Methods for treating disorders ameliorated by muscarinic receptor activation - Patents.com

Abstract

Provided herein is a method of treating a disorder ameliorated by activating muscarinic receptors in a patient 55 years of age or older in need of such treatment. The method includes administering to the patient a total daily dose of 25-200 mg of xanomeline and / or a salt thereof and 5-30 mg of a trospium salt, such as a total daily dose of 100-200 mg of xanomeline and / or a salt thereof and 20-30 mg of a trospium salt. The disclosure also provides methods for treating dementia-associated psychosis and methods of reducing the risk of relapse in patients with dementia-associated psychosis.

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 153,095, filed February 24, 2021, and also claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 213,998, filed June 23, 2021, the disclosures of each of which are incorporated by reference in their entirety for all purposes.

[0002] The present disclosure relates to compositions and their application as medicaments for treating disorders ameliorated by activating muscarinic receptors in human or animal subjects, for example in elderly subjects, or for treating dementia-associated psychosis. [Background technology]

[0003] Dementia-related psychosis (DRP) is a common symptom in people with dementia, whether due to Alzheimer's disease, Lewy body dementia, vascular dementia, Parkinson's disease-related dementia, frontotemporal dementia, other forms of dementia, or related disorders. DRP refers to behaviors that may include hallucinations, delusional thoughts, agitation, or aggressive behavior. These patients may have visual, auditory, and olfactory hallucinations, i.e., seeing, hearing, and smelling things that are not there, or paranoid delusions, such as suspecting that their caregivers want to harm them. Psychosis may become more common as dementia progresses, but visual hallucinations may be an early symptom of Lewy body dementia and Parkinson's disease-related dementia.

[0004] Atypical antipsychotics, such as risperidone, olanzapine, quetiapine, and aripiprazole, are currently the first-choice drugs in patients with psychotic symptoms of dementia. In patients with inadequate response to antipsychotics, divalproex (Depakote®) or carbamazepine (Tegretol®) are recommended as second-choice drugs. Nevertheless, these drugs exert adverse effects and provide limited efficacy, especially in elderly patients who are particularly sensitive to severe adverse reactions induced by atypical antipsychotics, such as excessive sedation, orthostatic hypotension, and associated complications such as falls, extrapyramidal symptoms, cognitive decline, cardiovascular complications, and anticholinergic side effects.

[0005] These drugs were specifically approved to treat schizophrenia, which mainly affects young adults with neurobiological deficits that are distinct from the behavioral and psychological symptoms of dementia. Aging induces changes in the quality and quantity of neurotransmitters, which may be responsible for the development of behavioral symptoms in patients with dementia. Perturbations in neurochemicals initiate changes in the expression of certain receptors, such as the muscarinic system, that should be targeted with specific drugs.

[0006] Activating the muscarinic system via muscarinic agonists may treat several diseases such as dementia-related psychosis, 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 in the CNS with a different tissue distribution. The M1 and M4 subtypes are of interest as therapeutic targets for various diseases. For example, the mood stabilizers lithium and valproic acid, used to treat bipolar depression, may exert their effects on the muscarinic system, specifically via the M4 subtype receptor. Genetic evidence directly links the muscarinic system to alcoholism.

[0007] In a double-blind, placebo-controlled study of schizophrenia patients with xanomeline (25-75 mg TID, 75-225 mg TDD), a muscarinic cholinergic receptor agonist with preferential activity at M1 and M4 subtype receptors, schizophrenia was alleviated. However, xanomeline also bound to muscarinic receptors outside the brain, resulting in a number of serious side effects, including GI side effects, cardiac side effects, and hypersalivation. Dose-limiting adverse events were problematic, leading to very high discontinuation rates (including a 56% dropout rate in a 26-week study of Alzheimer's disease), and ultimately leading to the cessation of xanomeline development. Despite early promise, development of xanomeline stalled for more than 15 years. Many companies have attempted and failed to develop muscarinic receptor agonists for CNS disorders that circumvent these intolerable side effects, but no such agonists have reached the market. Development efforts to date have typically focused on medicinal chemistry to develop better tolerated molecules by selecting M1 and M4 over M2 and M3 muscarinic receptor subtypes. However, M1 and M4 activation outside the brain can still lead to muscarinic intolerance. Little progress has been made to mitigate the adverse effects of peripheral muscarinic receptor activation. Summary of the Invention [Problem to be solved by the invention]

[0008] There remains a need in the art for pharmaceutical compositions that increase the tolerance of xanomeline, especially pharmaceutical compositions that treat cognitive and psychiatric disorders.The following embodiments and aspects thereof are described and illustrated using compositions and methods that are meant to be exemplary and illustrative, and are not limiting in scope.In various embodiments, one or more of the problems described above are reduced or eliminated, while other embodiments are directed to other improvements. [Means for solving the problem]

[0009] Provided herein is a method of treating a disorder ameliorated by activating muscarinic receptors in an elderly patient in need of such treatment, comprising administering to the patient a total daily dose of 25-200 mg of xanomeline and / or a salt thereof, and 5-40 mg of a trospium salt.

[0010] Also provided herein is a method of treating dementia-related psychosis in a patient in need thereof, comprising administering to the patient a total daily dose of 25-200 mg of xanomeline and / or a salt thereof, and 5-40 mg of a trospium salt.

[0011] The present disclosure further provides a method of reducing the risk of relapse in a patient with dementia-associated psychosis, comprising administering to the patient a total daily dose of 25-250 mg of xanomeline and / or a salt thereof and 5-60 mg of a trospium salt. In certain embodiments, if the patient is 55 years of age or older, the total daily dose is 25-200 mg of xanomeline and / or a salt thereof and 5-30 mg of a trospium salt. In certain embodiments, if the patient is under 55 years of age, the total daily dose is 100-250 mg of xanomeline and / or a salt thereof and 40-60 mg of a trospium salt.

[0012] Further aspects and advantages will become apparent to those of skill in the art upon review of the following detailed description: While the dosage forms, methods of making, and methods of treatment are susceptible to embodiment in various forms, the following description includes specific embodiments with the understanding that the disclosure is illustrative and is not intended to limit the disclosure to the specific embodiments described herein.

[0013] The present disclosure will be readily understood by the following detailed description taken in conjunction with the accompanying drawings, in which like reference numbers indicate like structural elements, and in which: The drawings provide exemplary embodiments or aspects of the present disclosure and are not intended to limit the scope of the disclosure. [Brief description of the drawings]

[0014] [Figure 1] Figure 1 shows the titration schedule for the Phase Ib clinical trial of Example 1. The doses shown are in mg. The titration schedule and study duration of subsequent cohorts were determined by the DSC and the investigators when relevant data from previous cohorts became available. BID = twice daily; DSC = dose selection committee; Max = maximum; N / A = not applicable; QD = once daily; TID = three times daily; TDD = total daily dose. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] The previous development of xanomeline, a muscarinic receptor agonist, was stopped due to peripheral cholinergic side effects.The present disclosure provides a dosage form with more effective therapeutic dissolution kinetics for both active ingredients, enhanced pharmacokinetics of trospium chloride, and higher administration compliance.The present disclosure also provides a dosage form with two active substances of different strengths or different ratios.

[0016] The following specific embodiments are provided herein. The present invention is not limited in scope by the specific embodiments described herein, which are for illustrative purposes only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

[0017] Embodiment 1. A method of treating a disorder ameliorated by activating muscarinic receptors in an elderly patient in need of such treatment, comprising administering to the patient a total daily dose of 25-200 mg of xanomeline and / or a salt thereof, and 5-30 mg of a trospium salt.

[0018] Embodiment 2. The method of embodiment 1, wherein the disorder is selected from dementia-related psychosis, schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy.

[0019] Embodiment 3. The method of embodiment 2, wherein the disorder is dementia-related psychosis.

[0020] Embodiment 4 The method of any embodiment, wherein the elderly patient is over 75 years old.

[0021] Embodiment 5. The method of any embodiment, wherein administration is oral.

[0022] Embodiment 6 The method of any embodiment, wherein the patient is treated for at least 7 days.

[0023] Embodiment 7. The method of any embodiment, wherein the xanomeline and / or salt thereof is xanomeline tartrate.

[0024] Embodiment 8. The method of any embodiment, wherein the trospium salt is trospium chloride.

[0025] Embodiment 9. The method of any embodiment, wherein the xanomeline and / or a salt thereof and the trospium salt are administered as a pharmaceutical composition comprising a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof, and a plurality of trospium beads having a core comprising a trospium salt.

[0026] Embodiment 10. The method of any embodiment, wherein the pharmaceutical composition is a capsule comprising a plurality of xanomeline beads and a plurality of trospium beads.

[0027] Embodiment 11. The method of any embodiment, wherein the xanomeline and / or salt thereof is administered as a first pharmaceutical composition comprising a plurality of xanomeline beads having a core comprising xanomeline or a salt thereof, and the trospium salt is administered as a second pharmaceutical composition comprising a plurality of trospium beads having a core comprising the trospium salt.

[0028] Embodiment 12. The method of any embodiment, wherein the first and second pharmaceutical compositions are administered simultaneously.

[0029] Embodiment 13. The method of any embodiment, wherein the first pharmaceutical composition is a first capsule comprising a plurality of xanomeline beads and the second pharmaceutical composition is a second capsule comprising a plurality of trospium beads.

[0030] Embodiment 14 The method of any embodiment, wherein the first and second pharmaceutical compositions are subjected to different administration schedules.

[0031] Embodiment 15. The method of any embodiment, further comprising orally administering to the patient an increased dose of a trospium salt and an increased dose of xanomeline and / or salts thereof, wherein the increased dose of trospium salt is greater than the initial dose of trospium salt and the increased dose of xanomeline and / or salts thereof is greater than the initial dose of xanomeline and / or salts thereof.

[0032] Embodiment 16. The total daily dose is 25 mg of xanomeline and / or its salts and 5 mg of trospium salts, 50 mg of xanomeline and / or its salts and 10 mg of trospium salt, 50 mg of xanomeline and / or its salts and 20 mg of trospium salt, 75 mg of xanomeline and / or its salts and 15 mg of trospium salt, 75 mg of xanomeline and / or its salts and 30 mg of trospium salts, 100 mg of xanomeline and / or its salts and 17.5 mg of trospium salt, 100 mg of xanomeline and / or its salts and 20 mg of trospium salt, 150 mg of xanomeline and / or its salts and 20 mg of trospium salts, 150 mg of xanomeline and / or its salts and 30 mg of trospium salts, 175 mg of xanomeline and / or its salts and 30 mg of trospium salts, and 200 mg of xanomeline and / or its salts and 30 mg of trospium salts 2. The method of any embodiment, wherein the

[0033] Embodiment 17. The method of any embodiment, wherein the total daily dose is 100-200 mg of xanomeline and / or salts thereof and 10-30 mg of a trospium salt.

[0034] Embodiment 18. The method of any embodiment, wherein the total daily dose is 100-200 mg of xanomeline and / or salts thereof and 20-30 mg of a trospium salt.

[0035] Embodiment 19. The method of any embodiment, wherein the total daily dose is 100-200 mg of xanomeline and / or a salt thereof and about 30 mg of a trospium salt.

[0036] Embodiment 20. The method of any embodiment, wherein the total daily dose is about 200 mg of xanomeline and / or a salt thereof and about 30 mg of a trospium salt.

[0037] Embodiment 21. The method of any embodiment, wherein the total daily dose is administered in 2 or 3 intervals.

[0038] Embodiment 22. A mean C of about 7.3±2.0 ng / mL of xanomeline. max The method of any embodiment, wherein

[0039] Embodiment 23. A mean C of about 14.2±5.3 ng / mL of xanomeline. max The method of any embodiment, wherein

[0040] Embodiment 24. The method of any embodiment, wherein the patient has an estimated globular filtration rate (eGFR) greater than 45.

[0041] Embodiment 25. The method of any embodiment, wherein the patient has an estimated bulbar filtration rate (eGFR) greater than 60.

[0042] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0043] The terms "comprise" and "comprising" are inclusive and open, meaning that additional elements may be included.

[0044] The term "consisting of" limits the elements to those specified, excluding impurities normally associated with the elements in addition.

[0045] The term "consisting essentially of" is limited to the elements specified and those elements that do not materially affect the basic and novel characteristics of the material or process.

[0046] All ranges described herein include all possible subsets of ranges and any combination of such subset ranges. By default, ranges include the stated endpoints unless otherwise specified, and when a range of values ​​is provided, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is included within the disclosure. The upper and lower limits of these smaller ranges may be independently included in these smaller ranges and are included within the disclosure, subject to any specifically excluded limit in the stated range. When a stated range includes one or both limits, ranges excluding either or both of those included limits are also considered to be part of the disclosure.

[0047] The term "wt. %" is weight percent based on the total weight of, for example, the core, or the enteric coating, or the total bead, as the context dictates. Unless otherwise stated, wt. % is intended to describe weight percent based on dry weight (e.g., for the core after drying).

[0048] The term "controlled release" is defined as a prolonged release pattern of one or more drugs, such that the drug is released over a period of time. A controlled release formulation has release kinetics that result in measurable serum levels of the drug for a longer period of time than is possible after intravenous injection or after administration of an immediate release oral dosage form. Controlled release, sustained release, extended release, prolonged release, and delayed release have the same definition.

[0049] The term "including" means "including but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0050] The term "mammal" is known in the art. Exemplary mammals include humans, primates, cows, pigs, dogs, cats, and rodents (e.g., mice and rats).

[0051] A "patient," "subject," or "host" treated by the subject method means either a human or non-human mammal.

[0052] "Elderly" or "elderly people" refers to people aged 65 or older.

[0053] The term "pharmaceutical acceptable carrier" is art-recognized. It refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, which is involved in carrying or transporting any subject composition or its components from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not harmful to the patient. Some examples of materials which may function as pharma- ceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations.

[0054] The term "pharmaceutically acceptable salt" or "salt" is art-recognized. It refers to salts prepared from relatively non-toxic acids or bases, including 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, ethylenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, saccharic acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid.

[0055] The term "treating" is art-recognized and refers to curing or ameliorating at least one symptom of any condition or disorder.

[0056] In jurisdictions that prohibit patents on methods administered to the human body, the meaning of "administering" a composition to a human subject shall be limited to prescribing a controlled substance to be self-administered by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit patents on methods administered to the human body, "administering" a composition includes both methods administered to the human body and the aforementioned activities.

[0057] The term "therapeutic agent" is recognized in the art and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of therapeutic agents, also referred to as "drugs," are described in well-known literature references such as the Merck Index (14th ed.), Physicians' Desk Reference (64th ed.), and The Pharmacological Basis of Therapeutics (12th ed.). These therapeutic agents include, but are not limited to, medicines; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or mitigate disease or illness; substances that affect the structure or function of the body, or prodrugs that become biologically active or more active after being placed in a physiological environment.

[0058] As used herein, "dose" refers to a measured amount of active agent that a patient takes at one time. In certain embodiments where the active agent is not xanomeline free base, the amount is the molar equivalent to the corresponding amount of xanomeline free base. For example, drugs are often packaged in a pharma- ceutically acceptable salt form, such as xanomeline tartrate, and the dosage for a strength refers to the mass of the corresponding free base, the molar equivalent of xanomeline. As an example, 76 mg of xanomeline tartrate is the molar equivalent of 50 mg of xanomeline free base. Similarly, in certain embodiments where the active agent is a trospium salt that is not trospium chloride, the amount of trospium salt is the molar equivalent to the corresponding amount of trospium chloride.

[0059] The term "psychotherapy" refers to non-pharmacological therapy. Practitioners use a variety of techniques, including verbal and other interactions with patients, to affect positive therapeutic outcomes. Such techniques include, but are not limited to, behavioral therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, occupational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also called person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavior therapy, reality therapy, response-based therapy, sandplay therapy, status dynamics therapy, hypnosis, and validation therapy. Psychotherapy may involve combining two or more techniques. Therapists can select and tailor techniques based on the needs and responses of individual patients.

[0060] The term "muscarinic disorder" refers to any disease or condition that is ameliorated by activating the muscarinic system, including those in which direct activation of the muscarinic receptors themselves or inhibition of the cholinesterase enzyme has a therapeutic effect.

[0061] The terms "schizophrenia-related disease" and "schizophrenia-related disorder" include, but are not limited to, schizoaffective disorder, psychosis including acute psychosis, delusional disorder, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, dementia with Lewy bodies, or any other disease with psychotic features.

[0062] "Psychosis" refers to an abnormal state of mind that makes it difficult to determine what is real and what is not. Symptoms of psychosis include, but are not limited to, false beliefs (delusions), seeing or hearing things that others do not see or hear (hallucinations), inconsistent speech, behavior that is inappropriate to the situation, sleep problems, social withdrawal, lack of motivation, and difficulty performing everyday activities.

[0063] "Acute psychosis" refers to the rapid or intense onset of psychotic symptoms in a patient, for example as defined in "Acute Transient Psychotic Disorder" (International Classification of Diseases-10) and "Brief Psychosis" (DSM-IV). In individuals with acute psychosis, after a brief preliminary period of anxiety, insomnia, and confusion, sudden, marked delusions with rapid structural changes occur. Acute psychosis may include acute psychotic exacerbations, when the patient may respond with hallucinations or delusions. Acute psychosis lasts for a short period of time, typically 1-2 weeks.

[0064] The term "activator" refers to a molecule described as an agonist, partial agonist, coagonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator, allosteric agonist, or a molecule that directly or indirectly increases receptor activity or signaling.

[0065] The term "inhibitor" refers to a molecule described as an antagonist, partial antagonist, competitive antagonist, noncompetitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist, or a molecule that directly or indirectly reduces receptor activity or signaling.

[0066] As used herein, an "adverse event" is any untoward medical occurrence associated with 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 discomfort enough to interfere with daily activities; intervention may be required. A "severe adverse event" interferes with daily activities; treatment or other intervention is usually required. A "serious adverse event" is fatal; life-threatening (immediate risk of death when the event occurs); requires or prolongs hospitalization; results in persistent or significant impairment / incapacity; or results in birth defects / injuries, 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.

[0067] As used herein, a patient is said to "tolerate" a dose of a compound if administering that dose to that patient does not result in unacceptable adverse events or an unacceptable combination of adverse events.Those skilled in the art will understand that tolerance is a subjective measure, and what one patient may be tolerable may not be tolerable to a different patient.For example, one patient may not be able to tolerate headache.In contrast, a second patient may find headache tolerable, but not be able to tolerate vomiting.A third patient may tolerate either headache alone or vomiting alone.Nevertheless, that patient cannot tolerate the combination of headache and vomiting, even if the severity of each is less than that experienced alone.

[0068] The term "maximum tolerated dose" refers to the highest dose of a drug or therapeutic agent that a patient can take without experiencing intolerable side effects. The maximum tolerated dose is typically determined empirically in clinical trials.

[0069] The term "muscarinic receptor" refers to a G protein-coupled receptor that binds to the neurotransmitter acetylcholine. To date, five subtypes of muscarinic receptors have been identified. "M1" refers to one muscarinic receptor subtype. "M2" refers to two muscarinic receptor subtypes. "M3" refers to three muscarinic receptor subtypes. "M4" refers to four muscarinic receptor subtypes. "M5" refers to five muscarinic receptor subtypes.

[0070] 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, pericyazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupentixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetrabenazine.

[0071] The term "anti-anxiety drug" refers to a drug that reduces anxiety, fear, panic, or related feelings. Such drugs include, but are not limited to, benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), and hydroxyzine.

[0072] The term "antidepressant" refers to a drug that relieves depression and related conditions (e.g., dysthymia). Such drugs include selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), mianserin, mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine, maloquifin, serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine ... serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desven Antidepressants include, but are not limited to, azindole, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline), and monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine).

[0073] The term "sedative" or "tranquilizer" refers to a drug that induces drowsiness, promotes a feeling of fatigue or a desire to sleep, or promotes a state of unconsciousness. Such drugs include, but are not limited to, benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), eszopiclone, zaleplon, zolpidem, and zopiclone.

[0074] The Mini-Mental State Examination (MMSE) is a brief 30-point questionnaire used to quantitatively assess cognition. The MMSE includes simple questions and problems in many areas, such as time and place of testing, repeated word lists, arithmetic, language use and comprehension, and copying drawings.

[0075] The Neuropsychiatric Inventory Clinician (NPI-C) is a valid and reliable clinical diagnostic interview scale used to assess the occurrence, severity, and meaningful changes of specific neuropsychiatric symptoms experienced by people with dementia. It has 14 domains: delusions, hallucinations, agitation, aggression, dysphoria, anxiety, elation / euphoria, apathy / indifference, disinhibition, irritability / lability, abnormal movement disorders, sleep disorders, appetite and feeding disorders, and abnormal vocalizations.

[0076] A clinical impression rating is assigned to each NPI-C item in a specific domain. Clinician raters assign ratings that incorporate all available sources of information (caregiver interviews, patient interviews, patient data, other relevant information) and focus on the previous 4-week time frame. Clinical impressions are rated on a 0-3 point scale; 0=none; 1=mild: causing little stress; 2=moderate: causing distress and substantial behavioral abnormalities; 3=marked: major cause of behavioral abnormalities.

[0077] The NPI-C core scale includes four domains from the NPI-C scale: delusions, hallucinations, agitation, and aggression. These four domains include the following number of items to be assessed by clinicians: delusions, 8 items (maximum score = 24); hallucinations, 7 items (maximum score = 21); agitation, 13 items (maximum score = 39); and aggression, 8 items (maximum score = 24). The maximum score of the NPI-C core scale is 108. In certain embodiments, the NPI-C assessment is performed before all other scale assessments at all visits where it is performed. The four domains of NPI-C can be analyzed together, independently, or in any combination thereof to evaluate the potential benefit to the patient. In particular, the NPI-C hallucinations and delusions domains are particularly appropriate when evaluating the potential benefit for psychosis.

[0078] Treatment Methods of treating disorders ameliorated by activating muscarinic receptors in patients 55 years of age or older in need of treatment are provided. Methods of treating dementia-related psychosis in patients in need of treatment, such as patients 55 years of age or older, e.g., 60 years of age or older, or 65 years of age or older, are also provided. Methods of preventing relapse in patients with dementia-related psychosis are also provided. In certain embodiments, the methods comprise administering to the patient a total daily dose of 25-200 mg of xanomeline and / or a salt thereof, and 5-30 mg of a trospium salt.

[0079] Activators of M1 and M4 muscarinic receptors have been suggested to be effective treatments for schizophrenia, but activation of muscarinic receptors located outside the brain results in side effects that preclude xanomeline from clinical use.For example, in both Phase I and subsequent trials, the muscarinic agonist xanomeline had unacceptable GI and other side effects associated with binding to muscarinic receptors in the periphery of the body.Combining xanomeline with trospium chloride achieves the desired therapeutic effect while reducing or eliminating the side effects of activating muscarinic receptors located outside the brain.

[0080] The tolerability of the muscarinic activator xanomeline is increased by co-administration of the muscarinic antagonist trospium chloride. The most common adverse events observed with administration of xanomeline are nausea, vomiting, diarrhea, excessive sweating, and hypersalivation (so-called cholinergic adverse events). A common anticholinergic adverse event observed with administration of trospium chloride is dry mouth (xerostomia). The disclosed compositions have reduced the occurrence of these adverse events in humans and demonstrated improved xanomeline tolerability. In certain embodiments, after at least 4 weeks of treatment, the occurrence of cholinergic or anticholinergic adverse events is statistically indistinguishable 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 untreated patients. In certain embodiments, at least one adverse event occurring at the start of oral administration is reduced to its pre-treatment level after 5 weeks of treatment.

[0081] KarXT is currently being investigated for the treatment of schizophrenia. It is expected to differ from established therapies by having a different mechanism of action from current antipsychotics, without directly affecting dopamine receptors. This suggests that KarXT does not have many of the common problematic side effects of current antipsychotics (dyskinesia, hyperprolactinemia, metabolic syndrome, etc.). KarXT may also be cognitive-promoting, which means that KarXT may have additional long-term benefits for schizophrenia subjects with cognitive impairment.

[0082] In one embodiment, xanomeline in combination with trospium chloride treats an animal. In a further embodiment, the animal is a mammal. In one embodiment, the mammal is a human.

[0083] In one embodiment, trospium chloride reduces the side effects associated with xanomeline. Such side effects include, but are not limited to, GI side effects, cardiac side effects, excessive sweating, and hypersalivation. The use of trospium with xanomeline allows xanomeline to be used clinically when xanomeline would not be used clinically due to its side effects. In another embodiment, the use of trospium chloride with xanomeline allows xanomeline to achieve a higher maximum tolerated dose than would otherwise be achieved with xanomeline.

[0084] Various time- and resource-intensive methods have demonstrated the efficacy of the combination of xanomeline and trospium chloride. For example, animal models demonstrate the efficacy of new therapeutic agents for schizophrenia, including pharmacological models (e.g., ketamine model) and genetic models (e.g., DISC1 mice). Similarly, animal models, including rodents, dogs, and non-human primates, show the side effect profile of pharmacological agents. Although animal models are experimental surrogates for humans, they may suffer from deficiencies in physiological differences between humans and animals and may have limited predictive power for human experiments, especially for central nervous system disorders. Alternatively, the disclosed combinations can be attempted in human controlled clinical trials. Standard measures based on patient self-reports can be used by those skilled in the art to assess various side effects, such as GI discomfort. As another example, objective physiological scales (e.g., EKG) can be used by those skilled in the art. A series of standard scales have also been developed to assess symptoms of schizophrenia, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression (CGI).Typically, clinical trials are double-blind, with one group of patients receiving an inactive placebo and the other group receiving the active intervention.

[0085] The Positive and Negative Syndrome Scale (PANSS) is a medical scale used to measure symptom severity in patients with schizophrenia. The name refers to two types of symptoms in schizophrenia as defined by the American Psychiatric Association: positive symptoms, which refer to an excess or distortion of normal functioning (e.g., hallucinations and delusions), and negative symptoms, which represent a decrease or loss of normal functioning. Some of these functions that may be lost include normal thinking, behavior, the ability to tell fantasy from reality, and the ability to express emotions appropriately.

[0086] The PANSS is a relatively short consultation of approximately 45-50 minutes. Examiners must be trained to a standardized level of reliability. Patients are rated from 1 to 7 on 30 different symptoms in three categories, based on the examination and the report of family members or primary care hospital workers. The first category of the PANSS is a positive scale, with 7 items (minimum score = 7, maximum score = 49): delusions, conceptual confusion, hallucinations, agitation, grandiosity, distrust / persecution, and hostility. The second category is a negative scale, with 7 items (minimum score = 7, maximum score = 49): blunted affect, emotional withdrawal, inadequate intimacy, passive / unemotional social withdrawal, difficulties with abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The third category was the General Psychopathology Scale, which included 16 items (minimum score = 16, maximum score = 112): hypochondria, anxiety, guilt, tension, eccentric movements and postures, depression, hypokinesia, uncoordination, unnatural thought content, disorientation, impaired attention, lack of judgment and awareness of illness, impaired volition, impaired impulse control, preoccupation, and voluntary social avoidance.

[0087] The PANSS Marder factor score is the sum of five negative scales and two overall scales (N1. Flat affect; N2. Emotional withdrawal; N3. Impaired communication; N4. Passive / amotivated social withdrawal; N6. Lack of spontaneity; G7. Hypokinesia; and G16. Voluntary social avoidance). If a patient has a recorded PANSS assessment but any items are missing, the last nonmissing score for the individual item from the previous assessment is carried over. If more than 30% of the items are missing at a particular visit, the respective positive scores are not calculated. This is treated as missing data in the analysis.

[0088] Since 1, not 0, gives the lowest score for each item, patients cannot score below 30 for the total PANSS score. Subscores can be given separately for positive items, negative items, and overall psychopathology. The maximum possible total score is 210. On the first version of the PANSS scale, 101 adult patients (aged 20-68 years) with schizophrenia were ranked. Their mean scores were 18.20 for the positive scale, 21.01 for the negative scale, and 37.74 for the overall psychopathology. The mean total PANSS score for these subjects was 76.95.

[0089] In certain embodiments, the subject's Positive and Negative Syndrome Scale (PANSS) total score is reduced by at least 10 points more than placebo, for example, after 5 weeks of treatment. In certain embodiments, the PANSS positive subscore is reduced by at least 3 points more than placebo, for example, after 5 weeks of treatment. In certain embodiments, the PANSS negative subscore is reduced by at least 2 points more than placebo, for example, after 5 weeks of treatment.

[0090] In certain embodiments, the PANSS total score of the subject is reduced by at least 10 points, for example, after 5 weeks of treatment, compared to the subject's baseline.In certain embodiments, the PANSS positive subscore is reduced by at least 3 points, for example, after 5 weeks of treatment, compared to the subject's baseline.In certain embodiments, the PANSS negative subscore is reduced by at least 2 points, for example, after 5 weeks of treatment, compared to the subject's baseline.

[0091] Another scale used to assess patients is the Clinical Global Impression-Severity Scale (CGI-S). This 7-point scale requires the clinician to assess the severity of the patient's illness at the time of assessment, compared to the clinician's experience with patients with the same diagnosis. Possible assessments are (1) normal, not ill at all, (2) borderline psychotic, (3) mildly ill, (4) moderately ill, (5) markedly ill, (6) severely ill, and (7) most severely ill patient. In patients with schizophrenia, changes in the CGI-S follow a consistent pattern compared to the more objective PANSS scores.

[0092] Prior to administering the disclosed combination, the patient may have a lead-in period of 1-14 days during which trospium chloride is administered alone. In one embodiment, trospium chloride is administered for one or more dosing periods prior to administering xanomeline to allow trospium chloride to accumulate in the body or to reach or approach a steady state exposure level. This accumulation or higher exposure level of trospium chloride increases the blockade of muscarinic receptors outside the brain, reducing adverse events when xanomeline is administered. In another embodiment, trospium chloride is administered for one or more days prior to xanomeline.

[0093] Before administering the disclosed combination, the patient may discontinue any previous use of antipsychotic drugs.In some embodiments, the patient discontinues such drugs for at least 1 week, for example 2 weeks.In some embodiments, the patient does not discontinue any previous use of such antipsychotic drugs, and the disclosed combination is administered simultaneously with such drugs.

[0094] The present disclosure further provides a method of treating acute psychosis in a patient in need thereof, comprising orally administering to the patient twice daily an oral pharmaceutical composition comprising xanomeline or a salt thereof and a trospium salt. 1. In certain embodiments, when the total daily dose is 200-250 mg of xanomeline and / or its salts and 40-60 mg of trospium salt, a mean reduction in the total PANNS score of at least about 11.6 points is achieved compared to placebo. In certain embodiments, a mean reduction in the PANSS positive subscore of at least 3 points is achieved compared to placebo. In certain embodiments, a reduction in the PANSS negative subscore of at least 2 points is achieved compared to placebo. In certain embodiments, the reduction in the PANSS score is achieved within about 5 weeks. In certain embodiments, the patient had a CGI-S score of 4-7 prior to administration of the oral pharmaceutical composition.

[0095] In certain embodiments, a total daily dose of 200-250 mg of xanomeline and / or salts thereof and 40-60 mg of trospium salt achieves a mean reduction in the patient's total PANSS score of at least about 11.6 points compared to the patient's baseline. In certain embodiments, a mean reduction in the patient's PANSS positive subscore of at least 3 points compared to the patient's baseline. In certain embodiments, a reduction in the patient's PANSS negative subscore of at least 2 points compared to the patient's baseline is achieved.

[0096] In certain embodiments, the patient has a diagnosis of 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.

[0097] In certain embodiments, the patient has previously been administered one or more antipsychotic drugs. In certain embodiments, the patient was a poor responder to such administration. In certain embodiments, the patient was treatment-resistant.

[0098] In certain embodiments, the patient is an adult. In certain embodiments, the patient is elderly, e.g., over 55 years of age, e.g., over 65 years of age. In certain embodiments, the patient has dementia-related psychosis.

[0099] Dose escalation In certain embodiments, the method further comprises orally administering to the patient an increased dose of trospium salt and an increased dose of xanomeline and / or a salt thereof, wherein the increased dose of trospium salt is greater than the initial dose of trospium salt and the increased dose of xanomeline and / or a salt thereof is greater than the initial dose of xanomeline and / or a salt thereof.

[0100] Treatment can be started with a lower dose. The dosage can then be increased in small increments until a balance between therapeutic effect and side effects is achieved. While the subject is being treated, the patient's health can be monitored by measuring one or more of the relevant indicators at predetermined times during the treatment period. Treatment, including composition, amount, administration, and preparation time, can be adjusted per such monitoring. The patient can be periodically reevaluated to determine improvement by measuring the same parameters. Adjustments to the disclosed compositions administered and possibly administration time can be made based on these reevaluations.

[0101] A method of treating dementia-related psychosis in a patient in need thereof is provided, comprising orally administering to the patient twice daily an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and a plurality of trospium beads comprising a trospium salt, via an escalating scheme comprising escalating doses of xanomeline or a salt thereof and the trospium salt.

[0102] Also provided is a method of treating dementia-related psychosis in a patient in need of treatment comprising orally administering an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and a plurality of trospium beads comprising a trospium salt, twice daily via an escalation scheme comprising titration of xanomeline or a salt thereof, until an amount equivalent to 200 mg of xanomeline free base and an amount equivalent to 20 mg of trospium chloride have been administered.

[0103] In certain embodiments, xanomeline or a salt thereof is administered in a first amount for a first period of time, and then the first amount is increased to a second amount. In certain embodiments, the first amount of xanomeline is equivalent to 50 mg of xanomeline free base. In certain embodiments, the first period of time for xanomeline administration is 1 to 5 days, for example 2 days. In certain embodiments, the second amount of xanomeline is equivalent to 100 mg of xanomeline free base.

[0104] In certain embodiments, the method further comprises administering xanomeline or a salt thereof in a second amount for a second period of time, and then increasing the second amount to a third amount. In certain embodiments, the second period of xanomeline administration is from 3 days to 1 week. In certain embodiments, the third amount of xanomeline is equivalent to 125 mg of xanomeline free base.

[0105] In certain embodiments, the trospium salt is administered in a first amount for a first period of time, and the first amount is increased to a second amount. In certain embodiments, the first amount of the trospium salt is equivalent to 20 mg of trospium chloride. In certain embodiments, the first period of time for trospium administration is at least one week. In certain embodiments, the second amount of the trospium salt is equivalent to 30 mg of trospium chloride.

[0106] In certain embodiments, if a patient does not tolerate higher doses of xanomeline or a salt thereof, and a trospium salt, the amount of xanomeline or a salt thereof, and a trospium salt administered to the patient is reduced.

[0107] In certain embodiments, xanomeline or a salt thereof and a trospium salt are administered without causing serious adverse events.

[0108] In certain embodiments, if the patient is 55 years of age or older, the initial dose is 60 mg of xanomeline and / or a salt thereof administered as three doses of 20 mg of xanomeline and / or a salt thereof and 2 mg of trospium salt, for a total daily dose of 6 mg of trospium salt.

[0109] In certain embodiments, if the patient is 55 years of age or older, after the first period of administration, the initial dose is increased to a total daily dose of 90 mg xanomeline and / or salts thereof and 9 mg trospium salt, administered as three doses of 30 mg xanomeline and / or salts thereof and 3 mg trospium salt. In certain embodiments, the first period is 1 to 14 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days. In certain embodiments, the first period is 7 days.

[0110] In certain embodiments, after the second period of administration, if the patient 55 years of age or older tolerates the increased dose, and if the patient has an adequate response, the increased dose is further increased to a total daily dose of 120 mg xanomeline and / or salts thereof and 12 mg trospium salt, administered as three doses of 40 mg xanomeline and / or salts thereof and 4 mg trospium salt. In certain embodiments, the second period is 7 to 21 days in total, such as 7 days in total, 8 days in total, 9 days in total, 10 days in total, 11 days in total, 12 days in total, 13 days in total, 14 days in total, 15 days in total, 16 days in total, 17 days in total, 18 days in total, 19 days in total, 20 days in total, and 21 days in total. In certain embodiments, the second period is 14 days in total. In certain embodiments, if the patient does not tolerate the increased dose, the optimized dose is the initial dose.

[0111] In certain embodiments, after about a full 21 days of administration, if the patient, who is 55 years or older, tolerates the further increased dose, and if the patient has an adequate response, the further increased dose is again increased to a total daily dose of 150 mg xanomeline and / or salts thereof and 15 mg trospium salt, administered as three doses of 50 mg xanomeline and / or salts thereof and 5 mg trospium salt. In certain embodiments, the third period is a full 14 to 28 days, such as a full 14 days, a full 15 days, a full 16 days, a full 17 days, a full 18 days, a full 19 days, a full 20 days, a full 21 days, a full 22 days, a full 23 days, a full 24 days, a full 25 days, a full 26 days, a full 27 days, and a full 28 days. In certain embodiments, the third period is a full 21 days. In certain embodiments, if the patient does not tolerate the further increased dose, the optimized dose is the increased dose.

[0112] In certain embodiments, after the fourth period, if the patient 55 years or older tolerates the increased dose again, and if the patient has an adequate response, the increased dose is increased again to a total daily dose of 200 mg xanomeline and / or salts thereof and 20 mg trospium salt administered as three doses of 66.7 mg xanomeline and / or salts thereof and 6.67 mg trospium salt. In certain embodiments, the fourth period is 21-35 days in total, such as 21 days in total, 22 days in total, 23 days in total, 24 days in total, 25 days in total, 26 days in total, 27 days in total, 28 days in total, 29 days in total, 30 days in total, 31 days in total, 32 days in total, 33 days in total, 34 days in total, and 35 days in total. In certain embodiments, the fourth period is 28 days in total. In certain embodiments, if the patient does not tolerate the increased dose again, the optimized dose is a further increased dose.

[0113] In certain embodiments, if the patient is under 55 years old, the initial dose is a total daily dose of 100 mg xanomeline and / or its salts, and 40 mg trospium salt, administered as two doses of 50 mg xanomeline and / or its salts, and 20 mg trospium salt. In certain embodiments, after the first period, the initial dose is increased to a total daily dose of 200 mg xanomeline and / or its salts, and 40 mg trospium salt, administered as two doses of 100 mg xanomeline and / or its salts, and 20 mg trospium salt. In certain embodiments, the first period is 1 to 7 days, such as 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In certain embodiments, the first period is 1 day or 2 days.

[0114] In certain embodiments, after the second period, if the patient under 55 tolerates the increased dose and if the patient has an adequate response, the increased dose is further increased to a total daily dose of 250 mg xanomeline and / or salts thereof and 60 mg trospium salt, administered as two doses of 125 mg xanomeline and / or salts thereof and / or 30 mg trospium salt. In certain embodiments, the second period is 3-14 days in total, such as 3 days in total, 4 days in total, 5 days in total, 6 days in total, 7 days in total, 8 days in total, 9 days in total, 10 days in total, 11 days in total, 12 days in total, 13 days in total, or 14 days in total. In certain embodiments, the second period is 3-7 days in total. In certain embodiments, if the patient does not tolerate the increased dose, the optimized dose is the initial dose.

[0115] "Total days" refers to the period of administration from the first dose. Thus, the first period is a subset of the second period. The second period is a subset of the third period. The third period is also a subset of the fourth period.

[0116] In certain embodiments, the total daily dose is 25 mg of xanomeline and / or its salts and 5 mg of trospium salts, 50 mg of xanomeline and / or its salts and 10 mg of trospium salt, 50 mg of xanomeline and / or its salts and 20 mg of trospium salt, 60 mg of xanomeline and / or its salts and 6 mg of trospium salt, 75 mg of xanomeline and / or its salts and 15 mg of trospium salt, 75 mg of xanomeline and / or its salts and 30 mg of trospium salts, 90 mg of xanomeline and / or its salts and 9 mg of trospium salt, 100 mg of xanomeline and / or its salts and 17.5 mg of trospium salt, 100 mg of xanomeline and / or its salts and 20 mg of trospium salt, 120 mg of xanomeline and / or its salts and 12 mg of trospium salt, 150 mg of xanomeline and / or its salts and 15 mg of trospium salt, 150 mg of xanomeline and / or its salts and 20 mg of trospium salts, 150 mg of xanomeline and / or its salts and 30 mg of trospium salts, 175 mg of xanomeline and / or its salts and 30 mg of trospium salts, 200 mg of xanomeline and / or its salts and 20 mg of trospium salts, and 200 mg of xanomeline and / or its salts and 30 mg of trospium salts is selected from.

[0117] In certain embodiments, the total daily dose is 60 mg of xanomeline and / or its salts and 6 mg of trospium salt, 90 mg of xanomeline and / or its salts and 9 mg of trospium salt, 120 mg of xanomeline and / or its salts and 12 mg of trospium salt, 150 mg of xanomeline and / or its salts and 15 mg of trospium salt, and 200 mg of xanomeline and / or its salts and 20 mg of trospium salts is selected from.

[0118] In a particular embodiment, the total daily dose is 25 mg of xanomeline and / or its salts and 5 mg of the trospium salt.

[0119] In a particular embodiment, the total daily dose is 50 mg of xanomeline and / or its salts and 10 mg of the trospium salt.

[0120] In a particular embodiment, the total daily dose is 50 mg of xanomeline and / or its salts and 20 mg of the trospium salt.

[0121] In a particular embodiment, the total daily dose is 75 mg of xanomeline and / or its salts and 15 mg of the trospium salt.

[0122] In a particular embodiment, the total daily dose is 75 mg of xanomeline and / or its salts and 30 mg of the trospium salt.

[0123] In a particular embodiment, the total daily dose is 100 mg of xanomeline and / or its salt and 17.5 mg of the trospium salt.

[0124] In a particular embodiment, the total daily dose is 100 mg of xanomeline and / or its salts and 20 mg of the trospium salt.

[0125] In a particular embodiment, the total daily dose is 100 mg of xanomeline and / or its salts and 40 mg of the trospium salt.

[0126] In a particular embodiment, the total daily dose is 150 mg of xanomeline and / or its salts and 20 mg of the trospium salt.

[0127] In a particular embodiment, the total daily dose is 150 mg of xanomeline and / or its salts and 30 mg of the trospium salt.

[0128] In a particular embodiment, the total daily dose is 150 mg of xanomeline and / or its salts and 40 mg of the trospium salt.

[0129] In a particular embodiment, the total daily dose is 175 mg of xanomeline and / or its salts and 30 mg of the trospium salt.

[0130] In a particular embodiment, the total daily dose is 175 mg of xanomeline and / or its salts and 40 mg of the trospium salt.

[0131] In a particular embodiment, the total daily dose is 200 mg of xanomeline and / or its salts and 30 mg of the trospium salt.

[0132] In a particular embodiment, the total daily dose is 200 mg of xanomeline and / or its salts and 40 mg of the trospium salt.

[0133] In one embodiment, the xanomeline and trospium chloride are administered to the patient six times during a 24 hour period. In another embodiment, the xanomeline and trospium chloride are administered to the patient five times during a 24 hour period. In another embodiment, the xanomeline and trospium chloride are administered to the patient four times during a 24 hour period. In one embodiment, the xanomeline and trospium chloride are administered to the patient three times during a 24 hour period. In another embodiment, the xanomeline and trospium chloride are administered to the patient two times during a 24 hour period. In another embodiment, the xanomeline and trospium chloride are administered to the patient once during a 24 hour period.

[0134] In a particular embodiment, administration comprises a twice daily administration schedule of 25 mg of xanomeline and / or a salt thereof and 5 mg of a trospium salt.

[0135] In a particular embodiment, administration comprises a three times daily administration schedule of 25 mg of xanomeline and / or a salt thereof and 5 mg of a trospium salt.

[0136] In certain embodiments, administration comprises a dosing schedule of 25 mg xanomeline and / or a salt thereof and 5 mg trospium salt twice daily, and 50 mg xanomeline and / or a salt thereof and 7.5 mg trospium salt once daily.

[0137] In a particular embodiment, administration comprises a twice daily administration schedule of 25 mg of xanomeline and / or a salt thereof and 10 mg of a trospium salt.

[0138] In certain embodiments, administration comprises a dosing schedule of 50 mg xanomeline and / or a salt thereof and 7.5 mg trospium salt twice daily, and 50 mg xanomeline and / or a salt thereof and 5 mg trospium salt once daily.

[0139] In a particular embodiment, administration comprises a twice daily administration schedule of 50 mg of xanomeline and / or a salt thereof and 10 mg of a trospium salt.

[0140] In a particular embodiment, administration comprises a three times daily administration schedule of 50 mg of xanomeline and / or a salt thereof and 10 mg of a trospium salt.

[0141] In certain embodiments, administration comprises a dosing schedule of 50 mg xanomeline and / or a salt thereof and 10 mg trospium salt twice daily, and 75 mg xanomeline and / or a salt thereof and 10 mg trospium salt once daily.

[0142] In certain embodiments, administration comprises a dosing schedule of 75 mg xanomeline and / or a salt thereof and 10 mg trospium salt twice daily, and 50 mg xanomeline and / or a salt thereof and 10 mg trospium salt once daily.

[0143] In certain embodiments, the low dose is split TID rather than BID. BID keeps the trospium dose as low as possible, with a minimum of 10 mg trospium per capsule. In certain embodiments, the starting dose of 50 / 5 mg or 50 / 7.5 mg xanomeline / trospium is split TID, so that the individual doses are 17 / 2.5 mg xanomeline / trospium.

[0144] In one embodiment, an extended release formulation of trospium chloride is used in combination with xanomeline. In another embodiment, the extended release of trospium chloride is administered to a patient 1 to 5 times during a 24 hour period. In one embodiment, the extended release of trospium chloride is administered 1 to 3 times during a 24 hour period. In another embodiment, 5 milligrams to 400 milligrams of extended release trospium chloride are used during a 24 hour period. In one embodiment, 20 milligrams to 200 milligrams of extended release trospium chloride are used during a 24 hour period.

[0145] In one embodiment, 225 mg of xanomeline and 40 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 100 mg of xanomeline and 20 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 125 mg of xanomeline and 20 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 125 mg of xanomeline and 30 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 125 mg of xanomeline and 40 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 200 mg of xanomeline and 40 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 200 mg of xanomeline and 80 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 250 mg of xanomeline and 60 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 250 mg of xanomeline and 80 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 300 mg of xanomeline and 40 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 300 mg of xanomeline and 60 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 300 mg of xanomeline and 80 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 350 mg of xanomeline and 40 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 350 mg of xanomeline and 60 mg of trospium chloride are administered to the patient in a 24 hour period. In another embodiment, 350 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24 hour period.

[0146] In a particular embodiment, the total daily dose is 60-200 mg of xanomeline and / or its salts and 6-30 mg of trospium salt. In a particular embodiment, the total daily dose is 120-200 mg of xanomeline and / or its salts and 12-20 mg of trospium salt. In a particular embodiment, the total daily dose is 60 mg of xanomeline and / or its salts and trospium salt administered as three doses of 20 mg of xanomeline and / or its salts and 2.0 mg of trospium salt. In a particular embodiment, the total daily dose is 90 mg of xanomeline and / or its salts and 9 mg of trospium salt administered as three doses of 30 mg of xanomeline and / or its salts and 3.0 mg of trospium salt. In a particular embodiment, the total daily dose is 120 mg xanomeline and / or its salt, administered as three doses of 40 mg xanomeline and / or its salt, and 4.0 mg trospium salt, and 12 mg trospium salt. In a particular embodiment, the total daily dose is 150 mg xanomeline and / or its salt, administered as three doses of 50 mg xanomeline and / or its salt, and 5.0 mg trospium salt, and 15 mg trospium salt. In a particular embodiment, the total daily dose is 200 mg xanomeline and / or its salt, administered as three doses of 66.7 mg xanomeline and / or its salt, and 6.67 mg trospium salt, and 20 mg trospium salt.

[0147] In certain embodiments, reducing the daily dose of a trospium salt improves the overall tolerability of xanomeline and / or its salts.

[0148] Reduced risk of discontinuation and relapse The present disclosure provides a method of reducing the risk of relapse in a patient with dementia-related psychosis, comprising administering to the patient a total daily dose of 25-250 mg of xanomeline and / or a salt thereof and 5-60 mg of trospium salt. In certain embodiments, if the patient is 55 years of age or older, the total daily dose is 25-200 mg of xanomeline and / or a salt thereof and 5-30 mg of trospium salt. In certain embodiments, if the patient is under 55 years of age, the total daily dose is 100-250 mg of xanomeline and / or a salt thereof and 40-60 mg of trospium salt.

[0149] In certain embodiments, the patient has psychosis and is treated with xanomeline and trospium for clinically meaningful therapeutic benefit, defined as, for example, at least a 30% reduction in NPI-C H+D and an improvement in CGI-I, for example, at least a 40% reduction, or at least a 50% reduction. For improved patients, xanomeline and trospium are continued. In this embodiment, the treatment prevents relapse and does not prevent the onset of symptoms, but provides the patient with maintenance therapy; these patients experience an initial recovery using the disclosed methods and then maintain the therapeutic benefits with continued use of xanomeline and trospium compared to the same patients taking a placebo.

[0150] In certain embodiments, relapse is indicated by at least a 40% increase in the Neuropsychiatric Inventory Clinician Hallucinations and Delusions (NPI-C H+D) score over 12 weeks of administration compared to before administration, and a Clinical Global Impression-Improvement (CGI-I) score of 6 or 7. In certain embodiments, relapse is indicated by at least a 40% increase in the Neuropsychiatric Inventory Clinician (NPI-C) core score over 12 weeks of administration compared to before administration, and a Clinical Global Impression-Improvement (CGI-I) score of 6 or 7. In certain embodiments, relapse is indicated by treatment with an antipsychotic other than xanomeline and / or its salts and trospium salts for dementia-related delusions or hallucinations during administration. In certain embodiments, relapse is indicated by a patient discontinuing administration of xanomeline and / or its salts and trospium salts. In certain embodiments, relapse is indicated by discontinuing administration of xanomeline and / or its salts and trospium salts due to lack of efficacy. In certain embodiments, relapse is indicated by a patient being hospitalized due to worsening psychotic, agitation, or aggressive symptoms during treatment.

[0151] In certain embodiments, the administration results in an improvement in the patient's NPI-C core score. In certain embodiments, the administration results in an improvement in the patient's Cohen-Mansfield Agitation Inventory (CMAI) total score.

[0152] In certain embodiments, the administration results in an improvement in an NPI-C psychosis score, an NPI-C agitation score, an NPI-C aggression score, an NPI-C total score, a Clinical Global Impression-Severity (CGI-S) scale score, or a CGI-I scale score related to psychosis, agitation, and aggression. In certain embodiments, the NPI psychosis score comprises the sum of the hallucinations and delusions domain scores.

[0153] In certain embodiments, said administration results in an improvement in the NPI-C core score.

[0154] In certain embodiments, prior to administration, the patient meets clinical criteria for possible or probable Alzheimer's disease.

[0155] In certain embodiments, prior to administration, the patient has a history of psychotic symptoms that meets International Psychogeriatric Association criteria.

[0156] In certain embodiments, prior to administration, the patient has a score of at least 4 on the Clinical Global Impression-Severity Scale.

[0157] In certain embodiments, prior to administration, the patient has moderate to severe delusions, defined as an NPI-C delusion domain score of at least 2 on two of eight items, and Alzheimer's dementia with an NPI agitation / aggression domain score of at least 4.

[0158] In certain embodiments, prior to administration, the patient has a Mini-Mental State Examination score of 8-22.

[0159] In certain embodiments, prior to administration, the patient is free of psychotic symptoms primarily attributable to a condition other than Alzheimer's disease that causes dementia.

[0160] Each and every method, composition, or use described herein also optionally includes the limitation that the dementia-related psychosis is not Alzheimer's disease associated psychosis, Parkinson's disease associated psychosis, psychotic depression, bipolar disorder, or bipolar disorder with psychosis.

[0161] In some embodiments, treatment is performed outside of a clinical trial setting.

[0162] Pharmaceutical Compositions Provided herein is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and optionally a first coating; and a plurality of trospium beads comprising a trospium salt and optionally a second coating. In certain embodiments, the trospium salt is selected from trospium chloride, trospium bromide, trospium iodide, and trospium saccharinate. In some embodiments, the first coating has the same composition as the second coating.

[0163] In certain embodiments, the oral pharmaceutical composition comprises a plurality of xanomeline beads comprising xanomeline or a salt thereof, hi certain embodiments, the oral pharmaceutical composition comprises a plurality of trospium beads comprising a trospium salt.

[0164] In certain embodiments, the plurality of xanomeline beads has a core comprising xanomeline or a salt thereof and optionally a first coating, hi certain embodiments, the plurality of trospium beads has a core comprising a trospium salt and optionally a second coating.

[0165] In certain embodiments, a capsule shell comprising hydroxypropylmethylcellulose (HPMC) containing a discrete population of drug beads comprising xanomeline tartrate or trospium chloride, where the drug beads are of comparable size and release the active agent rapidly and at substantially similar rates. Following dissolution of the capsule shell in the stomach, the drug beads may dissolve in the stomach or pass through the pyloric valve into the duodenum intact or partially intact, but the ratio of the two drugs in both dissolved and undissolved forms remains relatively constant in the gastrointestinal tract until the drugs are absorbed.

[0166] The formulation for each drug bead is designed to provide a substantially similar release rate of the active agent into serum or a substantially similar T maxThis allows for substantially similar performance from the two actives at different dose ranges, achieving a 100% dose. In a particular embodiment, the capsule contains 50 mg of xanomeline as the tartrate salt and 10 mg of trospium chloride. 50 mg of xanomeline as the free base is equivalent to approximately 76 mg of xanomeline tartrate.

[0167] The mismatch in the number of drug beads in the capsule increases the probability that the ratio of drug beads will not remain substantially constant after the beads are released and dispersed. Thus, in certain embodiments, the trospium beads are formulated with a lower drug load. The effective doses of trospium and xanomeline are contained in approximately the same number of beads. In certain embodiments, despite the difference in drug load, the trospium beads and xanomeline beads release at approximately the same rate. For example, when the capsule dissolution is evaluated using a United States Pharmacopeia (USP) dissolution apparatus, the percentage of dissolved xanomeline is substantially equal to the percentage of dissolved trospium chloride, for example, at 10 minutes, 20 minutes, or 30 minutes.

[0168] In certain embodiments, the oral pharmaceutical composition is a capsule, the capsule comprising a plurality of xanomeline beads, each of said plurality of xanomeline beads having a core comprising 50%-90% by weight xanomeline tartrate, 15%-65% by weight microcrystalline cellulose, and 0%-1% by weight ascorbic acid, and optionally a first coating comprising 0%-2% by weight talc, each of said plurality of xanomeline beads having a size of 0.6 mm-0.85 mm; each of the plurality of trospium beads has a core comprising 8% to 35% by weight trospium chloride, 45% to 50% by weight microcrystalline cellulose, and 35% to 40% by weight lactose monohydrate, and optionally a second coating comprising 0% to 2% by weight talc, each of the plurality of trospium beads having a size between 0.6 mm and 0.85 mm; and each of the plurality of xanomeline beads and the plurality of trospium beads has a dissolution rate of greater than about 95% within approximately the first 20 minutes after entry of the capsule into an aqueous solution.

[0169] In a particular embodiment, each xanomeline bead comprises 66% by weight xanomeline tartrate, 33% by weight microcrystalline cellulose, 0.5% by weight ascorbic acid, and 0.5% by weight talc.

[0170] In certain embodiments, the plurality of trospium beads have a core comprising 4% to 7% trospium chloride, 45% to 60% microcrystalline cellulose, and 35% to 50% lactose monohydrate by weight, and optionally a second coating comprising 0% to 2% talc by weight.

[0171] In a particular embodiment, each trospium bead comprises by weight 17.7% trospium chloride, 46.8% microcrystalline cellulose, 35% lactose monohydrate, and 0.5% talc.

[0172] In certain embodiments, each of the trospium beads comprises 4.4% trospium chloride, 54.5% microcrystalline cellulose, 40.6% lactose monohydrate, and 0.5% talc by weight. In certain embodiments, each of the trospium beads comprises a core comprising 4.4% trospium chloride, 54.5% microcrystalline cellulose, and 40.6% lactose monohydrate by weight, and optionally a coating comprising 0.5% talc by weight.

[0173] In certain embodiments, the capsule comprises an oral pharmaceutical composition, wherein each of the plurality of xanomeline beads has a core comprising 66% by weight xanomeline tartrate, 33% by weight microcrystalline cellulose, 0.5% by weight ascorbic acid, and a coating comprising 0.5% by weight talc; and each of the plurality of trospium beads has a core comprising 17.7% by weight trospium chloride, 46.8% by weight microcrystalline cellulose, 35% by weight lactose monohydrate, and a coating comprising 0.5% by weight talc.

[0174] The medicament may also include one or more pharma- ceutically acceptable salts. The drug may include one or more pharma- ceutically acceptable carriers. The drug may be administered orally. The drug may be delivered orally using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, caplets, or gel caps, and other oral administration methods known to those skilled in the art.

[0175] The medicament may be in a dosage form that immediately releases the drug. In an alternative embodiment, the medicament may have a controlled release dosage form.

[0176] The drugs may also be formulated using other controlled release formulations known to those skilled in the art.

[0177] 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 be classified into more than one drug category.For example, benzodiazepines may be considered as anxiolytics, sedatives, and tranquilizers.

[0178] Bead / Core Excipients The beads or cores may contain one or more excipients. In one embodiment, the excipients include one or more fillers, binders, and surfactants. Other optional ingredients include, but are not limited to, flow agents, lubricants, disintegrants, swelling agents, and antioxidants. Xanomeline or its pharma- ceutically acceptable salt and trospium salt may be in separate matrices within the same drug.

[0179] The amount of xanomeline free base in the core can be at least 10% by weight, or at least 15% by weight, or at least 20% by weight, or at least 25% by weight, or at least 30% by weight. For example, the amount of xanomeline tartrate can be at least 50% by weight, or at least 55% by weight, or at least 60% by weight, or at least 65% by weight, or at least 70% by weight, or at least 75% by weight, or at least 80% by weight, or at least 85% by weight, of the core, ranging from about 60% by weight to about 90% by weight, or from about 65% by weight to about 85% by weight. It is understood that all ranges including these values ​​as endpoints are contemplated, for example, at least about 15% by weight to about 90% by weight, about 20% by weight to about 85% by weight, about 30% by weight to about 85% by weight, or about 50% by weight to about 90% by weight. In certain embodiments, the xanomeline beads comprise between 30% and 80% xanomeline tartrate by weight, for example, 66% xanomeline tartrate by weight.

[0180] The amount of trospium salt in the core can be at least 10% by weight, or at least 15% by weight, or at least 20% by weight, or at least 25% by weight, or at least 30% by weight. For example, the amount of trospium chloride can be at least 50% by weight, or at least 55% by weight, or at least 60% by weight, or at least 65% by weight, or at least 70% by weight, or at least 75% by weight, or at least 80% by weight, or at least 85% by weight, of the core, ranging from about 60% by weight to about 90% by weight, or from about 65% by weight to about 85% by weight. It is understood that all ranges including these values ​​as endpoints are contemplated, for example, at least about 15% by weight to about 90% by weight, about 20% by weight to about 85% by weight, about 30% by weight to about 85% by weight, or about 50% by weight to about 90% by weight. In certain embodiments, the trospium is trospium chloride. In certain embodiments, the trospium beads contain between 8% and 35% trospium chloride by weight, for example 17.7% trospium chloride by weight.

[0181] In further embodiments, the matrix comprises a polymer, for example to modify the release profile of the active agent in the matrix. In further embodiments, the polymer comprises a water-soluble polymer. In further embodiments, the water-soluble polymer is selected from Eudragit™ RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof. In further embodiments, the polymer comprises a water-insoluble polymer. In further embodiments, the water insoluble polymer is selected from Eudragit® RS, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethanes, and mixtures thereof.

[0182] Fillers include, but are not limited to, lactose, saccharose, glucose, starch, microcrystalline cellulose, fine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch, and dibasic calcium phosphate dihydrate. In one embodiment, the filler is not water soluble but can absorb water. In one embodiment, the filler is a spheronization aid. The spheronization aid can include one or more of crospovidone, carrageenan, chitosan, pectic acid, glyceride, β-cyclodextrin (β-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide. In one embodiment, the filler includes microcrystalline cellulose.

[0183] The amount of filler in the xanomelin core is not particularly limited. In an embodiment, the amount of filler (e.g., microcrystalline cellulose) can be in the range of about 10% to about 70% by weight, or about 16% to about 23% by weight, or at least 19% by weight or at least 19.5% by weight, for example, about 20% by weight. In a specific embodiment, the xanomelin beads contain about 15% to about 65% by weight, for example, about 15% to about 20% by weight, about 20% to about 25% by weight, about 25% to about 30% by weight, about 30% to about 35% by weight, about 35% to about 40% by weight, about 40% to about 45% by weight, about 45% to about 50% by weight, about 50% to about 55% by weight, about 55% to about 60% by weight, or about 60% to about 65% by weight of microcrystalline cellulose. In a particular embodiment, the xanomelin beads comprise 33.5% by weight microcrystalline cellulose.

[0184] The amount of filler in the trospium core is not particularly limited. In an embodiment, the amount of filler (e.g., microcrystalline cellulose or lactose) can be in the range of about 10% to about 80% by weight, or about 16% to about 23% by weight, or at least 19% by weight or at least 19.5% by weight, for example, about 20% by weight. In a specific embodiment, the trospium beads contain 25% to 80% by weight, for example, about 25% to 30% by weight, about 30% to 35% by weight, about 35% to 40% by weight, about 40% to 45% by weight, about 45% to 50% by weight, about 50% to 55% by weight, about 55% to 60% by weight, about 60% to 65% by weight, about 65% to 70% by weight, about 70% to 75% by weight, or about 75% to 80% by weight of microcrystalline cellulose. In a particular embodiment, the trospium beads comprise 46.8% by weight microcrystalline cellulose.

[0185] In certain embodiments, the trospium beads comprise between 15% and 70% by weight lactose monohydrate, e.g., about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, or about 65% to 70% by weight. In certain embodiments, the trospium beads comprise 35% lactose monohydrate.

[0186] Binders include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose, e.g., hypromellose 2910, Methocel® E), carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinylpyrrolidone (povidone), cross-linked 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, e.g., hypromellose.

[0187] The amount of binder in the xanomelin core is not particularly limited. In an embodiment, the amount of binder (e.g., hypromellose) can be about 1% by weight to about 10% by weight, about 2% by weight to about 8% by weight, or about 4% by weight to about 6% by weight, for example, about 5% by weight.

[0188] The amount of binder in the trospium core is not particularly limited. In an embodiment, the amount of binder (e.g., hypromellose) can be about 1% by weight to about 10% by weight, about 2% by weight to about 8% by weight, or about 4% by weight to about 6% by weight, for example, about 5% by weight.

[0189] 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.

[0190] The amount of surfactant, for example as a processing aid, in the xanomelin core is not particularly limited. In an embodiment, the amount of surfactant (e.g., microcrystalline cellulose) can be in the range of about 0.1% to about 1% by weight, about 0.2% to about 0.8% by weight, or about 0.4% to about 0.6% by weight, for example about 0.5% by weight.

[0191] The amount of surfactant, for example, as a processing aid, in the trospium core is not particularly limited. In an embodiment, the amount of surfactant (e.g., sodium lauryl sulfate) can be in the range of about 0.1% to about 1% by weight, about 0.2% to about 0.8% by weight, or about 0.4% to about 0.6% by weight, for example, about 0.5% by weight.

[0192] Disintegrants include, but are not limited to, starch, sodium cross-linked carboxymethylcellulose, carmellose sodium, carmellose calcium, cross-linked polyvinylpyrrolidone, and sodium starch glycolate, low-substituted hydroxypropylcellulose, and hydroxypropyl starch.

[0193] Flow agents include, but are not limited to, polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silicon dioxide, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetanol, stearol, and talc.

[0194] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and silicone-treated talc. In certain embodiments, the xanomeline beads contain 0% to 2% talc by weight, e.g., 0.5% talc by weight. In certain embodiments, the trospium beads contain 0% to 2% talc by weight, e.g., 0.5% talc by weight.

[0195] In certain embodiments, the formulation further comprises one or more antioxidants. Examples of pharma- ceutically 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% by weight of an antioxidant, e.g., 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01%.

[0196] In certain embodiments, the oral pharmaceutical composition further comprises ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises 0.2% to 1% by weight of ascorbic acid. In certain embodiments, the oral pharmaceutical composition comprises about 0.5% by weight of ascorbic acid. In certain embodiments, the oral pharmaceutical composition further comprises butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises 0.01% to 0.1% by weight of butylated hydroxytoluene. In certain embodiments, the oral pharmaceutical composition comprises about 0.05% by weight of butylated hydroxytoluene. In certain embodiments, the formulation comprises about 0.05% by weight of BHT or 0.5% by weight of ascorbic acid. In certain embodiments, the antioxidant is present in the xanomelin core or the xanomelin beads.

[0197] In certain embodiments, the xanomeline beads comprise 30% to 80% by weight xanomeline tartrate, 15% to 65% by weight microcrystalline cellulose, and 0% to 2% by weight talc. In certain embodiments, the trospium beads comprise 0.2% to 2% by weight talc, such as 0.5% by weight talc. In certain embodiments, the trospium beads comprise 8% to 35% by weight trospium chloride, 25% to 80% by weight microcrystalline cellulose, 15% to 70% by weight lactose monohydrate, and 0.2% to 2% by weight talc.

[0198] In a particular embodiment, the xanomeline tartrate drug beads contain 66% xanomeline tartrate, 33-34% microcrystalline cellulose, and 0.5% talc by weight. In a particular embodiment, the trospium chloride beads contain 17.7% trospium chloride, 46.8% microcrystalline cellulose, 35% lactose monohydrate, and 0.5% talc by weight. In this example, the xanomeline tartrate beads contain at least about 2.5 times the amount of xanomeline as the trospium chloride beads contain.

[0199] Depending on the dosage requirements, the capsule can be prepared with different amounts of xanomeline tartrate and trospium chloride beads.In various embodiments, the capsule contains 25mg xanomeline and 10mg trospium chloride, 50mg xanomeline and 10mg trospium chloride, 50mg xanomeline and 20mg trospium chloride, 75mg xanomeline and 10mg trospium chloride, 75mg xanomeline and 20mg trospium chloride, 125mg xanomeline and 30mg trospium chloride, or 125mg xanomeline and 40mg trospium chloride.In a particular embodiment, the capsule contains 25mg xanomeline as xanomeline tartrate and 10mg trospium chloride. In a particular embodiment, the capsule contains 50 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In a particular embodiment, the capsule contains 50 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In a particular embodiment, the capsule contains 75 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In a particular embodiment, the capsule contains 75 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In a particular embodiment, the capsule contains 125 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In a particular embodiment, the capsule contains 125 mg of xanomeline as xanomeline tartrate and 40 mg of trospium chloride. In certain embodiments, the capsule contains 150 mg of xanomeline and 20 mg of trospium chloride. In certain embodiments, the capsule contains 150 mg of xanomeline and 30 mg of trospium chloride. In certain embodiments, the capsule contains 150 mg of xanomeline and 40 mg of trospium chloride. In certain embodiments, the capsule contains 175 mg of xanomeline and 20 mg of trospium chloride. In certain embodiments, the capsule contains 175 mg of xanomeline and 30 mg of trospium chloride. In certain embodiments, the capsule contains 175 mg of xanomeline and 40 mg of trospium chloride.

[0200] In another embodiment, the medicament comprises between 5 milligrams and 700 milligrams of xanomeline.According to one embodiment, the medicament comprises between 25 milligrams and 300 milligrams of xanomeline.

[0201] In another embodiment, the medicament contains between 1 milligram and 400 milligrams of trospium chloride.In one embodiment, the medicament contains between 6.5 milligrams and 200 milligrams of trospium chloride.

[0202] In one embodiment, trospium chloride extended release is used as the trospium chloride in the drug. In another embodiment, the drug contains 1 milligram to 400 milligrams of trospium chloride extended release. In one embodiment, the drug contains 6.5 milligrams to 200 milligrams of trospium chloride extended release.

[0203] In one embodiment, a medicament contains 75 mg or 225 mg of xanomeline and the same medicament contains 20 mg or 40 mg of trospium chloride, hi another embodiment, a medicament contains 75 mg or 225 mg of xanomeline and a different co-administered medicament contains 20 mg or 40 mg of trospium chloride.

[0204] In this patient population aged 55 years or older, a dose of <40 mg trospium chloride has been observed to work better than higher doses. In certain embodiments, the dose of trospium chloride is <30 mg, e.g., <20 mg. The trospium dose is co-administered with at least 200 mg xanomeline to patients in need thereof. This relationship can also be expressed as the ratio between xanomeline and trospium, where a 5:1 xanomeline / trospium ratio (used in the EMERGENT-1 study in patients with schizophrenia) resulted in undesirable tolerability in elderly patients, where a 6:1 xanomeline / trospium or 7.5:1 xanomeline / trospium ratio was better tolerated. In certain embodiments, the ratio of xanomeline to trospium is greater than 5:1, e.g., greater than 6:1, greater than 7.5:1, or greater than 10:1. In a particular implementation, the ratio of xanomeline to trospium is 10:1.

[0205] Bead Coating In other embodiments, the beads may be coated with functional or non-functional coatings, such as for aesthetics, handling, or stability. In certain embodiments, the beads may be coated with a pH-sensitive coating so that they do not dissolve at the low pH of the stomach. Non-functional coatings may be used to maintain chemical separation between the beads or for aesthetic reasons.

[0206] In certain embodiments, the beads include a coating of talc, for example to aid in flow and mixing. Typically, the beads include a coating of 0% to 2% by weight of talc, for example, 0% to 0.5% by weight of talc, 0.4% to 0.6% by weight of talc, 0.5% to 1% by weight of talc, 1% to 1.5% by weight of talc, or 1.5% to 2% by weight of talc. In certain embodiments, the beads include a coating of 0.5% by weight (based on the total weight of the beads) of talc. In certain embodiments, the first coating includes talc. In certain embodiments, the second coating includes talc. In further embodiments, the controlled release formulation includes a semipermeable coating. Xanomeline and trospium chloride may be present in different coatings in the same formulation. Xanomeline and trospium chloride may be present in different coatings in different formulations or administration vehicles in other embodiments. In further embodiments, the semipermeable coating includes a polymer. In a further embodiment, the controlled release formulation comprises a matrix that suspends the xanomeline and trospium chloride.

[0207] In certain embodiments, the coating thickness distribution can be described in terms of the weight gain of the coating material based on the total weight of the coated beads. Thus, in one embodiment, the coating thickness distribution is at least 2% based on the total weight of the coated beads. In another embodiment, the coating thickness distribution is at least 3%. In another embodiment, the coating thickness distribution is at least 4%. In another embodiment, the coating thickness distribution is at least 5%. In another embodiment, the coating thickness distribution is at least 6%. In another embodiment, the coating thickness distribution is at least 7%. In another embodiment, the coating thickness distribution is at least 8%. In another embodiment, the coating thickness distribution is at least 9%. In another embodiment, the coating thickness distribution is at least 10%. In another embodiment, the coating thickness distribution is at least 11%. In another embodiment, the coating thickness distribution is at least 12%. In another embodiment, the coating thickness distribution is at least 13%. In another embodiment, the coating thickness distribution is at least 14%.

[0208] For example, the difference in coating thickness between beads can range from + / - 1 to 7% based on the total weight of the coated beads. The distribution of coating thickness can be from about 2% to about 14%, e.g., from about 3% to about 13%, from about 4% to about 12%, from about 5% to about 11%, from about 6% to about 10%, from about 7% to 9%, from about 3% to 14%, from about 4% to 14%, from about 4% to 13%, or from 4% to about 12% based on the weight of the coated beads.

[0209] In one embodiment, the absorption (area under the curve, AUC) of the dosage form when administered orally is advantageously increased compared to other dosage forms of xanomeline or trospium chloride. Without intending to be bound by any theory, the increased absorption is influenced by the dosage form exhibiting a pseudo-extended release profile. The pseudo-extended release profile is influenced by one or more factors, including the distribution of coating thickness, if any, the distribution of bead particle sizes, and beads having irregular bead shapes. For example, in embodiments in which the beads have a distribution of coating thickness, for beads having a relatively thin coating, the coating will completely dissolve relatively quickly at the trigger pH to release the xanomeline and / or trospium chloride composition, while for beads having a relatively thick coating, it will take some longer for the coating to completely dissolve and release the xanomeline and / or trospium chloride composition. In embodiments in which the beads have a particle size distribution and / or irregular bead shape, the gastrointestinal transit time of the beads may vary depending on the size and / or shape of the beads, which may alter the transit time to reach the coating dissolution pH, thus contributing to the pseudo-extended release profile. In another embodiment, the dosage form has a substantially equivalent (e.g., bioequivalent) C max and / or AUC characteristics.

[0210] In certain embodiments, the dosage form provides a gradual and predictable absorption curve. In one embodiment, the T max is more stable on a dose-by-dose basis because the beads are individually coated. Predictable and consistent T maxis advantageous in achieving a more consistent and sustained therapeutic effect. For example, process-related variations in coating thickness or other effects on coating dissolution affect only a portion of the xanomeline and trospium chloride in the dosage form. They tend to result in pseudo-extended release behavior. In contrast, coated capsules containing xanomeline and trospium chloride microspheres show significant variability in absorption time from capsule to capsule.

[0211] In certain embodiments, an oral pharmaceutical composition comprises xanomeline and / or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, the composition exhibiting a median T of xanomeline at 2 hours when administered to a patient in need thereof. max and median trospium T at 1 hour max In certain embodiments, the in vivo plasma profile is sufficient to provide an in vivo plasma profile comprising a mean dose-normalized C of 48.5 to 121.3 pg / mL / mg. max In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized C of trospium of 156 to 375 pg / mL / mg. max In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC of xanomeline of 263-577 pg / mL / mg. 0-12 In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC of trospium of 881 to 2024 pg / mL / mg. 0-12 In certain embodiments, the in vivo plasma profile further comprises a mean C of trospium of 7850±3360 pg / mL. max In certain embodiments, the in vivo plasma profile further comprises a mean AUC of 41900±15500 pg / mL over time. 0-12 Further includes:

[0212] In another embodiment, the dosage form exhibits advantageous storage stability, for example, as measured by the amount of xanomeline and / or total amount of related substances present after storage. Storage stability can be assessed after storage at typical ambient conditions (e.g., 25° C. and 60% relative humidity) or at accelerated stability conditions, including elevated temperature and / or humidity.

[0213] The dosage forms and methods are intended to include embodiments of any combination of one or more of the additional optional elements, features, and steps further described below (including those shown in the figures and examples), unless otherwise indicated. References to beads and their properties apply equally to a population of beads (e.g., a plurality of such beads). Similarly, references to cores and their properties apply equally to a population of cores (e.g., a plurality of such cores).

[0214] Enteric (gastro-resistant) coating materials, e.g., polymers, can be those that dissolve in intestinal fluids, e.g., in the small intestine, at pH levels higher than those of the stomach, e.g., pH higher than 4.5, thus allowing release of the active agent in regions of the small intestine, but not substantially in the upper GI tract. In one embodiment, the enteric material begins to dissolve in aqueous solutions at a pH of about 4.5 to about 5.5. In another embodiment, the enteric material rapidly dissolves in aqueous solutions at a pH of about 5. In another embodiment, the enteric material rapidly dissolves in aqueous solutions at a pH of about 5.5.

[0215] For example, pH-sensitive materials do not dissolve significantly until the dosage form is 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 to about 7.2 in the distal part of the small intestine (ileum). To provide predictable dissolution corresponding to a small intestinal transit time of about 3 hours (e.g., 2-3 hours) and to 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 in the small intestine. Thus, the amount (thickness) of the enteric coating should be substantially dissolved during the transit time of about 3 hours in the small intestine (e.g., proximal and mid-small intestine).

[0216] Suitable enteric (gastro-resistant) materials include 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 phthalate succinate; methylcellulose phthalate half ester; ethylcellulose succinate; carboxymethylamide; potassium methacrylate. lylate divinylbenzene copolymers; 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. Evonik Examples of suitable enteric materials include, but are not limited to, Eudragit™-L and -S series available from Eudragit Industries (including L 100-55, L 30 D-55, L 100, S 100, L 12.5 and S12.5); polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; zein; gluten; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamic acid ester copolymer; carboxymethylcellulose glycerol monooctanoate; 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 pH 5.5 or above to provide rapid dissolution in the upper intestine. For example, the enteric material can be selected from copolymers of methacrylic acid and methyl methacrylate, and copolymers of methacrylic acid and ethyl acrylate. For example, the enteric polymer is poly(methacrylic acid-co-ethyl acrylate) 1:1 (Eudragit™ L 30 D-55 and Eudragit™ L 100-55).

[0217] Other suitable examples of enteric coatings include beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac, and shellac and stearic acid; polyvinyl acetate and ethylcellulose; and neutral copolymers of polymethacrylic acid esters (Eudragit® L 30D); copolymers of methacrylic acid and methacrylic acid methyl ester, or neutral copolymers of polymethacrylic acid esters with metal stearates. Such coatings include mixtures of fats and fatty acids, shellac and shellac derivatives, and cellulose acid phthalates, such as those with free carboxyl content.

[0218] As known in the art, one or more plasticizers can be added to enteric polymers to increase their flexibility and reduce their brittleness. Suitable plasticizers include, for example, butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol (PEG such as PEG 6000), acetyl triethyl citrate, and triacetin. In one embodiment, the plasticizer is triethyl citrate. Some enteric materials are flexible and do not require a plasticizer, while more brittle polymers (e.g., Eudragit™ L / S type, Eudragit™ RL / RS, and Eudragit™ FS 30 D) benefit from, for example, about 8% to about 12% by weight triethyl citrate with a plasticizer, poly(methacrylic acid-co-ethyl acetate) 1:1, in the range of 5% to 30% by weight based on the dry polymer mass.

[0219] In certain embodiments, the enteric coating includes one or more anti-adherents (anti-adherents) to reduce the stickiness of the film and prevent clumping, as known in the art. Suitable anti-adherents include, but are not limited to, talc, glyceryl monostearate, fumed silica (e.g., Aerosil™ 200), precipitated silica (e.g., Sipernat™ PQ), and magnesium stearate. The anti-adherents can be used in any suitable amount, for example, in the range of about 10% to 100% by weight, about 10% to about 50% by weight, about 10% to about 30% by weight, or about 15% to about 30% by weight based on the dry polymer weight. For example, in one embodiment, the anti-adherents can be used in the range of 15% to about 30% by weight based on the dry polymer weight.

[0220] One or more surfactants may also be added to the enteric coating mixture to increase the wettability of the substrate and / or stabilize the suspension, as is known in the art. Surfactants include polysorbate 80, sorbitan monooleate, and sodium dodecyl sulfate, as well as other surfactants described herein.

[0221] The enteric coating can be formed by any suitable process. Coating processes include, for example, pan coating, fluidized bed coating, and dry coating (e.g., heat-dried coating and electrostatic dry coating). Pan coating and fluidized bed coating using solvents are well-established processes. In liquid coating, the enteric material and optional excipients (e.g., pigments, plasticizers, anti-blocking agents) are mixed in organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed onto the solid dosage form in a pan coater or fluidized bed dryer and dried by hot air. For example, in the Wurster fluidized bed coating process, the coating fluid is sprayed from the bottom of the fluidized bed device. Alternatively, the coating fluid is applied by top spray. In certain embodiments, tangential spray is applied.

[0222] 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 is within the range of USP 100 / 1000 for a delayed release dosage form. <711> requirements (USP 36-NF 31) and thereby does not release 10.0 wt. % of the drug after 2 hours in 0.1 N HCl. In certain embodiments, the formulation meets, for example, USP 36-NF 31 section <711> Using the dissolution method of Example 1, the compound releases at least 80% of the active agent in 20 minutes in a pH 6.8 buffer solution.

[0223] In one embodiment, the enteric coating is present in an amount in the range of about 10% to 40%, or 25% to about 35%, or about 25% to about 31%, about 27% to about 31%, or about 28.5% to about 31% weight gain based on the weight of the uncoated particle core.

[0224] The formulation can include a capsule shell in which the beads are disposed. Soft 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 vegetable-based hard capsule shell. In certain embodiments, the capsule shell includes one or more enteric coatings as described herein. During accelerated storage, gelatin capsules may disintegrate. Thus, in certain embodiments, the formulation can include a hydroxypropyl methylcellulose capsule shell.

[0225] Thus, for example, one embodiment combining various features described above includes a pharmaceutical dosage form comprising a plurality of xanomeline beads, the beads comprising a core comprising xanomeline tartrate, a filler (optionally microcrystalline cellulose), a binder (optionally hypromellose), and an enteric coating (optionally Eudragit® L 30 D-55) surrounding the core, the plurality of beads having a particle size distribution ranging from about 0.7 mm to about 2.5 mm, the enteric coating ranging from about 20% to about 40% based on the weight of the bead core, and the beads disposed within a capsule shell.

[0226] Bead Size and Shape The plurality of beads has a distribution of particle sizes. The plurality of beads has a bead shape. The plurality of beads has a distribution of coating thickness, if present.

[0227] Beads with a distribution of particle sizes have been shown to exhibit favorable pharmacokinetics. Without intending to be bound by any theory, it is expected that pharmacokinetics is affected by beads with a distribution of core sizes.

[0228] In one embodiment, the particle size of the beads ranges from about 0.4 mm to about 1.2 mm, for example, from about 0.4 mm to about 0.5 mm, from about 0.5 mm to about 0.6 mm, from about 0.6 mm to about 0.7 mm, from about 0.7 mm to about 0.8 mm, from about 0.8 mm to about 0.9 mm, from about 0.9 mm to about 1.0 mm, from about 1.0 mm to about 1.1 mm, or from about 1.1 mm to about 1.2 mm. In a particular embodiment, the size of the xanomelin beads is from about 0.425 mm to about 1.18 mm. In a particular embodiment, the size of the xanomelin beads is from about 0.6 mm to about 0.85 mm. In a particular embodiment, the size of the trospium beads is from about 0.425 mm to about 1.18 mm. In a particular embodiment, the size of the trospium beads is from about 0.6 mm to about 0.85 mm.

[0229] The beads or bead mixtures can be used, for example, in 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 used as a sprinkle on the subject's food. In certain embodiments, the oral solid dosage form can be any of these forms. In certain embodiments, the dosage form is a capsule.

[0230] If the particle size of the beads becomes too small, the variability of the active substance content increases. If the particle size becomes too large, the beads are too large for the labeled pharmaceutical to be administered by sprinkling (e.g., on applesauce or other soft foods such as jelly), swallowing without chewing, or administering via an enteral feeding tube. Also, as particle size increases, the larger particles are more coated than the smaller particles, resulting in a lower relative assay compared to the smaller particles. Relatively more beads are needed to meet the labeling intensity per capsule. It becomes difficult or impossible to fill capsule shells with particles large enough to meet the labeling intensity per capsule (e.g., filling a size 0 capsule up to a 75 mg strength of xanomeline free base).

[0231] In one embodiment, the beads are formulated into capsules, for example, using an encapsulation machine. Various capsule sizes can accommodate the strength and fill weight of the target formulation. Capsule sizes range from 00 to 5, with fill weights ranging from about 15 mg to about 630 mg.

[0232] The beads can be screened (e.g., by sieving) to the desired particle size. In certain embodiments, the particle size range is any particle size range or combination described above for the cores. In one embodiment, the particle size range is the same as the particle size range of the uncoated cores. For example, the beads can be screened so that no more than 5% by weight of the bead cores are retained on a #12 mesh (1.68 mm) screen and no more than 10% by weight passes through a #20 mesh (0.84 mm) screen.

[0233] Manufacturing method A method is provided for preparing an oral pharmaceutical composition comprising mixing beads, including a plurality of xanomeline beads comprising xanomeline or a pharma- ceutically acceptable salt thereof, with a plurality of trospium beads comprising a salt of trospium, such as trospium chloride, hi certain embodiments, the method further comprises formulating the mixed beads into a capsule.

[0234] Also disclosed herein is a method for preparing a dosage form, comprising coating a core comprising xanomeline or a pharma- ceutically acceptable salt thereof and excipients with an enteric polymer to form an enteric coating, and coating a core comprising trospium chloride or a pharma- ceutically acceptable salt thereof and excipients with an enteric polymer to form an enteric coating. Optionally, the core can be formed by a wet granulation process. Optionally, the drug beads are screened (e.g., by sieving) to a desired particle size range before enteric coating, and optionally again after enteric coating.

[0235] Drug beads may be made by different processes, including but not limited to, spheronizing an extruded wet mass and coating an inert core sphere in a fluidized bed. In certain embodiments, the beads are prepared by extrusion and spheronization.

[0236] The beads are formulated to be free flowing and compatible with modern encapsulation equipment. In some embodiments, the beads are blended to form a homogenous mixture that is filled into capsules in a single stage. In other embodiments, the beads are filled into capsules separately using a two-stage capsule filler.

[0237] The cores comprising xanomeline or a pharma- ceutically acceptable salt thereof can be formed by any suitable process. In one embodiment, the cores are formed by granulating a mixture of xanomeline or a pharma- ceutically acceptable salt thereof and excipients and milling to the desired particle size range. In another embodiment, the cores can be formed by extrusion and spheronization of a mixture of xanomeline or a pharma- ceutically acceptable salt thereof and excipients.

[0238] The cores comprising trospium chloride or a pharma- ceutically acceptable salt thereof can be formed by any suitable process. In one embodiment, the cores are formed by granulating a mixture of trospium chloride or a pharma- ceutically acceptable salt thereof and excipients and milling to the desired particle size range. In another embodiment, the cores can be formed by extrusion and spheronization of a mixture of trospium chloride or a pharma- ceutically acceptable salt thereof and excipients.

[0239] Granulation processes can include fluid bed granulation, wet granulation, hot melt granulation, and spray congealing. Other processes include slugging and roller compaction. The mixture to be granulated can first be dry blended. The dry blended dry ingredients can be mixed with water before extrusion.

[0240] Extrusion and spheronization of a mixture of xanomeline or a pharma- ceutically acceptable salt thereof and trospium chloride with excipients provides desirable cores with particle size distribution as described herein and one or more other desirable properties. In certain embodiments, a short processing time can result in a more stable product. For example, reducing spheronization reduces friction and associated heat. Reducing the time the product is exposed to air (either when wet and / or before packaging) also reduces oxidation. On the other hand, rapid processing by extrusion and spheronization can result in a poor quality product, for example, in that a large portion of the bead cores are outside the desired particle size range. Moisture absorbed by the spheronization aid (which occurs over time) affects the spheronization properties of the beads.

[0241] Thus, in one embodiment, the moisture content of the granulated mixture prior to drying is in the range of about 20% to about 40% by weight, e.g., 25% to about 35% by weight, about 28% to about 32% by weight, at least about 28% by weight, at least about 28.5% by weight, about 20% to about 40% by weight, about 25% to about 35% by weight, about 27% to about 31% by weight, or about 28.5% to about 31% by weight.

[0242] In certain embodiments, the wet mass can be held prior to extrusion to allow the spheronization aid to swell with the granulation fluid. The holding 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 holding time ranges from about 15 minutes to about 120 minutes, such as from 30 to 100 minutes, or from 60 to 90 minutes.

[0243] As described above with respect to the cores, the method can include screening the cores (e.g., by sieving) prior to any coating to retain the particles within a predetermined size range, e.g., a size range of about 0.7 mm to about 2.8 mm, e.g., about 0.7 mm to about 2.5 mm, about 0.8 mm to about 1.7 mm, or any range described herein.

[0244] As discussed above with respect to beads, the method can include screening the beads (e.g., by sieving) after any coating to retain the particles within a size range, e.g., a size range of about 0.7 mm to about 2.8 mm, e.g., about 0.7 mm to about 2.5 mm, or about 0.8 mm to about 1.7 mm, or any range described herein.

[0245] In the extrusion and spheronization process, any of the following features may be used individually or in combination with one or more of them. Water may be a granulating agent. Microcrystalline cellulose may be present in the core as a spheronization aid. Hypromellose may be included in the core as a binder. The size of the extrusion screen may be 1.0 mm. The friction plate of the spheronizer may be cross-hatched. The friction plate of the spheronizer may be cross-hatched with a square pitch of at least about 3 mm, or more than about 3 mm, or at least about 4 mm, or more than about 4 mm, or in the range of about 3 mm to about 7 mm, or about 5 mm. The spheronization time may 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 spheroidized particles can include a substantial fraction thereof of non-spherical particles (i.e., irregularly shaped), such as, for example, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, at least about 50% by weight, at least about 60% by weight, or at least about 70% by weight.

[0246] In certain embodiments, the pharmaceutical compositions are stored with a desiccant, such as pharmaceutical grade silica gel, crystalline sodium, potassium or calcium aluminosilicates, colloidal silica, anhydrous calcium sulfate, and the like.

[0247] In certain embodiments, the pharmaceutical composition is stored with an oxygen absorber.

[0248] In certain embodiments, the pharmaceutical compositions are stored under a dry inert gas, such as nitrogen, helium, argon, neon, xenon, krypton, or mixtures thereof.

[0249] In certain embodiments, the pharmaceutical composition is stored under reduced pressure relative to the external ambient air.

[0250] In certain embodiments, the pharmaceutical composition is stored at a low temperature, such as a refrigerated temperature (e.g., 2° C. to 8° C.). In certain embodiments, the pharmaceutical composition is stored to contain fewer impurities, such as impurity A, than if the pharmaceutical composition were stored at 25° C.

[0251] In certain embodiments, the pharmaceutical composition is stored by the manufacturer, distributor, pharmacy, or hospital at a temperature of about 2° C. to about 8° C. prior to distributing the oral pharmaceutical composition to a subject. In certain embodiments, after the oral pharmaceutical composition is distributed to a subject, the pharmaceutical composition is stored at a temperature of about 20° C. to about 25° C.

[0252] Also provided is a method of stabilizing a pharmaceutical dosage form or composition described herein, comprising storing the dosage form at a temperature of about 2°C to about 8°C.

[0253] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising xanomeline beads comprises forming a wet mass comprising xanomeline tartrate and excipients, optionally microcrystalline cellulose, and having a moisture content in the range of about 20% to about 40% by weight, extruding and spheronizing the wet mass comprising xanomeline tartrate and excipients to produce cores, optionally screening the cores to a target particle size range of about 0.7 mm to about 2.5 mm, coating the screened cores with a polymer to form beads comprising the cores and coating, and optionally screening the bead particles to a target particle size range of about 0.7 mm to about 2.5 mm.

[0254] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising trospium beads comprises forming a wet mass comprising trospium chloride and excipients, optionally microcrystalline cellulose, having a moisture content in the range of about 20% to about 40% by weight; extruding, spheronizing, and drying the wet mass comprising trospium chloride and excipients to produce cores; optionally screening the cores to a target particle size range of about 0.7 mm to about 2.5 mm; coating the screened cores with a polymer to form beads comprising the cores and the coating; and optionally screening the bead particles to a target particle size range of about 0.7 mm to about 2.5 mm.

[0255] purity The compound 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium is also provided.

[0256] Also provided is a pharmaceutical composition comprising xanomeline and / or a salt thereof and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium (impurity A). In certain embodiments, the pharmaceutical composition comprises less than 0.30% by weight, such as less than 0.25% by weight, less than 0.20% by weight, less than 0.15% by weight, less than 0.14% by weight, or less than 0.1% by weight of impurity A. Also provided is a pharmaceutical composition comprising xanomeline and / or a salt thereof and less than 0.15% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium (impurity A).

[0257] Also provided is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium, and a plurality of trospium beads comprising a salt of trospium.Also provided is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.15% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium, and a plurality of trospium beads comprising a salt of trospium.

[0258] In certain embodiments, the pharmaceutical composition contains less than 0.5% by weight of impurity A after the pharmaceutical composition is stored at 40° C. and 75% relative humidity for at least 3 months.

[0259] In certain embodiments, the total impurities in the pharmaceutical compositions provided herein are about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2.5% by weight or less, about 2% by weight or less, about 1.5% by weight or less, about 1% by weight or less, about 0.5% by weight or less, or about 0.1% by weight or less. EXAMPLES

[0260] The following examples are offered for illustrative purposes and are not intended to limit the scope of the disclosure. Example 1 – A Phase 1, Randomized, Double-Blind, Multiple-Dose Study to Evaluate the Safety, Tolerability, and Exploratory PK of KarXT in Healthy Elderly Subjects

[0261] The objectives of this Phase 1b clinical trial were to evaluate the safety and tolerability of KarXT in healthy elderly volunteers and to evaluate its potential efficacy and safety in dementia-related psychosis (DRP). The Phase 1b study evaluated various doses and ratios of both xanomeline and trospium in healthy elderly volunteers, using a flexible dosing protocol that was titrated over approximately 2-3 weeks. Maximum doses were reached on days 12, 15, and 17 in cohort 1, cohort 2, and cohort 3, respectively. Dosing continued for a total of 14, 18, and 20 days, respectively. Each cohort consisted of 16 healthy elderly volunteers.

[0262] This was a Phase 1 randomized, double-blind, multiple dose adaptive design study evaluating the safety, tolerability, and exploratory PK of KarXT in healthy elderly subjects. The study consisted of a screening period of up to 28 days. This inpatient follow-up period included a treatment period and a post-treatment observation period. A follow-up visit was completed 7 ± 3 days after the last dose of study drug. For cohort 1, the inpatient follow-up period was up to 17 days, including hospitalization, a treatment period of up to 14 days, and a 2-day post-treatment observation period. For cohort 2, the inpatient follow-up period was up to 21 days, including hospitalization, a treatment period of up to 18 days, and a 2-day post-treatment observation period. For cohort 3, the inpatient follow-up period was up to 23 days, including hospitalization, a treatment period of up to 20 days, and a 2-day post-treatment observation period.

[0263] Subjects were randomized 3:1 in each planned cohort to receive KarXT (administered as a combined formulation of xanomeline tartrate and trospium chloride or as simultaneous administration of individual xanomeline tartrate [KarX] and trospium chloride [KarT] capsules) or placebo.

[0264] The study medication was oral capsules of xanomeline tartrate / trospium chloride (KarXT). For cohorts 1 and 2, the study medication strengths were xanomeline tartrate 25 mg and trospium chloride 10 mg (KarXT 25 / 10 mg), KarXT 50 / 10 mg, KarXT 75 / 10 mg, and KarXT 75 / 20 mg. For cohort 3, xanomeline and trospium were coadministered as individual KarX and KarT capsules. Each of the doses could be individually adjusted based on the following available dose strengths: KarX (xanomeline tartrate) 25 mg and 50 mg, and KarT (trospium chloride) 5 mg and 7.5 mg.

[0265] The placebo was visually matched to the active drug. For cohorts 1 and 2, microcrystalline cellulose was filled into opaque white hydroxypropyl methylcellulose capsules. For cohort 3, size 0 suglet and talc were filled into Swedish orange opaque hard-shell capsules without markings.

[0266] In each planned cohort, four subjects were dosed in the sentinel group (3 active:1 placebo) and their data were reviewed before the remaining subjects were dosed. The remaining 12 subjects were dosed after the safety and tolerability of the investigational drug was confirmed in the sentinel group upon completion of treatment. A maximum of three subjects per cohort were aged 60-64 years, and only one subject in this age range could be in the sentinel group.

[0267] Subjects assigned to active agent treatment in cohorts 1 and 2 began 2 days of treatment with an induction dose of KarXT. Subjects assigned to active agent treatment in cohort 3 began 4 days of treatment with an induction dose of KarXT. KarXT doses were escalated starting on day 3 (or day 5 for cohort 3) according to cohort-specific plans (Figure S1) to achieve the following final cohort-specific total daily doses (TDDs) of KarXT, if tolerated: Cohort 1: 200 / 40mg Cohort 2: 200 / 30 mg Cohort 3: 150 / 20 mg

[0268] After each cohort is completed, the timing of dose escalation steps can be adjusted and / or the dose intensity at a given escalation step can be reduced based on the safety and tolerability of KarXT administered in previous cohorts.

[0269] The main inclusion criteria were men aged 60–85 years and postmenopausal women, including those attending for screening. Body mass index was 18.0 kg / m 2 ~35.0kg / m 2 In the opinion of the investigator, the subject's general condition was good.

[0270] Exclusion criteria included the history or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immune, dermatological, neurological, oncological, or psychiatric disease, other than the following conditions, which must have been controlled by medical treatment for at least 3 months prior to dosing: osteoarthritis, osteopenia, type II diabetes, hypercholesterolemia, hypertension, hypothyroidism, hyperthyroidism, and vitamin B 12 Other chronic conditions were permitted as long as they were stable for at least 3 months prior to screening.

[0271] Subjects were also excluded if they had syncope, syncope or symptomatic hypotension at screening or admission, or symptomatic orthostatic hypotension, irritable bowel syndrome (with or without constipation) or severe constipation requiring treatment within the past 6 months, a history or high risk of urinary retention (including subjects with a history of symptomatic benign prostatic hyperplasia in cohort 2 and subsequent cohorts), gastric retention, or narrow-angle glaucoma (also known as angle-closure glaucoma).For male subjects, a score of >4 on the International Prostate Symptom Score (I-PSS) at screening and / or baseline was exclusionary. Also excluded were ethyl alcohol or drug abuse within the last year or current abuse as determined by urine drug screen or respiratory examination at screening, significant liver function test abnormalities, major depressive episode within the past year, significant suicidal ideation or attempt, or any other condition that, in the investigator's opinion, would compromise the safety of the subject or the validity of the physical examination, ECG, vital signs, or laboratory test results at screening (including a QTcF >450 ms in men and >470 ms in women). 2 An estimated glomerular filtration rate (eGFR) of less than 100% is a specific exclusion. Also excluded were ALT, ALP, AST, or TB outside the normal range at baseline and receiving an investigational drug within 30 days or within 5 half-lives, whichever is longer, prior to dosing, and prescription medication use within 14 days prior to enrollment, except for hormone replacement treatment for postmenopausal syndrome and treatment of permitted conditions. Such medications must be at a stable dose for at least 3 months prior to dosing and expected to remain stable for the duration of the study. Subjects who previously tested positive for HIV-1 or 2, Hepatitis B or C, or had positive tests for these conditions were obtained at screening.

[0272] Use of oral or inhaled steroids, other than those used as needed within 1 year prior to screening, vitamins, herbs, supplements, or over-the-counter (OTC) medications, except calcium, vitamin D, low-dose aspirin, glucosamine, and chondroitin, was excluded within 2 weeks prior to enrollment and for the entire duration of the study. Zofran was permitted for the treatment of nausea, and acetaminophen and / or ibuprofen were permitted during the study. Vitamin B 12 Vitamin B12 for deficiency 12 Patients were excluded if they had used any smoking cessation products, such as varenicline, within 30 days prior to screening.

[0273] Assessment of adverse events, clinical laboratory samples, electrocardiograms (ECGs), vital signs (including orthostatic vital signs), urine output monitoring, Columbia-Suicide Severity Rating Scale (C-SSRS), continuous PK sampling, and saliva collection to measure saliva volume were performed at specified time points throughout the study.

[0274] Data from cohorts 1 and 2 showed that lower oral doses of both drugs, xanomeline and trospium, resulted in higher blood levels in healthy elderly subjects than in adults under 65 years of age. Furthermore, oral doses of xanomeline of approximately 100-200 mg / day in healthy elderly volunteers resulted in mean plasma levels (C ) similar to or slightly higher than those observed in EMERGENT-1. max ), and a completed positive Phase 2 trial testing doses of 200-250 mg of xanomeline showed strong antipsychotic effects in adults with schizophrenia. (See U.S. Pat. Nos. 10,925,832 and 10,933,020, and U.S. Patent Application No. 16 / 950,203, which are incorporated herein by reference in their entireties.)

[0275] Furthermore, data from the completed cohort suggest that the lower ratio of trospium to xanomeline was better tolerated by healthy elderly subjects compared with the ratio used in adults <65 years of age. Cholinergic and anticholinergic adverse events (AEs) seen in cohorts 1, 2, and 3 were similar to those observed in previous studies of KarXT, with the majority (>80%) classified as mild.

[0276] Referring to Table 1, one drug-related serious adverse event (SAE) was reported in Cohort 1. The SAE was urinary retention in a subject receiving a total daily dose of 40 mg trospium. No cases of syncope were observed in any cohort. No SAEs were reported in Cohorts 2 and 3.

[0277] [Table 1]

[0278] The frequency and severity of trospium-related adverse events with 40 mg TDD trospium was unexpected given the low doses in previous schizophrenia trials (40-60 mg TDD) and the approved dose of trospium to treat overactive bladder. With the reduction in trospium dose, constipation decreased from 42% to 0% (placebo adjusted), dry mouth decreased from 50% to 17% (placebo adjusted), and urinary retention decreased from 17% to 0%. Serious adverse events decreased from 1 to 0.

[0279] Surprisingly, the overall tolerability of KarXT, which depends on the balance of xanomeline and trospium, was improved by reducing the trospium dose and thereby using a higher xanomeline:trospium ratio than that tested in normal healthy volunteers and patients with schizophrenia. This improvement was shown by a decrease in the severity of the overall adverse events. No serious or severe adverse events occurred in cohort 2. The proportion of patients who experienced no adverse events or only mild adverse events with KarXT increased by 25%. In certain embodiments, the dose for elderly subjects should be different from that for schizophrenia or normal healthy volunteers. A dose of 40-60 mg trospium chloride TDD was used successfully in normal healthy volunteers and patients living with schizophrenia, while a dose of 30 mg trospium chloride TDD worked better than 40 mg TDD in normal elderly volunteers. The trial of 60 mg TDD was not completed in elderly subjects based on AEs observed with 40 mg TDD. This association can also be expressed as the ratio between xanomeline and trospium, with xanomeline / trospium ratios of 5:1 or less being used in normal healthy volunteers and living patients with schizophrenia (xanomeline 200 mg, trospium 40 mg, ratio 5:1; xanomeline 250 mg, trospium 60 mg, ratio 4.2:1). This same 5:1 xanomeline:trospium ratio raises undesirable trospium-related tolerability concerns in elderly people, and ratios greater than 5:1 xanomeline / trospium, i.e., 6:1 xanomeline:trospium, or 7.5:1 xanomeline / trospium, are better tolerated. In certain embodiments, the ratio of xanomeline to trospium is greater than 5:1, for example, greater than 6:1, greater than 7.5:1, or greater than 10:1. In a particular implementation, the ratio of xanomeline to trospium is 10:1.

[0280] The subject with a serious adverse event of urinary retention was 66 years old. As above, all subjects were screened for estimated bulbar filtration rate (eGFR) and patients with an EGFR less than 45 were excluded from the study. Subjects with urinary retention, including the subject referenced above with an SAE of urinary retention, had eGFR values ​​of 65 and 67, respectively, and all subjects had eGFR values ​​of 54 or greater and therefore would not be expected to have a creatinine clearance less than 30 mL / min.

[0281] Table 2 shows the results of the EMERGENT-1 study in patients aged 18 to 60 years (inclusive) for the PK data collected on the last day of the dosing period in healthy elderly subjects for cohorts 1, 2, and 3 compared to day 28 (the last day for which PK data were collected). max Contains data.

[0282] [Table 2]

[0283] Although the mean total daily dose of xanomeline at the end of the study in cohort 2 was only 156 mg, the reported xanomeline C max was higher in elderly subjects than in schizophrenia patients. Given the strong antipsychotic effects observed in schizophrenia trials, these data suggested that xanomeline doses in elderly subjects of 100-200 mg could provide equivalent or greater xanomeline blood levels. Thus, these doses should be therapeutically effective to provide antipsychotic benefit in elderly populations with psychotic symptoms, such as dementia-associated psychosis.

[0284] Analysis of data from Cohort 3 alone and in combination with data from Cohorts 1 and 2 confirmed the findings of the preliminary analysis. For example, reports of urinary retention were associated with higher doses of trospium used in Cohort 1 than the doses used in Cohorts 2 and 3, where no urinary retention was observed. No serious or severe adverse events were observed in Cohorts 2 and 3.

[0285] Example 2 -A Phase 3, double-blind, placebo-controlled, relapse prevention study to evaluate the safety and efficacy of KarXT for the treatment of psychosis associated with Alzheimer's disease dementia This study will evaluate the treatment of psychosis and prevention of relapse in subjects with psychosis associated with AD dementia treated with KarXT or placebo. This study also aims to evaluate the time from randomization to discontinuation for any reason in these subjects to evaluate the PK of KarXT in subjects with psychosis associated with AD dementia using the Neuropsychiatric Inventory-Clinician (NPI-C) psychosis score (hallucinations and delusions), NPI-C core score, CGI-S scale, Clinical Global Impression-Improvement (CGI-I) scale, Cohen-Mansfield Agitation Inventory (CMAI), NPI-C total score, and Mini-Mental State Examination (MMSE), to evaluate the efficacy of KarXT compared to placebo during the double-blind randomized discontinuation treatment period, and KarXT compared to placebo during the single-blind treatment period, to evaluate the safety and tolerability of KarXT compared to placebo.

[0286] This study will be conducted as a Phase 3 randomized discontinuation study of KarXT in patients with AD dementia-related psychosis. Subjects with AD dementia must also have symptoms of agitation or aggression, which are common symptoms in AD dementia psychosis.

[0287] Male and female subjects aged 55-90 years with mild to severe AD dementia accompanied by moderate to severe psychosis will be enrolled in this study.

[0288] To be included in the study, individuals must meet all of the following criteria: Male or female, aged 55–90 years (inclusive) at screening (Visit 1A) Meets clinical criteria for possible or probable AD · A magnetic resonance imaging (MRI) or computed tomography (CT) scan of the brain (completed within the past 5 years) during or after the onset of dementia to rule out other central nervous system (CNS) diseases that could be causing the dementia syndrome (e.g., major stroke, neoplasm, subdural hematoma). History of psychotic symptoms meeting International Psychogeriatric Association (IPA) criteria for at least 2 months prior to screening (Visit 1A). See Table 3 in Cummings J, Pinto LC, Cruz M, et al. “Criteria for Psychosis in Major and Mild Neurocognitive Disorders: International Psychogeriatric Association (IPA) Consensus Clinical and Research Definition.” Am J Geriatr Psychiatry. 2020 Dec;28(12):1256-1269, incorporated herein by reference in its entirety. CGI-S scale score ≥ 4 (moderate) at screening (Visit 1A) AD Dementia Subjects, at Screening (Visit 1A): Moderate to severe delusions, defined as an NPI-C delusion domain score ≥ 2 on 2 of 8 items b. NPI Agitation / Aggression domain score ≥ 4 is required to have MMSE score 8–22 (inclusive) at Screening (Visit 1A) If the subject is taking a cholinesterase inhibitor and / or memantine, the subject must have been on a stable dose for 6 weeks prior to Screening (Visit 1A) and be willing to remain on a stable dose for the duration of the study.

[0289] Subjects will be excluded from the study if one or more of the following criteria apply at screening: Psychotic symptoms primarily attributable to a dementia-causing condition other than AD, e.g., schizophrenia, schizoaffective disorder, delusional disorder, or mood disorder with psychotic features History of a major depressive episode with psychotic features in the 12 months prior to Screening (Visit 1A) History of Axis I diagnosis of delirium, amnesic disorder, bipolar disorder, schizophrenia, or schizoaffective disorder Significant or severe medical conditions, such as pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunological, dermatological, neurological, or neoplastic diseases, or any other condition that may compromise the subject's safety, ability to complete or comply with study procedures, or the validity of the results of the clinical trial. History of ischemic stroke or evidence of hemorrhagic stroke within 12 months prior to Screening (Visit 1A) History of cerebral amyloid angiopathy (CAA), epilepsy, central nervous system (CNS) neoplasms, unstable thyroid function, or syncope of unknown etiology Any of the following: New York Heart Association (NYHA) Class 2 congestive heart failure b. Grade 2 or greater angina c. Sustained ventricular tachycardia D. Ventricular fibrillation e. Polymorphic ventricular tachycardia f. Implantable cardioverter defibrillators Myocardial infarction within 6 months prior to screening (Visit 1A) Personal or family history of symptoms of long QT syndrome Human immunodeficiency virus (HIV), cirrhosis, bile duct abnormalities, hepatobiliary cancer, and / or active hepatic viral infection as indicated by medical history or LFT results History or high risk of urinary retention, gastric retention, or narrow-angle glaucoma Irritable bowel syndrome (with or without constipation) or a history of severe constipation requiring treatment within the past 6 months Risk of suicidal behavior during the study as determined by investigator clinical assessment and / or C-SSRS by: a. Answer "yes" to items 4 or 5 (C-SSRS ideation) and the most recent episode occurred within 2 months prior to screening, or b. Answer "yes" to any of the five items (C-SSRS behaviors) and an episode occurred within the 12 months prior to screening Recent medical history of receiving any other psychotropic medication except monoamine oxidase inhibitors, anticonvulsants (e.g., lamotrigine, divalproex), lithium, tricyclic antidepressants (e.g., imipramine, desipramine), or anxiolytics (e.g., lorazepam, chloral hydrate) as needed a. Stable doses of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors for at least 8 weeks prior to Screening (Visit 1A) may be permitted b. Mirtazapine may be used as a hypnotic agent if initiated at least 8 weeks prior to Screening (Visit 1A)

[0290] Subjects will receive single-blind KarXT during the single-blind treatment period. Each subject will be titrated up to a maximum dose of 200 mg xanomeline / 20 mg trospium / day up to the maximum dose of single-blind KarXT appropriate for the subject based on tolerability and efficacy. Dosing is flexible, but subjects must reach a minimum dose of KarXT 90 / 9 mg / day by the end of week 6 to remain in the study.

[0291] KarXT is available in oral capsules expressed as mg xanomeline tartrate / mg trospium chloride: KarXT 20 / 2.0 mg, KarXT 30 / 3.0 mg, KarXT 40 / 4.0, KarXT 50 / 5.0 mg, and KarXT 66.7 / 6.67 mg. Capsules of each dosage strength were prepared with xanomeline beads (Table 3) and either 4.4% or 17.7% trospium beads (Table 4) by weight, depending on the dosage strength (Table 5). Specifically, for doses with 5.0 mg trospium chloride or less, beads with a drug load of 4.4% trospium chloride were used. KarXT 66.7 / 6.67 mg used trospium beads with 17.7% trospium chloride. All dosage forms complied with capsule appearance, identity by retention time (RT), identity by UV spectrum, dissolution (at least 80% at 30 minutes for each xanomeline and trospium), and content uniformity (as per USP < 905). Dosage forms also met assay specifications, impurities and related substances, moisture content, and microbial limits (Table 6).

[0292] [Table 3]

[0293] [Table 4]

[0294] [Table 5]

[0295] [Table 6]

[0296] In the absence of tolerability issues, subjects should increase the dose if efficacy is not observed. On Day 1, subjects will take one dose of study drug in the evening. Day 1: Subjects will begin on KarXT 60 / 6mg / day (20 / 2.0mg TID). End of week 1: Increase dose to 90 / 9mg / day (30 / 3.0mg TID) End of week 2: Doses should be increased to 120 / 12 mg / day (40 / 4.0 mg TID) unless the subject is experiencing tolerability issues. End of Week 3: Optional dose increase to 150 / 15 mg / day (50 / 5.0 mg TID) End of week 4: Optional dose escalation to 200 / 20mg / day (66.7 / 6.67mg TID) Week 5 and beyond: Continue dosing as per completion of week 5 or modify according to subject tolerance and clinical response.

[0297] Subjects must meet the following criteria at the end of the single-blind treatment period, prior to administration of the first dose of study drug in the randomization and double-blind randomized stopout periods: 1. Meet the following response criteria: a. ≥ 40% reduction in NPI-C H+D score (improvement from baseline at the end of the single-blind treatment period (beginning of the double-blind randomized withdrawal treatment period)); and b. CGI-I score of 1 (very improved) or 2 (much improved). The CGI-I requires raters to consider the dimensions of agitation / aggression and psychosis before making an overall rating of change. These dimensions include emotional or psychomotor agitation, verbal or physical aggression, delusions, and hallucinations. 2. Minimum KarXT dose of 90 / 9 mg / day (30 / 3.0 mg TID) taken by 12 (visit 10)

[0298] Definitions of responders and relapses are based on the NPI-C psychosis score (sum of hallucinations and delusions subscores).

[0299] The treatment period is based on the hallucinations and delusions domain, two domains of the NPI-C, the 14-domain scale, and the CGI-I scale. Each domain of the NPI-C scale has multiple items. Each item has a Clinical Impression Severity score ranging from 0 to 3. The study defines the NPI-C H+D score (maximum score = 45 points) to include two domains: the delusions domain has 8 items (maximum score = 24) and the hallucinations domain has 7 items (maximum score = 21).

[0300] Response criteria for entry into the double-blind randomized withdrawal treatment period were a ≥ 40% reduction (improvement) in NPI-C H+D score at the start of the double-blind randomized withdrawal treatment period compared to baseline (Day 1) and a CGI-I score of 1 (very improved) or 2 (much improved) at the start of the double-blind randomized withdrawal treatment period. The CGI-I requires assessors to consider aspects of agitation / aggression and psychosis before making an overall rating of change. These aspects include emotional or psychomotor agitation, verbal or physical aggression, delusions, and hallucinations.

[0301] The primary endpoint of the study is the time from randomization to relapse during the double-blind randomized withdrawal treatment period. Subjects must meet at least one of the following four criteria to be considered to have relapsed: ≥ 40% increase (worsening) in NPI-C H+D score from the start of the double-blind randomized withdrawal treatment period and a CGI-I score of 6 (much worse) or 7 (very worse) compared to the start of the double-blind period (both criteria met at the same visit). The CGI-I requires that assessors consider aspects of agitation / aggression and psychosis before making an overall assessment of change. The single-blind treatment period can be 8, 10, 12, 14, or 16 weeks, and the double-blind treatment period can be 22, 24, 26, 28, or 30 weeks.

[0302] A subject must meet at least one of the following four criteria to be considered to have relapsed: o ≥ 40% increase (worsening) from the start of the double-blind randomized withdrawal treatment period in NPI-C H+D score and a CGI-I score of 6 (much worse) or 7 (very worse) compared to the start of the double-blind randomized withdrawal treatment period (both criteria met at the same visit). These aspects include emotional or psychomotor agitation, verbal or physical aggression, delusions, and hallucinations. o Subjects will be treated with an antipsychotic (other than KarXT) for dementia-related delusions and / or hallucinations within the double-blind randomized stop-treatment period. o Subject discontinues study drug or discontinues the study during the double-blind randomized discontinuation treatment period due to lack of efficacy (as reported by the subject or caregiver / study partner) or the investigator discontinues study drug due to lack of efficacy. o Subject was hospitalized for worsening psychotic, agitation, or aggression symptoms during the double-blind randomized withdrawal treatment period.

[0303] Exploratory efficacy endpoints included: o Change from baseline to the end of the single-blind treatment period in NPI-C:H+D score, NPI-C core score (hallucinations, delusions, agitation, and aggression domains), CGI-S, CMAI, NPI-C total score, and MMSE. The CGI-S requires assessors to consider aspects of psychosis before making an overall rating of change. These aspects include hallucinations and delusions. o Change from randomization to endpoint in NPI-C:H+D score, NPI-C core score (hallucinations, delusions, agitation, and aggression domains), CGI-S, CMAI, NPI-C total score and MMSE. o CGI-I scores at the end of the single-blind treatment period and endpoints. The CGI-I requires assessors to take into account aspects of psychiatric illness before making an overall rating of change. These aspects include hallucinations and delusions. o Treatment response (≥ 40% reduction in NPI-C:H+D score at the end of the single-blind treatment period and 2 weeks prior and a CGI-I score of 1 [very improved] or 2 [much improved]) Treatment response (≥ 40% reduction in NPI-C Core:H+D score at the 10-week visit and the end of the 12-week single-blind treatment period and a CGI-I score of 1 [very improved] or 2 [much improved]).

[0304] Example 3 – A Phase 3, double-blind, placebo-controlled, parallel-group study to evaluate the safety and efficacy of KarXT for the treatment of psychosis associated with Alzheimer's disease dementia The objectives of this study are to evaluate the efficacy of KarXT compared to placebo in treating subjects with psychosis associated with AD as measured by NPI-C Psychosis Score (Hallucinations and Delusions) score, and to evaluate the efficacy of KarXT compared to placebo for treating subjects with psychosis associated with AD as measured by CMAI. This study also aims to characterize the pharmacokinetics (PK) of KarXT in subjects with psychosis associated with AD dementia, to evaluate the efficacy of KarXT compared to placebo on NPI-C Core Score, NPI-C Agitation / Aggression Score (Agitation and Aggression Domain), NPI-C Total Score, and CGI-I Score, and to evaluate the impact of KarXT on cognition using the Mini-Mental State Examination (MMSE).

[0305] Male and female subjects aged 55-90 years with mild to severe AD dementia accompanied by moderate to severe psychosis will be enrolled in this study. Exclusion and inclusion criteria are the same as in Example 2.

[0306] The primary endpoint was the change from baseline in the NPI-C H+D score, which includes two domains: hallucinations and delusions. The delusions domain has 8 items (maximum score = 24) and the hallucinations domain has 7 items (maximum score = 21). The complete NPI-C core score can also be used.

[0307] Subjects may receive a placebo during the lead-in period, and subjects with a 40% or greater reduction in NPI-H+D score (change from baseline to the end of week 2) will not be randomized. In addition, subjects must have a CGI-S score of ≥4 (moderate), an NPI-C delusion domain score of ≥2 on two of eight items, and an NPI agitation / aggression domain score of ≥4. An NPI agitation / aggression domain score of ≥4 has been used as an inclusion criterion in two brexpiprazole and one escitalopram agitation in AD subject studies.

[0308] Subjects receive double-blind KarXT or placebo during a randomized treatment period lasting 12 weeks in some embodiments. Each subject is titrated up to the maximum dose of KarXT appropriate for the subject, up to a maximum of 200 / 20 mg / day, based on tolerability and efficacy. Dosing is flexible, but subjects should reach a minimum dose of KarXT 120 / 12 mg / day by the end of week 6.

[0309] KarXT is expressed as mg xanomeline as the tartrate salt / mg trospium chloride in oral capsules: KarXT 20 / 2.0 mg, KarXT 30 / 3.0 mg, KarXT 40 / 4.0 mg, KarXT 50 / 5.0 mg, and KarXT 66.7 / 6.67 mg. The dosage forms described in Example 2 are also used in this study. Dosing of KarXT is flexible from the third week of treatment on the basis of tolerability and clinical response. Day 1: Subjects will be initiated on KarXT 60 / 6mg / day (20 / 2.0m TID). End of week 1: Increase dose to 90 / 9mg / day (30 / 3.0mg TID) End of week 2: Doses should be increased to 120 / 12 mg / day (40 / 4.0 mg TID) unless tolerance issues are experienced. End of Week 3: Optional dose increase to 150 / 15 mg / day (50 / 5.0 mg TID) End of week 4: Optional dose escalation to 200 / 20mg / day (66.7 / 6.67mg TID) Week 5 onwards: Continue dosing as per end of week 5 or modify depending on subject tolerance and clinical response

[0310] The primary efficacy endpoint was the change from baseline to endpoint in NPI-C H+D score, analyzed using a mixed model for repeated measures (MMRM) with unstructured variance-covariance matrices and with fixed class effects for treatment, study center, and visit at 1 week, a treatment by visit week interaction term, and a baseline NPI-C H+D score by visit week interaction term as covariates.The key secondary efficacy endpoint was the change from baseline to endpoint in CMAI total score, analyzed using a MMRM with unstructured variance-covariance matrices and with fixed class effects for treatment, study center, and visit at 1 week, a treatment by visit week interaction term, and a baseline CMAI total score by visit week interaction term as covariates.

[0311] Secondary efficacy analyses included, in order: Change from baseline to endpoint in NPI-C psychosis score, NPI-C core score, NPI-C agitation, and NPI-C aggression scores, and NPI-C total score Change from baseline to endpoint in CGI-S related to psychosis, agitation, and aggression Percentage of subjects with a 50% reduction in NPI-C core score from baseline to endpoint at endpoint · CGI-I related to endpoints of psychosis, agitation, and aggression.

[0312] Example 4 The objectives of this study are to evaluate the efficacy of KarXT compared to placebo in treating subjects with psychosis associated with AD as measured by NPI-C H+D score, and to evaluate the efficacy of KarXT compared to placebo for treating subjects with psychosis associated with AD as measured by CMAI. This study also aims to characterize the pharmacokinetics (PK) of KarXT in subjects with psychosis associated with AD dementia, to evaluate the efficacy of KarXT compared to placebo on NPI-C core score, NPI-C agitation / aggression score (agitation and aggression domains), NPI-C total score, and CGI-I score, and to evaluate the impact of KarXT on cognition using the Mini-Mental State Examination (MMSE).

[0313] Male and female subjects aged 55-90 years with mild to severe AD dementia accompanied by moderate to severe psychosis will be enrolled in this study. Exclusion and inclusion criteria are the same as in Example 2.

[0314] The primary endpoint was the change from baseline in the NPI-H+D score, which includes two domains: hallucinations and delusions. The delusions domain has 8 items (maximum score = 24) and the hallucinations domain has 7 items (maximum score = 21).

[0315] For the first 12 weeks, subjects are divided into two cohorts. The first cohort is treated with KarXT and the second cohort is treated with placebo. The improvement in NPI-C H+D between the first and second cohorts is recorded. Each subject in the first cohort is titrated to the maximum dose of KarXT appropriate for the subject, up to a maximum of 200 / 20mg / day, based on tolerability and efficacy. Dosing is flexible, but subjects must reach a minimum dose of KarXT 120 / 12mg / day by the end of the 12th week.

[0316] Improvement is measured as an increase in NPI-H+D score of <40% (change from baseline to endpoint between the first and second cohorts). In addition, subjects must have a CGI-S score >4 (moderate), an NPI-C delusion domain score >2 on 2 of 8 items, and an NPI agitation / aggression domain score >4. This embodiment is similar to the open-label portion of the relapse study in Example 2, but instead is double-blind to look for acute benefits on psychosis (similar to the clinical design of EMERGENT-1).

[0317] The foregoing description is given only for clarity of understanding. No unnecessary limitations should be understood therefrom, as modifications within the scope of the present disclosure may be apparent to those skilled in the art. Throughout this specification, when a composition is described as comprising an ingredient or material, it is contemplated that the composition may essentially consist of, or consist of, any combination of the listed ingredients or materials, unless otherwise stated. Similarly, when a method is described as comprising steps, it is contemplated that the method may essentially consist of, or consist of, any combination of the listed steps, unless otherwise stated. The disclosure illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0318] The implementation of the methods disclosed herein, and their individual steps, can be performed manually and / or with the aid of automation provided by electronic devices. Although the processes have been described with reference to embodiments, one skilled in the art will readily recognize that other ways of performing the operations associated with the methods can be used. For example, the order of various steps can be changed without departing from the scope or spirit of the methods, unless otherwise noted. Some of the individual steps can also be combined, omitted, or further subdivided into additional steps.

[0319] It is recognized that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable subcombination. All combinations of the embodiments relating to the chemical groups represented by the variables contained in the general chemical formulas described herein, to the extent that such combinations include stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically encompassed by the present invention as if each combination were individually and explicitly described. Furthermore, all subcombinations of the chemical groups listed in the embodiments describing such variables, as well as all subcombinations of the uses and medical indications described herein, are also specifically encompassed by the present invention as if each and every subcombination of the chemical groups, as well as the subcombinations of the uses and medical indications, were individually and explicitly listed herein.

[0320] 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. 1. An oral pharmaceutical composition comprising 20 mg to 66.7 mg of xanomeline or a pharma- ceutically acceptable salt thereof, and 2 mg to 6.67 mg of trospium chloride, wherein the ratio of xanomeline free base to trospium chloride in the composition is greater than 7.5:

1.

2. 2. The oral pharmaceutical composition of claim 1, wherein the ratio of xanomeline free base to trospium chloride is 10:

1.

3. 3. An oral pharmaceutical composition according to claim 1 or 2, comprising the tartrate salt of xanomeline.

4. 5. An oral pharmaceutical composition comprising: (i) a dosage strength of xanomeline in an amount of 20 mg and a dosage strength of trospium chloride in an amount of 2.0 mg; (ii) a dosage strength of xanomeline in an amount of 30 mg and a dosage strength of trospium chloride in an amount of 3.0 mg; (iii) a dosage strength of xanomeline in an amount of 40 mg and a dosage strength of trospium chloride in an amount of 4.0 mg; (iv) a dosage strength of xanomeline in an amount of 50 mg and a dosage strength of trospium chloride in an amount of 5.0 mg; or (v) a dose strength of xanomeline in an amount of 66.7 mg and a dose strength of trospium chloride in an amount of 6.67 mg. The oral pharmaceutical composition according to any one of claims 1 to 3, comprising:

5. 5. The oral pharmaceutical composition according to any one of claims 1 to 4, wherein xanomeline or a pharma- ceutically acceptable salt thereof is formulated as a first component, and trospium chloride is formulated as a second component.

6. 6. The oral pharmaceutical composition of claim 5, wherein the first component is a first plurality of beads and the second component is a second plurality of beads.

7. The oral pharmaceutical composition according to any one of claims 1 to 6, wherein the oral pharmaceutical composition is a capsule.

8. 8. The oral pharmaceutical composition of any one of claims 1 to 7, wherein the oral pharmaceutical composition further comprises 0.1% to 0.25% of 3-[(4-hexyloxy)-1,2,5-thiadiazaol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium.

9. An oral pharmaceutical composition for use in the treatment of dementia-related psychosis in a human patient, the oral pharmaceutical composition being any one of claims 1 to 8.

10. 10. The oral pharmaceutical composition of claim 9, wherein the pharmaceutical composition is administered three times in a 24 hour period.

11. The oral pharmaceutical composition according to claim 9 or 10, wherein the dementia-related psychosis is caused by Alzheimer's disease.

12. The oral pharmaceutical composition according to any one of claims 9 to 11, wherein the human patient is aged 55 years or older.

13. The composition is administered to a human patient. (i) an initial dose of xanomeline or a salt thereof and an initial dose of trospium chloride during a first period; and (ii) a second dose of xanomeline or a salt thereof and a second dose of trospium chloride during a second period; the second dose of xanomeline or a salt thereof is greater than the first dose of xanomeline or a salt thereof and the second dose of trospium chloride is greater than the first dose of trospium chloride; The oral pharmaceutical composition according to any one of claims 9 to 12.

14. The composition is administered to a human patient, where the patient is 55 years of age or older. (i) an initial dose of xanomeline or a salt thereof of 20 mg three times daily and an initial dose of trospium chloride of 2 mg three times daily; and (ii) a second dose of xanomeline or a salt thereof in an amount of 30 mg three times a day and a second dose of trospium chloride in an amount of 3 mg three times a day 14. The oral pharmaceutical composition for use according to claim 13, wherein the composition is administered intravenously.

15. After said second period, if the patient 55 years of age or older tolerates the second dose of xanomeline or a salt thereof and the second dose of trospium chloride, and if the patient has an adequate response, administering to the patient a third dose of xanomeline or a salt thereof in an amount of 40 mg three times daily and a third dose of trospium chloride in an amount of 4 mg three times daily during a third period; Alternatively, if after the second period, the patient is unable to tolerate the second dose of xanomeline or a salt thereof and the second dose of trospium chloride, then in a third period, the dose of xanomeline or a salt thereof is returned to the first dose of xanomeline or a salt thereof, and in a third period, the dose of trospium chloride is returned to the first dose of trospium chloride.

15. The oral pharmaceutical composition of claim 14.

16. After the third period, if the patient is 55 years of age or older and tolerates the third dose, the patient is administered a fourth dose of xanomeline or a salt thereof in an amount of 50 mg three times daily during the fourth period, and a fourth dose of trospium chloride in an amount of 5 mg three times daily during the fourth period; Alternatively, if the patient is unable to tolerate the third dose, then the patient is administered the second dose in a fourth period.

16. An oral pharmaceutical composition for use according to claim 15.

17. After said fourth period, if the patient 55 years of age or older tolerates the fourth dose, the patient is administered a fifth dose of xanomeline or a salt thereof in an amount of 66.7 mg three times daily during a fifth period, and a fifth dose of trospium chloride in an amount of 6.67 mg three times daily during a fifth period; Alternatively, if the patient is unable to tolerate the fourth dose, then the patient is administered the third dose in a fifth period.

17. The oral pharmaceutical composition of claim 16.

18. 18. The oral pharmaceutical composition of claim 17, wherein the first period of time is a total of 7 days, the second period of time is a total of 14 days, the third period of time is a total of 21 days, and / or the fourth period of time is a total of 28 days.

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