Compositions and methods for treating disorders ameliorated by muscarinic receptor activation

Abstract

Provided herein is a method of treating schizophrenia or a disease associated with schizophrenia in a patient in need thereof. The method comprises orally administering to the patient, twice a day, an oral pharmaceutical composition comprising a plurality of xanthene beads comprising xanthene or a salt thereof, and a plurality of trospium beads comprising a trospium salt, via a titration regimen comprising an increased titration of the xanthene or a salt thereof, and the trospium salt.

Description

This application is a divisional application of the Chinese patent application with application number 202080093687.1, invention name “Compositions and methods for treating disorders alleviated by muscarinic receptor activation” and application date November 17, 2020 (PCT application number PCT / US2020 / 060859).

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 936,837, filed on November 18, 2019, and also claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 030,780, filed on May 27, 2020, the disclosures of each of which are incorporated by reference in their entirety for all purposes.

[0002] The present invention relates to compositions and their use as medicaments for treating disorders alleviated by muscarinic receptor activation in human or animal subjects.

[0003] Schizophrenia affects approximately 0.5% to 1% of the population. The disorder is characterized by a constellation of symptoms, which are categorized as positive symptoms (e.g., hallucinations, delusions), negative symptoms (e.g., social isolation, anhedonia), and cognitive symptoms (e.g., inability to process information, poor working memory). People with schizophrenia experience a significant decrease in their quality of life. They are at increased risk of mortality due to a number of factors, such as increased suicide rates. The cost of schizophrenia to society is high, as people living with schizophrenia are more likely to be incarcerated, homeless, or unemployed.

[0004] Existing schizophrenia treatments rely on dopamine and serotonin receptors, as exemplified by the discovery of chlorpromazine, the first antipsychotic drug, in 1952. This same basic pharmacology has been the standard of care for schizophrenia for over 60 years. Current antipsychotics are only effective against positive symptoms, failing to address negative and cognitive symptoms. Alzheimer's disease is another therapeutic area where developing new therapies has proven extremely difficult, with a success rate of only 0.4% for molecules that enter clinical development and achieve market approval. Patients in these areas desperately need new treatments, but development has been exceedingly difficult, despite the tremendous efforts of scientists and drug developers worldwide.

[0005] Activation of the muscarinic system by muscarinic agonists can treat several diseases, such as schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegeneration, such as tauopathy or synucleinopathies. Muscarinic cholinergic receptors are G protein-coupled receptors with five different receptor subtypes (M1-M5), each of which is found in the CNS with different tissue distribution. The M1 and M4 subtypes have attracted attention as therapeutic targets for various diseases. For example, the mood stabilizers lithium and valproic acid used to treat bipolar depression can affect the muscarinic system, particularly through the M4 subtype receptor. Genetic evidence directly links the muscarinic system to alcohol addiction.

[0006] In a double-blind, placebo-controlled trial of xanomeline, a muscarinic cholinergic receptor agonist with preferential activity at M1 and M4 subtypes, schizophrenia symptoms were alleviated in patients with schizophrenia. However, because it also binds to muscarinic receptors outside the brain, xanomeline has numerous serious side effects, including gastrointestinal (GI) side effects, cardiac side effects, and excessive salivation. Dose-limiting adverse events were problematic and led to high discontinuation rates (including a 56% dropout rate in a 26-week Alzheimer's disease study), ultimately leading to the discontinuation of xanomeline's development. Despite early promise, xanomeline's development stalled for over 15 years. Numerous companies have attempted, but none have succeeded in developing a muscarinic receptor agonist for CNS disorders that avoids these unacceptable side effects, and no such agonist has reached the market. Past development efforts have focused on medicinal chemistry to develop more tolerable molecules, typically targeting M1 and M4 rather than M2 and M3 muscarinic receptor subtypes. However, M1 and M4 activation outside the brain can still lead to muscarinic-related intolerance. Little progress has been made in mitigating adverse effects caused by activation of peripheral muscarinic receptors.

[0007] There remains a need in the art for pharmaceutical compositions that provide improved tolerability to xanomeline, particularly for the treatment of cognitive and psychiatric disorders. The following embodiments and aspects thereof are described and illustrated using compositions and methods, which are exemplary and illustrative, not limiting, in scope. In various embodiments, one or more of the aforementioned problems have been reduced or eliminated, while other embodiments are directed to other improvements.

[0008] Provided herein is a method for treating schizophrenia or a disorder related to schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and a plurality of trospium beads comprising a trospium salt via a titration regimen, the titration regimen comprising increasing titration of the xanomeline or a salt thereof and the trospium salt.

[0009] Also provided is a method of treating schizophrenia or a disorder related to schizophrenia in a patient in need thereof, the method comprising orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and a plurality of trospium chloride beads comprising a trospium chloride salt via a titration regimen, the titration regimen comprising incrementally titrating the xanomeline or a salt thereof and the trospium chloride salt until an amount equivalent to 125 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered.

[0010] The present disclosure further provides a method of treating acute psychosis in a patient in need thereof, comprising orally administering to the patient twice daily an oral pharmaceutical composition comprising xanomeline or a salt thereof and a trospium salt to achieve a mean reduction of at least 10 points in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo.

[0011] By reading the following detailed description, additional aspects and advantages will be apparent to those of ordinary skill in the art. Although dosage forms, preparation methods, and methods of treatment can have various forms of embodiments, the following description includes specific embodiments with the understanding that this disclosure is illustrative and is not intended to limit this disclosure to the specific embodiments described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] The present disclosure can be easily understood through the following detailed description in conjunction with the accompanying drawings, in which the same reference numerals represent the same structural elements. The accompanying drawings provide exemplary embodiments or aspects of the present disclosure and do not limit the scope of the present disclosure.

[0013] Figure 1 Depicted are the mean (± standard deviation) xanomeline pharmacokinetic concentrations on Day 1 for the twice daily KarXT50 / 20 treatment cohort of the KAR-003 pharmacokinetic population.

[0014] Figure 2 Depicted are the mean (± standard deviation) xanomeline pharmacokinetic concentrations by treatment on Day 3 for all cohorts of the KAR-003 pharmacokinetic population, twice daily KarXT treatment.

[0015] Figure 3 Depicted are the mean (± standard deviation) xanomeline pharmacokinetic concentrations by treatment on Day 7 for the twice daily KarXT 100 / 20, 125 / 40, and 150 / 40 treatment cohorts of the KAR-003 pharmacokinetic population.

[0016] Figure 4 Depicted are the mean (± standard deviation) xanomeline pharmacokinetic concentrations by treatment and follow-up for the KAR-003 pharmacokinetic population.

[0017] Figure 5 Depicted are the mean (± standard deviation) xanomeline pharmacokinetic trough concentrations by treatment for the KAR-003 pharmacokinetic population.

[0018] Figure 6 Depicted are the mean (± standard deviation) trospium pharmacokinetic concentrations on Day 1 for the twice-daily KarXT50 / 20 treatment cohort of the KAR-003 pharmacokinetic population.

[0019] Figure 7 Depicted are the mean (± standard deviation) trospium pharmacokinetic concentrations by treatment on Day 3 for the KAR-003 pharmacokinetic population.

[0020] Figure 8 Depicted are the mean (± standard deviation) trospium pharmacokinetic concentrations by treatment on Day 7 for the KAR-003 pharmacokinetic population.

[0021] Figure 9 Depicted are the mean (± standard deviation) trospium pharmacokinetic concentrations by treatment and follow-up for the KAR-003 pharmacokinetic population.

[0022] Figure 10 Depicted are mean (± standard deviation) trospium pharmacokinetic trough concentrations by treatment and follow-up for the KAR-003 pharmacokinetic population.

[0023] Figure 11 Depicted are the change from baseline in total PANSS score (LS mean difference) over time by week for subjects in the modified intent-to-treat (mITT) population of the KAR-004 Phase II study (***p<0.0001).

[0024] Figure 12 Depicted are the change from baseline in the PANSS positive subscore (LS mean difference) over time by week for subjects in the mITT population of the KAR-004 Phase II study (***p<0.0001).

[0025] Figure 13 Depicted are the change from baseline in the PANSS negative subscore (LS mean difference) over time by week for subjects in the mITT population of the KAR-004 Phase II study (*p<0.05, **p≤0.001).

[0026] Figure 14 Plotted are the PANSS Marder factor scores of subjects in the mITT population of the KAR-004 Phase II study relative to follow-up days.

[0027] Figure 15 Statistically significant and clinically meaningful improvements in the Clinical Global Impression-Severity (CGI-S) at baseline were described for patients receiving KarXT relative to patients receiving placebo.

[0028] Figure 16 Statistically significant and clinically meaningful improvements in CGI-S at the Week 5 endpoint were described for patients receiving KarXT relative to patients receiving placebo.

[0029] Figure 17 Depicted is a decrease in the rate of adverse events related to muscarinic receptor agonism (nausea and vomiting) over time in KarXT-treated patients.

[0030] Figure 18 Depicted is a reduction in the rate of peripheral anticholinergic adverse events (dry mouth) over time in KarXT-treated patients.

[0031] Figure 19 Depicted are box plots of standing heart rate (beats / min, bpm) from the KarXT safety population plotted by follow-up.

[0032] Figure 20 Depicted are box plots of orthostatic heart rate (beats / min, bpm) from the KarXT safety population plotted by follow-up.

[0033] Figure 21 Depicted are box plots of orthostatic diastolic pressure (mmHg) from the KarXT safety population plotted by follow-up.

[0034] Figure 22 Depicted are box plots of orthostatic systolic pressure (mmHg) from the KarXT safety population plotted by follow-up. DETAILED DESCRIPTION

[0035] Early development of the muscarinic receptor agonist xanomeline was terminated due to peripheral cholinergic side effects. The present disclosure provides dosage forms with dissolution kinetics that provide more effective therapeutic effects for both active ingredients, enhanced pharmacokinetics for trospium chloride, and greater dose compliance. The present disclosure also provides dosage forms with different strengths or different ratios of the two active ingredients.

[0036] The following specific embodiments are provided herein:

[0037] Example 1: A method for treating schizophrenia or a disorder related to schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient an oral pharmaceutical composition twice daily via a titration regimen, the oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof, and a plurality of trospamine beads containing a trospamine salt, the titration regimen comprising increasing titration of the xanomeline or a salt thereof, and the trospamine salt.

[0038] Example 2: A method for treating schizophrenia or a disorder related to schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient an oral pharmaceutical composition twice daily for at least five weeks, the oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof, and a plurality of trospamine beads containing a trospamine salt, wherein at least one adverse event occurring at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment.

[0039] Embodiment 3: The method of embodiment 1 or 2, wherein the administration is performed via a titration regimen comprising increasing titration of the xanomeline or its salt and the trospium chloride salt until an amount equivalent to 125 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered twice daily.

[0040] Embodiment 4: The method of embodiment 1 or 2, wherein the administration is performed via a titration regimen comprising titrating the xanomeline or its salt and the trospium chloride salt incrementally until an amount equivalent to 150 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered twice daily.

[0041] Embodiment 5: The method of embodiment 1 or 2, wherein the administration is performed via a titration regimen comprising titrating the xanomeline or its salt and the trospium chloride salt incrementally until an amount equivalent to 175 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered twice daily.

[0042] Embodiment 6: The method of embodiment 1 or 2, wherein the administration is performed via a titration regimen comprising increasing titration of the xanomeline or its salt and the trospium chloride salt until an amount equivalent to 175 mg of xanomeline free base and an amount equivalent to 40 mg of trospium chloride are administered twice daily.

[0043] Embodiment 7: The method of any one of the preceding embodiments, wherein the patient is diagnosed with schizophrenia.

[0044] Embodiment 8: The method of any one of the preceding embodiments, wherein before administration of the oral pharmaceutical composition, the patient has a Clinical Global Impression Severity Scale (CGI-S) score of 4-7, and after administration the patient has a CGI-S score equal to 1 or 2.

[0045] Embodiment 9: The method of any one of the preceding embodiments, wherein the xanomeline or salt thereof is administered in a first amount for a first period of time and then the first amount is increased to a second amount.

[0046] Embodiment 10: The method of embodiment 9, wherein the first amount of xanomeline or its salt is equivalent to 50 mg of xanomeline free base.

[0047] Embodiment 11: The method of embodiment 9 or 10, wherein the first period of time for administering xanomeline is 1 to 5 days.

[0048] Example 12: The method of Example 11, wherein the first period of time for administering xanomeline is 2 days.

[0049] Embodiment 13: The method of any one of embodiments 9 to 12, wherein the second amount of xanomeline or a salt thereof is equivalent to 100 mg of xanomeline free base.

[0050] Embodiment 14: The method of any one of embodiments 9 to 13, further comprising administering the xanomeline or salt thereof in the second amount for a second period of time and then increasing the second amount to a third amount.

[0051] Embodiment 15: The method of embodiment 14, wherein the second period of time for which xanomeline is administered is three days to one week.

[0052] Embodiment 16: The method of embodiment 14 or 15, wherein the third amount of xanomeline or its salt is equivalent to 125 mg of xanomeline free base.

[0053] Embodiment 17: The method of any preceding embodiment, wherein the trospium chloride salt is administered in a first amount for a first period of time, and the first amount is increased to a second amount.

[0054] Embodiment 18: The method of embodiment 17, wherein the first amount of trospium chloride salt is equivalent to 20 mg of trospium chloride.

[0055] Embodiment 19: The method of embodiment 17 or 18, wherein the first period of time for which trospium is administered is at least one week.

[0056] Embodiment 20: The method of any one of embodiments 15 to 17, wherein the second amount of trospium chloride salt is equivalent to 30 mg of trospium chloride.

[0057] Embodiment 21: The method of any one of the preceding embodiments, wherein at least one of vomiting, nausea, and dry mouth occurring at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment.

[0058] Embodiment 22: The method of any one of the preceding embodiments, wherein administration of the xanomeline or salt thereof, and the trospium salt does not cause an increase in heart rate of more than about 5 beats per minute.

[0059] Embodiment 23: The method of any one of the preceding embodiments, wherein the xanomeline or its salt, and the trospium salt are administered without causing syncope.

[0060] Embodiment 24: The method of any one of the preceding embodiments, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing a change in diastolic blood pressure of more than about 5 mmHg.

[0061] Embodiment 25: The method of any one of the preceding embodiments, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing a change in systolic blood pressure of more than about 5 mmHg.

[0062] Embodiment 26: The method of any one of the preceding embodiments, wherein administration of the xanomeline or its salt, and the trospium salt does not result in serious adverse events.

[0063] Embodiment 27: The method of any one of the preceding embodiments, wherein administration of the xanomeline or its salt, and the trospium salt does not result in serious adverse events related to heart rate.

[0064] Embodiment 28: The method of any one of the preceding embodiments, wherein administration of the xanomeline or salt thereof, and the trospium salt does not result in serious adverse events related to changes in heart rate.

[0065] Embodiment 29: The method of any one of the preceding embodiments, wherein administration of the xanomeline or its salt, and the trospium chloride salt does not result in serious adverse events related to blood pressure.

[0066] Embodiment 30: The method of any one of the preceding embodiments, wherein the xanomeline or its salt, and the trospium salt are administered without causing serious adverse events related to changes in blood pressure.

[0067] Embodiment 31: The method of any one of the preceding embodiments, wherein the xanomeline or salt thereof, and the trospium salt are administered without increasing liver function tests (LFTs).

[0068] Embodiment 32: The method of any one of the preceding embodiments, wherein after five weeks of treatment, the patient's Positive and Negative Syndrome Scale (PANSS) total score is reduced by at least 10 points compared to placebo.

[0069] Embodiment 33: The method of any one of the preceding embodiments, wherein after five weeks of treatment, the PANSS positive subscore is reduced by at least 3 points compared to placebo.

[0070] Embodiment 34: The method of any one of the preceding embodiments, wherein after five weeks of treatment, the PANSS negative subscore is reduced by at least 2 points compared to placebo.

[0071] Embodiment 35: The method of any preceding embodiment, wherein the size of the xanomeline beads is 0.425 mm to 1.18 mm.

[0072] Embodiment 36: The method of any preceding embodiment, wherein the size of the xanomeline beads is 0.6 mm to 0.85 mm.

[0073] Embodiment 37: The method of any preceding embodiment, wherein the size of the trospium beads is 0.425 mm to 1.18 mm.

[0074] Embodiment 38: The method of any preceding embodiment, wherein the size of the trospium beads is 0.6 mm to 0.85 mm.

[0075] Embodiment 39: The method of any preceding embodiment, wherein the xanomeline beads contain about 2.5 times more xanomeline free base than the trospium salt contained in the trospium beads.

[0076] Embodiment 40: The method of any preceding embodiment, wherein the dissolution rate of the plurality of xanomeline beads and the plurality of trospamine beads is greater than about 95% within about the first 45 minutes after the dosage form enters the aqueous solution.

[0077] Embodiment 41: The method of embodiment 40, wherein the dissolution rate is greater than about 95% within about the first 20 minutes after the dosage form enters the aqueous solution.

[0078] Embodiment 42: The method of any one of the preceding embodiments, wherein the salt of xanomeline is xanomeline tartrate.

[0079] Embodiment 43: The method of embodiment 42, wherein the xanomeline beads comprise 30 wt.% to 80 wt.% xanomeline tartrate.

[0080] Embodiment 44: The method of embodiment 43, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate.

[0081] Embodiment 45: The method of any preceding embodiment, wherein the xanomeline beads comprise 15 wt.% to 65 wt.% microcrystalline cellulose.

[0082] Embodiment 46: The method of embodiment 45, wherein the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose.

[0083] Embodiment 47: The method of any preceding embodiment, wherein the xanomeline beads comprise 0 wt.% to 2 wt.% talc.

[0084] Embodiment 48: The method of embodiment 46, wherein the xanomeline beads contain 0.5 wt.% talc.

[0085] Embodiment 49: The method of any preceding embodiment, wherein the xanomeline beads comprise 30 wt.% to 80 wt.% xanomeline tartrate, 15 wt.% to 65 wt.% microcrystalline cellulose, and 0 wt.% to 2 wt.% talc.

[0086] Embodiment 50: The method of embodiment 49, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc.

[0087] Embodiment 51: The method of any preceding embodiment, wherein the trospium chloride salt is trospium chloride.

[0088] Embodiment 52: The method of embodiment 51, wherein the trospium chloride beads comprise 8 wt.% to 35 wt.% trospium chloride.

[0089] Embodiment 53: The method of embodiment 52, wherein the trospium chloride beads comprise 17.7 wt.% trospium chloride.

[0090] Embodiment 54: The method of any preceding embodiment, wherein the trospium chloramine beads comprise 25 wt.% to 80 wt.% microcrystalline cellulose.

[0091] Example 55: The method of Example 54, wherein the trospium chloride beads comprise 46.8 wt.% microcrystalline cellulose.

[0092] Embodiment 56: The method of any preceding embodiment, wherein the trospamine beads comprise 15 wt.% to 70 wt.% lactose monohydrate.

[0093] Example 57: The method of Example 56, wherein the trospium chloride beads comprise 35 wt.% lactose monohydrate.

[0094] Embodiment 58: The method of any preceding embodiment, wherein the trospium chloride beads comprise 0 to 2 wt.% talc.

[0095] Embodiment 59: The method of embodiment 58, wherein the trospium chloride beads contain 0.5 wt.% talc.

[0096] Embodiment 60: The method of any one of the preceding embodiments, wherein the trospium chloride beads comprise 8 to 35 wt.% trospium chloride, 25 to 80 wt.% microcrystalline cellulose, 15 to 70 wt.% lactose monohydrate, and 0 to 2 wt.% talc.

[0097] Example 61: The method of Example 60, wherein the trospium chloride beads comprise 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc.

[0098] Embodiment 62: The method of any preceding embodiment, wherein the oral pharmaceutical composition further comprises ascorbic acid.

[0099] Embodiment 63: The method of embodiment 62, wherein the oral pharmaceutical composition comprises 0.2 wt.% to 1 wt.% of ascorbic acid.

[0100] Embodiment 64: The method of embodiment 63, wherein the oral pharmaceutical composition comprises about 0.5 wt.% ascorbic acid.

[0101] Embodiment 65: The method of any preceding embodiment, wherein the oral pharmaceutical composition further comprises butylated hydroxytoluene.

[0102] Embodiment 66: The method of embodiment 64, wherein the oral pharmaceutical composition comprises 0.01 wt.% to 0.1 wt.% of butylated hydroxytoluene.

[0103] Embodiment 67: The method of embodiment 66, wherein the oral pharmaceutical composition comprises about 0.05 wt.% of butylated hydroxytoluene.

[0104] Embodiment 68: The method of any preceding embodiment, wherein the oral pharmaceutical composition further comprises a capsule containing the plurality of xanomeline beads and the plurality of trospamine beads.

[0105] Example 69: A method of treating acute psychosis in a patient in need thereof, the method comprising: orally administering to the patient an oral pharmaceutical composition comprising xanomeline or a salt thereof, and a trospium salt twice daily to achieve a mean reduction of at least 10 points in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo.

[0106] Embodiment 70: The method of embodiment 69, wherein a mean reduction in PANNS total score of at least 11.6 points is achieved.

[0107] Embodiment 71: The method of any one of Embodiments 69 or 70, wherein a mean reduction in the PANSS positive subscore of at least 3 points compared to placebo is achieved.

[0108] Embodiment 72: The method of any one of embodiments 69 to 71, wherein a reduction in PANSS negative subscore of at least 2 points compared to placebo is achieved.

[0109] Embodiment 73: The method of any one of Embodiments 69 to 72, wherein the reduction in PANSS score is achieved within about 5 weeks.

[0110] Embodiment 74: The method of any one of embodiments 69 to 73, wherein prior to administration of the oral pharmaceutical composition, the patient has a Clinical Global Impression Severity Scale (CGI-S) score of 4-7, and after administration the patient has a CGI-S score equal to 1 or 2.

[0111] Embodiment 75: The method of any one of embodiments 69 to 74, wherein the patient is diagnosed with schizophrenia.

[0112] Embodiment 76: The method of any one of Embodiments 69 to 75, wherein the xanomeline is xanomeline tartrate and the trospium chloride salt is trospium chloride.

[0113] Embodiment 77: The method of any one of embodiments 69 to 76, wherein at least one adverse event occurring at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment.

[0114] Embodiment 78: The method of embodiment 77, wherein at least one adverse event is selected from vomiting, nausea, and dry mouth.

[0115] The articles "a" and "an" refer to one or to more than one (ie, to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0116] The terms "comprise" and "comprising" are inclusive and open-ended, meaning that additional elements may be included.

[0117] The term "consisting of" limits the elements to those specified, except for impurities normally associated therewith.

[0118] The term "consisting essentially of" is limited to those elements specified and to those elements that do not materially affect the basic and novel characteristics of the material or process.

[0119] All ranges set forth herein include all possible subsets of ranges and any combination of such subset ranges. By default, ranges include the specified endpoints, and unless otherwise stated, where a range of values is provided, each intermediate value between the upper and lower limits of that range and any other specified or intermediate values in the specified range are encompassed in this disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed in this disclosure, subject to any expressly excluded limits in the specified ranges. Where the specified range includes one or both limits, ranges excluding one or both of those included limits are also considered part of this disclosure.

[0120] The term "wt.%" is the weight percentage of, for example, the core, or the enteric coating or the total beads as described above or below, based on the total weight. Unless otherwise stated, wt.% is intended to describe the weight percentage on a dry weight basis (e.g. for the core after drying).

[0121] The term "controlled-release" is defined as an extended release profile of one or more drugs so that the drug is released over a period of time. The release kinetics of a controlled-release formulation result in serum levels of the drug being measurable over a potentially longer period of time than after intravenous injection or administration of an immediate-release oral dosage form. Controlled-release, sustained-release, sustained-release, extended-release, and delayed-release have the same definition.

[0122] The term "including" means "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0123] The term "mammal" is art-recognized. Exemplary mammals include humans, primates, cows, pigs, dogs, cats, and rodents (eg, mice and rats).

[0124] A "patient," "subject," or "host" treated by the subject methods refers to a human or non-human mammal.

[0125] The term "pharmaceutically acceptable carrier" is art-recognized. It refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, that participates in carrying or transporting any subject composition or its components from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered gum tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic, compatible substances employed in pharmaceutical formulations.

[0126] The term "pharmaceutically acceptable salt" or "salt" is art-recognized. It refers to a salt prepared from a relatively nontoxic acid or base, including inorganic acids and bases and organic acids and bases, including, for example, those contained in the compositions of the present disclosure. Suitable nontoxic acids include inorganic and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, saccharinic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, among others.

[0127] The terms "treat" and "treating" are art-recognized and refer to curing as well as alleviating at least one symptom of any condition or disorder.

[0128] In jurisdictions that prohibit patenting of methods performed on human subjects, the meaning of "administering" a composition to a human subject should be limited to providing that the human subject will self-administer a controlled substance by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). This is intended to be consistent with the broadest reasonable interpretation of the law or regulation defining patentable subject matter. In jurisdictions that do not prohibit patenting of methods performed on human subjects, "administering" a composition includes both methods performed on human subjects and the aforementioned activities.

[0129] The term "therapeutic agent" is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of therapeutic agents (also referred to as "drugs") are described in well-known reference texts such as the Merck Index (14th ed.), the Physicians' Desk Reference (64th ed.), and The Pharmacological Basis of Therapeutics (12th ed.). These therapeutic agents include, but are not limited to, drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or alleviate a disease or condition; substances that affect the structure or function of the body, or prodrugs that become biologically active or more active when placed in a physiological environment.

[0130] The term "psychotherapy" refers to non-pharmacological therapy. Those skilled in the art use the various techniques related to oral and other interactions with the patient to influence positive treatment outcomes. Such techniques include, but are not limited to, behavioral therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, occupational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also referred to as person-centered therapy), Gestalt therapy (Gestalt therapy), biofeedback therapy, rational emotive behavior therapy, reality therapy, response-based therapy, sandplay therapy, state dynamics therapy, hypnosis and validation therapy. Psychotherapy can involve a combination of two or more techniques. The therapist can select and adjust technology according to the needs of each patient and the patient's response.

[0131] The term "muscarinic disorder" refers to any disease or condition that is ameliorated by activation of the muscarinic system. Such diseases include those in which direct activation of the muscarinic receptors themselves or inhibition of cholinesterase has produced a therapeutic effect.

[0132] The terms "diseases associated with schizophrenia" and "disorders associated with schizophrenia" include, but are not limited to, schizoaffective disorder, psychosis (including acute psychosis), delusional disorder, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar psychosis, Huntington's disease, Lewy body dementia, or any other disorder with psychotic features.

[0133] "Psychosis" is an abnormal state of mind that makes it difficult to determine what is real and what is not. Symptoms of psychosis include, but are not limited to, false beliefs (delusions), seeing or hearing things that others cannot see or hear (hallucinations), incoherent speech, erratic behavior, sleep problems, social withdrawal, lack of motivation, and difficulty carrying out daily activities.

[0134] "Acute psychosis" refers to a rapid or intense onset of psychotic symptoms in a patient, such as those defined in "Acute Brief Psychotic Disorder" (International Classification of Diseases-10) and "Brief Psychotic Disorder" (DSM-IV). After a brief preparatory period of anxiety, insomnia, and confusion, individuals with acute psychosis experience rapid onset of delusions that change rapidly in structure. Acute psychosis can include an acute exacerbation of psychosis, in which the patient may react to hallucinations or delusions. Acute psychosis is short-lived, typically one to two weeks.

[0135] The term "activator" means a molecule described as an agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulant, allosteric potentiator, positive allosteric modulator, allosteric agonist, or a molecule that directly or indirectly increases receptor activity or signaling.

[0136] The term "inhibitor" means a molecule described as an antagonist, partial antagonist, competitive antagonist, noncompetitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist, or a molecule that directly or indirectly reduces receptor activity or signaling.

[0137] As used herein, an "adverse event" is any untoward medical occurrence associated with treatment with a pharmaceutical composition described herein. A "mild adverse event" is easily tolerated by the subject, causes minimal discomfort, and does not interfere with daily activities. A "moderate adverse event" is severe enough to cause discomfort and interfere with daily activities; intervention may be required. A "serious adverse event" interferes with daily activities; treatment or other intervention is usually required. A "severe adverse event" results in death; is life-threatening (there is an immediate risk of death from the event when it occurs); requires hospitalization or prolonged hospitalization; results in persistent or severe disability / incapacity; or results in a congenital anomaly / disability, cancer, or drug overdose. An adverse event is incapacitating or disabling if it results in a substantial or permanent disruption of the subject's ability to carry out normal life functions.

[0138] As used herein, a patient is said to "tolerate" a dose of a compound if the dose administered to the patient does not result in an unacceptable adverse event or combination of unacceptable adverse events. It will be appreciated by those skilled in the art that tolerance is a subjective measure and that a substance tolerated by one patient may not be tolerated by a different patient. For example, one patient may not tolerate a headache. In contrast, a second patient may consider a headache tolerable, but not vomiting. For a third patient, either the headache alone or the vomiting alone may be tolerated. Nevertheless, the patient may not tolerate the combination of the headache and vomiting, even though each of the headache and vomiting is less severe than when experienced alone.

[0139] The term "maximum tolerated dose" means the maximum dose of a drug or therapeutic agent that a patient can take without experiencing intolerable side effects. The maximum tolerated dose is typically determined empirically in clinical trials.

[0140] The term "muscarinic receptor" refers to a G protein-linked receptor that binds the neurotransmitter acetylcholine. To date, five subtypes of muscarinic receptors have been identified. "M1" refers to subtype I muscarinic receptors. "M2" refers to subtype II muscarinic receptors. "M3" refers to subtype III muscarinic receptors. "M4" refers to subtype IV muscarinic receptors. "M5" refers to subtype V muscarinic receptors.

[0141] The term "antipsychotic" refers to a drug that reduces psychosis, hallucinations, or delusions. Antipsychotics include, but are not limited to, haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, percynanil, promazine, triflupromazine, levomepromazine, promethazine, pamoxifen, chlorprothixene, trifluthixene, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifenazine, and tetrabenazine.

[0142] The term "anxiolytic" refers to a drug that reduces anxiety, fear, panic, or related feelings. Such drugs include, but are not limited to, benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), and hydroxyzine.

[0143] The term "antidepressant" refers to drugs that alleviate depression and related conditions (eg, mood disorders). Such drugs include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipram, venlafaxine), mianserin, mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline), and monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine).

[0144] The term "sedative" or "tranquilizer" refers to a drug that induces sleepiness, promotes a feeling of tiredness or a desire to sleep, or promotes an unconscious state. Such drugs include, but are not limited to, benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), eszopiclone, zaleplon, zolpidem, and zopiclone. Pharmaceutical composition

[0145] Provided herein is an oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof; and a plurality of trospium beads containing a trospium salt. In certain embodiments, the trospium salt is selected from trospium chloride, trospium bromide, trospium iodide, and trospium saccharinate.

[0146] In certain embodiments, the plurality of xanomeline beads have a core comprising xanomeline or a salt thereof. In certain embodiments, the plurality of trospium beads have a core comprising a trospium salt.

[0147] In certain embodiments, a capsule shell comprising hydroxypropyl methylcellulose (HPMC) contains separate populations of beads containing xanomeline tartrate or trospium chloride, wherein the beads are of comparable size and rapidly release the active ingredient at substantially similar rates. After the capsule shell dissolves in the stomach, the beads may dissolve in the stomach or pass through the pyloric valve intact or partially intact into the duodenum. Nevertheless, the ratio of the two drugs remains relatively constant in the gastrointestinal tract, whether in dissolved or undissolved form, until the drugs are absorbed.

[0148] Each bead formulation allows for substantially similar performance from both active ingredients at different dose ranges. The active ingredients are released into the serum at substantially similar rates or to substantially similar T 最大 In certain embodiments, the capsule contains 50 mg of xanomeline as the tartrate salt and 10 mg of trospium chloride. Fifty mg of xanomeline as the free base corresponds to approximately 76 mg of xanomeline tartrate.

[0149] The difference in the number of drug beads in the capsule increases the likelihood that the drug-bead ratio will not remain substantially constant after the beads are released and dispersed. Therefore, in certain embodiments, trospium chloride beads are formulated with a lower drug loading. Effective doses of trospium chloride and xanomeline are contained in approximately equal numbers of beads. Despite the differences in drug loading in certain embodiments, trospium chloride and xanomeline beads are released at approximately similar rates. For example, if the dissolution of the capsule is assessed using a United States Pharmacopeia (USP) dissolution apparatus, the percentage of xanomeline dissolved at, for example, 10 min, 20 min, or 30 min is substantially equivalent to the percentage of trospium chloride dissolved.

[0150] The drug may also include one or more pharmaceutically acceptable salts. The drug may include one or more pharmaceutically acceptable carriers. The drug may be administered orally. The drug may be delivered orally using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, caplets or gel caps, and other oral administration methods known to those skilled in the art.

[0151] The drug may be in a dosage form that releases the drug immediately. In an alternative embodiment, the drug may have a controlled release dosage form.

[0152] The drug may be in dosage form using other controlled-release formulation methods known to those skilled in the art.

[0153] In another embodiment, the drug is combined with one or more therapies, including psychotherapy and medication. Therapeutic agents include, but are not limited to, antipsychotics, antianxiety drugs, antidepressants, sedatives, tranquilizers, analgesics, and other pharmacological interventions known to those skilled in the art. Therapeutic agents may belong to more than one class of drugs. For example, benzodiazepines may be considered antianxiety drugs, sedatives, and tranquilizers. Bead / core excipients

[0154] The beads or cores may contain one or more excipients. In one embodiment, the excipients include one or more fillers, binders, and surfactants. Other optional ingredients include, but are not limited to, glidants, lubricants, disintegrants, swelling agents, and antioxidants. Xanomeline or a pharmaceutically acceptable salt thereof and trospium chloride salt may be in separate matrices within the same pharmaceutical composition.

[0155] The amount of xanomeline free base in the core may be at least 10 wt.%, or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.%. For example, the amount of xanomeline tartrate may be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.%, of the core, within a range of about 60 wt.% to about 90 wt.%, or about 65 wt.% to about 85 wt.%. It should be understood that all ranges including these values as endpoints are contemplated, for example, at least about 15 wt.% to about 90 wt.%, about 20 wt.% to about 85 wt.%, about 30 wt.% to about 85 wt.%, or about 50 wt.% to about 90 wt.%. In certain embodiments, the xanomeline beads comprise 30 wt.% to 80 wt.% xanomeline tartrate, such as 66 wt.% xanomeline tartrate.

[0156] The amount of trospium chloride salt in the core can be at least 10 wt.%, or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.%. For example, the amount of trospium chloride can be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.%, of the core, within a range of about 60 wt.% to about 90 wt.%, or about 65 wt.% to about 85 wt.%. It should be understood that all ranges including these values as endpoints are contemplated, for example, at least about 15 wt.% to about 90 wt.%, about 20 wt.% to about 85 wt.%, about 30 wt.% to about 85 wt.%, or about 50 wt.% to about 90 wt.%. In certain embodiments, trospium chloride is trospium chloride. In certain embodiments, the trospium chloride beads comprise 8 wt.% to 35 wt.% trospium chloride, such as 17.7 wt.% trospium chloride.

[0157] In other embodiments, the matrix comprises a polymer, for example, to modify the release profile of the active ingredient in the matrix. In other embodiments, the polymer comprises a water-soluble polymer. In other embodiments, the water-soluble polymer is selected from Eudragit TM RL, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and mixtures thereof. In further embodiments, the polymer comprises a water-insoluble polymer. In further embodiments, the water-insoluble polymer is selected from Eudragit TM RS, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), low density poly(ethylene), high density poly(ethylene), poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethanes, and mixtures thereof.

[0158] Fillers include but are not limited to lactose, sucrose, glucose, starch, microcrystalline cellulose, ultrafine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silicon dioxide and sodium chloride, starch and dicalcium hydrogen phosphate dihydrate. In one embodiment, although the filler can absorb water, it is insoluble in water. In one embodiment, the filler is a spheronization aid. The spheronization aid can include one or more of crospovidone, carrageenan, chitosan, pectic acid, glyceride, beta-cyclodextrin (beta-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone cross-linked polyvinyl ketone and polyethylene oxide. In one embodiment, the filler includes microcrystalline cellulose.

[0159] The amount of filler in the xanomeline core is not particularly limited. In an embodiment, the amount of filler (e.g., microcrystalline cellulose) may be in the range of about 10 wt.% to about 70 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.%, or at least 19.5 wt.%, for example, about 20 wt.%. In certain embodiments, the xanomeline beads comprise about 15 wt.% to about 65 wt.% microcrystalline cellulose, for example, about 15 wt.% to about 20 wt.%, about 20 wt.% to about 25 wt.%, about 25 wt.% to about 30 wt.%, about 30 wt.% to about 35 wt.%, about 35 wt.% to about 40 wt.%, about 40 wt.% to about 45 wt.%, about 45 wt.% to about 50 wt.%, about 50 wt.% to about 55 wt.%, about 55 wt.% to about 60 wt.%, or about 60 wt.% to about 65 wt.%. In certain embodiments, the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose.

[0160] The amount of filler in the trospium chloride core is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose or lactose) can be in the range of about 10 wt.% to about 80 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, such as about 20 wt.%. In certain embodiments, the trospium beads comprise 25 to 80 wt.% microcrystalline cellulose, e.g., about 25 to 30 wt.%, about 30 to 35 wt.%, about 35 to 40 wt.%, about 40 to 45 wt.%, about 45 to 50 wt.%, about 50 to 55 wt.%, about 55 to 60 wt.%, about 60 to 65 wt.%, about 65 to 70 wt.%, about 70 to 75 wt.%, or about 75 to 80 wt.%. In certain embodiments, the trospium beads comprise 46.8 wt.% microcrystalline cellulose.

[0161] In certain embodiments, the trospium beads comprise 15 to 70 wt.% lactose monohydrate, such as about 15 to 20 wt.%, about 20 to 25 wt.%, about 25 to 30 wt.%, about 30 to 35 wt.%, about 35 to 40 wt.%, about 40 to 45 wt.%, about 45 to 50 wt.%, about 50 to 55 wt.%, about 55 to 60 wt.%, about 60 to 65 wt.%, or about 65 to 70 wt.%. In certain embodiments, the trospium beads comprise 35 wt.% lactose monohydrate.

[0162] Binders include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hydroxypropylmethylcellulose, such as Hydroxypropyl Methylcellulose 2910, Methocel TM E), carboxymethyl cellulose, starch, pregelatinized starch, gum arabic, tragacanth, gelatin, polyvinyl pyrrolidone (povidone), cross-linked polyvinyl pyrrolidone, sodium alginate, microcrystalline cellulose, and lower alkyl substituted hydroxypropyl cellulose. In one embodiment, the binder is selected from a wet binder. In one embodiment, the binder is selected from a cellulose ether, such as hypromellose.

[0163] The amount of the binder in the xanomeline core is not particularly limited. In an embodiment, the amount of the binder (e.g., hypromellose) may be in the range of about 1 wt.% to about 10 wt.%, about 2 wt.% to about 8 wt.%, or about 4 wt.% to about 6 wt.%, for example, about 5 wt.%.

[0164] The amount of binder in the trospium chloride core is not particularly limited. In an embodiment, the amount of binder (e.g., hypromellose) can be in the range of about 1 wt.% to about 10 wt.%, about 2 wt.% to about 8 wt.%, or about 4 wt.% to about 6 wt.%, for example, about 5 wt.%.

[0165] Surfactants include, but are not limited to, anionic surfactants (including sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate), nonionic surfactants (including polyoxyethylene ether and polysorbate 80), and cationic surfactants (including quaternary ammonium compounds). In one embodiment, the surfactant is selected from anionic surfactants, such as sodium lauryl sulfate.

[0166] The amount of surfactant (e.g., as a processing aid) in the xanomeline core is not particularly limited. In an embodiment, the amount of surfactant (e.g., microcrystalline cellulose) may be in the range of about 0.1 wt.% to about 1 wt.%, about 0.2 wt.% to about 0.8 wt.%, or about 0.4 wt.% to about 0.6 wt.%, for example, about 0.5 wt.%.

[0167] The amount of surfactant (e.g., as a processing aid) in the trospium chloride core is not particularly limited. In an embodiment, the amount of surfactant (e.g., sodium lauryl sulfate) can be in the range of about 0.1 wt.% to about 1 wt.%, about 0.2 wt.% to about 0.8 wt.%, or about 0.4 wt.% to about 0.6 wt.%, for example, about 0.5 wt.%.

[0168] Disintegrants include, but are not limited to, starch, crosslinked sodium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, crosslinked polyvinyl pyrrolidone, and sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0169] Glidants include, but are not limited to, polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silica, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetyl alcohol, stearyl alcohol, and talc.

[0170] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and silicified talc. In certain embodiments, the xanomeline beads contain 0 to 2 wt% talc, such as 0.5 wt% talc. In certain embodiments, the trospium chloride beads contain 0 to 2 wt% talc, such as 0.5 wt% talc.

[0171] In certain embodiments, the formulation further comprises one or more antioxidants. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelators, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc. In certain embodiments, the formulation comprises less than 1 wt.% antioxidant, such as 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.%, 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, or 0.01 wt.%.

[0172] In certain embodiments, the oral pharmaceutical composition further comprises ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises 0.2 wt.% to 1 wt.% ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises about 0.5 wt.% ascorbic acid. In certain embodiments, the oral pharmaceutical composition further comprises butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises 0.01 wt.% to 0.1 wt.% butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises about 0.05 wt.% butylated hydroxytoluene. In certain embodiments, the formulation comprises about 0.05 wt.% BHT or 0.5 wt.% ascorbic acid. In certain embodiments, the antioxidant is present in the xanomeline core or xanomeline beads.

[0173] In certain embodiments, the xanomeline beads comprise 30 to 80 wt.% xanomeline tartrate, 15 to 65 wt.% microcrystalline cellulose, and 0 to 2 wt.% talc. In certain embodiments, the trospium chloride beads comprise 0.2 to 2 wt.% talc, such as 0.5 wt.% talc. In certain embodiments, the trospium chloride beads comprise 8 to 35 wt.% trospium chloride, 25 to 80 wt.% microcrystalline cellulose, 15 to 70 wt.% lactose monohydrate, and 0.2 to 2 wt.% talc.

[0174] In certain embodiments, xanomeline tartrate beads contain 66 wt.% xanomeline tartrate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc. In certain embodiments, trospium chloride beads contain 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc. In this example, the amount of xanomeline contained in the xanomeline tartrate beads is approximately 2.5 times the amount of trospium chloride contained in the trospium chloride beads.

[0175] Depending on the dosage requirements, capsules can be prepared using varying amounts of xanomeline tartrate beads and trospium chloride beads. In various embodiments, the capsules contain 25 mg of xanomeline and 10 mg of trospium chloride, 50 mg of xanomeline and 10 mg of trospium chloride, 50 mg of xanomeline and 20 mg of trospium chloride, 75 mg of xanomeline and 10 mg of trospium chloride, 75 mg of xanomeline and 20 mg of trospium chloride, 125 mg of xanomeline and 30 mg of trospium chloride, or 125 mg of xanomeline and 40 mg of trospium chloride. In certain embodiments, the capsules contain 25 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In certain embodiments, the capsules contain 50 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In certain embodiments, the capsule contains 50 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In certain embodiments, the capsule contains 75 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In certain embodiments, the capsule contains 75 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In certain embodiments, the capsule contains 125 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In certain embodiments, the capsule contains 125 mg of xanomeline as xanomeline tartrate and 40 mg of trospium chloride. In certain embodiments, the capsule contains 150 mg of xanomeline and 20 mg of trospium chloride. In certain embodiments, the capsule contains 150 mg of xanomeline and 30 mg of trospium chloride. In certain embodiments, the capsule contains 150 mg of xanomeline and 40 mg of trospium chloride. In certain embodiments, the capsule contains 175 mg of xanomeline and 20 mg of trospium chloride. In certain embodiments, the capsule contains 175 mg of xanomeline and 30 mg of trospium chloride. In certain embodiments, the capsule contains 175 mg of xanomeline and 40 mg of trospium chloride.

[0176] In another embodiment, the medicament contains 5 mg to 700 mg of xanomeline. In an embodiment, the medicament contains 25 mg to 300 mg of xanomeline.

[0177] In another embodiment, the medicament contains 1 mg to 400 mg of trospium chloride. In an embodiment, the medicament contains 6.5 mg to 200 mg of trospium chloride.

[0178] In one embodiment, trospium chloride extended-release is used as trospium chloride in a medicament. In another embodiment, the medicament contains 1 mg to 400 mg of trospium chloride extended-release. In another embodiment, the medicament contains 6.5 mg to 200 mg of trospium chloride extended-release.

[0179] In an embodiment, the drug contains 75 mg or 225 mg of xanomeline and the same drug contains 20 mg or 40 mg of trospium chloride. In another embodiment, the drug contains 75 mg or 225 mg of xanomeline and a different drug to be co-administered contains 20 mg or 40 mg of trospium chloride. Bead coating

[0180] In other embodiments, functional or non-functional coatings can be applied to the beads, for example, for aesthetics, handling, or stability. In certain embodiments, the beads can be coated with a pH-sensitive coating so that they do not dissolve in the low pH of the stomach. Non-functional coatings can be used to maintain chemical separation between the beads or for decorative reasons.

[0181] In another embodiment, the controlled-release formulation comprises a semipermeable coating. Xanomeline and trospium chloride in the same formulation can be in different coatings. In another embodiment, xanomeline and trospium chloride in different formulations or administration vehicles can be in different coatings. In another embodiment, the semipermeable coating comprises a polymer. In another embodiment, the controlled-release formulation comprises a matrix in which the xanomeline and trospium chloride are suspended.

[0182] In certain embodiments, the coating thickness distribution can be described as the weight gain of the coating material based on the total weight of the coated beads. Thus, in one embodiment, the coating thickness distribution is at least 2% based on the total weight of the coated beads. In another embodiment, the coating thickness distribution is at least 3%. In another embodiment, the coating thickness distribution is at least 4%. In another embodiment, the coating thickness distribution is at least 5%. In another embodiment, the coating thickness distribution is at least 6%. In another embodiment, the coating thickness distribution is at least 7%. In another embodiment, the coating thickness distribution is at least 8%. In another embodiment, the coating thickness distribution is at least 9%. In another embodiment, the coating thickness distribution is at least 10%. In another embodiment, the coating thickness distribution is at least 11%. In another embodiment, the coating thickness distribution is at least 12%. In another embodiment, the coating thickness distribution is at least 13%. In another embodiment, the coating thickness distribution is at least 14%.

[0183] For example, the coating thickness difference between different beads can be in the range of + / - 1%-7% based on the total weight of the coated beads. The coating thickness distribution can be from about 2% to about 14%, such as from about 3% to about 13%, from about 4% to about 12%, from about 5% to about 11%, from about 6% to about 10%, from about 7% to 9%, from about 3% to 14%, from about 4% to 14%, from about 4% to 13%, or from 4% to about 12% based on the weight of the coated beads.

[0184] In one embodiment, the absorption (area under the curve, AUC) of this dosage form is advantageously increased upon oral administration compared to other dosage forms of xanomeline or trospium chloride. Without being bound by any theory, the increased absorption is influenced by the dosage form exhibiting a pseudo-extended release profile. The pseudo-extended release profile is influenced by one or more factors, including the distribution of coating thickness (if present), the distribution of bead size, and beads having irregular bead shapes. For example, in embodiments where the beads have a distribution of coating thicknesses, for beads having a relatively thin coating, the coating dissolves relatively quickly and completely at the triggering pH, thereby releasing the xanomeline and / or trospium chloride composition, while for beads having a relatively thick coating, the coating takes longer to completely dissolve and release the xanomeline and / or trospium chloride composition. In embodiments where the beads have a particle size distribution and / or irregular bead shape, the intestinal transit time of the beads may vary due to the bead size and / or shape, such that the transit time until the coating dissolution pH is reached varies, thereby contributing to a pseudo-extended release profile. In another embodiment, the dosage form exhibits substantially equivalent (e.g., bioequivalent) C when administered orally, either within a capsule shell or without a capsule shell. 最大 and / or AUC features.

[0185] In certain embodiments, the dosage form provides a gradual and predictable absorption profile. In one embodiment, when administered orally, the dosage form has a T 最大 More stable on a dose-to-dose basis because beads are individually coated. Predictable, consistent T 最大 This facilitates a more consistent, sustained therapeutic effect. For example, process-related variations in coating thickness or other effects on coating dissolution affect only a portion of the xanomeline and trospium chloride in the dosage form. They tend to result in a pseudo-extended release behavior. In contrast, coated capsules containing xanomeline and trospium chloride microspheres exhibit significant variability in absorption time between capsules.

[0186] In certain embodiments, an oral pharmaceutical composition comprising xanomeline and / or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, wherein when administered to the patient in need thereof, the composition is sufficient to provide an in vivo plasma profile comprising a median T of xanomeline at 2 hours. 最大 and 1-hour median T of trospium 最大 In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized C of 48.5 to 121.3 pg / mL / mg. 最大 In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized Cmax of trospium ranging from 156 to 375 pg / mL / mg. In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC of xanomeline ranging from 263 to 577 hr·pg / mL / mg. 0-12 In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC of trospium ranging from 881 to 2024 hr·pg / mL / mg. 0-12 In certain embodiments, the in vivo plasma profile further comprises a mean C of trospium of 7850 ± 3360 pg / mL. 最大 In certain embodiments, the in vivo plasma profile further comprises a mean AUC of 41900 ± 15500 hr·pg / mL 0-12 .

[0187] In another embodiment, the dosage form exhibits favorable storage stability, for example, as measured by the amount of xanomeline present after storage and / or by the total amount of related substances. Storage stability can be assessed after storage under typical ambient conditions (e.g., 25° C. and 60% relative humidity) or under accelerated stability conditions involving elevated temperature and / or humidity.

[0188] Unless otherwise indicated, it is contemplated that dosage forms and methods include embodiments of any combination of one or more of the additional optional elements, features, and steps described further below (including those shown in the Figures and Examples). References to beads and their properties apply equally to a collection of beads (e.g., a plurality of such beads). Similarly, references to cores and their properties apply equally to a collection of cores (e.g., a plurality of such cores).

[0189] An enteric (gastro-resistant) coating material (e.g., a polymer) can be a material that will dissolve in intestinal fluid at a pH level higher than that of the stomach, such as a pH greater than 4.5 (e.g., in the small intestine), and thus allow the active substance to be released in the small intestine region and not substantially released in the upper gastrointestinal (GI) tract. In one embodiment, the enteric material begins to dissolve in an aqueous solution having a pH of about 4.5 to about 5.5. In another embodiment, the enteric material dissolves rapidly in an aqueous solution having a pH of about 5. In another embodiment, the enteric material dissolves rapidly in an aqueous solution having a pH of about 5.5.

[0190] In some embodiments, the pH of the coating is soluble in water.For example, before the dosage form is emptied from the stomach, the pH sensitive material will not significantly dissolve. The pH of the small intestine is increased to about 6.5 of the duodenal bulb from about 4.5 gradually, then increased to about 7.2 of the distal small intestine part (ileum). In order to provide the predictable dissolving corresponding to the small intestine transit time of about 3 hours (such as 2-3 hours) and allow reproducible release thereof, coating should start to dissolve within the pH range of the duodenum, and continue to dissolve within the pH range of the small intestine. Therefore, the amount (thickness) of enteric coating should be dissolved substantially during the transit time of about three hours in the small intestine (such as, proximal small intestine and mid-section small intestine).

[0191] Suitable enteric (gastric resistant) materials include, but are not limited to, cross-linked polyvinyl pyrrolidone; non-cross-linked polyvinyl pyrrolidone; hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate; cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate; polyvinyl acetate phthalate; carboxymethyl cellulose; methylcellulose phthalate; methylcellulose succinate; methylcellulose phthalate succinate; methylcellulose phthalate half ester; ethyl Cellulose succinate; carboxymethylamide; potassium methacrylate divinylbenzene copolymer; polyvinyl alcohol; polyoxyethylene glycol; polyethylene glycol; sodium alginate; galactomannan; carboxypolymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with a monomer selected from the group consisting of methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate (e.g., Eudragit TM Enteric materials include, but are not limited to, styrene-maleic anhydride copolymers, styrene-maleic acid copolymers, 2-ethyl-hexyl-acrylate maleic anhydride copolymers, crotonic acid-vinyl acetate copolymers, glutamic acid / glutamic acid ester copolymers, carboxymethylethylcellulose monocaprylate, polyarginine, poly(ethylene), poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl chloride), and polyurethanes. Combinations of enteric materials may also be used. In one embodiment, the enteric material dissolves rapidly at a pH of 5.5 and above to provide rapid dissolution in the upper intestine. For example, the enteric material can be selected from copolymers of methacrylic acid and methyl methacrylate, and copolymers of methacrylic acid and ethyl acrylate. For example, the enteric polymer is poly(methacrylic acid-ethyl acrylate) 1:1 (Eudragit TM L 30D-55 and Eudragit TM L 100-55).

[0192] Other suitable examples of enteric coatings include beeswax and glyceryl monostearate; beeswax, shellac, and cellulose; and cetyl alcohol, mastic, and shellac, and shellac and stearic acid; polyvinyl acetate and ethylcellulose; and neutral copolymers of polymethacrylates (EudragitTM L 30D); copolymers of methacrylic acid and methyl methacrylate, or neutral copolymers of polymethacrylates containing metal stearates. Such coatings contain mixtures of fats and fatty acids, shellac and shellac derivatives, and cellulose acid phthalates, such as those with free carboxyl groups.

[0193] As known in the art, one or more plasticizers can be added to the enteric polymer to improve its pliability and reduce brittleness. Suitable plasticizers include for example butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol (PEG, such as PEG6000), acetyl triethyl citrate and triacetin. In one embodiment, plasticizer is triethyl citrate. Although some enteric materials are flexible and do not need plasticizers, more fragile polymers (such as Eudragit TM L / S type, Eudragit TM RL / RS and Eudragit TM FS 30D) benefits from a plasticizer, for example, in the range of 5 wt.% to 30 wt.%, about 8 wt.% to about 12 wt.% triethyl citrate to poly(methacrylic acid-co-ethyl acrylate) 1:1 based on dry polymer mass.

[0194] In certain embodiments, the enteric coating comprises one or more anti-adherents (anti-sticking agents) as known in the art to reduce the stickiness of the film and prevent caking. Suitable anti-adherents include, but are not limited to, talc, glyceryl monostearate, fumed silica (e.g., Aerosil TM 200), precipitated silica (such as Sipernat TM PQ) and magnesium stearate. The anti-adherent can be used in any suitable amount, for example, in a range of about 10 wt.% to 100 wt.%, about 10 wt.% to about 50 wt.%, about 10 wt.% to about 30 wt.%, or about 15 wt.% and about 30 wt.% based on the dry polymer mass. For example, in one embodiment, the range is 15 wt.% to about 30 wt.% based on the dry polymer mass.

[0195] As is known in the art, one or more surfactants may also be added to the enteric coating mixture to improve the wettability of the substrate and / or stabilize the suspension. Surfactants include polysorbate 80, sorbitan monooleate, and sodium lauryl sulfate, as well as other surfactants described herein.

[0196] Any suitable method can form enteric coating.Coating methods include pan coating, fluidized bed coating and dry coating (e.g., hot dry coating and electrostatic dry coating). Pan coating and fluidized bed coating using solvents are generally recognized methods. In liquid coating, enteric material and optional excipients (e.g., pigment, plasticizer, anti-adherent) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed into a solid dosage form in a pan coater or fluidized bed dryer and dried by hot air. For example, in the Wurster fluidized bed coating method, a coating fluid is sprayed from the bottom of the fluidized bed apparatus. Alternatively, the coating fluid is applied by top spraying. In certain embodiments, a tangential spray is applied.

[0197] The amount of enteric material applied is sufficient to achieve the desired acid resistance and release characteristics. For example, in one embodiment, the amount of enteric coating meets the USP for delayed release dosage forms. <711> The formulation is preferably formulated to release less than 10.0 wt.% of the drug in 0.1 N HCl after 2 hours, as required by USP 36-NF 31. In certain embodiments, the formulation is formulated to release less than 10.0 wt.% of the drug in 0.1 N HCl after 2 hours. In certain embodiments, the formulation is formulated to release less than 10.0 wt.% of the drug in 0.1 N HCl after 2 hours, as required by USP 36-NF 31. <711> The dissolution method of the section releases at least 80% of the active ingredient.

[0198] In one embodiment, the enteric coating is present in an amount ranging from about 10% to 40%, or 25% to about 35% (as measured by weight gain compared to the uncoated granule core), or in a range of about 25% to about 31% weight gain, about 27% to about 31% weight gain, or about 28.5% to about 31% weight gain based on the weight of the uncoated granule core.

[0199] The formulation can include a capsule shell in which the beads are placed. Soft capsule shells and hard capsule shells are known. In one embodiment, the capsule shell is a hard capsule shell, such as a gelatin capsule shell or a plant-based hard capsule shell. In certain embodiments, the capsule shell comprises one or more enteric coatings described herein. During accelerated storage, gelatin capsules may collapse. Therefore, in certain embodiments, the formulation can include a hydroxypropyl methylcellulose capsule shell.

[0200] Thus, for example, one embodiment combining the various features described above includes a pharmaceutical dosage form comprising a plurality of xanomeline beads comprising a core comprising xanomeline tartrate, a filler (optionally microcrystalline cellulose), a binder (optionally hypromellose) and an enteric coating (optionally Eudragit®) surrounding the core. TML30D-55), wherein the plurality of beads have a particle size distribution ranging from about 0.7 mm to about 2.5 mm, wherein the enteric coating ranges from about 20% to about 40% based on the weight of the bead core, and wherein the beads are disposed in a capsule shell. Bead size and shape

[0201] The plurality of beads have a distribution of particle sizes. The plurality of beads have a bead shape. When present, the plurality of beads have a distribution of coating thicknesses.

[0202] Beads having a distribution of particle sizes were shown to exhibit favorable pharmacokinetics. Without being bound by any theory, it is expected that pharmacokinetics is affected by having multiple beads having a distribution of core sizes.

[0203] In one embodiment, the beads have a particle size range of about 0.4 mm to about 1.2 mm, such as about 0.4 mm to about 0.5 mm, about 0.5 mm to about 0.6 mm, about 0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, or about 1.1 mm to about 1.2 mm. In certain embodiments, the size of the xanomeline beads is about 0.425 mm to about 1.18 mm. In certain embodiments, the size of the xanomeline beads is about 0.6 mm to about 0.85 mm. In certain embodiments, the size of the trospium beads is about 0.425 mm to about 1.18 mm. In certain embodiments, the size of the trospium beads is about 0.6 mm to about 0.85 mm.

[0204] The beads or bead mixture can be used, for example, as a suspension, filled into capsules, compressed into tablets, or filled into sachets. One or more types of modified release beads can be mixed and encapsulated, or sprinkled on the subject's food. In certain embodiments, the oral solid dosage form can be any of these forms. In certain embodiments, the dosage form is a capsule.

[0205] As the particle size of the beads becomes too small, the variability of the active ingredient content increases. As the particle size becomes too large, the beads are too large to allow the drug product to be labeled for administration by sprinkling (e.g., on applesauce or other soft foods such as jelly) and swallowing without chewing, or for administration via an enteral feeding tube. Likewise, as the particle size increases, larger particles are coated more than smaller particles, resulting in lower relative assay values for the smaller particles. Relatively more beads are required to meet the labeled strength per capsule. Filling the capsule shell with particles large enough to meet the labeled strength per capsule becomes difficult or impossible (e.g., filling a size 0 capsule to a strength of 75 mg of xanomeline free base).

[0206] In one embodiment, for example, the beads are formulated into capsules using an encapsulation machine. A variety of capsule sizes can be adapted to the strength and fill weight of the target formulation. For a fill weight range of about 15 mg to about 630 mg, capsule sizes range from 0.00 to 5.00.

[0207] The beads can be sorted (e.g., by sieving) to a desired particle size. In certain embodiments, the particle size range is any of the particle size ranges or combinations described above for the core. In one embodiment, the particle size range is the same as the particle size range for the uncoated core. For example, the beads can be sieved so that 5% or less by weight of the bead core remains on a #12 mesh (1.68 mm) sieve and 10% or less by weight passes through a #20 mesh (0.84 mm) sieve. Preparation method

[0208] A method for preparing an oral pharmaceutical composition is provided, comprising mixing a plurality of xanomeline beads containing xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads containing a trospium salt (e.g., trospium chloride). In certain embodiments, the method further comprises formulating the mixed beads into a capsule.

[0209] Also disclosed herein is a method for preparing a dosage form, comprising coating a core comprising xanomeline or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form an enteric coating, and coating a core comprising trospium chloride or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form an enteric coating. Optionally, the core can be formed by a wet granulation method. Optionally, before enteric coating, and optionally after enteric coating, the beads are sorted (e.g., by screening) to a desired particle size range.

[0210] These beads can be made by different methods, including but not limited to spheronization of the extruded wet mass and coating of inert core spheres in a fluidized bed. In certain embodiments, the beads are prepared by extrusion and spheronization.

[0211] The beads are formulated to be free-flowing and compatible with modern encapsulation equipment. In some embodiments, the beads are blended to form a homogenous mixture that can be filled into capsules in a single stage. In other embodiments, the beads are filled into capsules separately using a two-stage capsule filling machine.

[0212] The core comprising xanomeline or a pharmaceutically acceptable salt thereof can be formed by any suitable method. In one embodiment, the core is formed by granulating a mixture of xanomeline or a pharmaceutically acceptable salt thereof and an excipient and then grinding the mixture to a desired particle size range. In another embodiment, the core can be formed by extruding a mixture of xanomeline or a pharmaceutically acceptable salt thereof and an excipient and then spheronizing the mixture.

[0213] The core comprising trospium chloride or a pharmaceutically acceptable salt thereof can be formed by any suitable method. In one embodiment, the core is formed by granulating and grinding a mixture of trospium chloride or a pharmaceutically acceptable salt thereof and an excipient to a desired particle size range. In another embodiment, the core can be formed by extruding and spheronizing a mixture of trospium chloride or a pharmaceutically acceptable salt thereof and an excipient.

[0214] Granulation methods can include fluidized bed granulation, wet granulation, hot melt granulation, and spray congealing. Other methods include slugging and roller compaction. The mixture to be granulated is first dry blended. The dry blended dry ingredients can be mixed with water before extrusion.

[0215] Extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof and trospium chloride with excipients provides a desired core having a particle size distribution as described herein and one or more other desired properties. In certain embodiments, shorter processing times can result in a more stable product. For example, reduced spheronization reduces friction and associated heat, and reduced exposure of the product to air (when wet and / or prior to packaging) reduces oxidation. On the other hand, rapid processing by extrusion and spheronization can result in a poor quality product, for example, resulting in a majority of the bead core falling outside the desired particle size range. Water absorption by the spheronization aid (which occurs over time) affects the spheronization characteristics of the beads.

[0216] Accordingly, in one embodiment, the moisture content of the granulation mixture before drying ranges from about 20 wt.% to about 40 wt.%, e.g., from 25 wt.% to about 35 wt.%, from about 28 wt.% to about 32 wt.%, at least about 28 wt.%, at least about 28.5, from about 20 wt.% to about 40 wt.%, from about 25 wt.% to about 35 wt.%, from about 27 wt.% to about 31 wt.%, or from about 28.5 wt.% to about 31 wt.%.

[0217] In certain embodiments, the wet mass may be held prior to extrusion to allow the spheronization aid to swell with the granulation fluid. The hold time may be at least 15 minutes, such as at least 30 minutes, at least 45 minutes, or at least 60 minutes. In certain embodiments, the hold time ranges from about 15 minutes to about 120 minutes, such as from about 30 to 100 minutes, or from 60 to 90 minutes.

[0218] As described above with respect to the cores, the method may include the step of sorting the cores (e.g., by sieving) prior to optional coating to retain the particles within a predetermined size range, e.g., a size range of about 0.7 mm to about 2.8 mm, e.g., about 0.7 mm to about 2.5 mm, about 0.8 mm to about 1.7 mm, or any range described herein.

[0219] As described above with respect to the beads, the method can include the step of sorting the beads (e.g., by sieving) after optional coating to retain the particles within a size range, e.g., a size range of about 0.7 mm to about 2.8 mm, e.g., about 0.7 mm to about 2.5 mm, or about 0.8 mm to about 1.7 mm, or any range described herein.

[0220] In the extrusion and spheronization process, the following optional features can be used alone or in combination with one or more thereof. Water can be a granulating agent. Microcrystalline cellulose can be used in the core as a spheronization aid. Hydroxypropyl methylcellulose can be included in the core as a binder. The extrusion screen size can be 1.0 mm. The friction plate of the spheronizer can be cross-hatched. The friction plate of the spheronizer can be cross-hatched with a grid of at least about 3 mm, or greater than about 3 mm, or at least about 4 mm, or greater than about 4 mm, or in the range of about 3 mm to about 7 mm, or about 5 mm. The spheronization time can be less than about 5 minutes, or less than about 4 minutes, or less than about 3 minutes, or less than about 2 minutes, or up to 1 minute. The spheronized particles can include non-spherical particles (i.e., irregular shapes), for example, a significant portion thereof, for example, at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, or at least about 70 wt.%.

[0221] In certain embodiments, the pharmaceutical composition is stored with a desiccant, such as pharmaceutical grade silica gel, crystalline sodium, potassium or calcium aluminosilicate, colloidal silicon dioxide, anhydrous calcium sulfate, or the like.

[0222] In certain embodiments, the pharmaceutical composition is stored with an oxygen absorber.

[0223] In certain embodiments, the pharmaceutical composition is stored under a dry inert gas such as nitrogen, helium, argon, neon, xenon, krypton, or mixtures thereof.

[0224] In certain embodiments, the pharmaceutical composition is stored under reduced pressure compared to the external ambient air.

[0225] In certain embodiments, the pharmaceutical composition is stored at a reduced temperature, for example, at a refrigerated temperature (e.g., 2° C. to 8° C.). In certain embodiments, the pharmaceutical composition is stored with fewer impurities (e.g., impurity A) than when stored at 25° C.

[0226] In certain embodiments, prior to dispensing the oral pharmaceutical composition to a subject, the pharmaceutical composition is stored by the manufacturer, distributor, pharmacy, or hospital at a temperature of about 2° C. to about 8° C. In certain embodiments, after dispensing the oral pharmaceutical composition to a subject, the pharmaceutical composition is stored at a temperature of about 20° C. to about 25° C.

[0227] Also provided is a method of stabilizing a pharmaceutical dosage form or composition described herein, the method comprising storing the dosage form at a temperature of about 2°C to about 8°C.

[0228] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising xanomeline beads comprises forming a wet mass comprising xanomeline tartrate and an excipient (optionally microcrystalline cellulose) having a moisture content ranging from about 20 wt.% to about 40 wt.%, extruding and spheronizing the wet mass comprising xanomeline tartrate and the excipient to form cores, sorting the cores to a target size range (optionally about 0.7 mm to about 2.5 mm), coating the sorted cores with a polymer to form beads comprising the core and the coating, and sorting the bead particles to a target size range (optionally about 0.7 mm to about 2.5 mm).

[0229] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising trospium chloride beads comprises forming a wet mass comprising trospium chloride and an excipient (optionally microcrystalline cellulose) (having a moisture content ranging from about 20 wt.% to about 40 wt.%), extruding, spheronizing, and drying the wet mass comprising trospium chloride and the excipient to form cores, sorting the cores to a target size range (optionally about 0.7 mm to about 2.5 mm), coating the sorted cores with a polymer to form beads comprising the core and the coating, and sorting the bead particles to a target size range (optionally about 0.7 mm to about 2.5 mm). purity

[0230] Also provided is the compound 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium.

[0231] Also provided is a pharmaceutical composition comprising xanomeline and / or its salt and less than 0.5 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium (impurity A). In certain embodiments, the pharmaceutical composition comprises less than 0.30 wt.% of impurity A, for example, less than 0.25 wt.%, less than 0.20 wt.%, less than 0.15 wt.%, less than 0.14 wt.%, or less than 0.1 wt.%. Also provided is a pharmaceutical composition comprising xanomeline and / or its salt and less than 0.15 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium (impurity A).

[0232] Also provided is an oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof and less than 0.5 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium; and a plurality of trospium beads containing a trospium salt. Also provided is an oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof and less than 0.15 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium; and a plurality of trospium beads containing a trospium salt.

[0233] In certain embodiments, the pharmaceutical composition comprises less than 0.5 wt. % of Impurity A after storage of the pharmaceutical composition at 40° C. and 75% relative humidity for at least 3 months.

[0234] In certain embodiments, the total impurities in the pharmaceutical compositions provided herein are no more than about 5% by weight, no more than about 4% by weight, no more than about 3% by weight, no more than about 2.5% by weight, no more than about 2% by weight, no more than about 1.5% by weight, no more than about 1% by weight, no more than about 0.5% by weight, or no more than about 0.1% by weight. Treatment

[0235] Further provided is a method of activating a muscarinic receptor in a biological sample, the method comprising contacting the biological sample with any of the oral pharmaceutical compositions described herein. Also provided is a method of treating a disorder alleviated by activating a muscarinic receptor in a subject in need thereof, the method comprising administering to a subject in need thereof any of the oral pharmaceutical compositions described herein.

[0236] While M1 and M4 muscarinic receptor activators are considered effective treatments for schizophrenia, activation of muscarinic receptors located outside the brain leads to side effects that have precluded the clinical use of xanomeline. For example, in Phase I and subsequent trials, the muscarinic agonist xanomeline has unacceptable gastrointestinal (GI) and other side effects related to the binding of muscarinic receptors in peripheral regions of the human body. By combining xanomeline with trospium chloride, the desired therapeutic effect can be achieved while reducing or eliminating the side effects of activating muscarinic receptors located outside the brain.

[0237] The tolerability of the muscarinic activator xanomeline can be improved by co-administration with the muscarinic antagonist trospium chloride. The most common adverse events observed with xanomeline administration are nausea, vomiting, diarrhea, excessive sweating, and excessive salivation (so-called cholinergic adverse events). The most common anticholinergic adverse event observed with trospium chloride administration is dry mouth (xerostomia). The disclosed compositions reduce the incidence of these adverse events in humans, thereby demonstrating improved xanomeline tolerability. In certain embodiments, after at least four weeks of treatment, the occurrence of cholinergic or anticholinergic adverse events is statistically indistinguishable from placebo controls. In certain embodiments, after at least four weeks of treatment, at least one of nausea, vomiting, and dry mouth occurs at approximately the same rate as in untreated patients. In certain embodiments, at least one adverse event that occurs at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment.

[0238] In one embodiment, xanomeline is combined with trospium chloride to treat an animal. In another embodiment, the animal is a mammal. In one embodiment, the mammal is a human.

[0239] In one embodiment, trospium chloride reduces side effects associated with xanomeline. Such side effects include, but are not limited to, GI side effects, cardiac side effects, excessive sweating, and excessive salivation. The use of trospium chloride with xanomeline allows for the clinical use of xanomeline when its side effects preclude its use. In another embodiment, the use of trospium chloride with xanomeline allows for a higher maximum tolerated dose of xanomeline than would otherwise be achieved with xanomeline.

[0240] Various time- and resource-intensive methods have demonstrated the efficacy of the combination of xanomeline and trospium chloride. For example, animal models have demonstrated the efficacy of new therapeutic agents for schizophrenia, including pharmacological models (e.g., ketamine models) and genetic models (e.g., DISC1 mice). Similarly, animal models (including rodents, dogs, and non-human primates) have demonstrated the side effect profiles of pharmacological agents. Animal models are experimental substitutes for humans, but may have defects in physiological differences between humans and animals, and may have limited predictive power for human experiments (particularly for central nervous system disorders). Alternatively, the disclosed combination can be tried in controlled clinical trials in humans. Standard measures based on patient self-report can be used by those skilled in the art to assess various side effects, such as GI discomfort. As another example, those skilled in the art can use objective physiological measurements (e.g., EKG). A set of standard measures for assessing schizophrenia symptoms has also been developed, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression (CGI). Typically, clinical trials are double-blind, with one group of patients receiving an inactive placebo and the other group receiving active intervention.

[0241] The Positive and Negative Syndrome Scale (PANSS) is a medical scale used to measure the severity of symptoms in patients with schizophrenia. The name refers to the two types of schizophrenia symptoms, as defined by the American Psychiatric Association: positive symptoms, which refer to excesses or distortions of normal functioning (for example, hallucinations and delusions), and negative symptoms, which represent a reduction or loss of normal functioning. Some of these functions that may be lost include normal thinking, acting, the ability to distinguish fantasy from reality, and the ability to express emotions appropriately.

[0242] PANSS is a relatively brief interview of approximately 45 to 50 minutes. The interviewer must be trained to achieve standardized reliability levels. Based on the interview and the report of family members or primary care hospital staff, the patient's 30 different symptoms in three categories are rated from 1 to 7. The first category of PANSS is a positive scale, comprising 7 items (minimum score = 7, maximum score = 49): delusions, confusion, hallucinations, excitement, exaggeration, suspicion / persecution, and hostility. The second category is a negative scale, comprising 7 items (minimum score = 7, maximum score = 49): blunted emotions, emotional withdrawal, emotional communication disorder, passive / indifferent social withdrawal, abstract thinking difficulties, lack of spontaneity and fluency in conversation, and stereotyped thinking. The third category is the General Psychopathology Scale, which includes 16 items (minimum score = 16, maximum score = 112): somatization, anxiety, guilt, tension, pretense and posturing, depression, bradykinesia, uncooperativeness, unusual thought content, disorientation, attention disorder, lack of judgment and insight, volitional disorder, impulse control disorder, preoccupation, and active social avoidance.

[0243] The PANSS Marder factor score is the sum of five negative scales and two general scales (N1. Blunted Affect; N2. Emotional Withdrawal; N3. Impaired Communication of Affect; N4. Passive / Aloof Social Withdrawal; N6. Lack of Spontaneity; G7. Motor Delay; and G16. Active Social Withdrawal). If a patient had a PANSS assessment but any of these items were missing, the last non-missing score for that individual item from the previous assessment was used. If more than 30% of the items were missing at a particular follow-up visit, the corresponding positive score was not calculated. It was treated as missing data in the analysis.

[0244] Because each item is assigned a minimum score of 1 rather than 0, a patient's total PANSS score cannot be lower than 30. Separate subscores can be assigned for positive items, negative items, and general psychopathology. The maximum possible total score is 210. In the original publication of the PANSS, 101 adult patients with schizophrenia (aged 20-68) were rated. Their average scores were: 18.20 for the positive scale, 21.01 for the negative scale, and 37.74 for general psychopathology. The average PANSS total score for these subjects was 76.95.

[0245] In certain embodiments, for example, after five weeks of treatment, the subject's Positive and Negative Syndrome Scale (PANSS) total score is reduced by at least 10 points compared to placebo. In certain embodiments, for example, after five weeks of treatment, the PANSS positive subscore is reduced by at least 3 points compared to placebo. In certain embodiments, for example, after five weeks of treatment, the PANSS negative subscore is reduced by at least 2 points compared to placebo.

[0246] Another scale used to assess patients is the Clinical Global Impression - Severity scale (CGI-S). This 7-point scale asks the clinician to rate the severity of the patient's illness at the time of the assessment relative to the clinician's experience with patients with the same diagnosis. Possible ratings are: (1) normal, no illness at all; (2) borderline mental illness; (3) mild illness, (4) moderate illness; (5) marked illness; (6) severe illness, and (7) among the most severely ill patients. In patients with schizophrenia, changes in the CGI-S follow a consistent pattern relative to the more objective PANSS scores.

[0247] Prior to administration of the disclosed combination, the patient may have a one to fourteen-day run-in period during which trospium chloride is administered alone. In one embodiment, trospium chloride is administered for one or more dosing periods prior to administration of xanomeline to allow for accumulation of trospium chloride in the body or to allow trospium chloride to reach or approach steady-state exposure levels. This accumulation or elevated exposure to trospium chloride increases blockade of extracerebral muscarinic receptors and reduces adverse events associated with xanomeline administration. In another embodiment, trospium chloride is administered one or more days prior to xanomeline administration.

[0248] Prior to administration of the disclosed combinations, the patient may discontinue any previously used antipsychotic medication. In some embodiments, the patient will discontinue such medication for at least one week, such as two weeks. In some embodiments, the patient does not discontinue any previously used antipsychotic medication, and the disclosed combinations are co-administered with such medication.

[0249] In one embodiment, xanomeline and trospium chloride are administered to a patient six times during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient five times during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient four times during a 24-hour period. In an embodiment, xanomeline and trospium chloride are administered to a patient three times during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient two times during a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient once during a 24-hour period.

[0250] In one embodiment, an extended-release formulation of trospium chloride is used in combination with xanomeline. In another embodiment, the extended-release formulation of trospium chloride is administered to the patient one to five times during a 24-hour period. In an embodiment, the extended-release formulation of trospium chloride is administered one to three times during a 24-hour period. In another embodiment, from five milligrams to 400 milligrams of extended-release formulation of trospium chloride is used during a 24-hour period. In an embodiment, from 20 milligrams to 200 milligrams of extended-release formulation of trospium chloride is used during a 24-hour period.

[0251] In one embodiment, 225 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 100 mg of xanomeline and 20 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 125 mg of xanomeline and 20 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 125 mg of xanomeline and 30 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 125 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 200 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 200 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 250 mg of xanomeline and 60 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 250 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 300 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 300 mg of xanomeline and 60 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 300 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 350 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 350 mg of xanomeline and 60 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 350 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24 hour period.

[0252] Treatment can be started with a smaller dose. Thereafter, the dose can be increased in small increments until a balance between therapeutic effect and side effects is achieved. When treating a subject, the patient's health can be monitored by measuring one or more relevant indicators at predetermined times during the treatment period. Treatment can be adjusted based on this monitoring, including composition, amount, administration, and formulation frequency. Patients can be reassessed regularly to determine improvement by measuring the same parameters. The disclosed compositions administered and possibly the administration time can be adjusted based on these reassessments.

[0253] Provided is a method for treating schizophrenia or a disorder related to schizophrenia in a patient in need thereof, the method comprising orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof and a plurality of trospamine beads containing a trospamine salt via a titration regimen, the titration regimen comprising increasing titration of the xanomeline or a salt thereof and the trospamine salt.

[0254] Also provided is a method of treating schizophrenia or a disorder related to schizophrenia in a patient in need thereof, the method comprising: orally administering an oral pharmaceutical composition twice daily via a titration regimen, the oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and a plurality of trospium chloride beads comprising a trospium chloride salt, the titration regimen comprising incrementally titrating the xanomeline or a salt thereof, and the trospium chloride salt until an amount equivalent to 125 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered.

[0255] In certain embodiments, xanomeline or a salt thereof is administered in a first amount for a first period of time, and then the first amount is increased to a second amount. In certain embodiments, the first amount of xanomeline is equivalent to 50 mg of xanomeline free base. In certain embodiments, the first period of administration of xanomeline is 1 to 5 days, such as 2 days. In certain embodiments, the second amount of xanomeline is equivalent to 100 mg of xanomeline free base.

[0256] In certain embodiments, the method further comprises administering the xanomeline or a salt thereof in a second amount for a second period of time, and then increasing the second amount to a third amount. In certain embodiments, the second period of time during which xanomeline is administered is from three days to one week. In certain embodiments, the third amount of xanomeline is equivalent to 125 mg of xanomeline free base.

[0257] In certain embodiments, a trospium salt is administered in a first amount for a first period of time, and the first amount is increased to a second amount. In certain embodiments, the first amount of the trospium salt is equivalent to 20 mg of trospium chloride. In certain embodiments, the first period of time for which trospium is administered is at least one week. In certain embodiments, the second amount of the trospium salt is equivalent to 30 mg of trospium chloride.

[0258] In certain embodiments, if a patient cannot tolerate higher doses of xanomeline, or a salt thereof, and trospium salt, the amount of xanomeline, or a salt thereof, and trospium salt administered to the patient is reduced.

[0259] In certain embodiments, xanomeline or a salt thereof, and trospium chloride salt are administered without resulting in serious adverse events.

[0260] "Blood pressure" refers to the pressure of circulating blood against the walls of blood vessels. Most of this pressure is caused by the heart pumping blood through the circulatory system. When used without further explanation, "blood pressure" generally refers to the pressure in the large arteries that circulate throughout the body. Blood pressure is usually expressed as systolic pressure (the highest value during one heartbeat) relative to diastolic pressure (the lowest value between two heartbeats) and is measured in millimeters of mercury (mmHg) above the surrounding atmospheric pressure. Normal resting blood pressure for an adult is approximately 120 mmHg (16 kPa) systolic and 80 mmHg (11 kPa) diastolic, abbreviated as "120 / 80 mmHg."

[0261] Adverse events related to blood pressure refer to unfavorable medical events that affect systolic or diastolic blood pressure, or changes in systolic or diastolic blood pressure, and include hypertension, hypotension, and syncope (fainting). In certain embodiments, xanomeline or a salt thereof, and a trospium salt are administered without causing a change in diastolic blood pressure of more than about 5 mmHg. In certain embodiments, xanomeline or a salt thereof, and a trospium salt are administered without causing a change in systolic blood pressure of more than about 5 mmHg. In certain embodiments, xanomeline or a salt thereof, and a trospium salt are administered without resulting in a serious adverse event related to blood pressure. In certain embodiments, xanomeline or a salt thereof, and a trospium salt are administered without resulting in a serious adverse event related to changes in blood pressure.

[0262] "Heart rate" refers to the speed of the heart, measured in terms of the number of contractions (beats) per minute (bpm). It is usually equal to or close to the pulse measured at any peripheral point. The American Heart Association states that a normal resting heart rate for adults is 60-100 bpm. Tachycardia is a fast heart rate, defined as above 100 bpm at rest. Bradycardia is a slow heart rate, defined as below 60 bpm at rest, except during sleep, when a slow heartbeat of around 40-50 bpm is common and normal. When the heart beats in an irregular pattern, it is called an arrhythmia.

[0263] Adverse events related to heart rate refer to unfavorable medical events and include tachycardia, bradycardia, and arrhythmia. In certain embodiments, administration of xanomeline or a salt thereof and trospium chloride salts does not result in serious adverse events related to heart rate. In certain embodiments, administration of xanomeline or a salt thereof and trospium chloride salts does not result in serious adverse events related to changes in heart rate.

[0264] Liver function tests (LFTs or LFs), also known as hepatic panels, are a series of blood tests that provide information about a patient's liver status. These tests include prothrombin time (PT / INR), aPTT, albumin, bilirubin (direct and indirect), and the liver transaminases aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT). Patient blood samples are tested for functionality (e.g., albumin), integrity (e.g., transaminases), and conditions related to the bile duct (gamma-glutamyl transferase and alkaline phosphatase).

[0265] In certain embodiments, xanomeline or a salt thereof and trospium chloride salts are administered without increasing liver function tests (LFTs). In certain embodiments, xanomeline or a salt thereof and trospium chloride salts are administered without causing an increase in LFTs. In some embodiments, the liver function tests are selected from prothrombin time (PT / INR), aPTT, albumin, bilirubin (direct and indirect), the liver transaminase aspartate aminotransferase (AST or SGOT), and alanine aminotransferase (ALT or SGPT). In some embodiments, xanomeline or a salt thereof and trospium chloride salts are administered without increasing at least one of ALT, AST, Alk-phos, or bilirubin. In some embodiments, xanomeline or a salt thereof and trospium chloride salts are administered without increasing ALT, AST, Alk-phos, or bilirubin.

[0266] The present disclosure further provides a method of treating acute psychosis in a patient in need thereof, comprising orally administering to the patient twice daily an oral pharmaceutical composition comprising xanomeline or a salt thereof and a trospium salt.

[0267] In certain embodiments, a mean reduction of at least about 11.6 points in the PANNS total score is achieved. In certain embodiments, a mean reduction of at least 3 points in the PANSS positive subscore is achieved compared to placebo. In certain embodiments, a reduction of at least 2 points in the PANSS negative subscore is achieved compared to placebo. In certain embodiments, a reduction in the PANSS score is achieved within about 5 weeks. In certain embodiments, prior to administration of the oral pharmaceutical composition, the patient has a Clinical Global Impression Severity Scale (CGI-S) score of 4-7.

[0268] In certain embodiments, the patient is diagnosed with schizophrenia. In certain embodiments, the patient suffers from acute psychosis. In certain embodiments, the patient suffers from psychosis associated with Alzheimer's disease. In certain embodiments, the patient suffers from schizoaffective disorder. In certain embodiments, the patient suffers from psychosis. In certain embodiments, the patient suffers from delusional disorder. In certain embodiments, the patient suffers from psychosis associated with Parkinson's disease. In certain embodiments, the patient suffers from psychotic depression. In certain embodiments, the patient suffers from bipolar disorder. In certain embodiments, the patient suffers from bipolar disorder with psychosis. In certain embodiments, the patient suffers from Huntington's disease. In certain embodiments, the patient suffers from dementia with Lewy bodies.

[0269] In certain embodiments, the patient has been previously administered one or more antipsychotic drugs. In certain embodiments, the patient has had an inadequate response to such administration. In certain embodiments, the patient is treatment resistant.

[0270] In certain embodiments, the patient is an adult. In certain embodiments, the patient is an elderly person, for example, older than 65 years of age. In certain embodiments, the patient suffers from a dementia-related psychosis. Examples

[0271] The following examples are provided for illustration and are not intended to limit the scope of the present disclosure. Example 1 - Immediate Release Beads

[0272] Beads of xanomeline tartrate (Table 1) and trospium chloride (Table 2) were prepared. Table 1: Xanomeline tartrate (66%) beads without talc *Remove during drying period. Table 2: Trospium Chloride (17.7%) Beads without Talc *Remove during drying period.

[0273] The powder was sieved using a Quadro Comil Model 197 equipped with a 457-μm round hole screen and a 0.2-inch spacer at 1625 rpm and mixed in a Hobart low shear mixer / granulator (Model N-50) at a fixed speed of 60 rpm for 2 minutes. The dry blending step is optional because the blend uniformity is driven by the subsequent wet granulation. The beads were screened by hand through a 40 mesh (425 μm) screen.

[0274] Wetting was performed in Hobart. Water was added using a Cole-Parmer peristaltic pump. The water addition rate (water volume / dosing time) was a process variable.

[0275] The wet mass was extruded through a porous screen (dome configuration) single screw extruder using an LCI Multi Granulator MG-55 at 30 rpm (shaft speed). The wet mass was extruded directly after wetting. The hold time, shaft speed, and extrusion rate (load) were process variables.

[0276] The extrudate was placed in an LCI Marumerizer QJ-230T equipped with a 2.0 mm friction plate. The extrudate was spheronized at different plate speeds for a total of no more than 4 minutes. Spheronization speed and time were process variables.

[0277] Using Aeromatic TM The beads were dried in a Strea-1 fluidized bed at an inlet temperature of 60°C until a water content of no more than 3% was obtained. The beads melted after a few minutes at 60°C, so they were dried at 30°C.

[0278] Water content was assessed gravimetrically by loss on drying (LOD) using a Mettler Toledo Halogen Moisture Analyzer, Model HR83. The beads were heated at 105°C until the weight loss decreased to less than or equal to 0.0% within 60 seconds. Table 3: Extrusion / spheronization process parameters Example 2 - Extended Immediate Release Bead Formulation

[0279] The beads of Example 1 were expanded with and without talc (Tables 4-7). The extrusion / spheronization process parameters are shown in Table 8. Table 4: Xanomeline tartrate (66%) beads without talc *Remove during drying period. Table 5: Xanomeline tartrate (66%) beads with talc Abbreviations: Ph.Eur = European Pharmacopoeia, USP = United States Pharmacopoeia *- evaporates during processing and therefore not included in the total weight Table 6: Trospium Chloride (17.7%) Beads without Talc *Remove during drying period. Table 7: Trospium Chloride (17.7%) Beads with Talc Abbreviations: NF = National Formulary, Ph.Eur = European Pharmacopoeia, USP = United States Pharmacopoeia. * - evaporated during processing Table 8: Extrusion / spheronization process parameters Example 3 - Capsule stability and dissolution testing

[0280] An oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof, and a plurality of trospium chloride beads containing a trospium chloride salt is referred to as "KarXT." KarXT can be formulated in various dosage strengths, for example, as exemplified by the following: KarXT 50 / 10, KarXT 50 / 20, and KarXT 75 / 20, where the number before the slash is the milligrams of xanomeline free base (X) in the composition, and the number after the slash is the milligrams of trospium chloride (T) in the composition.

[0281] Capsules were produced by weighing the beads and manually filling them into HPMC capsules. Tm The beads were encapsulated manually by a capsule filling machine, where the beads pre-mixed with talc (0.5%) were filled in capsules individually / one by one as shown in Table 19. Table 9: Composition of Xanomeline / Trosamine Chloride Capsules. Ingredients are listed in mg / capsule.

[0282] After drying, the beads were sieved through 16 mesh (1.18 mm) and 40 mesh (0.425 mm) sieves by shaking for 5 min. Beads with sizes between sieves 1.18 mm and 0.425 mm were retained for further analysis.

[0283] Using a JSM-6010LV InTouchScope with a Backscattered Electron Detector (BES) TM The morphology and surface characteristics of the beads were examined by scanning electron microscopy (SEM) (JEOL Ltd, Tokyo, Japan). The samples were mounted on metal stubs using double-sided carbon conductive tape. Images were acquired at an accelerating voltage of 20 kV under low vacuum (60 Pa) and 30x magnification.

[0284] The tap density was measured using a JV 1000, Copley Scientific, using USP <616> Methods: Determine bulk density and tapped density in duplicate. Bulk density is measured from the volume of a powder sample of known mass in a graduated cylinder. Tapped density is measured by mechanically tapping the cylinder until the volume no longer changes.

[0285] Powder flow properties were evaluated using the Carr's Compressibility Index and the Hausner ratio. Both are derived using measured bulk and tapped density values. The Carr's Compressibility Index (CI) was calculated using the bulk and tapped density data when fitted to the following equation: Compressibility Index = (Tap Density - Bulk Density) / Tap Density x 100%. The Hausner ratio (H) was calculated as the ratio of tapped density to bulk density. The capsules were analyzed for appearance, assay, related substances, water content, and dissolution.

[0286] The beads further ranged in size from 0.6 mm to 0.85 mm. Some beads exhibited similar morphological properties. Modifications in other beads reduced bead density and resulted in a rough surface and loss of sphericity. Scanning electron microscopy (SEM) images of 66% xanomeline tartrate beads and 17.7% trospium chloride beads at 30x magnification showed that the beads ranged in size from 0.6 mm to 0.85 mm. These beads were used in xanomeline / trospium chloride capsules. The particle size distribution (PSD) of the beads was determined by mechanical sieving. As shown in Table 10, the majority of beads for both APIs ranged in size from 0.425 mm to 1.18 mm. Table 10: Particle size distribution of beads by mechanical sieving

[0287] Table 11 shows the density and flow properties of beads collected between the 0.425 mm and 1.18 mm sieves. Xanomeline tartrate and trospium chloride IR beads exhibit different density and flow properties, which can be critical when mixing bead systems. Table 11: Density and flow properties of 0.425-1.18 mm beads

[0288] The analysis in Table 12 shows good results for assay and related substances, as well as moisture content, for 50 mg xanomeline and 20 mg trospium chloride capsules. The data in Table 13 show that these attributes were retained during the storage stability study. Similar data for 50 mg xanomeline and 10 mg trospium chloride capsules are provided in Table 14. Tables 15 and 16 provide dissolution data for these two dosage forms. Table 12: Analysis results Table 13: Stability of KarXT 50 / 20 Table 14: Dissolution of KarXT 50 / 20 Table 15: KarXT 50 / 10 assay and related substances Table 16: Dissolution of KarXT 50 / 10

[0289] Subsequent testing showed that KarXT 50 / 10, 50 / 20, and 75 / 20 in hard shell capsules were stable for at least 12 months at 25°C / 60% RH. Based on available data, a shelf life of 15 months at 25°C / 60% RH was recommended.

[0290] Dissolution results showed that both compounds were released rapidly, which could increase their bioavailability. Despite significant compositional differences between the two bead formulations, they were released at comparable rates. Xanomeline and trospium chloride both have low bioavailability, and rapid release could increase bioavailability by overriding saturable processes that limit absorption into the general circulation.

[0291] During stability studies of combination drug products, an unknown xanomeline impurity was observed with a relative retention time of approximately 1.09. During testing, the impurity was first observed at the three-month time point for the 50 mg xanomeline / 10 mg trospium chloride drug product and at the initial time point for the other three combination products, both occurring simultaneously. The impurity peak increased over time and with increasing storage temperature. This impurity had not been observed prior to this study.

[0292] Preliminary studies have shown that the impurity in RRT 1.09 is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium (C 14 H 20 N3O2S + , MW=294.1271Da):

[0293] RRT 1.09 impurity is compound V (C 14 H 20 N3OS + , MW = 278.1322 Da), which is the penultimate intermediate with negative mutagenic potential in the synthesis of xanomeline:

[0294] To reduce the presence of impurities, the drug product is stored at a lower temperature. During packaging, the bottles are flushed with argon to minimize headspace oxygen. In certain embodiments, the xanomeline bead formulation is formulated with an antioxidant (e.g., 0.5 wt.% ascorbic acid or 0.05 wt.% BHT). Example 4 - KAR-001 Phase I Study of the Combination of Xanomeline and Trospium Chloride

[0295] A phase I, double-blind, randomized, multiple-dose pilot study was conducted in normal healthy volunteers comparing xanomeline alone to xanomeline and trospium chloride. The primary objectives of this study were to (1) evaluate the safety and tolerability of xanomeline 225 mg daily and trospium chloride 40 mg daily for 7 days compared to xanomeline 225 mg daily for 7 days; and (2) determine whether the addition of trospium 40 mg daily (20 mg BID) to xanomeline 225 mg daily (75 mg TID) significantly reduces peripheral cholinergic side effects (nausea, diarrhea, vomiting, sweating, and excessive salivation) over 7 days compared to xanomeline 225 mg daily alone. Table 17 lists the study parameters. Table 17: Parameters of the KAR-001 Study

[0296] A total of seventy study subjects were randomized, and 68 of these study subjects received at least one assessment on Day 3, the first day of xanomeline administration.Table 18 lists the demographics of the study subjects. Table 18: Demographics of KAR-001 Study Subjects

[0297] The most common adverse events with xanomeline are so-called cholinergic adverse events, including nausea, vomiting, diarrhea, excessive sweating, and excessive salivation. In this study, co-administration of trospium chloride with xanomeline resulted in a statistically significant 43% reduction in the incidence of cholinergic adverse events compared to xanomeline co-administered with placebo (p=0.016). In the xanomeline plus placebo group of the study, 63% of participants reported at least one cholinergic adverse event, compared to only 34% of participants in the xanomeline plus trospium chloride group of the study.

[0298] Furthermore, in this study, the incidence of each type of individual cholinergic adverse event was also reduced in subjects who received xanomeline + trospium chloride compared to the incidence in subjects who received xanomeline + placebo. The reduction in the incidence of sweating itself was statistically significant, with an incidence of 20.0% in the xanomeline + trospium chloride group compared to 48.5% in the xanomeline + placebo group, a 59% reduction (p = 0.013).

[0299] The overall cholinergic adverse event rate in the xanomeline plus trospium chloride group in this study was very similar to the 32% rate reported in participants who received placebo plus placebo during the two-day run-in period. Although these two data points did not occur during different time periods of the study, the fact that the cholinergic adverse event rate was comparable to placebo suggests that the 43% reduction in adverse events with trospium chloride may have been close to the maximum reduction possible in this study.

[0300] Table 19 shows the incidence and number of cholinergic adverse events in the evaluable population of this study as follows, where all p values are based on chi-square tests, except those marked with *, which are based on Fisher's exact test. Table 19: Cholinergic Adverse Events

[0301] There were no meaningful differences between the treatment groups in heart rate, resting blood pressure, orthostatic blood pressure, or electrocardiogram (ECG) parameters (including QT). A small number of subjects in both treatment groups experienced transient increases in heart rate and orthostatic blood pressure variability, which may have contributed to syncope and postural dizziness in those subjects. Two subjects (both in the xanomeline alone group) experienced syncope. The incidence of orthostatic adverse events in the xanomeline plus trospium group was approximately half that of subjects in the xanomeline alone group. In the xanomeline plus trospium group, only one subject discontinued due to a treatment-emergent adverse event related to blood pressure.

[0302] In addition to evaluating whether the addition of trospium chloride improves the tolerability of xanomeline, the study also provides data on the overall safety and tolerability of xanomeline plus trospium chloride. Table 20 shows that the combination was well tolerated, with no severe adverse events or critical adverse events, and most adverse events were mild. Table 20: Tolerance

[0303] The tolerability profile of this study allows for future combination studies of xanomeline and trospium chloride. Example 5 - KAR-003 Phase I Study of KarXT (Xanomeline + Trospium Combination Formulation)

[0304] This study was a Phase 1, randomized, multiple-dose, adaptive-design, inpatient study to evaluate the safety and tolerability of KarXT in normal, healthy volunteers aged 18 to 60 years. Participants provided informed consent and underwent screening assessments on Days -21 to -1. After completing all screening assessments, participants returned to the research clinic on Day 0 for baseline safety assessments and enrollment in the study. Within each cohort, participants were randomly assigned in a 3:1 ratio to one of two treatment groups: KarXT or placebo. Participants were assigned to one of four cohorts (cohorts 1, 2, 3, or 4).

[0305] Study drug was administered BID on days 1 to 7. A combination dose formulation of xanomeline and trospium was used in all cohorts. All cohorts began with a 2-day introduction of KarXT 50 / 20 BID (for subjects randomized to active treatment); after a 2-day introduction period, a non-blinded pharmacist dispensed the study drug to each subject based on their random assignment for 5 days of designated cohort dosing, for a total of 7 days of treatment. Matching placebo was administered throughout the study to maintain the blind. For cohorts 2 to 4, a sentinel group was introduced into the study. The Data Safety Evaluation Group (DSEG) monitored their safety and tolerability so that approximately 30% of the proposed cohort had received treatment and undergone safety assessments before dosing the remaining subjects in the cohort. Subjects and study clinic staff were blinded to the treatment. The Dose Selection Committee (DSC) was non-blinded to determine the doses for subsequent treatment groups.

[0306] Serial blood samples were drawn on days 1, 3, and 7 for PK assessment of xanomeline and trospium. Additional blood was collected at regular intervals for monitoring trough concentrations of xanomeline and trospium and for clinical laboratory assessments. On day 1, saliva was collected twice. Saliva was measured on day 1 before dosing and then daily (in the afternoon) at approximately the same time each day from day 1 to day 7 to avoid diurnal variations. Other assessments included pupil size measurement and Bristol stool scale assessment. Subjects remained in the study clinic throughout the treatment period (7 days). Following a safety assessment on day 8, subjects were discharged from the study clinic and asked to return approximately 14 days after administration of the study drug for a final safety assessment.

[0307] During the study, following a 2-day run-in of KarXT 50 / 20 BID (for subjects randomized to active treatment) in each cohort, subjects were dosed as follows: In Cohort 1, subjects completed Days 3 to 7 of KarXT 100 / 20 BID (200 mg of xanomeline + 40 mg of trospium total daily dose (TDD)) or placebo. In Cohort 2, the sentinel group (Group 2a) discontinued dosing after the morning dose on Day 4. Subjects in Cohort 2 were dosed with KarXT 150 / 20 BID (300 mg of xanomeline + 40 mg of trospium chloride TDD) or placebo. Dosing for Cohort 2 was discontinued (based on the DSEG decision due to observed tolerability issues). Because the DSC determined that further dosing of Cohort 2 with KarXT 150 / 20 BID was unlikely to be well tolerated enough to warrant further development of this dose combination for the clinical population, the study dosed the Cohort 3 sentinel group (Group 3a). In Cohort 3, the sentinel group (Group 3a) completed KarXT 150 / 40 BID (300 mg xanomeline + 80 mg trospium TDD) or placebo on Days 3 to 7. The second group in Cohort 3 (Group 3b) discontinued dosing after the morning dose on Day 5. In Cohort 4, the sentinel group (Group 4a), the second group (Group 4b), and the remaining group (Group 4c) completed Days 3 to 7 of KarXT 125 / 40 BID (250 mg xanomeline + 80 mg trospium TDD) or placebo.

[0308] Ninety-six subjects were planned, 248 subjects were screened, 69 subjects were randomized, 51 subjects completed the study, and 18 subjects discontinued the study. The population included healthy male and female subjects aged 18 to 60 years at screening with a body mass index of 18 to 40 kg / m 2 . Subjects were excluded from the study if they had a history of irritable bowel syndrome or severe constipation requiring treatment within 6 months prior to screening. Subjects were also excluded from the study if they had a history of or were present with any disease or condition, including psychiatric or neurological disorders, that would compromise the subject's safety or, in the opinion of the investigator, compromise the validity of the study results. Table 21 summarizes the demographic and baseline characteristics by treatment group. The demographic and baseline characteristics were consistent between the safety and PK populations. Table 21: Summary of Demographics and Baseline Characteristics by Treatment Group - Safety Population

[0309] Serial blood samples were collected from all subjects in each cohort on days 1, 3, and 7 before the morning dose, and 1, 2, 3, 4, 6, 8, 10, and 12 hours after the morning dose, for the evaluation of the PK of xanomeline and trospium. The PK parameters listed below were calculated from the individual xanomeline and trospium concentration-time curves using standard non-compartmental methods. Dose-normalized parameters were calculated for Cmax and area under the concentration-time curve (AUC) values. Additional blood samples were collected during the study to monitor trough concentrations of xanomeline and trospium on days 2, 4, 5, and 6 before the morning dose and on day 8 before discharge.

[0310] Safety assessments included spontaneously reported adverse events, ECG, laboratory assessments, vital signs, saliva volume assessment, Bristol stool scale, pupil size, and physical examination. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) summarized continuous data across treatment groups. Geometric means (GM), geometric percentage coefficient of variation (CV%), quartiles, or box plots were generated. Although formal statistics were not performed, counts and frequencies were tabulated for categorical measurements.

[0311] Unless otherwise noted, treatment groups are summarized as follows: KarXT 50 / 20 BID (for adverse events and Day 1 PK summary only), KarXT 100 / 20 BID, KarXT 125 / 40 BID, KarXT 150 / 20 BID, KarXT 150 / 40 BID, and placebo (empty dose). Capsules and All placebo groups were combined. Safety assessments were based on reported adverse events, ECGs, laboratory assessments, and vital signs. Exploratory analyses were also performed on saliva volume, the Bristol Stool Scale, and pupil size.

[0312] Xanomeline was well absorbed into the systemic circulation following oral administration of the KAR-003 formulation at all doses. Peak xanomeline concentrations were observed at a median of 2 hours across all treatment groups and study days.

[0313] The median t values of xanomeline were 0.04 and 0.06, respectively, across treatment groups and all study days. 1 / 2 The values are similar, which indicates that t 1 / 2 Not dose-dependent. Median t 1 / 2 The range was 3.4 to 5.8 hours.

[0314] GM xanomeline exposure on Day 3 did not increase dose proportionally from 100 to 150 mg (when xanomeline was administered with 20 mg trospium) or from 125 to 150 mg (when administered with 40 mg trospium). Lower xanomeline exposure was observed following treatment with KarXT150 / 40 compared to KarXT125 / 40. GM xanomeline exposure (Cmax, AUCmax, and AUCmax) on Day 3 was significantly lower when a 150 mg dose of xanomeline was administered with 20 mg and 40 mg of trospium. 0- Finally, AUC 0-12hr On day 7, when xanomeline was administered with 40 mg trospium, GM xanomeline exposure increased slightly more than dose proportionally from 125 mg to 150 mg.

[0315] There was minimal to no xanomeline accumulation in plasma from day 3 to day 7 following treatment with KarXT 100 / 20 BID and KarXT 125 / 40 BID; however, 3 of the 4 subjects who completed the study experienced accumulation following administration of KarXT 150 / 40 BID. The mean accumulation ratios for the KarXT 150 / 40 BID group were 366.2% (RAUC) and 445.4% (RC). 最大 ). Example 6 - Xanomeline Pharmacokinetics of KAR-003 Compared to KAR-001

[0316] Comparison of xanomeline GM exposure between KAR-001 (75 mg xanomeline TID ± 20 mg trospium BID) and the KarXT 100 / 20 BID group from KAR-003 showed that the C 最大 Value and AUC 0-6hr (KAR-003) or AUC 0-tau (KAR-001) values (Day 3 and Day 7) were greater than the corresponding exposures from KAR-001 (Day 3 and Day 9). A median T was observed at 2 hours in both studies and on both days (Day 3 and Day 9 for KAR-001 and Day 3 and Day 7 for KAR-003). 最大 These data suggest that the KarXT formulation enhances xanomeline exposure.

[0317] Following oral administration of the KarXT formulation, trospium was absorbed into the systemic circulation at all doses. Peak trospium concentrations were observed at a median time of 1.0 hour across all treatment groups and study days.

[0318] On day 3, the median t of trospium between treatment groups was 1 / 2 The values were similar, ranging from 4.1 to 4.8 hours. On day 7, the median t 1 / 2 The values were similar but slightly longer for the KarXT 150 / 40 BID group (7.1 hours).

[0319] When administered with 150 mg of xanomeline, GM trospium exposure on day 3 increased slightly less than dose proportionally from 20 mg to 40 mg. When a 20 mg BID dose of trospium was administered with 100 mg BID xanomeline, GM trospium exposure on day 3 (C 最大 , AUC 0-最后 and AUC 0-12hrGM trospamide exposure on day 3 was similar when the 40 mg trospamide BID dose was given with 125 mg xanomeline BID and 150 mg xanomeline BID.

[0320] After administration of KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID, trospium did not accumulate in plasma from day 3 to day 7. For the KarXT 100 / 20 BID group, trospium accumulated in plasma from day 1 to day 7. The mean day 7 / day 1 accumulation ratios were 348.7% (RAUC) and 379.9% (RC). 最大 ).

[0321] Comparison of trospium GM exposure between KAR-001 and KarXT 100 / 20 BID groups from KAR-003 showed that C 最大 and AUC 0-12hr The values were greater than the corresponding exposures from KAR-001 on two days (Days 3 and 9 for KAR-001 and Days 3 and 7 for KAR-003). Median T values for trospium were observed on both days in both studies. 最大 These data indicate that the KarXT formulation enhances trospium exposure.

[0322] All cohorts of KAR-003 began with a 2-day run-in period of KarXT 50 / 20 BID (for subjects randomized to KarXT). Figure 1 Xanomeline PK concentration mean values (± SD) are presented, and xanomeline PK parameters for KarXT 50 / 20 BID treatment day 1 for all cohorts in the PK population are summarized in Table 22. Samples collected before the first dose of xanomeline on Day 1 did not show measurable xanomeline concentrations. Xanomeline concentrations were quantifiable (> 50 pg / mL) at all time points from the morning dose of Day 1 to 12 hours. Table 22: Xanomeline PK Parameters on Day 1 of KarXT 50 / 20 BID (All Cohorts) feature n statistics <![CDATA[C 最大 (pg / mL)]]> 53 1972.3(131.8) <![CDATA[T 最大 (h)]]> 53 2.0(1.0、8.0) <![CDATA[t 1 / 2 (h)]]> 48 3.4(2.0、4.6) <![CDATA[AUC 0-最后 (h*pg / mL)]]> 53 10775.5(102.2) <![CDATA[AUC 0-12hr (h*pg / mL)]]> 52 10810.3(103.5) <![CDATA[AUC 0-inf (h*pg / mL)]]> 48 12836.1(97.7)

[0323] Figure 2The mean (±SD) xanomeline PK concentrations generated by treatment on Day 3 for the PK population are presented, and these parameters are summarized in Table 23. For all cohorts, xanomeline concentrations were quantifiable in samples taken before the morning dose of study drug on Day 3 and at all time points up to 12 hours after the morning dose on Day 3, with the exception of one subject whose xanomeline plasma concentration at 12 hours post-dose was <50.0 pg / mL. Across the four treatment groups, the inter-subject variability ranged from 0.1 to 0.6 for T. 最大 is 23.7% to 58.2% (CV%), for C 最大 is 79.8% to 136.3% (geometric CV%), for t 1 / 2 was 21.6% to 26.3% (CV%), and for AUC 0-12hr The median T values for xanomeline on day 3 were 77.1% to 96.1% (geometric CV%) for the KarXT 100 / 20 BID, KarXT 125 / 40 BID, KarXT 150 / 20 BID, and KarXT 150 / 40 BID groups. 最大 Across the four treatment groups, a single T 最大 The values ranged from 1.0 to 6.0 hours. Compared to the previous study, KAR-001, in which the elimination phase was not well characterized, t 1 / 2 Estimated in 51 of 53 subjects. Across the four treatment groups, the median xanomeline dose on Day 3 was t 1 / 2 Similar in value. Median t 1 / 2 The range was 3.4 to 4.3 hours. Across the four treatment groups, a single t 1 / 2 The values range from 2.4 to 8.6 hours. Table 23: Xanomeline PK parameters by treatment on Day 3

[0324] When KarXT was administered BID, the dose-normalized GM exposure on day 3 (dose-normalized GM C ) for xanomeline was significantly higher due to the increase in the xanomeline dose from 100 mg (cohort 1) to 150 mg (cohort 2) without changing the trospium dose (20 mg). 最 Large and dose-normalized GM AUC 0- Finally, AUC 0-12hr) decreased. Similarly, due to increasing the xanomeline dose from 125 mg (Cohort 4) to 150 mg (Cohort 3) without changing the trospium dose (40 mg), the dose-normalized GM exposure on Day 3 for xanomeline was slightly reduced (i.e., xanomeline exposure was lower after treatment with KarXT 150 / 40 BID compared to treatment with KarXT 125 / 40 BID). Comparison of xanomeline exposure after administration of 150 mg xanomeline BID with either 20 mg or 40 mg trospium BID showed that for xanomeline, GM, C, and D on Day 3 were significantly lower. 最大 , AUC 0-最后 and AUC 0-12hr resemblance.

[0325] Figure 3 The mean (±SD) xanomeline PK concentrations generated by treatment on Day 7 for the PK population are presented and summarized in Table 24. For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID groups, xanomeline concentrations were quantifiable in samples collected before the morning dose of study drug on Day 7 and at all time points up to 12 hours after the morning dose on Day 7. The inter-subject variability ranged from 0.04 to 0.13 for the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups for T 最大 is 38.3% to 47.9% (CV%), for C 最大 is 81.4% to 106.8% (geometric CV%), for t 1 / 2 was 15.4% to 42.1% (CV%), and for AUC 0-12hr The median T values for xanomeline on day 7 were 45.2% to 71.2% (geometric CV%) for the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID groups. 最大 is 2.0 hours. Across KarXT 100 / 20BID, KarXT 150 / 40BID and KarXT 125 / 40BID groups, a single T 最大 The values ranged from 0.0 to 6.0 hours. The median xanomeline t values on Day 7 were 0.0 to 6.0 hours for the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID groups. 1 / 2 The median value of xanomeline is similar. 1 / 2 The range was 4.6 to 5.8 hours. Across the KarXT 100 / 20BID, KarXT 150 / 40BID, and KarXT 125 / 40BID groups, a single t 1 / 2The range of values is 3.6 to 14.0 hours. Table 24: Xanomeline PK parameters by treatment on Day 7

[0326] When KarXT was administered BID, the dose-normalized GM exposure on day 7 (dose-normalized GM C ) for xanomeline was significantly higher due to the increase in the xanomeline dose from 125 mg (cohort 4) to 150 mg (cohort 3) without changing the trospium dose (40 mg). 最 Large, AUC 0- Finally, AUC 0-12hr )Increase.

[0327] Table 25 summarizes the xanomeline PK accumulation ratios (Day 7 / Day 3) by treatment population. Based on the mean xanomeline accumulation ratios following treatment with KarXT 100 / 20 BID (Cohort 1) and KarXT 125 / 40 BID (Cohort 4), minimal to no xanomeline accumulated in plasma from Day 3 to Day 7. The mean accumulation ratios for the KarXT 100 / 20 BID group were 133.4% (RAUC) and 130.5% (RC). max ), and the average accumulation ratios of the KarXT 125 / 40 BID group were 143.9% (RAUC) and 151.0% (RC 最大 Only one subject in the KarXT 100 / 20 BID group showed lower exposure on Day 7 compared to Day 3. In contrast, three of the four subjects in the KarXT 150 / 40 BID group who completed the study had moderate accumulation of xanomeline. The other subject in the KarXT 150 / 40 BID group showed similar exposure on Days 3 and 7. The mean accumulation ratios in the KarXT 150 / 40 BID group were 366.2% (RAUC) and 445.4% (RC). 最大 ). Table 25: Xanomeline PK Accumulation Ratio by Treatment (Day 7 / Day 3)

[0328] Figure 4 The mean (±SD) xanomeline PK concentration-time profiles were compared across treatment and follow-up (days) for the PK population. Figure 5 Mean (±SD) xanomeline PK trough concentrations by treatment are presented for the PK population. Achieving steady-state was not assessed.

[0329] Comparison of xanomeline GM exposure between KAR-001 (75 mg xanomeline TID ± 20 mg trospium BID) (Table 23) and the KarXT 100 / 20 BID group from KAR-003 (Table 21) showed that the KarXT 100 / 20 BID group (KAR-003) had a significantly higher GM exposure at day 3 of C 最大 Value and AUC 0-6hr (KAR-003) or AUC 0-tau The (AUC from 0 to 6 hours) values (KAR-001) were approximately 2.3- to 2.6-fold higher than the corresponding exposures from KAR-001 on day 3.

[0330] Comparison of the GM exposures on day 7 for the KarXT 100 / 20 BID group from KAR-003 (Table 22) with the exposures on day 9 for xanomeline alone and xanomeline + trospium from KAR-001 (Table 23) indicated that the values for the KarXT 100 / 20 BID group (KAR-003) on day 7 were approximately 1.4 to 1.8 times higher than the corresponding exposures from KAR-001 on day 9. The median T values were 2.5 to 3.5 times higher on days 3 and 7 for KAR-003 (Table 22) and 3 and 9 for KAR-001 (Table 23). 最大 These data suggest that the KAR-003 formulation provides adequate exposure and PK properties.

[0331] Table 26 summarizes a subset of KAR-003 xanomeline PK parameters for the PK population for the KarXT 100 / 20 BID group on Days 3 and 7. Table 27 presents a summary of a subset of KAR-001 xanomeline PK parameters for the PK population for the KAR-001 treatment on Days 3 and 9. Table 26: Subset of Xanomeline PK Parameters on Days 3 and 7 for KarXT 100 / 20 BID Table 27: Subset of Xanomeline PK Parameters for KAR-001 on Days 3 and 9

[0332] Figure 6 The mean (±SD) trospium PK concentrations for the KarXT 50 / 20 BID treatment (all cohorts) on Day 1 for the PK population are presented and summarized in Table 28. Samples collected before the first dose of trospium on Day 1 did not show measurable trospium concentrations. Trospium concentrations were quantifiable (>20 pg / mL) at all time points after the morning dose on Day 1 through 12 hours. Table 28: Trospium PK Parameters for KarXT 50 / 20 BID on Day 1 (All Cohorts)

[0333] Figure 7 The mean (±SD) trospium PK concentrations generated by treatment on Day 3 for the PK population are presented, and these parameters are summarized in Table 29. Trospium concentrations were quantifiable in samples collected before the morning dose of study drug on Day 3 and at all time points up to 12 hours after the morning dose on Day 3 for all treatment groups, with the exception of one subject whose plasma trospium concentration at 12 hours post-dose was <20.0 pg / mL. Across the four treatment groups, the inter-subject variability ranged for T 最大 is 0.0% to 83.0% (CV%), for C 最 The maximum is 54.8% to 80.7% (geometric CV%), for t 1 / 2 was 9.1% to 34.0% (CV%), and for AUC 0-12hr It was 59.0% to 67.6% (geometric CV%). Table 29: Trospium PK parameters by treatment on day 3

[0334] For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, KarXT 150 / 20 BID, and KarXT 150 / 40 BID groups, the median T of trospium on day 3 was 最大 is 1.0 hour. Across the 4 treatment groups, a single T 最大 The values ranged from 1.0 to 6.0 hours. Across the four treatment groups, the median t 1 / 2 Numerically similar; median t 1 / 2 The range was 4.1 to 4.8 hours. Across the four treatment groups, a single t 1 / 2 The values ranged from 2.8 to 9.0 hours.

[0335] When KarXT was administered BID, dose-normalized GM exposure on Day 3 increased for trospamide due to increasing the trospamide dose from 20 mg (Cohort 2) to 40 mg (Cohort 3) without changing the xanomeline dose (150 mg). Comparison of trospamide exposure on Day 3 following administration of 20 mg trospamide BID and 100 mg (Cohort 1) or 150 mg (Cohort 2) xanomeline BID demonstrated that GM exposure of trospamide was significantly increased when the 20 mg BID dose of trospamide was administered with 100 mg xanomeline BID compared to when administered with 150 mg xanomeline BID. 最大 , AUC 0-最后 and AUC 0-12hr Bigger.

[0336] Similarly, comparison of trospamide exposure following administration of 40 mg trospamide BID and 125 mg (cohort 4) or 150 mg (cohort 3) xanomeline BID indicated that GM C of trospamide was significantly higher when trospamide was administered on day 3 with 125 and 150 mg xanomeline BID. 最大 、AUC0- 最后 Generally similar to AUC0-12hr.

[0337] Figure 8 The mean (±SD) PK concentrations of trospium produced by treatment on Day 7 for the PK population are presented, and these parameters are summarized in Table 30. For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID groups, trospium concentrations were quantifiable in samples collected before the morning dose of study drug on Day 7 and at all time points up to 12 hours after the morning dose on Day 7. The inter-subject variability ranged from 0.04 to 0.13 for T-statin 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups. 最大 is 0.0% to 86.3% (CV%), for C 最大 is 51.2% to 93.8% (geometric CV%), for t 1 / 2 was 23.0% to 44.5% (CV%), and for AUC 0-12hr It was 59.4% to 76.7% (geometric CV%). Table 30: Trospium PK parameters by treatment on day 7

[0338] For KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID treatments, the median T of trospium on day 7 was 最大 is 1.0 hour. Across the KarXT 100 / 20BID, KarXT 150 / 40BID and KarXT 125 / 40BID groups, a single T 最大 The value range is 0.0 to 6.0 hours.

[0339] The median t of trospium on day 7 was 2.5 t for the KarXT 100 / 20 BID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) groups. 1 / 2 The median t of the KarXT 150 / 40BID group was similar. 1 / 2 is 7.1 hours. Across the KarXT 100 / 20BID, KarXT150 / 40BID and KarXT 125 / 40BID groups, a single t 1 / 2 The values range from 3.1 to 11.9 hours.

[0340] Comparison of trospamide exposure on day 7 following administration of 40 mg trospamide BID and 125 mg (cohort 4) or 150 mg (cohort 3) xanomeline BID, as observed on day 3, indicated that the GM C of trospamide was significantly increased when trospamide was administered with 125 and 150 mg of xanomeline BID. 最大 , AUC 0-最后 and AUC 0-12hr resemblance.

[0341] Table 31 summarizes the PK accumulation ratios of trospamide by treatment (Day 7 / Day 3; Day 7 / Day 1) for the PK population. Based on the mean trospamide PK accumulation ratios, trospamide accumulated minimally in plasma from Day 3 to Day 7 after administration of KarXT 100 / 20 BID (Cohort 1), with little or no accumulation after administration of KarXT 125 / 40 BID (Cohort 4) and KarXT 150 / 40 BID (Cohort 3). Both subjects showed lower exposure on Day 7 compared to Day 3 in the KarXT 100 / 20 BID group.

[0342] The accumulation ratios varied widely between subjects in the KarXT 125 / 40 BID and KarXT 150 / 20 BID groups on days 3 to 7. The mean accumulation ratios ranged from 108.6% to 141.4% for RAUC and from 108.6% to 141.4% for RC. 最大The mean accumulation ratio was 348.7% for RAUC and 135.8% for RC. 最大 A possible effect of the increased dose of xanomeline (from 50 mg BID to 100 mg BID starting on day 3) on the PK and bioavailability of trospium cannot be excluded, as this contributed to the increased exposure from day 1 to day 7. Table 31: Trospamine PK accumulation ratios by treatment (Day 7 / Day 3; Day 7 / Day 1)

[0343] Figure 9 The mean (±SD) trospium PK concentration-time profiles were compared across treatment and follow-up (days) for the PK population. Figure 10 Mean (± SD) trospium PK trough concentrations by treatment and follow-up (days) are presented for the PK population. Achieving steady-state was not assessed. Example 7 - Trospium Pharmacokinetics of KAR-003 Compared to KAR-001

[0344] Comparison of trospamide GM exposures on day 1 of KAR-001 (first dose of trospamide alone without prior treatment) (Table 33) and day 1 of KAR-003 (first dose of xanomeline + trospamide without prior treatment) (Table 32) showed that trospamide exposures from KAR-003 were approximately 2.1 to 2.5 times higher than those obtained from KAR-001. Although the comparison of GM exposures on day 3 between the studies was not a head-to-head comparison (xanomeline administration was not started until day 3 of the KAR-003 study), the number of trospamide doses and daily doses administered to the subjects were the same. KAR-003 day 3 GM trospamide exposures (Table 32) were also approximately 2.4 to 3.3 times higher than those obtained from KAR-001 (Table 33). Comparison of the Day 7 GM exposures from the KarXT 100 / 20 BID cohort (Cohort 1) of KAR-003 (Table 32) with the Day 9 exposures from the xanomeline + trospium group of KAR-001 (Table 33) indicated that exposures were again higher than those obtained from KAR-001 (approximately 3.5 to 4.3 fold higher).

[0345] Median T values for trospium were 0.04 (P < 0.05) on days 3 and 7 for the KarXT 100 / 20 BID group and 0.06 (P < 0.05) on days 3 and 9 for the Xanomeline + Trospium group in the KAR-001 group. 最大 The median T value of trospium chloride on day 1 in the group treated with trospium chloride alone (KAR-001) was 1.0 hour. 最大 The median T of trospium on day 1 was 3.0 hours compared to the KarXT 50 / 20 BID group (KAR-003). 最大 Lower (1.0 hour).

[0346] Table 32 summarizes a subset of KAR-003 trospamide PK parameters for the PK population for KarXT 50 / 20 BID treatment (all cohorts) on Day 1 and KarXT 100 / 20 BID treatment on Days 3 and 7. Table 33 summarizes a subset of KAR-001 trospamide PK parameters for the PK population for trospamide alone treatment on Day 1 and xanomeline + trospamide treatment on Days 3 and 9. Table 32: Subset of KAR-003 Trospium PK Parameters for KarXT 50 / 20 BID (all cohorts) on Day 1 and KarXT 100 / 20 BID on Days 3 and 7 Table 33: Subset of Trospium PK Parameters for KAR-001 on Days 1, 3, and 9

[0347] Table 34 lists the incidence of cholinergic TEAEs by system organ class (SOC) and preference for the safety population in the KAR-001 study. The overall subject incidence of cholinergic TEAEs was similar between the xanomeline + trospium group (12 [34.3%] subjects), the KarXT 100 / 20 BID group (7 [38.9%] subjects), and the KarXT 125 / 40 BID group (6 [33.3%] subjects) in KAR-001. Table 34: Incidence and Preference of KAR-001 Cholinergic Treatment-Emergent Adverse Events by System Organ Class - Safety Population

[0348] Hypersalivation, excessive sweating, and diarrhea occurred more frequently in the xanomeline + trospium group of KAR-001 compared to the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups. Excessive salivation occurred in 25.7% of subjects in the xanomeline + trospium group of KAR-001, 5.6% of subjects in the KarXT 100 / 20 BID group, and no subjects in the KarXT 125 / 40 BID group. Excessive sweating occurred in 20.0% of subjects in the xanomeline + trospium group of KAR-001, 5.6% of subjects in the KarXT 100 / 20 BID group, and 11.1% of subjects in the KarXT 125 / 40 BID group. Diarrhea occurred in 5.7% of subjects in the xanomeline + trospium group of KAR-001 and in no subjects in the KarXT 100 / 20 BID group or the KarXT 125 / 40 BID group.

[0349] For nausea and vomiting, the xanomeline + trospium group in KAR-001 showed no other significant trends compared to the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups. Nausea occurred in 17.1% of subjects in the xanomeline + trospium group in KAR-001 and in 22.2% of subjects in each of the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups. Vomiting occurred in 5.7% of subjects in the xanomeline + trospium group in KAR-001, 27.8% of subjects in the KarXT 100 / 20 BID group, and 5.6% of subjects in the KarXT 125 / 40 BID group.

[0350] Following oral administration of the KAR-003 formulation, xanomeline and trospium were absorbed into the systemic circulation at all doses. PK results demonstrated that neither xanomeline nor trospium significantly impacted the PK behavior of the other. Compared to KAR-001, which administers the two compounds separately, the KAR-003 formulation provided enhanced blood levels of xanomeline and trospium.

[0351] No new safety signals were reported with the KarXT formulation. All TEAEs were mild or moderate in severity, and there were no SAEs or deaths. Hypersalivation, hyperhidrosis, and diarrhea were more common in the xanomeline + trospium groups in KAR-001 compared to the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups in KAR-003. Example 8 - KAR-004 Phase II Study

[0352] This Phase II, randomized, double-blind, placebo-controlled, inpatient study was designed to evaluate the efficacy of KarXT (a fixed combination of xanomeline and trospium) compared to placebo in reducing the total score on the Positive and Negative Syndrome Scale (PANSS) in inpatients diagnosed with schizophrenia. Five secondary objectives were to evaluate the overall safety and tolerability of KarXT in inpatients diagnosed with schizophrenia according to DSM-5, to assess the adverse events (AEs) spontaneously reported by subjects treated with KarXT compared to placebo, to assess the cholinergic symptoms spontaneously reported by subjects treated with KarXT compared to placebo, to assess the orthostatic vital signs of subjects treated with KarXT compared to placebo, and to assess the ECG parameters of subjects treated with KarXT compared to placebo.

[0353] The total study duration was up to 7 weeks, including a 7-day screening phase (which was extended to 7 days if necessary) and a 5-week treatment period. Subjects were randomly assigned to either the KarXT group or the placebo group in a 1:1 ratio. The key inclusion and exclusion criteria for the Phase II study are shown in Table 35. The demographic and baseline characteristics of the enrolled patients are shown in Table 36. Table 35: Key inclusion and exclusion criteria Table 36: Demographics and baseline characteristics of enrolled patients Placebo (n=92) KarXT (n=90) Average age (years) 41.6 43.4 Gender, male (%) 74 80 Race (% White / % Non-White) 19 / 81 22 / 78

[0354] The study was a two-arm, flexible-dose trial with randomization at a 1:1 ratio to KarXT or placebo for five weeks: - Days 1-2: 50 / 20 KarXT BID (50 mg xanomeline / 20 mg trospium chloride) -Days 3-7: 100 / 20KarXT BID - Days 8-35: 100 / 20 KarXT BID, optional increase to 125 / 30 KarXT BID; titration based on tolerability only.

[0355] The primary endpoint was the change in PANSS total score compared to placebo at week 5. Other endpoints included CGI, PANSS positive and negative subscales, PANSS Marder factors, cognitive battery, etc. CGI-S responders were defined as subjects with a CGI-S score of 1 or 2. CGI-S non-responders were defined as subjects with a CGI-S scale of 3 to 7. Subjects were required to have a CGI-S score ≥ 4 at screening and baseline follow-up. CGI-S score legend: 1 for normal, 2 for borderline disease, 3 for mild disease, 4 for moderate disease, 5 for obvious disease, 6 for severe disease, and 7 for extreme disease. Safety endpoints included monitoring of spontaneous adverse events, orthostatic vital signs (supine and after 2 minutes of standing), blood pressure (systolic and diastolic) and heart rate (beats per minute), clinical laboratory evaluations (hematology, clinical chemistry, coagulation, urinalysis, and drug screen), 12-lead ECG, physical examination, and assessment of suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0356] The intention-to-treat (ITT) population included all subjects randomly assigned to the study. The safety population included all subjects who received at least one dose of study drug. The safety population was used for all analyses of safety endpoints. The modified intention-to-treat (mITT) population included all subjects who were randomly assigned, received at least one dose of study drug, and had a baseline and at least one post-baseline PANSS assessment. The mITT population was used for all analyses of efficacy endpoints. The PK population included all subjects who received at least one dose of study drug and had at least one measurable PK concentration. If any subject was found to be non-compliant with dosing, had incomplete data, or had other clinical events that potentially interfered with the pharmacokinetic profile, they were determined to be excluded from the PK analysis. The completer population included all mITT subjects with a valid PANSS total score at visit 9. The completer population was used for sensitivity analysis of the primary efficacy endpoint. The per-protocol (PP) population included all subjects who were randomly assigned, received at least one dose of study drug, had a baseline and at least one post-baseline PANSS assessment, and had no major protocol deviations. The PP population was used for sensitivity analysis of the primary efficacy endpoint. All subjects were analyzed according to their randomly assigned treatment.

[0357] The demographics of the ITT population are shown in Table 37. There were no significant differences between the treatment groups. Table 37: Key Demographics and Baseline Characteristics of the mITT Population Placebo (n=87) KarXT (n=83) Average age (years) 41.8±10.0 43.7±10.0 Gender, male (%) 73.6 80.7 Race (% non-white) 80.4 77.1 Mean baseline PANSS score 96.6±8.4 97.3±9.3 Mean baseline PANSS positive score 26.3±3.3 26.3±3.4 Mean baseline PANSS negative score 22.9±4.6 22.5±4.3 Mean baseline PANSS Marder negative score 22.4±5.1 22.3±4.6 Mean baseline CGI-S score 4.9±0.6 5.0±0.5 Positive and negative values are mean ± SD

[0358] For the primary endpoint, KarXT treatment demonstrated a clinically meaningful and statistically significant improvement in PANSS total score compared to placebo ( Figure 11 Compared to placebo, participants improved by 11.6 points at week 5 (p < 0.0001). Statistical separation occurred at every assessment time point. Cohen's d effect size was 0.75. Historically, changes as small as 5 points in the PANSS total score have been considered effective for antipsychotics currently used as standard of care.

[0359] For the secondary endpoint, KarXT treatment demonstrated a clinically meaningful and statistically significant improvement in the PANSS positive total subscore compared to placebo ( Figure 12 Compared to placebo, subjects improved by 3.2 points at week 5 (p<0.0001). Statistical separation occurred at every assessment time point.

[0360] KarXT treatment also demonstrated clinically meaningful and statistically significant improvements in PANSS negative sum compared to placebo ( Figure 13 Compared to placebo, subjects improved by 2.3 points at week 5 (p<0.001). Statistical separation occurred at every assessment time point. Figure 14 Plotted are PANSS Marder factor scores relative to follow-up days for subjects in the mITT population of the KAR-004 Phase II study.

[0361] In addition, the CGI-S showed highly significant improvements in a pattern consistent with the PANSS. A nonparametric comparison of KarXT versus placebo using the Mann-Whitney Wilcoxon test showed a shift in CGI-S scores from baseline (p < 0.001). At baseline, the percentage of patients with a score of 5 or 6 was 84% versus 80% for KarXT versus placebo (P < 0.001). Figure 15 At endpoint, the percentage of patients with a score of 5-7 was 33% versus 60% for KarXT compared to placebo, and the percentage of patients with mild disease or better (a score of 1, 2, or 3) was 37% versus 11% for KarXT compared to placebo. Figure 16 Statistical separation occurred at each evaluation time point (weeks 2, 4, and 5).

[0362] Overall, KarXT was safe and well tolerated. The overall discontinuation rate for KarXT (20%) was similar to that for placebo (21%). The number of discontinuations due to treatment-emergent adverse events (TEAEs) was equal in the KarXT and placebo groups (n=2 in each group). The dose escalation rate for KarXT was high and similar to that for placebo: 91% of KarXT subjects were escalated to the 125 / 30 KarXT dose (compared to 97% for placebo), and 4% of subjects were deescalated to the 100 / 20 KarXT dose (compared to 1% for placebo).

[0363] The overall adverse event rate was 54% for KarXT compared to 43% for placebo (Table 38): Table 38: Adverse events during the study Values are number (percentage) of patients. SAE = severe adverse event, GGT = gamma-glutamyl transferase

[0364] The most common adverse events were constipation, nausea, dry mouth, dyspepsia, and vomiting. These adverse events represent a balance of events caused by xanomeline and those caused by trospium. For example, xanomeline alone can cause sweating, nausea, vomiting, diarrhea, and excessive salivation, as well as orthostasis and syncope. Trospium causes constipation, dry mouth, and stomach discomfort. Unlike earlier xanomeline trials, sweating was not reported or observed.

[0365] The majority of the most common cholinergic / anticholinergic adverse events associated with KarXT treatment were reduced throughout the study. In particular, cholinergic adverse events (in Figure 17 nausea and vomiting) and anticholinergic adverse events (dry mouth, Figure 18 The rates of nausea, vomiting, and dry mouth were consistently reduced in the KarXT group (data not shown). By the end of week 5, the rates of nausea, vomiting, and dry mouth in the KarXT group were statistically indistinguishable from those in the placebo group. The rate of constipation in the KarXT group showed a smaller downward trend (data not shown). The black bars represent the corresponding AE rates in the placebo group throughout the study.

[0366] There were no syncope episodes in the KarXT treatment group. Mean resting orthostatic and standing heart rates increased by only 4.4 bpm compared to placebo ( Figure 19 and 20 The effect on heart rate was significantly lower and tended to resolve compared with previous studies. There was no mean change in orthostatic systolic or diastolic blood pressure ( Figure 21 and 22 There were no significant postural effects between orthostatic and standing measurements.

[0367] Somnolence, weight gain, and extrapyramidal symptoms / akathisia were similar to those seen with placebo. No significant changes were observed on the Barnes Akathisia Scale, the Simpson-Angus Scale, or the Abnormal Involuntary Movement Scale. These adverse events are typically observed with current standard of care. These adverse events were not observed with KarXT treatment.

[0368] Liver enzymes in LFTs were comparable to placebo (Table 39). Two patients treated with KarXT had elevated GGT (>2X ULN), and one patient treated with placebo had elevated ALT (>3X ULN), AST (>3X ULN), and GGT (>2X ULN). In particular, one subject discontinued due to elevated gamma-glutamyl transferase (GGT) present in LFTs. Table 39: Adverse events during the study Laboratory testing Placebo (n=90) KarXT (n=89) ALT-U / L 2.1±32.4 2.8±16.2 AST-U / L -0.5±16.9 -0.4±10.9 Alk phos-U / L -1.7±14.5 -0.6±15.3 GGT-U / L 2.1±26.0 1.5±34.1 Bilirubin-mmol / L -0.3±4.3 -0.4±3.2 Plus and minus values are mean ± SD; Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Alk phos = alkaline phosphatase; GGT = gamma-glutamyl transferase.

[0369] One severe adverse event was documented with KarXT: the patient discontinued treatment and sought hospital care due to worsening psychosis. Although this event met the regulatory technical definition of a severe adverse event, the psychosis was attributable to schizophrenia, not KarXT. The patient did not withdraw due to symptoms caused by KarXT administration. Therefore, this result reflects a lack of efficacy of KarXT in one patient, rather than new symptoms arising from drug-induced intolerance.

[0370] This Phase 2 study showed that KarXT has strong antipsychotic efficacy and favorable safety / tolerability in hospitalized patients with schizophrenia. KarXT showed early (2 weeks) and sustained (throughout 5 weeks) separation from the placebo group on the primary efficacy measure (PANSS sum) and four of the five secondary outcome measures. The safety profile was consistent with previous work conducted with the KarXT combination. With the exception of one treatment-emergent adverse event, all adverse events were rated as mild or moderate. Throughout the study, most cholinergic and anticholinergic adverse events were reduced to levels that were statistically indistinguishable from the placebo group.

[0371] The foregoing description is given only for clarity of understanding, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the present disclosure will be apparent to those of ordinary skill in the art. Throughout the specification, when a composition is described as comprising a component or material, unless otherwise stated, it is contemplated that the composition may also consist essentially of or consist of any combination of the enumerated components or materials. Similarly, where a method is described as comprising steps, it is contemplated that these methods may also consist essentially of or consist of any combination of the enumerated steps, unless otherwise stated. The present disclosure illustratively disclosed herein may be suitably practiced in the absence of any element or step not specifically disclosed herein.

[0372] The practice of the methods disclosed herein and their individual steps can be performed manually and / or with the aid of electronic devices or automation provided by electronic devices. Although the methods have been described with reference to the embodiments, it will be readily understood by those skilled in the art that other ways of performing the actions associated with these methods can be used. For example, unless otherwise indicated, the order of the individual steps can be changed without departing from the scope or spirit of the method. In addition, some individual steps can be combined, omitted, or further subdivided into additional steps.

[0373] It should be understood that, for the sake of clarity, certain features of the present invention described in the context of a separate embodiment may also be provided in combination in a single embodiment. On the contrary, for the sake of brevity, the various features of the present invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination. All combinations of embodiments of the chemical groups represented by the variables included in the general chemical formula as described herein are clearly encompassed by the present invention, as if each combination were individually and clearly stated, to the extent that such combinations encompass stable compounds (i.e., compounds that can be separated, characterized, and tested for biological activity). In addition, all sub-combinations of the chemical groups listed in the embodiments describing such variables, as well as all sub-combinations of uses and medical indications as described herein, are also specifically encompassed in the present invention, as if each sub-combination of chemical groups and sub-combinations of uses and medical indications are individually and clearly stated herein.

[0374] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure controls.

[0375] This application also relates to the following: 1. A method for treating schizophrenia or a disorder associated with schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and a plurality of trospamine beads comprising a trospamine salt via a titration regimen, the titration regimen comprising increasing titration of the xanomeline or a salt thereof and the trospamine salt. 2. A method for treating schizophrenia or a disorder related to schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient an oral pharmaceutical composition twice daily for at least five weeks, the oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and a plurality of trospamine beads comprising a trospamine salt, wherein at least one adverse event occurring at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment. 3. The method of claim 1 or 2, wherein the administration is performed via a titration regimen comprising titrating the xanomeline or a salt thereof, and the trospium chloride salt incrementally up to twice daily administration of an amount equivalent to 125 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride. 4. The method of claim 1 or 2, wherein the administration is performed via a titration regimen comprising titrating the xanomeline or a salt thereof, and the trospium chloride salt incrementally up to twice daily administration of an amount equivalent to 150 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride. 5. The method of claim 1 or 2, wherein the administration is performed via a titration regimen comprising titrating the xanomeline or a salt thereof, and the trospium chloride salt incrementally up to twice daily administration of an amount equivalent to 175 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride. 6. The method of claim 1 or 2, wherein the administration is performed via a titration regimen comprising titrating the xanomeline or a salt thereof, and the trospium chloride salt incrementally up to twice daily administration of an amount equivalent to 175 mg of xanomeline free base and an amount equivalent to 40 mg of trospium chloride. 7. The method of any of the preceding items, wherein the patient is diagnosed with schizophrenia. 8. The method of any one of the preceding items, wherein before administration of the oral pharmaceutical composition, the patient has a Clinical Global Impression Severity Scale (CGI-S) score of 4-7, and after administration the patient has a CGI-S score equal to 1 or 2. 9. The method of any of the preceding items, wherein the xanomeline or salt thereof is administered in a first amount for a first period of time and then the first amount is increased to a second amount. 10. The method of claim 9, wherein the first amount of xanomeline or a salt thereof is equivalent to 50 mg of xanomeline free base. 11. The method of item 9 or 10, wherein the first period of time for which xanomeline is administered is 1 to 5 days. 12. The method of claim 11, wherein the first period of time for which xanomeline is administered is 2 days. 13. The method of any one of items 9 to 12, wherein the second amount of xanomeline or a salt thereof is equivalent to 100 mg of xanomeline free base. 14. The method of any one of items 9 to 13, further comprising administering the xanomeline or salt thereof in the second amount for a second period of time and then increasing the second amount to a third amount. 15. The method of claim 14, wherein the second period of time during which xanomeline is administered is from three days to one week. 16. The method of item 14 or 15, wherein the third amount of xanomeline or a salt thereof is equivalent to 125 mg of xanomeline free base. 17. The method of any of the preceding items, wherein the trospium chloride salt is administered in a first amount for a first period of time, and the first amount is increased to a second amount. 18. The method of claim 17, wherein the first amount of trospium chloride salt is equivalent to 20 mg of trospium chloride. 19. The method of claim 17 or 18, wherein the first period of time for which trospium is administered is at least one week. 20. The method of any one of items 15 to 17, wherein the second amount of trospium chloride salt is equivalent to 30 mg of trospium chloride. 21. The method of any of the preceding items, wherein at least one of vomiting, nausea and dry mouth occurring at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment. 22. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing an increase in heart rate of more than about 5 beats per minute. 23. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing syncope. 24. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing a change in diastolic blood pressure of more than about 5 mmHg. 25. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing a change in systolic blood pressure of more than about 5 mmHg. 26. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing serious adverse events. 27. The method of any of the preceding items, wherein administration of the xanomeline or salt thereof, and the trospium salt does not result in serious adverse events related to heart rate. 28. The method of any of the preceding items, wherein administration of the xanomeline or salt thereof, and the trospium salt does not result in serious adverse events related to changes in heart rate. 29. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing serious adverse events related to blood pressure. 30. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without causing serious adverse events related to changes in blood pressure. 31. The method of any of the preceding items, wherein the xanomeline or salt thereof, and the trospium salt are administered without increasing liver function tests (LFTs). 32. The method of any of the preceding items, wherein after five weeks of treatment, the patient's Positive and Negative Syndrome Scale (PANSS) total score is reduced by at least 10 points compared to placebo. 33. The method of any of the preceding items, wherein after five weeks of treatment the PANSS positive subscore is reduced by at least 3 points compared to placebo. 34. The method of any of the preceding items, wherein after five weeks of treatment the PANSS negative subscore is reduced by at least 2 points compared to placebo. 35. The method of any of the preceding items, wherein the xanomeline beads are 0.425 mm to 1.18 mm in size. 36. The method of any of the preceding items, wherein the size of the xanomeline beads is 0.6 mm to 0.85 mm. 37. The method of any of the preceding items, wherein the size of the trospamine beads is 0.425 mm to 1.18 mm. 38. The method of any of the preceding items, wherein the size of the trospium beads is 0.6 mm to 0.85 mm. 39. The method of any preceding item, wherein the xanomeline beads contain about 2.5 times more xanomeline free base than the trospium salt contained in the trospium beads. 40. The method of any of the preceding items, wherein the dissolution rate of the plurality of xanomeline beads and the plurality of trospamine beads is greater than about 95% within about the first 45 minutes after the dosage form enters the aqueous solution. 41. The method of claim 40, wherein the dissolution rate is greater than about 95% within about the first 20 minutes after the dosage form enters the aqueous solution. 42. The method of any of the preceding items, wherein the salt of xanomeline is xanomeline tartrate. 43. The method of clause 42, wherein the xanomeline beads comprise 30 wt.% to 80 wt.% xanomeline tartrate. 44. The method of any one of clause 43, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate. 45. The process of any of the preceding items, wherein the xanomeline beads comprise 15 to 65 wt.% microcrystalline cellulose. 46. The method of claim 45, wherein the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose. 47. The process of any of the preceding items, wherein the xanomeline beads comprise 0 to 2 wt.% talc. 48. The method of item 46, wherein the xanomeline beads comprise 0.5 wt.% talc. 49. The process of any of the preceding items, wherein the xanomeline beads comprise 30 to 80 wt.% xanomeline tartrate, 15 to 65 wt.% microcrystalline cellulose, and 0 to 2 wt.% talc. 50. The method of item 49, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc. 51. The method of any of the preceding items, wherein the trospium chloride salt is trospium chloride. 52. The method of clause 51, wherein the trospium chloride beads comprise 8 to 35 wt.% trospium chloride. 53. The method of clause 52, wherein the trospium chloride beads comprise 17.7 wt.% trospium chloride. 54. The method of any of the preceding items, wherein the trospium chloride beads comprise 25 to 80 wt.% microcrystalline cellulose. 55. The method of claim 54, wherein the trospium chloride beads comprise 46.8 wt.% microcrystalline cellulose. 56. The method of any of the preceding items, wherein the trospium chloride beads comprise 15 to 70 wt.% lactose monohydrate. 57. The method of item 56, wherein the trospium chloride beads comprise 35 wt.% lactose monohydrate. 58. The method of any of the preceding items, wherein the trospium chloride beads comprise 0 to 2 wt.% talc. 59. The method of clause 58, wherein the trospium chloride beads comprise 0.5 wt.% talc. 60. The process of any of the preceding items, wherein the trospium chloride beads comprise 8 to 35 wt.% trospium chloride, 25 to 80 wt.% microcrystalline cellulose, 15 to 70 wt.% lactose monohydrate, and 0 to 2 wt.% talc. 61. The method of claim 60, wherein the trospium chloride beads comprise 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc. 62. The method of any of the preceding items, wherein the oral pharmaceutical composition further comprises ascorbic acid. 63. The method of claim 62, wherein the oral pharmaceutical composition comprises 0.2 wt.% to 1 wt.% ascorbic acid. 64. The method of claim 63, wherein the oral pharmaceutical composition comprises about 0.5 wt.% ascorbic acid. 65. The method of any of the preceding items, wherein the oral pharmaceutical composition further comprises butylated hydroxytoluene. 66. The method of claim 64, wherein the oral pharmaceutical composition comprises 0.01 wt.% to 0.1 wt.% of butylated hydroxytoluene. 67. The method of claim 66, wherein the oral pharmaceutical composition comprises about 0.05 wt.% butylated hydroxytoluene. 68. The method of any of the preceding items, wherein the oral pharmaceutical composition further comprises a capsule containing the plurality of xanomeline beads and the plurality of trospamine beads. 69. A method of treating acute psychosis in a patient in need thereof, the method comprising: orally administering to the patient twice daily an oral pharmaceutical composition comprising xanomeline or a salt thereof, and a trospium salt to achieve a mean reduction in Positive and Negative Syndrome Scale (PANSS) total score of at least 10 points compared to placebo. 70. The method of claim 69, wherein a mean reduction in PANNS total score of at least 11.6 points is achieved. 71. The method of any one of items 69 or 70, wherein a mean reduction in PANSS positive subscore of at least 3 points compared to placebo is achieved. 72. The method of any one of items 69 to 71, wherein a reduction in the PANSS negative subscore of at least 2 points compared to placebo is achieved. 73. The method of any one of items 69 to 72, wherein the reduction in PANSS score is achieved within about 5 weeks. 74. The method of any one of items 69 to 73, wherein prior to administration of the oral pharmaceutical composition, the patient has a Clinical Global Impression Severity Scale (CGI-S) score of 4-7, and after administration, the patient has a CGI-S score of 1 or 2. 75. The method of any one of items 69 to 74, wherein the patient is diagnosed with schizophrenia. 76. The method of any one of items 69 to 75, wherein the xanomeline is xanomeline tartrate and the trospium chloride salt is trospium chloride. 77. The method of any one of items 69 to 76, wherein at least one adverse event occurring at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment. 78. The method of claim 77, wherein at least one adverse event is selected from vomiting, nausea, and dry mouth.

Claims

1. A method of treating acute psychosis in a patient in need thereof, the method comprising: An oral pharmaceutical composition comprising xanomeline or a salt thereof, and a trospium salt is orally administered to the patient twice daily to achieve a mean reduction of at least 10 points in the Positive and Negative Syndrome Scale (PANSS) total score compared to placebo.

2. The method of claim 1, wherein a mean reduction in PANNS total score of at least 11.6 points is achieved.

3. The method of any one of claims 1 or 2, wherein a mean reduction in the PANSS positive subscore of at least 3 points compared to placebo is achieved.

4. The method of any one of claims 1 to 3, wherein a reduction of at least 2 points in the PANSS negative subscore compared to placebo is achieved.

5. The method of any one of claims 1 to 4, wherein the reduction in PANSS score is achieved within about 5 weeks.

6. The method of any one of claims 1 to 5, wherein before administration of the oral pharmaceutical composition, the patient has a Clinical Global Impression Severity Scale (CGI-S) score of 4-7, and after administration the patient has a CGI-S score equal to 1 or 2.

7. The method of any one of claims 1 to 6, wherein the patient is diagnosed with schizophrenia.

8. The method of any one of claims 1 to 7, wherein the xanomeline is xanomeline tartrate and the trospium chloride salt is trospium chloride.

9. The method of any one of claims 1 to 8, wherein at least one adverse event occurring at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment.

10. The method of claim 9, wherein the at least one adverse event is selected from vomiting, nausea, and dry mouth.

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