phosphatidic acid (DSPA), dimyristoylphosphatidylinositol nasal administration, formulations for inhalation may be (DMPI), dipalmitoylphosphatidylinositol (DPPI), di prepared as an aerosol, either a solution aerosol in which the stearoylphosphatidylinositol (DSPI), dimyristoylphosphati active agent is solubilized in a carrier, Such as a propellant, dylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), or a dispersion aerosol, in which the active agent is sus distearoylphosphatidylserine (DSPS), N-acylated phospho pended or dispersed throughout a carrier and an optional rylethanolamine (NAPE), and combinations thereof solvent. For ocular administration, the Activator and Inhibi (0103. In a further embodiment, the controlled release tor may be delivered in drops, sprays, injections, Solutions, formulation comprises a semi-permeable membrane. The emulsions, Suspensions, or ointments, or by other methods muscarinic Activator and muscarinic Inhibitor may be in known to one skilled in the art. Forrectal administration, the different membranes in the same formulation. In another Activator and Inhibitor may be delivered using Supposito embodiment, the muscarinic Activator and muscarinic ries, enemas, creams, foams, gels, or ointments or by other Inhibitor can be in different membranes in different formu methods known to one skilled in the art. For sublingual lations or dosing vehicles. In a further embodiment, the US 2017/00954.65 A1 Apr. 6, 2017

semi-permeable membrane comprises a polymer. In a fur with the Inhibitor. In another embodiment from 10 micro ther embodiment, the controlled release formulation com grams to 10 grams of Inhibitor is used in the combination prises a matrix that Suspends the muscarinic Activator(s) and with the Activator. In another embodiment, from 1 milligram muscarinic Inhibitor(s). The muscarinic Activator and to 1 gram of Inhibitor is used in the combination with the Inhibitor may be in separate matrices within the same Activator. medicament. In a further embodiment, the matrix comprises 0108. In one embodiment, the medicament is adminis a polymer. In a further embodiment, the polymer comprises tered to a patient 6 times during a 24 hour period. In another a water soluble polymer. In a further embodiment, the water embodiment, the medicament is administered to a patient 5 soluble polymer is selected from Eudragit RL, polyvinyl times during a 24 hour period. In another embodiment, the alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxy medicament is administered to a patient 4 times during a 24 propyl cellulose, hydroxypropylmethyl cellulose, polyeth hour period. In another embodiment, the medicament is ylene glycol, and mixtures thereof. In a further embodiment, administered to a patient 3 times during a 24 hour period. In the polymer comprises a water insoluble polymer. In a another embodiment, the medicament is administered to a further embodiment, the water insoluble polymer is selected patient 2 times during a 24 hour period. In another embodi from Eudragit RS, ethylcellulose, cellulose acetate, cellulose ment, the medicament is administered to a patient one time propionate, cellulose acetate propionate, cellulose acetate during a 24 hour period. In a preferred embodiment, the butyrate, cellulose acetate phthalate, cellulose triacetate, medicament is administered from one to 3 times during a 24 poly(methyl methacrylate), poly(ethyl methacrylate), poly hour period. (butyl methacrylate), poly(isobutyl methacrylate), poly 0109. In one embodiment of the invention, the medica (hexyl methacrylate), poly(isodecyl methacrylate), poly(lau ment contains a combination of a muscarinic Activator and ryl methacrylate), poly(phenyl methacrylate), poly(methyl a muscarinic Inhibitor with a theta score of 230 or greater as acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), determined by in silico testing using the above described poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low algorithm. In another embodiment of the invention, the density, poly(ethylene) high density, poly(propylene), poly medicament contains a combination of a muscarinic Acti (ethylene terephthalate), poly(vinyl isobutyl ether), poly vator and a muscarinic Inhibitor with a theta score of 200 or (vinyl acetate), poly(vinyl chloride), polyurethane, and mix greater as determined by in silico testing using the above tures thereof. In a further embodiment, the matrix comprises described algorithm. In another embodiment of the inven a fatty compound. In a further embodiment, the fatty com tion, the medicament contains a combination of a muscarinic pound is a wax or glyceryl tristearate. In a further embodi Activator and a muscarinic Inhibitor with a theta score of ment, the polymer comprises a water soluble polymer and a 150 or greater as determined by in silico testing using the water insoluble polymer. In a further embodiment, the above described algorithm. In a further embodiment of the matrix further comprises a fatty compound. invention, the medicament contains a combination of a 0104. The muscarinic Activator and muscarinic Inhibitor muscarinic Activator and a muscarinic Inhibitor with a theta may be in dosage forms that use other methods of controlled score of 149 or lower as determined by in silico testing using release formulation known to one skilled in the art (for the above described algorithm. In a further embodiment, example, Dixit & Puthli. J. Control Release. 2:94. 2009: Xanomeline is used as the muscarinic Activator in the Mizrahi & Domb. Recent Pat Drug Deliv Formul. 2:108. medicament. In another embodiment, the medicament con 2008: Forqueri & Singh. Recent Pat Drug Deliv Formul. tains from five milligrams to 700 milligrams of xanomeline. 3:40. 2009: Kalantzi et al. Recent Pat Drug Deliv Formul. In a preferred embodiment, the medicament contains from 3:49. 2009; Iconomopoulou et al. Recent Pat Drug Deliv 25 milligrams to 300 milligrams of xanomeline. Formul. 2:94. 2008: Panos et al. Curr Drug Discov Technol. 0110. In one embodiment, sabcomeline is used as the 5:333. 2008; 2008. Wan et al. Nanomed. 2:483. 2007. Wang muscarinic Activator in the medicament. In another embodi et al. Drug Delivery: Principles & Applications. Wiley ment, the medicament contains from 10 micrograms to five 2005). milligrams of Sabcomeline. In a preferred embodiment, the 0105. In another embodiment, the combination of the medicament contains from 50 micrograms to 450 micro muscarinic Activator and Inhibitor is used in combination grams of sabcomeline. with one or more therapies that can include both psycho 0111. In one embodiment, milameline is used as the therapy and drugs. Therapeutic agents include but are not muscarinic Activator in the medicament. In another embodi limited to antipsychotics, anxiolytics, anti-depressants, ment, the medicament contains from 0.1 milligrams to 50 sedatives, tranquilizers and other pharmacological interven milligrams of milameline. In a preferred embodiment, the tions known to one skilled in the art. Atherapeutic agent may medicament contains from one milligram to 16 milligrams fall under the category of more than one type of drug. For of milameline. instance benzodiazepines can be considered anxiolytics, 0.112. In one embodiment, talsaclidine is used as the sedatives and tranquilizers. muscarinic Activator in the medicament. In another embodi ment, the medicament contains from one milligram to one Medicament Containing One or More Muscarinic Activators gram of talsaclidine. In a preferred embodiment, the medi & Muscarinic Inhibitors cament contains from 40 milligrams to 480 milligrams of 0106. One embodiment of the invention is a medicament talsaclidine. comprising one or more muscarinic Activators and one or 0113. In one embodiment, cevimeline is used as the more muscarinic Inhibitors. muscarinic Activator in the medicament. In another embodi 0107. In one embodiment, from 10 micrograms to 10 ment, the medicament contains from nine milligrams to 750 grams of Activator is used in the combination with the milligrams of cevimeline. In a preferred embodiment, the Inhibitor in the medicament. In another embodiment, from 1 medicament contains from 30 milligrams to 360 milligrams milligram to 1 gram of Activator is used in the combination of cevimeline. US 2017/00954.65 A1 Apr. 6, 2017

0114. In one embodiment, pilocarpine is used as the amount(s) of Subject composition administered and possibly muscarinic Activator in the medicament. In another embodi to the time of administration may be made based on these ment, the medicament contains from 1.5 milligrams to 500 reevaluations. milligrams of pilocarpine. In a preferred embodiment, the I0123 Treatment may be initiated with smaller dosages medicament contains from 10 milligrams to 200 milligrams that are less than the optimum dose of the compound. of pilocarpine. Thereafter, the dosage may be increased by Small increments 0115. In one embodiment, trospium chloride is used as until the optimum balance between therapeutic effect and the muscarinic Inhibitor in the medicament. In another side effects is attained. This principle of drug titration is well embodiment, the medicament contains from one milligram understood by those of skill in the art. to 400 milligrams of trospium chloride. In a preferred 0.124. The medicament may also include one or more embodiment, the medicament contains from 6.5 milligrams pharmaceutically-acceptable salts. The medicament may to 200 milligrams of trospium chloride. include one or more pharmaceutically-acceptable carriers. 0116. In one embodiment, trospium chloride extended The medicament may be administered orally. The medica release is used as the muscarinic Inhibitor in the medica ment may be delivered orally using tablets, troches, liquids, ment. In another embodiment, the medicament contains emulsions, Suspensions, drops, capsules, caplets or gel caps from one milligram to 400 milligrams of trospium chloride and other methods of oral administration known to one extended release. In a preferred embodiment, the medica skilled in the art. The medicament may also be administered ment contains from 6.5 milligrams to 200 milligrams of parentally. Other routes of administration include but are not trospium chloride extended release. limited to: topical, transdermal, nasal, rectal, ocular, Sublin 0117. In one embodiment, solifenacin is used as the gual, inhalation, and vaginal. For topical and transdermal muscarinic Inhibitor in the medicament. In another embodi administration, the medicament may be delivered in a ment, the medicament contains from 0.25 milligram to 100 cream, gel, ointment, spray, Suspension, emulsion, foam, or milligrams of Solifenacin. In a preferred embodiment, the patch or by other methods known to one skilled in the art. medicament contains from 1 milligrams to 30 milligrams of For nasal administration, the medicament may be delivered Solifenacin. by sprays, drops, emulsions, foams, creams, or ointments or 0118. In one embodiment, tolterodine is used as the by other methods known to one skilled in the art. For nasal muscarinic Inhibitor in the medicament. In another embodi administration, formulations for inhalation may be prepared ment, the medicament contains from 0.2 milligrams to 16 as an aerosol, either a solution aerosol in which the active milligrams of tolterodine. In a preferred embodiment, the agent is solubilized in a carrier, such as a propellant, or a medicament contains from 0.7 milligrams to eight milli dispersion aerosol, in which the active agent is suspended or grams of tolterodine. dispersed throughout a carrier and an optional Solvent. For 0119. In one embodiment, fesoterodine is used as the rectal administration, the medicament may be delivered muscarinic Inhibitor in the medicament. In another embodi using Suppositories, enemas, creams, foams, gels, or oint ment, the medicament contains from 0.4 milligrams to 56 ments or by other methods known to one skilled in the art. milligrams of fesoterodine. In a preferred embodiment, the For ocular administration, the medicament may be delivered medicament contains between one milligrams to 28 milli in drops, sprays, injections, Solutions, emulsions, Suspen grams of fesoterodine. sions, or ointments, or by other methods known to one 0120 In one embodiment, darifenacin is used as the skilled in the art. For sublingual administration, the medi muscarinic Inhibitor in the medicament. In another embodi cament may be delivered in tablets, troches, liquids, emul ment, the medicament contains from n 0.8 milligrams to 150 sions, Suspensions, drops, capsules, caplets or gel caps and milligrams of darifenacin. In a preferred embodiment, the by other methods of oral administration known to one medicament contains from 2.5 milligrams to 30 milligrams skilled in the art. For administration by inhalation, the of darifenacin. medicament may be delivered in vapor, mist, powder, aero 0121. In a further embodiment, Xanomeline is used as the sol, or nebulized form, or by other methods known to one muscarinic Activator in the medicament, and trospium chlo skilled in the art. For vaginal administration, the medica ride is used as the muscarinic Inhibitor in the same medi ment may be delivered in Solutions, emulsions, Suspensions, cament. In another embodiment, Xanomeline is used as the ointments, gels, foams, or vaginal rings or by other methods muscarinic Activator in the medicament, and trospium chlo known to one skilled in the art. ride is used as the muscarinic Inhibitor in a different medi 0.125. The medicament may be in a dosage form that cament. In a preferred embodiment, the medicament con immediately releases the drug. In an alternative embodi tains 75 mg or 225 milligrams of Xanomeline, and the same ment, the medicament may have a controlled release dosage medicament contains 20 mg or 40 milligrams of trospium form. In one embodiment, the medicament is packaged in chloride. In another preferred embodiment, the medicament liposomes. In a further embodiment, the liposome comprises contains 75 mg or 225 milligrams of Xanomeline, and a a phospholipid. In a further embodiment, the phospholipid in different medicament to be co-administered contains 20 mg the liposome is selected from phosphatidylcholine (PC), or 40 milligrams of trospium chloride. phosphatidylglycerol (PG), phosphatidylinositol (PI), phos 0122) While the subject is being treated, the health of the phatidylserine (PS), phosphatidylethanolamine (PE), phos patient may be monitored by measuring one or more of the phatidic acid (PA), egg phosphatidylcholine (EPC), egg relevant indices at predetermined times during the treatment phosphatidylglycerol (EPG), egg phosphatidylinositol period. Treatment, including composition, amounts, times of (EPI), egg phosphatidylserine (EPS), egg phosphatidyletha administration and formulation, may be optimized according nolamine (EPE), egg phosphatidic acid (EPA), soy phos to the results of Such monitoring. The patient may be phatidylcholine (SPC), soy phosphatidylglycerol (SPG), soy periodically reevaluated to determine the extent of improve phosphatidylserine (SPS), soy phosphatidylinositol (SPI), ment by measuring the same parameters. Adjustments to the soy phosphatidylethanolamine (SPE), soy phosphatidic acid US 2017/00954.65 A1 Apr. 6, 2017

(SPA), hydrogenated egg phosphatidylcholine (HEPC), Deliv Formul. 2:108. 2008: Forqueri & Singh. Recent Pat hydrogenated soy phosphatidylcholine (HSPC), dipalmi Drug Deliv Formul. 3:40, 2009: Kalantzi et al. Recent Pat toylphosphatidylcholine (DPPC), dioleoylphosphatidylcho Drug Deliv Formul. 3:49. 2009; Iconomopoulou et al. line (DOPC), dimyristoylphosphatidylcholine (DMPC), Recent Pat Drug Deliv Formul. 2:94. 2008: Panos et al. Curr dimyristoylphosphatidylglycerol (DMPG), dipalmitoyl Drug Discov Technol. 5: 333. 2008;. Wan et al. Nanomed. phosphatidylglycerol (DPPG), di stearoylphosphatidylcho 2:483. 2007. Wang et al. Drug Delivery: Principles & line (DSPQ), di stearoylphosphatidylglycerol (DSPG), dio Applications. Wiley 2005). leoylphosphatidyl-ethanolamine (DOPE), 0128. In another embodiment, the medicament is used in palmitoylstearoylphosphatidyl-choline (PSPC), palmitoyl combination with one or more therapies that can include stearolphosphatidylglycerol (PSPG), mono-oleoyl-phospha both psychotherapy and drugs. Therapeutic agents include tidylethanolamine (MOPE), dilauroyl ethylphosphocholine but are not limited to antipsychotics, anxiolytics, anti (DLEP), dimyristoyl ethylphosphocholine (DMEP), depressants, sedatives, tranquilizers and other pharmaco dipalmitoyl ethylphosphocholine (DPEP), distearoyl ethyl logical interventions known to one skilled in the art. A phosphocholine (DSEP), dimyristoylphosphatidic acid therapeutic agent may fall under the category of more than (DMPA), dipalmitoylphosphatidic acid (DPPA), distearoyl one type of drug. For instance benzodiazepines can be phosphatidic acid (DSPA), dimyristoylphosphatidylinositol considered anxiolytics, sedatives and tranquilizers. (DMPI), dipalmitoylphosphatidylinositol (DPPI), di 0129. The above-described benefits of the novel methods stearoylphosphatidylinositol (DSPI), dimyristoylphosphati and compositions of the present invention are illustrated by dylserine (DMPS), dipalmitoylphosphatidylserine (DPPS), the non-limiting examples that follow. distearoylphosphatidylserine (DSPS), N-acylated phospho rylethanolamine (NAPE), and combinations thereof EXAMPLES 0126. In a further embodiment, the controlled release formulation comprises a semi-permeable membrane. The Example 1 muscarinic Activator and muscarinic Inhibitor may be in different membranes in the same formulation. In another 0.130. In one example, the invention is a single capsule embodiment, the muscarinic Activator and muscarinic formulation containing 75 milligrams of Xanomeline and 20 Inhibitor can be in different membranes in different formu milligrams of trospium chloride. The capsule consists of a lations or dosing vehicles. In a further embodiment, the gelatin shell Surrounding a fill material composed of the semi-permeable membrane comprises a polymer. In a fur active compounds, a vehicle, a surfactant and a modifier. ther embodiment, the controlled release formulation com The vehicle is polyethylene glycol with a molecular weight prises a matrix that Suspends the muscarinic Activator(s) and in the range of from 500 to 10,000 Daltons and is 10% of the Inhibitor(s). The muscarinic Activator and Inhibitor may be fill material by weight. The surfactant is polysorbate 80 and in separate matrices within the same medicament. In a represents 0.1% by weight of the fill material. The modifier further embodiment, the matrix comprises a polymer. In a is fumed silica present at 0.25% by weight of the fill further embodiment, the polymer comprises a water soluble material. The total fill material represents 50% of the total polymer. In a further embodiment, the water soluble poly capsule weight and the gelatin shell is 50% of the total mer is selected from Eudragit RL, polyvinyl alcohol, poly capsule weight. vinylpyrrolidone, methyl cellulose, hydroxypropyl cellu lose, hydroxypropylmethyl cellulose, polyethylene glycol, Example 2 and mixtures thereof. In a further embodiment, the polymer I0131) A second formulation is the capsule in Example 1 comprises a water insoluble polymer. In a further embodi with an additional outer controlled release layer comprising ment, the water insoluble polymer is selected from Eudragit an enteric material (material that is relatively insoluble in the RS, ethylcellulose, cellulose acetate, cellulose propionate, acidic environment of the stomach). There are a variety of cellulose acetate propionate, cellulose acetate butyrate, cel enteric materials known to one skilled in the art. For this lulose acetate phthalate, cellulose triacetate, poly(methyl specific formulation we use hydroxyethylcellulose which methacrylate), poly(ethyl methacrylate), poly(butyl meth would compose 20% of total capsule weight. acrylate), poly(isobutyl methacrylate), poly(hexyl meth acrylate), poly(isodecyl methacrylate), poly(lauryl meth Example 3 acrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octa 0.132. A third example is a formulation prepared as in decyl acrylate), poly(ethylene), poly(ethylene) low density, Example 2, with the capsule containing 225 mg of Xanome poly(ethylene) high density, poly(propylene), poly(ethylene line and 60 milligrams of trospium chloride. terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and a mixtures Example 4 thereof In a further embodiment, the matrix comprises a I0133. In one example, the invention is a single capsule fatty compound. In a further embodiment, the fatty com formulation containing 75 milligrams of Xanomeline and 5 pound is a wax or glyceryl tristearate. In a further embodi milligrams of Solifenacin. The capsule consists of a gelatin ment, the polymer comprises a water soluble polymer and a shell Surrounding a fill material composed of the active water insoluble polymer. In a further embodiment, the compounds, a vehicle, a Surfactant and a modifier. The matrix further comprises a fatty compound. vehicle is polyethylene glycol with a molecular weight in the 0127. The medicament may be in dosage forms that use range of from 500 to 10,000 Daltons and is 10% of the fill other methods of controlled release formulation known to material by weight. The surfactant is polysorbate 80 and one in the art (for example, Dixit & Puthli. J. Control represents 0.1% by weight of the fill material. The modifier Release. 2:94. 2009; Mizrahi & Domb. Recent Pat Drug is fumed silica present at 0.25% by weight of the fill US 2017/00954.65 A1 Apr. 6, 2017 20 material. The total fill material represents 50% of the total Example 7 capsule weight and the gelatin shell is 50% of the total 0.136 Clinical Study to Evaluate the Ability of Trospium capsule weight. Chloride to Reduce Adverse Events Associated with Xanomeline and to Evaluate the Overall Tolerability of the Example 5 Combination of Xanomeline and Trospium Chloride 0.137 We conducted a Phase I, double-blind, randomized 0134. A second formulation is the capsule in Example 4 multiple-dose pilot study of Xanomeline administered alone with an additional outer controlled release layer comprising compared to Xanomeline administered in combination with an enteric material (material that is relatively insoluble in the trospium chloride in normal healthy volunteers. The primary acidic environment of the stomach). There are a variety of objectives of this study were (1) to assess the safety and enteric materials known to one skilled in the art. For this tolerability of administering, for 7 days, 225 mg daily of specific formulation we use hydroxyethylcellulose which Xanomeline with 40 mg daily of trospium chloride, Versus would compose 20% of total capsule weight. administering 225 mg daily of Xanomeline alone for 7 days; and (2) to determine whether the addition of trospium 40 mg Example 6 daily (20 mg BID) to xanomeline 225 mg daily (75 mg TID) over 7 days significantly reduces peripheral cholinergic side 0135 A third example is a formulation prepared as in effects (nausea, diarrhea, vomiting, Sweating, excess saliva Example 52, with the capsule containing 225 mg of Xanome tion) versus xanomeline 225 mg daily, alone. The param line and 10 milligrams of Solifenacin. eters of the study were as follows:

Sample Size: N = 70 subjects Study Population: Normal healthy volunteers; ages 18-60 Study Duration: Treatment: Nine days; a two-day run-in period of either placebo or trospium 40 mg/day, followed by 7 days of active treatment Follow-up: 14 days following discharge from clinic Test product, Xanomeline, 75 mg capsules, TID, for a 225 mg total daily dose dose and mode of Trospium chloride, 20 mg tablet, over-encapsulated, for a 40 mg administration: total daily dose, BID Matching placebo Study Design The study was an inpatient study conducted in normal healthy (see also FIG. 2) volunteers. Between study days -21 to -7, normal healthy volunteers visited the clinic to receive and sign Informed Consent and undergo Screening procedures. Patients entered the clinic on Study Day 0 for baseline safety assessment and enrollment in the study. On the morning of Study Day 1 subjects began administration of study drug. Subjects randomized to the Xanomeline-only arm received placebo for the first two days, and began TID Xanomeline treatment on Day 3. Subjects randomized to the Xanomeline + trospium arm received BID trospium chloride for the first two days, and then TID xanomeline plus BID trospium starting on Day 3. Matching placebo was administered to maintain the blind. Patients remained in clinic under observation for the full duration of treatment (9 days). Main criteria Age 18-60 for inclusion: Female Subjects had to be postmenopausal (at least 2 years prior to dosing) or agree to use an acceptable form of birth control from screening until 14 days after completion of the study. If on birth control pills, had to have been on a stable dose for a 12 months. Good general health Ability to give informed consent and understand verbal instructions Willingness to spend 10 days in an in-patient facility Main criteria History or presence of clinically significant cardiovascular, for exclusion: pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the investigator, would jeopardize the safety of the Subject or the validity of the study results. (Subjects with any history of resolved cancer that was >5 years passed could be included.) Body Mass Index <18 or >40 kg/m’ History of or high risk of urinary retention, gastric retention, or narrow-angle glaucoma History of alcohol or drug abuse within the last 24 months, or current abuse as determined by urine toxicology screen Clinically significant abnormal finding on the physical exam, medical history, ECG, or clinical laboratory results at Screening Had participated in another clinical trial within 90 days prior to the first dose of study medication Needed to take any prescription medication besides the investigational product or those specifically noted above. Use of any vitamins, herbs, Supplements, or over the counter US 2017/00954.65 A1 Apr. 6, 2017 21

-continued medications are excluded within one week of enrollment, and during the course of the trial. Specifically, Subjects were not permitted to take Benadryl (R) for one week prior to and during the course of the study. Use of any tobacco products within the past 30 days Previous positive test for HIV 1 and/or 2, or Hepatitis A, B, or C, or a positive test obtained at Screening. Selected Treatment emergent signs and symptoms (adverse event incidence Endpoints: rates) Cholinergic treatment emergent signs and symptoms (salivation, Sweating, nausea, vomiting, diarrhea) (cholinergic adverse event incidence rates). These adverse events were observed at high rates in past Xanomeline studies and were drivers of Subject discontinuation.

0138 70 total study subjects were randomized, and of follows, with all p-values based on a chi-squared test, with these, 68 study Subjects received at least one assessment on the exception of those marked with a * which werebased on day 3, which was the first day of Xanomeline administration. a Fisher's exact test: The demographics of the study subjects were as follows:

Xanomeline + Xanomeline + Xanomeline Xanomeline + alone Trospium placebo (N = 34) Trospium (N = 35) P-value Characteristic (N = 33) (N = 35) (in 96 # (in 96 # for % Re Category of events) of events) difference duction Age (years; Mean SDI) 34.8 (8.8 40.9 (12.3 Gender (M/F; %) 21,12 27.8 64%.36% 77%.23% Any 21 (63.6%) 64 12 (34.3%) 33 0.0155 46% Race (White/ 924 13,21 TEAES Non-White; %) 279.70% 37%.60% Nausea 8 (24.2%) 11 6 (17.1%) 8 O.4693 29% Weight (kg; Mean SDI) 88 (17) 88 (16) BMI (kg/m2; Mean SDI) 29.1 (5.0) 28.8 (5.0) Vomiting 5 (15.2%) 5 2 (5.7%) 2 0.2522* 62% Diarrhea 7 (21.2%) 8 2 (5.7%) 4 O.O794: 73% Sweating 16 (48.5%) 24 7 (20.0%) 8 O.O131 S9% 0139. The most common adverse events with Xanomeline Salivation 12 (36.4%) 16 9 (25.7%) 11 0.342 39% are the so-called cholinergic adverse events of nausea, Vomiting, diarrhea, excessive Sweating, and excessive Sali Vation. In this study, the co-administration of trospium chloride with Xanomeline led to a statistically significant 0143. In addition to evaluating whether the addition of 43% reduction (p=0.016) in the incidence rate of cholinergic trospium chloride improved the tolerability of xanomeline, adverse events compared to Xanomeline co-administered the study also provided data about the overall safety and with placebo. In the xanomeline-placebo arm of the study, tolerability of xanomeline--trospium chloride. Overall, the 63% of subjects reported at least one cholinergic adverse combination was well tolerated with no severe adverse event, compared to only 34% of Subjects reporting Such an events and no serious adverse events, and with the vast event in the Xanomeline--trospium chloride arm of the study. majority of adverse events being classified as mild, as shown 0140. Further, in the study, each kind of individual cho in the following: linergic adverse event also had a decreased incidence rate in Subjects administered Xanomeline--trospium chloride, com Xanomeline + Xanomeline + pared to the incidence rate in Subjects administered Xanome placebo Trospium line-placebo. The decrease in incidence rate of Sweating Category (n (%) # events) (N = 33) (N = 35) was statistically significant on its own, at 20.0% in the Subjects with any TEAE 27 (81.8) 23 (65.7) 73 Xanomeline--trospium chloride arm, down from 48.5% in the 108 Xanomeline-placebo arm, which was a reduction of 59% Max Severity of TEAE (p=0.013). Mild 22 (66.7) N/A 20 (57.1) N/A 0141. In addition, the overall cholinergic adverse event Moderate 5 (15.2) N/A 3 (8.6) N/A rate in the Xanomeline--trospium chloride arm of the study Severe 0 (0.0) 0 (0.0) Any clinically significant TEAE 5 (15.2) 5 3 (8.6) 6 was very similar to the 32% incidence rate reported during Any study drug related TEAE 23 (69.7) 92 18 (51.4) 57 the two day run-in period for Subjects on placebo-placebo. Max severity of study drug Although these two data points are not perfectly comparable related TEAE given that they occurred during different periods of the Mild 19 (5776) N/A 15 (42.9) N/A study, the fact that the cholinergic adverse event rate was Moderate 4 (12.1) N/A 3 (8.6) N/A comparable to that of placebo Suggests that the 43% reduc Severe 0 (0.0) N/A 0 (0.0) N/A tion in adverse events due to trospium chloride may have Any SAE 0 (0.0) 0 0 (0.0) 0 AE leading to discontinuation (DC) 2 (6.1) 2 1 (2.9) 1 been close to the maximum reduction possible in this study. Study drug related AE leading to DC 1 (3.0) 1 0 (0.0) 0 0142. The incidence and number of cholinergic adverse events in the evaluable population of the study was as US 2017/00954.65 A1 Apr. 6, 2017 22

0144. The tolerability profile that we found in this study What is claimed is: allows future studies of the combination of Xanomeline and 1. A method of treating a central nervous system disorder trospium chloride to proceed. in a patient, the method comprising administering Xanome line and trospium chloride to the patient, the central nervous References system disorder being selected from Schizophrenia, Disor ders Related To Schizophrenia, Muscarinic Disorder, Move 0145 All publications and patents mentioned herein are ment Disorder, Mood Disorder, Cognitive Disorder, Atten hereby incorporated by reference in their entirety as if each tion Disorder, and Addictive Disorder. individual publication or patent was specifically and indi 2. The method of claim 1, wherein the central nervous vidually incorporated by reference. In case of conflict, the system disorder is schizophrenia. present application, including any definitions herein, will 3. The method of claim 1, wherein the central nervous system disorder is Alzheimer's disease. control. 4. The method of claim 1, wherein the central nervous system disorder is Huntington's disease. Equivalents 5. The method of claim 1, wherein the central nervous system disorder is Parkinson's disease. 0146 While specific embodiments of the subject inven 6. The method of claim 1, wherein the central nervous tion have been discussed, the above specification is illustra system disorder is Lewy Body dementia. tive and not restrictive. Many variations of the invention will 7. The method of claim 1, wherein 225 mg of xanomeline become apparent to those skilled in the art upon review of and 40 mg of trospium chloride are administered to the this specification. The full scope of the invention should be patient during a 24-hour period. determined by reference to the claims, along with their full 8. A method of improving the tolerability of xanomeline Scope of equivalents, and the specification, along with Such in a patient, comprising administering to the patient variations. Xanomeline in combination with troSpium chloride. 0147 Unless otherwise indicated, all numbers expressing 9. The method of claim 8, wherein the Xanomeline and the quantities of ingredients, reaction conditions, and so forth trospium chloride are in the same dosage vehicle. used in the specification and claims are to be understood as 10. The method of claim 8, wherein the Xanomeline and being modified in all instances by the term “about.” Accord the trospium chloride are in different dosage vehicles. ingly, unless indicated to the contrary, the numerical param 11. The method of claim 8, wherein 225 mg of xanome eters set forth in this specification and attached claims are line and 40 mg of trospium chloride are administered to the approximations that may vary depending upon the desired patient during a 24-hour period. properties sought to be obtained by the present invention. k k k k k