Compositions and methods for treating disorders alleviated by activation of muscarinic receptors

Abstract

The present disclosure provides a method of treating schizophrenia or a schizophrenia-related disorder in a patient in need thereof. The method comprises orally administering to the patient, twice daily via a titration regimen, 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, the titration regimen comprising increasing titration of the xanomeline or a salt thereof and the trospium chloride salt.

Description

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

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

[0003] Schizophrenia affects approximately 0.5% to 1% of the population. The disease is characterized by a range of symptoms, classified into positive symptoms (such as hallucinations, delusions, etc.), negative symptoms (such as social isolation, anhedonia, etc.), and cognitive symptoms (such as inability to process information, poor working memory, etc.). The quality of life of patients with schizophrenia is greatly reduced. Their risk of mortality is increased due to many factors (such as increased suicide rate). Schizophrenia is costly to society because people living with schizophrenia are more likely to be incarcerated, homeless, or unemployed.

[0004] Existing treatments for schizophrenia rely on dopamine and serotonin receptors, as in the case of chlorpromazine, the first antipsychotic discovered in 1952. For over 60 years, the same basic pharmacology has been the standard of care for schizophrenia. Current antipsychotics are only effective against positive symptoms and fail to treat negative and cognitive symptoms. Alzheimer's disease is another area of treatment. Developing new therapies has proven extremely difficult, with a success rate of only 0.4% for molecules that enter clinical development and obtain market approval. Patients in these areas are in urgent need of new treatments, but development has been very difficult despite the great 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 tauopathies or synucleinopathies. Muscarinic cholinergic receptors are G protein-coupled receptors with five different receptor subtypes (M1 - M5), each of which is found to have a different tissue distribution in the CNS. 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 for M1 and M4 subtypes of receptors) in patients with schizophrenia, schizophrenia was alleviated. However, because it also binds to muscarinic receptors outside the brain, xanomeline has many serious side effects, including gastrointestinal (GI) side effects, cardiac side effects, and excessive salivation. Dose-limiting adverse events were problematic and led to a high discontinuation rate (including a discontinuation rate of 56% in a 26-week Alzheimer's disease study), and ultimately led to the discontinuation of the development of xanomeline. Despite early promise, the development of xanomeline stalled for more than 15 years. Many companies have tried but have not developed 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 by targeting M1 and M4 subtypes rather than M2 and M3 muscarinic receptor subtypes. However, activation of M1 and M4 outside the brain can still lead to muscarinic-related intolerance. Little progress has been made in alleviating adverse reactions caused by activation of peripheral muscarinic receptors.

[0007] In the art, there remains a need for a pharmaceutical composition that is more tolerable to xanomeline, particularly for treating cognitive and psychiatric disorders. The following examples and aspects thereof are described and illustrated with compositions and methods that are exemplary and illustrative, and do not limit the scope. In various embodiments, one or more of the above problems have been reduced or eliminated, while other embodiments are directed to other improvements.

[0008] There is provided a method of treating schizophrenia or a disease associated with schizophrenia in a patient in need thereof, the method comprising: orally administering to the patient, twice daily via a titration regimen, an oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof, and a plurality of trospium beads containing a salt of trospium chloride, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the salt of trospium chloride.

[0009] There is also provided a method of treating schizophrenia or a disease associated with schizophrenia in a patient in need thereof, the method comprising orally administering to the patient, twice daily via a titration regimen, an oral pharmaceutical composition comprising a plurality of xanomeline beads containing xanomeline or a salt thereof, and a plurality of trospium beads containing a salt of trospium chloride, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the salt of trospium chloride 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 for treating acute psychosis in a patient in need thereof. The method comprises orally administering to the patient a pharmaceutical composition comprising xanomeline or a salt thereof, and trospium chloride salt, twice daily, to achieve an average reduction of at least 10 points in the total score of the Positive and Negative Syndrome Scale (PANSS) compared to placebo.

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

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

[0013] Figure 1 Depicts the mean (± standard deviation) of the xanomeline pharmacokinetic concentration on Day 1 for the twice-daily KarXT 50 / 20 treatment cohort for the KAR-003 pharmacokinetic population.

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

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

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

[0017] Figure 5 Depicts the mean (± standard deviation) of the xanomeline pharmacokinetic trough concentration by treatment for the KAR-003 pharmacokinetic population.

[0018] Figure 6Depicts the mean tropicamide pharmacokinetic concentration (± standard deviation) on Day 1 in the twice-daily KarXT 50 / 20 treatment cohort for the KAR-003 pharmacokinetic population.

[0019] Figure 7 Depicts the mean tropicamide pharmacokinetic concentration (± standard deviation) on Day 3 through treatment for the KAR-003 pharmacokinetic population.

[0020] Figure 8 Depicts the mean tropicamide pharmacokinetic concentration (± standard deviation) on Day 7 through treatment for the KAR-003 pharmacokinetic population.

[0021] Figure 9 Depicts the mean tropicamide pharmacokinetic concentration (± standard deviation) through treatment and follow-up for the KAR-003 pharmacokinetic population.

[0022] Figure 10 Depicts the mean tropicamide pharmacokinetic trough concentration (± standard deviation) through treatment and follow-up for the KAR-003 pharmacokinetic population.

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

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

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

[0026] Figure 14 Depicts the PANSS Marder factor score for subjects in the mITT population of the KAR-004 Phase II study relative to the number of follow-up days.

[0027] Figure 15 Describes a statistically significant and clinically meaningful improvement in Clinical Global Impression-Severity (CGI-S) at baseline for patients receiving KarXT (relative to patients receiving placebo).

[0028] Figure 16 It describes a statistically significant and clinically meaningful improvement in CGI-S at the end point of week 5 for patients receiving KarXT (compared to patients receiving placebo).

[0029] Figure 17 It depicts that the rates of adverse events (nausea and vomiting) related to muscarinic receptor agonists decrease over time in patients treated with KarXT.

[0030] Figure 18 It depicts that the rate of peripheral anticholinergic adverse events (dry mouth) decreases over time in patients treated with KarXT.

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

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

[0033] Figure 21 It depicts a box plot of orthostatic diastolic pressure (mmHg) from the KarXT safety population plotted by follow-up.

[0034] Figure 22 It depicts a box plot of orthostatic systolic pressure (mmHg) from the KarXT safety population plotted by follow-up. Detailed implementation manners

[0035] Due to peripheral cholinergic side effects, the early development of the muscarinic receptor agonist xanomeline was terminated. This disclosure provides dosage forms with dissolution kinetics that have a more effective therapeutic effect for two active ingredients, enhanced pharmacokinetics for trospium chloride, and greater dose compliance. This disclosure also provides dosage forms with two active ingredients of different strengths or different ratios.

[0036] The following specific examples are provided herein:

[0037] Example 1: A method for treating schizophrenia or a disease associated with 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 trospium chloride beads containing a trospium chloride salt, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the trospium chloride salt.

[0038] Example 2: A method for treating schizophrenia or a disease associated with 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 trospium chloride beads containing a trospium chloride 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] Example 3: The method according to Example 1 or 2, wherein the administration is carried out via a titration regimen, the titration regimen comprising increasing the titration of 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 twice daily.

[0040] Example 4: The method according to Example 1 or 2, wherein the administration is carried out via a titration regimen, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the trospium chloride salt, 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] Example 5: The method according to Example 1 or 2, wherein the administration is carried out via a titration regimen, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the trospium chloride salt, 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] Example 6: The method according to Example 1 or 2, wherein the administration is carried out via a titration regimen, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, 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] Example 7: The method according to any one of the preceding examples, wherein the patient is diagnosed with schizophrenia.

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

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

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

[0047] Example 11: The method according to Example 9 or 10, wherein the first period of time for which the xanomeline is administered is 1 to 5 days.

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

[0049] Example 13: The method according to any one of Examples 9 to 12, wherein the second amount of xanomeline or its salt is equivalent to 100 mg of xanomeline free base.

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

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

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

[0053] Example 17: The method according to any one of the preceding examples, 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] Example 18: The method according to Example 17, wherein the first amount of trospium chloride salt is equivalent to 20 mg of trospium chloride.

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

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

[0057] Example 21: In the method according to any one of the preceding examples, at least one of vomiting, nausea, and dry mouth that occurs at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment.

[0058] Example 22: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing an increase in heart rate of more than about 5 beats per minute.

[0059] Example 23: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing syncope.

[0060] Example 24: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing a diastolic blood pressure change of more than about 5 mmHg.

[0061] Example 25: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing a systolic blood pressure change of more than about 5 mmHg.

[0062] Example 26: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing serious adverse events.

[0063] Example 27: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing serious adverse events related to heart rate.

[0064] Example 28: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing serious adverse events related to heart rate changes.

[0065] Example 29: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing serious adverse events related to blood pressure.

[0066] Example 30: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without causing serious adverse events related to blood pressure changes.

[0067] Example 31: In the method according to any one of the preceding examples, the xanomeline or its salt, and the trospium chloride salt are administered without increasing liver function tests (LFT).

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

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

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

[0071] Example 35: The method according to any one of the preceding examples, wherein the size of the xanomeline beads is from 0.425 mm to 1.18 mm.

[0072] Example 36: The method according to any one of the preceding examples, wherein the size of the xanomeline beads is from 0.6 mm to 0.85 mm.

[0073] Example 37: The method according to any one of the preceding examples, wherein the size of the trospium chloride beads is from 0.425 mm to 1.18 mm.

[0074] Example 38: The method according to any one of the preceding examples, wherein the size of the trospium chloride beads is from 0.6 mm to 0.85 mm.

[0075] Example 39: The method according to any one of the preceding examples, wherein the xanomeline free base contained in these xanomeline beads is about 2.5 times that of the trospium chloride salt contained in these trospium chloride beads.

[0076] Example 40: The method according to any one of the preceding examples, wherein within about the first 45 minutes after the dosage form enters the aqueous solution, the dissolution rate of the plurality of xanomeline beads and the plurality of trospium chloride beads is greater than about 95%.

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

[0078] Example 42: The method according to any one of the preceding examples, wherein the salt of xanomeline is xanomeline tartrate.

[0079] Example 43: The method according to Example 42, wherein these xanomeline beads contain 30 wt.% to 80 wt.% of xanomeline tartrate.

[0080] Example 44: The method according to Example 43, wherein these xanomeline beads contain 66 wt.% of xanomeline tartrate.

[0081] Example 45: The method according to any one of the preceding examples, wherein the xanomeline beads comprise from 15 wt.% to 65 wt.% microcrystalline cellulose.

[0082] Example 46: The method according to Example 45, wherein the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose.

[0083] Example 47: The method according to any one of the preceding examples, wherein the xanomeline beads comprise from 0 wt.% to 2 wt.% talc.

[0084] Example 48: The method according to Example 46, wherein the xanomeline beads comprise 0.5 wt.% talc.

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

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

[0087] Example 51: The method according to any one of the preceding examples, wherein the trospium salt is trospium chloride.

[0088] Example 52: The method according to Example 51, wherein the trospium beads comprise from 8 wt.% to 35 wt.% trospium chloride.

[0089] Example 53: The method according to Example 52, wherein the trospium beads comprise 17.7 wt.% trospium chloride.

[0090] Example 54: The method according to any one of the preceding examples, wherein the trospium beads comprise from 25 wt.% to 80 wt.% microcrystalline cellulose.

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

[0092] Example 56: The method according to any one of the preceding examples, wherein the trospium beads comprise from 15 wt.% to 70 wt.% lactose monohydrate.

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

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

[0095] Example 59: The method according to Example 58, wherein the trospium chloride beads comprise 0.5 wt.% of talc.

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

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

[0098] Example 62: The method according to any one of the preceding examples, wherein the oral pharmaceutical composition further comprises ascorbic acid.

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

[0100] Example 64: The method according to Example 63, wherein the oral pharmaceutical composition comprises approximately 0.5 wt.% of ascorbic acid.

[0101] Example 65: The method according to any one of the preceding examples, wherein the oral pharmaceutical composition further comprises butylated hydroxytoluene.

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

[0103] Example 67: The method according to Example 66, wherein the oral pharmaceutical composition comprises approximately 0.05 wt.% of butylated hydroxytoluene.

[0104] Example 68: The method according to any one of the preceding examples, wherein the oral pharmaceutical composition further comprises a capsule containing the plurality of xanomeline beads and the plurality of trospium chloride beads.

[0105] Example 69: A method for 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 tropicamide salt, to achieve an average reduction in the total score of the Positive and Negative Syndrome Scale (PANSS) of at least 10 points compared to placebo.

[0106] Example 70: The method according to Example 69, wherein an average reduction in the total PANNS score of at least 11.6 points is achieved.

[0107] Example 71: The method according to any one of Examples 69 or 70, wherein an average reduction in the PANSS positive subscore of at least 3 points compared to placebo is achieved.

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

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

[0110] Example 74: The method according to any one of Examples 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] Example 75: The method according to any one of Examples 69 to 74, wherein the patient is diagnosed with schizophrenia.

[0112] Example 76: The method according to any one of Examples 69 to 75, wherein the xanomeline is xanomeline tartrate and the tropicamide salt is tropicamide chloride.

[0113] Example 77: The method according to any one of Examples 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] Example 78: The method according to Example 77, wherein at least one adverse event is selected from vomiting, nausea, and dry mouth.

[0115] The articles "a" and "an" mean one or more than one (i.e., 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 used in an inclusive and open sense, meaning that additional elements may be included.

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

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

[0119] All ranges set forth herein include all possible sub-ranges of the range and any combination of such sub-ranges. By default, a range includes the specified endpoints, and in the case of a range providing values, each intermediate value between the upper and lower limits of the range and any other specified or intermediate value within the specified range is covered by this disclosure. The upper and lower limits of these smaller ranges may be independently included within the smaller ranges and are also covered by this disclosure, subject to any explicit exclusions within the specified range. In the case where the specified range includes one or both of the limits, a range excluding one or both of the included limits is also considered to be part of this disclosure.

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

[0121] The term "controlled release" is defined as a mode of extended release of one or more drugs such that the drugs are released over a period of time. The release kinetics of a controlled release formulation result in measurable serum levels of the drug for a potentially longer period of time than after intravenous injection or administration of an immediate release oral dosage form. Controlled 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 known in the art. Exemplary mammals include humans, primates, cattle, pigs, dogs, cats, and rodents (e.g., 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 well recognized in the art. It refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in carrying or transporting any subject composition or its components from one organ or part of the body to another organ or part of the body. 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 be used 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0126] The term "pharmaceutically acceptable salt" or "salt" is well recognized in the art. It refers to a salt prepared from a relatively non-toxic acid or base, which includes inorganic and organic acids and bases, including, for example, those contained in the compositions of the present disclosure. Suitable non-toxic 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, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, saccharic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid, etc.

[0127] The term "treatment" is well recognized in the art and refers to curing as well as alleviating at least one symptom of any disease or disorder.

[0128] In jurisdictions that prohibit patenting methods of treatment of the human body, the meaning of "administering" a composition to a human subject shall be limited to a controlled substance that is prescribed for the human subject to self-administer by any technique (e.g., orally, inhaled, topically applied, injected, inserted, etc.). This is intended to conform to the broadest reasonable interpretation of the laws or regulations defining patentable subject matter. In jurisdictions that do not prohibit patenting methods of treatment of the human body, "administering" a composition includes both methods of treatment of the human body and the foregoing activities.

[0129] The term "therapeutic agent" is well recognized in the art and refers to any chemical moiety that acts as a biological, physiological, or pharmacological active substance that acts locally or systemically in a subject. Examples of therapeutic agents (also referred to as "drugs") are described in well-known references such as the Merck Index (14th Edition), Physicians’ Desk Reference (64th Edition), and The Pharmacological Basis of Therapeutics (12th Edition). These therapeutic agents include, but are not limited to, drugs; vitamins; mineral supplements; substances for treating, preventing, diagnosing, curing, or alleviating a disease or disorder; 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 therapies. Those skilled in the art use a variety of techniques involving verbal and other interactions with patients to effect a positive therapeutic outcome. 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, biofeedback therapy, rational emotive behavior therapy, reality therapy, response-based therapy, sandplay therapy, state dynamic therapy, hypnosis, and validation therapy. Psychotherapy can involve a combination of two or more techniques. The therapist can select and adapt the techniques based on the needs of each patient and the patient's response.

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

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

[0133] "Mental illness" refers to an abnormal state of mind that results in difficulty in determining what is real and not real. Symptoms of mental illness include, but are not limited to, false beliefs (delusions), seeing or hearing things that others do not see or hear (hallucinations), incoherent speech, inappropriate behavior, sleep problems, social withdrawal, lack of motivation, and difficulty performing daily activities.

[0134] "Acute psychosis" refers to a rapid or intense onset of a patient's psychotic symptoms, such as those defined in "Acute transient psychotic disorder" (International Classification of Diseases - 10) and "Brief psychotic disorder" (DSM-IV). After a brief period of anxiety, insomnia, and confusion, individuals with acute psychosis develop acute delusions with rapidly changing structures. Acute psychosis can include an acute exacerbation of psychosis, during which the patient may respond to hallucinations or delusions. Acute psychosis has a very short duration, 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 signal transduction.

[0136] The term "inhibitor" means a molecule described as an antagonist, partial antagonist, competitive antagonist, non-competitive 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 decreases receptor activity or signal transduction.

[0137] As used herein, an "adverse event" is any adverse medical event associated with the treatment with the pharmaceutical compositions 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 uncomfortable enough to interfere with daily activities and may require intervention. A "severe adverse event" interferes with daily activities and usually requires treatment or other intervention. A "serious adverse event" results in death; is life-threatening (there is an immediate risk of death from the event when it occurs); requires hospitalization or an extended hospital stay; results in persistent or severe disability / incapacity; or results in congenital anomaly / disability, cancer, or drug overdose. An adverse event is disabling or incapacitating if it results in substantial or permanent disruption of the subject's ability to perform normal life functions.

[0138] As used herein, a patient is said to "tolerate" a dose of a compound if administration of that dose to the patient does not result in unacceptable adverse events or a combination of unacceptable adverse events. One of ordinary skill in the art will appreciate that tolerance is a subjective measure and that a substance that one patient can tolerate 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 tolerate vomiting. For a third patient, either a headache alone or vomiting alone may be tolerable. Nevertheless, the patient cannot tolerate the combination of a headache and vomiting, even if the severity of each is less 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 coupled receptor that binds the neurotransmitter acetylcholine. To date, five subtypes of muscarinic receptors have been identified. "M1" means muscarinic receptor subtype one. "M2" means muscarinic receptor subtype two. "M3" means muscarinic receptor subtype three. "M4" means muscarinic receptor subtype four. "M5" means muscarinic receptor subtype five.

[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, piperacetazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox and tetrabenazine.

[0142] The term "anxiolytic" refers to a drug that reduces anxiety, fear, panic or related sensations. 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 a drug that alleviates depression and related disorders (e.g., mood disorders). Such drugs include, but are not limited to, selective serotonin reuptake inhibitors (SSRI, e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRI, 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., isoniazid, moclobemide, phenelzine, selegiline, tranylcypromine).

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

[0145] Pharmaceutical composition

[0146] Provided herein is an oral pharmaceutical composition that comprises a plurality of xanomeline beads containing xanomeline or a salt thereof; and a plurality of trospium chloride beads containing a trospium salt. In certain embodiments, the trospium salt is selected from trospium chloride, trospium bromide, trospium iodide, and trospium saccharinate.

[0147] In certain embodiments, the plurality of xanomeline beads have a core containing xanomeline or a salt thereof. In certain embodiments, the plurality of trospium chloride beads have a core containing a trospium salt.

[0148] In certain embodiments, a capsule shell containing hydroxypropyl methylcellulose (HPMC) contains separate groups of drug beads that contain xanomeline tartrate or trospium chloride, wherein the beads have comparable sizes and rapidly release the active ingredient at substantially similar rates. After the capsule shell dissolves in the stomach, the drug 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.

[0149] The formulation of each bead allows for substantially similar performance from two active ingredients in different dose ranges. These active ingredients are released into the serum at substantially similar rates or reach substantially similar T 最大 . In certain embodiments, the capsule contains 50 mg of xanomeline as the tartrate and 10 mg of trospium chloride. Fifty mg of xanomeline as the free base corresponds to approximately 76 mg of xanomeline tartrate.

[0150] Differences in the number of beads in the capsule increase the likelihood that the bead ratio will not remain substantially constant after these beads are released and dispersed. Accordingly, in certain embodiments, the trospium chloride beads are formulated at a lower drug loading. An effective dose of trospium chloride and xanomeline is included in a substantially equivalent number of beads. Although the drug loadings vary in certain embodiments, the trospium chloride and xanomeline beads are released at substantially similar rates. For example, if the dissolution of the capsule is evaluated using a United States Pharmacopeia (USP) dissolution apparatus, the percentage of xanomeline dissolved is substantially equivalent to the percentage of trospium chloride dissolved at, for example, 10 min, 20 min, or 30 min.

[0151] 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 orally delivered using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, cachets, or gel caps and other oral administration methods known to those skilled in the art.

[0152] The drug may be in the form of an immediate release drug dosage form. In alternative embodiments, the drug may have a controlled release dosage form.

[0153] The drug may be in a dosage form using other controlled release formulation methods known to those skilled in the art.

[0154] In another embodiment, the drug is combined with one or more therapies, including psychotherapy and drugs. Therapeutic agents include, but are not limited to, antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers, analgesics, and other pharmacological interventions known to those skilled in the art. Therapeutic agents may belong to more than one drug class. For example, benzodiazepines may be considered anxiolytics, sedatives, and tranquilizers.

[0155] Bead / Core Excipient

[0156] The bead or core 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 its pharmaceutically acceptable salts and trospium chloride salts may be in separate matrices within the same drug.

[0157] The amount of xanomeline free base 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 xanomeline tartrate 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 the 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.% of xanomeline tartrate, such as 66 wt.% of xanomeline tartrate.

[0158] 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 the 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.% of trospium chloride, such as 17.7 wt.% of trospium chloride.

[0159] In additional embodiments, the matrix comprises a polymer, such as for modifying the release profile of the active ingredient in the matrix. In additional embodiments, the polymer comprises a water-soluble polymer. In additional embodiments, the water-soluble polymer is selected from Eudragit TM RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof. In additional embodiments, the polymer comprises a water-insoluble polymer. In additional embodiments, the water-insoluble polymer is selected from Eudragit TMRS, 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 glycol terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and mixtures thereof.

[0160] The fillers include, but are not limited to, lactose, sucrose, glucose, starch, microcrystalline cellulose, ultramicrofine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch and calcium hydrogen phosphate dihydrate. In one embodiment, the filler is water absorbable but 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, glycerides, β-cyclodextrin (β-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide. In one embodiment, the filler includes microcrystalline cellulose.

[0161] The amount of the filler in the xanomeline core is not particularly limited. In an embodiment, the amount of the filler (e.g., microcrystalline cellulose) can 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.%, such as about 20 wt.%. In certain embodiments, the xanomeline beads contain about 15 wt.% to about 65 wt.% of microcrystalline cellulose, such as 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 contain 33.5 wt.% of microcrystalline cellulose.

[0162] The amount of the filler in the trospium chloride core is not particularly limited. In embodiments, the amount of the filler (such as 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 chloride beads contain 25 wt.% to 80 wt.% of microcrystalline cellulose, such as about 25 wt.% to 30 wt.%, about 30 wt.% to 35 wt.%, about 35 wt.% to 40 wt.%, about 40 wt.% to 45 wt.%, about 45 wt.% to 50 wt.%, about 50 wt.% to 55 wt.%, about 55 wt.% to 60 wt.%, about 60 wt.% to 65 wt.%, about 65 wt.% to 70 wt.%, about 70 wt.% to 75 wt.% or about 75 wt.% to 80 wt.%. In certain embodiments, the trospium chloride beads contain 46.8 wt.% of microcrystalline cellulose.

[0163] In certain embodiments, the trospium chloride beads contain 15 wt.% to 70 wt.% of lactose monohydrate, such as about 15 wt.% to 20 wt.%, about 20 wt.% to 25 wt.%, about 25 wt.% to 30 wt.%, about 30 wt.% to 35 wt.%, about 35 wt.% to 40 wt.%, about 40 wt.% to 45 wt.%, about 45 wt.% to 50 wt.%, about 50 wt.% to 55 wt.%, about 55 wt.% to 60 wt.%, about 60 wt.% to 65 wt.% or about 65 wt.% to 70 wt.%. In certain embodiments, the trospium chloride beads contain 35 wt.% of lactose monohydrate.

[0164] Binders include but are not limited to cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose, such as hypromellose 2910, Methocel TM E), carboxymethylcellulose, starch, pregelatinized starch, gum arabic, tragacanth, gelatin, polyvinylpyrrolidone (povidone), crosslinked polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, and lower alkyl-substituted hydroxypropylcellulose. In one embodiment, the binder is selected from wet binders. In one embodiment, the binder is selected from cellulose ethers, such as hypromellose.

[0165] The amount of the binder in the xanomeline core is not particularly limited. In embodiments, the amount of the binder (such as 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.%, such as about 5 wt.%.

[0166] The amount of binder in the trospium chloride core is not particularly limited. In embodiments, the amount of binder (such as hypromellose) can range from about 1 wt.% to about 10 wt.%, from about 2 wt.% to about 8 wt.%, or from about 4 wt.% to about 6 wt.%, such as about 5 wt.%.

[0167] 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 ethers 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.

[0168] The amount of surfactant (such as as a processing aid) in the xanomeline core is not particularly limited. In embodiments, the amount of surfactant (such as microcrystalline cellulose) can range from about 0.1 wt.% to about 1 wt.%, from about 0.2 wt.% to about 0.8 wt.%, or from about 0.4 wt.% to about 0.6 wt.%, such as about 0.5 wt.%.

[0169] The amount of surfactant (such as as a processing aid) in the trospium chloride core is not particularly limited. In embodiments, the amount of surfactant (such as sodium lauryl sulfate) can range from about 0.1 wt.% to about 1 wt.%, from about 0.2 wt.% to about 0.8 wt.%, or from about 0.4 wt.% to about 0.6 wt.%, such as about 0.5 wt.%.

[0170] Disintegrants include but are not limited to starch, croscarmellose sodium, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, crospovidone, sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0171] Glidants include but are not limited to polyethylene glycols 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.

[0172] 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 wt.% to 2 wt.% of talc, such as 0.5 wt.% of talc. In certain embodiments, the trospium chloride beads contain 0 wt.% to 2 wt.% of talc, such as 0.5 wt.% of talc.

[0173] 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.% of the 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.%.

[0174] In certain embodiments, the oral pharmaceutical composition further comprises ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises from 0.2 wt.% to 1 wt.% of ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises about 0.5 wt.% of ascorbic acid. In certain embodiments, the oral pharmaceutical composition further comprises butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises from 0.01 wt.% to 0.1 wt.% of butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises about 0.05 wt.% of butylated hydroxytoluene. In certain embodiments, the formulation comprises about 0.05 wt.% of BHT or 0.5 wt.% of ascorbic acid. In certain embodiments, the antioxidant is present in the xanomeline core or xanomeline beads.

[0175] In certain embodiments, the xanomeline beads comprise from 30 wt.% to 80 wt.% of xanomeline tartrate, from 15 wt.% to 65 wt.% of microcrystalline cellulose, and from 0 wt.% to 2 wt.% of talc. In certain embodiments, the trospium chloride beads comprise from 0.2 wt.% to 2 wt.% of talc, such as 0.5 wt.% of talc. In certain embodiments, the trospium chloride beads comprise from 8 wt.% to 35 wt.% of trospium chloride, from 25 wt.% to 80 wt.% of microcrystalline cellulose, from 15 wt.% to 70 wt.% of lactose monohydrate, and from 0.2 wt.% to 2 wt.% of talc.

[0176] In certain embodiments, xanomeline tartrate beads comprise 66 wt.% xanomeline tartrate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc. In certain embodiments, trospium chloride beads comprise 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 in the xanomeline tartrate beads is about 2.5 times the amount of trospium chloride in the trospium chloride beads.

[0177] Capsules can be prepared with different amounts of xanomeline tartrate beads and trospium chloride beads according to dosage requirements. In various embodiments, the capsules contain 25 mg xanomeline and 10 mg trospium chloride, 50 mg xanomeline and 10 mg trospium chloride, 50 mg xanomeline and 20 mg trospium chloride, 75 mg xanomeline and 10 mg trospium chloride, 75 mg xanomeline and 20 mg trospium chloride, 125 mg xanomeline and 30 mg trospium chloride, or 125 mg xanomeline and 40 mg trospium chloride. In certain embodiments, the capsules contain 25 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsules contain 50 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsules contain 50 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsules contain 75 mg xanomeline as xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsules contain 75 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsules contain 125 mg xanomeline as xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsules contain 125 mg xanomeline as xanomeline tartrate and 40 mg trospium chloride. In certain embodiments, the capsules contain 150 mg xanomeline and 20 mg trospium chloride. In certain embodiments, the capsules contain 150 mg xanomeline and 30 mg trospium chloride. In certain embodiments, the capsules contain 150 mg xanomeline and 40 mg trospium chloride. In certain embodiments, the capsules contain 175 mg xanomeline and 20 mg trospium chloride. In certain embodiments, the capsules contain 175 mg xanomeline and 30 mg trospium chloride. In certain embodiments, the capsules contain 175 mg xanomeline and 40 mg trospium chloride.

[0178] In another embodiment, the medicament contains from five milligrams to 700 milligrams of xanomeline. In an embodiment, the medicament contains from 25 milligrams to 300 milligrams of xanomeline.

[0179] In another embodiment, the medicament contains from 1 milligram to 400 milligrams of trospium chloride. In an embodiment, the medicament contains from 6.5 milligrams to 200 milligrams of trospium chloride.

[0180] In one embodiment, a trospium chloride extended-release agent is used as the trospium chloride in the medicament. In another embodiment, the medicament contains from 1 milligram to 400 milligrams of a trospium chloride extended-release agent. In an embodiment, the medicament contains from 6.5 milligrams to 200 milligrams of a trospium chloride extended-release agent.

[0181] In an embodiment, the medicament contains 75 mg or 225 milligrams of xanomeline, and the same medicament contains 20 mg or 40 milligrams of trospium chloride. In another embodiment, the medicament contains 75 mg or 225 milligrams of xanomeline, and a different medicament to be co-administered contains 20 mg or 40 milligrams of trospium chloride.

[0182] Bead Coating

[0183] In other embodiments, the beads can be coated with a functional or non-functional coating, e.g., an aesthetic, handling, or stability coating. In certain embodiments, the beads can be coated with a pH-sensitive coating such that they do not dissolve in the low pH of the stomach. Non-functional coatings can be used to maintain chemical separation between these beads or for decorative reasons.

[0184] In additional embodiments, 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 dosing vehicles can be in different coatings. In additional embodiments, the semipermeable coating comprises a polymer. In additional embodiments, the controlled-release formulation comprises a matrix suspending xanomeline and trospium chloride.

[0185] In certain embodiments, the distribution of the coating thickness can be described in terms of the weight increase of the coating material based on the total weight of the coated beads. Thus, in one embodiment, based on the total weight of the coated beads, the distribution of the coating thickness is at least 2%. In another embodiment, the distribution of the coating thickness is at least 3%. In another embodiment, the distribution of the coating thickness is at least 4%. In another embodiment, the distribution of the coating thickness is at least 5%. In another embodiment, the distribution of the coating thickness is at least 6%. In another embodiment, the distribution of the coating thickness is at least 7%. In another embodiment, the distribution of the coating thickness is at least 8%. In another embodiment, the distribution of the coating thickness is at least 9%. In another embodiment, the distribution of the coating thickness is at least 10%. In another embodiment, the distribution of the coating thickness is at least 11%. In another embodiment, the distribution of the coating thickness is at least 12%. In another embodiment, the distribution of the coating thickness is at least 13%. In another embodiment, the distribution of the coating thickness is at least 14%.

[0186] For example, the difference in the coating thickness of different beads can be in the range of + / -1% - 7% based on the total weight of the coated beads. Based on the weight of the coated beads, the distribution of the coating thickness 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%.

[0187] In one embodiment, compared to other dosage forms of xanomeline or trospium chloride, the absorption (area under the curve, AUC) of this dosage form is advantageously increased upon oral administration. Without being bound by any theory, the increased absorption is affected by a dosage form that exhibits a pseudo - extended release profile. The pseudo - extended release profile is affected by one or more factors, including the distribution of the coating thickness (when present), the distribution of the bead particle size, and beads having an irregular bead shape. For example, in an embodiment where the beads have a distribution of coating thickness, for beads with a relatively thin coating, the coating dissolves relatively quickly and completely at the trigger pH to release the xanomeline and / or trospium chloride composition, while for beads with a relatively thick coating, it takes longer for the coating to completely dissolve and release the xanomeline and / or trospium chloride composition. In an embodiment where the beads have a particle size distribution and / or an irregular bead shape, the intestinal transit time of the beads can vary due to the bead size and / or shape, such that the transit time until the coating dissolution pH is reached varies, thus contributing to the pseudo - extended release profile. In another embodiment, when orally administered within a capsule shell or without a capsule shell, the dosage form exhibits substantially equivalent (e.g., bioequivalent) C 最大 and / or AUC characteristics.

[0188] In certain embodiments, the dosage form provides a stepwise and predictable absorption profile. In one embodiment, when administered orally, the T of the dosage form 最大 is more stable on a dose-to-dose basis because the beads are individually coated. The predictable, consistent T 最大 facilitates achieving a more consistent and sustained therapeutic effect. For example, process-related variations in coating thickness or other effects on coating dissolution only affect part of the xanomeline and trospium chloride in the dosage form. They tend to result in pseudo-extended release behavior. In contrast, coated capsules containing xanomeline and trospium chloride microspheres exhibit significant variability in absorption time between capsules.

[0189] In certain embodiments, an oral pharmaceutical composition comprises xanomeline and / or its salts and trospium chloride for treating a muscarinic disorder in a patient in need thereof, which, when administered to the patient in need, is sufficient to provide an in vivo plasma profile that comprises a median T of xanomeline of 2 hours 最大 and a median T of trospium chloride of 1 hour 最大 . In certain embodiments, the in vivo plasma profile further comprises an average 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 maximum average dose-normalized C of trospium chloride of 156 to 375 pg / mL / mg. In certain embodiments, the in vivo plasma profile further comprises an average dose-normalized AUC of xanomeline of 263 to 577 hr·pg / mL / mg 0-12 . In certain embodiments, the in vivo plasma profile further comprises an average dose-normalized AUC of trospium chloride of 881 to 2024 hr·pg / mL / mg 0-12 . In certain embodiments, the in vivo plasma profile further comprises an average C of trospium chloride of 7850 ± 3360 pg / mL 最大 . In certain embodiments, the in vivo plasma profile further comprises an average AUC of 41900 ± 15500 hr·pg / mL 0-12 .

[0190] In another embodiment, the dosage form exhibits favorable storage stability, e.g., as measured by the amount of xanomeline present after storage and / or by the total amount of related substances. Storage stability can be evaluated after storage under typical environmental conditions (e.g., 25 °C and 60% relative humidity) or under accelerated stability conditions involving elevated temperature and / or humidity.

[0191] Unless otherwise indicated, the expected dosage forms and methods include embodiments of any combination of one or more of the additional optional elements, features, and steps (including those shown in the figures and examples) further described below. References to beads and their properties apply equally to collections of beads (e.g., multiple such beads). Similarly, references to cores and their properties apply equally to collections of cores (e.g., multiple such cores).

[0192] Enteric (gastric resistant) coating materials (e.g., polymers) can be materials that will dissolve in intestinal fluids 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 substantially not in the upper part of the gastrointestinal (GI) tract. In one embodiment, the enteric material begins to dissolve in an aqueous solution at a pH of about 4.5 to about 5.5. In another embodiment, the enteric material rapidly dissolves in an aqueous solution at a pH of about 5. In another embodiment, the enteric material rapidly dissolves in an aqueous solution at a pH of about 5.5.

[0193] For example, the pH-sensitive material does not significantly dissolve until the dosage form has emptied from the stomach. The pH of the small intestine gradually increases from about 4.5 to about 6.5 in the duodenal bulb and then to about 7.2 in the distal part of the small intestine (ileum). To provide predictable dissolution corresponding to a small intestine transit time of about 3 hours (e.g., 2 - 3 hours) and allow reproducible release therein, the coating should begin to dissolve within the pH range of the duodenum and continue to dissolve within the pH range of the small intestine. Thus, the amount (thickness) of the enteric coating should substantially dissolve during a transit time of about three hours in the small intestine (e.g., proximal small intestine and mid-small intestine).

[0194] Suitable enteric (anti-gastric) materials include, but are not limited to, cross-linked polyvinylpyrrolidone; non-cross-linked polyvinylpyrrolidone; 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; carboxymethylcellulose; methylcellulose phthalate; methylcellulose succinate; methylcellulose succinate phthalate; methylcellulose phthalate semi-ester; ethylcellulose 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 monomers selected from: 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 -L and -S series, including L 100-55, L 30D-55, L 100, S 100, L 12.5, and S12.5, available from Evonik Industries); polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; zein; gluten; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic copolymer; 2-ethyl-hexyl acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamate / glutamate ester copolymer; carboxymethylethylcellulose glycerol monocaprylate; polyarginine; poly(ethylene); poly(propylene); poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride); and polyurethane. Combinations of enteric materials may also be used. In one embodiment, the enteric material dissolves rapidly at a pH of 5.5 and higher to provide rapid dissolution in the upper intestine. For example, the enteric material may 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 co ethyl acrylate) 1:1 (Eudragit TM L 30 D-55 and Eudragit TM L 100-55).

[0195] Other suitable examples of one or more enteric coatings include beeswax and glyceryl monostearate; beeswax, shellac, and cellulose; and cetyl alcohol, myrrh resin, and shellac, and shellac and stearic acid; polyvinyl acetate and ethylcellulose; and neutral copolymers of polymethacrylates (EudragitTM copolymers of methacrylic acid and methyl methacrylate, or neutral copolymers of polymethacrylates containing metal stearates. Such coatings comprise a mixture of fats and fatty acids, shellac and shellac derivatives, and cellulose acid phthalates, such as those having a free carboxyl component.

[0196] As is known in the art, one or more plasticizers can be added to enteric polymers to improve their flexibility and reduce brittleness. Suitable plasticizers include, for example, butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol (PEG, such as PEG6000), triethyl acetyl citrate, and triacetin. In one embodiment, the plasticizer is triethyl citrate. Although some enteric materials are flexible and do not require a plasticizer, more brittle polymers (such as Eudragit TM L / S type, Eudragit TM RL / RS and Eudragit TM FS 30 D) benefit from plasticizers, for example, in the range of 5 wt.% to 30 wt.%, about 8 wt.% to about 12 wt.% triethyl citrate with poly(methacrylic acid co - ethyl acrylate) 1:1, based on the dry polymer mass.

[0197] In certain embodiments, as is known in the art, enteric coatings comprise one or more anti - sticking agents (anti - tack agents) to reduce the stickiness of the film and prevent caking. Suitable anti - sticking agents include, but are not limited to, talc, glyceryl monostearate, fumed silica (such as Aerosil TM 200), precipitated silica (such as Sipernat TM PQ), and magnesium stearate. The anti - sticking agents can be used in any suitable amount, for example, in the 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 30 wt.%, based on the dry polymer mass. For example, in one embodiment, it ranges from 15 wt.% to about 30 wt.%, based on the dry polymer mass.

[0198] As is known in the art, one or more surfactants can 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 dodecyl sulfate, as well as other surfactants described herein.

[0199] Any suitable method can be used to form an 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 well-known methods. In liquid coating, an enteric material and optional excipients (e.g., pigments, plasticizers, anti-adhesives) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed onto a solid dosage form in a pan coater or fluidized bed dryer and dried with hot air. For example, in the Wurster fluidized bed coating method, the coating fluid is sprayed from the bottom of the fluidized bed apparatus. Alternatively, the coating fluid is applied by top spraying. In certain embodiments, tangential spraying is applied.

[0200] 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 <711> requirements (USP 36-NF 31) for a delayed release dosage form, such that less than 10.0 wt.% of the drug is released in 0.1N HCl after 2 hours. In certain embodiments, the formulation releases at least 80% of the active ingredient in a pH 6.8 buffer solution in 20 minutes, for example using the dissolution method of Section <711> of USP 36-NF 31.

[0201] In one embodiment, the amount of enteric coating present ranges from about 10% to 40%, or 25% to about 35% (as measured by weight gain compared to the uncoated particle core), or based on the weight of the uncoated particle core, ranges from about 25% to about 31% weight gain, about 27% to about 31% weight gain, or about 28.5% to about 31% weight gain.

[0202] The formulation may 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 of the enteric coatings described herein. During accelerated storage, gelatin capsules may collapse. Thus, in certain embodiments, the formulation may include a hydroxypropyl methylcellulose capsule shell.

[0203] Thus, for example, one embodiment that combines the various features described above includes a pharmaceutical dosage form that comprises a plurality of xanomeline beads, the beads comprising a core (the core comprising xanomeline tartrate, a filler (optionally microcrystalline cellulose), and a binder (optionally hypromellose)) and an enteric coating (optionally Eudragit) surrounding the core. TML30 D-55), wherein the particle size distribution of the plurality of beads ranges 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 placed in a capsule shell.

[0204] Bead Size and Shape

[0205] The plurality of beads has a particle size distribution. The plurality of beads has a bead shape. When present, the plurality of beads has a distribution of coating thickness.

[0206] Beads having a particle size distribution exhibit favorable pharmacokinetics. Without being bound by any theory, it is expected that the pharmacokinetics are affected by the plurality of beads having a core size distribution.

[0207] In one embodiment, the particle size of the beads ranges from 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 xanomeline beads have a size of about 0.425 mm to about 1.18 mm. In certain embodiments, the xanomeline beads have a size of about 0.6 mm to about 0.85 mm. In certain embodiments, the trospium chloride beads have a size of about 0.425 mm to about 1.18 mm. In certain embodiments, the trospium chloride beads have a size of about 0.6 mm to about 0.85 mm.

[0208] The beads or bead mixture can be used, for example, as a suspension, filled into a capsule, compressed into a tablet or filled into a sachet. One or more types of modified release beads can be mixed and encapsulated, or sprinkled on the subject's food for use. In certain embodiments, the oral solid dosage form can be any of these forms. In certain embodiments, the dosage form is a capsule.

[0209] 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 such that the drug is labeled as not being administrable via sprinkling (e.g., on applesauce or other soft foods (such as jelly)) and swallowing without chewing, or via an enteral feeding tube. Also, as the particle size increases, the larger particles are coated more than the smaller particles, resulting in a lower relative assay value for the smaller particles. Relatively more beads are required to meet the labeled strength per capsule. It becomes difficult or impossible to fill the capsule shell with particles large enough to meet the labeled strength per capsule (e.g., filling a size 0 capsule to a xanomeline free base strength of 75 mg).

[0210] In one embodiment, for example, beads are formulated into capsules using a encapsulation machine. Various capsule sizes can accommodate the strength and fill weight of the target formulation. For fill weights ranging from about 15 mg to about 630 mg, the capsule size ranges from 00 to 5.

[0211] The beads can be sorted (e.g., via screening) into a desired particle size. In certain embodiments, the particle size range is any of the particle size ranges or combinations thereof described above for the core. In one embodiment, the particle size range is the same as that of the uncoated core. For example, the beads can be screened such that 5% or less by weight of the bead cores remain on a #12 mesh (1.68 mm) screen and 10% or less by weight pass through a #20 mesh (0.84 mm) screen.

[0212] Preparation Method

[0213] A method of preparing an oral pharmaceutical composition is provided, the method comprising mixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium chloride beads comprising trospium chloride salt (such as trospium chloride). In certain embodiments, the method further comprises formulating the mixed beads into capsules.

[0214] Also disclosed herein is a method of preparing a dosage form, the method 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, the drug beads are sorted (e.g., via screening) to a desired particle size range before the enteric coating, and optionally after the enteric coating.

[0215] These drug beads can be made by different methods, including but not limited to rolling the extruded wet mass and coating an inert core sphere in a fluidized bed. In certain embodiments, the beads are prepared by extrusion and rolling.

[0216] The beads are formulated to be free-flowing and compatible with modern encapsulation equipment. In some embodiments, the beads are blended to form a homogeneous mixture, which can be filled into capsules in a single stage. In other embodiments, a two-stage capsule filling machine is used to fill the beads into capsules separately.

[0217] Any suitable method can form a core comprising xanomeline or a pharmaceutically acceptable salt thereof. In one embodiment, the core is formed by granulating and grinding a mixture of xanomeline 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 rolling a mixture of xanomeline or a pharmaceutically acceptable salt thereof and an excipient.

[0218] Any suitable method can be used to form a core comprising trospium chloride or a pharmaceutically acceptable salt thereof. In one embodiment, the core is formed by granulating and milling 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.

[0219] Granulation methods can include fluid bed granulation, wet granulation, hot melt granulation, and spray congealing. Other methods include slugging and roller compaction. First, the mixture to be granulated is dry blended. The dry ingredients of the dry blend can be mixed with water prior to extrusion.

[0220] Extruding and spheronizing a mixture of xanomeline or a pharmaceutically acceptable salt thereof and trospium chloride with an excipient provides a desired core having a particle size distribution and one or more other desired properties as described herein. In certain embodiments, shorter processing times can result in a more stable product. For example, reducing spheronization reduces friction and associated heat, and reducing the time the product is exposed to air (when moist and / or prior to packaging) reduces oxidation. On the other hand, rapid processing by extrusion and spheronization can result in a poor quality product, e.g., such that most of the bead cores fall outside the desired particle size range. The water absorbed by the spheronization aid (over time) affects the spheronization characteristics of the beads.

[0221] Accordingly, in one embodiment, the moisture content of the granulation mixture ranges from about 20 wt.% to about 40 wt.% prior to drying, such as 25 wt.% to about 35 wt.%, about 28 wt.% to about 32 wt.%, at least about 28 wt.%, at least about 28.5, about 20 wt.% to about 40 wt.%, about 25 wt.% to about 35 wt.%, about 27 wt.% to about 31 wt.%, or about 28.5 wt.% to about 31 wt.%.

[0222] In certain embodiments, the wet mass can be held prior to extrusion to allow the spheronization aid to swell with the granulation fluid. The hold time can 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 about 30 to 100 minutes, or 60 to 90 minutes.

[0223] As described above with respect to the core, the method can include the step of sorting the cores (e.g., by screening) prior to optional coating to retain the particles within a predetermined size range, such as a size range of about 0.7 mm to about 2.8 mm, such as about 0.7 mm to about 2.5 mm, about 0.8 mm to about 1.7 mm, or any range described herein.

[0224] As described above with respect to the beads, the method can include the following steps: sorting the beads (e.g., by sieving) after optional coating to retain the particles within a size range, such as a size range of from about 0.7 mm to about 2.8 mm, such as from about 0.7 mm to about 2.5 mm, or from about 0.8 mm to about 1.7 mm, or any range described herein.

[0225] In the extrusion and spheronization methods, the following optional features can be used alone or in any combination thereof. Water can be a granulating agent. Microcrystalline cellulose can be used as a spheronization aid in the core. Hydroxypropyl methylcellulose can be included as a binder in the core. 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 grid lines 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 from 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., irregularly shaped), such as a large portion thereof, such as 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.%.

[0226] In certain embodiments, the pharmaceutical composition is stored with a desiccant, such as pharmaceutical grade silica gel, crystalline sodium aluminosilicate, potassium aluminosilicate or calcium aluminosilicate, colloidal silica, anhydrous calcium sulfate, etc.

[0227] In certain embodiments, the pharmaceutical composition is stored with an oxygen absorber.

[0228] In certain embodiments, the pharmaceutical composition is stored under a dry inert gas (such as nitrogen, helium, argon, neon, xenon, krypton, or a mixture thereof).

[0229] In certain embodiments, the pharmaceutical composition is stored under reduced pressure compared to the external ambient air.

[0230] In certain embodiments, the pharmaceutical composition is stored at a reduced temperature (e.g., at refrigerated temperature (e.g., 2°C to 8°C)). In certain embodiments, the pharmaceutical composition is stored in a manner that has fewer impurities (such as impurity A) compared to when stored at 25°C.

[0231] In certain embodiments, the oral pharmaceutical composition is stored by the manufacturer, distributor, pharmacy, or hospital at a temperature of about 2°C to about 8°C before being dispensed to a subject. In certain embodiments, the oral pharmaceutical composition is stored at a temperature of about 20°C to about 25°C after being dispensed to a subject.

[0232] 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.

[0233] In certain embodiments, a method of preparing a pharmaceutical dosage form comprising xanomeline beads includes 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 into a target particle size range (optionally about 0.7 mm to about 2.5 mm), coating the sorted cores with a polymer to form beads comprising the cores and the coating, and sorting the bead particles into a target particle size range (optionally about 0.7 mm to about 2.5 mm).

[0234] In certain embodiments, a method of preparing a pharmaceutical dosage form comprising trospium chloride beads includes 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 into a target particle size range (optionally about 0.7 mm to about 2.5 mm), coating the sorted cores with a polymer to form beads comprising the cores and the coating, and sorting the bead particles into a target particle size range (optionally about 0.7 mm to about 2.5 mm).

[0235] Purity

[0236] Also provided is the compound 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium.

[0237] There is also provided 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, such as 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.%. There is also provided 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).

[0238] There is also provided an oral pharmaceutical composition comprising a plurality of xanomeline beads, the plurality of xanomeline beads comprising xanomeline 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; and a plurality of trospium chloride beads containing a trospium chloride salt. There is also provided an oral pharmaceutical composition comprising a plurality of xanomeline beads, the plurality of xanomeline beads comprising xanomeline 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; and a plurality of trospium chloride beads containing a trospium chloride salt.

[0239] In certain embodiments, after storing the pharmaceutical composition at 40 °C and 75% relative humidity for at least 3 months, the pharmaceutical composition comprises less than 0.5 wt.% of Impurity A.

[0240] 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.

[0241] Treatment methods

[0242] There is further provided a method of activating muscarinic receptors in a biological sample, the method comprising contacting the biological sample with any of the oral pharmaceutical compositions described herein. There is also provided a method of treating a disorder alleviated by activating muscarinic receptors in a subject in need thereof, the method comprising administering to the subject in need thereof any of the oral pharmaceutical compositions described herein.

[0243] Although M1 and M4 muscarinic receptor agonists are considered effective treatments for schizophrenia, activation of muscarinic receptors located outside the brain causes side effects that have precluded the clinical use of xanomeline. For example, in phase I and subsequent trials, the muscarinic agonist xanomeline had unacceptable gastrointestinal (GI) and other side effects that were associated with binding of the muscarinic receptor in peripheral regions of the 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.

[0244] The tolerability of the muscarinic agonist xanomeline can be improved by co - administration with the muscarinic antagonist trospium chloride. The most common adverse events observed upon administration of xanomeline are nausea, vomiting, diarrhea, excessive sweating, and excessive salivation (so - called cholinergic adverse events). The most common anticholinergic adverse event observed upon administration of trospium chloride is dry mouth (xerostomia). The disclosed compositions reduce the incidence of these adverse events in humans, thus demonstrating improved xanomeline tolerability. In certain embodiments, after at least 4 weeks of treatment, the occurrence of cholinergic or anticholinergic adverse events is not statistically distinguishable from placebo controls. In certain embodiments, after at least 4 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.

[0245] In one embodiment, xanomeline is combined with trospium chloride to treat an animal. In additional embodiments, the animal is a mammal. In an embodiment, the mammal is a human.

[0246] 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. When xanomeline cannot be used clinically due to its side effects, the use of trospium chloride together with xanomeline allows xanomeline to be used clinically. In another embodiment, the use of trospium chloride together with xanomeline allows xanomeline to achieve a higher maximum tolerated dose than xanomeline could achieve on its own.

[0247] A variety of time- and resource-intensive methods have demonstrated the combined efficacy of xanomeline and trospium chloride. For example, animal models have demonstrated the efficacy of the new therapeutic agent for schizophrenia, including pharmacological models (such as the ketamine model) and genetic models (such as 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 limitations in terms of physiological differences between humans and animals and may have limited predictive ability for human experiments (especially for central nervous system disorders). Alternatively, the disclosed combinations 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 evaluate 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 evaluating 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 while the other group receives an active intervention.

[0248] 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 two types of schizophrenia symptoms as defined by the American Psychiatric Association: positive symptoms and negative symptoms. Positive symptoms refer to an excess or distortion of normal function (e.g., hallucinations and delusions), and negative symptoms represent a reduction or loss of normal function. Some of the functions that may be lost include normal thinking, action, the ability to distinguish fantasy from reality, and the ability to express emotions correctly.

[0249] PANSS is a relatively brief interview of about 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, including 7 items (minimum score = 7, maximum score = 49): delusions, confusion, hallucinations, excitement, exaggeration, suspicion / persecution, and hostility. The second category is a negative scale, including 7 items (minimum score = 7, maximum score = 49): emotional blunting, 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.

[0250] The PANSS Marder factor score is the sum of five negative scales and two general scales (N1. Blunted affect; N2. Emotional withdrawal; N3. Impaired emotional communication; N4. Passive / indifferent social withdrawal; N6. Lack of spontaneity; G7. Slow movement; and G16. Active social avoidance). If a patient had a record of a PANSS assessment but any of these items were missing, the last non-missing score for that individual item from the previous assessment was continued to be used. If more than 30% of the items were missing at a particular follow-up, the corresponding positive score was not calculated. It was treated as missing data in the analysis.

[0251] Because the lowest score given for each item is 1 instead of 0, the patient's total PANSS score cannot be less than 30. Subscores can be given separately for positive items, negative items, and general psychopathology. The highest possible total score is 210. In the original publication of the PANSS scale, 101 adult patients with schizophrenia (20-68 years old) 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.

[0252] 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.

[0253] Another scale used to evaluate patients is the Clinical Global Impression - Severity scale (CGI - S). This 7 - point scale asks clinicians to rate the severity of the patient's illness at the time of evaluation relative to the clinician's experience with patients having the same diagnosis. The 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, the changes in CGI - S follow a consistent pattern relative to the more objective PANSS scores.

[0254] Before administering the disclosed combination, the patient may have a lead - in period of one to fourteen days, during which time trospium chloride for the lead - in period is administered alone. In one embodiment, one or more dosing periods of trospium chloride are administered before administering xanomeline to accumulate trospium chloride in the body or to bring trospium chloride to or near a steady - state exposure level. This accumulation or higher exposure level of trospium chloride increases the blockade of muscarinic receptors outside the brain and reduces adverse events when xanomeline is administered. In another embodiment, trospium chloride is administered one day or more days before xanomeline.

[0255] Before administering the disclosed combination, the patient may discontinue any previously used antipsychotic drugs. In some embodiments, the patient will discontinue such drugs for at least one week, such as two weeks. In some embodiments, the patient does not discontinue any previously used such antipsychotic drugs, and the disclosed combination is co - administered with such drugs.

[0256] In one embodiment, xanomeline and trospium chloride are administered to the patient 6 times during a 24 - hour period. In another embodiment, xanomeline and trospium chloride are administered to the patient 5 times during a 24 - hour period. In another embodiment, xanomeline and trospium chloride are administered to the patient 4 times during a 24 - hour period. In an embodiment, xanomeline and trospium chloride are administered to the patient 3 times during a 24 - hour period. In another embodiment, xanomeline and trospium chloride are administered to the patient twice during a 24 - hour period. In another embodiment, xanomeline and trospium chloride are administered to the patient once during a 24 - hour period.

[0257] In one embodiment, the extended release formulation of trospium chloride is used in combination with xanomeline. In another embodiment, the extended release agent of trospium chloride is administered to a patient one to five times during a 24-hour period. In an embodiment, the extended release agent of trospium chloride is administered one to three times during a 24-hour period. In another embodiment, an extended release agent of trospium chloride from five milligrams to 400 milligrams is used during a 24-hour period. In an embodiment, an extended release agent of trospium chloride from 20 milligrams to 200 milligrams is used during a 24-hour period.

[0258] In one embodiment, 225 mg of xanomeline and 40 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 100 mg of xanomeline and 20 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 125 mg of xanomeline and 20 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 125 mg of xanomeline and 30 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 125 mg of xanomeline and 40 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 200 mg of xanomeline and 40 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 200 mg of xanomeline and 80 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 250 mg of xanomeline and 60 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 250 mg of xanomeline and 80 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 300 mg of xanomeline and 40 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 300 mg of xanomeline and 60 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 300 mg of xanomeline and 80 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 350 mg of xanomeline and 40 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 350 mg of xanomeline and 60 mg of trospium chloride are administered to a patient during a 24-hour period. In another embodiment, 350 mg of xanomeline and 80 mg of trospium chloride are administered to a patient during a 24-hour period.

[0259] Treatment can be started at a lower 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 health of the patient can be monitored by measuring one or more relevant metrics at predetermined times during the treatment period. The treatment can be adjusted based on such monitoring, including composition, amount, administration, and frequency of formulation. The patient can be re-evaluated periodically to determine improvement by measuring the same parameters. Adjustments to the disclosed compositions administered and possibly to the administration times can be made based on these re-evaluations.

[0260] There is provided a method of treating schizophrenia or a schizophrenia-related disorder in a patient in need thereof, the method comprising: orally administering to the patient, twice daily via a titration regimen, 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 salt of trospium chloride, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the salt of trospium chloride.

[0261] There is also provided a method of treating schizophrenia or a schizophrenia-related disorder in a patient in need thereof, the method comprising: orally administering, twice daily via a titration regimen, 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 salt of trospium chloride, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the salt of trospium chloride until an amount equivalent to 125 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered.

[0262] In certain embodiments, the 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 time for which the xanomeline is administered is from 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.

[0263] In certain embodiments, the method further comprises administering the xanomeline or a salt thereof in the 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 for which the 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.

[0264] In certain embodiments, trospium chloride 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 trospium chloride is equivalent to 20 mg of trospium chloride. In certain embodiments, the first period of time for trospium chloride administration is at least one week. In certain embodiments, the second amount of trospium chloride is equivalent to 30 mg of trospium chloride.

[0265] In certain embodiments, if a patient is intolerant to a higher dose of xanomeline or its salt, and trospium chloride, the amount of xanomeline or its salt, and trospium chloride administered to the patient is reduced.

[0266] In certain embodiments, xanomeline or its salt, and trospium chloride are administered without causing serious adverse events.

[0267] "Blood pressure" refers to the pressure of circulating blood on the walls of blood vessels. Most of this pressure is caused by the heart pumping blood through the circulatory system. When used without further specification, "blood pressure" generally refers to the pressure in the large arteries of the systemic circulation. Blood pressure is typically expressed as systolic pressure (the maximum value during one heartbeat) relative to diastolic pressure (the minimum value between two heartbeats), and is measured in millimeters of mercury (mmHg) above ambient atmospheric pressure. The 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".

[0268] Adverse events related to blood pressure involve adverse medical events that affect systolic or diastolic blood pressure, or changes in systolic or diastolic blood pressure, including hypertension, hypotension, and syncope (fainting). In certain embodiments, xanomeline or its salt, and trospium chloride are administered without causing a change in diastolic blood pressure of more than about 5 mmHg. In certain embodiments, xanomeline or its salt, and trospium chloride are administered without causing a change in systolic blood pressure of more than about 5 mmHg. In certain embodiments, xanomeline or its salt, and trospium chloride are administered without causing serious adverse events related to blood pressure. In certain embodiments, xanomeline or its salt, and trospium chloride are administered without causing serious adverse events related to changes in blood pressure.

[0269] "Heart rate" refers to the speed of the heartbeat measured as the number of heart 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 the normal resting heart rate for an adult is 60 - 100 bpm. Tachycardia is a rapid 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 the heart beats slowly and the heart rate is around 40 - 50 bpm, which is common and normal. When the heart beats in an irregular manner, it is called arrhythmia.

[0270] Adverse events related to heart rate involve adverse medical events, including tachycardia, bradycardia, and arrhythmia. In certain embodiments, administering xanomeline or a salt thereof, and trospium chloride does not result in serious adverse events related to heart rate. In certain embodiments, administering xanomeline or a salt thereof, and trospium chloride does not result in serious adverse events related to heart rate changes.

[0271] Liver function tests (LFT or LF), also known as a hepatic panel, are a group 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), liver transaminases aspartate transaminase (AST or SGOT), alanine transaminase (ALT or SGPT), etc. The tests assess the functionality (e.g., albumin), integrity (e.g., transaminases), and biliary-related conditions (γ-glutamyl transferase and alkaline phosphatase) of a patient's blood sample.

[0272] In certain embodiments, administering xanomeline or a salt thereof, and trospium chloride does not increase liver function tests (LFT). In certain embodiments, administering xanomeline or a salt thereof, and trospium chloride does not cause an elevation in LFT. In some embodiments, the liver function tests are selected from prothrombin time (PT / INR), aPTT, albumin, bilirubin (direct and indirect), liver transaminases aspartate transaminase (AST or SGOT), and alanine transaminase (ALT or SGPT). In some embodiments, administering xanomeline or a salt thereof, and trospium chloride does not increase at least one of ALT, AST, Alk phos, or bilirubin. In some embodiments, administering xanomeline or a salt thereof, and trospium chloride does not increase ALT, AST, Alk phos, or bilirubin.

[0273] The present disclosure further provides a method of treating acute psychosis in a patient in need thereof. The method includes orally administering to the patient an oral pharmaceutical composition twice a day, the oral pharmaceutical composition comprising xanomeline or a salt thereof, and trospium chloride.

[0274] In certain embodiments, an average reduction of at least about 11.6 points in the PANNS total score is achieved. In certain embodiments, an average reduction of at least 3 points in the PANSS positive subscore compared to placebo is achieved. In certain embodiments, a reduction of at least 2 points in the PANSS negative subscore compared to placebo is achieved. In certain embodiments, a reduction in the PANSS score is achieved within about 5 weeks. In certain embodiments, the patient has a Clinical Global Impression - Severity Scale (CGI - S) score of 4 - 7 before administering the oral pharmaceutical composition.

[0275] In certain embodiments, the patient is diagnosed with schizophrenia. In certain embodiments, the patient has acute psychosis. In certain embodiments, the patient has psychosis associated with Alzheimer's disease. In certain embodiments, the patient has schizoaffective disorder. In certain embodiments, the patient has psychosis. In certain embodiments, the patient has delusional disorder. In certain embodiments, the patient has psychosis associated with Parkinson's disease. In certain embodiments, the patient has psychotic depression. In certain embodiments, the patient has bipolar disorder. In certain embodiments, the patient has bipolar disorder with psychosis. In certain embodiments, the patient has Huntington's disease. In certain embodiments, the patient has Lewy body dementia.

[0276] In certain embodiments, the patient has previously been administered one or more antipsychotics. In certain embodiments, the patient has an inadequate response to such administration. In certain embodiments, the patient has treatment resistance.

[0277] In certain embodiments, the patient is an adult. In certain embodiments, the patient is an elderly person, for example, over 65 years of age. In certain embodiments, the patient has dementia-related psychosis.

[0278] Example

[0279] The following examples are provided for illustration and are not intended to limit the scope of the present disclosure.

[0280] Example 1 - Immediate Release Beads

[0281] Beads of xanomeline tartrate (Table 1) and trospium chloride (Table 2) were prepared.

[0282] Table 1: Xanomeline tartrate (66%) beads without talc

[0283] Ingredient % w / w (Dry Basis Weight) g / Batch Xanomeline Tartrate 66 99 Microcrystalline Cellulose 34 51 Purified Water* (30) (45) Total: 100 150

[0284] * Removed during drying.

[0285] Table 2: Trospium chloride (17.7%) beads without talc

[0286] Ingredient % w / w (Dry Basis Weight) g / Batch Trospium Chloride 17.7 17.7 Microcrystalline Cellulose 35 35 Lactose Monohydrate 47.3 47.3 Purified Water* (45) (45) Total: 100 100

[0287] * Removed during drying.

[0288] The powder was sieved using a Quadro Comil model 197 equipped with a 457-μm round-hole sieve 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 min. The dry blending step is optional as blending uniformity is driven by the subsequent wet granulation. The beads were screened by hand through a 40-mesh (425-μm) sieve.

[0289] Wetting was carried out in a Hobart. Water was added using a Cole-Parmer peristaltic pump. The water addition rate (amount of water / time given) is a process variable.

[0290] The wet mass was extruded through a porous sieve (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 holding time, shaft speed, and extrusion rate (load) are process variables.

[0291] The extrudate was placed in an LCI Marumerizer QJ-230T equipped with a 2.0-mm friction plate. The extrudate was rounded at different plate speeds for a total of no more than 4 min. The rounding speed and time are process variables.

[0292] Using Aeromatic TM The beads were dried in a Strea-1 fluidized bed at an inlet temperature of 60 °C until the water content obtained was no more than 3%. The beads melted after a few minutes at 60 °C, so the beads were dried at 30 °C.

[0293] The water content was evaluated gravimetrically by loss on drying (LOD) using an HR83 Mettler Toledo halogen moisture analyzer. The beads were heated at 105 °C until the weight loss rate dropped to less than or equal to 0.0% within 60 s.

[0294] Table 3: Extrusion / rounding processing parameters

[0295]

[0296]

[0297] Example 2 - Scale-up of immediate-release bead formulation

[0298] The beads of Example 1 with and without talc were scaled up (Tables 4 - 7). The extrusion / rounding processing parameters are shown in Table 8.

[0299] Table 4: Xanomeline tartrate (66%) beads without talc

[0300] Ingredient % w / w (Dry Basis Weight) g / Batch Xanomeline Tartrate 66 660 Microcrystalline Cellulose 34 340 Purified Water* (24) (240) Total: 100 1000

[0301] *Removed during drying.

[0302] Table 5: Xanomeline tartrate (66%) beads with talc

[0303]

[0304]

[0305] Abbreviations: Ph.Eur = European Pharmacopoeia, USP = United States Pharmacopoeia

[0306] *- Evaporated during processing and thus not included in the total weight

[0307] Table 6: Trospium chloride (17.7%) beads without talc

[0308] Ingredient % w / w (Dry Basis Weight) g / Batch Trospium Chloride 17.7 88.7 Microcrystalline Cellulose 35 175.0 Lactose Monohydrate 47.3 236.3 Purified Water* (59) (295) Total: 100 500

[0309] *Removed during drying.

[0310] Table 7: Trospium chloride (17.7%) beads with talc

[0311]

[0312] Abbreviations: NF = National Formulary, Ph.Eur = European Pharmacopoeia, USP = United States Pharmacopoeia. *- Evaporated during processing

[0313] Table 8: Extrusion / spheronization processing parameters

[0314]

[0315] Example 3 - Capsule stability and dissolution testing

[0316] 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 is referred to as "KarXT". KarXT can be formulated in a variety of dose strengths, for example, as exemplified below: KarXT 50 / 10, KarXT 50 / 20, and KarXT 75 / 20, where the number before the slash is the milligram number of xanomeline free base (X) in the composition, and the number after the slash is the milligram number of trospium chloride (T) in the composition.

[0317] Capsules were produced by weighing the beads and manually filling them into HPMC capsules. Using an Accofil TM capsule filling machine, the beads were manually encapsulated, where the beads premixed with talc (0.5%) were filled into the capsules separately / one by one, as shown in Table 19.

[0318] Table 9: Composition of xanomeline / trospium chloride capsules. Ingredients are listed in milligrams per capsule.

[0319]

[0320] After drying, the beads were screened by shaking for 5 min through a 16-mesh (1.18 mm) and a 40-mesh (0.425 mm) sieve. Beads with sizes between 1.18 mm and 0.425 mm were retained for further analysis.

[0321] The morphology and surface features of the beads were examined by scanning electron microscopy (SEM) using a JSM-6010LV InTouchScope TM (JEOL Ltd, Tokyo, Japan) microscope with a backscattered electron detector (BES). The samples were placed on metal stubs using double-sided carbon conductive tape. Images were obtained at an accelerating voltage of 20 kV at low vacuum (60 Pa) and a magnification of 30×.

[0322] The tapped density tester (JV 1000, Copley Scientific) was used to determine the bulk density and tapped density in duplicate using the USP <616> method. The bulk density was measured from the volume of a powder sample of known mass in a graduated cylinder. The tapped density was measured by mechanically tapping the graduated cylinder until the volume no longer changed.

[0323] The powder flow properties were evaluated using Carr's Compressibility Index and Hausner ratio. Both were derived from the measurements of bulk density and tapped density. Carr's Compressibility Index (CI) was calculated using bulk density and tapped density data when fitted to the following equation: Compressibility Index = (tapped density - bulk density) / tapped density × 100%. The Hausner ratio (H) was calculated as the ratio of tapped density to bulk density. The appearance, assay, related substances, water content, and dissolution of the capsules were analyzed.

[0324] The further dimensions of the beads are between 0.6 mm and 0.85 mm. Some beads exhibit similar morphological properties. Modifications in some of the other beads reduce the density of the beads and result in a rough surface and loss of sphericity. Scanning electron microscope (SEM) images of xanomeline tartrate 66% beads and trospium chloride 17.7% beads at 30x magnification show that the dimensions of these beads are between 0.6 mm and 0.85 mm. These beads are used in xanomeline / trospium capsules. The particle size distribution (PSD) of the beads is determined by mechanical sieving. As shown in Table 10, the majority of the beads of both APIs are between 0.425 mm and 1.18 mm in size.

[0325] Table 10: Particle Size Distribution of Beads by Mechanical Sieving

[0326]

[0327] Table 11 shows the density and flow properties of the beads collected between the 0.425 mm and 1.18 mm sieves. Xanomeline tartrate and trospium chloride IR beads show different density and flow properties, which may be crucial when mixing bead systems.

[0328] Table 11: Density and Flow Properties of 0.425 - 1.18 mm Beads

[0329]

[0330]

[0331] The analysis in Table 12 shows good results in the following aspects: assay and related substances, and moisture content of the 50 mg xanomeline and 20 mg trospium chloride capsules. The data in Table 13 show that these properties are retained during the storage stability study. Similar data for the 50 mg xanomeline and 10 mg trospium chloride capsules are provided in Table 14. Dissolution data for these two dosage forms are provided in Tables 15 and 16.

[0332] Table 12: Analysis Results

[0333]

[0334] Table 13: Stability of KarXT 50 / 20

[0335]

[0336]

[0337] Table 14: Dissolution of KarXT 50 / 20

[0338]

[0339]

[0340]

[0341] Table 15: Assay and related substances of KarXT 50 / 10

[0342]

[0343]

[0344] Table 16: Dissolution of KarXT 50 / 10

[0345]

[0346]

[0347]

[0348] Subsequent tests showed that KarXT 50 / 10, 50 / 20, and 75 / 20 in hard gelatin capsules were stable for at least 12 months at 25°C / 60% RH. Based on the available data, a shelf life of 15 months at 25°C / 60% RH is recommended.

[0349] The dissolution results showed that the two compounds were rapidly released, which could increase their bioavailability. Although there were significant differences in the composition between the two bead formulations, they were released at a comparable rate. Both xanomeline and trospium chloride had low bioavailability, and rapid release could increase bioavailability by overriding saturable processes that limit absorption into the systemic circulation.

[0350] During the stability study of the combination drug product, an unknown xanomeline impurity with a relative retention time of approximately 1.09 was observed. 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, and it occurred simultaneously for both. The impurity peak increased over time and with increasing storage temperature. This impurity had not been observed prior to this study.

[0351] Preliminary studies indicated that the RRT 1.09 impurity was 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium (C 14 H 20 N3O2S + , MW = 294.1271 Da):

[0352]

[0353] The RRT 1.09 impurity is the hydroxylated form of Compound V (C 14 H 20 N3OS + , MW = 278.1322 Da), which is the penultimate intermediate with negative mutagenic potential in xanomeline synthesis:

[0354]

[0355] To reduce the presence of the impurity, the storage temperature of the drug was lowered. During packaging, the bottles were flushed with argon to minimize the oxygen in the headspace. In certain embodiments, the xanomeline bead formulation was formulated with an antioxidant (such as 0.5 wt.% ascorbic acid or 0.05 wt.% BHT).

[0356] Example 4 - Phase I Study of KAR-001 of the Combination of Xanomeline and Trospium Chloride

[0357] In normal healthy volunteers, a Phase I, double-blind, randomized, multi-dose pilot study was conducted comparing the administration of xanomeline alone with the administration of xanomeline and trospium chloride together. The primary objectives of this study were (1) to evaluate the safety and tolerability of: administering 225 mg of xanomeline per day and 40 mg of trospium chloride per day for 7 days, compared to administering 225 mg of xanomeline alone per day for 7 days; and (2) to determine whether adding 40 mg of trospium chloride (20 mg BID) per day to 225 mg of xanomeline (75 mg TID) for 7 days compared to 225 mg of xanomeline alone per day significantly reduces peripheral cholinergic side effects (nausea, diarrhea, vomiting, sweating, excessive salivation). Table 17 lists the parameters of this study.

[0358] Table 17: Parameters of the KAR-001 Study

[0359]

[0360]

[0361]

[0362] A total of seventy study subjects were randomly assigned, and 68 of the study subjects received at least one assessment on Day 3 (i.e., the first day of xanomeline administration). Table 18 lists the demographics of the study subjects.

[0363] Table 18: Demographics of the KAR-001 Study Subjects

[0364]

[0365] The most common adverse events with xanomeline were the so-called cholinergic adverse events of nausea, vomiting, diarrhea, excessive sweating, and hypersalivation. In this study, coadministration of trospium chloride with xanomeline resulted in a 43% reduction in the incidence of cholinergic adverse events compared to xanomeline coadministered with placebo (statistically significant (p = 0.016)). In the xanomeline + placebo group of the study, 63% of subjects reported at least one cholinergic adverse event, compared with only 34% of subjects in the xanomeline + trospium chloride group of the study reporting such an event.

[0366] Further, in this study, the incidence of each individual cholinergic adverse event was also reduced in subjects receiving xanomeline + trospium chloride compared to the incidence in subjects receiving xanomeline + placebo. The reduction in the incidence of sweating was itself statistically significant, with an incidence of 20.0% in the xanomeline + trospium chloride group compared with 48.5% in the xanomeline + placebo group, a 59% reduction (p = 0.013).

[0367] The overall incidence of cholinergic adverse events in the xanomeline + trospium chloride group in this study was very similar to the 32% incidence reported in subjects receiving placebo + placebo during a two-day run-in period. Although these two data points did not occur during different time periods of the study, the fact that the incidence of cholinergic adverse events 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.

[0368] 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 the chi-square test, except those marked with an asterisk, which are based on Fisher's exact test.

[0369] Table 19: Cholinergic Adverse Events

[0370]

[0371] There were no meaningful differences between the treatment groups with respect to heart rate, resting blood pressure, orthostatic blood pressure, or electrocardiogram (ECG) parameters, including QT. A small number of subjects in both treatment groups had transient increases in heart rate and orthostatic blood pressure changes, which could contribute to syncope and postural dizziness in those subjects. Two subjects (both in the individual xanomeline group) experienced syncope. The incidence of orthostatic adverse events in the xanomeline + trospium chloride group was approximately half that of subjects in the individual xanomeline group. In the xanomeline + trospium chloride group, only one subject discontinued due to a treatment-emergent adverse event related to blood pressure.

[0372] In addition to evaluating whether the addition of trospium chloride can improve the tolerability of xanomeline, this study also provided data on the overall safety and tolerability of xanomeline + trospium chloride. Table 20 shows good tolerability of the combination, with no severe or critical adverse events, and most adverse events being mild.

[0373] Table 20: Tolerability

[0374]

[0375] The tolerability profile of this study allows for future combination studies of xanomeline and trospium chloride.

[0376] Example 5 - Phase I Study of KAR - 003 of KarXT (Combination Formulation of Xanomeline + Trospium Chloride)

[0377] This study was a Phase 1, randomized, multi - dose, adaptive - design inpatient study to evaluate the safety and tolerability of KarXT in normal healthy volunteers aged 18 to 60 years. Subjects signed an informed consent form and underwent screening evaluations from day - 21 to day - 1. After completing all screening evaluations, subjects returned to the study clinic on day 0 for baseline safety assessment and were enrolled in the study. They were randomly assigned in a 3:1 ratio to one of two treatment groups in each cohort: KarXT or placebo. Subjects were assigned to one of 4 cohorts (cohort 1, 2, 3, or 4).

[0378] The study drug was administered BID from day 1 to day 7. A combined - dose formulation of xanomeline and trospium chloride was used in all cohorts. All cohorts started with a 2 - day lead - in of KarXT 50 / 20 BID (for subjects randomly assigned to active treatment); after the 2 - day lead - in period, a non - blinded pharmacist distributed the study drug to each subject according to their random assignment for 5 days of assigned - cohort dosing, for a total of 7 days of treatment. A matching placebo was administered throughout the study to maintain blinding. For cohorts 2 to 4, a sentinel group was introduced into the study. It was monitored for safety and tolerability by a Data Safety Evaluation Group (DSEG) so that approximately 30% of the subjects in the proposed cohort had been treated and had safety evaluations before dosing the remaining subjects in the cohort. Subjects and study - clinic personnel were blinded to the treatment. The Dose - Selection Committee (DSC) was non - blinded to decide on the doses for subsequent treatment groups.

[0379] Serial blood samples were drawn on Days 1, 3, and 7 for PK assessment of xanomeline and trospium chloride. Additional blood was collected at regular intervals to monitor the trough concentrations of xanomeline and trospium chloride and for clinical laboratory assessments. On Day 1, saliva volume was collected twice. Saliva volume was measured before dosing on Day 1 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 pupillary size measurement and Bristol Stool Scale assessment. Subjects remained in the study clinic throughout the treatment period (7 days). After safety assessment on Day 8, subjects were discharged from the study clinic and were asked to return approximately 14 days after administration of the study drug for a final safety assessment.

[0380] During the study, after a 2-day lead-in of KarXT 50 / 20 BID (for subjects randomized to active treatment) in each cohort, subjects were dosed as follows:

[0381] · In Cohort 1, subjects completed dosing with KarXT 100 / 20 BID (total daily dose (TDD) of 200 mg of xanomeline + 40 mg of trospium chloride) or placebo from Day 3 to Day 7.

[0382] · In Cohort 2, the sentinel group (Group 2a) discontinued dosing after the morning dose on Day 4. The dose for subjects in Cohort 2 was KarXT 150 / 20 BID (TDD of 300 mg of xanomeline + 40 mg of trospium chloride) or placebo. Dosing in Cohort 2 was discontinued (per DSEG decision based on observed tolerability issues). Since 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 sentinel group of Cohort 3 (Group 3a).

[0383] · In Cohort 3, the sentinel group (Group 3a) completed dosing with KarXT 150 / 40 BID (TDD of 300 mg of xanomeline + 80 mg of trospium chloride) or placebo from Day 3 to Day 7. The second group in Cohort 3 (Group 3b) discontinued dosing after the morning dose on Day 5.

[0384] · In Cohort 4, the sentinel group (Group 4a), the second group (Group 4b), and the remaining group (Group 4c) completed dosing with KarXT 125 / 40 BID (TDD of 250 mg of xanomeline + 80 mg of trospium chloride) or placebo from Day 3 to Day 7.

[0385] Ninety-six subjects were planned, 248 subjects were screened, 69 subjects were randomly assigned, 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 if they had a history or presence of any disease or disorder, including psychiatric or neurological disorders, that would compromise the safety of the subject or that the investigator considered would compromise the validity of the study results. Table 21 summarizes the demographics and baseline characteristics by treatment group. The demographics and baseline characteristics were consistent between the safety population and the PK population.

[0386] Table 21: Summary of Demographics and Baseline Characteristics by Treatment Group - Safety Population

[0387]

[0388]

[0389] Serial blood samples were collected from all subjects in each cohort on Days 1, 3, and 7 before the morning dose and at 1, 2, 3, 4, 6, 8, 10, and 12 hours after the morning dose for the assessment of the PK of xanomeline and trospium chloride. The PK parameters listed below were calculated from the individual xanomeline and trospium chloride concentration-time curves by standard non-compartmental methods. Calculate C 最大 and dose-normalized parameters of the area under the concentration-time curve (AUC) values. During the study, additional blood samples were collected on Days 2, 4, 5, and 6 before the morning dose and before discharge on Day 8 for monitoring the trough concentrations of xanomeline and trospium chloride.

[0390] Safety evaluations included spontaneously reported adverse events, ECG, laboratory evaluations, vital signs, saliva volume evaluations, Bristol Stool Scale, pupil size, and physical examinations. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) summarized the continuous data for the treatment groups. Geometric means (GM), geometric percent coefficient of variation (CV%), quartiles, or box plots were generated. Counts and frequencies were tabulated for categorical measurements although no formal statistics were performed.

[0391] Unless otherwise stated, the 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 + capsule and all cohorts placebo groups were combined). Safety evaluations were based on reported adverse events, ECG, laboratory assessments, and vital signs. Exploratory analyses were also conducted on salivary volume, Bristol Stool Scale, and pupil size.

[0392] After oral administration of the KAR-003 formulation at all doses, xanomeline was well absorbed into the systemic circulation. Peak concentrations of xanomeline were observed at a median time of 2 hours across all treatment groups and study days.

[0393] Among treatment groups and across all study days, the median t 1 / 2 value of xanomeline was similar, indicating that t 1 / 2 was not dose-dependent. The median t 1 / 2 ranged from 3.4 to 5.8 hours.

[0394] On Day 3, GM xanomeline exposure did not increase proportionally with dose from 100 to 150 mg (when xanomeline was co-administered with 20 mg trospium chloride) or from 125 to 150 mg (when co-administered with 40 mg trospium chloride). Lower xanomeline exposure was observed after treatment with KarXT 150 / 40 compared to KarXT125 / 40. When the 150 mg dose of xanomeline was co-administered with 20 mg and 40 mg of trospium chloride, GM xanomeline exposure on Day 3 (C 最大 , AUC 0-最后 and AUC 0-12hr ) was similar. On Day 7, when xanomeline was co-administered with 40 mg trospium chloride, GM xanomeline exposure increased slightly more than proportionally from 125 mg to 150 mg.

[0395] After treatment with KarXT 100 / 20 BID and KarXT 125 / 40 BID, there was minimal to no xanomeline accumulation in plasma from Day 3 to Day 7; however, 3 out of 4 subjects who completed the study had accumulation after administration of KarXT 150 / 40 BID. The mean accumulation ratios in the KarXT 150 / 40 BID group were 366.2% (RAUC) and 445.4% (RC 最大 ).

[0396] Example 6 - Tacrine Pharmacokinetics of KAR-003 Compared to KAR-001

[0397] Comparison of tacrine GM exposure between KAR-001 (75 mg tacrine TID ± 20 mg trospium chloride 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 (on Day 3 and Day 7) were greater than the corresponding exposures from KAR-001 (on Day 3 and Day 9). Median T 最大 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). These data suggest that the KarXT formulation enhances tacrine exposure.

[0398] After oral administration of the KarXT formulation at all doses, trospium chloride was absorbed into the systemic circulation. Peak concentration of trospium chloride was observed at a median time of 1.0 hour in all treatment groups and study days.

[0399] On Day 3, median t 1 / 2 values of trospium chloride were similar between treatment groups, with a value range of 4.1 to 4.8 hours. On Day 7, median t 1 / 2 values were similar for KarXT 100 / 20 BID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) treatments, but were slightly longer for the KarXT 150 / 40 BID group (7.1 hours).

[0400] When co-administered with 150 mg of tacrine, GM trospium chloride exposure on Day 3 increased slightly less than proportionally from 20 mg to 40 mg. When a 20 mg BID dose of trospium chloride was co-administered with 100 mg BID tacrine, GM trospium chloride exposure on Day 3 (C 最大 , AUC 0-最后 and AUC 0-12hr ) was greater compared to co-administration with 150 mg BID tacrine. When a 40 mg trospium chloride BID dose was given with 125 mg BID tacrine and 150 mg BID tacrine, GM trospium chloride exposure on Day 3 was similar.

[0401] 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 ratio was 348.7% (RAUC) and 379.9% (RC 最大 ).

[0402] Comparison of trospium GM exposure between KAR-001 and the KarXT 100 / 20 BID group from KAR-003 showed that C 最大 and AUC 0-12hr values on two days (Day 3 and Day 9 for KAR-001 and Day 3 and Day 7 for KAR-003) were greater than the corresponding exposures from KAR-001. Median T 最大 of trospium was 1.0 hour on both days in both studies. These data suggest that the KarXT formulation enhances trospium exposure.

[0403] All cohorts of KAR-003 started with a 2-day lead-in period of KarXT 50 / 20 BID (for subjects randomized to KarXT). Figure 1 Mean (±SD) PK concentrations of xanomeline are presented, and Table 22 summarizes the xanomeline PK parameters on Day 1 of KarXT 50 / 20 BID treatment for all cohorts of the PK population. Samples collected before administration of 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 after administration of the morning dose on Day 1 up to 12 hours.

[0404] Table 22: Xanomeline PK Parameters on Day 1 of KarXT 50 / 20 BID (All Cohorts)

[0405] Characteristic 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)

[0406] Figure 2 Mean (±SD) PK concentrations of xanomeline generated by treatment on Day 3 are presented for the PK population, and Table 23 summarizes these parameters. For all cohorts, xanomeline concentrations were quantifiable in samples taken before administration of the morning dose of the study drug on Day 3 and at all time points from after administration of the morning dose on Day 3 up to 12 hours, except for one subject whose plasma xanomeline concentration at 12 hours after dosing was <50.0 pg / mL. Across the four treatment groups, the range of variability between subjects for T 最大was 23.7% to 58.2% (CV%), for C 最大 was 79.8% to 136.3% (geometric CV%), for t 1 / 2 was 21.6% to 26.3% (CV%), and for AUC 0-12hr was 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, the median T of xanomeline on Day 3 最大 was 2 hours. Across the four treatment groups, the individual T 最大 values ranged from 1.0 to 6.0 hours. Compared to the previous study KAR-001 (where the elimination phase was not well characterized), t 1 / 2 was estimated in 51 out of 53 subjects. Across the four treatment groups, the median t of xanomeline on Day 3 1 / 2 was numerically similar. The median t 1 / 2 ranged from 3.4 to 4.3 hours. Across the four treatment groups, the individual t 1 / 2 values ranged from 2.4 to 8.6 hours.

[0407] Table 23: Xanomeline PK Parameters Generated by Treatment on Day 3

[0408]

[0409] When KarXT was administered BID, due to increasing the xanomeline dose from 100 mg (cohort 1) to 150 mg (cohort 2) without changing the trospium chloride dose (20 mg), for xanomeline, the dose-normalized GM exposure (dose-normalized GM C 最大 and dose-normalized GM AUC 0-最后 and 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 chloride dose (40 mg), for xanomeline, the dose-normalized GM exposure slightly decreased on Day 3 (i.e., the xanomeline exposure after treatment with KarXT 150 / 40 BID was lower compared to treatment with KarXT 125 / 40 BID). The comparison of xanomeline exposure after administration of 150 mg xanomeline BID with 20 mg or 40 mg trospium chloride BID showed that for xanomeline, the GM, C 最大 , AUC 0-最后 and AUC 0-12hr on Day 3 were similar.

[0410] Figure 3Presents the mean (±SD) of xanomeline PK concentrations generated by treatment in the PK population on Day 7, and Table 24 summarizes these parameters. 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 the study drug on Day 7 and at all time points from the morning dose on Day 7 up to 12 hours. Across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups, the range of variability between subjects for T 最大 was 38.3% to 47.9% (CV%), for C 最大 was 81.4% to 106.8% (geometric CV%), for t 1 / 2 was 15.4% to 42.1% (CV%), and for AUC 0-12hr was 45.2% to 71.2% (geometric CV%). For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID groups, the median T 最大 of xanomeline on Day 7 was 2.0 hours. Across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups, the range of individual T 最大 values was 0.0 to 6.0 hours. For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID groups, the median t 1 / 2 of xanomeline on Day 7 was numerically similar. The median t 1 / 2 of xanomeline ranged from 4.6 to 5.8 hours. Across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups, the range of individual t 1 / 2 values was 3.6 to 14.0 hours.

[0411] Table 24: Xanomeline PK Parameters Generated by Treatment on Day 7

[0412]

[0413]

[0414] When KarXT is administered BID, due to increasing the xanomeline dose from 125 mg (cohort 4) to 150 mg (cohort 3) without changing the trospium chloride dose (40 mg), for xanomeline, the dose-normalized GM exposure (dose-normalized GM C最大 , AUC 0-最后 and AUC 0-12hr ) increased.

[0415] Table 25 summarizes the xanomeline PK accumulation ratio (Day 7 / Day 3) for treatment through the PK population. Based on the average xanomeline accumulation ratio after treatment with KarXT 100 / 20 BID (cohort 1) and KarXT 125 / 40 BID (cohort 4), there was minimal to no xanomeline accumulation in plasma from Day 3 to Day 7. The average accumulation ratio for the KarXT 100 / 20 BID group was 133.4% (RAUC) and 130.5% (RC max ), and the average accumulation ratio for the KarXT 125 / 40 BID group was 143.9% (RAUC) and 151.0% (RC 最大 ). Compared to Day 3, only one subject in the KarXT 100 / 20 BID group showed lower exposure on Day 7. In contrast, xanomeline moderately accumulated in three of the four subjects who completed the study in the KarXT 150 / 40 BID group. Another subject in the KarXT 150 / 40 BID group showed similar exposure on Day 3 and Day 7. The average accumulation ratio for the KarXT 150 / 40 BID group was 366.2% (RAUC) and 445.4% (RC 最大 ).

[0416] Table 25: Xanomeline PK Accumulation Ratio (Day 7 / Day 3) by Treatment

[0417]

[0418] Figure 4 Compared the mean (±SD) - time curves of xanomeline PK concentrations for the PK population by treatment and follow-up (days). Figure 5 Presented the mean (±SD) xanomeline PK trough concentrations for the PK population by treatment. Steady state was not evaluated.

[0419] The comparison of xanomeline GM exposure between KAR-001 (75 mg xanomeline TID ± 20 mg trospium chloride 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 C 最大 values and AUC 0-6hr (KAR-003) or AUC 0-tau (AUC from 0 to 6 hours) values (KAR-001) that were approximately 2.3 to 2.6 times higher than the corresponding exposures from KAR-001 on Day 3.

[0420] Comparison of the Day 7 GM exposure in the KarXT 100 / 20 BID group from KAR-003 (Table 22) with the Day 9 exposure from xanomeline alone and the xanomeline + trospium exposure from KAR-001 (Table 23) showed that the values in the KarXT 100 / 20 BID group (KAR-003) on Day 7 were approximately 1.4 to 1.8 times higher than the corresponding exposure on Day 9 from KAR-001. At Day 3 and Day 7 in KAR-003 (Table 22) and Day 3 and Day 9 in KAR-001 (Table 23), the median T 最大 was 2.0 hours. These data indicate that the KAR-003 formulation provides adequate exposure and PK characteristics.

[0421] Table 26 summarizes a subset of the KAR-003 xanomeline PK parameters for the KarXT 100 / 20 BID group on Day 3 and Day 7 for the PK population. Table 27 presents a summary of a subset of the KAR-001 xanomeline PK parameters for the treatment with KAR-001 on Day 3 and Day 9 for the PK population.

[0422] Table 26: Subset of xanomeline PK parameters for KarXT 100 / 20 BID on Day 3 and Day 7

[0423]

[0424] Table 27: Subset of xanomeline PK parameters for KAR-001 on Day 3 and Day 9

[0425]

[0426]

[0427] Figure 6 The mean (±SD) PK concentration of trospium for the KarXT 50 / 20 BID treatment (all cohorts) on Day 1 for the PK population is presented, and Table 28 summarizes these parameters. Samples collected prior to the administration of 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 from the morning dose administration on Day 1 up to 12 hours.

[0428] Table 28: Trospium PK parameters for KarXT 50 / 20 BID on Day 1 (all cohorts)

[0429]

[0430] Figure 7Presents the mean (±SD) trospium chloride PK concentrations generated by treatment in the PK population on Day 3, and Table 29 summarizes these parameters. For all treatment groups, the concentration of trospium chloride in samples collected before the morning dose of the study drug on Day 3 and at all time points from the administration of the morning dose on Day 3 to 12 hours was quantifiable, except for one subject whose plasma concentration of trospium chloride at 12 hours post-dose was <20.0 pg / mL. Across the four treatment groups, the range of variability among subjects for T 最大 was 0.0% to 83.0% (CV%), for C 最大 was 54.8% to 80.7% (geometric CV%), for t 1 / 2 was 9.1% to 34.0% (CV%), and for AUC 0-12hr was 59.0% to 67.6% (geometric CV%).

[0431] Table 29: Trospium Chloride PK Parameters Generated by Treatment on Day 3

[0432]

[0433] For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, KarXT 150 / 20 BID, and KarXT 150 / 40 BID groups, the median T 最大 of trospium chloride on Day 3 was 1.0 hour. Across the 4 treatment groups, the range of individual T 最大 values was 1.0 to 6.0 hours. Across the 4 treatment groups, the median t 1 / 2 of trospium chloride on Day 3 was numerically similar; the median t 1 / 2 ranged from 4.1 to 4.8 hours. Across the 4 treatment groups, the range of individual t 1 / 2 values was 2.8 to 9.0 hours.

[0434] When KarXT was administered BID, due to increasing the trospium chloride dose from 20 mg (cohort 2) to 40 mg (cohort 3) without changing the xanomeline dose (150 mg), the dose-normalized GM exposure of trospium chloride increased on Day 3. Comparison of the exposure of trospium chloride on Day 3 after administration of 20 mg trospium chloride BID and 100 mg (cohort 1) or 150 mg (cohort 2) xanomeline BID showed that the GM C 最大 , AUC 0-最后 and AUC 0-12hr of trospium chloride were greater when 20 mg BID dose of trospium chloride was administered with 100 mg xanomeline BID compared to when with 150 mg xanomeline BID.

[0435] Similarly, comparison of trospium exposure following administration of 40 mg trospium BID and 125 mg (cohort 4) or 150 mg (cohort 3) xanomeline BID showed that the GM C of trospium when administered with 125 and 150 mg xanomeline BID on day 3 最大 , AUC0- 最后 and AUC0-12hr were generally similar.

[0436] Figure 8 Figure PK population-averaged (±SD) trospium PK concentrations generated by treatment on day 7 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 prior to the morning dose of the study drug on day 7 and at all time points from the morning dose on day 7 through 12 hours. Across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups, the range of variability among subjects for T 最大 was 0.0% to 86.3% (CV%), for C 最大 was 51.2% to 93.8% (geometric CV%), for t 1 / 2 was 23.0% to 44.5% (CV%), and for AUC 0-12hr was 59.4% to 76.7% (geometric CV%).

[0437] Table 30: Trospium PK Parameters Generated by Treatment on Day 7

[0438]

[0439]

[0440] For KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID treatments, the median T of trospium on day 7 最大 was 1.0 hour. Across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups, the range of individual T 最大 values was 0.0 to 6.0 hours.

[0441] For the KarXT 100 / 20 BID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) groups, the median t of trospium on day 7 1 / 2 was similar. The median t of the KarXT 150 / 40 BID group1 / 2 was 7.1 hours. Across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups, the individual t 1 / 2 values ranged from 3.1 to 11.9 hours.

[0442] As observed on Day 3, comparison of trospium chloride exposure on Day 7 after administration of 40 mg trospium chloride BID and 125 mg (cohort 4) or 150 mg (cohort 3) xanomeline BID showed that the GM C of trospium chloride when administered with 125 and 150 mg xanomeline BID 最大 , AUC 0-最后 and AUC 0-12hr were similar.

[0443] Table 31 summarizes the PK population-based ratios of trospium chloride PK accumulation by treatment (Day 7 / Day 3; Day 7 / Day 1). Based on the mean trospium chloride PK accumulation ratios, trospium chloride accumulated the least in plasma from Day 3 to Day 7 after administration of KarXT 100 / 20 BID (cohort 1), and accumulated little or not at all after administration of KarXT 125 / 40 BID (cohort 4) and KarXT 150 / 40 BID (cohort 3). Compared to Day 3 in the KarXT 100 / 20 BID group, two subjects showed lower exposure on Day 7.

[0444] From Day 3 to Day 7, there was a large variation in the accumulation ratios between subjects in the KarXT 125 / 40 BID and KarXT 150 / 20 BID groups. The mean accumulation ratio ranges were from 108.6% to 141.4% for RAUC and from 111.0% to 135.8% for RC 最大 . For the KarXT 100 / 20 BID group, trospium chloride accumulated moderately in plasma from Day 1 to Day 7. Compared to Day 1, all subjects except one showed higher trospium chloride exposure on Day 7. The mean accumulation ratio was 348.7% for RAUC and 379.9% for RC 最大 . The possible effect of the increase in xanomeline dose (from 50 mg BID starting on Day 3 to 100 mg BID) on the PK and bioavailability of trospium chloride cannot be excluded, as this contributed to the increased exposure from Day 1 to Day 7.

[0445] Table 31: Ratios of Trospium Chloride PK Accumulation by Treatment (Day 7 / Day 3; Day 7 / Day 1)

[0446]

[0447]

[0448] Figure 9 The mean (±SD) trospium chloride PK concentration-time curves for the PK population over treatment and follow-up (days) were compared. Figure 10 The mean (±SD) trough trospium chloride PK concentrations for the PK population over treatment and follow-up (days) are presented. Steady state was not evaluated.

[0449] Example 7 - Trospium chloride pharmacokinetics of KAR-003 compared to KAR-001

[0450] Comparison of trospium chloride GM exposure on Day 1 of KAR-001 (single trospium chloride dose for first dose without prior treatment) (Table 33) and on Day 1 of KAR-003 (xanomeline + trospium chloride for first dose without prior treatment) (Table 32) showed that trospium chloride exposure from KAR-003 was approximately 2.1 to 2.5 times higher than those obtained from KAR-001. Although the comparison of GM exposure on Day 3 between the studies was not a head-to-head comparison (xanomeline administration started on Day 3 of the KAR-003 study), the number of trospium chloride doses and the daily dose administered to the subjects were the same. The Day 3 GM trospium chloride exposure of KAR-003 (Table 32) was also approximately 2.4 to 3.3 times higher than those obtained from KAR-001 (Table 33). Comparison of the Day 7 GM exposure of the KarXT 100 / 20 BID cohort (cohort 1) of KAR-003 (Table 32) with the Day 9 exposure of the xanomeline + trospium chloride group of KAR-001 (Table 33) indicated that the exposure was again higher than those obtained from KAR-001 (approximately 3.5 to 4.3 times higher).

[0451] For KAR-003, the median T of trospium chloride for the KarXT 100 / 20 BID group on Day 3 and Day 7 and for KAR-001, the median T of trospium chloride for the xanomeline + trospium chloride group on Day 3 and Day 9 最大 was 1.0 hour. Compared to the median T of trospium chloride of the group with single trospium chloride (KAR-001) on Day 1 最大 which was 3.0 hours, the median T of trospium chloride of the KarXT 50 / 20 BID group (KAR-003) on Day 1 最大 was lower (1.0 hour).

[0452] Table 32 summarizes subsets of the KAR-003 trospium PK parameters for the PK population for KarXT 50 / 20 BID treatment (all cohorts) on Day 1 and for KarXT 100 / 20 BID treatment on Days 3 and 7. Table 33 summarizes subsets of the KAR-001 trospium PK parameters for the PK population for trospium alone treatment on Day 1 and for xanomeline + trospium treatment on Days 3 and 9.

[0453] Table 32: Subsets of the KAR-003 trospium PK parameters for KarXT 50 / 20 BID (all cohorts) on Day 1 and for KarXT 100 / 20 BID on Days 3 and 7

[0454]

[0455] Table 33: Subsets of the trospium PK parameters for KAR-001 on Days 1, 3, and 9

[0456]

[0457]

[0458] Table 34 lists the incidence of cholinergic TEAEs and the preferred terms for the safety population in the KAR-001 study by System Organ Class (SOC). The overall subject incidence of cholinergic TEAEs was similar among 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.

[0459] Table 34: Incidence and Preferred Terms of KAR-001 Cholinergic Treatment Emergent Adverse Events by System Organ Class - Safety Population

[0460]

[0461]

[0462] Compared with the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups, a higher incidence of subjects with hypersalivation, hyperhidrosis, and diarrhea was observed in the xanomeline + trospium chloride group in KAR-001. Hypersalivation occurred in 25.7% of the subjects in the xanomeline + trospium chloride group of KAR-001, 5.6% of the subjects in the KarXT 100 / 20 BID group, and no subjects in the KarXT 125 / 40 BID group had hypersalivation. Hyperhidrosis occurred in 20.0% of the subjects in the xanomeline + trospium chloride group of KAR-001, 5.6% of the subjects in the KarXT 100 / 20 BID group, and 11.1% of the subjects in the KarXT 125 / 40 BID group. Diarrhea occurred in 5.7% of the subjects in the xanomeline + trospium chloride group of KAR-001, and no subjects in either the KarXT 100 / 20 BID group or the KarXT 125 / 40 BID group had diarrhea.

[0463] For nausea and vomiting, compared with the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups, no other significant trends were shown in the xanomeline + trospium chloride group in KAR-001. Nausea occurred in 17.1% of the subjects in the xanomeline + trospium chloride group of KAR-001 and 22.2% of the subjects in each of the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups. Vomiting occurred in 5.7% of the subjects in the xanomeline + trospium chloride group of KAR-001, 27.8% of the subjects in the KarXT 100 / 20 BID group, and 5.6% of the subjects in the KarXT 125 / 40 BID group.

[0464] After oral administration of the KAR-003 formulation at all doses, xanomeline and trospium chloride were absorbed into the systemic circulation. The PK results indicated that neither xanomeline nor trospium chloride meaningfully affected the PK behavior of the other drug. Compared with KAR-001 in which the two compounds were administered separately, the KAR-003 formulation provided enhanced blood levels of xanomeline and trospium chloride.

[0465] No new safety signals were reported in the case of the KarXT formulation. The severity of all TEAEs was mild or moderate, with no SAEs or deaths. Compared with the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups in KAR-003, a higher incidence of hypersalivation, hyperhidrosis, and diarrhea was observed in the xanomeline + trospium chloride group in KAR-001.

[0466] Example 8 - KAR-004 Phase II Study

[0467] 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 chloride) compared to placebo in reducing the total score on the Positive and Negative Syndrome Scale (PANSS) in adult inpatients diagnosed with schizophrenia. Five secondary objectives were to evaluate the overall safety and tolerability of KarXT in adult inpatients diagnosed with schizophrenia according to DSM-5, to evaluate spontaneously reported adverse events (AEs) in subjects treated with KarXT compared to placebo, to evaluate spontaneously reported cholinergic symptoms in subjects treated with KarXT compared to placebo, to evaluate orthostatic vital signs in subjects treated with KarXT compared to placebo, and to evaluate ECG parameters in subjects treated with KarXT compared to placebo.

[0468] The total study duration was up to 7 weeks, including a 7-day screening phase (allowing for an extended screening phase of up to 7 days if necessary) and a 5-week treatment period. Subjects were randomly assigned to the KarXT group or the placebo group at a 1:1 ratio. The key inclusion and exclusion criteria for the Phase II study are shown in Table 35. The demographics and baseline characteristics of the enrolled patients are shown in Table 36.

[0469] Table 35: Key Inclusion and Exclusion Criteria

[0470]

[0471]

[0472] Table 36: Demographics and Baseline Characteristics of Enrolled Patients

[0473] 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

[0474] The study was a two-arm trial with flexible dosing, randomized 1:1 to KarXT or placebo, with a five-week treatment period:

[0475] - Days 1 - 2: 50 / 20 KarXT BID (50 mg xanomeline / 20 mg trospium chloride)

[0476] - Days 3 - 7: 100 / 20 KarXT BID

[0477] - Days 8 - 35: 100 / 20 KarXT BID, with the option to increase to 125 / 30 KarXT BID; titration was based only on tolerability.

[0478] The primary endpoint was the change in the total PANSS score at week 5 compared to baseline relative to placebo. 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 equal to 1 or 2. CGI-S non-responders were defined as subjects with a CGI-S scale equal to 3 to 7. At screening and baseline follow-up, subjects were required to have a CGI-S score ≥ 4. The ratings of the CGI-S score legend were: 1 for normal, 2 for borderline disease, 3 for mild disease, 4 for moderate disease, 5 for marked disease, 6 for severe disease, and 7 for extreme disease. Safety endpoints included monitoring spontaneous adverse events, orthostatic vital signs (after 2 minutes of supine and standing), blood pressure (systolic and diastolic) and heart rate (beats / minute), clinical laboratory evaluations (hematology, clinical chemistry, coagulation, urine analysis and drug screening), 12-lead ECG, physical examination, and assessment of suicidal ideation using the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0479] 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 the 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 the 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 the 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 who had a valid total PANSS score at follow-up 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 the 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 the randomly assigned treatment.

[0480] The demographics of the ITT population are shown in Table 37. There were no significant differences between the treatment groups.

[0481] Table 37: Key demographics and baseline characteristics of the mITT population

[0482] 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 Average Baseline PANSS Score 96.6±8.4 97.3±9.3 Average Baseline PANSS Positive Score 26.3±3.3 26.3±3.4 Average Baseline PANSS Negative Score 22.9±4.6 22.5±4.3 Average Baseline PANSS Marder Negative Score 22.4±5.1 22.3±4.6 Average Baseline CGI-S Score 4.9±0.6 5.0±0.5

[0483] Positive and negative values are mean ± SD

[0484] For the primary endpoint, compared to placebo, the KarXT treatment group showed a clinically meaningful and statistically significant improvement in the total PANSS score ( Figure 11 ). Compared to placebo, subjects improved by 11.6 points at week 5 (p<0.0001). Statistical separation occurred at each assessment time point. The Cohen’s d effect size was 0.75. Historically, changes in the total PANSS score as small as 5 points have been determined to be effective for current antipsychotics used as the standard of care.

[0485] For the secondary endpoints, compared to placebo, the KarXT treatment group showed a clinically meaningful and statistically significant improvement in the total positive PANSS subscore ( Figure 12 ). Compared to placebo, subjects improved by 3.2 points at week 5 (p<0.0001). Statistical separation occurred at each assessment time point.

[0486] Compared to placebo, the KarXT treatment group also showed a clinically meaningful and statistically significant improvement in the total negative PANSS ( Figure 13 ). Compared to placebo, subjects improved by 2.3 points at week 5 (p<0.001). Statistical separation occurred at each assessment time point. Figure 14 Plots of the PANSS Marder factor scores of subjects in the mITT population of the KAR-004 Phase II study relative to the number of follow-up days are shown.

[0487] In addition, the CGI-S showed highly significant improvement in a pattern consistent with the PANSS. Nonparametric comparison of KarXT compared to placebo using the Mann-Whitney Wilcoxon test showed a shift in the CGI-S score relative to baseline (p<0.001). At baseline, the percentage of patients with a score of 5 or 6 was 84% for KarXT compared to 80% for placebo ( Figure 15 ). At the endpoint, the percentage of patients with a score of 5–7 was 33% for KarXT compared to 60% for placebo, and the percentage of patients rated as having mild disease or better (score of 1, 2, or 3) was 37% for KarXT compared to 11% for placebo ( Figure 16 ). Statistical separation occurred at each assessment time point (weeks 2, 4, and 5).

[0488] Overall, KarXT was safe and well tolerated. The overall discontinuation rate of KarXT (20%) was similar to that of 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 of KarXT was high and similar to that of placebo: 91% of KarXT subjects escalated to 125 / 30 KarXT (compared to 97% of placebo), and 4% of subjects de-escalated to the 100 / 20 KarXT dose (compared to 1% of placebo).

[0489] The overall adverse event rate for KarXT was 54% compared to 43% for placebo (Table 38):

[0490] Table 38: Adverse events during the study

[0491]

[0492]

[0493] Values are number (percentage) of patients. SAE = serious adverse event, GGT = gamma-glutamyl transferase

[0494] 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 events caused by trospium chloride. For example, xanomeline alone causes sweating, nausea, vomiting, diarrhea, and excessive salivation, as well as orthostasis and syncope. Trospium chloride causes constipation, dry mouth, and stomach discomfort. Unlike earlier xanomeline trials, sweating was not reported or observed.

[0495] During the entire study, most of the most common cholinergic / anticholinergic adverse events associated with KarXT treatment decreased. In particular, the rates of cholinergic adverse events (nausea and vomiting shown in Figure 17 and anticholinergic adverse events (dry mouth, shown in Figure 18 ) in the KarXT group (gray bars) decreased consistently. By the end of week 5, the rates of nausea, vomiting, and dry mouth for KarXT were not statistically distinguishable from those of the placebo group. The constipation rate in the KarXT group showed a small downward trend (data not shown). The black bars represent the corresponding AE rates for the placebo group throughout the study.

[0496] There were no syncopes in the KarXT treatment group. The 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 compared to previous studies and tended to resolve. There was no mean change in orthostatic systolic or diastolic blood pressure (Figure 21 and 22 )。There was no significant postural effect between orthostatic and standing measurements.

[0497] Somnolence, weight gain, and extrapyramidal symptoms / akathisia were similar to placebo. No significant changes were observed on the Barnes Akathisia Scale, Simpson-Angus Scale, or Abnormal Involuntary Movement Scale. These are adverse events typically observed under current standards of care. These adverse events were not manifested in KarXT treatment.

[0498] Liver enzymes in the LFT were comparable to placebo (Table 39). Two KarXT-treated patients had elevated GGT (>2X ULN), and one placebo-treated patient had elevated ALT (>3X ULN), AST (>3X ULN), and GGT (>2X ULN). In particular, one subject discontinued due to elevated gamma-glutamyl transferase (GGT) in the LFT.

[0499] Table 39: Adverse Events During the Study

[0500] Laboratory Test 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

[0501] Positive and negative values are mean ± SD; abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Alk phos = alkaline phosphatase; GGT = gamma-glutamyl transferase.

[0502] One serious adverse event of KarXT was recorded - the patient discontinued and sought hospital care due to worsening psychosis. Although this event met the regulatory technical definition of a serious adverse event, the psychosis was caused by schizophrenia, not by KarXT. The patient did not withdraw due to symptoms caused by KarXT administration. Therefore, this result reflects the lack of efficacy of KarXT in one patient, rather than the emergence of new symptoms due to drug-induced lack of tolerance.

[0503] This Phase 2 study showed that KarXT has potent antipsychotic efficacy and favorable safety / tolerability in hospitalized patients with schizophrenia. KarXT showed early (2 weeks) and sustained (over the entire 5 weeks) separation from the placebo group on the primary efficacy measure (PANSS total) and four of the five secondary outcome measures. The safety profile was consistent with previous work with the KarXT combination. All adverse events, except one treatment-emergent adverse event, were rated as mild or moderate. Throughout the study, most cholinergic and anticholinergic adverse events decreased to levels statistically indistinguishable from the placebo group.

[0504] The foregoing description is provided for clarity of understanding only and should not be construed as imposing any unnecessary limitations, as modifications within the scope of this disclosure will be apparent to those of ordinary skill in the art. Throughout the specification, when a composition is described as including components or materials, unless otherwise stated, it is contemplated that the composition may also consist essentially of or consist of any combination of the listed components or materials. Similarly, in cases where a method is described as including steps, unless otherwise stated, it is contemplated that these methods may also consist essentially of or consist of any combination of the listed steps. The disclosure illustratively disclosed herein may be practiced appropriately in the absence of any element or step not specifically disclosed herein.

[0505] The practice of the methods disclosed herein and their various steps can be performed manually and / or with the aid of an electronic device or automation provided by an electronic device. Although the methods have been described with reference to embodiments, those of ordinary skill in the art will readily understand that other ways of performing the actions associated with these methods can be used. For example, unless otherwise stated, the order of the individual steps can be changed without departing from the scope or spirit of the method. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0506] It should be understood that, for clarity, certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, the various features of the invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination. All combinations of embodiments regarding chemical groups represented by variables contained in the general chemical formulas described herein are expressly covered by the invention as if each combination were individually and expressly stated, to the extent that such combinations cover stable compounds (i.e., compounds that can be isolated, 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 the uses and medical indications described herein, are specifically covered in the invention as if each sub-combination of chemical groups and each sub-combination of uses and medical indications were individually and expressly stated herein.

[0507] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between this disclosure and the incorporated patents, publications, and references, this disclosure shall control.

Claims

1. Use of a pharmaceutical composition for the preparation of a medicament for treating schizophrenia or a disease associated with schizophrenia in a patient in need thereof, wherein the pharmaceutical composition comprises a first plurality of xanomeline beads containing xanomeline or a salt thereof, and a second plurality of trospium chloride beads containing a trospium chloride salt, wherein the medicament is orally administered to the patient twice a day via a titration regimen, the titration regimen comprising increasing the titration of the xanomeline or a salt thereof, and the trospium chloride salt.

2. Use of a pharmaceutical composition for the preparation of a medicament for treating schizophrenia or a disease associated with schizophrenia in a patient in need thereof, wherein the pharmaceutical composition comprises a first plurality of xanomeline beads containing xanomeline or a salt thereof, and a second plurality of trospium chloride beads containing a trospium chloride salt, wherein the medicament is orally administered to the patient twice a day for at least five weeks, wherein at least one adverse event occurring at the start of oral administration is reduced to its pre-treatment level after said five weeks of treatment.

3. Use according to claim 1 or 2, wherein the administration is carried out via a titration regimen which comprises increasing the titration of 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 twice a day.

4. Use according to claim 1 or 2, wherein the administration is carried out via a titration regimen which comprises increasing the titration of the xanomeline or a salt thereof, and the trospium chloride salt, until an amount equivalent to 150 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered twice a day.

5. Use according to claim 1 or 2, wherein the administration is carried out via a titration regimen which comprises increasing the titration of the xanomeline or a salt thereof, and the trospium chloride salt, until an amount equivalent to 175 mg of xanomeline free base and an amount equivalent to 30 mg of trospium chloride are administered twice a day.

6. Use according to claim 1 or 2, wherein the administration is carried out via a titration regimen which comprises increasing the titration of the xanomeline or a salt thereof, 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 a day.

7. Use according to any one of the preceding claims 1 or 2, wherein the patient is diagnosed with schizophrenia.

8. Use according to any one of the preceding claims 1 or 2, wherein before administration of the medicament, the patient has a Clinical Global Impression - Severity (CGI - S) score of 4 - 7, and after administration the patient has a CGI - S score equal to 1 or 2.

9. Use according to any one of the preceding claims 1 or 2, wherein the xanomeline or a salt thereof is used to administer a first amount to the patient for a first period of time, and then the first amount is increased to a second amount.

10. The use according to claim 9, wherein the first amount of xanomeline or a salt thereof is equivalent to 50 mg of free xanomeline.

11. The use according to claim 9, wherein the first time period for administering the xanomeline is from 1 to 5 days.

12. The use according to claim 11, wherein the first time period for administering the xanomeline is 2 days.

13. The use according to claim 9, wherein the second amount of xanomeline or a salt thereof is equivalent to 100 mg of free xanomeline.

14. The use according to claim 9, wherein the xanomeline or a salt thereof is used to administer a second amount to the patient for a second time period and then the second amount is increased to a third amount.

15. The use according to claim 14, wherein the second time period for administering the xanomeline is from three days to one week.

16. The use according to claim 14 or 15, wherein the third amount of xanomeline or a salt thereof is equivalent to 125 mg of free xanomeline.

17. The use according to claim 1 or 2, wherein the trospium chloride salt is used to administer a first amount to the patient for a first time period and the first amount is increased to a second amount.

18. The use according to claim 17, wherein the first amount of the trospium chloride salt is equivalent to 20 mg of trospium chloride.

19. The use according to claim 17, wherein the first time period for administering the trospium chloride is at least one week.

20. The use according to claim 15, wherein the second amount of the trospium chloride salt is equivalent to 30 mg of trospium chloride.

21. The use according to claim 1 or 2, wherein at least one of vomiting, nausea, and dry mouth that occur at the start of oral administration is reduced to its pre-treatment level after five weeks of treatment.

22. The use according to claim 1 or 2, wherein the xanomeline or a salt thereof, and the trospium chloride salt are used to administer to the patient without causing an increase in heart rate of more than 5 beats per minute.

23. The use according to claim 1 or 2, wherein the xanomeline or a salt thereof, and the trospium chloride salt are used to administer to the patient without causing syncope.

24. The use according to claim 1 or 2, wherein the xanomeline or a salt thereof, and the trospium chloride salt are used to administer to the patient without causing a diastolic blood pressure change of more than 5 mmHg.

25. The use according to claim 1 or 2, wherein the xanomeline or a salt thereof, and the trospium chloride salt are used to administer to the patient without causing a systolic blood pressure change of more than 5 mmHg.

26. The use according to claim 1 or 2, wherein the xanomeline or its salt, and the trospium chloride salt are used for administration to the patient without causing serious adverse events.

27. The use according to claim 1 or 2, wherein the xanomeline or its salt, and the trospium chloride salt are used for administration to the patient without causing serious adverse events related to heart rate.

28. The use according to claim 1 or 2, wherein the xanomeline or its salt, and the trospium chloride salt are used for administration to the patient without causing serious adverse events related to heart rate changes.

29. The use according to claim 1 or 2, wherein the xanomeline or its salt, and the trospium chloride salt are used for administration to the patient without causing serious adverse events related to blood pressure.

30. The use according to claim 1 or 2, wherein the xanomeline or its salt, and the trospium chloride salt are used for administration to the patient without causing serious adverse events related to blood pressure changes.

31. The use according to claim 1 or 2, wherein the xanomeline or its salt, and the trospium chloride salt are used for administration to the patient without increasing liver function tests (LFT).

32. The use according to claim 1 or 2, wherein after five weeks of treatment, the total score of the Positive and Negative Syndrome Scale (PANSS) of the patient is reduced by at least 10 points compared to the placebo.

33. The use according to claim 1 or 2, wherein after five weeks of treatment, the positive subscore of the PANSS is reduced by at least 3 points compared to the placebo.

34. The use according to claim 1 or 2, wherein after five weeks of treatment, the negative subscore of the PANSS is reduced by at least 2 points compared to the placebo.

35. The use according to claim 1 or 2, wherein the size of these xanomeline beads is from 0.425 mm to 1.18 mm.

36. The use according to claim 1 or 2, wherein the size of these xanomeline beads is from 0.6 mm to 0.85 mm.

37. The use according to claim 1 or 2, wherein the size of these trospium chloride beads is from 0.425 mm to 1.18 mm.

38. The use according to claim 1 or 2, wherein the size of these trospium chloride beads is from 0.6 mm to 0.85 mm.

39. The use according to claim 1 or 2, wherein the free base of xanomeline contained in these xanomeline beads is 2.5 times that of the trospium chloride salt contained in these trospium chloride beads.

40. The use according to claim 1 or 2, wherein within the first 45 minutes after the dosage form enters an aqueous solution, the dissolution rate of the plurality of xanomeline beads and the plurality of trospium chloride beads is greater than 95%.

41. The use according to claim 40, wherein within the first 20 minutes after the dosage form enters an aqueous solution, the dissolution rate is greater than 95%.

42. The use according to claim 1 or 2, wherein the salt of xanomeline is xanomeline tartrate.

43. The use according to claim 42, wherein the xanomeline beads comprise 30 wt.% to 80 wt.% of xanomeline tartrate.

44. The use according to claim 43, wherein the xanomeline beads comprise 66 wt.% of xanomeline tartrate.

45. The use according to claim 1 or 2, wherein the xanomeline beads comprise 15 wt.% to 65 wt.% of microcrystalline cellulose.

46. The use according to claim 45, wherein the xanomeline beads comprise 33.5 wt.% of microcrystalline cellulose.

47. The use according to claim 1 or 2, wherein the xanomeline beads comprise 0 wt.% to 2 wt.% of talc.

48. The use according to claim 46, wherein the xanomeline beads comprise 0.5 wt.% of talc.

49. The use according to claim 1 or 2, wherein the xanomeline beads comprise 30 wt.% to 80 wt.% of xanomeline tartrate, 15 wt.% to 65 wt.% of microcrystalline cellulose, and 0 wt.% to 2 wt.% of talc.

50. The use according to claim 49, wherein the xanomeline beads comprise 66 wt.% of xanomeline tartrate, 33.5 wt.% of microcrystalline cellulose, and 0.5 wt.% of talc.

51. The use according to claim 1 or 2, wherein the trospium chloride salt is trospium chloride.

52. The use according to claim 51, wherein the trospium chloride beads comprise 8 wt.% to 35 wt.% of trospium chloride.

53. The use according to claim 52, wherein the trospium chloride beads comprise 17.7 wt.% of trospium chloride.

54. The use according to claim 1 or 2, wherein the trospium chloride beads comprise 25 wt.% to 80 wt.% of microcrystalline cellulose.

55. The use according to claim 54, wherein the trospium chloride beads comprise 46.8 wt.% of microcrystalline cellulose.

56. The use according to claim 1 or 2, wherein these trospium chloride beads contain 15 wt.% to 70 wt.% of lactose monohydrate.

57. The use according to claim 56, wherein these trospium chloride beads contain 35 wt.% of lactose monohydrate.

58. The use according to claim 1 or 2, wherein these trospium chloride beads contain 0 wt.% to 2 wt.% of talc.

59. The use according to claim 58, wherein these trospium chloride beads contain 0.5 wt.% of talc.

60. The use according to claim 1 or 2, wherein these trospium chloride beads contain 8 wt.% to 35 wt.% of trospium chloride, 25 wt.% to 80 wt.% of microcrystalline cellulose, 15 wt.% to 70 wt.% of lactose monohydrate, and 0 wt.% to 2 wt.% of talc.

61. The use according to claim 60, wherein these trospium chloride beads contain 17.7 wt.% of trospium chloride, 46.8 wt.% of microcrystalline cellulose, 35 wt.% of lactose monohydrate and 0.5 wt.% of talc.

62. The use according to claim 1 or 2, wherein the oral pharmaceutical composition further comprises ascorbic acid.

63. The use according to claim 62, wherein the oral pharmaceutical composition contains 0.2 wt.% to 1 wt.% of ascorbic acid.

64. The use according to claim 63, wherein the oral pharmaceutical composition contains 0.5 wt.% of ascorbic acid.

65. The use according to claim 1 or 2, wherein the oral pharmaceutical composition further comprises butylated hydroxytoluene.

66. The use according to claim 64, wherein the oral pharmaceutical composition contains 0.01 wt.% to 0.1 wt.% of butylated hydroxytoluene.

67. The use according to claim 66, wherein the oral pharmaceutical composition contains 0.05 wt.% of butylated hydroxytoluene.

68. The use according to claim 1 or 2, wherein the oral pharmaceutical composition further comprises a capsule, and the capsule contains the plurality of xanomeline beads and the plurality of trospium chloride beads.

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