Method and compositions relating to the treatment of neuro-degenerative and psychiatric diseases

Abstract

Provided herein are pharmaceutical compositions comprising an immediate-release component comprising xanomeline or a salt thereof, an immediate-release component comprising a trospium salt, and a modified-release component comprising xanomeline or a salt thereof for treating muscarinic disorders in a patient.

Description

METHOD AND COMPOSITIONS RELATING TO THE TREATMENT OF NEURO- DEGENERATIVE AND PSYCHIATRIC DISEASESCROSS REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of U.S. Provisional Application Serial No. 63 / 696,936 filed September 20, 2024 and U.S. Provisional Application Serial No. 63 / 831,526 filed June 27, 2025 which are incorporated herein in their entirety.FIELD OF THE INVENTION

[0001] The present disclosure relates to oral pharmaceutical compositions comprising xanomeline or a salt thereof and a trospium salt. The oral pharmaceutical composition employs a combination of immediate- and modified-release formulations to control the release of xanomeline. The pharmaceutical composition is useful for the treatment of muscarinic disorders.BACKGROUND OF THE INVENTION

[0002] KarXT (or KarXT-IR / IR hereinafter) is a combined formulation of xanomeline tartrate and trospium chloride. The product consists of two active components — immediate-release (IR) xanomeline tartrate beads and IR trospium chloride beads — combined in the same IR capsule shell to produce the doses of xanomeline and trospium. In addition to KarXT, KarX (xanomeline tartrate beads without trospium chloride beads in IR capsule) and KarT (trospium chloride beads without xanomeline tartrate beads in IR capsule) have been used for flexible dose adjustments.

[0003] KarXT capsules combine the muscarinic agonist xanomeline with the peripheral muscarinic antagonist trospium to mitigate some of the procholinergic adverse events (AEs) reported in earlier studies of xanomeline alone. Xanomeline crosses the blood-brain barrier while trospium does not, so trospium can mitigate the procholinergic AEs caused by xanomeline in peripheral tissues while not counteracting the beneficial effects of xanomeline in the brain. KarXT can be used to treat bipolar disorder, schizophrenia, cognitive impairment associated with schizophrenia, psychosis in Alzheimer disease, Alzheimer’s disease with agitation, Alzheimer’s disease with cognitive impairment, and autism. KarXT dosed three times a day (TID) is being evaluated in a Phase 3 study for the treatment of psychosis associated with Alzheimer’s disease.

[0004] KarXT has been shown to be safe and well-tolerated in patients and in healthy subjects. The most common treatment-emergent adverse events (TEAEs) associated with KarXT are procholinergic-related effects (e.g., nausea, vomiting, tremor, excess salivation, excess sweating, diarrhea) and anticholinergic symptoms (e.g., dry mouth, blurred vision, dry eyes, constipation, urinary retention). While trospium in the KarXT capsule mitigates some of the procholinergic AEs reported in earlier studies of xanomeline alone, the incidence of nausea and vomiting still occurs.

[0005] Therefore, there remains a need in the art for a pharmaceutical composition or dosage form that can provide increased tolerability for xanomeline to patients.

[0006] There also remains a need for a pharmaceutical composition or dosing regimen that can provide for once or twice daily dosing, instead of TID, that is sufficient to maintain steady plasma concentrations of xanomeline with reduced peak-to-trough fluctuations during daily dosing.

[0007] There further remains a need for a pharmaceutical composition or dosing regimen that provides a longer duration-of-effect than the current xanomeline and trospium dosing regimen.SUMMARY

[0008] The present disclosure accomplishes the foregoing needs and other needs by providing a combination of an immediate-release and a modified release dose form of xanomeline or a salt thereof, which could reduce the number of xanomeline doses per day, thereby improving patient compliance and efficacy.

[0009] Provided herein is a pharmaceutical composition that delivers an initial fraction of the xanomeline dose rapidly through an intermediate-release (IR) component and delivers the remaining dose after a delay of several hours through a modified-release (MR) component from one administration. The pharmaceutical composition comprises(1) a MR component comprising xanomeline or a salt thereof;(2) an IR component comprising xanomeline or a salt thereof; and(3) an IR component comprising a trospium salt.

[0010] The IR and MR components of xanomeline or a salt thereof release at least two consecutive pulses of xanomeline or a salt thereof, each pulse separated in time by from about 0.5 to about 12 hours.

[0011] Also provided herein is a pharmaceutical composition comprising:(1) an IR component comprising xanomeline or a salt thereof and a trospium salt; and(2) a MR component comprising xanomeline or a salt thereof, wherein the IR and MR components of xanomeline or a salt thereof release at least two consecutive pulses of xanomeline or a salt thereof, each pulse separated in time by from about 0.5 to about 12 hours.

[0012] In some embodiments, the pharmaceutical composition comprising (1) the IR component of xanomeline or a salt thereof and a trospium salt and (2) the MR component of xanomeline or a salt thereof releases at least two consecutive pulses of xanomeline or a salt thereof, each pulse separated in time by from about 0.5, 1, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5 to about 12 hours.

[0013] In some embodiments, the pharmaceutical composition comprising (1) the IR component of xanomeline or a salt thereof and a trospium salt and (2) the MR component of xanomeline or a salt thereof releases three or four consecutive pulses of xanomeline or a salt thereof.

[0014] More specifically, provided herein is a pharmaceutical composition comprising:(1) a MR component comprising a plurality of beads comprising xanomeline or a salt thereof;(2) an IR component comprising a plurality of beads comprising xanomeline or a salt thereof;(3) an IR component comprising a plurality of beads comprising a trospium salt.

[0015] It was found that administration of the pharmaceutical composition of the present disclosure to human subjects produced a “dual burst” (DB) pattern of xanomeline release (FIG. 2). This mixed MR and IR pharmaceutical composition (KarXT DB / IR) reduced Cmax and AUC of xanomeline in the plasma and flattened the concentration-time curve of xanomeline compared to the KarXT-IR / IR pharmaceutical composition.Unexpectedly, it was found that the pharmaceutical composition of the present application also reduced the Cmax of trospium even though only the IR form of trospium was administered to the human subjects. The human subjects received the pharmaceutical composition of the present disclosure reported decreased procholinergic AEs compared to the human subjects receiving the KarXT-IR / IR pharmaceutical composition.

[0016] In one embodiment, the DB release pattern of xanomeline was achieved by giving to the human subject half the dose of xanomeline in an IR form and the other half in a modified form, along with the full dose of trospium in the IR form.

[0017] Provided herein is a pharmaceutical composition wherein the IR component is in the form of an IR capsule. Thus, the IR capsule may comprise a plurality of IR beads of only xanomeline or a salt thereof. The IR capsule may comprise a plurality of IR beads of a trospium salt. The IR capsule may comprise a plurality of IR beads of xanomeline or a salt thereof and a plurality of IR beads of a trospium salt. The xanomeline or a salt thereof in the IR capsule can be xanomeline free base or xanomeline salt. Preferably, the xanomeline salt is xanomeline tartrate. The trospium salt in the IR capsule can be trospium chloride.

[0018] Provided herein is a pharmaceutical composition wherein the MR component comprises enteric (gastro-resistant) capsules (ECs,) or enteric-coated beads. Thus, a plurality of beads of xanomeline or a salt thereof is encapsulated in an enteric capsule or a plurality of enteric-coated beads encapsulated in a non-enteric capsule. The xanomeline or a salt thereof in the ECs or enteric-coated beads can be xanomeline free base or xanomeline salt. Preferably, the xanomeline salt is xanomeline tartrate.

[0019] Also provided herein is a coated xanomeline and trospium IR bead comprising:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and optionally one or more pharmaceutically acceptable carriers coated over said sugar core;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and optionally one or more pharmaceutically acceptable carriers coated over said active ingredient layer; and(4) an active ingredient layer comprising a trospium salt and optionally one or more pharmaceutically acceptable carriers coated over said seal coat layer.

[0020] Also provided herein is an enteric- coated xanomeline bead comprising:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and optionally one or more pharmaceutically acceptable carriers;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and optionally one or more pharmaceutically acceptable carriers; and(4) an enteric coating layer comprising an enteric polymer and optionally one or more pharmaceutically acceptable carriers.

[0021] Provided herein is a method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising xanom eline or a salt thereof and a trospium salt; and (2) a MR component comprising xanom eline or a salt thereof.

[0022] Also provided herein is a method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising a plurality of beads comprising xanomeline or a salt thereof and a plurality of beads comprising a trospium salt; and (2) a MR component comprising a plurality of beads comprising xanomeline or a salt thereof.

[0023] Also provided herein is a method of treating a muscarinic disorder comprising administering the pharmaceutical composition of the present disclosure to a patient once or twice daily.

[0024] Also provided herein is a method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising xanomeline or a salt thereof and a trospium salt; and (2) a MR component comprising xanomeline or a salt thereof with a total daily dose of xanomeline equivalent to between 25 and 250 mg of xanomeline as the tartrate salt and a total daily dose of trospium equivalent to between 2.5 and 40 mg trospium chloride.

[0025] Further aspects and advantages will be apparent to those of ordinary skill in the art from a review of the following detailed description. The disclosure is illustrative and is not intended to limit the disclosure to the specific embodiments described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0026] The disclosure will be readily understood by the following detailed description in conjunction with the accompanying drawings, wherein like reference numerals designate like structural elements. The drawings provide exemplary embodiments or aspects of the disclosure and do not limit the scope of the disclosure.

[0027] FIG. 1 is a schematic representation of the design of the clinal trial described in Example 3.

[0028] FIG. 2 shows the Day 10 in vivo xanom eline plasma profiles for the formulations KarXT-IR / IR and KarXT-DB / IR tested in the clinical trial described in Example 3.

[0029] FIG. 3 shows the Day 10 in vivo trospium plasma profiles for the formulations KarXT-IR / IR and KarXT-DB / IR tested in the clinical trial described in Example 3.

[0030] FIG. 4 is a schematic representation of the design of the clinal trial described in Example 4.

[0031] FIG. 5 shows the results of the dissolution study of the xanomeline enteric- coated MR beads and the xanomeline and trospium coated IR beads described in Examples 5 and 6. FIG 5A shows the percentage release of xanomeline of the xanomeline enteric- coated MR beads. FIG. 5B shows the percentage release of trospium of the xanomeline and trospium coated IR beads.

[0032] FIG. 6 shows the dissolution profile of the capsule comprising xanomeline enteric- coated MR beads and xanomeline and trospium coated IR beads.

[0033] FIG. 7 shows the results of the stability study of the capsule comprising xanomeline enteric-coated MR beads and xanomeline and trospium coated IR beads described in Example 7.

[0034] FIG. 8A shows the in vivo xanomeline plasma profiles of the KarXT-IR / IR and KarXT-DB / IR formulations described in Examples 1 and 2 and non-enteric capsules comprising xanomeline enteric-coated MR beads and xanomeline and trospium coated IR beads described in Examples 5 and 6. FIG. 8B shows the in vivo trospium plasma profiles of the KarXT-IR / IR and KarXT-DB / IR formulations described in Examples 1 and 2 and non-enteric capsules comprising xanomeline enteric-coated MR beads and xanomeline and trospium coated IR beads described in Example 8.DETAILED DESCRIPTION

[0035] The present disclosure provides an oral pharmaceutical composition comprising (1) an immediate-release (IR) component comprising xanomeline or a salt thereof; (2) a modified-release (MR) component comprising xanomeline or a salt thereof; and (3) an IR component comprising a trospium salt.

[0036] The present disclosure provides an oral pharmaceutical composition comprising (1) an IR component comprising xanom eline or a salt thereof; (2) a MR component comprising xanom eline or a salt thereof; and (3) an IR component comprising a trospium salt, wherein the IR and MR components of xanomeline or a salt thereof releases at least two consecutive pulses of xanomeline or a salt thereof, each pulse separated in time by from about 0.5 to about 12 hours.

[0037] The present also disclosure provides an oral pharmaceutical composition comprising (1) an IR component comprising a plurality of beads comprising xanomeline or a salt thereof; (2) a MR component comprising a plurality of beads comprising xanomeline or a salt thereof; and (3) an IR component comprising a plurality of beads comprising a trospium salt. Each of the plurality of beads contains an inert core, such as a sugar core.

[0038] The MR component, which can be in the form of enteric capsules or enteric coated beads, releases xanomeline in an elevated pH environment like intestine instead of the stomach, reducing local irritation of the stomach. The MR and IR components comprising xanomeline or a salt thereof produce a dual burst pattern of xanomeline release. The combined IR and MR components of the oral pharmaceutical formulation lower xanomeline’ s maximum observed concentration (Cmax) to reduce procholinergic side effects (including nausea and vomiting) while preserving its area under the concentration-time curve (AUC) to maintain efficacy. Thus, the pharmaceutical composition of the present disclosure achieves an effective therapeutic effect for both xanomeline and trospium, reduces AEs, and potentially increases dosing compliance, especially for elderly patients. The current disclosure also provides dosage forms with different strengths or different ratios of the two active agents.

[0039] In one embodiment, the pharmaceutical composition comprising the MR and IR components comprising xanomeline or a salt thereof reduces the geometric mean Cmax by at least 36% compared to the pharmaceutical composition comprising the IR and IR components (KarXT-IR / IR).

[0040] In another embodiment, the pharmaceutical composition comprising the MR and IR components comprising xanomeline or a salt thereof reduces the geometric mean Cmax by at least 30% compared to the pharmaceutical composition comprising the IR and IR components.

[0041] In another embodiment, the pharmaceutical composition comprising the MR and IR components comprising xanomeline or a salt thereof reduces the geometric meanCmax by at least 20% compared to the pharmaceutical composition comprising the IR and IR components.

[0042] In another embodiment, the pharmaceutical composition comprising the MR and IR components comprising xanomeline or a salt thereof reduces the geometric mean Cmax by at least 10% compared to the pharmaceutical composition comprising the IR and IR components (KarXT-IR / IR).

[0043] In another embodiment, the pharmaceutical composition of the present disclosure is combined with one or more pharmaceutical agents, including psychotherapy and drugs. Therapeutic agents include, but are not limited, to antipsychotics, anxiolytics, anti-depressants, sedatives, tranquilizers, analgesics, and other pharmacological interventions known to one skilled in the art. A therapeutic agent may fall under the category of more than one drug. For instance, benzodiazepines can be considered anxiolytics, sedatives, and tranquilizers.Definitions

[0044] The articles “a” and “an” refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0045] The terms “comprise” and “comprising” are inclusive, open sense, meaning that additional elements may be included.

[0046] The term “consisting” limits the elements to those specified except for impurities ordinarily associated in addition to that.

[0047] The term “consisting essentially of’ limits those specified elements and those that do not materially affect the basic and novel characteristics of the material or steps.

[0048] All ranges set forth herein include all possible subsets of ranges and any combinations of such subset ranges. By default, ranges include the stated endpoints, unless stated otherwise, where a range of values is provided, each intervening value between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both limits, ranges excluding either or both of those included limits are also contemplated to be part of the disclosure.

[0049] The term “wt.%” is the weight percent based on the total weight, e.g., of the core, or enteric coating, or total bead, as described in context. Unless stated otherwise, the wt.% is intended to describe the weight percent based on dry weight (e.g., for a core following drying).

[0050] The term “component” is used in its broadest conventional interpretation unless dictated by context or specifically stated. More specifically, a component may be an element, a constituent part, a single ingredient or a mixture of ingredients. For example, an immediate-release component may include a single ingredient such as a drug itself or it may be a combination of a drug and one or more pharmaceutically acceptable excipients provided the “immediate-release component” will release the drug immediately upon administration.”

[0051] The term “KarXT” or “KarXT-IR / IR” means immediate-release beads or pellets of xanomeline tartrate and immediate-release beads or pellets of trospium chloride in an immediate-release capsule.

[0052] The term “KarXT -DB / IR” means immediate-release beads or pellets of xanomeline tartrate and immediate-release beads or pellets of trospium chloride in an immediate-release capsule, plus immediate-release beads or pellets of xanomeline tartrate in an enteric capsule.

[0053] The term “KarX-EC” means immediate-release beads or pellets of xanomeline or a salt thereof in an enteric capsule or enteric-coated beads or pellets of xanomeline or a salt thereof in an IR capsule.

[0054] The term “controlled-release” or “modified-release” is defined as a prolonged- release pattern of one or more drugs, such that the drugs are released over a period. A modified-release formulation has release kinetics that results in measurable serum levels of the drug over a period longer than what would be possible following intravenous injection or following administration of an immediate-release oral dosage form. Modified-release, slow-release, sustained-release, extended-release, prolonged-release, and delayed-release have the same definitions.

[0055] The term “immediate-release” refers to an oral dosage form or composition that releases the specified amount of the active ingredient such as xanomeline and / or trospium within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less following oral administration of the dosage form or composition to a patient or subject to be adsorbed into the bloodstream via the gastrointestinal tract, or when tested in aUnited States Pharmacopeia Type I or Type II dissolution apparatus using 500-900 ml of an aqueous media.

[0056] The term “including” means “including but not limited to.” “Including” and “including but not limited to” are used interchangeably.

[0057] The term “mammal” is known in the art. Exemplary mammals include humans, primates, bovines, porcines, canines, felines, and rodents (e.g., mice and rats).

[0058] The term a “patient,” “subject,” or “host” to be treated by the subject method means either a human or non-human mammal.

[0059] The term “elderly” or “geriatric” refer to a person aged 60 years or older, for example, between 60 to 90 years.

[0060] The term “pharmaceutically acceptable carrier” is art-recognized. It refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials that may serve as pharmaceutically acceptable carriers include sugars, such as lactose, glucose, and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, 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; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol; phosphate buffer solutions; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0061] The term “pharmaceutically acceptable salt” or “salt” is art-recognized. It refers to a salt prepared from relatively nontoxic acids or bases, including inorganic acids and bases and organic acids and bases, including, for example, those contained in compositions of the present disclosure. Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, saccharinate, succinic, sulfuric, tartaric acid, p-toluenesulfonic, hydrochloric, hydrobromic, phosphoric, and sulfuric acids and the like.

[0062] The term “treating” is art-recognized and refers to curing as well as ameliorating at least one symptom of any condition or disorder.

[0063] In jurisdictions that forbid the patenting of methods practiced on the human body, the meaning of “administering” of a composition to a human subject shall be restricted to prescribing a controlled substance that a human subject will self-administer by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with laws or regulations defining patentable subject matter is intended. In jurisdictions that do not forbid the patenting of methods practiced on the human body, the “administering” of compositions includes both methods practiced on the human body and the foregoing activities.

[0064] The term “therapeutic agent” is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance acting 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 edition), the Physicians ’ Desk Reference (64th edition), and The Pharmacological Basis of Therapeutics (12th edition). These therapeutic agents include without limitation medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure, or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.

[0065] The term “dose” or “dose strength” means the measured quantity of an active agent to be taken at one time by a patient. In certain embodiments, wherein the active agent is not xanomeline free base, the quantity is the molar equivalent to the corresponding amount of xanomeline free base. For example, often a drug is packaged in a pharmaceutically acceptable salt form, for example xanomeline tartrate, and the dosage for strength refers to the mass of the molar equivalent of the corresponding xanomeline free base. The conversion factor from xanomeline free base to xanomeline tartrate is 1.53.Thus, a dose strength of 50 mg xanomeline as the tartrate salt has the dose strength based on 50 mg of xanomeline free base but contains 76.5 mg of xanomeline tartrate. In certain embodiments, wherein the active agent is a trospium salt that is not trospium chloride, thequantity of the trospium salt is the molar equivalent to the corresponding amount of trospium chloride.

[0066] The term “psychotherapy” refers to non-pharmacological therapies. Those skilled in the art use various techniques involving verbal and other interactions with a patient to affect a positive therapeutic outcome. Such techniques include, but are not limited to, behavior therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, vocational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also called person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavioral therapy, reality therapy, response-based therapy, sandplay therapy, status dynamics therapy, hypnosis, and validation therapy. Psychotherapy may involve combining two or more techniques. A therapist can select and adjust the techniques based on the individual patient's needs and responses.

[0067] The term “muscarinic disorder” refers to any disease or condition ameliorated by activating the muscarinic system. Such diseases include ones in which direct activation of muscarinic receptors themselves or inhibition of cholinesterase enzymes has produced a therapeutic effect.

[0068] The terms “diseases related to schizophrenia” and “disorders related to schizophrenia” include, but are not limited to, schizoaffective disorder, psychosis, including acute psychosis, delusional disorders, psychosis associated with Alzheimer’s disease, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis, Huntington’s disease, Lewy Body dementia, or any other disease with psychotic features.

[0069] The term “psychosis” refers to an abnormal condition of the mind that results in difficulties determining what is real and 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), incoherent speech, behavior that is inappropriate for the situation, sleep problems, social withdrawal, lack of motivation, and difficulties carrying out daily activities.

[0070] The term “acute psychosis” refers to the quick or strong onset of psychotic symptoms in a patient, for example, as defined in “Acute and Transient Psychotic Disorder” (International Classification of Diseases- 10) and “Brief Psychosis” (DSM-IV). A sharp striking delusion with quick changes in the structure occurs in the individual whohas acute psychosis after a short preliminary period of anxiety, insomnia, and confusion. Acute psychosis can include acute psychotic exacerbation when a patient may respond to hallucinations or delusions. Acute psychosis lasts for a short time, typically from one to two weeks.

[0071] The term “activator” means a molecule described as an agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator, allosteric agonist, or a molecule that increases the activity or signaling of receptors directly or indirectly.

[0072] The term “inhibitor” means a molecule described as an antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist, or a molecule that decreases the activity or signaling of receptors directly or indirectly.

[0073] The term “adverse event” is any untoward medical occurrence associated with treatment with a pharmaceutical composition described herein. A “mild adverse event” is easily tolerated by the subject, causes minimal discomfort, and does not interfere with everyday activities. A “moderate adverse event” is sufficiently discomforting to interfere with everyday activities; intervention may be needed. A “severe adverse event” prevents everyday activities; treatment or other intervention is usually needed. A “serious adverse event” results in death; is life-threatening (immediate risk of death from the event as it occurred); requires or prolongs inpatient hospitalization; results in persistent or significant disability / incapacity; or results in a congenital anomaly / disability, cancer, or drug overdose. An adverse event is incapacitating or disabling if it results in a substantial or permanent disruption of the subject’s ability to carry out normal life functions.

[0074] 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 an unacceptable adverse event or an unacceptable combination of adverse events. One of skill in the art will appreciate that tolerance is a subjective measure and that what may be tolerable to one patient may not be tolerable to a different patient. For example, one patient may not be able to tolerate a headache. In contrast, a second patient may find headaches tolerable but is not able to tolerate vomiting. For a third patient, either headache alone or vomiting alone is tolerable.Still, the patient cannot tolerate the combination of headache and vomiting, even if the severity of each is less than when experienced alone.

[0075] The term “maximum tolerated dose” means the highest dose of a drug or therapeutic that a patient can take without the patient experiencing intolerable side effects. The maximum tolerated dose is typically determined empirically in clinical trials.

[0076] The term “muscarinic receptors” refers to G-protein linked receptors that bind the neurotransmitter acetylcholine. To date, five subtypes of the muscarinic receptor have been identified. “Ml” means the subtype one muscarinic receptor. “M2” means the subtype two muscarinic receptor. “M3” means the subtype three muscarinic receptor. “M4” means the subtype four muscarinic receptor. “M5” means the subtype five muscarinic receptor.

[0077] The term “antipsychotic” refers to a drug that diminishes psychosis, hallucinations, or delusions. Antipsychotics include, but are not limited to haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, periciazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupenthixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetrabenazine.

[0078] The term “anxiolytics” refers to drugs that reduce 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.

[0079] The term “anti-depressants” refers to drugs that alleviate depression and related conditions (e.g., dysthymia). Such drugs include, but are not limited to, selective serotonin-reuptake inhibitors (SSRIs, e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), mianserin, mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline), and monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine).

[0080] The terms “sedatives” or “tranquilizers” refer to drugs that induce somnolence, promote a feeling of being tired or desire to sleep, or promote 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.Oral Pharmaceutical Composition with IR and MR Components

[0081] Provided herein is a combined IR and MR oral pharmaceutical composition of xanomeline or a salt thereof and a trospium salt. Such a pharmaceutical composition enables absorption of the xanomeline and trospium not only in the stomach but also in the gastrointestinal tract of a subject, providing a steadier plasma concentration profile of xanomeline and trospium over a prolonged period of time.

[0082] The oral pharmaceutical composition may comprise: (1) an IR component comprising xanomeline or a salt thereof, (2) a MR component comprising xanomeline or a salt thereof, and (3) an IR component comprising a trospium salt. The immediate-release component provides immediate-release of the active agents, i.e., xanomeline and trospium and the MR component provides a delayed release of xanomeline. The IR and MR components can be each independently formulated into unit dosage forms or can be coformulated into one unit dosage form.

[0083] In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR component is from 1 :3 to 3 : 1. In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR component is 1 : 1. In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR ratio is 2: 1. In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR component is 3 : 1. In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR component is 1 :2. In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR component is 1 :3.

[0084] In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR component is from 1 : 1 to 1 :3, e.g., from 1 : 1.5 to 1 :2, from 1 :2 to 1 :2.5, and from 1 :2.5 to 1 :3.

[0085] In certain embodiments, the weight ratio of xanomeline in the IR component to xanomeline in the MR component is from 2: 1 to 2:3, e.g., from 2: 1.5 to 2:2, from 2:2 to 2:2.5, and from 2:2.5 to 2:3.

[0086] In certain embodiments, the weight ratio of xanomeline in the MR component to xanomeline in the IR component is from 1 : 1 to 1 :3, e.g., from 1 : 1.5 to 1 :2, from 1 :2 to 1 :2.5, and from 1 :2.5 to 1 :3.

[0087] In certain embodiments, the oral pharmaceutical composition may comprise: (1) an IR component comprising a plurality of beads comprising xanomeline or a salt thereof, (2) a MR component comprising a plurality of beads comprising xanomeline or a salt thereof, and (3) an IR component comprising a plurality of beads comprising a trospium salt.

[0088] In certain embodiments, the MR component contains a plurality of beads comprising xanomeline or a salt thereof encapsulated in an enteric capsule. In some embodiments, the plurality of beads is the plurality of immediate-release beads and the enteric capsule (EC) is composed of enteric polymers.

[0089] In certain embodiments, the oral pharmaceutical composition of the present disclosure may comprise (1) an IR capsule comprising both a plurality of beads comprising xanomeline or a salt thereof and a plurality of beads comprising a trospium salt, (2) an EC comprising a plurality of beads comprising xanomeline or a salt thereof. The salt of trospium is chosen from trospium chloride, trospium bromide, trospium iodide, and trospium saccharinate.

[0090] In certain embodiments, the oral pharmaceutical composition of the present disclosure may comprise (1) an IR capsule comprising a plurality of beads comprising xanomeline or a salt thereof, and (2) an IR capsule comprising a plurality of beads comprising a trospium salt, and (3) an EC comprising a plurality of beads comprising xanomeline or a salt thereof.

[0091] The IR component of the pharmaceutical composition of the present disclosure comprises IR capsules. The making of IR capsules comprising xanomeline or a salt thereof, a trospium salt, or a combination thereof, has been described in U.S. Pat. No. 10,925,832, which is incorporated herein by reference in its entirety. In one embodiment, the IR capsule contains one population of drug beads containing xanomeline or a salt thereof. In one embodiment, an IR capsule comprises one population of drug beads containing a trospium salt. In another embodiment, the IR capsule comprises separatepopulations of drug beads containing xanomeline or a salt thereof and a trospium salt. The drug beads containing xanomeline or a salt thereof and a trospium salt are of comparable size and release the actives rapidly.

[0092] A discrepancy in the number of drug beads in the capsule increases the probability that the drug beads’ ratio would not remain substantially constant after the beads are released and disperse. Thus, in certain embodiments, the trospium beads are formulated with a lower drug load. Effective doses of trospium and xanomeline are contained in roughly equivalent numbers of beads.

[0093] In certain embodiments, the oral pharmaceutical composition is a capsule comprising a plurality of xanomeline beads, each of said plurality of xanomeline beads having a core comprising between about 50 wt.% and about 90 wt.% xanomeline tartrate, between about 15 wt.% and about 65 wt.% microcrystalline cellulose, and between about 0 wt.% and about 1 wt.% ascorbic acid, and optionally between about 0 wt.% and about 2 wt.% talc, wherein each of said plurality of xanomeline beads has a size between 0.4 mm and 1 mm; a plurality of trospium beads, each of said plurality of trospium beads having a core comprising between about 4 wt.% and about 35 wt.% trospium chloride, between about 40 wt.% and about 60 wt.% microcrystalline cellulose, and between about 30 wt.% and about 50 wt.% lactose monohydrate, and optionally between about 0 wt.% and about 2 wt.% talc, wherein each of said plurality of trospium beads has a size between 0.6 mm and 0.85 mm; and the plurality of xanomeline beads and the plurality of trospium beads each having a dissolution rate of more than about between 85%-100% within about the first 20 minutes following entry of the capsule into an aqueous solution.

[0094] In another embodiment, each of the xanomeline beads comprises about 66 wt.% xanomeline tartrate, about 33 wt.% microcrystalline cellulose, about 0.5 wt.% ascorbic acid, and about 0.5 wt.% talc. Or each of the xanomeline beads comprises about 66 wt.% xanomeline tartrate and about 34 wt.% microcrystalline cellulose.

[0095] In certain embodiments, the plurality of trospium beads have a core comprising between about 3 wt.% and about 20 wt.% trospium chloride, between about 45 wt.% and about 60 wt.% microcrystalline cellulose, and between about 35 wt.% and about 50 wt.% lactose monohydrate, and optionally a second coating comprising between about 0 wt.% and about 2 wt.% talc.

[0096] In another embodiment, each of the trospium beads comprises about 17.7 wt.% trospium chloride, about 46.8 wt.% microcrystalline cellulose, about 35 wt.% lactosemonohydrate, and about 0.5 wt.% talc, or 17.7 wt.% trospium chloride, 35 wt.% microcrystalline cellulose, and 47.3wt.% lactose monohydrate.

[0097] In certain embodiments, each of the trospium beads comprises about 4.4 wt.% trospium chloride, about 54.5 wt.% microcrystalline cellulose, about 40.6 wt.% lactose monohydrate, and about 0.5 wt.% talc. In certain embodiments, each of the trospium beads comprises a core comprising about 4.4 wt.% trospium chloride, about 54.5 wt.% microcrystalline cellulose, and about 40.6 wt.% lactose monohydrate, and optionally about 0.5 wt.% talc.

[0098] In another embodiment, the oral pharmaceutical composition comprises an IR capsule wherein each of said plurality of xanomeline beads having a core comprising between about 66 wt.% xanomeline tartrate, between about 33 wt.% microcrystalline cellulose, about 0.5 wt.% ascorbic acid, and about 0.5 wt.% talc; each of said a plurality of trospium beads having a core comprising between about 17.7 wt.% trospium chloride, about 46.8 wt.% microcrystalline cellulose, about 35 wt.% lactose monohydrate, and about 0.5 wt.% talc.Beads and excipients therein

[0099] The bead can comprise one or more excipients. In certain embodiments, the excipients include one or more fillers, binders, and surfactants. Other optional ingredients include, but are not limited to, glidants, lubricants, disintegrants, swelling agents, and antioxidants. The xanomeline or a pharmaceutically acceptable salt thereof and the salt of trospium may be in separate matrices within the same medicament.

[0100] The amount of xanomeline free base or tartrate in the bead can be at least 10 wt.% or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.% of the bead. For example, the amount of xanomeline tartrate can be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% of the bead, in a range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%. It is understood that all ranges including these values as endpoints are contemplated, for example, at least between about 15 wt.% and about 90 wt.%, between about 20 wt.% and about 85 wt.%, between about 30 wt.% and about 85 wt.%, or between about 50 wt.% and about 90 wt.%. In certain embodiments, the xanomeline beads comprise between about 30 wt.% and about 80 wt.% xanomeline tartrate, such as about 66 wt.% xanomeline tartrate.

[0101] The amount of trospium salt in the bead can be at least 3 wt.%, or at least 10 wt.% or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.%, or at least 30 wt.% of the baed. For example, the amount of trospium chloride can be at least 50 wt.%, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% of the bead, in a range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%. It is understood that all ranges including these values as endpoints are contemplated, for example, at least between about 15 wt.% and about 90 wt.%, between about 20 wt.% and about 85 wt.%, between about 30 wt.% and about 85 wt.%, or between about 50 wt.% and about 90 wt.%. In certain embodiments, the trospium is trospium chloride. In certain embodiments, the trospium beads comprise between about 8 wt.% and about 35 wt.% trospium chloride, such as about 17.7 wt.% trospium chloride.

[0102] Fillers include, but are not limited to, lactose, saccharose, glucose, starch, microcrystalline cellulose, microfine 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, although it may absorb water. In one embodiment, the filler is a spheronization aid. Spheronization aids can include one or more of crospovidone, carrageenan, chitosan, pectinic acid, glycerides, P-cyclodextrin (P-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide. In one embodiment, the filler includes microcrystalline cellulose.

[0103] The amount of filler in the xanomeline bead is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose) can range from about 10 wt.% to about 70 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, for example, about 20 wt.%. In certain embodiments, the xanomeline beads comprise between about 15 wt.% and about 65 wt.% microcrystalline cellulose, such as between about 15 wt.% and about 20 wt.%, between about 20 wt.% and about 25 wt.%, between about 25 wt.% and about 30 wt.%, between about 30 wt.% and about 35 wt.%, between about 35 wt.% and about 40 wt.%, between about 40 wt.% and about 45 wt.%, between about 45 wt.% and about 50 wt.%, between about 50 wt.% and about 55 wt.%, between about 55 wt.% and about 60 wt.%, or between about 60 wt.% and about 65 wt.%. In certain embodiments, the xanomeline beads comprise 33.5 wt.% microcrystalline cellulose.

[0104] The amount of filler in the trospium bead is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose or lactose) can be in a range of about 10 wt.% to about 80 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, for example about 20 wt.%. In certain embodiments, the trospium beads comprise between about 25 wt.% and about 80 wt.% microcrystalline cellulose, such as between about 25 wt.% and about 30 wt.%, between about 30 wt.% and about 35 wt.%, between about 35 wt.% and about 40 wt.%, between about 40 wt.% and about 45 wt.%, between about 45 wt.% and about 50 wt.%, between about 50 wt.% and about 55 wt.%, between about 55 wt.% and about 60 wt.%, between about 60 wt.% and about 65 wt.%, between about 65 wt.% and about 70 wt.%, between about 70 wt.% and about 75 wt.%, or between about 75 wt.% and about 80 wt.%. In certain embodiments, the trospium beads comprise about 46.8 wt.% microcrystalline cellulose.

[0105] In certain embodiments, the trospium beads comprise between about 15 wt.% and about 70 wt.% lactose monohydrate, such as between about 15 wt.% and about 20 wt.%, between about 20 wt.% and about 25 wt.%, between about 25 wt.% and about 30 wt.%, between about 30 wt.% and about 35 wt.%, between about 35 wt.% and about 40 wt.%, between about 40 wt.% and about 45 wt.%, between about 45 wt.% and about 50 wt.%, between about 50 wt.% and about 55 wt.%, between about 55 wt.% and about 60 wt.%, between about 60 wt.% and about 65 wt.%, or between about 65 wt.% and about 70 wt.%. In certain embodiments, the trospium beads comprise about 35 wt.% lactose monohydrate.

[0106] Binders include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propyl cellulose, hydroxypropyl cellulose, lower- substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose (hypromellose, e.g., hypromellose 2910, Methocel™ E), carboxymethyl cellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinyl pyrrolidone (povidone), cross-linked polyvinyl pyrrolidone, sodium alginate, microcrystalline cellulose, and lower-alkyl-substituted hydroxypropyl cellulose. In one embodiment, the binders are selected from wet binders. In one embodiment, the binder is selected from cellulose ethers, e.g., hypromellose.

[0107] The amount of binder in the xanomeline bead is not particularly limited. In embodiments, the amount of binder (e.g., hypromellose) can be between about 1 wt.% and about 10 wt.%, between about 2 wt.% and about 8 wt.%, or between about 4 wt.% and about 6 wt.%, for example, about 5 wt.% of the bead.

[0108] The amount of binder in the trospium bead is not particularly limited. In embodiments, the amount of binder (e.g., hypromellose) can be between about 1 wt.% and about 10 wt.%, between about 2 wt.% and about 8 wt.%, or between about 4 wt.% and about 6 wt.%, for example, about 5 wt.%.

[0109] 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, e.g., sodium lauryl sulfate.

[0110] The amount of surfactant, e.g., as a processing aid, is not particularly limited in the xanomeline bead. In embodiments, the amount of surfactant (e.g., microcrystalline cellulose) can range between about 0.1 wt.% and about 1 wt.%, between about 0.2 wt.% and about 0.8 wt.%, or between about 0.4 wt.% and about 0.6 wt.%, for example, about 0.5 wt.% of the bead.[OHl] The amount of surfactant, e.g., as a processing aid, is not particularly limited in the trospium bead. In embodiments, the amount of surfactant (e.g., sodium lauryl sulfate) can range between about 0.1 wt.% and about 1 wt.%, between about 0.2 wt.% and about 0.8 wt.%, or between about 0.4 wt.% and about 0.6 wt.%, for example, about 0.5 wt.% of the bead.

[0112] Disintegrants include, but are not limited to, starch, sodium cross-linked carboxymethyl cellulose, carmellose sodium, carmellose calcium, cross-linked polyvinyl pyrrolidone, and sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0113] Glidants include but are not limited to polyethylene glycols 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.

[0114] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and siliconized talc. In certain embodiments, the xanomeline beads comprise between about 0 wt.% and about 2 wt.% talc, such as about 0.5 wt.% talc. In certain embodiments, the trospium beads comprise between about 0 wt.% and 2 wt.% talc, such as about 0.5 wt.% talc of the bead.

[0115] In certain embodiments, the formulation further comprises one or more antioxidants. Examples of pharmaceutically-acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. In certain embodiments, the bead comprises less than 1 wt.% antioxidant, such as 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.%, 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.% , 0.08 wt.% , 0.07 wt.% , 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, or 0.01 wt.%.

[0116] In certain embodiments, the bead further comprises ascorbic acid. In certain embodiments, the bead comprises between about 0.2 wt.% and about 1 wt.% ascorbic acid. In certain embodiments, the bead comprises about 0.5 wt.% ascorbic acid. In certain embodiments, the bead further comprises butylated hydroxytoluene. In certain embodiments, the bead comprises between about 0.01 wt.% and about 0.1 wt.% butylated hydroxytoluene. In certain embodiments, the bead comprises about 0.05 wt.% butylated hydroxytoluene. In certain embodiments, the bead comprises about 0.05 wt.% BHT or 0.5 wt.% ascorbic acid. In certain embodiment, the oral pharmaceutical composition comprises of about 0.1% propyl gallate In certain embodiments, the antioxidant is present in the xanomeline beads.

[0117] In certain embodiments, the xanomeline beads comprise between about 30 wt.% and 80 wt.% xanomeline tartrate, between about 15 wt.% and about 65 wt.% microcrystalline cellulose, and about between about 0 wt.% and about 2 wt.% talc. In certain embodiments, the trospium beads comprise between about 0.2 wt.% and about 2 wt.% talc, such as about 0.5 wt.% talc. In certain embodiments, the trospium beads comprise between about 3 wt.% and about 35 wt.% trospium chloride, between about 25 wt.% and about 80 wt.% microcrystalline cellulose, between about 15 wt.% and about 70 wt.% lactose monohydrate, and between about 0.2 wt.% and about 2 wt.% talc.

[0118] In certain embodiments, the xanomeline beads comprise about 66 wt.% xanomeline tartrate, between about 33 to about 34 wt.% microcrystalline cellulose, and about 0.5 wt.% talc. In certain embodiments, the trospium chloride beads comprise about 17.7 wt.% trospium chloride, about 46.8 wt.% microcrystalline cellulose, about 35 wt.%lactose monohydrate, and about 0.5 wt.% talc. In certain embodiments, the xanomeline beads contain at least about 2.5 times as much xanomeline as the trospium chloride beads contain trospium chloride.

[0119] Depending on dosing requirements, IR capsules can be prepared with different amounts of xanomeline tartrate and trospium chloride beads. In various embodiments, IR capsules each contain 25 mg xanomeline as the tartrate salt and 10 mg trospium chloride, 50 mg xanomeline as the tartrate salt and 10 mg trospium chloride, 50 mg xanomeline as the tartrate salt and 20 mg trospium chloride, 75 mg xanomeline as the tartrate salt and 10 mg trospium chloride, 75 mg xanomeline as the tartrate salt and 20 mg trospium chloride, 125 mg xanomeline as the tartrate salt and 30 mg trospium chloride, or 125 mg xanomeline as a tartrate salt and 40 mg trospium chloride.

[0120] In one embodiment, each IR capsule contains 25 mg xanomeline as the tartrate salt and 10 mg trospium chloride.

[0121] In another embodiment, each IR capsule contains 50 mg xanomeline as the tartrate salt and 10 mg trospium chloride.

[0122] In another embodiments, each IR capsule contains 50 mg xanomeline as the tartrate salt and 20 mg trospium chloride.

[0123] In another embodiments, each IR capsule contains 75 mg xanomeline as the tartrate salt and 10 mg trospium chloride.

[0124] In another embodiments, each IR capsule contains 75 mg xanomeline as the tartrate salt and 20 mg trospium chloride.

[0125] In another embodiments, each IR capsule contains 125 mg xanomeline as the tartrate salt and 20 mg trospium chloride.

[0126] In another embodiments, each IR capsule contains 125 mg xanomeline as the tartrate salt and 40 mg trospium chloride.

[0127] In another embodiments, each IR capsule contains 150 mg xanomeline as the tartrate salt and 20 mg trospium chloride.

[0128] In another embodiments, each IR capsule contains 150 mg xanomeline as the tartrate salt and 30 mg trospium chloride.

[0129] In another embodiments, each IR capsule contains 150 mg xanomeline as the tartrate salt and 40 mg trospium chloride.

[0130] In another embodiments, each IR capsule contains 175 mg xanomeline as the tartrate salt and 20 mg trospium chloride.

[0131] In another embodiments, each IR capsule contains 175 mg xanom eline as the tartrate salt and 30 mg trospium chloride.

[0132] In another embodiments, each IR capsule contains 175 mg xanom eline as the tartrate salt and 40 mg trospium chloride.

[0133] In another embodiment, each IR capsule contains 14 mg xanom eline as the tartrate salt and 3 mg trospium chloride.

[0134] In another embodiment, each IR capsule contains 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride.

[0135] In another embodiment, each IR capsule contains 56 mg xanomeline as the tartrate salt and 12 mg trospium chloride,

[0136] In another embodiment, each IR capsule contains 84 mg xanomeline as the tartrate salt and 18 mg trospium chloride.

[0137] In another embodiment, each IR capsule contains 112 mg xanomeline as the tartrate salt and 24 mg trospium chloride.

[0138] In one embodiment, each IR capsule contains 14 mg xanomeline as the tartrate salt and 3 mg trospium chloride.

[0139] In another embodiment, each IR capsule contains 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride.

[0140] In another embodiment, each IR capsule contains 42 mg xanomeline as the tartrate salt and 9 mg trospium chloride.

[0141] In another embodiment, each IR capsule contains 56 mg xanomeline as the tartrate salt and 12 mg trospium chloride.

[0142] In another embodiment, the pharmaceutical composition contains from 5 mg to 300 mg xanomeline. In an embodiment, the medicament contains from 25 mg to 250 mg xanomeline.

[0143] In another embodiment, the pharmaceutical composition contains from 1 mg to 100 mg trospium chloride. In an embodiment, the pharmaceutical composition contains from 6.5 mg to 200 mg trospium chloride.

[0144] In another embodiment, the pharmaceutical composition contains 75 mg to 225 mg xanomeline, and the same pharmaceutical composition contains 20 mg or 40 mg trospium chloride. In another embodiment, the pharmaceutical composition contains 75 mg or 225 mg xanomeline, and a different pharmaceutical composition to be coadministered contains 20 mg or 40 mg trospium chloride.

[0145] It has been observed that, in the patient population aged 55 years and older, a dose of less than 40 mg trospium chloride performed better than did higher doses. In certain embodiments, the dose of trospium chloride is less than 30 mg, such as less than 20 mg or less than 10 mg. The trospium doses are co-administered to patients in need thereof with at least 200 mg xanomeline. This relationship can also be expressed as weight ratios between xanomeline and trospium chloride, where a weight ratio of 5: 1 xanomeline / trospium chloride (as used in the EMERGENT- 1 trial in patients with schizophrenia), led to undesirable tolerability in the elderly, where weight ratios of 6: 1 xanomeline / trospium chloride or 7.5: 1 xanomeline / trospium chloride were better tolerated. In certain embodiments, the weight ratio of xanomeline to trospium chloride is greater than 4: 1 such as 4.7: 1. In certain embodiments, the weight ratio of xanomeline to trospium chloride is greater than 5: 1, such as greater than 6: 1, greater than 7.5: 1, or greater than 10: 1. In certain embodiments, the weight ratio of xanomeline to trospium chloride is 10: 1.

[0146] In one embodiment, the IR capsule contains 20 mg xanomeline and 2 mg trospium chloride. In another embodiment, the IR capsule contains 30 mg xanomeline and 3 mg trospium chloride. In another embodiment, the IR capsule contains 50 mg xanomeline and 5 mg trospium chloride. In another embodiment, the IR capsule contains 66.7 mg xanomeline and 6.7 mg trospium chloride. In another embodiment, the IR capsule contains 14 mg xanomeline and 3 mg trospium chloride. In another embodiment, the IR capsule contains 28 mg xanomeline and 6 mg trospium chloride. In another embodiment, the IR capsule contains 42 mg xanomeline and 9 mg trospium chloride. In another embodiment, the IR capsule contains 56 mg xanomeline and 12 mg trospium chloride.Coated IR Beads

[0147] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising an MR component of xanomeline or a salt thereof and IR component xanomeline or a salt thereof and an IR component of a salt of trospium wherein the IR and MR components comprise coated beads.

[0148] In one aspect, the IR component is coated IR beads with an inert core, such as a sugar core. The sugar core may be first coated with one or multiple layers of materials such as polymers or active ingredients and then coated with a thin protective coating such as a seal coating and thereafter optionally coated with one or multiplelayers of materials such as other polymers or active ingredients (with or without further optional coatings).

[0149] In one embodiment, the IR component comprises a population of coated IR beads comprising a sugar core, coated with an active ingredient layer of xanomeline or a salt thereof. The active ingredient layer of xanomeline is further coated with a seal coating, which, in turn, is coated with an active ingredient layer of a salt of trospium.

[0150] It was reported that xanomeline tartrate and trospium chloride were incompatible when formulated together. In order to minimize the interaction between the active ingredient layer of xanomeline or a salt thereof and the active ingredient layer of a salt of trospium, additional barrier coating, or a seal coating, is present between the active ingredient layer of xanomeline or a salt thereof and the active ingredient layer of a salt of trospium. The seal coating provided herein not only promotes drug stability but also protects the active ingredient layer of xanomeline or a salt thereof from being oxidized by air. The seal coating also serves a substrate for applying the enteric polymer. Seal coating polymers can be hydroxypropyl methylcellulose (HPMC) based (aqueous) or ethylcellulose (organic solvent). In one embodiment, the seal coating is HPMC E5.

[0151] In embodiments where beads with an inert core are involved, the active ingredients may be mixed with further ingredients prior to being coated onto the beads. Ingredients include, but are not limited to, binders, surfactants, fillers, disintegrating agents, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures. Binders include, for example, celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and carb oxy methyl -cellulose sodium, polyvinyl pyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties. Examples of suitable ingredients include Klucel® and Kollicoat®, such as Klucel® LF and Kollicoat® IR.

[0152] The aforementioned beads can be prepared by using spray coating / drying or spray congealing technique. Before applying enteric-coating layer(s) onto the inert core, the core may optionally be covered with one or more separating (intermediate) layers.

[0153] In certain embodiments, the pharmaceutical composition provides a coated xanomeline and trospium IR bead comprising:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and optionally one or more pharmaceutically acceptable carriers coated over said sugar core;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and optionally one or more pharmaceutically acceptable carriers coated over said active layer; and(4) an active ingredient layer comprising a trospium salt and optionally one or more pharmaceutically acceptable carriers coated over said seal coat layer.

[0154] In certain embodiments, the xanomeline and trospium coated IR bead is prepared by a process comprising:(a) coating the sugar core with a suspension of xanomeline or a salt and a pharmaceutically acceptable carrier;(b) coating the xanomeline loaded sugar core of step (a) with a pharmaceutically acceptable seal coat polymer and a pharmaceutically acceptable carrier;(c) coating the seal coated xanomeline sugar core of step (b) with a trospium salt and optionally a pharmaceutically acceptable carrier.Enteric-Coated MR Component

[0155] In certain embodiments, the MR component may comprise a plurality of enteric- coated beads comprising xanomeline or a salt thereof.

[0156] Suitable enteric materials include, but are not limited to, cross-linked polyvinyl pyrrolidone; non-crosslinked polyvinylpyrrolidone; hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate succinate; cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate; polyvinyl acetate phthalate; carboxymethyl cellulose; methyl cellulose phthalate; methyl cellulose succinate; methyl cellulose phthalate succinate; methyl cellulose phthalic acid half ester; ethyl cellulose succinate; carboxymethylamide; potassium methacrylate divinylbenzene copolymer; polyvinyl alcohols; polyoxyethylene glycols; polyethylene glycol; sodium alginate; galactomannan; carboxypolymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with a monomer selected from the following: methylmethacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, e.g. Eudragit™ -L and -S series, including L 100-55, L 30 D-55, L 100, S 100, L 12.5, and S 12.5, available from Evonik Industries; polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; zein; gluten; ethylacrylatemaleic acid anhydride copolymer; maleic acid anhydride-vinyl methyl ether copolymer; styrol-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic acid anhydride; crotonic acidvinyl acetate copolymer; glutaminic acid / glutamic acid ester copolymer; carboxymethylethylcellulose glycerol monooctanoate; polyarginine; poly(ethylene); poly(propylene); poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride); and polyurethane.

[0157] The enteric material, e.g., polymer, can be one that will dissolve in intestinal juices at a pH level higher than that of the stomach, e.g., a pH of greater than 4.5, such as within the small intestine, and therefore permit the release of the active substance in the regions of the small intestine and substantially not in the upper portion of the GI tract. In one embodiment, the enteric material begins to dissolve in an aqueous solution at pH between about 4.5 and about 7.5. In another embodiment, the enteric material rapidly dissolves in an aqueous solution at a pH of about 5. In another embodiment, the enteric material rapidly dissolves in an aqueous solution at a pH of about 5.5.

[0158] In one embodiment, the enteric material rapidly dissolves at pH 5.5 and higher to provide fast dissolution in the upper bowel. For example, the enteric material can be selected from a copolymer of methacrylic acid and methyl methacrylate and a copolymer of methacrylic acid and ethyl acrylate. For example, an enteric polymer is poly(methacrylic acid co-ethyl acrylate)l : 1 (Eudragit™ L 30 D-55 and Eudragit™ L 1 GO- 55).

[0159] Other suitable examples of enteric materials include beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and acetyl alcohol, mastic and shellac, and shellac and stearic acid; polyvinyl acetate and ethyl cellulose; and a neutral copolymer of polymethacrylic acid esters (Eudragit™ LI 00); copolymers of methacrylic acid and methacrylic acid methylester, or a neutral copolymer of polymethacrylic acid esters containing metallic stearates. Such enteric materials comprise mixtures of fats and fatty acids, shellac and shellac derivatives, and cellulose acid phthalates, e.g., those with free carboxyl content.

[0160] One or more plasticizers can be added to enteric polymers to increase their pliability and reduce brittleness, as known in the art. Suitable plasticizers include, for example, butyl citrates, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycols (PEGs, such as PEG 6000), acetyl triethyl citrate, and triacetin. In one embodiment, the plasticizer is triethyl citrate. While some enteric materials are flexible and do not require plasticizers, more brittle polymers (e.g., Eudragit™ L / S types, Eudragit™ RL / RS, and Eudragit™ FS 30 D) benefit from plasticizers, for example, ranging from between 5 wt.% and 30 wt.% based on the dry polymer mass, between about 8 wt.% and about 12 wt.% tri ethyl citrate with poly(methacrylic acid co-ethyl acrylate) 1 : 1.

[0161] In certain embodiments, the enteric coatings comprise one or more antitacking agents (anti adherents) to reduce the film's tackiness and prevent agglomeration, as it is known in the art. Suitable anti-tacking agents include, but are not limited to, talc (magnesium silicate), glyceryl monostearate, fumed silica (e.g., Aerosil™ 200), precipitated silica (e.g., Sipemat™ PQ), and magnesium stearate. Anti -tacking agents can be used in any suitable quantity, for example ranging between about 10 wt.% and 100 wt.% based on dry polymer mass, between about 10 wt.% and about 50 wt.%, between about 10 wt.% and about 30 wt. %, or between about 15 wt.% and about 30 wt.%. For example, in one embodiment, it ranges between 15 wt.% and about 30 wt.% based on dry polymer mass.

[0162] One or more surfactants can also be added to an enteric coating mixture to increase substrate wettability and / or stabilize suspensions, as it is known in the art. Surfactants include Polysorbate 80, sorbitan monooleate, sodium dodecyl sulfate, and other surfactants described herein.

[0163] Any suitable process can form the enteric coating. Coating processes include pan coating, fluid bed coating, and dry coating (e.g., heat dry coating and electrostatic dry coating). Pan coating and fluid bed coating using solvent are well-established processes. In liquid coating, the enteric material and optional excipients (e.g., pigments, plasticizers, anti-tacking agents) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed onto solid dosage forms in a pan coater or a fluid bed dryer and dried by hot air. For example, in a Wurster fluid bed coating process, the coating fluid is sprayed from the fluid bed apparatus's bottom. Alternatively, the coating fluid is applied by top spraying. In certain embodiments, a tangential spray is applied.

[0164] The amount of enteric material applied is sufficient to achieve the desired acid resistance and release characteristics. In one embodiment, the enteric coating is present in an amount in a range between about 10% and 50%, or between 25% and about 35% as measured by the weight gain compared to the uncoated particle cores or particles with precoated layers, or ranging between about 25% and about 31% weight gain, between about 27% and about 31% weight gain, or between about 28.5% and about 31% weight gain, based on the weight of the uncoated particle cores or particles with pre-coated layers.

[0165] In some embodiments, the MR component is enteric-coated beads with an inert core, such as a sugar core. The sugar core is coated or layered with one or multiple layers of materials such as polymers or active ingredients, and outmost layer coated with an enteric material, preferably an enteric polymer. The MR component may also contain a rate controlling material that will contribute to the MR of the active ingredient. The MR component is essential to provide extended absorption, thereby providing prolonged and steady therapeutic coverage. In other embodiments, the beads may be coated with functional or non-functional coatings, such as aesthetic, handling, or stability. In certain embodiments, the beads might be coated with a pH-sensitive coating so that they do not dissolve in the low pH of the stomach.

[0166] In another embodiment, the MR component comprises a population of enteric-coated beads comprising an inert core, such as a sugar core, coated with an active ingredient layer of xanomeline or a salt thereof. The active ingredient layer of xanomeline is further coated with a seal layer, which, in turn, is enteric-coated. The enteric coating layer(s) coating the actively ingredient layer of xanomeline or a salt thereof is preferably sufficient to provide acid resistance to the substrates. Preferably, the enteric coating layer coating the actively ingredient layer of xanomeline or a salt thereof disintegrates / dissolves rapidly in near neutral or alkaline media. Thus, the pharmaceutical composition comprises two populations of beads, one population of MR beads comprising xanomeline or a salt thereof, the other population of IR beads comprising two active ingredients, xanomeline or a salt thereof and a salt of trospium.

[0167] Preferably, one or more enteric coating layers are applied onto the substrate using a suitable coating technique. The enteric coating layer materials may be dispersed or dissolved in either water or in suitable organic solvents. As enteric coating layer polymers include, but not limited to, methacrylic acid copolymers, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, polyvinyl acetate phthalate, cellulose acetate trimellitate, carboxymethylethylcellulose, shellac or other suitable enteric coating layer polymer(s) such as Eudragit L100-55 or Eudragit S 100.

[0168] The enteric coating layers preferably contain effective amounts of pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters, phthalic acid eaters, dibutyl sebacate, acetyl alcohol, polyethylene glycols, polysorbates or other plasticizers. The amount of plasticizer is optimized for the particular situation.

[0169] Additives such as dispersants, colorants, pigments, polymers e.g. poly (ethylacryfate, methylmethacrylate), anti-tacking and antifoaming agents may also be included into the enteric coating layer(s). Other compounds may be added to increase film thickness and to decrease diffusion of acidic gastric juices into the susceptible material.

[0170] Coatings may be applied to the substrates coated as set forth above, e.g., by coating or layering procedures in suitable equipment such as coating pan, coating granulator or in a fluidized bed apparatus using water and / or organic solvents for the coating or layering process. Suitable coating materials include sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methyl cellulose, carboxymethylcellulose and the like. Additives such as plasticizers, colorants, pigments, fillers, anti-lacking and ani-static agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included into the coating layer(s).

[0171] In certain embodiments, the enteric-coated xanomeline bead is prepared by a process comprising:(a) coating the sugar core with a suspension of xanomeline or a salt thereof or a pharmaceutically acceptable carrier;(b) coating the xanomeline loaded sugar core of step (a) with at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable carrier;(c) enteric coating the seal coated xanomeline sugar core of step (b) with a pharmaceutically acceptable enteric coat polymer; and(d) optionally, mixing the enteric-coated beads of xanomeline or a salt thereof with one or more pharmaceutically acceptable excipients for improving downstream processability.

[0172] Thus, for example, one embodiment combining various features described above includes a pharmaceutical composition comprising a plurality of xanomeline beads comprising a sugar core, a xanomeline tartrate coating, and an intermediate coating comprising a filler (optionally, e.g., microcrystalline cellulose), a binder (optionally e.g., hypromellose), and an outer enteric coating (e.g., Eudragit L100-55) surrounding the core, wherein the plurality of beads has a distribution of particle sizes ranging between about 0.4 mm and about 2.5 mm, wherein the enteric coating ranges between about 20% and about 40% based on the weight of the bead, and wherein the beads are disposed in a capsule shell.

[0173] The coated IR and MR beads may then be incorporated as unit doses in appropriately sized gelatin or HPMC capsules according to the present disclosure. In certain preferred embodiments, where the IR xanomeline and trospium beads and MR xanomeline beads are incorporated into separate or same capsules, the formulation allows both rapid release and delayed release of xanomeline.

[0174] Besides solvent, tablet auxiliary substances and other active ingredient excipients, it is possible to use, for example, coating compositions, plasticizers, antioxidants, preservatives, and dyes. Where incompatibilities between the active ingredients or between the active ingredients and ancillary substances are expected, suitable separating layers are provided where appropriate (for example in layered or multilayer tablets).

[0175] In certain embodiments, the beads comprise a coating of talc, which, for example, aids flowability and mixing. Generally, the beads comprise a coating of between 0 wt.% and 20 wt.% talc. In certain embodiments, the beads comprise a coating of 15 wt.% talc (in relation to the total weight of the bead). In certain embodiments, the first coating comprises talc. In certain embodiments, the second coating comprises talc.

[0176] In certain embodiments, the distribution of coating thicknesses can be stated in the weight gain of coating material based on the total weight of the coated beads.

[0177] For example, the difference in coating thickness from bead to bead can be in a range of + / - 1-7% based on the coated beads’ total weight. The distribution of coating thicknesses can be between about 2% and about 20% based on the weight of the coatedbeads, such as between about 3% and about 13%, between about 4% and about 12%, between about 5% and about 11%, between about 6% to about 10%, between about 7% and 9%, between about 3% and 14%, between about 4% and 14%, between about 4% and 13%, or between 4% and about 12%.

[0178] Coating thickness plays a role in the release of the active drug in the digestive system. Enteric materials should not significantly dissolve until the coated dosage forms have emptied from the stomach. The small intestine's pH gradually increases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2 in the small intestine's distal portions (ileum). To provide predictable dissolution corresponding to the small intestine transit time of about 3 hours (e.g., 2-3 hours) and permit reproducible release therein, the enteric material should begin to dissolve within the pH range of the duodenum and continue to dissolve at the pH range within the small intestine. Therefore, the thickness of the enteric materials should be substantially dissolved during the about three-hour transit time within the small intestine (e.g., the proximal and mid-small intestine). A combination of enteric materials may also be used.Bead Size and Shape

[0179] The plurality of beads has a distribution of particle sizes. The plurality of beads has bead shapes. The plurality of beads has a distribution of coating thicknesses when present.

[0180] Beads having a distribution of particle sizes were shown to exhibit advantageous pharmacokinetics. Without intending to be bound by any theory, it is contemplated that the pharmacokinetics are influenced by the plurality of beads having a distribution of core sizes.

[0181] In one embodiment, the particle sizes of the beads range between about 0.4 mm and about 1.5 mm, such as between about 0.4 mm and about 0.5 mm, between about 0.5 mm and about 0.6 mm, between about 0.6 mm and about 0.7 mm, between about 0.7 mm and about 0.8 mm, between about 0.8 mm and about 0.9 mm, between about 0.9 mm and about 1.0 mm, between about 1.0 mm and about 1.1 mm, or between about 1.1 mm and about 1.2 mm. In certain embodiments, the size of the xanomeline IR beads is between about 0.425 mm and about 1.18 mm. In certain embodiments, the size of the xanomeline IR beads is between about 0.6 mm and about 0.85 mm. In certain embodiments, the size of the trospium IR beads is between about 0.425 mm and about 1.18 mm. In certainembodiments, the size of the trospium IR beads is between about 0.6 mm and about 0.85 mm.

[0182] The beads or bead mixtures may be used, for example, in suspensions, filled into capsules, compressed into tablets, or filled into sachets. 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 may be any of these forms. In certain embodiments, the dosage form is a capsule.

[0183] As the particle size of the beads becomes too small, the variability in the content of the active increases. As the particle size becomes too large, the beads are too large for drug products labeled to be administered via sprinkling (e.g., on applesauce or other soft foods, such as jellies) and swallowed without chewing or administered via an enteral feeding tube. Also, as the particle size increases, the larger particles get coated more than the smaller particles, resulting in lower relative dissolution than smaller particles. Relatively more beads are needed to meet the label strength per capsule. Filling a capsule shell with enough large particles to meet the label strength per capsule becomes difficult or impossible (e.g., to fill a size 0 capsule to more than 75-mg strength of xanomeline free base).

[0184] In one embodiment, the beads are formulated into capsules, e.g., with an encapsulation machine. Various capsule sizes may accommodate the strength and fill weight of the target formulations. Capsule size ranges from 00 to 5 for fill weights ranging between about 15 mg and about 630 mg.

[0185] The beads can be sorted (e.g., via sieving) to the desired particle size. In certain embodiments, the particle size range is any particle size range or combination described above regarding the cores. For example, the beads can be sieved such that 5% or less of the bead cores by weight is retained on a #12 mesh (1.68 mm) screen, and 10% or less by weight pass through a #20 mesh (0.84 mm) screen.Enteric Capsules

[0186] The formulation can include a capsule shell in which the beads are disposed. Soft and hard capsule shells are known. The capsule shell is a hard-capsule shell in one embodiment, e.g., a gelatin capsule shell or a vegetable-based hard capsule shell. In certain embodiments, the capsule shell comprises one or more enteric coatings. During accelerated storage, gelatin capsules may collapse. Thus, in certain embodiments, the formulation caninclude a hydroxypropyl methylcellulose capsule shell, e.g., Enprotect® or Capsugel® capsules.

[0187] Soft shell capsules can be manufactured by filling a composition comprising the two populations of beads and ingredients as mentioned above and a known vegetable oil into capsules. Hard shell capsules can also be manufactured by filing into capsules the beads, each comprising in an active ingredient as mentioned above, and a solid particulate carrier such as lactose, sucrose, sorbitol, mannitol, potato starch, com starch, amylopectin, a cellulose derivative or gelatin.

[0188] In certain embodiments, each enteric capsule contains 14-200 mg xanom eline as the tartrate salt.

[0189] In one embodiment, each enteric capsule contains 25 mg xanomeline as the tartrate salt.

[0190] In another embodiment, each enteric capsule contains 50 mg xanomeline as the tartrate salt.

[0191] In one embodiment, each enteric capsule contains 14 mg xanomeline as the tartrate salt.Method of Making

[0192] Provided is a method for preparing an oral pharmaceutical composition comprising admixing a plurality of xanomeline IR beads with a plurality of trospium IR in an IR capsule. Provided is a method for preparing an oral pharmaceutical composition comprising a plurality of xanomeline IR beads in an EC.

[0193] Also disclosed herein are a method for preparing the dosage form, comprising coating a sugar core comprising xanomeline or a salt thereof and an excipient with an enteric polymer to form the enteric coating. Optionally, drug beads are sorted (e.g., via sieving) to a desired particle size range before enteric coating and optionally again following enteric coating.

[0194] The drug beads may be made by different processes, including, but not limited to, spheronizing an extruded wet mass and coating of inert core spheres in a fluidized bed. In certain embodiments, the beads are prepared by extrusion and spheronization.

[0195] The beads are formulated to flow freely and to be compatible with modern encapsulation equipment. In some embodiments, the beads are blended to form a uniformmixture filled into capsules in a single stage. In other embodiments, the beads are filled separately into capsules using a two-stage capsule filler.

[0196] Any suitable process can form the cores comprising xanomeline or pharmaceutically acceptable salts thereof. In one embodiment, the core is formed by granulating a mixture of xanomeline or a pharmaceutically acceptable salt thereof with an excipient and milling to a desired particle size range. In another embodiment, the core can be formed by extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof with an excipient.

[0197] Any suitable process can form the cores comprising trospium chloride or pharmaceutically acceptable salts thereof. In one embodiment, the core is formed by granulating a mixture of trospium chloride or a pharmaceutically acceptable salt thereof with an excipient and milling to a desired particle size range. In another embodiment, the core can be formed by extrusion and spheronization of a mixture of trospium chloride or a pharmaceutically acceptable salt thereof with an excipient.

[0198] Granulating processes can include fluid bed granulation, wet granulation, hot melt granulation, and spray congealing. Other processes include slugging and roller compaction. The mixtures to be granulated can first be dry -blended. The dry -blended dry ingredients can be mixed with water before extrusion.

[0199] Extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof and trospium chloride with an excipient provide desirable cores with a distribution of particle sizes as described herein and one or more other desirable properties. In certain embodiments, short processing times can lead to a more stable product. For example, reducing spheronization reduces friction and related heat, reducing the time the product is exposed to air (either when moist and / or before packaging) diminishes oxidation. On the other hand, rapid processing by extrusion and spheronization can lead to a poor-quality product, such as having a large fraction of the bead cores falling outside a desired particle size range. The moisture absorbed by spheronization aids (which happens over time) influences the beads' spheronization characteristics.

[0200] Accordingly, in one embodiment, the moisture content of the granulation mixture, before drying, ranging between about 20 wt.% and about 40 wt.%, such as between 25 wt.% and about 35 wt.%, between about 28 wt.% and about 32 wt.%, at least about 28 wt.%, at least about 28.5, between about 20 wt.% and about 40 wt.%, betweenabout 25 wt.% and about 35 wt.%, between about 27 wt.% and about 31 wt.%, or between about 28.5 wt.% and about 31 wt.%.

[0201] In certain embodiments, the wet mass can be held before extrusion, allowing the spheronization aid to swell with granulating fluid. The hold time can be at least 15 minutes, such as at least 30 minutes, at least 45 minutes, or at least 60 minutes. In certain embodiments, the hold time ranges between about 15 minutes and about 120 minutes, such as between 30 and 100 minutes or between 60 and 90 minutes.

[0202] As described above relating to cores, the method can include a step of sorting (e.g., by sieving) the cores before optional coating to retain particles in a predetermined size range, for example, sizes ranging between about 0.7 mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, between about 0.8 mm and about 1.7 mm, or any range described herein.

[0203] As described above relating to beads, the method can include a step of sorting (e.g., by sieving) the beads after optional coating to retain particles in a size range, for example, sizes ranging between about 0.7 mm and about 2.8 mm, such as between about 0.7 mm and about 2.5 mm, or between about 0.8 mm and about 1.7 mm, or any range described herein.

[0204] In an extrusion and spheronization process, the following optional features can be employed, individually or in one or more combinations thereof. Water can be a granulation agent. Microcrystalline cellulose can be in the cores as a spheronization aid. Hypromellose can be included in the cores as a binder. The extrusion screen size can be 1.0 mm. The friction plate of the spheronizer can be cross-hatched. The friction plate of the spheronizer can be cross-hatched with a square pitch of at least about 3 mm, or greater than about 3 mm, or at least about 4 mm, or greater than about 4 mm, or ranging between about 3 mm and about 7 mm, or about 5 mm. The spheronization time can be less than about 5 minutes, or less than about 4 minutes, or less than about 3 minutes, or less than about 2 minutes, or up to 1 minute. The spheronized particles can include non-spherical particles (i.e., irregular shapes), for example, a substantial fraction thereof, such as at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, or at least about 70 wt.% thereof.

[0205] In certain embodiments, the pharmaceutical composition is stored with a desiccant, for example, pharmaceutical grades of silica gel, crystalline sodium, potassium or calcium aluminosilicate, colloidal silica, anhydrous calcium sulfate, and the like.

[0206] In certain embodiments, the pharmaceutical composition is stored with an oxygen absorber.

[0207] In certain embodiments, the pharmaceutical composition is stored under a dry inert gas such as nitrogen, helium, argon, neon, xenon, krypton, or a mixture thereof.

[0208] In certain embodiments, the pharmaceutical composition is stored under reduced pressure compared to the external ambient air.

[0209] In certain embodiments, the pharmaceutical composition is stored at a reduced temperature, e.g., at refrigerated temperatures (e.g., 2 °C to 8 °C). In certain embodiments, the pharmaceutical composition is stored in such a manner that has fewer impurities, such as Impurity A, than when stored at 25 °C.

[0210] In certain embodiments, the pharmaceutical composition is stored by a manufacturer, a distributor, a pharmacy, or a hospital at a temperature of between about 2 °C and about 8 °C before dispensing the oral pharmaceutical composition to the subject. In certain embodiments, after the oral pharmaceutical composition is dispensed to the subject, the pharmaceutical composition is stored at a temperature of between about 20 °C and about 25 °C.

[0211] 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.

[0212] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising xanomeline beads comprises forming a wet mass comprising xanomeline tartrate and an excipient, optionally microcrystalline cellulose, with a moisture content ranging between about 20 wt.% and about 40 wt.%, extruding and spheronizing the wet mass comprising xanomeline tartrate and excipient to make cores, sorting the cores to a target particle size range, optionally between about 0.7 mm and about 2.5 mm, coating the sorted cores with a polymer to form beads comprising a core and a coating, and sorting the bead particles to a target particle size range, optionally between about 0.7 mm and about 2.5 mm.

[0213] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising trospium beads comprises forming a wet mass comprising trospium chloride and an excipient, optionally microcrystalline cellulose, with a moisture content ranging between about 20 wt.% and about 40 wt.%, extruding, spheronizing, and drying the wet mass comprising trospium chloride and excipient to make cores, sorting the cores to atarget particle size range, optionally between about 0.7 mm and about 2.5 mm, coating the sorted cores with a polymer to form beads comprising a core and a coating, and sorting the bead particles to a target particle size range, optionally between about 0.7 mm and about 2.5 mm.Purity

[0214] Also provided is the compound 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5- hydroyl- 1 -methylpyridin-1 -ium.

[0215] Also provided is a pharmaceutical composition, comprising xanomeline and / or a salt thereof and less than 0.5 wt.% 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5- hydroxyl-1 -methylpyridin-1 -ium (Impurity A). In certain embodiments, the pharmaceutical composition comprises less than 0.30 wt.% of Impurity A, such as less than 0.25 wt.%, less than 0.20 wt.%, less than 0.15 wt.%, less than 0.14 wt.% or less than 0.1 wt.%. Also provided is a pharmaceutical composition, comprising xanomeline and / or a salt thereof and less than 0.15 wt.% 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroyl-l-methylpyridin-l- ium (Impurity A).

[0216] Also provided is an oral pharmaceutical composition, comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.5 wt.% 3-[(4- hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroxyl-l-methylpyridin-l-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 wt.% 3-[(4-hexyloxy)-l,2,5-thiadizaol-3-yl]-5-hydroxyl-l- methylpyridin-l-ium; and a plurality of trospium beads comprising a salt of trospium.

[0217] In certain embodiments, the pharmaceutical composition comprises less than 0.5 wt.% of Impurity A after the pharmaceutical composition is stored for at least 3 months at 40 °C and 75% relative humidity.

[0218] In certain embodiments, the total impurities in the pharmaceutical compositions provided herein are no greater than about 5% by weight, no greater than about 4% by weight, no greater than about 3% by weight, no greater than about 2.5% by weight, no greater than about 2% by weight, no greater than about 1.5% by weight, no greater than about 1% by weight, no greater than about 0.5% by weight, or no greater than about 0.1% by weight.Method of Treating

[0219] Provide herein is a pharmaceutical composition comprising (1) an IR component comprising xanomeline or a salt thereof; (2) a MR component comprising xanomeline or a salt thereof; and (3) an IR component comprising a trospium salt.

[0220] Also provided herein is a method for treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising xanomeline or a salt thereof and a trospium salt; and (2) a MR component comprising xanomeline or a salt thereof.

[0221] In certain embodiments, the method comprises administering a total daily dose of between 25 and 250 mg xanomeline as the tartrate salt and between 2.5 and to 40 mg of trospium chloride to the patient. A fraction of the total daily dose of xanomeline is given by an IR component comprising xanomeline as the tartrate salt and the remaining xanomeline dose by a MR component comprising xanomeline as the tartrate salt.

[0222] In certain embodiments, 25% to 75% of the total daily dose of xanomeline as the tartrate is administered by the IR component and the other 75% to 25% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0223] In certain embodiments, 25% to 30% of the total daily dose of xanomeline as the tartrate salt is administered by the IR component and the other 75% to 70% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0224] In certain embodiments, 30% to 40% of the total daily dose of xanomeline as the tartrate salt is administered by the IR component and the other 70% to 60% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0225] In certain embodiments, 40% to 50% of the total daily dose of xanomeline as the tartrate is administered by the IR component and the other 60% to 50% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0226] In certain embodiments, 50% of the total daily dose of xanomeline as the tartrate salt is administered by the IR component and the other 50% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0227] In certain embodiments, 50% to 60% of the total daily dose of xanomeline as the tartrate salt is administered by the IR component and the other 50% to 40% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0228] In certain embodiments, 60% to 70% of the total daily dose of xanomeline as the tartrate salt is administered by the IR component and the other 40% to 30% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0229] In certain embodiments, 70% to 75% of the total daily dose of xanomeline as the tartrate salt is administered by the IR component and the other 30% to 25% of the total daily dose of xanomeline as the tartrate is by the MR component.

[0230] Provided herein is a method for treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising a plurality of beads comprising xanomeline or a salt thereof and a plurality of beads comprising a trospium salt; and (2) a modified- release component comprising a plurality of beads comprising xanomeline or a salt thereof.

[0231] Provided herein is also a method for treating a muscarinic disorder in a patient in need thereof aged 55 years or older, for example, 60 years or older, or 65 years or older comprising administrating to the patient a pharmaceutical composition comprising (1) an IR component comprising a plurality of beads comprising xanomeline or a salt thereof and a plurality of beads comprising a trospium salt; and (2) a MR component comprising a plurality of beads comprising xanomeline or a salt thereof. In certain embodiments, the method comprises administering a total daily dose of between 25 and 250 mg xanomeline as the tartrate salt and between 5 and 30 mg of trospium chloride to the patient. A fraction of the total daily dose of xanomeline is given by an IR component comprising a plurality of beads comprising xanomeline or a salt thereof and the remaining xanomeline dose by a MR component comprising a plurality of beads comprising xanomeline or a salt thereof.

[0232] Treatment may be initiated with lower dosages. After that, small increments may increase the dosage until a balance between therapeutic effect and side effects is attained. While the subject is being treated, the patient's health may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period. Treatment, including composition amounts and administration times, may be adjusted per such monitoring. The patient may be periodically reevaluated to determine improvement by measuring the same parameters. Adjustments to the disclosed composition administered and possibly to the administration time may be made based on these reevaluations.

[0233] In certain embodiments, provided herein is a pharmaceutical composition comprises a total daily dose of xanomeline equivalent to about 25 - 250 mg of xanomeline as the tartrate salt and the total daily dose of trospium equivalent to about 2.5 - 40 mg of trospium chloride.

[0234] In certain embodiments, the initial dose for a patient is 50 mg xanomeline as the tartrate salt and 20 mg trospium chloride administered in one IR capsule containing 25 mg xanomeline as the tartrate salt, one IR capsule containing 20 mg trospium chloride, and one EC containing 25 mg xanomeline as the tartrate salt twice daily.

[0235] In certain embodiments, the initial dose is increased dose of 100 mg xanomeline as the tartrate salt and 20 mg trospium chloride administered in one IR capsule containing 50 mg xanomeline as the tartrate salt and one IR capsule containing 20 mg trospium chloride, and one EC containing 50 mg xanomeline as the tartrate salt twice daily.

[0236] In certain embodiments, the increased dose is further increased to the dose of 125 mg xanomeline as the tartrate salt and 30 mg trospium chloride administered in one IR capsule containing 50 mg xanomeline as the tartrate salt, two IR capsules containing 5 mg trospium chloride, one IR capsule containing 20 mg trospium chloride, and one EC containing 75 mg xanomeline as the tartrate salt twice daily.

[0237] In certain embodiments, when the patient is 55 years or older, the initial dose is a total daily dose of 56 mg xanomeline as the tartrate salt and 6 mg trospium chloride administered in one IR capsule containing 14 mg xanomeline as the tartrate salt, 3 mg trospium chloride, and one EC containing 14 mg xanomeline as the tartrate salt.

[0238] In certain embodiments, when the patient is 55 years or older, after a first time period of the administration, the initial dose is increased to a total daily dose of 84 mg xanomeline as the tartrate salt and 9 mg trospium chloride administered as one IR capsule containing 14 mg xanomeline as the tartrate salt and 3 mg trospium chloride and one EC containing 14 mg xanomeline as the tartrate salt in the morning and one IR capsule containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride and one EC containing 28 mg xanomeline as the tartrate salt. The first time period is between 1 and 10 days, such as 1 day, 2 days, 3 days, 4 days. In certain embodiments, the first time period is 4 days.

[0239] In certain embodiments, after a second time period of the administration, if the patient who is 55 years or older tolerates the increased dose and if the patient has had an adequate response, the increased dose is further increased to the total daily dose of 112 mgxanomeline as the tartrate salt and 12 mg trospium chloride administered as one IR capsule containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride and one EC containing 28 mg xanomeline as the tartrate salt. The second time period is between 1-10 total days, such as 4 total days, 5 total days, and 6 total days. In certain embodiments, the second time period is 5 total days. In certain embodiments, if the patient does not tolerate the increased dose, an optimized dose is the initial dose.

[0240] In certain embodiments, after a third period of the administration, if the patient who is 55 years or older tolerates the further increased dose and if the patient has had an adequate response, the further increased dose is again increased to the total daily dose of 140 mg xanomeline as the tartrate salt and 15 mg trospium chloride administered as one IR capsule containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride and one EC containing 28 mg xanomeline as the tartrate salt in the morning and one IR capsule containing 14 mg xanomeline as the tartrate salt and 3 mg trospium chloride, and one IR capsule containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride, one EC containing 14 mg xanomeline as the tartrate salt, one EC containing 28 mg xanomeline as the tartrate salt in the evening. The third time period is between 1 and 10 total days, such as 8 total days, 9 total days, and 10 total days. In certain embodiments, the third time period is 10 total days. In certain embodiments, if the patient does not tolerate the further increased dose, an optimized dose is the increased dose.

[0241] In certain embodiments, after a fourth time period, if the patient who is 55 years or older tolerates the again increased dose and if the patient has had an adequate response, the again increased dose is increased to the total daily dose of 168 mg xanomeline as the tartrate salt and 18 mg trospium chloride administered as one IR capsule containing 14 mg xanomeline as the tartrate salt and 3 mg trospium chloride, one IR capsule containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride, one EC containing 14 mg xanomeline as the tartrate salt and one EC containing 28 mg xanomeline as the tartrate salt twice daily. In certain embodiments, the fourth time period is between 1 and 10 total days. In certain embodiments, the fourth time period is 4 total days. In certain embodiments, if the patient does not tolerate the again increased dose, an optimized dose is the further increased dose.

[0242] In certain embodiments, after a fifth time period, if the patient who is 55 years or older tolerates the again increased dose and if the patient has had an adequate response, the again increased dose is increased to the total daily dose of 196 mg xanomeline as thetartrate salt and 21 mg trospium chloride administered as one IR capsule containing 14 mg xanomeline as the tartrate salt and 3 mg trospium chloride, one IR capsule containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride, one EC containing 14 mg xanomeline as the tartrate salt and one EC containing 28 mg xanomeline as the tartrate salt in the morning, and two capsules containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride, and one EC containing 28 mg xanomeline as the tartrate salt in the evening. In certain embodiments, the fifth time period is between 1 and 10 total days. In certain embodiments, the fourth time period is 5 total days. In certain embodiments, if the patient does not tolerate the again increased dose, an optimized dose is the further increased dose.

[0243] In certain embodiments, after a sixth time period, if the patient who is 55 years or older tolerates the again increased dose and if the patient has had an adequate response, the again increased dose is increased to the total daily dose of 224 mg xanomeline as the tartrate salt and 24 mg trospium chloride administered in two IR capsule containing 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride, and two EC containing 28 mg xanomeline as the tartrate salt twice daily. In certain embodiments, the sixth time period is between 1 and 10 total days.

[0244] In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the xanomeline and trospium PK profiles of the subjects are characterized by a steady state geometric mean Cmax of xanomeline of about 10000 to 12000 pg / mL and a steady state geometric mean Cmax of trospium of about 3000 to 4000 pg / mL

[0245] In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the xanomeline and trospium PK profiles of the subjects are characterized by a steady state geometric mean Cmax of xanomeline of about 11400 pg / mL and a steady state geometric mean Cmax of trospium of about 3750 pg / mL

[0246] In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the xanomeline and trospium PK profiles of the subjects are characterized by a geometric mean Cmax ofxanomeline that is between about 15% and about 40% lower than that of xanomeline produced by a similar dose of IR / IR pharmaceutical composition and the geometric mean Cmax of trospium that is between about 5% to about 30% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of xanomeline at least 20% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of xanomeline at least 25% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of xanomeline at least 30% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of xanomeline at least 35% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of trospium at least 5% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of trospium at least 10% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of trospium at least 15% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of trospium at least 25% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.In certain embodiments, following oral administration of a pharmaceutical composition comprising (1) an IR component comprising xanomeline tartrate and trospium chloride and (2) a MR component comprising xanomeline tartrate, the PK profile of the subjects is characterized by the geometric mean Cmax of trospium at least 30% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

[0247] Each and every method, composition, or use described herein also optionally includes the limitation that the dementia-related psychosis is not psychosis associated with Alzheimer’s disease, psychosis associated with Parkinson’s disease, psychotic depression, bipolar disorder, bipolar with psychosis.

[0248] In some embodiments, the treatment occurs outside of a clinical trial setting.

[0249] The pharmaceutical composition and methods are contemplated 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 stated otherwise. Reference to a bead and properties thereof apply equally to a collection of beads (e.g., a plurality of such beads). Likewise, referring to a core and properties thereof apply equally to a collection of cores (e.g., a plurality of such cores).EXAMPLES

[0250] The following examples are provided for illustration and are not intended to limit the scope of the disclosure.Example 1 - Immediate-Release Beads

[0251] Beads were prepared for xanomeline tartrate (Table 1) and trospium chloride (Table 2).Table 1 : Xanomeline tartrate (66%) Bead without Talc*Removed during drying.Table 2a: Trospium chloride (17.7%) Bead without TalcTable 2b: Trospium chloride (4.4%) Bead with Talc*Removed during drying.

[0252] The powders were screened using Quadro Comil Model 197 equipped with 457-pm round hole screen, 0.2-inch spacer at 1625 rpm and mixed for 2 min in a Hobartlow shear mixer / granulator (model N-50) at a fixed speed of 60 rpm. The dry blending step is optional, as blend uniformity is driven by subsequent wet granulation. Beads were screened by hand through a 40 mesh (425 pm) sieve.

[0253] Wetting was carried out in the Hobart. The water was added using a Cole- Parmer peristaltic pump. Water addition rate (amount of water / dose time) is a process variable.

[0254] The wet mass was extruded through a perforated screen (dome configuration) single screw extruder using a LCI Multi Granulator MG-55 at 30 rpm (shaft speed). The wet mass was extruded directly after wetting. Hold time, shaft speed, and extrusion rate (load) were process variables.

[0255] The extrudates were placed into a LCI Marumerizer (spheronizer) QJ-230T equipped with 2.0 mm friction plate. The extrudates were spheronized at different plate speed for a total of not more than 4 minutes. Spheronization speed and time are process variables.

[0256] The beads were dried using an Aeromatic™ Strea-1 fluid bed at inlet temperature of 60 °C until a water content of not more than 3% was obtained. Because beads melted after a few minutes at 60 °C, the beads were dried at 30 °C.

[0257] Water content was evaluated gravimetrically by loss-on-drying (LOD) using a Mettler Toledo halogen Moisture Analyser, type HR83. The beads were heated at 105 °C until the rate of weight loss dropped to less or equal to 0.0 % within 60 seconds.Table 3: Extrusion / Spheronization Process ParametersExample 2 - Immediate-Release Beads of Xanomeline in Enteric Capsules

[0258] A two-station encapsulation machine is used for dual active capsulation with both xanomeline tartrate and trospium chloride pellets filling in sequence.

[0259] The dual active capsules include, but not limited, KarXT IR / IR or the immediate-release component of KarXT DB / IR.

[0260] Encapsulation is started at a target speed of 70,000 capsules / hr (Range: 60,000 - 80,000 capsules / hr). Encapsulation is performed with repeated in-process checks every 15 min for visual observation and proper closure until the batch is completed or the pellets lot is exhausted. A composite capsule sample is collected for release, micro, AQL, and retain samples. Control limits are generally set at average limits (5%), internal limits (7.5%), and rejection limit (10%). An IMA weight checker is used to check the filled capsule weight with target gross weight limits.

[0261] For smaller scale production in support of clinical trials exemplified in Examples 3 and 4, Bonapace IN-CAP encapsulation machine with 2 x Pellet filler is used. The encapsulation rate is about 2,000-4,000 capsules / hr.

[0262] Bonapace IN-CAP encapsulation machine is also used to manufacture single active capsule like KarX-IR, KarT-IR, and KarX-EC for clinical trials exemplified in Examples 3 and 4.Example 3 - A Phase 1 Study to Assess the Safety, Tolerability, and Pharmacokinetics of Multiple Ascending Doses of Xanomeline Tartrate and Trospium Chloride When Coadministered as Enteric and / or Immediate-Release Capsules in Healthy Adults

[0263] The purpose of this Phase 1 clinical trial was to evaluate the safety and tolerability, and PK of two 10-day treatment regimens, 1 of KarXT— IR / IR and 1 of KarXT-DB- / IR. An overview of the study design is shown in FIG. 1.

[0264] Up to 76 healthy adult male and female subjects were to be enrolled. Per clinical research unit (CRU) preference and standard practices, subjects were dosed in batches across 4 cohorts. Screening of subjects occurred within 28 days prior to the first dosing.

[0265] On Day 1, subjects were randomized to 1 of the 2 treatments. The Sponsor, subjects, and site staff (except for unblinded pharmacy staff preparing the drug) were blinded to the treatment. KarXT-IR / IR or KarXT -DB / IR was dosed twice daily (BID) on Days 1 through 9 followed by a morning dose on Day 10. Serial PK blood samples were collected on Day 6 pre-moming dose through 12 hours post-morning dose and on Day 10 pre-moming dose through 48 hours post-morning dose. Additional PK blood samples were collected pre-moming-dose on Days 4, 5, 8, and 9 to assess attainment of steady-state.

[0266] KarXT-IR / IR (Treatment A) was supplied as 25, 50, and 75 mg IR capsules containing xanomeline (KarX-IR) and 5, 10, and 20 mg IR capsules containing trospium chloride (KarT-IR). The clinical doses created by these capsules were abbreviated KarXT- IR / IR 50 / 20 mg, 100 / 20 mg, or 125 / 30 mg.

[0267] KarXT -DB / IR (Treatment B) was supplied as 25 and 50 mg KarX-IR capsules; 25, 50, and 75 mg ECs containing xanomeline (KarX-EC); and 5, 10, and 20 mg KarT-IR capsules. The clinical doses created by these capsules were abbreviated KarXT - DB / IR 50 / 20 mg, 100 / 20 mg, or 125 / 30 mg.

[0268] Treatments were as follows:Treatment A: Days 1 and 2: KarXT-IR / IR 50 / 20 mg given BID as 2 * 25 mg KarX-IR capsules and 1 x 20 mg KarT-IR capsule.Days 3 to 6: KarXT-IR / IR 100 / 20 mg given BID as 2 * 50 mg KarX-IR capsules and 1 x 20 mg KarT-IR capsule.Days 7 to 9: KarXT-IR / IR 125 / 30 mg given BID as 1x75 mg and1 x 50 mg KarX-IR capsule and 2 x 5 mg and 1 x 20 mg KarT-IR capsules.Day 10: KarXT-IR / IR 125 / 30 mg given once in the morning as 1 x 75 mg and 1 x 50 mg KarX-IR capsule and 2 x 5 mg and 1 * 20 mg KarT-IR capsules.Treatment B: Days 1 and 2: KarXT-DB / IR 50 / 20 mg given BID as 1 x 25 mg KarX-EC, 1 x 25 mg KarX-IR capsule, and 1 x 20 mg KarT-IR capsule.Days 3 to 6: KarXT-DB / IR 100 / 20 mg given BID as 1x50 mg KarX-EC, 1 x 50 mg KarX-IR capsule, and 1 x 20 mg KarT-IR capsule.Days 7 to 9: KarXT-DB / IR 125 / 30 mg given BID as 1x75 mg KarX-EC, 1 x 50 mg KarX-IR capsule, and 2 x 5 mg and 1 x 20 mg KarT-IR capsules.Day 10: KarXT-DB / IR 125 / 30 mg given once in the morning as1 x 75 mg KarX-EC, 1 x 50 mg KarX-IR capsule, and 2 x 5 mg and1 x 20 mg KarT-IR capsules.

[0269] All subjects within a dosing group received the same number of capsules. All study drugs were dosed orally with approximately 240 mL of water. For each treatment, morning doses on Days 2 through 10 were given within ± 1 hour of the morning dosing clock time established on Day 1. Each evening dose on Days 1 through 9 was given approximately 12 hours after the morning dose on that day. The exact clock time of each dose was recorded.

[0270] The main inclusion criteria were Healthy, adult, male or female, 19 to 55 years of age, including the screening. The body mass index was 18.0 kg / m2to 32.0 kg / m2, inclusive. The included subjects had good general health, in the opinion of the study investigator.

[0271] Exclusion criteria included a history or presence of CS medical or psychiatric condition or disease, alcohol or drug abuse within the past 2 years prior to the first dosing, cancer that had not been in full remission for > 5 years (except basal cell skin cancer or squamous cell skin cancer with history of curative treatment and no recurrence for > 1 year prior to the Screening visit), hypersensitivity or idiosyncratic reaction to any of the study drugs or related compounds, any CS health condition (e.g., chronic diarrhea) within 14 days prior to first dosing, or prior surgery (e.g., gastric bypass),

[0272] Subjects were also excluded if they were mentally or legally incapacitated or had significant emotional problems at the time of the Screening visit or expected during the study. Female subjects with a positive pregnancy test at the Screening visit or check-inor who was lactating were also excluded. Exclusion criteria also included subjects with positive urine drug or alcohol results, positive urine cotinine, positive results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) at the Screening visit or check-in.

[0273] Subjects were also excluded if they had a history of CS drug allergies including a history of anaphylactic reaction, incomplete bladder emptying with voiding or awakening more than once at night to void, or if they were unable to refrain from or anticipated the use of the following: (1) any medication (including prescription and non prescription medications; topical medications; vitamin, mineral, plant, and other dietary supplements; traditional Chinese medicine; or herbal remedies) beginning 14 days prior to the first dosing or 5 half lives, if known, whichever was longer, (2) any drug known to be a significant inducer of cytochrome P450 (CYP) 2D6 and CYP3 A4 beginning 28 days prior to the first dosing, had been on a diet incompatible with the on-study diet within the 30 days prior to the first dosing.

[0274] Subjects were also excluded if they had a loss or donation of more than 500 mL blood within 60 days prior to the first dosing, a donation of bone marrow or peripheral stem cells within 90 days prior to the first dosing, and a donation of plasma within 30 days prior to the first dosing, had a family history of long QT syndrome or of unexplained sudden death in a first-degree relative under 50 years of age, documented congenital or acquired long-QT syndrome.

[0275] Excluded were subjects with excessive consumption of alcohol, defined as > 3 alcoholic beverages per day for males and > 2 alcoholic beverages per day for females. Ten (10) ounces (oz) (284 mL) of beer, 4 oz (125 mL) of wine, or 1 oz (25 mL) of distilled spirits are each considered 1 alcoholic beverage, consumption of foods and beverages containing caffeine or xanthine for 48 hours prior to check-in, consumption of foods or beverages containing alcohol for 48 hours prior to check-in, consumption of foods or beverages containing grapefruit, grapefruit juice, juices containing grapefruit, cranberry, or Seville oranges / juice for 7 days prior to check-in, consumption of foods or beverages containing poppy seeds for 48 hours prior to check in.

[0276] Subjects were also excluded if their venous access was considered inadequate for PK sample collection and had history or evidence of adverse symptoms associated with phlebotomy or blood donation, had elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 * upper limit of normal (ULN) or elevated alkalinephosphatase (ALP) or total bilirubin > 1.5 x ULN at the Screening visit or check-in, had Had a history or high risk of urinary retention, gastric retention, or narrow-angle(i.e., angle closure) glaucoma, Gilbert’s disease, and had a risk for suicidal behavior during the study. Male subjects with a history of bladder stones, history of recurrent urinary tract infection, or serum prostate-specific antigen (PSA) > 10 ng / mL, at the Screening visit, were excluded.

[0277] Also excluded are employee or family member of the PI, study site personnel, or Sponsor, or subjects who have participated in a previous KarXT clinical study, or another clinical study within 30 days (or 5 half-lives, if known, whichever was longer) prior to the first dosing, or any other reason that, in the opinion of the PI, rendered the subject unsuitable for study enrollment.

[0278] The 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), serial PK sampling, and collecting saliva to measure saliva volume were performed at defined time points during the study.

[0279] Demographic and baseline characteristics for subjects in the safety population are summarized in Table 4.Table 4:Pharmacokinetics of Xanomeline

[0280] Plasma was analyzed for xanomeline concentrations. The geometric mean plasma concentration-time profiles of xanomeline following multiple doses of IR / IR and DB / IR on Day 10 are shown in FIG. 2.

[0281] Xanomeline’ s PK parameter estimates on Day 10 are summarized in Table 5 for IR / IR treatment and in Table 6 for DB / IR treatment.Table 5: Xanomeline Pharmacokinetic Parameter Estimates on Day 10 Following MultipleDoses of KarXT-IR / IRAbbreviations: AUCtau= area under the concentration-time curve during a dosing interval (tau) at steady-state; AUCo-iast = area under the concentration-time curve from time 0 to last postdose sample; Cnh = concentration 12 hours after the morning dose; CLSS / F = apparent clearance at steady state; Cmax.ss = maximum concentration at steady state; Ctrough, DI OHO = concentration measured on Day 10 Hour 0 before the morning dose; CV = coefficient of variation; Kei,eff = apparent first-order elimination rate constant during a 12-hour dosing interval; Kei,z= apparent first-order elimination rate constant during the terminal phase after the morning dose on Day 10; n = number of subjects withevaluable values; PK = pharmacokinetic; SD = standard deviation; ti / 2,eff = effective elimination halflife during a 12-hour dosing interval, calculated as In (2) / Xefr; ti / 2,z= apparent terminal elimination half-life after the morning dose on Day 10; Tmax= time to reach maximum concentration. Tmax,ss = time to reach steady state Cmax.Table 6: Xanomeline Pharmacokinetic Parameter Estimates on Day 10 FollowingMultiple Doses of KarXT-DB / IRAbbreviations: AUCtau= area under the concentration-time curve during a dosing interval (tau) at steady-state; AUCo-w = area under the concentration-time curve from time 0 to last postdose sample; Cnh = concentration 12 hours after the morning dose; CLSS / F = apparent clearance at steady state; Cmax,ss = maximum concentration at steady state; Ctrough, DI OHO = concentration measured on Day 10 Hour 0 before the morning dose; CV = coefficient of variation; Kei,eff = apparent first-order elimination rate constant during a 12-hour dosing interval; Kei,z= apparent first-order elimination rate constant during the terminal phase after the morning dose on Day 10; n = number of subjects with evaluable values; PK = pharmacokinetic; SD = standard deviation; ti / 2,eff = effective elimination halflife during a 12-hour dosing interval, calculated as In (2) / Xefr; ti / 2,z= apparent terminal elimination half-life after the morning dose on Day 10; Tmax= time to reach maximum concentration. Tmax,ss = time to reach steady state Cmax.

[0282] Table 7 shows the results of statistical comparisons of xanomeline AUCtau and Cmax,ss at Day 10 following multiple doses of IR / IR and DB / IR. On Day 10 during treatment with 125 / 30 mg BID, xanomeline Cmax,ss was 18% lower, and AUCtau was 6% lower, for DB / IR than for IR / IR.Table 7 : Statistical Comparisons of Xanomeline Pharmacokinetic Parameter EstimatesFollowing Multiple Doses of KarXT -DB / IR Versus KarXT-IR / IR - Day 10 (Pharmacokinetic Analysis Population)Abbreviations: ANOVA = analysis of variance; AUCtau = area under the concentration-time curve during a 12-hour dosing interval (tau) at steady-state; BID = twice daily; Cmax,ss = maximum concentration at steady state; CV = coefficient of variation; LSM = least-squares means; n = number of subjects with evaluable values. KarXT-DB / IR: KarXT-DB / IR 50 / 20 mg BID on Days 1 and 2, 100 / 20 mg BID on Days 3 through 6, and 125 / 30 mg BID on Days 7 through 9 and in the morning of Day 10 (test). KarXT-IR / IR: KarXT-IR / IR 50 / 20 mg BID on Days 1 and 2, 100 / 20 mg BID on Days 3 through 6, and 125 / 30 mg BID on Days 7 through 9 and in the morning of Day 10 (reference).Parameters were In-transformed prior to analysis.Geometric LSMs are calculated by exponentiating the LSMs derived from the ANOVA. Geometric Mean Ratios are calculated by exponentiating the difference in LSMs derived from the ANOVA, multiplied by 100%.Inter-subject CV was calculated as 100% x square root[exp(subject)-l],

[0283] The data above showed that the Geom Mean Tmax at Day 10 was twice as long for DB / IR (3.41 hr) than for IR / IR (1.68 hr). The ti / 2,eir at Day 10 was the same for both treatments (Geom Mean of 4.86 hr for IR / IR and 4.84 hr for DB / IR).

[0284] Measurement of pre-morning-dose concentrations of xanomeline on Days 4, 5, and 6 at 100 / 20 BID and on Days 8, 9, and 10 at 125 / 30 BID show that xanomeline was close to or at steady state on Day 10. The Ctrough at Day 10 was about 20% lower for IR / IR than for DB / IR (Geom Mean of 4,260 pg / mL for IR / IR and 5,370 pg / mL for DB / IR).Pharmacokinetics of Trospium

[0285] Plasma was analyzed for trospium concentrations. The Geom Mean plasma concentration-time profiles of trospium on Day 10 following multiple doses of IR / IR and DB / IR are shown in FIG. 3.

[0286] Trospium’s PK parameter estimates on Day 10 are summarized in Table 8 forIR / IR and in Table 9 for DB / IR.Table 8: Trospium Pharmacokinetic Parameter Estimates on Day 10 FollowingMultiple Doses of KarXT-IR / IRAbbreviations: AUCtau = area under the concentration-time curve during a dosing interval (tau) at steady-state; AUCo-iast = area under the concentration-time curve from time 0 to last postdose sample; Cnh = concentration 12 hours after the morning dose; CLss / F = apparent clearance at steady state; Cmax,ss = maximum concentration at steady state; Ctrough, DI OHO = concentration measured on Day 10 Hour 0 before the morning dose; CV = coefficient of variation; Kei,eff = apparent first-order elimination rate constant during a 12-hour dosing interval; Kei,z= apparent first-order elimination rate constant during the terminal phase after the morning dose on Day 10; n = number of subjects with evaluable values; PK = pharmacokinetic; SD = standard deviation; ti / 2,eff = effective elimination half-life during a 12-hour dosing interval, calculated as In (2) / Acrr; ti / 2,z = apparent terminal elimination half-life after the morning dose on Day 10; Tmax = time to reach maximum concentration. Tmax,ss = time to reach steady state Cmax.Table 9: Trospium Pharmacokinetic Parameter Estimates on Day 10 FollowingMultiple Doses of KarXT-DB / IRAbbreviations: AUCtau= area under the concentration-time curve during a dosing interval (tau) at steady-state; AUCo-iast = area under the concentration-time curve from time 0 to last postdose sample; Cnh = concentration 12 hours after the morning dose; CLSS / F = apparent clearance at steady state; Cmax,ss = maximum concentration at steady state; Ctrough, DI OHO = concentration measured on Day 10 Hour 0 before the morning dose; CV = coefficient of variation; Kei,eff = apparent first-order elimination rate constant during a 12-hour dosing interval; Kei,z= apparent first-order elimination rate constant during the terminal phase after the morning dose on Day 10; n = number of subjects with evaluable values; PK = pharmacokinetic; SD = standard deviation; ti / 2,eff = effective elimination halflife during a 12-hour dosing interval, calculated as In (2) / Xefr; ti / 2,z= apparent terminal elimination half-life after the morning dose on Day 10; Tmax= time to reach maximum concentration. Tmax,ss = time to reach steady state Cmax.|02871 Table 10 shows the results of statistical comparisons of trospium AUCtau and Cmax,ss at Day 10 following multiple doses of IR / IR and DB / IR. On Day 10 during treatment with 125 / 30 mg BID, trospium Cmax,ss and AUCtau were both approximately 9% lower for DB / IR than for IR / IR.Table 10: Statistical Comparisons of Trospium Pharmacokinetic Parameter Estimates Following Multiple Doses of KarXT -DB / IR Versus KarXT-IR / IR - Day 10Abbreviations: ANOVA = analysis of variance; AUCtau = area under the concentration-time curve during a 12-hour dosing interval (tau) at steady-state; BID = twice daily; Cmax,ss = maximum concentration at steady state; CV = coefficient of variation; LSM = least-squares means; n = Number of subjects with evaluable values. Geometric LSMs are calculated by exponentiating the LSMs derived from the ANOVA. Geometric Mean Ratios are calculated by exponentiating the difference in LSMs derived from the ANOVA, multiplied by 100%.Inter-subject CV was calculated as 100% x square root[exp(subject)-l],

[0288] As shown in Table 8 and Table 9, the Geom Mean Tmax,ss at Day 10 was 50 minutes longer for IR / IR (1.09 hr) than for DB / IR (1.93 hr).

[0289] Estimates of Geom Mean ti / 2,eff at Day 10 were similar between treatments at5.81 hr for IR / IR and 6.51 hr for DB / IR.

[0290] Trospium was at steady state by Day 10. The Ctrough at Day 10 was similar for both IR / IR and DB / IR (Geom Mean of 1,260 pg / mL for IR / IR and 1,140 pg / mL forDB / IR).

[0291] The DB approach to xanomeline release is designed to deliver half of the xanomeline dose rapidly from the IR capsule and deliver the other half after a delay ofseveral hours, thus spreading the release of xanomeline over a wider time interval. This strategy flattened the concentration-time curve for xanomeline, compared to IR / IR(FIG. 2)

[0292] The DB / IR treatment also flattened the concentration-time curve for trospium when compared to IR / IR (Fig. 3), which was not anticipated. Trospium was dosed in an IR capsule in both treatments, so trospium PK was expected to behave similarly between the formulations. However, xanomeline enhances trospium absorption through a mechanism not yet known and having only about half of the xanomeline released early appears to have reduced the magnitude of xanomeline’ s early effect on trospium absorption, thus reducing trospium’ s C max-

[0293] Table 11 summarizes the differences in Cmax,ss and AUCtau across treatments and dosages in this study for ease of review. The xanomeline Cmax and AUC were reduced by the DB / IR treatment but the reduction in Cmax exceeded that in AUC.Table 11 : Summary of Differences in Cmax,ss and AUCtau Between TreatmentsAbbreviations: AUCtau = area under the concentration-time curve during a dosing interval (tau) at steady-state; BID = twice daily; Cmax,ss = maximum concentration at steady state a The indicated changes are based on the geometric mean ratios (DB / IR / IR / IR) determined by the statistical analyses.

[0294] The DB release pattern of xanomeline flattened xanomeline’ s concentrationtime curve, reducing its median Cmax,ss and AUCtau on average by 27% and 12%, respectively, across profiles on Day 6 (at 100 / 20 mg BID) and Day 10 (at 125 / 30 mg BID). The DB release pattern of xanomeline also flattened trospium’ s concentration-time curve, reducing trospium’ s median Cmax,ss and AUCtau on average by 19% and 15%, respectively, across the 2 dosages.Adverse Events

[0295] Table 12 shows the most frequently occurring TEAEs per dose.Table 12: Summary of Incidence of the Most Frequently Reported Treatment-EmergentAdverse Events by Dose

[0296] The overall frequency of AEs was reduced with DB / IR treatment compared with IR / IR treatment. TEAEs that were most reduced in subjects with DB / IR treatment compared to those with IR / IR treatment included tachycardia (reported by 18% and 42% of subjects, respectively) and orthostatic hypotension (reported by 37% and 68% of subjects, respectively), hyperhidrosis (reported by 18% and 32% of subjects, respectively), and dizziness (reported by 26% and 42% of subjects, respectively).

[0297] This trend is believed to be due primarily to the lower Cmax of xanomeline and trospium with DB / IR treatment.Example 4 - A Phase 1 Study to Assess the Pharmacokinetics, Safety, and Tolerability of Multiple Doses of Dual Burst Release of Xanomeline with Immediate-Release Trospium Chloride versus KarXT in Healthy Elderly Subjects

[0298] This is a Phase 1, open-label, multiple-dose, parallel-group, 3-treatment, PK, safety, and tolerability study in healthy elderly subjects.

[0299] Approximately 114 healthy adult male and female subjects will be enrolled, approximately 38 subjects per treatment. Every effort will be made to enroll subjects with an age distribution of approximately 30% age 60 to 64 years, approximately 60% age 65 to 74 years, and approximately 10% age 75 years to 90 years.

[0300] As per CRU preference and standard practices, subjects may be dosed in cohorts.

[0301] Additional subjects may be enrolled if deemed appropriate by the Sponsor to explore different doses and / or populations or to replace dropouts.

[0302] Screening of subjects will occur within 28 days prior to the first dosing. FIG.4 is a schematic presentation of the study design.

[0303] A 5 -day dosing regimen was chosen to achieve steady state at each dose level based on the data from previous clinical trials.

[0304] On Day 1 to Day 20, KarXT will be dosed either as KarXT TID (Treatment A) or KarXT + KarX-EC BID (Treatment B) or KarXT BID (Treatment C) according to the dosages outlined below.Treatment A:KarXT (20 / 2): KarXT capsule containing 20 mg xanomeline and 2 mg trospium chloride KarXT (30 / 3): KarXT capsule containing 30 mg xanomeline and 3 mg trospium chloride KarXT (50 / 5): KarXT capsule containing 50 mg xanomeline and 5 mg trospium chloride KarXT (66.7 / 6.67): KarXT capsule containing 66.7 mg xanomeline and 6.67 mg trospium chlorideTreatment B:KarXT (14 / 3): KarXT capsule containing 14 mg xanomeline and 3 mg trospium chloride. KarXT (28 / 6): KarXT capsule containing 28 mg xanomeline and 6 mg trospium chloride. KarX-EC (14): Enteric capsule containing 14 mg xanomeline.KarX-EC (28): Enteric capsule containing 28 mg xanomeline.Treatment C:KarXT (30 / 3) - KarXT capsule containing 30 mg xanomeline and 3 mg trospium chloride. KarXT (50 / 5) - KarXT capsule containing 50 mg xanomeline and 5 mg trospium chloride.

[0305] Different treatments are shown in Table 13.Table 13

[0306] All study drugs will be dosed orally with approximately 240 mL of water. Treatment A:

[0307] After initial morning dosing on Day 1, the morning doses on Days 2 through 20 will be administered within ± 1 hour of the morning dosing time established on Day 1. Each afternoon and evening dose on Days 1 through 19 will be given approximately 8 hours and 16 hours after the morning dose on that day.Treatment B and Treatment C:

[0308] After initial morning dosing on Day 1, the morning doses on Days 2 through 20 will be administered within ± 1 hour of the morning dosing time established on Day 1. Each evening dose on Days 1 through 19 will be given approximately 12 hours after the morning dose on that day.

[0309] Blood for PK of xanomeline and trospium will be sampled predose and up to 8 hours (for Treatment A) or up to 12 hours (for Treatment B and Treatment C) post morning dose on Days 1, 5, 10, and 15.

[0310] For Treatments A, B, and C, blood for PK of xanomeline and trospium will be sampled predose and up to 48 hours after the morning dose on Day 20.

[0311] Safety will be monitored throughout the study by repeated clinical and laboratory evaluations.

[0312] For PK purposes, Hour 0 will be set as the morning dosing time of KarXT. For PK purposes, TID dosing hence corresponds to Hour 0, Hour 8 and Hour 16 and BID dosing will correspond to Hour 0 and Hour 12.

[0313] Blood samples for the analysis of xanomeline and trospium in plasma were collected for all subjects at the following time points:• Days 1, 5, 10, and 15: predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours postdose. A sample was collected at 12 hours postdose for Treatment B and Treatment C only.• Days 18 and 19: prior to morning dose.• Day 20: predose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 16 (Days 20 / 21), 24 (Day 21), 36 (Day 21), and 48 (Day 22) hours postdose.Inclusion Criteria

[0314] Individuals must meet all of the following criteria to be included in the study:1. Healthy, adult, male or female, 60- 90 years of age, inclusive, at the screening visit.2. Female and male subjects must follow protocol-specified contraception guidance.3. Continuous non-smoker who has not used nicotine- and tobacco-containing products for at least 6 months prior to check-in.4. Body mass index (BMI) > 18.0 and < 35.0 kg / m2at the screening visit.5. Medically healthy with no clinically significant medical history, physical examination, laboratory profiles, vital signs, orthostatic vital signs, and ECGs, as deemed by the PI or designee, including the following:• Seated blood pressure is 90 / 50 mmHg to 140 / 90 mmHg, inclusive, at the screening visit. One repeat measurement is allowed.• Seated heart rate is 40 bpm to 99 bpm, inclusive, at the screening visit. One repeat measurement is allowed.• Orthostatic vital sign results with a decrease in systolic blood pressure< 20 mmHg and decrease in diastolic blood pressure < 10 mmHg at the screening visit.• QTcF interval is < 450 msec (males) and < 470 msec (females) and has ECG findings considered normal or not clinically significant by the PI or designee at the screening visit and check-in.• Has an estimated glomerular filtration rate (eGFR) of 60 mL / min / 1.73m2(calculated with Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation) at the screening visit. One repeat measurement is allowed.6. Able to swallow multiple capsules.7. Understands the study procedures in the informed consent form (ICF) and be willing and able to comply with the protocol.Exclusion CriteriaSubjects must not be enrolled in the study if they meet any of the following criteria:1. Is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study.2. History or presence of clinically significant medical or psychiatric condition or disease in the opinion of the PI or designee.3. History of any illness that, in the opinion of the PI or designee, might confound the results of the study or poses an additional risk to the subject by their participation in the study.4. History of cancer that has not been in full remission for >5 years (except basal cell skin cancer or squamous cell skin cancer with history of curative treatment and no recurrence for > 1 year prior to the screening visit).5. History or presence of alcohol or drug abuse within the past 2 years prior to the first dosing.6. History or presence of hypersensitivity or idiosyncratic reaction to the study drug or related compounds.7. History or presence of any clinically significant health condition (e.g., chronic diarrhea) within 14 days prior to first dosing, or prior surgery (e.g., gastric bypass) that in the opinion of the PI may affect absorption of the study drugs. Removal of wisdom teeth, cholecystectomy (at least 1 month prior to first dosing), and appendectomy is acceptable.8. Any hepatic impairment in the opinion of the PI or designee, at screening or check-in.9. Acute illness within 14 days prior to first dosing, unless mild in severity and enrollment is approved by both the PI and Sponsor’s medical representative.10. Female subject with a positive pregnancy test at the screening visit or at check-in or who is lactating.11. Positive urine drug or alcohol results at the screening visit or check-in.12. Positive COVID-19 results at check-in.13. Positive urine cotinine at the screening visit or check-in.14. Positive results for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) at the screening visit.15. History of clinically significant drug allergies including a history of anaphylactic reaction.16. For males only, any one of the following:• History of bladder stones• History of recurrent urinary tract infections• Serum prostate specific antigen (PSA) >10 ng / mL at the screening visit.• An International Prostate Symptom Score (IPSS) of 5 (almost always) on items 1, 3, 5, or 6.• A sum of scores on IPSS items 1, 3, 5, and 6 of > 917. Unable to refrain from or anticipates the use of:• Acute use of medication (including prescription and non-prescription medications; topical medications; vitamin, mineral, plant, and other dietary supplements; traditional Chinese medicine; or herbal remedies) beginning 14 days prior to the first dosing or 5 half-lives, if known, whichever is longer. Medication listed as part of permitted medication will be allowed.• Chronic use of medication which is a strong inhibitor of CYP2D6, CYP3 A4 and P-gp. Appropriate sources (e.g., Flockhart Table™) will be consulted to confirm lack of PK / pharmacodynamic interaction with study drug. Medication listed as part of acceptable birth control methods and stable chronic use of medications will be permitted• Meformin beginning 14 days prior to the first dose and throughout the study.• Any drugs known to be strong inducers of CYP3 A4, CYP2D6, and / or P-gp, including St. John’s Wort, beginning 28 days prior to the first dosing. Appropriate sources (e.g., FDA Drug Development and Drug Interactions | Table of Substrates, Inhibitors and Inducers [FDA website 2024]) will be consulted to confirm lack of PK / pharmacodynamic interaction with study drug.18. Subjects who have received or are receiving COVID-19 vaccines must have completed the vaccination schedule no less than 14 days prior to the first dosing of study drug.19. Has been on a diet incompatible with the on-study diet, in the opinion of the PI or designee, within the 30 days prior to the first dosing.20. Donation of blood or significant blood loss within 56 days prior to the first dosing.21. Plasma donation within 7 days prior to the first dosing.22. Family history of long QT syndrome or of unexplained sudden death in a first-degree relative under 50 years of age.23. Documented congenital or acquired long-QT syndrome.24. Excessive consumption of alcohol, defined as > 3 alcoholic beverages per day for males and > 2 alcoholic beverages per day for females. Ten (10) ounces (oz) (284 mL) of beer, 4 oz (125 mL) of wine, or 1 oz (25 mL) of distilled spirits are each considered 1 alcoholic beverage.25. Consumption of foods and beverages containing caffeine or xanthine for 48 hours prior to check-in with exception.26. Consumption of foods or beverages including grapefruit or grapefruit juice and poppy seeds.27. Venous access considered inadequate for PK sample collection; history or evidence of adverse symptoms associated with phlebotomy or blood donation.28. Has elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 x upper limit of normal (ULN) or elevated alkaline phosphatase (ALP) or total bilirubin > 1.5 x ULN at the screening visit or check-in. A single repeat assessment is allowed for eligibility determination per sample time.29. Has a history or high risk of urinary retention, gastric retention, or narrowangle (i.e., angle closure) glaucoma.30. Myocardial infarction within 6 months prior to the screening visit.31. Has a history of Gilbert’s disease.32. Has a risk for suicidal behavior during the study, as determined by the Pi’s clinical judgment and C-SSRS, confirmed by the following:• Answers “Yes” on items 4 or 5 (C-SSRS - ideation) with the most recent episode occurring within the 6 months before the screening visit;• Answers “Yes” to any of the 5 items (C-SSRS - behavior) with an episode occurring within the 12 months before the screening visit;Non-suicidal self-injurious behavior is not exclusionary.33. Employee or family member of the PI, study site personnel, or Sponsor.34. Participation in a previous KarXT clinical study.35. Participation in another clinical study within 30 days (or 5 half-lives, if known, whichever is longer) prior to the first dosing. The aforementioned window will be derived from the date of the last blood collection or dosing, whichever is later, in the previous study to Day 1 of the current study.36. Any other reason that, in the opinion of the PI, would render the subject unsuitable for study enrollment.Example 5 - Enteric-Coated MR Beads

[0315] The following flow diagram shows the schemes of developing the enteric- coated MR beads. Six formulations with different combinations of binder, seal coat material, and functional polymer were developed as shown in the flow diagram.Xanomeline Layer Seal Coat Functional Polymers

[0316] The full names of each excipient and manufacturers are provided in Table 14. The compositions of MR-3 and MR-6 beads are provided in Table 15 and Table 16 respectively. The manufacture process of enteric-coated MR beads can be divided into three steps, 1) coating of xanomeline or the salt of thereof, 2) seal coating, 3) enteric / functional polymer coating. The coating equipment, solvent system, and the coating conditions of steps 1 and 2 are summarized in Table 17 and those of step 3 (MR-3 and MR-6 only) in Table 18.Table 14: Materials and manufacturers for making the enteric-coated MR beadsTable 15: Composition of enteric-coated beads, Formulatio MR-3Table 16: Composition of enteric-coated beads, Formulation NIR-6Table 17: Manufacture and Process ParametersTable 18: Processing parameters of Prototypes MR-3 and MR-6Example 6 - Coated IR Beads

[0317] The scheme of developing the xanomeline tartrate and trospium chloride (XT / TC1) coated IR beads is shown below7. The HPMC E5 seal coated bead is chosen to add trospium chloride layer as the final IR bead. Table 19 shows the formulation composition of two IR beads at two different trospium chloride weight gain.

[0318] The manufacture process of IR beads can be divided into three steps, 1) coating of xanomeline or the salt of thereof, 2) seal coating, 3) trospium layer coating. The details of the individual step can be found in the Oral Pharmaceutical Composition with IR and MR Components section. The coating equipment, solvent system, and the coating conditions of steps 1-3 are summarized in Table 20.Xanomeline Layer Seal Coat Trospiuni LayerTable 19 Composition of xanomeline Tartrate and trospium chloride coated IR Beads, Formulations IR-1 and IR-2.IR- 1 : High TCI; IR-2: Low TCITable 20: Processing parameters of Prototypes IR-1 and IR-2

[0319] Bead size distribution was determined with sieve analysis (US 14 / 16 / 35 meshes) and is summarized in Table 21 below.Table 21 : Bead size distributionExample 6 - Dissolution Test

[0320] Dissolution tests of the KarXT-DB / IR capsules, the xanomeline MR beads capsules, and the xanomeline tartrate / trospium chloride (XT / TC1) IR capsules were conducted with USP <711> Apparatus 2 at two stages of dissolution conditions - acid phase (0.1N HC1 (Stage 1)) for 2 hours followed by buffer phase (0.05M Sodium Phosphate, pH 6.8 (Stage 2)) for 30 minutes. In each of the six 1-Liter vessels, place 450 mL dissolution media I (0.1 N HC1) and equilibrate to 37°C. Prior to weighing the capsule, perform a visual inspection of the capsule and note any noticeable defect. Weigh capsules, placing with a wire sinker add one to each vessel. Commence the dissolution test with paddle speed of 100 rpm. At 120 minutes, manually withdraw 5 mL of sample from the vessel, filter through a 0.45 pm PTFE hydrophobic membrane filter with glass syringe, discarding the first 2 mL of filtrate. After 120 minutes pull, add 450 mL dissolution media II (prewarmed at 37°C, 0.1 M Sodium Phosphate Buffer, pH 11.4) to bring to Stage 2 dissolution condition. Continue performing the dissolution and pull samples at 125, 130, 135, 150, 165 and 180 minutes. After 180 minutes sample pull, the paddle speed is increased to 200 rpm as the infinity spin for 15 minutes and the last sample is taken at 195 minutes of the dissolution time. No media replacement after each sample pull.

[0321] The dissolution sample is analyzed by a HPLC method, which utilizes a Thermo UltiMate 3000 system or similar systems equipped with an autosampler and column heater, operating with a UV detector set at a wavelength of 215 nm. The chromatographic separation is performed on an Agilent Zorbax Eclipse XDB-C18 column(75 x 4.6 mm, 3.5 pm) maintained at a temperature of 25°C. Samples are kept at ambient temperature with an injection volume of 20 pL. The mobile phase is comprised of two components: Mobile Phase A, which is a mixture of 0.1% triethylamine (TEA) and 0.3% phosphoric acid in water, and Mobile Phase B consisting of acetonitrile. The flow rate is set at 1.5 mL / min. A gradient elution is employed starting with 70% Mobile Phase A and 30% Mobile Phase B, transitioning to Mobile A / Mobile B 25 / 75 in 1 minutes. At 1. 2 minutes, the gradient starts to change to Mobile A / Mobile B 15 / 85 in 0.1 minutes (run time 1.3 minutes), and eventually returning to the initial conditions at 1.9 minutes over a total run time of 3.1 minutes. The needle wash solution is 50% acetonitrile, and methanol along with 0.05M sodium phosphate buffer at pH 6.8 is used as the diluent.

[0322] FIG. 5A shows a dissolution overlay of the xanomeline MR beads. The 75 mg xanomeline strength was tested for MR-3 (75 rpm) and both MR-6A and MR-6B (100 rpm). The strength and paddle speed were adjusted to be consistent with the KarXT-DB / IR dissolution method. The Eudragit L100-55 prototypes (MR-3 and MR-6A / B) met the USP requirements. The faster xanomeline release from Kollicoat-based prototypes (MR-6A and MR-6B) compared to Klucel-based (MR-3) may be attributed to the higher paddle speed.

[0323] FIG. 5B shows a dissolution overlay of the XT / TC1 IR beads. The lower drugload trospium prototype (IR-2) shows greater variability than higher drug-load trospium prototype (IR-1) due to the coating consistency challenge associated with the lower TCI weight gain.

[0324] The prototypes MR-6B and IR-1 were mixed, lubricated with 0.3%, and encapsulated in an immediate-release capsule (Vcap, Size 0, containing a total 56 mg of xanomeline and 6 mg of trospium chloride) for dissolution testing, storage stability studies, and animal dosing. The dissolution profiles of both active ingredients, as shown in FIG. 6, indicate that: 1) encapsulating the two beads in the same capsule does not affect their individual performance, and 2) half the dose of xanomeline is released simultaneously with the full dose of trospium within 20 minutes. These dissolution profiles are comparable to those of the KarXT-DB / IR capsule tested at the same strength and under the same dissolution conditions.Example 7 - Stability Study

[0325] The capsules containing IR / MR beads were stored at 25°C / 60% RH and 40°C / 75% RH to test drug stability for 6 months and 3 months, respectively. The commonlyobserved degradants, such as Impurity A and related compound A of Trospium from the XT / TC1 co-formulated formulations or the oxidized xanomeline from the Cobenfy™ product, were either not detected (<0.05%) or were below the limit of quantification (0.1%). There were no significant changes in dissolution performance, as shown in FIG. 7. The slightly increased final release observed for both active ingredients during stability storage could be explained by the higher assay values of both actives at the time points.Example 8 - Animal Study

[0326] An immediate-release capsule containing XT / TC1 IR-2 and XT MR-6B beads was administered to non-human primates (Rhesus monkeys, n=7, 4 males and 3 females) to 1) explore the pharmacokinetic (PK) profile of xanomeline and trospium, and 2) compare it with the PK profile of the KarXT-DB / IR capsule dosed in the same group of animals. The total doses of xanomeline and trospium were 56 mg and 6 mg, respectively. For the IR / DR capsule, the 56 mg xanomeline dose was equally split between the XT DR bead and the XT / TC1 IR bead, which also included the 6 mg trospium. For the KarXT-DB / IR capsules, 28 mg of xanomeline was given in an enteric capsule, and the other 28 mg of xanomeline was encapsulated together with the 6 mg trospium bead in an immediate-release capsule. The animals were fasted overnight (>12 hours) prior to dosing and were fed approximately 4 hours after dosing. All animals had free access to water. Blood samples were taken at predose, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 18 hours, 24 hours, and 28 hours post-dose. Plasma concentrations of xanomeline and trospium were analyzed using an LC-MS / MS method with established ULOD and LLOD for both xanomeline (0.05 - 50 ng / mL) and trospium (0.05 - 50 ng / mL).

[0327] The PK profiles of both xanomeline and trospium from the two dosing regimens are plotted in FIGs. 8A and 8B. For xanomeline, both groups show similar profiles, with the IR / DR beads producing a flatter PK profile. At the 4- and 8-hour time points, one animal in each group showed exceedingly high exposure, which could be due to returning to the fed state. The trospium profiles of both groups are also similar, except for one animal in the KarXT-DB / IR group that showed a high plasma concentration at the 30-minute time point.

[0328] The PK parameters of both xanomeline and trospium from the two groups were calculated using WinNonlin, and the results are presented in the table below. Compared to the IR / DR beads, the KarXT-DB / IR capsule resulted in approximately 1.5 to 2 times higherexposure. However, both Cmax and AUCiast showed noticeable variability. Tmax and Tl / 2 were fairly comparable between the two groups.Table 22 : PK parameters of xanomeline in non-human primates (mean & %CV)XanomelineNA: not applicableTable 22 PK parameters of trospsium in non-human primates (mean & % coefficient of variabtion (CV)TrospiumNA: not applicableASPECTS

[0329] The disclosure is also directed to the following Aspects:Formulations1. An oral pharmaceutical composition, comprising:(1) an IR component comprising xanomeline or a salt thereof;(2) a MR component comprising xanomeline or a salt thereof; and(3) an IR component comprising a trospium salt.2. The oral pharmaceutical composition of aspect 1, wherein the IR component comprises a plurality of beads.3. The oral pharmaceutical composition of aspect 1, wherein the MR component comprises a plurality of beads.4. The oral pharmaceutical composition of aspect 2, wherein the IR component comprises a plurality of beads comprising xanomeline or a salt thereof encapsulated in an IR capsule.The oral pharmaceutical composition of aspect 2, wherein the IR component comprises a plurality of beads comprising a salt of trospium encapsulated in an IR capsule. The oral pharmaceutical composition of aspect 2, wherein the IR component comprises a plurality of beads comprising xanom eline or a salt thereof and a plurality of beads of a salt of trospium encapsulated in an IR capsule. The oral pharmaceutical composition of aspect 3, wherein the MR component comprises a plurality of beads comprising xanomeline or a salt thereof encapsulated in an enteric capsule (EC). he oral pharmaceutical composition of any one of aspects 1, 4, 6 and 7, wherein the xanomeline or a salt thereof is xanomeline free base or xanomeline tartrate. he oral pharmaceutical composition of any one of aspects 1 to 3, wherein the salt of trospium is trospium chloride. The oral pharmaceutical composition of any one of aspects 1, 2, 5 and 6, wherein the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate. The oral pharmaceutical composition of aspect 10, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate. The oral pharmaceutical composition of any one of aspects 1, 2, 4 and 6, wherein the xanomeline beads comprise between 15 wt.% and 65 wt.% microcrystalline cellulose. The oral pharmaceutical composition of aspect 12, wherein the xanomeline beads comprise 33.0 wt.% microcrystalline cellulose. The oral pharmaceutical composition of any one of aspects 1, 2, 4, and 6, wherein the xanomeline beads comprise between 0 wt.% and 2 wt.% talc. The oral pharmaceutical composition of aspect 14, wherein the xanomeline beads comprise 0.5 wt.% talc. The oral pharmaceutical composition of any one of aspects 1, 2, 4, and 6, wherein the xanomeline beads comprise between 0 wt.% and 2 wt.% ascorbic acid. The oral pharmaceutical composition of aspect 16, wherein the xanomeline beads comprise 0.5 wt.% ascorbic acid. The oral pharmaceutical composition of any one of aspects 1, 2, 4, and 6, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate, 33.0 wt.% microcrystalline cellulose, 0.5 wt.% talc, and 0.5 wt.% ascorbic acid. The oral pharmaceutical composition of any one of aspects 1, 2, 4 and 5, wherein the trospium beads comprise between 3 wt.% and 35 wt.% trospium chloride.The oral pharmaceutical composition of aspect 19, wherein the trospium beads comprise17.7 wt.% trospium chloride. The oral pharmaceutical composition of aspect 19, wherein the trospium beads comprise 4.4 wt.% trospium chloride. The oral pharmaceutical composition of any one of aspects 1, 2, 4 and 5, wherein the trospium beads comprise between 25 wt.% and 80 wt.% microcrystalline cellulose. The oral pharmaceutical composition of aspect 22, wherein the trospium beads comprise46.8 wt.% microcrystalline cellulose. The oral pharmaceutical composition of any one of aspects 1, 2, 4 and 5, wherein the trospium beads comprise between 15 wt.% and 70 wt.% lactose monohydrate. The oral pharmaceutical composition of aspect 24, wherein the trospium beads comprise 35 wt.% lactose monohydrate. The oral pharmaceutical composition of any one of aspects 1, 2, 4 and 5, wherein the trospium beads comprise between 0 wt.% and 2 wt.% talc. The oral pharmaceutical composition of aspect 26, wherein the trospium beads comprise 0.5 wt.% talc. The oral pharmaceutical composition of any one of aspects 1, 2, 4 and 5, wherein the trospium beads comprise 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc. The oral pharmaceutical composition of any one of aspects 5, 19 to 28, wherein the trospium beads comprise 4.4 wt.% trospium chloride, 54.5 wt.% microcrystalline cellulose, 40.6 wt.% lactose monohydrate, and 0.5 wt.% talc. The oral pharmaceutical composition of aspect 4 or 6, wherein the IR capsule has a dose strength of 25 mg xanomeline as the tartrate salt. The oral pharmaceutical composition of aspect 4 or 6, wherein the IR capsule has a dose strength of 50 mg xanomeline as the tartrate salt. The oral pharmaceutical composition of aspect 4 or 6, wherein the IR capsule has a dose strength of 75 mg xanomeline as the tartrate salt. The oral pharmaceutical composition of aspect 5 or 6, wherein the IR capsule has a dose strength of 5 mg trospium chloride. The oral pharmaceutical composition of aspect 5 or 6, wherein the IR capsule has a dose strength of 20 mg trospium chloride.The oral pharmaceutical composition of aspect 7, wherein the EC comprises a cellulose polymer or a mixture thereof. The oral pharmaceutical composition of aspect 35, wherein the cellulose polymer is selected from HPMCAC, HPMCAS and HPMC, or a mixture thereof. The oral pharmaceutical composition of aspect 36, wherein the cellulose polymer is HPMCAS-M. The pharmaceutical composition of any one of aspects 7 and 35 to 37, wherein the EC has a dose strength of 25 mg xanomeline as the tartrate salt. The oral pharmaceutical composition of any one of aspects 7 and 35 to 37, wherein the EC has a dose strength of 50 mg xanomeline as the tartrate salt. The oral pharmaceutical composition of any one of aspects 7 and 35 to 37, wherein the EC has a dose strength of 75 mg xanomeline as the tartrate salt. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 20 mg xanomeline as the tartrate salt and 2 mg trospium chloride. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 30 mg xanomeline as the tartrate salt and 3 mg trospium chloride. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 50 mg xanomeline as the tartrate salt and 5 mg trospium chloride. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 66.7 mg xanomeline as the tartrate salt and 6.67 mg trospium chloride. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 14 mg xanomeline as the tartrate salt and 3 mg trospium chloride. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 42 mg xanomeline as the tartrate salt and 9 mg trospium chloride. The oral pharmaceutical composition of aspect 6, wherein the IR capsule has a dose strength of 56 mg xanomeline as the tartrate salt and 12 mg trospium chloride. The oral pharmaceutical composition of any one of aspects 7 and 35 to 37, wherein the EC has a dose strength of 14 mg xanomeline as the tartrate salt. The oral pharmaceutical composition of any one of aspects 7 and 35 to 37, wherein the EC has a dose strength of 28 mg xanomeline as the tartrate salt.The oral pharmaceutical composition of any one of aspects 1 to 50, wherein said pharmaceutical composition is administered to a patient once or twice daily. The oral pharmaceutical composition of aspect 51, wherein the xanomeline or a salt thereof is administered in an IR capsule and an EC capsule and the trospium salt is administered in one or more IR capsules twice daily. The oral pharmaceutical composition of aspect 52, wherein 25 mg of xanomeline as the tartrate salt is administered in an IR capsule, 25 mg of xanomeline as the tartrate salt is administered in an EC, and 20 mg of trospium chloride is administered in an IR capsule. The oral pharmaceutical composition of aspect 52, wherein 50 mg of xanomeline as the tartrate salt is administered in an IR capsule, 50 mg of xanomeline as the tartrate salt is administered in an EC capsule, and 20 mg of trospium chloride is administered in an IR capsule. The oral pharmaceutical composition of aspect 52, wherein 50 mg of xanomeline as the tartrate salt is administered in an IR capsule, 75 mg of xanomeline as the tartrate salt is administered in an EC capsule, and 30 mg of trospium chloride is administered in two 5 mg IR capsules and one 20 mg IR capsule. The oral pharmaceutical composition of aspect 52, wherein 50 mg of xanomeline as the tartrate salt is administered in an IR capsule, 75 mg of xanomeline as the tartrate salt is administered in an EC capsule, and 30 mg of trospium chloride is administered in two 5 mg IR capsules and one 20 mg IR capsule once daily. The oral pharmaceutical composition of aspect 52, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of xanomeline of about 10000 to 12000 pg / mL and a steady state geometric mean Cmax of trospium of about 3000 to 4000 pg / mL. The oral pharmaceutical composition of aspect 57, wherein the geometric mean Cmax of xanomeline is between about 18% and about 36% lower than that of xanomeline produced by a similar dose of IR pharmaceutical composition and the geometric mean Cmax of trospium is between about 8% to about 29% lower than that of trospium produced by a similar dose of the IR pharmaceutical composition.Method of TreatmentA method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition, comprising:(1) an immediate-release (IR) component comprising xanomeline or a salt thereof;(2) a modified-release (MR) component comprising xanomeline or a salt thereof; and(3) an IR component comprising a trospium salt. The method of claim 59 comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising xanomeline or a salt thereof and a trospium salt; and (2) a MR component comprising xanomeline or a salt thereof. The method of aspect 59, wherein the disorder is selected from bipolar disorder, schizophrenia (optionally schizophrenia with cognitive impairment), schizoaffective disorder, cognitive impairment associated with schizophrenia, Alzheimer disease (optionally Alzheimer’s disease with psychosis, Alzheimer’s disease with agitation, and / or Alzheimer’s disease with cognitive impairment), autism, Parkinson’s disease, depression, dementia, movement disorders, pain, drug addiction, addictive disorder, tauopathy, Tourette syndrome, and synucleinopathy. The method of aspect 61, wherein the disease is selected from Alzheimer’s disease with agitation and Alzheimer’s disease with cognitive impairment. The method of any one of aspect 59 to 62, wherein the patient is 55 years or older. The method of aspect 63, wherein the patient is 65 years or older. The method of any one of aspects 59 to 64, wherein the pharmaceutical composition is administered to the patient once or twice daily. The method of any one of aspects 59 to 65, wherein the IR and the MR components of the pharmaceutical composition are administered simultaneously. The method of any one of aspects 59 to 66, further comprising orally administering to the patient an increased dose of xanomeline or the salt thereof and an increased dose of a trospium salt. The method of any one of aspects 59 to 66, wherein a total daily dose of xanomeline equivalent to between about 25 and 250 mg of xanomeline as the tartrate salt and a total daily dose of trospium equivalent to between about 5 and 30 mg of a trospium chloride are administered to the patient. The method of any one of aspects 59 to 67, wherein 50% of the total daily dose of xanomeline as the tartrate salt is administered by the IR component and the other 50% by the MR component.70. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 28 mg of xanomeline as the tartrate salt and 3 mg of a trospium chloride.71. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 56 mg of xanomeline as the tartrate salt and 6 mg of a trospium chloride.72. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 84 mg of xanomeline as the tartrate salt and 9 mg of a trospium chloride.73. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 112 mg of xanomeline as the tartrate salt and 12 mg of a trospium chloride.74. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 140 mg of xanomeline as the tartrate salt and 15 mg of a trospium chloride.75. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 168 mg of xanomeline as the tartrate salt and 18 mg of a trospium chloride.76. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 196 mg of xanomeline as the tartrate salt and 21 mg of a trospium chloride.77. The method of any one of aspects 59 to 66, wherein the dose is a total daily dose of 224 mg of xanomeline as the tartrate salt and 24 mg of a trospium chloride.78. A method of any one of aspects 59 to 66, wherein the total daily dose of xanomeline is equivalent to about 25- 250 mg of xanomeline as the tartrate salt and the total daily dose of trospium is equivalent to about 2.5 - 40 mg of trospium chloride.Coated IR Beads79. The oral pharmaceutical composition of aspect 2, wherein the IR component comprises a plurality of non-enteric-coated beads and the MR component comprises a plurality of enteric- coated beads.80. The oral pharmaceutical composition of aspect 79, wherein each of the non-enteric- coated beads comprises a sugar core, an active ingredient layer of xanomeline or a salt thereof and an active ingredient layer of a trospium salt, wherein the two active ingredient layers are separated by a seal coat layer.81. The oral pharmaceutical composition of aspect 79 or 80, wherein each of the non-enteric coated IR beads comprises:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and optionally one or more pharmaceutically acceptable carriers coated over said sugar core;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and optionally one or more pharmaceutically acceptable carriers coated over said active ingredient layer comprising xanomeline or a salt thereof; and(4) an active ingredient layer comprising a trospium salt and optionally one or more pharmaceutically acceptable carriers coated over said seal coat layer. The oral pharmaceutical composition of aspect 81, wherein the pharmaceutically acceptable carrier in (2) and (4) is a binder or an anti-tacking agent. The oral pharmaceutical composition of aspect 82, wherein the binder is selected from the group consisting of hydroxypropyl cellulose, polyvinyl alcohol, and polyethylene glycol, or a mixture thereof, and the anti-tacking agent is talc. The oral pharmaceutical composition of any one of aspects 79 to 81, wherein the seal coat in (3) comprises a polymer selected from the group consisting of HPMC and the pharmaceutically acceptable carrier is talc. The oral pharmaceutical composition of any one of aspects 79 to 82, wherein the nonenteric-coated IR bead is prepared by a process comprising:(a) coating the sugar core with a suspension of xanomeline or a salt and a pharmaceutically acceptable carrier;(b) coating the xanomeline loaded sugar core of step (a) with a pharmaceutically acceptable seal coat polymer and a pharmaceutically acceptable carrier;(c) coating the seal coated xanomeline sugar core of step (b) with a trospium salt and a pharmaceutically acceptable carrier. The oral pharmaceutical composition of aspect 79, wherein the non-enteric coated IR beads have a D50 particle size in a range from about 0.4 mm to about 1.1 mm. The oral pharmaceutical composition of aspect 86, wherein the non-enteric coated IR beads have a D50 particle size in a range from about 0.5 mm to about 0.6 mm. The oral pharmaceutical composition of any one of aspects 79 to 87, wherein the non- enteric coated IR beads have a dissolution profile such that greater than 90% of trospium is released in 30 minutes in the buffer. The oral pharmaceutical composition of any one of aspects 81 to 87, where the non- enteric coated IR bead comprises between 10 wt.% and 20 wt.% sugar core.90. The oral pharmaceutical composition of any one of aspects 81 to 88, where active ingredient layer (2) comprises between 30 wt.% and 60 wt.% xanomeline tartrate and between 5 wt.% and 15 wt.% Kollicoat® .91. The oral pharmaceutical composition of any one of aspects 81 to 89, where the seal coating layer comprises between 5 wt.% and 10 wt.% HPMC E5 and 1 wt.% and 7 wt.% talc.92. The oral pharmaceutical composition of any one of aspects 80 to 90, wherein the active ingredient layer (3) comprises between 3 wt.% and 20 wt.% trospium chloride and between 0.5 wt.% and 5 wt.% Kollicoat®.Enteric-Coated Xanomeline Beads93. The oral pharmaceutical composition of any one of aspects 3 and 79-92, wherein the MR component comprises a plurality of enteric-coated xanomeline beads, each bead comprising(i) a sugar core;(ii) an active ingredient layer comprising xanomeline or a salt thereof, and optionally one or more pharmaceutically acceptable carriers coated over said sugar core;(iii) a seal coat layer comprising at least pharmaceutically acceptable polymer and optionally one or more pharmaceutically acceptable carriers coated over said active ingredient layer; and(iv) an enteric coating layer comprising an enteric coating polymer and optionally one or more pharmaceutically acceptable carriers.94. The oral pharmaceutical composition of aspect 93, wherein the pharmaceutically acceptable carrier in (ii) is selected from hydroxypropyl cellulose, polyvinyl alcohol, polyethylene glycol, or a mixture thereof, and talc.95. The oral pharmaceutical composition of aspect 93 or 94, wherein the polymer in (iii) is HPMC E5 or Opadry® and the pharmaceutically acceptable carrier is talc.96. The oral pharmaceutical composition of any one of aspects 93 to 95, wherein the enteric coating polymer is selected from the group consisting of a copolymer of poly(methacrylic acid, ethyl acrylate), preferably Eudragit L100, Eudragit L100-55, and Eudragit S 100.97. The oral pharmaceutical composition of any one of aspects 93 to 96, wherein the enteric- coated xanomeline bead is prepared by a process comprising:(a) coating the sugar core with a suspension of xanomeline or a salt or a pharmaceutically acceptable carrier;(b) coating the xanomeline loaded sugar core of step (a) with at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable carrier;(c) enteric coating the seal coated xanomeline sugar core of step (b) with a pharmaceutically acceptable enteric coating polymer; and(d) optionally, mixing the enteric-coated beads of xanomeline or a salt thereof with one or more pharmaceutically acceptable excipients. The oral pharmaceutical composition of any one of aspects 93 to 97, where the enteric- coated bead comprises between 10 wt.% and 20 wt.% sugar core. The oral pharmaceutical composition of any one of aspects 93 to 98, wherein the active ingredient layer comprising xanomeline (ii) comprises between 30 wt.% and 60 wt.% xanomeline tartrate, between 1 wt.% to 10 wt.% Klucel®, and between 1 wt.% and 5 wt.% talc. . The oral pharmaceutical composition of any one of aspects 93 to 98, wherein the active ingredient layer comprising xanomeline (ii) comprises between 30 wt.% and 60 wt.% xanomeline tartrate, between 5 wt.% to 15 wt.% Kollicoat®. . The oral pharmaceutical composition of any one of aspects 93 to 100, wherein the enteric-coating layer comprises between 10 wt.% and 20 wt.% Eudragit L100-55, between 1 wt.% and 5 wt.% tri ethyl citrate, and between 5 wt.% and 15 wt.% talc. . The oral pharmaceutical composition of any one of aspects 93 to 101, wherein the enteric- coated xanomeline bead has a D50 particle size in a range about 0.4 mm to about 1.25 mm. . The oral pharmaceutical composition of any one of aspects 79 to 102, wherein the enteric- coated bead has a dissolution profile in which 30-65% of xanomeline or a salt thereof has lower than 10% release within 120 minutes during acid stage of dissolution and rapidly and / or completely released in 30-45 minutes in a solution buffered at pH 6.8.. The oral pharmaceutical composition of any one of aspects 79 to 103, wherein the beads of the IR and MR components are encapsulated in one capsule. . The oral pharmaceutical composition of aspect 104, having the dissolution profile of xanomeline tartrate and trospium chloride as shown in FIG. 6. . A coated xanomeline and trospium IR bead comprising:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and at least one pharmaceutically acceptable carrier coated over said sugar core;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable carrier coated over said active layer; and(4) an active ingredient layer comprising a trospium salt and at least one pharmaceutically acceptable carrier coated over said seal coat layer. . An enteric-coated xanomeline bead comprising:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and at least one pharmaceutically acceptable carrier;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable carrier; and(4) an enteric coating layer and at least one pharmaceutically acceptable carrier. . The method of aspect 59, wherein the IR and MR components of xanomeline or a salt thereof releases at least two consecutive pulses of xanomeline or a salt thereof, each pulse separated in time by from about 0.5 to about 12 hours. . The method of aspect 1 or 108, wherein the IR and MR components each independently comprises a plurality of beads. . The method of aspect 109, wherein the beads of the IR component are IR xanomeline and trospium beads encapsulated in a non-enteric capsule and the beads of the MR component are IR xanomeline beads encapsulated in an enteric capsule, optionally wherein the IR xanomeline beads are as defined in any one of aspects 10 to 18, optionally wherein the IR trospium beads are as defined in any one of aspects 19 to 29, optionally wherein the non-enteric capsule is as defined in any one of aspects 30 to 34, and 41 to 48, and / or optionally wherein the enteric capsule is as defined in any one of aspects 35 to 40, 49, and 50. . The method of aspect 109, wherein the two capsules are taken simultaneously.112. The method of aspect 108, wherein the beads are a) a plurality of non-enteric-coated IR xanomeline and trospium beads and b) a plurality of enteric-coated MR xanomeline beads.113. The method of aspect 111, wherein the non-enteric-coated IR xanomeline and trospium beads and the enteric-coated MR xanomeline beads are encapsulated together in a nonenteric capsule.114. The method of aspects 60 and 61, comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising xanomeline or a salt thereof and a trospium salt; and (2) a MR component comprising xanomeline or a salt thereof, wherein the disorder Alzheimer’s disease with agitation and Alzheimer’s disease with cognitive impairment, and wherein the pharmaceutical composition is administered twice daily and provides a total daily dose of about 56-224 mg xanomeline as the tartrate salt and 6-24 mg trospium chloride.115. The bead of aspect 106 or 107, wherein the bead is stable for at least six months at 40 °C at about 75% relative humidity.116. A method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition, comprising:(1) an immediate-release (IR) component comprising xanomeline or a salt thereof;(2) a modified-release (MR) component comprising xanomeline or a salt thereof; and(3) an IR component comprising a trospium salt, wherein the total daily dose of xanomeline is equivalent to about 25 - 250 mg of xanomeline as the tartrate salt and the total daily dose of trospium is equivalent to about 2.5 - 40 mg of trospium chloride.117. The method of aspect 116, wherein the in-vivo xanomeline plasma profile of the patient is characterized by a geometric mean Cmax at least 36% lower than the geometric mean Cmax produced by IR / IR pharmaceutical composition.118. The method of aspect 117, wherein the in-vivo xanomeline plasma profile of the patient is characterized by a geometric mean Cmax at least 30% lower than the geometric mean Cmax produced by the IR / IR pharmaceutical composition.119. The method of aspect 118, wherein the in-vivo xanomeline plasma profile of the patient is characterized by a geometric mean Cmax at least 20% lower than the geometric mean Cmax of produced by the IR / IR pharmaceutical composition.120. The method of aspect 119, wherein the in-vivo xanomeline plasma profile of the patient is characterized by a geometric mean Cmax at least 10% lower than the geometric mean Cmax produced by IR / IR pharmaceutical composition.121. The oral pharmaceutical composition of aspect 57, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of xanomeline of about 10000 to 12000 pg / mL122 The oral pharmaceutical composition of aspect 121, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of xanomeline of about 11400 pg / mL.123 The oral pharmaceutical composition of aspect 57, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of trospium of about 3000 to 4000 pg / mL.124. The oral pharmaceutical composition of aspect 123, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of trospium of about 3750 pg / mL.125. The method of aspect 116, wherein the pharmaceutical composition reduces the occurrence of adverse events.126. The method of aspect 125, wherein the adverse event is selected from heart rate increase, orthostatic hypotension, dizziness, nausea, constipation, and tachycardia.

[0330] The foregoing description is given for clearness of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the disclosure may be apparent to those having ordinary skill in the art. Throughout the specification, where compositions are described as including components or materials, it is contemplated that the compositions can also consist essentially of, or consist of, any combination of the recited components or materials, unless described otherwise. Likewise, where methods are described as including steps, it is contemplated that the methods can also consist essentially of, or consist of, any combination of the recited steps, unless described otherwise. The disclosure illustratively disclosed herein suitably may be practiced in the absence of any element or step which is not specifically disclosed herein.

[0331] The practice of a method disclosed herein, and individual steps thereof, can be performed manually and / or with the aid of or automation provided by electronic equipment. Although processes have been described with reference to embodiments, a person of ordinary skill in the art will readily appreciate that other ways of performing the acts associated with the methods may be used. For example, the order of various of the steps may be changed without departing from the scope or spirit of the method, unless described otherwise. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0332] It is appreciated that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0333] All patents, publications and references cited herein are hereby fully incorporated by reference. In case of conflict between the present disclosure and incorporated patents, publications and references, the present disclosure should control.

Claims

What is claimed is:

1. A method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition, comprising:(1) an immediate-release (IR) component comprising xanomeline or a salt thereof;(2) a modified-release (MR) component comprising xanomeline or a salt thereof; and(3) an IR component comprising a trospium salt.

2. An oral pharmaceutical composition, comprising:(1) an IR component comprising xanomeline or a salt thereof;(2) a MR component comprising xanomeline or a salt thereof; and(3) an IR component comprising a trospium salt.

3. The oral pharmaceutical composition of claim 2, wherein the IR and MR components each independently comprise a plurality of beads.

4. The oral pharmaceutical composition of claim 3, wherein the IR component comprises a plurality of beads comprising xanomeline or a salt thereof encapsulated in an IR capsule.

5. The oral pharmaceutical composition of claim 3, wherein the IR component comprises a plurality of beads comprising a salt of trospium encapsulated in an IR capsule.

6. The oral pharmaceutical composition of claim 3, wherein the IR component comprises a plurality of beads comprising xanomeline or a salt thereof and a plurality of beads of a salt of trospium encapsulated in an IR capsule.

7. The oral pharmaceutical composition of claim 3, wherein the MR component comprises a plurality of beads comprising xanomeline or a salt thereof encapsulated in an enteric capsule (EC).

8. The oral pharmaceutical composition of any one of claims 1 to 7, wherein the xanomeline or a salt thereof is xanomeline free base or xanomeline tartrate.

9. The oral pharmaceutical composition of any one of claims 1 to 7, wherein the salt of trospium is trospium chloride.

10. The oral pharmaceutical composition of claim 4, wherein the xanomeline beads comprise between 30 wt.% and 80 wt.% xanomeline tartrate.

11. The oral pharmaceutical composition of claim 10, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate.

12. The oral pharmaceutical composition of any one of claims 4, 10, and 11, wherein the xanomeline beads comprise between 15 wt.% and 65 wt.% microcrystalline cellulose.

13. The oral pharmaceutical composition of claim 12, wherein the xanom eline beads comprise 33 wt.% microcrystalline cellulose.

14. The oral pharmaceutical composition of any one of claims 4 and 10 to 13, wherein the xanomeline beads comprise between 0 wt.% and 2 wt.% talc.

15. The oral pharmaceutical composition of claim 14, wherein the xanomeline beads comprise 0.5 wt.% talc.

16. The oral pharmaceutical composition of any one of claims 4 and 10 to 15, wherein the xanomeline beads comprise between 0 wt.% and 2 wt.% ascorbic acid.

17. The oral pharmaceutical composition of claim 16, wherein the xanomeline beads comprise 0.5 wt.% ascorbic acid.

18. The oral pharmaceutical composition of any one of claims 4 and 10 to 17, wherein the xanomeline beads comprise 66 wt.% xanomeline tartrate, 33 wt.% microcrystalline cellulose, 0.5 wt.% talc, and 0.5 wt. % ascorbic acid.

19. The oral pharmaceutical composition of claim 5, wherein the trospium beads comprise between 3 wt.% and 35 wt.% trospium chloride.

20. The oral pharmaceutical composition of claim 19, wherein the trospium beads comprise17.7 wt.% trospium chloride.

21. The oral pharmaceutical composition of claim 19, wherein the trospium beads comprise 4.4 wt.% trospium chloride.

22. The oral pharmaceutical composition of any one of claims 5 and 19 to 21, wherein the trospium beads comprise between 25 wt.% and 80 wt.% microcrystalline cellulose.

23. The oral pharmaceutical composition of claim 22, wherein the trospium beads comprise46.8 wt.% microcrystalline cellulose.

24. The oral pharmaceutical composition of any one of claims 5 and 19 to 23, wherein the trospium beads comprise between 15 wt.% and 70 wt.% lactose monohydrate.

25. The oral pharmaceutical composition of claim 24, wherein the trospium beads comprise 35 wt.% lactose monohydrate.

26. The oral pharmaceutical composition of any one of claims 5 and 19 to 25, wherein the trospium beads comprise between 0 wt.% and 2 wt.% talc.

27. The oral pharmaceutical composition of claim 26, wherein the trospium beads comprise 0.5 wt.% talc.

28. The oral pharmaceutical composition of any one of claims 5, 19, 20, and 22 to 27, wherein the trospium beads comprise 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc.

29. The oral pharmaceutical composition of any one of claims 5, 19, 22, 24 and 26, wherein the trospium beads comprise 4.4 wt.% trospium chloride, 54.5 wt.% microcrystalline cellulose, 40.6 wt.% lactose monohydrate, and 0.5 wt.% talc.

30. The oral pharmaceutical composition of claim 4, wherein the IR capsule has a dose strength of 25 mg xanomeline as the tartrate salt.

31. The oral pharmaceutical composition of claim 4, wherein the IR capsule has a dose strength of 50 mg xanomeline as the tartrate salt.

32. The oral pharmaceutical composition of claim 4, wherein the IR capsule has a dose strength of 75 mg xanomeline as the tartrate salt.

33. The oral pharmaceutical composition of claim 5, wherein the IR capsule has a dose strength of 5 mg trospium chloride.

34. The oral pharmaceutical composition of claim 5, wherein the IR capsule has a dose strength of 20 mg trospium chloride.

35. The oral pharmaceutical composition of claim 7, wherein the EC comprises a cellulose polymer.

36. The oral pharmaceutical composition of claim 35, wherein the cellulose polymer is selected from HPMCAC, HPMCAS and HPMC, or a mixture thereof.

37. The oral pharmaceutical composition of claim 36, wherein the cellulose polymer is HPMCAS-M.

38. The pharmaceutical composition of any one of claims 7 and 35 to 37, wherein the EC has a dose strength of 25 mg xanomeline as the tartrate salt.

39. The oral pharmaceutical composition of any one of claims 7 and 35 to 37, wherein the EC has a dose strength of 50 mg xanomeline as the tartrate salt.

40. The oral pharmaceutical composition of any one of claims 7 and 35 to 37, wherein the EC has a dose strength of 75 mg xanomeline as the tartrate salt.

41. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 20 mg xanomeline as the tartrate salt and 2 mg trospium chloride.

42. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 30 mg xanomeline as the tartrate salt and 3 mg trospium chloride.

43. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 50 mg xanomeline as the tartrate salt and 5 mg trospium chloride.

44. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 66.7 mg xanomeline as the tartrate salt and 6.67 mg trospium chloride.

45. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 14 mg xanomeline as the tartrate salt and 3 mg trospium chloride.

46. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 28 mg xanomeline as the tartrate salt and 6 mg trospium chloride.

47. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 42 mg xanomeline as the tartrate salt and 9 mg trospium chloride.

48. The oral pharmaceutical composition of claim 6, wherein the IR capsule has a dose strength of 56 mg xanomeline as the tartrate salt and 12 mg trospium chloride.

49. The oral pharmaceutical composition of any one of claims 7 and 35 to 37, wherein the EC has a dose strength of 14 mg xanomeline as the tartrate salt.

50. The oral pharmaceutical composition of any one of claims 7 and 35 to 37, wherein the EC has a dose strength of 28 mg xanomeline as the tartrate salt.

51. The oral pharmaceutical composition of any one of claims 2 to 50, wherein said pharmaceutical composition is administered to a patient once or twice daily.

52. The oral pharmaceutical composition of claim 51, wherein the xanomeline or a salt thereof is administered in an IR capsule and an EC capsule and the trospium salt is administered in one or more IR capsules twice daily.

53. The oral pharmaceutical composition of claim 52, wherein 25 mg of xanomeline as the tartrate salt is administered in an IR capsule, 25 mg of xanomeline as the tartrate salt is administered in an EC, and 20 mg of trospium chloride is administered in an IR capsule.

54. The oral pharmaceutical composition of claim 52, wherein 50 mg of xanomeline as the tartrate salt is administered in an IR capsule, 50 mg of xanomeline as the tartrate salt is administered in an EC capsule, and 20 mg of trospium chloride is administered in an IR capsule.

55. The oral pharmaceutical composition of claim 52, wherein 50 mg of xanomeline as the tartrate salt is administered in an IR capsule, 75 mg of xanomeline as the tartrate salt is administered in an EC capsule, and 30 mg of trospium chloride is administered in two 5 mg IR capsules and one 20 mg IR capsule.

56. The oral pharmaceutical composition of claim 52, wherein 50 mg of xanomeline as the tartrate salt is administered in an IR capsule, 75 mg of xanomeline as the tartrate salt is administered in an EC capsule, and 30 mg of trospium chloride is administered in two 5 mg IR capsules and one 20 mg IR capsule once daily.

57. The oral pharmaceutical composition of claim 52, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of xanomeline of about 10000 to 12000 pg / mL and a steady state geometric mean Cmax of trospium of 3000 to 4000 pg / mL.

58. The oral pharmaceutical composition of claim 57, wherein the geometric mean Cmax of xanomeline is between about 15% and about 40% lower than that of xanomeline produced by a similar dose of IR / IR pharmaceutical composition and the geometric mean Cmax of trospium is between about 5% to about 30% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

59. A method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising (1) an IR component comprising xanomeline or a salt thereof and a trospium salt; and (2) a MR component comprising xanomeline or a salt thereof.

60. The method of claim 59, wherein the disorder is selected from bipolar disorder, schizophrenia (optionally schizophrenia with cognitive impairment), schizoaffective disorder, cognitive impairment associated with schizophrenia, Alzheimer disease (optionally Alzheimer’s disease with psychosis, Alzheimer’s disease with agitation, and / or Alzheimer’s disease with cognitive impairment), autism, Parkinson’s disease, depression, dementia, movement disorders, pain, drug addiction, addictive disorder, tauopathy, Tourette syndrome, and synucleinopathy.

61. The method of claim 59 or 60, wherein the disease is selected from Alzheimer’s disease with agitation and Alzheimer’s disease with cognitive impairment.

62. The method of any one of claims 59 to 61, wherein the patient is 55 years or older.

63. The method of claim 62, wherein the patient is 65 years or older.

64. The method of any one of claims 59 to 63, wherein the pharmaceutical composition is administered to the patient once or twice daily.

65. The method of any one of claims 59 to 64, wherein the IR and the MR components of the pharmaceutical composition are administered simultaneously.

66. The method of any one of claims 59 to 65, further comprising orally administering to the patient an increased dose of xanomeline or the salt thereof and an increased dose of a trospium salt.

67. The method of any one of claims 59 to 66, wherein a total daily dose of xanomeline equivalent to between 25 and 250 mg of xanomeline as the tartrate salt and a total daily dose of trospium equivalent to between 5 and 30 mg of trospium chloride is administered to the patient.

68. The method of any one of claims 59 to 67, wherein 50% of the total daily dose of xanomeline or a salt is administered by the IR component and the other 50% by the MR component.

69. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 28 mg of xanomeline as the tartrate salt and 3 mg of a trospium salt thereof.

70. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 56 mg of xanomeline as the tartrate salt and 6 mg of a trospium salt thereof.

71. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 84 mg of xanomeline as the tartrate salt and 9 mg of a trospium salt thereof.

72. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 112 mg of xanomeline as the tartrate salt and 12 mg of a trospium salt.

73. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 140 mg of xanomeline as the tartrate salt and 15 mg of a trospium salt.

74. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 168 mg of xanomeline as the tartrate salt and 18 mg of a trospium salt.

75. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 196 mg of xanomeline as the tartrate salt and 21 mg of a trospium salt.

76. The method of any one of claims 59 to 68, wherein the dose is a total daily dose of 224 mg of xanomeline as the tartrate salt and 24 mg of a trospium salt.

77. A method of any one of claims 59 to 68, wherein the total daily dose of xanomeline is equivalent to about between 25 and 250 mg of xanomeline as the tartrate salt and the total daily dose of trospium is equivalent to about between 2.5 and 40 mg of trospium chloride.

78. The oral pharmaceutical composition of claim 3, wherein the IR component comprises a plurality of non-enteric-coated beads and the MR component comprises a plurality of enteric- coated beads.

79. The oral pharmaceutical composition of claim 78, wherein each of the non-enteric-coated beads comprises a sugar core, an active ingredient layer of xanomeline or a salt thereof or an active ingredient layer of a trospium salt separated by a seal coat layer.

80. The oral pharmaceutical composition of claim 78 or 79, wherein each of the non-enteric coated IR beads comprises:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and optionally one or more pharmaceutically acceptable carriers coated over said sugar core;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and optionally one or more pharmaceutically acceptable carriers coated over said active ingredient layer comprising xanomeline or a salt thereof; and(4) an active ingredient layer comprising a trospium salt and optionally one or more pharmaceutically acceptable carriers coated over said seal coat layer.

81. The oral pharmaceutical composition of claim 80, wherein the pharmaceutically acceptable carrier in (2) and (4) is a binder and an anti-tacking agent.

82. The oral pharmaceutical composition of claim 81, wherein the binder is Klucel® or Kollicoat®, and the anti-tacking agent is talc.

83. The oral pharmaceutical composition of any one of claims 80 to 82, wherein the seal coat in (3) comprises a polymer selected from the group consisting of HPMC E5 and the pharmaceutically acceptable carrier is talc.

84. The oral pharmaceutical composition of any one of claims 80 to 83, wherein the non- enteric-coated IR bead is prepared by a process comprising:(a) coating the sugar core with a suspension of xanomeline or a salt and a pharmaceutically acceptable carrier;(b) coating the xanomeline loaded sugar core of step (a) with a pharmaceutically acceptable seal coat polymer and a pharmaceutically acceptable carrier;(c) coating the seal coated xanomeline sugar core of step (b) with a trospium salt and a pharmaceutically acceptable carrier.

85. The oral pharmaceutical composition of claim 80, wherein the non-enteric-coated IR beads have a D50 particle size in a range from about 0.4 mm to about 1.1 mm.

86. The oral pharmaceutical composition of claim 85, wherein non-enteric-coated IR beads have a D50 particle size in a range from about 0.5 mm to about 0.6 mm.

87. The oral pharmaceutical composition of any one of claims 80 to 86, wherein the nonenteric-coated IR beads have a dissolution profile such that greater than 90% of trospium is released in 30 minutes in the buffer.

88. The oral pharmaceutical composition of any one of claims 80 to 87, where the nonenteric-coated IR bead comprises between 10 wt.% and 20 wt.% sugar core.

89. The oral pharmaceutical composition of any one of claims 80 to 88, where active ingredient layer (2) comprises between 30 wt.% and 60 wt.% xanomeline tartrate and between 5 wt.% and 15 wt.% Kollicoat® .

90. The oral pharmaceutical composition of any one of claims 80 to 89, where the seal coating layer comprises between 5 wt.% and 10 wt.% HPMC E5 and 1 wt.% and 7 wt.% talc.

91. The oral pharmaceutical composition of any one of claims 80 to 90, wherein the active ingredient layer (3) comprises between 3 wt.% and 20 wt.% trospium chloride and between 0.5 wt.% and 5 wt.% Kollicoat®.

92. The oral pharmaceutical composition of any one of claims 3 and 78, wherein the MR component comprises a plurality of enteric-coated xanomeline beads, each bead comprising(i) a sugar core;(ii) an active ingredient layer comprising xanomeline or a salt thereof, and optionally one or more pharmaceutically acceptable carriers coated over said sugar core;(iii) a seal coat layer comprising at least pharmaceutically acceptable polymer and optionally one or more pharmaceutically acceptable carriers coated over said active ingredient layer; and(iv) an enteric coating layer comprising an enteric coating polymer and optionally one or more pharmaceutically acceptable carriers.

93. The oral pharmaceutical composition of claim 92, wherein the pharmaceutically acceptable carrier in (ii) is selected from Klucel ®, Kollicoat®, and talc.

94. The oral pharmaceutical composition of claim 92 or 93, wherein the polymer in (iii) is HPMC E5 or Opadry® and the pharmaceutically acceptable carrier is talc.

95. The oral pharmaceutical composition of any one of claims 92 to 94, wherein the enteric coating polymer in (iv) is selected from the group consisting of Eudragit L100, Eudragit L100-55, and Eudragit S 100.

96. The oral pharmaceutical composition of any one of claims 92 to 95, wherein the enteric- coated xanomeline bead is prepared by a process comprising:(a) coating the sugar core with a suspension of xanomeline or a salt or a pharmaceutically acceptable carrier;(b) coating the xanomeline loaded sugar core of step (a) with at least one pharmaceutically acceptable seal coat polymer and at least one pharmaceutically acceptable carrier;(c) enteric coating the seal coated xanomeline sugar core of step (b) with a pharmaceutically acceptable enteric coat polymer; and(d) optionally, mixing the enteric-coated beads of xanomeline or a salt thereof with one or more pharmaceutically acceptable excipients.

97. The oral pharmaceutical composition of any one of claims 92 to 96, where the enteric- coated bead comprises between 10 wt.% and 20 wt.% sugar core.

98. The oral pharmaceutical composition of any one of claims 92 to 97, wherein the active ingredient layer comprising xanomeline (ii) comprises between 30 wt.% and 60 wt.% xanomeline tartrate, between 1 wt.% to 10 wt.% Klucel®, and between 1 wt.% and 5 wt.% talc.

99. The oral pharmaceutical composition of any one of claims 92 to 97, wherein the active ingredient layer comprising xanomeline (ii) comprises between 30 wt.% and 60 wt.% xanomeline tartrate, between 5 wt.% to 15 wt.% Kollicoat®.

100. The oral pharmaceutical composition of any one of claims 92 to 99, wherein the entericcoating layer comprises between 10 wt.% and 20 wt.% Eudragit L100-55, between 1 wt.% and 5 wt.% tri ethyl citrate, and between 5 wt.% and 15 wt.% talc.

101. The oral pharmaceutical composition of any one of claims 78 to 100, wherein the enteric- coated xanomeline bead has a D50 particle size in a range about 0.4 mm to about 1.25 mm.

102. The oral pharmaceutical composition of any one of claims 78 to 101, wherein the enteric- coated bead has a dissolution profile in which 30-65% of xanomeline or a salt thereof has lower than 10% release within 120 minutes during acid stage of dissolution and rapidly and / or completely released in 30-45 minutes in a solution buffered at pH 6.8.

103. The oral pharmaceutical composition of any one of claims 78 to 102, wherein the beads of the IR and MR components are encapsulated in one capsule.

104. The oral pharmaceutical composition of claim 103, having the dissolution profile of xanomeline tartrate and trospium chloride as shown in FIG. 6.

105. A coated xanomeline and trospium IR bead comprising:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and at least one pharmaceutically acceptable carrier coated over said sugar core;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable carrier coated over said active layer; and(4) an active ingredient layer comprising a trospium salt and at least one pharmaceutically acceptable carrier coated over said seal coat layer.

106. An enteric-coated xanomeline bead comprising:(1) a sugar core;(2) an active ingredient layer comprising xanomeline or a salt thereof, and at least one pharmaceutically acceptable carrier;(3) a seal coat layer comprising at least one pharmaceutically acceptable polymer and at least one pharmaceutically acceptable carrier; and(4) an enteric coating layer and at least one pharmaceutically acceptable carrier.

107. The method of claim 1, wherein the IR and MR components of xanomeline or a salt thereof releases at least two consecutive pulses of xanomeline or a salt thereof, each pulse separated in time by from about 0.5 to about 12 hours.

108. The method of claim 1 or 107, wherein the IR and MR components each independently comprises a plurality of beads.

109. The method of claim 108, wherein the beads of the IR component are IR xanomeline and trospium beads encapsulated in an IR capsule and the beads of the MR component are IR xanomeline beads encapsulated in an enteric capsule, optionally wherein the IR xanomeline beads are as defined in any one of claims 10 to 18, optionally wherein the IR trospium beads are as defined in any one of claims 19 to 29, optionally wherein the IR capsule is as defined in any one of claims 30 to 34, and 41 to 48, and / oroptionally wherein the enteric capsule is as defined in any one of claims 35 to 40, 49, and 50.

110. The method of claim 109, wherein the two capsules are taken simultaneously.

111. The method of claim 108, wherein the beads are a) a plurality of non-enteric-coated IR xanomeline and trospium beads and b) a plurality of enteric-coated MR xanomeline beads.

112. The method of claim 111, wherein the non-enteric-coated IR xanomeline and trospium beads and the enteric-coated MR xanomeline beads are encapsulated together in an IR capsule.

113. The method of any one of claims 1 and 107 to 112, wherein the disorder is selected from schizophrenia, autism, Alzheimer’s disease (optionally Alzheimer’s disease with agitation, and / or Alzheimer’s disease with cognitive impairment), bipolar disorder, dementia-related psychosis, Parkinson’s disease, depression, movement disorders, pain, drug addiction or addictive disorder, schizoaffective disorder, tauopathy, Tourette syndrome, and synucleinopathy.

114. A method of treating a muscarinic disorder in a patient in need thereof comprising administering to the patient a pharmaceutical composition, comprising:(1) an IR component comprising xanomeline or a salt thereof;(2) a MR component comprising xanomeline or a salt thereof; and(3) an IR component comprising a trospium salt, wherein the total daily dose of xanomeline is equivalent to about 25 - 250 mg of xanomeline as the tartrate salt and the total daily dose of trospium is equivalent to about 2.5 - 40 mg of trospium chloride.

115. The method of claim 114, wherein the in-vivo xanomeline plasma profile of the patient is characterized by a geometric mean Cmax at least 36% lower than the geometric mean Cmax produced by the IR / IR pharmaceutical composition.

116. The method of claim 115, wherein the in-vivo xanomeline plasma profile of the patient is characterized by a geometric mean Cmax at least 30% lower than the geometric mean Cmax produced by the IR / IR pharmaceutical composition.

117. The method of claim 116, wherein the in-vivo xanomeline plasma profile of the patient is characterized by a geometric mean Cmax at least 20% lower than the geometric mean Cmax produced by the IR / IR pharmaceutical composition.

118. The method of claim 117, wherein the in-vivo xanom eline plasma profile of the patient is characterized by a geometric mean Cmax at least 10% lower than the geometric mean Cmax produced by IR / IR pharmaceutical composition.

119. The oral pharmaceutical composition of claim 57, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of xanomeline of about 10000 to 12000 pg / mL120 The oral pharmaceutical composition of claim 119, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of xanomeline of about 11400 pg / mL.121 The oral pharmaceutical composition of claim 57, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of trospium of about 3000 to 4000 pg / mL.

122. The oral pharmaceutical composition of claim 121, wherein, when administered to a human subject, the oral pharmaceutical composition is sufficient to provide an in-vivo plasma profile comprising a steady state geometric mean Cmax of trospium of about 3750 pg / mL.

123. The method of claim 114, wherein the pharmaceutical composition reduces the occurrence of adverse events.

124. The method of claim 123, wherein the adverse event is selected from heart rate increase, orthostatic hypotension, dizziness, nausea, constipation, and tachycardia.

125. The oral pharmaceutical composition of claim 57, wherein the geometric mean Cmax of xanomeline is between about 10% and about 40% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.

126. The oral pharmaceutical composition of claim 125, wherein the geometric mean Cmax of xanomeline is at least 15% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.

127. The oral pharmaceutical composition of claim 125, wherein the geometric mean Cmax of xanomeline is at least 20% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.

128. The oral pharmaceutical composition of claim 125, wherein the geometric mean Cmax of xanomeline is at least 25% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.

129. The oral pharmaceutical composition of claim 125, wherein the geometric mean Cmax of xanomeline is at least 30% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.

130. The oral pharmaceutical composition of claim 125, wherein the geometric mean Cmax of xanomeline is at least 35% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.

131. The oral pharmaceutical composition of claim 125, wherein the geometric mean Cmax of xanomeline is at least 40% lower than that of xanomeline produced by a similar dose of the IR / IR pharmaceutical composition.

132. The oral pharmaceutical composition of claim 57, wherein the geometric mean Cmax of trospium is between about 5% to about 30% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

133. The oral pharmaceutical composition of claim 131, wherein the geometric mean Cmax of trospium is at least 10% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

134. The oral pharmaceutical composition of claim 131, wherein the geometric mean Cmax of trospium is at least 15% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

135. The oral pharmaceutical composition of claim 131, wherein the geometric mean Cmax of trospium is at least 20% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

136. The oral pharmaceutical composition of claim 131, wherein the geometric mean Cmax of trospium is at least 25% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

137. The oral pharmaceutical composition of claim 131, wherein the geometric mean Cmax of trospium is at least 30% lower than that of trospium produced by a similar dose of the IR / IR pharmaceutical composition.

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