Compositions and methods for treating disorders ameliorated by muscarinic receptor activation

Abstract

To provide a composition for treating a muscarinic disorder in a patient in need of treatment of the disorder.SOLUTION: An oral pharmaceutical composition comprises xanomeline and / or a salt thereof and trospium chloride, wherein, when administered to a patient in need of treatment of the disorder, the composition is sufficient to provide an in-vivo plasma profile comprising a median Tmax for xanomeline of 2 hours and a median Tmax for trospium of 1 hour.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 738,333, filed September 28, 2018, the disclosure of which is incorporated by reference in its entirety for all purposes.

[0002] The present disclosure relates to compositions and their application as pharmaceuticals for treating disorders ameliorated by activating muscarinic receptors in human or animal subjects. [Background technology]

[0003] Schizophrenia affects approximately 0.5-1% of the population. The disease is characterized by a range of symptoms, which can be divided into positive symptoms (e.g., hallucinations, delusional thinking, etc.), negative symptoms (e.g., social isolation, anhedonia, etc.), and cognitive symptoms (e.g., inability to process information, poor working memory, etc.). Patients with schizophrenia experience a significant decline in quality of life and are at increased risk of death due to many factors, including increased suicide rates. The cost of schizophrenia to society is high, as patients with schizophrenia are significantly more likely to be incarcerated, homeless, or unemployed.

[0004] Existing treatments for schizophrenia rely on dopamine and serotonin receptors, similar to the first antipsychotic drug, chlorpromazine, discovered in 1952. For over 60 years, the same basic pharmacology has been the standard of care for schizophrenia. Current antipsychotics are only effective against positive symptoms, leaving negative and cognitive symptoms untreated. Alzheimer's disease is another therapeutic area where developing new treatments has proven extremely challenging, with only a 0.4% success rate for molecules entering clinical development and receiving marketing approval. Patients in this area desperately need new treatments, but despite significant efforts by scientists and drug developers worldwide, development remains extremely challenging.

[0005] Activation of the muscarinic system via muscarinic agonists has the potential to treat several diseases, including schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, drug addiction, pain, and neurodegenerative disorders such as tauopathies and synucleinopathies. Muscarinic cholinergic receptors are G protein-coupled receptors with five distinct receptor subtypes (M1-M5), each of which is found in the CNS with distinct tissue distributions. The M1 and M4 subtypes are attractive therapeutic targets for various diseases. For example, the mood stabilizers lithium and valproate, used to treat bipolar depression, may exert their effects via the muscarinic system, particularly via the M4 subtype receptor. Genetic evidence directly links the muscarinic system to alcoholism.

[0006] In a double-blind, placebo-controlled study of schizophrenia patients treated with xanomeline, a muscarinic cholinergic receptor agonist with preferential activity at M1 and M4 subtype receptors, schizophrenia was alleviated. However, xanomeline also binds to muscarinic receptors outside the brain, resulting in numerous serious side effects, including GI side effects, cardiac side effects, and excessive salivation. Dose-limiting adverse events were problematic, resulting in very high discontinuation rates (including a 56% dropout rate in a 26-week study of Alzheimer's disease), ultimately leading to the halt of xanomeline development. Despite early promise, development of xanomeline stalled for over 15 years. Many companies have attempted and failed to develop muscarinic receptor agonists for CNS disorders that circumvent these intolerable side effects, but no such agonists have reached the market. Previous development efforts have typically focused on medicinal chemistry, developing more tolerable molecules by selecting for the M1 and M4 muscarinic receptor subtypes over the M2 and M3 muscarinic receptor subtypes. However, M1 and / or M4 activation outside the brain can still lead to muscarinic intolerance, and little progress has been made to alleviate the adverse effects of peripheral muscarinic receptor activation. Summary of the Invention [Problem to be solved by the invention]

[0007] There remains a need in the art for pharmaceutical compositions that increase the tolerability of xanomeline, particularly for treating cognitive and psychiatric disorders. The following embodiments and aspects thereof are described and illustrated using compositions and methods that are meant to be exemplary and illustrative, and not limiting in scope. In various embodiments, one or more of the problems discussed above are reduced or eliminated, while other embodiments are directed to other improvements. [Means for solving the problem]

[0008] Provided herein is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof, and a plurality of trospium beads comprising a salt of trospium.

[0009] In certain embodiments, the size of the xanomelin beads is between 0.425 mm and 1.18 mm. In certain embodiments, the size of the xanomelin beads is between 0.6 mm and 0.85 mm. In certain embodiments, the size of the trospium beads is between 0.425 mm and 1.18 mm. In certain embodiments, the size of the trospium beads is between 0.6 mm and 0.85 mm.

[0010] In certain embodiments, the xanomelin beads contain about 2.5 times the amount of xanomelin as the trospium beads contain trospium chloride.

[0011] In certain embodiments, the plurality of xanomeline and plurality of trospium beads have a dissolution rate of greater than about 95% within the first about 45 minutes after contact with the aqueous solution, hi certain embodiments, the dissolution rate of greater than about 95% occurs within the first about 20 minutes after contact with the aqueous solution.

[0012] In certain embodiments, the oral pharmaceutical composition provides a mean C of trospium of 7850±3360 pg / mL when administered to a patient at 20 mg trospium twice daily for at least 7 days.max In certain embodiments, the oral pharmaceutical composition provides a mean AUC of 41900±15500 h pg / mL when administered to a patient at 20 mg trospium twice daily for at least 7 days. 0-12 to provide.

[0013] In certain embodiments, the xanomeline salt is xanomeline tartrate. In certain embodiments, the xanomeline beads comprise 30% to 80% by weight of xanomeline tartrate, e.g., 66% by weight of xanomeline tartrate. In certain embodiments, the xanomeline beads comprise 15% to 65% by weight of microcrystalline cellulose, e.g., 33.5% by weight of microcrystalline cellulose. In certain embodiments, the xanomeline beads comprise 0% to 2% by weight of talc, e.g., 0.5% by weight of talc. In certain embodiments, the xanomeline beads comprise 30% to 80% by weight of xanomeline tartrate, 15% to 65% by weight of microcrystalline cellulose, and 0% to 2% by weight of talc. In a particular embodiment, the xanomeline beads comprise 66% by weight xanomeline tartrate, 33.5% by weight microcrystalline cellulose, and 0.5% by weight talc.

[0014] In certain embodiments, the trospium salt is trospium chloride. In certain embodiments, the trospium beads comprise 8% to 35% by weight of trospium chloride, e.g., 17.7% by weight of trospium chloride. In certain embodiments, the trospium beads comprise 25% to 80% by weight of microcrystalline cellulose, e.g., 46.8% by weight of microcrystalline cellulose. In certain embodiments, the trospium beads comprise 15% to 70% by weight of lactose monohydrate, e.g., 35% by weight of lactose monohydrate. In certain embodiments, the trospium beads comprise 0% to 2% by weight of talc, e.g., 0.5% by weight of talc. In certain embodiments, the trospium beads comprise 8% to 35% by weight of trospium chloride, 25% to 80% by weight of microcrystalline cellulose, 15% to 70% by weight of lactose monohydrate, and 0% to 2% by weight of talc. In a particular embodiment, the trospium beads comprise 17.7% by weight trospium chloride, 46.8% by weight microcrystalline cellulose, 35% by weight lactose monohydrate, and 0.5% by weight talc.

[0015] In certain embodiments, the oral pharmaceutical composition further comprises a capsule comprising a plurality of xanomeline beads and a plurality of trospium beads. In certain embodiments, the capsule has a dosage strength of 50 mg of xanomeline free base and 20 mg of trospium chloride. In certain embodiments, the capsule has a dosage strength of 50 mg of xanomeline free base and 10 mg of trospium chloride. In certain embodiments, the capsule has a dosage strength of 75 mg of xanomeline free base and 20 mg of trospium chloride. In certain embodiments, the capsule has a dosage strength of 75 mg of xanomeline free base and 10 mg of trospium chloride. In certain embodiments, the capsule has a dosage strength of 125 mg of xanomeline free base and 30 mg of trospium chloride. In certain embodiments, the capsule has a dosage strength of 125 mg of xanomeline free base and 40 mg of trospium chloride.

[0016] The disclosure also provides a dosage form comprising a plurality of xanomeline beads having a size of 0.425 mm to 1.18 mm and a core comprising 30% to 80% by weight of xanomeline tartrate, 15% to 65% by weight of microcrystalline cellulose, and 0.2% to 2% by weight of talc; and a plurality of trospium beads having a size of 0.425 mm to 1.18 mm and a core comprising 8% to 35% by weight of trospium, 25% to 80% by weight of microcrystalline cellulose, 15% to 70% by weight of lactose monohydrate, and 0.2% to 2% by weight of talc, wherein the plurality of xanomeline and the plurality of trospium beads have a dissolution rate of greater than about 95% within the first about 45 minutes after placing the dosage form in an aqueous solution, and a mean C of trospium of 7850±3360 pg / mL when 20 mg of trospium is administered to a patient twice daily for at least 7 days. max , and a mean AUC of 41,900 ± 15,500 pg / mL over time. 0-12 An oral pharmaceutical A composition is provided.

[0017] The present disclosure also provides an oral pharmaceutical composition comprising a capsule including a plurality of xanomeline beads and a plurality of trospium beads, wherein the plurality of xanomeline beads have a size of 0.6 mm to 0.85 mm and a core comprising 66% by weight xanomeline tartrate, 33.5% by weight microcrystalline cellulose, and 0.5% by weight talc, and the plurality of trospium beads have a size of 0.6 mm to 0.85 mm and a core comprising 17.7% by weight trospium chloride, 46.8% by weight microcrystalline cellulose, 35% by weight lactose monohydrate, and 0.5% by weight talc, wherein the plurality of xanomeline and the plurality of trospium beads have a dissolution rate of greater than about 95% within about the first 20 minutes after placing the dosage form in an aqueous solution, and wherein the dosage form has a mean C of 7850±3360 pg / mL of trospium when administered to a patient at 20 mg of trospium twice daily for at least 7 days. max and mean AUC of 41,900 ± 15,500 pg / mL. 0-12 to provide.

[0018] Additionally provided is a method of activating muscarinic receptors in a biological sample comprising contacting the biological sample with any of the oral pharmaceutical compositions described herein.

[0019] Also provided is a method for treating a disorder ameliorated by activating muscarinic receptors in a subject in need of such treatment, comprising administering any of the oral pharmaceutical compositions described herein to a patient in need of such treatment. In certain embodiments, the subject is a human. In certain aspects, the disorder is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy.

[0020] Further provided is a method of treating a disorder ameliorated by activating muscarinic receptors in a subject in need thereof, comprising the sequential or simultaneous administration of any oral pharmaceutical composition described herein; and a second therapeutic agent.

[0021] The present disclosure also provides an oral pharmaceutical composition comprising xanomeline and / or a salt thereof and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium. Also provided is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium; and a plurality of trospium beads comprising a salt of trospium.

[0022] The present invention further provides an oral pharmaceutical composition comprising xanomeline and / or a salt thereof and trospium chloride for treating a muscarinic disorder in a subject in need thereof, wherein the composition, when administered to a subject in need thereof, reduces the median T for xanomeline at 2 hours. max and median T for trospium at 1 hour maxIn certain embodiments, the in vivo plasma profile comprises a mean dose-normalized C of 48.5 to 121.3 pg / mL / mg. max , and mean dose-normalized C of trospium of 156–375 pg / mL / mg. max In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC of xanomeline of 263 to 577 pg / mL / mg. 0-12 , and mean dose-normalized AUC of trospium from 881 to 2024 pg / mL / mg 0-12 Further includes:

[0023] Further aspects and advantages will become apparent to those skilled in the art upon review of the following detailed description. While the dosage forms, methods of making, and methods of treatment are susceptible to embodiment in various forms, the following description includes specific embodiments, with the understanding that the disclosure is illustrative and is not intended to limit the disclosure to the specific embodiments described herein.

[0024] The present disclosure will be readily understood by the following detailed description taken in conjunction with the accompanying drawings, in which like reference numerals indicate like structural elements, and in which: The drawings provide exemplary embodiments or aspects of the present disclosure and are not intended to limit the scope of the disclosure. [Brief explanation of the drawings]

[0025] [Figure 1] 1 shows the stability schedule and protocol for xanomeline / trospium capsules. [Figure 2] 1 is a scanning electron microscope (SEM) image of xanomeline tartrate 66% beads at 30× magnification showing that the beads are the 0.6 mm to 0.85 mm size used in xanomeline / trospium capsules. [Figure 3] FIG. 10 is an SEM image of trospium chloride 17.7% beads at 30× magnification showing that the beads are the 0.6 mm to 0.85 mm size used in xanomeline / trospium capsules. [Figure 4]Dissolution profiles of 50 / 20 mg capsules containing xanomeline / trospium Cl, xanomeline beads, and trospium Cl beads measured at 0, 1, 2, 3, and 6 months after storage at 40°C / 75% RH, and at 3 months after storage at 25°C / 60% RH. [Figure 5] Dissolution profiles of 50 / 10 mg capsules containing xanomeline / trospium Cl, xanomeline beads, and trospium Cl beads measured at 0, 1, 2, and 3 months after storage at 40°C / 75% RH, and at 3 months after storage at 25°C / 60% RH. [Figure 6] 1 shows stability data for xanomeline / trospium Cl, 50 / 10 mg capsules stored at 25° C. / 60% RH and measured at 0, 3 months, 6 months, and 9 months. [Figure 7] 1 shows stability data for xanomeline / trospium Cl, 50 / 10 mg capsules stored at 30° C. / 65% RH and measured at 0, 3 months, and 6 months. [Figure 8] 1 shows stability data for xanomeline / trospium Cl, 50 / 10 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 9] Dissolution of xanomeline / trospium Cl, 50 / 10 mg capsules stored at 25° C. / 60% RH measured at 0, 3, 6, and 9 months. [Figure 10] 10 is the dissolution profile of xanomeline / trospium Cl, 50 / 10 mg capsules stored at 30° C. / 65% RH and measured at 0, 3 months, and 6 months. [Figure 11] 10 is the dissolution profile of xanomeline / trospium Cl, 50 / 10 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 12] Figure 1 shows the xanomeline active pharmaceutical ingredient-related substance profile measured at 0, 3, 6, and 9 months for xanomeline / trospium Cl 50 / 10 mg capsules. [Figure 13] Trospium chloride active pharmaceutical ingredient-related substance profile measured at 0, 3, 6, and 9 months for xanomeline / trospium Cl 50 / 10 mg capsules. [Figure 14] The specifications are for xanomeline / trospium Cl 50 / 10 mg capsules. [Figure 15] 1 shows stability data for xanomeline / trospium Cl, 50 / 20 mg capsules stored at 25° C. / 60% RH and measured at 0, 3 months, and 6 months. [Figure 16] 1 shows stability data for xanomeline / trospium Cl, 50 / 20 mg capsules stored at 30° C. / 65% RH and measured at 0 and 6 months. [Figure 17] 1 shows stability data for xanomeline / trospium Cl, 50 / 20 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 18] Dissolution of xanomeline / trospium Cl, 50 / 20 mg capsules stored at 25° C. / 60% RH measured at 0, 3, 6, and 9 months. [Figure 19] Dissolution profile of xanomeline / trospium Cl, 50 / 20 mg capsules stored at 30° C. / 65% RH and measured at 0 and 6 months. [Figure 20] 10 is the dissolution profile of xanomeline / trospium Cl, 50 / 20 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 21] Figure 1 shows the xanomeline active pharmaceutical ingredient-related substance profile measured at 0, 3, and 6 months for xanomeline / trospium Cl 50 / 20 mg capsules. [Figure 22] Trospium chloride active pharmaceutical ingredient-related substance profile measured at 0, 3, and 6 months for xanomeline / trospium Cl 50 / 20 mg capsules. [Figure 23]The specifications are for xanomeline / trospium Cl 50 / 20 mg capsules. [Figure 24] 1 shows stability data for xanomeline / trospium Cl, 75 / 10 mg capsules stored at 25° C. / 60% RH and measured at 0, 3 months, and 6 months. [Figure 25] 1 shows stability data for xanomeline / trospium Cl, 75 / 10 mg capsules stored at 30° C. / 65% RH and measured at 0 and 6 months. [Figure 26] 1 shows stability data for xanomeline / trospium Cl, 75 / 10 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 27] Dissolution of xanomeline / trospium Cl, 75 / 10 mg capsules stored at 25° C. / 60% RH measured at 0, 3, and 6 months. [Figure 28] Dissolution profile of xanomeline / trospium Cl, 75 / 10 mg capsules stored at 30° C. / 65% RH and measured at 0 and 6 months. [Figure 29] 10 is the dissolution profile of xanomeline / trospium Cl, 75 / 10 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 30] Xanomeline active pharmaceutical ingredient-related substance profile measured at 0, 3, and 6 months for xanomeline / trospium Cl 75 / 10 mg capsules. [Figure 31] Trospium chloride active pharmaceutical ingredient-related substance profile measured at 0, 3, and 6 months for xanomeline / trospium Cl 75 / 10 mg capsules. [Figure 32] The specifications are for xanomeline / trospium Cl 75 / 10 mg capsules. [Figure 33] Dissolution of xanomeline / trospium Cl, 75 / 20 mg capsules stored at 25° C. / 60% RH measured at 0, 3, and 6 months. [Figure 34] Dissolution of xanomeline / trospium Cl, 75 / 20 mg capsules stored at 30° C. / 65% RH and measured at time 0 and 6 months. [Figure 35] 1 shows stability data for xanomeline / trospium Cl, 75 / 20 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 36] Dissolution of xanomeline / trospium Cl, 75 / 20 mg capsules stored at 25° C. / 60% RH measured at 0, 3, and 6 months. [Figure 37] Dissolution profile of xanomeline / trospium Cl, 75 / 20 mg capsules stored at 30° C. / 65% RH and measured at 0 and 6 months. [Figure 38] 10 is the dissolution profile of xanomeline / trospium Cl, 75 / 20 mg capsules stored at 40° C. / 75% RH and measured at 0, 3, and 6 months. [Figure 39] Xanomeline active pharmaceutical ingredient-related substance profile measured at 0, 3, and 6 months for xanomeline / trospium Cl 75 / 20 mg capsules. [Figure 40] Trospium chloride active pharmaceutical ingredient-related substance profile measured at 0, 3, and 6 months for xanomeline / trospium Cl 75 / 20 mg capsules. [Figure 41] The specifications are for xanomeline / trospium Cl 75 / 20 mg capsules. [Figure 42] 1 shows the mean (±standard deviation) xanomeline pharmacokinetic concentrations on day 1 when treated twice daily with KarXT 50 / 20 for all cohorts in the KAR-003 pharmacokinetic population. [Figure 43] 1 shows the mean (±standard deviation) xanomeline pharmacokinetic concentrations by treatment on day 3 when treated twice daily with KarXT 50 / 20 for all cohorts in the KAR-003 pharmacokinetic population. [Figure 44]1 shows the mean (±standard deviation) xanomeline pharmacokinetic concentrations by treatment on day 7 for the entire cohort of the KAR-003 pharmacokinetic population when treated twice daily with KarXT 50 / 20. [Figure 45] 1 shows the mean (±standard deviation) xanomeline pharmacokinetic concentrations by treatment and visit for the KAR-003 pharmacokinetic population. [Figure 46] 1 shows the mean (±standard deviation) xanomeline pharmacokinetic trough concentrations by treatment for the KAR-003 pharmacokinetic population. [Figure 47] 1 shows the mean (±standard deviation) trospium pharmacokinetic concentrations on Day 1 when treated with KarXT 50 / 20 twice daily for the entire cohort of the KAR-003 pharmacokinetic population. [Figure 48] 1 shows the mean (±standard deviation) trospium pharmacokinetic concentrations by treatment on Day 3 for the KAR-003 pharmacokinetic population. [Figure 49] 1 shows the mean (±standard deviation) trospium pharmacokinetic concentrations by treatment on Day 7 for the KAR-003 pharmacokinetic population. [Figure 50] Mean (±standard deviation) trospium pharmacokinetic concentrations by treatment and visit for the KAR-003 pharmacokinetic population are shown. [Figure 51] Mean (±standard deviation) trospium pharmacokinetic trough concentrations by treatment and visit for the KAR-003 pharmacokinetic population are shown. DETAILED DESCRIPTION OF THE INVENTION

[0026] The articles "a" and "an" refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. For example, "an element" means one element or more than one element.

[0027] The terms "comprise" and "comprising" are inclusive and open, meaning that additional elements may be included.

[0028] The term "consisting of" limits the elements to those specified, excluding impurities normally associated with the elements.

[0029] The term "consisting essentially of" limits the elements to those specified and to those that do not materially affect the basic and novel characteristics of the material or process.

[0030] All ranges described herein include all possible subsets of ranges and any combination of such subset ranges. By default, ranges are inclusive of the stated endpoints unless otherwise specified. When a range of values is provided, each intervening value between the upper and lower limits of that range, and any other stated or intervening value within that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in those smaller ranges and are also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. When a stated range includes one or both limits, ranges excluding either or both of those included limits are also considered to be part of the disclosure.

[0031] The term "wt. %" refers to weight percent based on the total weight of, for example, the core, or the enteric coating, or the total beads, as the context dictates. Unless otherwise specified, wt. % is intended to describe weight percent based on dry weight (e.g., for the core after drying).

[0032] The term "controlled release" is defined as a prolonged release pattern of one or more drugs, such that the drug is released over a period of time. Controlled-release formulations have release kinetics that result in measurable serum levels of the drug for a longer period of time than is possible after intravenous injection or administration of an immediate-release oral dosage form. Controlled release, sustained release, sustained release, extended release, prolonged release, and delayed release have the same definition herein.

[0033] The term "including" means "including, but not limited to." "Including" and "including but not limited to" are used interchangeably.

[0034] The term "mammal" is known in the art. Exemplary mammals include humans, primates, cows, pigs, dogs, cats, and rodents (e.g., mice and rats).

[0035] The terms "parenteral administration" and "parenterally administered" are art-recognized and refer to modes of administration other than enteral and topical administration, usually by injection. These modes include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion.

[0036] A "patient," "subject," or "host" treated by the present method means either a human or non-human mammal.

[0037] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which is involved in carrying or transporting any subject composition or its components from one organ or body part to another. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components, and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; phosphate buffers; and other non-toxic compatible substances used in pharmaceutical formulations.

[0038] The term "pharmaceutically acceptable salts" is art-recognized and refers to salts prepared from relatively non-toxic acids or bases, including inorganic and organic acids and bases, including, for example, those contained in the compositions of the present disclosure. Suitable non-toxic acids include inorganic and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid.

[0039] The term "treating" is art-recognized and refers to curing and ameliorating at least one symptom of any condition or disorder.

[0040] In jurisdictions that prohibit patents on methods administered to the human body, the meaning of "administering" a composition to a human subject shall be limited to prescribing a controlled substance that the human subject self-administers by any technique (e.g., orally, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation consistent with the statute or regulation defining patentable subject matter is intended. In jurisdictions that do not prohibit patents on methods administered to the human body, "administering" a composition includes both the method administered to the human body and the aforementioned activities.

[0041] The term "therapeutic agent" is art-recognized and refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that acts locally or systemically in a subject. Examples of therapeutic agents, also referred to as "drugs," are described in well-known literature references such as the Merck Index (14th ed.), the Physicians' Desk Reference (64th ed.), and The Pharmacological Basis of Therapeutics (12th ed.). These therapeutic agents include, but are not limited to, pharmaceuticals; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure, or mitigate disease or illness; substances that affect the structure or function of the body; or prodrugs that become biologically active or more active after being placed in a physiological environment.

[0042] The term "psychotherapy" refers to non-pharmacological therapies in which practitioners use a variety of techniques, including verbal and other interactions with patients, to affect positive therapeutic outcomes. These techniques include, but are not limited to, behavioral therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, occupational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also known as person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavior therapy, reality therapy, response-based therapy, sandplay therapy, status dynamics therapy, hypnosis, and validation therapy. Psychotherapy may involve combining two or more approaches. Therapists can select and tailor techniques based on the individual patient's needs and responses.

[0043] The term "muscarinic disorder" refers to any disease or condition that is ameliorated by activating the muscarinic system, including those in which direct activation of the muscarinic receptor itself or inhibition of the cholinesterase enzyme has a therapeutic effect.

[0044] The terms "schizophrenia-related disease" and "schizophrenia-related disorder" include, but are not limited to, schizoaffective disorder, psychosis, delusional disorder, psychosis associated with Alzheimer's disease, psychosis associated with Parkinson's disease, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's disease, dementia with Lewy bodies, or any other disease with psychotic features.

[0045] The term "movement disorder" includes, but is not limited to, Gilles-de-la-Tourette syndrome, Friedreich's ataxia, Huntington's chorea, restless legs syndrome, and other diseases or disorders whose symptoms include excessive movements, ticks, and convulsions.

[0046] The term "mood disorders" includes major depressive disorder, dysthymia, recurrent brief depression, minor depressive disorder, bipolar disorder, mania and anxiety.

[0047] The term "cognitive disorder" refers to a disease or disorder characterized by cognitive deficits (e.g., having abnormal working memory, problem-solving ability, etc.). Diseases include, but are not limited to, Alzheimer's disease, Parkinson's disease, dementia (including, but not limited to, AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies, and idiopathic dementia), Pick's disease, tauopathy, synucleinopathy, cognitive deficits associated with confusion, fatigue, learning disabilities, traumatic brain injury, autism, age-related cognitive decline, and Cushing's disease, a cognitive disorder associated with autoimmune diseases.

[0048] The term "attention deficit" refers to diseases or conditions characterized by an abnormal or reduced attention span, including, but not limited to, attention deficit hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz syndrome, FG syndrome, Down syndrome, insulin-like growth factor I (IGF1) deficiency growth retardation, hepatic encephalopathy syndrome, and Strauss syndrome.

[0049] The term "addictive disorder" refers to a disease or condition characterized by addiction or substance dependence as defined by the Diagnostic & Statistical Manual V (DSM-5). Such disorders are characterized by physical dependence, withdrawal, and tolerance to the substance. Such substances include, but are not limited to, alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, and cannabis. Addictive disorders also encompass behaviors that patients engage in compulsively or persistently despite apparent negative consequences. For example, lurdomania (gambling addiction, or compulsive gambling) is recognized by those skilled in the art as an addictive behavior that often has destructive consequences. In certain embodiments, the addictive behavior may be internet gaming disorder (gaming addiction) as defined by DSM-5.

[0050] The term "pain" refers to physical pain or discomfort caused by disease or injury. Pain is a subjective experience, and pain perception occurs in parts of the central nervous system (CNS). Although noxious (peripheral) stimuli are usually pre-transmitted to the CNS, pain is not necessarily associated with nociception. There are many different types of clinical pain that result from different underlying pathophysiological mechanisms and require different treatment approaches. Three main types of clinical pain have been characterized: acute pain, chronic pain, and neuropathic pain.

[0051] Acute clinical pain can result from, for example, inflammation or soft tissue injury. This type of pain has an adaptive and biologically relevant warning function, allowing the healing and repair of already damaged body parts to occur unhindered. The protective function is achieved by making the damaged or inflamed area and surrounding tissues hypersensitive to all stimuli so that contact with any external stimuli can be avoided. The neural mechanisms underlying this type of clinical pain are well understood, and pharmacological control of acute clinical pain is available and effective, for example, by nonsteroidal anti-inflammatory drugs (NSAIDs) up to opioids, depending on the type and degree of pain sensation.

[0052] Chronic clinical pain may manifest as persistent paresthesia due to ongoing peripheral pathology such as cancer or chronic inflammation (e.g., arthritis), or may be unrelated to such an initiating trigger. Chronic pain unrelated to an initiating trigger is maladaptive, confers no survival advantage, and very often has no effective treatment.

[0053] Neuropathic pain can be classified as peripheral or central. Peripheral neuropathic pain is caused by damage or infection of peripheral sensory nerves, while central neuropathic pain is caused by damage to the CNS and / or spinal cord. Both peripheral and central neuropathic pain can occur without obvious initial nerve damage.

[0054] The term "activator" refers to 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 directly or indirectly increases receptor activity or signaling.

[0055] The term "inhibitor" refers to a molecule described as an antagonist, partial antagonist, competitive antagonist, noncompetitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist, or a molecule that directly or indirectly decreases receptor activity or signaling.

[0056] The term "maximum tolerated dose" means the highest dose of a drug or therapeutic agent that a patient can take without experiencing intolerable side effects. The maximum tolerated dose is typically determined empirically in clinical trials.

[0057] The term "muscarinic receptor" refers to a G protein-coupled receptor that binds to the neurotransmitter acetylcholine. To date, five subtypes of muscarinic receptors have been identified: "M1" refers to one muscarinic receptor subtype; "M2" refers to two muscarinic receptor subtypes; "M3" refers to three muscarinic receptor subtypes; "M4" refers to four muscarinic receptor subtypes; and "M5" refers to five muscarinic receptor subtypes.

[0058] The term "antipsychotic" refers to a drug that reduces psychosis, hallucinations, or delusions. Antipsychotic drugs include, but are not limited to, haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, pericyazine, promazine, triflupromazine, levomepromazine, promethazine, pimozide, chlorprothixene, flupentixol, thiothixene, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetrabenazine.

[0059] The term "anti-anxiety drug" refers to a drug that reduces anxiety, fear, panic, or related feelings. Such drugs include, but are not limited to, benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbitol), and hydroxyzine.

[0060] The term "antidepressant" refers to a drug that relieves depression and related conditions (e.g., dysthymia). Such drugs include selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipran, venlafaxine), mianserin, mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine, maloquito steroids, methadone ... antidepressants (e.g., zindol, 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).

[0061] The term "sedative" or "tranquilizer" refers to a drug that induces somnolence, promotes a feeling of tiredness or a desire to sleep, or promotes a state of unconsciousness. Such drugs include, but are not limited to, benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbitol), eszopiclone, zaleplon, zolpidem, and zopiclone.

[0062] Pharmaceutical Composition Early development of the muscarinic receptor agonist xanomeline as a monotherapy was discontinued due to peripheral cholinergic side effects. The present disclosure provides dosage forms with more effective therapeutic effects for both active ingredients, enhanced pharmacokinetics for trospium chloride, and dissolution kinetics with higher administration compliance. The present disclosure also provides dosage forms with two active substances of different strengths and / or different ratios.

[0063] Provided herein is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and a plurality of trospium beads comprising a salt of trospium. In certain embodiments, the plurality of xanomeline beads has a core comprising xanomeline or a salt thereof. In certain embodiments, the plurality of trospium beads has a core comprising a trospium salt.

[0064] In certain embodiments, a capsule shell comprising hydroxypropyl methylcellulose (HPMC) containing a discrete population of drug beads comprising xanomeline tartrate or trospium chloride, where the drug beads are of comparable size and release the active agent rapidly and at substantially similar rates. Following dissolution of the capsule shell in the stomach, the drug beads can dissolve in the stomach and / or pass through the pyloric valve into the duodenum intact or partially intact, while the ratio of the two drugs in both dissolved and undissolved forms remains relatively constant in the gastrointestinal tract until the drugs are absorbed.

[0065] The formulation for each drug bead is selected so that the active agent is released into serum at a substantially similar rate and / or has a substantially similar T max This allows for substantially similar performance from the two active substances at different dose ranges. In a specific embodiment, the capsule contains 50 mg of xanomeline as the tartrate salt and 10 mg of trospium chloride. Because 50 mg of xanomeline as the free base is equivalent to approximately 76 mg of xanomeline tartrate, the active ingredient ratio in such a formulation is approximately 7.6 to 1.

[0066] The discrepancy in the number of drug beads in the capsule increases the likelihood that the ratio of drug beads will not remain substantially constant after the beads are released and dispersed. Thus, in certain embodiments, trospium beads are formulated with a lower drug load so that the effective doses of trospium and xanomeline are contained in approximately the same number of beads. In certain embodiments, despite the difference in drug load, the trospium beads and xanomeline beads release at approximately the same rate. For example, when capsule dissolution is assessed using a United States Pharmacopeia (USP) dissolution apparatus, the percentage of dissolved xanomeline is substantially equal to the percentage of dissolved trospium chloride, e.g., at 10 minutes, 20 minutes, or 30 minutes.

[0067] The medicament may also include one or more pharmaceutically acceptable salts. The medicament may include one or more pharmaceutically acceptable carriers. The medicament can be administered orally. The medicament can be delivered orally using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, caplets, or gel caps, and other oral administration methods known to those skilled in the art.

[0068] The medicament may be in a dosage form that immediately releases the drug. In an alternative embodiment, the medicament may have a controlled release dosage form.

[0069] The drug may also be formulated using other methods of controlled release formulation known to those skilled in the art.

[0070] In another embodiment, the drug is combined with one or more therapies, including psychotherapy and medication. Therapeutic agents include, but are not limited to, antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers, analgesics, and other pharmacological interventions known to those skilled in the art. Therapeutic agents may be classified into more than one drug category. For example, benzodiazepines may be considered anxiolytics, sedatives, and tranquilizers.

[0071] Bead / Core Excipients The beads and / or cores may contain one or more excipients. In one embodiment, the excipients include one or more fillers, binders, and surfactants. Other optional ingredients include, but are not limited to, glidants, lubricants, disintegrants, swelling agents, and antioxidants. Xanomeline or a pharmaceutically acceptable salt thereof and a trospium salt may be in separate matrices within the same dosage form.

[0072] The amount of xanomeline free base in the core can be at least 10%, or at least 15%, or at least 20%, or at least 25%, or at least 30% by weight. For example, the amount of xanomeline tartrate can be at least 50%, or at least 55%, or at least 60%, or at least 65%, or at least 70%, or at least 75%, or at least 80%, or at least 85% by weight of the core, e.g., in the range of about 60% to about 90%, or about 65% to about 85% by weight. It is understood that all ranges including these values as endpoints are contemplated, e.g., at least about 15% to about 90%, about 20% to about 85%, about 30% to about 85%, or about 50% to about 90% by weight. In certain embodiments, the xanomeline beads comprise 30% to 80% xanomeline tartrate by weight, for example, 66% xanomeline tartrate by weight.

[0073] The amount of trospium salt in the core can be at least 10% by weight, or at least 15% by weight, or at least 20% by weight, or at least 25% by weight, or at least 30% by weight. For example, the amount of trospium chloride can be at least 50% by weight, or at least 55% by weight, or at least 60% by weight, or at least 65% by weight, or at least 70% by weight, or at least 75% by weight, or at least 80% by weight, or at least 85% by weight, such as from about 60% to about 90% by weight, or from about 65% to about 85% by weight. It is understood that all ranges inclusive of these endpoints are contemplated, such as at least about 15% to about 90% by weight, from about 20% to about 85% by weight, from about 30% to about 85% by weight, or from about 50% to about 90% by weight. In certain embodiments, the trospium is trospium chloride. In certain embodiments, the trospium beads comprise between 8% and 35% trospium chloride by weight, for example 17.7% trospium chloride by weight.

[0074] In a further embodiment, the matrix comprises a polymer, for example, to modify the release profile of the active agent in the matrix. In a further embodiment, the polymer comprises a water-soluble polymer. In a further embodiment, the water-soluble polymer is selected from Eudragit™ RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyethylene glycol, and mixtures thereof. In a further embodiment, the polymer comprises a water-insoluble polymer. In further embodiments, the water-insoluble polymer is selected from Eudragit® RS, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene) high density, poly(propylene), poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and mixtures thereof.

[0075] Fillers include, but are not limited to, lactose, sucrose, glucose, starch, microcrystalline cellulose, fine cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate, amorphous silica, and sodium chloride, starch, and dibasic calcium phosphate dihydrate. In one embodiment, the filler is not water-soluble but can absorb water. In one embodiment, the filler is a spheronization aid. Spheronization aids can include one or more of crospovidone, carrageenan, chitosan, pectic acid, glycerides, β-cyclodextrin (β-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide. In one embodiment, the filler comprises microcrystalline cellulose.

[0076] The amount of filler in the xanomelin core is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose) can range from about 10% to about 70% by weight, or from about 16% to about 23% by weight, or at least 19% or at least 19.5% by weight, for example, about 20% by weight. In certain embodiments, the xanomelin beads contain 15% to 65% by weight, e.g., about 15% to 20% by weight, about 20% to 25% by weight, about 25% to 30% by weight, about 30% to 35% by weight, about 35% to 40% by weight, about 40% to 45% by weight, about 45% to 50% by weight, about 50% to 55% by weight, about 55% to 60% by weight, or about 60% to 65% by weight. In certain embodiments, the xanomelin beads contain 33.5% by weight of microcrystalline cellulose.

[0077] The amount of filler in the trospium core is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose or lactose) can be in the range of about 10% to about 80% by weight, or about 16% to about 23% by weight, or at least 19% or at least 19.5% by weight, e.g., about 20% by weight. In certain embodiments, the trospium beads contain 25% to 80% by weight, e.g., about 25% to 30% by weight, about 30% to 35% by weight, about 35% to 40% by weight, about 40% to 45% by weight, about 45% to 50% by weight, about 50% to 55% by weight, about 55% to 60% by weight, about 60% to 65% by weight, about 65% to 70% by weight, about 70% to 75% by weight, or about 75% to 80% by weight of microcrystalline cellulose. In a particular embodiment, the trospium beads comprise 46.8% by weight microcrystalline cellulose.

[0078] In certain embodiments, the trospium beads comprise 15% to 70% by weight of lactose monohydrate, e.g., about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, or about 65% to 70%. In certain embodiments, the trospium beads comprise 35% by weight of lactose monohydrate.

[0079] Binders include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose (hypromellose, e.g., hypromellose 2910, Methocel™ E), carboxymethylcellulose, starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinylpyrrolidone (povidone), cross-linked polyvinylpyrrolidone, sodium alginate, microcrystalline cellulose, and lower alkyl-substituted hydroxypropylcellulose. In one embodiment, the binder is selected from wet binders. In one embodiment, the binder is selected from cellulose ethers, such as hypromellose.

[0080] The amount of binder in the xanomelin core is not particularly limited. In embodiments, the amount of binder (e.g., hypromellose) can be in the range of about 1% to about 10% by weight, about 2% to about 8% by weight, or about 4% to about 6% by weight, for example, about 5% by weight.

[0081] The amount of binder in the trospium core is not particularly limited. In an embodiment, the amount of binder (e.g., hypromellose) may be in the range of about 1% to about 10% by weight, about 2% to about 8% by weight, or about 4% to about 6% by weight, for example, about 5% by weight.

[0082] Surfactants include, but are not limited to, anionic surfactants including sodium lauryl sulfate, sodium deoxycholate, dioctyl sodium sulfosuccinate, and sodium stearyl fumarate, nonionic surfactants including polyoxyethylene ethers and polysorbate 80, and cationic surfactants including quaternary ammonium compounds. In one embodiment, the surfactant is selected from anionic surfactants, such as sodium lauryl sulfate.

[0083] The amount of surfactant, e.g., a processing aid, in the xanomelin core is not particularly limited. In embodiments, the amount of surfactant (e.g., microcrystalline cellulose) can be in the range of about 0.1% to about 1% by weight, about 0.2% to about 0.8% by weight, or about 0.4% to about 0.6% by weight, e.g., about 0.5% by weight.

[0084] The amount of surfactant, e.g., as a processing aid, in the trospium core is not particularly limited. In embodiments, the amount of surfactant (e.g., sodium lauryl sulfate) can be in the range of about 0.1% to about 1% by weight, about 0.2% to about 0.8% by weight, or about 0.4% to about 0.6% by weight, e.g., about 0.5% by weight.

[0085] Disintegrants include, but are not limited to, starch, sodium cross-linked carboxymethylcellulose, carmellose sodium, carmellose calcium, cross-linked polyvinylpyrrolidone, and sodium starch glycolate, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch.

[0086] Glidants include, but are not limited to, polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silicon dioxide, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetyl alcohol, stearol, and talc.

[0087] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and silicone-treated talc. In certain embodiments, xanomeline beads contain 0% to 2% by weight of talc, e.g., 0.5% by weight. In certain embodiments, trospium beads contain 0% to 2% by weight of talc, e.g., 0.5% by weight.

[0088] 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, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid. In certain embodiments, the formulation comprises less than 1% by weight of an antioxidant, e.g., 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, or 0.01% by weight. In certain embodiments, the formulation comprises about 0.05% by weight of BHT or 0.5% by weight of ascorbic acid. In certain embodiments, the antioxidant is present in the xanomelin core or xanomelin beads.

[0089] In certain embodiments, the xanomeline beads comprise 30% to 80% by weight of xanomeline tartrate, 15% to 65% by weight of microcrystalline cellulose, and 0% to 2% by weight of talc. In certain embodiments, the trospium beads comprise 0.2% to 2% by weight of talc, e.g., 0.5% by weight of talc. In certain embodiments, the trospium beads comprise 8% to 35% by weight of trospium chloride, 25% to 80% by weight of microcrystalline cellulose, 15% to 70% by weight of lactose monohydrate, and 0.2% to 2% by weight of talc.

[0090] In a specific embodiment, the xanomeline tartrate drug beads contain 66% xanomeline tartrate, 33.5% microcrystalline cellulose, and 0.5% talc by weight. In a specific embodiment, the trospium chloride beads contain 17.7% trospium chloride, 46.8% microcrystalline cellulose, 35% lactose monohydrate, and 0.5% talc by weight. In this example, the xanomeline tartrate beads contain about 2.5 times the amount of xanomeline than the trospium chloride beads contain.

[0091] Depending on the dosage requirements, capsules can be prepared with different amounts of xanomeline tartrate and trospium chloride beads. In various embodiments, the capsule contains 50 mg of xanomeline and 10 mg of trospium chloride, 50 mg of xanomeline and 20 mg of trospium chloride, 75 mg of xanomeline and 10 mg of trospium chloride, 75 mg of xanomeline and 20 mg of trospium chloride, 125 mg of xanomeline and 30 mg of trospium chloride, or 125 mg of xanomeline and 40 mg of trospium chloride. In certain embodiments, the capsule contains 25 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In certain embodiments, the capsule contains 50 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In certain embodiments, the capsule contains 50 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In certain embodiments, the capsule contains 75 mg of xanomeline as xanomeline tartrate and 10 mg of trospium chloride. In certain embodiments, the capsule contains 75 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In certain embodiments, the capsule contains 125 mg of xanomeline as xanomeline tartrate and 20 mg of trospium chloride. In certain embodiments, the capsule contains 125 mg of xanomeline as xanomeline tartrate and 40 mg of trospium chloride.

[0092] In another embodiment, the medicament contains 5 milligrams to 700 milligrams of xanomeline. According to one embodiment, the medicament contains 25 milligrams to 300 milligrams of xanomeline.

[0093] In another embodiment, the medicament contains between 1 milligram and 400 milligrams of trospium chloride.In one embodiment, the medicament contains between 6.5 milligrams and 200 milligrams of trospium chloride.

[0094] In one embodiment, trospium chloride extended-release is used as the trospium chloride in the formulation. In another embodiment, the formulation contains 1 milligram to 400 milligrams of trospium chloride extended-release. In one embodiment, the formulation contains 6.5 milligrams to 200 milligrams of trospium chloride extended-release.

[0095] In one embodiment, a medicament contains 75 mg or 225 mg of xanomeline and the same medicament contains 20 mg or 40 mg of trospium chloride, hi another embodiment, a medicament contains 75 mg or 225 mg of xanomeline and a different co-administered medicament contains 20 mg or 40 mg of trospium chloride.

[0096] Bead Coating In other embodiments, the beads may be coated with functional or non-functional coatings, for example, for aesthetics, handling, or stability. In certain embodiments, the beads may be coated with a pH-sensitive coating to prevent dissolution at the low pH of the stomach. Non-functional coatings may be used to maintain chemical separation between the beads or for aesthetic reasons.

[0097] In a further embodiment, the controlled-release formulation comprises a semipermeable coating. Xanomeline and trospium chloride may be present in different coatings of the same formulation. In another embodiment, xanomeline and trospium chloride may be present in different coatings of different formulations or administration vehicles. In a further embodiment, the semipermeable coating comprises a polymer. In a further embodiment, the controlled-release formulation comprises a matrix in which xanomeline and trospium chloride are suspended.

[0098] In certain embodiments, the coating thickness distribution can be described in terms of the weight gain of the coating material based on the total weight of the coated beads. Thus, in one embodiment, the coating thickness distribution is at least 2% based on the total weight of the coated beads. In another embodiment, the coating thickness distribution is at least 3%. In another embodiment, the coating thickness distribution is at least 4%. In another embodiment, the coating thickness distribution is at least 5%. In another embodiment, the coating thickness distribution is at least 6%. In another embodiment, the coating thickness distribution is at least 7%. In another embodiment, the coating thickness distribution is at least 8%. In another embodiment, the coating thickness distribution is at least 9%. In another embodiment, the coating thickness distribution is at least 10%. In another embodiment, the coating thickness distribution is at least 11%. In another embodiment, the coating thickness distribution is at least 12%. In another embodiment, the coating thickness distribution is at least 13%. In another embodiment, the coating thickness distribution is at least 14%.

[0099] For example, the difference in coating thickness between beads can range from + / - 1 to 7% based on the total weight of the coated beads. The distribution of coating thickness can be from about 2% to about 14%, e.g., from about 3% to about 13%, from about 4% to about 12%, from about 5% to about 11%, from about 6% to about 10%, from about 7% to 9%, from about 3% to 14%, from about 4% to 14%, from about 4% to 13%, or from 4% to about 12% based on the weight of the coated beads.

[0100] In one embodiment, the absorption (area under the curve, AUC) of the dosage form when administered orally is advantageously increased compared to other dosage forms of xanomeline or trospium chloride. Without intending to be bound by any theory, the increased absorption is influenced by the dosage form exhibiting a pseudo-extended-release profile. The pseudo-extended-release profile is influenced by one or more factors, including the distribution of coating thickness, if any, the distribution of bead particle sizes, and beads having irregular bead shapes. For example, in embodiments in which the beads have a distribution of coating thickness, beads with a relatively thin coating will completely dissolve relatively quickly at the trigger pH to release the xanomeline and / or trospium chloride composition, while beads with a relatively thick coating will require a somewhat longer time for the coating to completely dissolve and release the xanomeline and / or trospium chloride composition. In embodiments in which the beads have a particle size distribution and / or irregular bead shape, the gastrointestinal transit time of the beads may vary depending on the size and / or shape of the beads, thereby varying the transit time to reach the coating dissolution pH and thus contributing to the pseudo-extended-release profile. In another embodiment, the dosage form has a substantially equivalent (e.g., bioequivalent) C when administered orally within a capsule shell or when administered without a capsule shell. max and / or AUC characteristics.

[0101] In certain embodiments, the dosage form provides a gradual and predictable absorption curve. In one embodiment, the T maxis more stable on a dose-to-dose basis because the beads are individually coated. Predictable and consistent T max is advantageous for achieving a more consistent and sustained therapeutic effect. For example, process-related variations in coating thickness or other effects on coating dissolution tend to affect only a portion of the xanomeline and trospium chloride in the dosage form, resulting in pseudo-extended-release behavior. In contrast, coated capsules containing xanomeline and trospium chloride microspheres exhibit significant variability in absorption time from capsule to capsule.

[0102] In certain embodiments, an oral pharmaceutical composition comprises xanomeline and / or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, wherein the composition, when administered to a patient in need thereof, exhibits a median T of xanomeline at 2 hours. max and median trospium T at 1 hour max In certain embodiments, the in vivo plasma profile comprises a mean dose-normalized C of 48.5 to 121.3 pg / mL / mg. max In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized C of trospium of 156 to 375 pg / mL / mg. max In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC of xanomeline of 263 to 577 pg / mL / mg. 0-12 In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC of trospium of 881 to 2024 pg / mL / mg. 0-12 In certain embodiments, the in vivo plasma profile further comprises a mean C of trospium of 7850±3360 pg / mL. max In certain embodiments, the in vivo plasma profile further comprises a mean AUC of 41900±15500 pg / mL. 0-12 Further includes:

[0103] In another embodiment, the dosage form exhibits advantageous storage stability, e.g., as measured by the amount of xanomeline and / or total amount of related substances present after storage. Storage stability can be assessed after storage at typical ambient conditions (e.g., 25°C and 60% relative humidity) or at accelerated stability conditions, including elevated temperature and / or humidity.

[0104] The dosage forms and methods are intended to include embodiments of any combination of one or more of the additional optional elements, features, and steps further described below (including those shown in the figures and examples), unless otherwise indicated. References to beads and their properties apply equally to a collection of beads (e.g., a plurality of such beads). Similarly, references to cores and their properties apply equally to a collection of cores (e.g., a plurality of such cores).

[0105] Enteric (gastro-resistant) coating materials, e.g., polymers, can be those that dissolve in intestinal fluids, e.g., in the small intestine, at pH levels higher than those of the stomach, e.g., above 4.5, thereby allowing release of the active agent in the small intestine region, rather than substantially in the upper GI tract. In one embodiment, the enteric material begins to dissolve in aqueous solution at a pH of about 4.5 to about 5.5. In another embodiment, the enteric material rapidly dissolves in aqueous solution at a pH between about 5. In another embodiment, the enteric material rapidly dissolves in aqueous solution at a pH between about 5.5.

[0106] For example, pH-sensitive materials do not significantly dissolve until the dosage form is emptied from the stomach. The pH of the small intestine gradually increases from about 4.5 to about 6.5 in the duodenal bulb and to about 7.2 in the distal part of the small intestine (ileum). To provide predictable dissolution corresponding to a small intestinal transit time of about 3 hours (e.g., 2-3 hours) and enable reproducible release therein, the coating should begin to dissolve within the pH range of the duodenum and continue to dissolve throughout the pH range of the small intestine. Therefore, the amount (thickness) of the enteric coating should be sufficient to be substantially dissolved during the transit time of about 3 hours in the small intestine (e.g., the proximal and mid-small intestine).

[0107] Suitable enteric (gastro-resistant) materials include cross-linked polyvinylpyrrolidone; non-cross-linked polyvinylpyrrolidone; hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate; cellulose acetate succinate; cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate; polyvinyl acetate phthalate; carboxymethylcellulose; methylcellulose phthalate; methylcellulose succinate; methylcellulose phthalate succinate; methylcellulose phthalate half ester; ethylcellulose succinate; carboxymethylamide; potassium methacrylate. acrylate divinylbenzene copolymer; polyvinyl alcohol; polyoxyethylene glycol; polyethylene glycol; sodium alginate; galactomannan; carboxypolymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with monomers selected from: methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate; lauryl methacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, e.g., Evonik Examples of suitable enteric coating materials include, but are not limited to, the Eudragit™-L and -S series (including L 100-55, L 30 D-55, L 100, S 100, L 12.5, and S12.5) available from Eudragit Industries; polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; zein; gluten; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethyl-hexyl-acrylate maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamic acid ester copolymer; carboxymethylcellulose glycerol monooctanoate; polyarginine; poly(ethylene); poly(propylene); poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride); and polyurethane. Combinations of enteric materials may also be used.In one embodiment, the enteric material dissolves rapidly at a pH of 5.5 or above, providing rapid dissolution in the upper intestine. For example, the enteric material can be selected from copolymers of methacrylic acid and methyl methacrylate and copolymers of methacrylic acid and ethyl acrylate. For example, the enteric polymer is poly(methacrylic acid-co-ethyl acrylate) 1:1 (Eudragit™ L 30 D-55 and Eudragit™ L 100-55).

[0108] Other suitable enteric coatings include beeswax and glyceryl monostearate; beeswax, shellac and cellulose; and cetyl alcohol, mastic and shellac, and shellac and stearic acid; polyvinyl acetate and ethylcellulose; and neutral copolymers of polymethacrylic acid esters (Eudragit® L 30D); copolymers of methacrylic acid and methacrylic acid methyl ester, or neutral copolymers of polymethacrylic acid esters with metal stearates. Such coatings include mixtures of fats and fatty acids, shellac and shellac derivatives, and cellulose acid phthalates, such as those with free carboxyl content.

[0109] As is known in the art, one or more plasticizers can be added to enteric polymers to increase their flexibility and reduce their brittleness. Suitable plasticizers include, for example, butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol (PEG, such as PEG 6000), acetyltriethyl citrate, and triacetin. In one embodiment, the plasticizer is triethyl citrate. While some enteric materials are flexible and do not require a plasticizer, more brittle polymers (e.g., Eudragit™ L / S, Eudragit™ RL / RS, and Eudragit™ FS 30 D) benefit from, for example, about 8% to about 12% by weight triethyl citrate with a plasticizer, poly(methacrylic acid-co-ethyl acetate) 1:1, in the range of 5% to 30% by weight, based on the dry polymer mass.

[0110] In certain embodiments, the enteric coating contains one or more anti-blocking agents (antiadherents), as known in the art, to reduce film stickiness and prevent clumping. Suitable anti-blocking agents include, but are not limited to, talc, glyceryl monostearate, fumed silica (e.g., Aerosil™ 200), precipitated silica (e.g., Sipernat™ PQ), and magnesium stearate. The anti-blocking agent can be used in any suitable amount, for example, in a range of about 10% to 100% by weight, about 10% to 50% by weight, about 10% to 30% by weight, or about 15% to 30% by weight based on the dry polymer weight. For example, in one embodiment, the anti-blocking agent can be used in a range of about 15% to 30% by weight based on the dry polymer weight.

[0111] One or more surfactants may also be added to the enteric coating mixture to increase the wettability of the substrate and / or stabilize the suspension, as known in the art. Surfactants include polysorbate 80, sorbitan monooleate, and sodium dodecyl sulfate, as well as other surfactants described herein.

[0112] The enteric coating can be formed by any suitable process. Coating processes include, for example, pan coating, fluidized bed coating, and dry coating (e.g., heat-dry coating and electrostatic dry coating). Pan coating and fluidized bed coating using a solvent are well-established processes. In liquid coating, the enteric material and optional excipients (e.g., pigments, plasticizers, anti-blocking agents) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed onto the solid dosage form in a pan coater or fluidized bed dryer and dried by hot air. For example, in the Wurster fluidized bed coating process, the coating fluid is sprayed from the bottom of the fluidized bed apparatus. Alternatively, the coating fluid is applied by top spray. In certain embodiments, tangential spraying is applied.

[0113] The amount of enteric material applied is sufficient to achieve the desired acid resistance and release characteristics. For example, in one embodiment, the amount of enteric coating is greater than or equal to the USP 1000 0.1% for a delayed release dosage form. <711> requirements (USP 36-NF 31), thereby not releasing 10.0 wt. % of the drug after 2 hours in 0.1 N HCl. In certain embodiments, the formulation meets, for example, USP 36-NF 31 section <711> Using the dissolution method of the present invention, the active agent releases at least 80% in 20 minutes in a pH 6.8 buffer solution.

[0114] In one embodiment, the enteric coating is present in an amount ranging from about 10% to 40%, or 25% to about 35%, as measured by weight gain compared to the uncoated particle core, or from about 25% to about 31%, from about 27% to about 31%, or from about 28.5% to about 31% weight gain based on the weight of the uncoated particle core.

[0115] The formulation can include a capsule shell in which the beads are disposed. Soft and hard capsule shells are known. In one embodiment, the capsule shell is a hard capsule shell, such as a gelatin capsule shell or a vegetable-based hard capsule shell. In certain embodiments, the capsule shell includes one or more enteric coatings described herein. During accelerated storage, gelatin capsules may disintegrate. Therefore, in certain embodiments, the formulation can include a hydroxypropyl methylcellulose capsule shell.

[0116] Thus, for example, one embodiment combining various features described above includes a pharmaceutical dosage form comprising a plurality of xanomeline beads, the beads comprising a core comprising xanomeline tartrate, a filler (optionally microcrystalline cellulose), a binder (optionally hypromellose), and an enteric coating (optionally Eudragit® L 30 D-55) surrounding the core, the plurality of beads having a particle size distribution ranging from about 0.7 mm to about 2.5 mm, the enteric coating ranging from about 20% to about 40% by weight of the bead core, and the beads disposed within a capsule shell.

[0117] Bead size and shape The plurality of beads has a distribution of particle sizes, the plurality of beads has a bead shape, and the plurality of beads has a distribution of coating thickness, if present.

[0118] Beads with a distribution of particle sizes have been shown to exhibit favorable pharmacokinetics. Without intending to be bound by any theory, it is expected that pharmacokinetics is affected by multiple beads with a distribution of core sizes.

[0119] In one embodiment, the particle size of the beads is in the range of about 0.4 mm to about 1.2 mm, e.g., about 0.4 mm to about 0.5 mm, about 0.5 mm to about 0.6 mm, about 0.6 mm to about 0.7 mm, about 0.7 mm to about 0.8 mm, about 0.8 mm to about 0.9 mm, about 0.9 mm to about 1.0 mm, about 1.0 mm to about 1.1 mm, or about 1.1 mm to about 1.2 mm. In certain embodiments, the size of the xanomelin beads is about 0.425 mm to about 1.18 mm. In certain embodiments, the size of the xanomelin beads is about 0.6 mm to about 0.85 mm. In certain embodiments, the size of the trospium beads is about 0.425 mm to about 1.18 mm. In certain embodiments, the size of the trospium beads is about 0.6 mm to about 0.85 mm.

[0120] The beads or bead mixtures can be used, for example, in a suspension, filled into capsules, compressed into tablets, or filled into sachets. One or more types of modified-release beads can be mixed together and encapsulated, or used as a sprinkle on the subject's food. In certain embodiments, the oral solid dosage form can be any of these forms. In certain embodiments, the dosage form is a capsule.

[0121] If the particle size of the beads becomes too small, the variability of the active substance content increases. If the particle size becomes too large, the beads are too large to administer the labeled pharmaceutical by sprinkling (e.g., onto other soft foods such as applesauce or jelly), swallowing without chewing, or administering via an enteral feeding tube. Also, as particle size increases, larger particles are more heavily coated than smaller particles, resulting in a lower relative assay compared to smaller particles. To compensate, relatively more beads are required to meet the labeling intensity per capsule. It becomes difficult or impossible to fill capsule shells with particles large enough to meet the labeling intensity per capsule (e.g., filling size 0 capsules with up to 75 mg of xanomeline free base).

[0122] In one embodiment, the beads are formulated into capsules, for example, using an encapsulation machine. Various capsule sizes can accommodate target formulation strengths and fill weights. Capsule sizes range from 00 to 5, with fill weights ranging from about 15 mg to about 630 mg.

[0123] The beads can be screened (e.g., by sieving) to a desired particle size. In certain embodiments, the particle size range is any particle size range or combination thereof described above for the cores. In one embodiment, the particle size range is the same as the particle size range of the uncoated cores. For example, the beads can be screened so that no more than 5% by weight of the bead cores are retained on a #12 mesh (1.68 mm) screen and no more than 10% by weight passes through a #20 mesh (0.84 mm) screen.

[0124] Manufacturing method A method for preparing an oral pharmaceutical composition is provided, comprising mixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads comprising a salt of trospium, such as trospium chloride. In certain embodiments, the method further comprises formulating the mixed beads into a capsule.

[0125] Also disclosed herein is a method for preparing a dosage form, comprising coating a core comprising xanomeline or a pharmaceutically acceptable salt thereof and excipients with an enteric polymer to form an enteric coating, and coating a core comprising trospium chloride or a pharmaceutically acceptable salt thereof and excipients with an enteric polymer to form an enteric coating. Optionally, the core can be formed by a wet granulation method. Optionally, the drug beads are screened (e.g., by sieving) to a desired particle size range before enteric coating, and optionally again after enteric coating.

[0126] Drug beads may be made by different processes, including but not limited to, spheronizing an extruded wet mass and coating an inert core sphere in a fluidized bed. In certain embodiments, the beads are prepared by extrusion and spheronization.

[0127] The beads are formulated to be free-flowing and compatible with modern encapsulation equipment. In some embodiments, the beads are blended together to form a homogenous mixture that can be filled into capsules in a single stage. In other embodiments, the beads are filled into capsules separately using a two-stage capsule filler.

[0128] The cores comprising xanomeline or a pharmaceutically acceptable salt thereof can be formed by any suitable process. In one embodiment, the cores are formed by granulating a mixture of xanomeline or a pharmaceutically acceptable salt thereof and excipients and milling to the desired particle size range. In another embodiment, the cores can be formed by extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof and excipients.

[0129] The cores containing trospium chloride or a pharmaceutically acceptable salt thereof can be formed by any suitable process. In one embodiment, the cores are formed by granulating a mixture of trospium chloride or a pharmaceutically acceptable salt thereof and excipients and milling to the desired particle size range. In another embodiment, the cores can be formed by extrusion and spheronization of a mixture of trospium chloride or a pharmaceutically acceptable salt thereof and excipients.

[0130] Granulation processes can include, for example, fluidized bed granulation, wet granulation, hot melt granulation, and spray congealing. Other processes include slugging and roller compaction. The mixture to be granulated can first be dry blended. The dry blended dry ingredients can be mixed with water before extrusion.

[0131] Extrusion and spheronization of a mixture of xanomeline or a pharmaceutically acceptable salt thereof, trospium chloride, and excipients provides desirable cores having the particle size distribution and one or more other desirable properties described herein. In certain embodiments, a shorter processing time can result in a more stable product. For example, reducing spheronization reduces friction and associated heat. Reducing the time the product is exposed to air (either while wet and / or before packaging) also reduces oxidation. On the other hand, rapid processing by extrusion and spheronization can result in a poor-quality product, for example, in that a large portion of the bead cores are outside the desired particle size range. Moisture absorption by the spheronization aid (which occurs over time) affects the spheronization properties of the beads.

[0132] Thus, in one embodiment, the moisture content of the granulated mixture, prior to drying, is in the range of about 20% to about 40% by weight, e.g., 25% to about 35% by weight, about 28% to about 32% by weight, at least about 28% by weight, at least about 28.5% by weight, about 20% to about 40% by weight, about 25% to about 35% by weight, about 27% to about 31% by weight, or about 28.5% to about 31% by weight.

[0133] In certain embodiments, the wet mass can be held prior to extrusion, e.g., to allow the spheronization aid to swell with the granulation fluid. The holding time can be at least 15 minutes, e.g., at least 30 minutes, at least 45 minutes, or at least 60 minutes. In certain embodiments, the holding time ranges from about 15 minutes to about 120 minutes, e.g., from about 30 minutes to 100 minutes, or from 60 minutes to 90 minutes.

[0134] As described above with respect to the cores, the method can include screening the cores (e.g., by sieving) prior to any coating to retain particles within a predetermined size range, e.g., a size range of about 0.7 mm to about 2.8 mm, e.g., about 0.7 mm to about 2.5 mm, about 0.8 mm to about 1.7 mm, or any range described herein.

[0135] As described above with respect to beads, the method can include sorting the beads (e.g., by sieving) after any coating to retain the particles within a size range, e.g., from about 0.7 mm to about 2.8 mm, e.g., from about 0.7 mm to about 2.5 mm, or from about 0.8 mm to about 1.7 mm, or any range described herein.

[0136] In the extrusion and spheronization process, any of the following features can be used individually or in combination with one or more of them. Water can be a granulating agent. Microcrystalline cellulose can be present in the core as a spheronization aid. Hypromellose can be included in the core as a binder. The size of the extrusion screen can be 1.0 mm. The friction plates of the spheronizer can be cross-hatched. The friction plates 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 in the range of about 3 mm to about 7 mm, or about 5 mm. The spheronization time can be less than about 5 minutes, or less than about 4 minutes, or less than about 3 minutes, or less than about 2 minutes, or up to 1 minute. The spheroidized particles can include a substantial fraction thereof of non-spherical particles (i.e., irregularly shaped), such as, for example, at least about 20% by weight, at least about 30% by weight, at least about 40% by weight, at least about 50% by weight, at least about 60% by weight, or at least about 70% by weight.

[0137] In certain embodiments, the pharmaceutical composition is stored with a desiccant, such as pharmaceutical grade silica gel, crystalline sodium, potassium, or calcium aluminosilicate, colloidal silica, anhydrous calcium sulfate, or the like.

[0138] In certain embodiments, the pharmaceutical composition is stored with an oxygen absorber.

[0139] In certain embodiments, the pharmaceutical compositions are stored under a dry, inert gas such as nitrogen, helium, argon, neon, xenon, krypton, or mixtures thereof.

[0140] In certain embodiments, the pharmaceutical composition is stored under reduced pressure relative to the external ambient air.

[0141] In certain embodiments, the pharmaceutical composition is stored at a low temperature, such as a refrigerated temperature (e.g., 2° C. to 8° C.). In certain embodiments, the pharmaceutical composition is stored to contain fewer impurities, such as impurity A, than when stored at 25° C.

[0142] In certain embodiments, the pharmaceutical composition is stored by the manufacturer, distributor, pharmacy, or hospital at a temperature of about 2° C. to about 8° C. prior to dispensing the oral pharmaceutical composition to a subject. In certain embodiments, after the oral pharmaceutical composition is dispensed to a subject, the pharmaceutical composition is stored at a temperature of about 20° C. to about 25° C.

[0143] 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.

[0144] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising xanomeline beads includes forming a wet mass comprising xanomeline tartrate and excipients, optionally microcrystalline cellulose, and having a moisture content in the range of about 20% to about 40% by weight; extruding and spheronizing the wet mass comprising xanomeline tartrate and excipients to produce cores; optionally sieving the cores to a target particle size range of about 0.7 mm to about 2.5 mm; coating the sieved cores with a polymer to form beads comprising the cores and coating; and optionally sieving the bead particles to a target particle size range of about 0.7 mm to about 2.5 mm.

[0145] In certain embodiments, a method for preparing a pharmaceutical dosage form comprising trospium beads includes forming a wet mass comprising trospium chloride and excipients, optionally microcrystalline cellulose, having a moisture content ranging from about 20% to about 40% by weight; extruding, spheronizing, and drying the wet mass comprising trospium chloride and excipients to produce cores; optionally screening the cores to a target particle size range of about 0.7 mm to about 2.5 mm; coating the screened cores with a polymer to form beads comprising the cores and coating; and optionally screening the bead particles to a target particle size range of about 0.7 mm to about 2.5 mm.

[0146] purity The compound 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium is also provided.

[0147] Also provided is a pharmaceutical composition comprising xanomeline and / or a salt thereof and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium (impurity A). In certain embodiments, the pharmaceutical composition contains less than 0.30% by weight, e.g., less than 0.25%, less than 0.20%, less than 0.15%, less than 0.14%, or less than 0.1% by weight of impurity A. Also provided is a pharmaceutical composition comprising xanomeline and / or a salt thereof and less than 0.15% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium (impurity A).

[0148] Also provided is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium, and a plurality of trospium beads comprising a salt of trospium. Also provided is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof and less than 0.15% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium, and a plurality of trospium beads comprising a salt of trospium.

[0149] In certain embodiments, the pharmaceutical composition contains less than 0.5% by weight of impurity A after the pharmaceutical composition has been stored at 40° C. and 75% relative humidity for at least 3 months.

[0150] In certain embodiments, the total impurities in the pharmaceutical compositions provided herein are about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2.5% by weight or less, about 2% by weight or less, about 1.5% by weight or less, about 1% by weight or less, about 0.5% by weight or less, or about 0.1% by weight or less.

[0151] Treatment method Further provided is a method for activating muscarinic receptors in a biological sample, the method comprising contacting the biological sample with any of the oral pharmaceutical compositions described herein. Also provided is a method for treating a disorder ameliorated by activating muscarinic receptors in a subject in need of such treatment, the method comprising administering to the subject any of the oral pharmaceutical compositions described herein.

[0152] Activators of M1 and M4 muscarinic receptors have been suggested as an effective treatment for schizophrenia, but activating muscarinic receptors located outside the brain results in side effects that have led to the exclusion of oxanomeline from clinical use. For example, in both Phase I and subsequent studies, the muscarinic agonist xanomeline exhibited unacceptable GI and other side effects associated with binding to muscarinic receptors in the periphery of the body. By combining xanomeline with trospium chloride, the desired therapeutic effect can be achieved while reducing or eliminating the side effects associated with activating muscarinic receptors located outside the brain.

[0153] The tolerability of the muscarinic activator xanomeline is increased by coadministration of the muscarinic antagonist trospium chloride. The most common adverse events observed with xanomeline administration are nausea, vomiting, diarrhea, excessive sweating, and hypersalivation (so-called cholinergic adverse events). The disclosed compositions reduced the incidence of these adverse events in humans, demonstrating increased tolerability of xanomeline.

[0154] In one embodiment, xanomeline is combined with trospium chloride to treat muscarinic disorders, improving symptoms in response to muscarinic activation by xanomeline in living tissues found outside the brain. In one embodiment, such diseases or disorders include schizophrenia and disorders related to schizophrenia, cognitive impairment in neurodegenerative diseases such as Alzheimer's, and pain, such as nociceptive or neuropathic pain. The combination of xanomeline and trospium chloride is a safer way to treat these diseases, which have been shown to respond to activation of muscarinic receptors.

[0155] In another embodiment, xanomeline and trospium chloride treat mood disorders. In another embodiment, xanomeline and trospium chloride treat movement disorders. In another embodiment, xanomeline and trospium chloride treat cognitive disorders, including enhancing cognitive function not related to a specific pathology. In another embodiment, xanomeline and trospium chloride treat attention deficits. In another embodiment, xanomeline and trospium chloride treat pain. Besides treating diseases, enhancing attention accelerates learning and reduces fatigue due to both sleep deprivation and circadian rhythm disorders such as jet lag. In another embodiment, xanomeline and trospium chloride treat addictive disorders.

[0156] In one embodiment, xanomeline in combination with trospium chloride treats an animal. In a further embodiment, the animal is a mammal. In one embodiment, the mammal is a human.

[0157] In one embodiment, trospium chloride reduces the side effects associated with xanomeline. Such side effects include, but are not limited to, GI side effects, cardiac side effects, excessive sweating, and hypersalivation. The use of trospium with xanomeline allows xanomeline to be used clinically in situations where its side effects prevent its clinical use. In another embodiment, the use of trospium chloride with xanomeline allows xanomeline to achieve a higher maximum tolerated dose than would otherwise be achieved with xanomeline.

[0158] Various time- and resource-intensive methods have demonstrated the efficacy of the combination of xanomeline and trospium chloride. For example, animal models, including both pharmacological models (e.g., the ketamine model) and genetic models (e.g., the DISC1 mouse), demonstrate the efficacy of novel therapeutic agents for schizophrenia. Similarly, animal models, including rodents, dogs, and non-human primates, demonstrate the side-effect profiles of pharmacological agents. While animal models are surrogates for human experiments, they may be flawed due to physiological differences between humans and animals, and therefore may have limited predictive power for human experiments, particularly for central nervous system disorders. Alternatively, the disclosed combinations can be tested in controlled clinical trials in humans. Those skilled in the art can assess various side effects, such as GI discomfort, using standard measures based on patient self-report. As another example, objective physiological measures (e.g., EKG) may be used by those skilled in the art. Additionally, a series of standard scales have been developed to assess schizophrenia symptoms, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression (CGI).Typically, clinical trials are double-blind, with one group of patients receiving an inert placebo and the other receiving the active intervention.

[0159] Prior to administering the claimed combination, patients may have a 1-14 day lead-in period during which trospium chloride is administered alone. In one embodiment, trospium chloride is administered over one or more dose periods to allow trospium chloride to accumulate in the body or to reach or approach a steady-state exposure level prior to administering xanomeline. This accumulation or higher exposure level of trospium chloride increases blockage of muscarinic receptors outside the brain, reducing adverse events associated with xanomeline administration. In another embodiment, trospium chloride is administered one or more days prior to xanomeline administration.

[0160] In one embodiment, xanomeline and trospium chloride are administered to a patient six times over a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient five times over a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient four times over a 24-hour period. In one embodiment, xanomeline and trospium chloride are administered to a patient three times over a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient two times over a 24-hour period. In another embodiment, xanomeline and trospium chloride are administered to a patient once over a 24-hour period.

[0161] In one embodiment, an extended-release formulation of trospium chloride is used in combination with xanomeline. In another embodiment, the extended-release trospium chloride is administered to a patient 1 to 5 times over a 24-hour period. In one embodiment, the extended-release trospium chloride is administered 1 to 3 times over a 24-hour period. In another embodiment, 5 milligrams to 400 milligrams of extended-release trospium chloride are used over a 24-hour period. In one embodiment, 20 milligrams to 200 milligrams of extended-release trospium chloride are used over a 24-hour period.

[0162] In one embodiment, 225 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 100 mg of xanomeline and 20 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 125 mg of xanomeline and 20 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 125 mg of xanomeline and 30 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 125 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 200 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 200 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 250 mg of xanomeline and 60 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 250 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 300 mg of xanomeline and 40 mg of trospium chloride are administered to a patient over a 24-hour period. In another embodiment, 300 mg of xanomeline and 80 mg of trospium chloride are administered to a patient over a 24-hour period.

[0163] Treatment can be initiated with a lower dose. Thereafter, the dosage can be increased in small increments until a balance between therapeutic effect and side effects is achieved. While the subject is being treated, the patient's health can be monitored by measuring one or more relevant indicators at predetermined times during the treatment period. Treatment, including composition, amount, administration time, and formulation, can be adjusted following such monitoring. The patient can be periodically reevaluated by measuring the same parameters to determine improvement. Based on these reevaluations, adjustments can be made to the disclosed compositions administered, and possibly to the administration time. [Example]

[0164] The following examples are provided for illustrative purposes and are not intended to limit the scope of the present disclosure.

[0165] Example 1 - Immediate Release Beads Beads were prepared for xanomeline tartrate (Table 1) and trospium chloride (Table 2).

[0166] [Table 1]

[0167] [Table 2]

[0168] The powder was screened using a Quadro Comil Model 197 equipped with a 457 μm round hole screen and 0.2 inch spacers at 1625 rpm and mixed in a Hobart low shear mixer / granulator (Model N-50) at a fixed speed of 60 rpm for 2 minutes. A dry blending step is optional, as blend uniformity is promoted by subsequent wet granulation. The beads were hand screened through a 40 mesh (425 μm) sieve.

[0169] Wetting was performed in a Hobart. Water was added using a Cole-Parmer peristaltic pump. The water addition rate (amount of water / time of administration) was a process variable.

[0170] The wet mass was extruded through a perforated screen (dome configuration) single screw extruder at 30 rpm (shaft speed) using an LCI Multi Granulator MG-55. The wet mass was extruded directly after wetting. Retention time, shaft speed, and extrusion rate (load) were process variables.

[0171] The extrudate was placed in an LCI Spheronizer QJ-230T equipped with a 2.0 mm friction plate. The extrudate was spheronized at different plate speeds for a total of up to 4 minutes. Spheronization speed and time were process variables.

[0172] The beads were dried in an Aeromatic™ Strea-1 fluid bed at an inlet temperature of 60° C. until a moisture content of 3% or less was obtained. The beads melted after a few minutes at 60° C., so the beads were dried at 30° C.

[0173] Moisture content was assessed gravimetrically by loss on drying (LOD) using a Mettler Toledo Halogen Moisture Analyzer, model HR83. The beads were heated at 105°C until the weight loss rate dropped to 0.0% or less within 60 seconds.

[0174] [Table 3]

[0175] Example 2 - Scale-up of immediate release bead formulation The beads of Example 1 were scaled up with and without talc (Tables 4-7). The extrusion / spheronization process parameters are shown in Table 8.

[0176] [Table 4]

[0177] [Table 5]

[0178] [Table 6]

[0179] [Table 7]

[0180] [Table 8]

[0181] Example 3 - Capsule Stability and Dissolution Testing Capsules were prepared by weighing the beads and manually filling them into HPMC capsules. The beads were manually encapsulated using an Accofil™ capsule filling machine, where the beads, premixed with talc (0.5%), were individually / sequentially filled into capsules as shown in Table 9.

[0182] [Table 9]

[0183] After drying, the beads were screened through 16 mesh (1.18 mm) and 40 mesh (0.425 mm) screens by shaking for 5 minutes. Beads with sizes between 1.18 mm and 0.425 mm were retained for further analysis.

[0184] The morphology and surface properties of the beads were examined by scanning electron microscopy (SEM) using a JSM-6010LV InTouchScope™ (JEOL Ltd, Tokyo, JP) microscope equipped with a backscattered electron detector (BES). Samples were mounted on metal stubs using double-sided carbon conductive tape. Images were obtained at an accelerating voltage of 20 kV under low vacuum (60 Pa) and a magnification of 30×.

[0185] Bulk density and tapped density were measured using a tapped density tester (JV 1000, Copley Scientific) according to USP <616> The bulk density was measured twice using the .DELTA. method. Bulk density was determined from the volume of a known mass of powder sample in a graduated cylinder. Tapped density was measured by mechanically tapping the measuring cylinder until the volume no longer changed.

[0186] Powder flow properties were evaluated using the Carr Compressibility Index and Hausner Ratio, both of which were derived using bulk and tapped density measurements. The Carr Compressibility Index (CI) was calculated using bulk and tapped density data fitted to the following equation: Compressibility Index = (Tapped Density - Bulk Density) / Tapped Density x 100%. The Hausner Ratio (H) was calculated as the ratio of tapped density to bulk density. Capsules were analyzed for appearance, assay, related substances, moisture content, and dissolution. Figure 1 shows the stability schedule and protocol for xanomeline / trospium capsules.

[0187] The beads also ranged in size from 0.6 mm to 0.85 mm. Some beads exhibited similar morphological characteristics. Modifications in some other beads reduced the bead density, resulting in a rough surface and loss of sphericity. Scanning electron microscope (SEM) images of xanomeline tartrate 66% beads (Figure 2) and trospium chloride 17.7% beads (Figure 3) at 30x magnification showed that the beads ranged in size from 0.6 mm to 0.85 mm. These beads were used in xanomeline / trospium capsules. The particle size distribution (PSD) of the beads was measured by mechanical sieving. As shown in Table 10, most beads for both APIs ranged in size from 0.425 to 1.18 mm.

[0188] [Table 10]

[0189] Table 11 shows the density and flow properties of beads collected between the 0.425 mm and 1.18 mm sieves. Xanomeline tartrate and trospium chloride IR beads exhibit different density and flow properties, which can be important when blending bead systems.

[0190] [Table 11]

[0191] The analysis in Table 12 showed favorable results for the assay and related substances, as well as The water content for Sanomelin and 20 mg Trospium Chloride capsules is shown in Table 13. The data show that these attributes were maintained during storage stability testing. Similar data for Melin and 10 mg trospium chloride capsules are presented in Table 14. Dissolution data for these two dosage forms are provided in Tables 15 and 16. Other tables showing the stability of sanomelin / trospium chloride formulations are shown in Figures 6-41.

[0192] [Table 12]

[0193] [Table 13]

[0194] [Table 14]

[0195] [Table 15]

[0196] [Table 16]

[0197] [Table 17]

[0198] [Table 18]

[0199] Subsequent testing has shown that KarXT 50 / 10, 50 / 20, and 75 / 20 in hard-shell capsules are stable for at least 12 months at 25°C / 60% RH. Based on available data, a shelf life of 15 months at 25°C / 60% RH is proposed.

[0200] Dissolution results show that the two compounds release rapidly, which may increase their bioavailability, and also show that the two bead formulations release at comparable rates despite substantial differences in composition. Both xanomeline and trospium chloride have low bioavailability, and rapid release may increase bioavailability through predominantly saturable processes that limit absorption into the systemic circulation.

[0201] During stability testing of the combination drug products, an unknown xanomeline impurity with a relative retention time of approximately 1.09 was observed. The impurity was observed at the 3-month time point for the 50 mg xanomeline / 10 mg trospium chloride drug product and at the first time point for the other three combination drug products, both of which occurred simultaneously during testing. The impurity peak increased with time and with increasing storage temperature. The impurity had not been observed prior to this study.

[0202] Preliminary studies have shown that the RRT 1.09 impurity is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium (C 14 H 20 N3O2S + , MW=294.1271Da): [ka]

[0203] The RRT 1.09 impurity is compound V(C 14 H 20 N3OS +, MW=278.1322 Da), which is the penultimate intermediate in the synthesis of xanomeline, with a negative mutational potential. [ka]

[0204] To reduce the presence of impurities, the storage temperature of the drug product was reduced. To minimize oxygen in the headspace during packaging, the bottle was flushed with argon. In certain embodiments, the xanomelin bead formulation was formulated with an antioxidant, such as 0.5% by weight ascorbic acid or 0.05% by weight BHT.

[0205] Example 4 - KAR-001 Phase I Study of Xanomeline in Combination with Trospium Chloride A Phase 1, double-blind, randomized, multiple-dose pilot study of xanomeline alone compared with xanomeline administered with trospium chloride was conducted in healthy volunteers. The primary objectives of the study were (1) to evaluate the safety and tolerability of xanomeline 225 mg administered daily for 7 days with trospium chloride 40 mg versus xanomeline 225 mg administered alone for 7 days, and (2) to determine whether peripheral cholinergic side effects (nausea, diarrhea, vomiting, sweating, hypersalivation) were significantly reduced by administering xanomeline 225 mg daily (75 mg TID) for 7 days plus trospium 40 mg daily (20 mg BID) compared with xanomeline 225 mg daily alone for 7 days. Table 17 lists the parameters of this study.

[0206] [Table 19]

[0207] [Table 20]

[0208] A total of 70 study subjects were randomized, of which 68 study subjects underwent at least one assessment on the first day of xanomeline administration, Day 3. The demographics of the study subjects are shown in Table 18.

[0209] [Table 21]

[0210] The most common adverse events with xanomeline are so-called cholinergic adverse events: nausea, vomiting, diarrhea, excessive sweating, and hypersalivation. In this study, coadministration of xanomeline with trospium chloride resulted in a statistically significant (p=0.016) 43% reduction in the incidence of cholinergic adverse events compared with xanomeline coadministered with placebo. In the xanomeline plus placebo arm of the study, 63% of subjects reported at least one cholinergic adverse event, whereas only 34% of subjects in the xanomeline plus trospium chloride arm of the study reported such an event.

[0211] Furthermore, in this study, the incidence of each type of individual cholinergic adverse event was also reduced in subjects receiving xanomeline plus trospium chloride compared with the incidence in subjects receiving xanomeline plus placebo. The reduction in the incidence of sweating was itself statistically significant: 20.0% in the xanomeline plus trospium chloride group, down from 48.5% in the xanomeline plus placebo group, a reduction of 59% (p=0.013).

[0212] The overall incidence of cholinergic adverse events in the xanomeline plus trospium chloride group of this study was very similar to the 32% incidence reported during the 2-day run-in period for placebo plus placebo subjects. Although these two data points did not occur during different periods of the study, the fact that the incidence of cholinergic adverse events was similar to placebo suggests that the 43% reduction in adverse events with trospium chloride may have been close to the maximum reduction possible in this study.

[0213] Table 19 shows the incidence and number of cholinergic adverse events in the evaluable population of this study as follows; all p-values are based on Fisher's exact test. * Based on chi-squared test except where marked.

[0214] [Table 22]

[0215] In addition to assessing whether the addition of trospium chloride increases the tolerability of xanomeline, this study also provided data on the overall safety and tolerability of xanomeline plus trospium chloride. Table 20 shows that the combination was generally well tolerated, with no severe adverse events, no serious adverse events, and most adverse events being mild.

[0216] [Table 23]

[0217] The tolerability profile found in this study allows for future studies of the combination of xanomeline and trospium chloride to proceed.

[0218] Example 5 - KarXT, a xanomeline + trospium combination formulation, KAR-003 Phase I trials This study was a phase 1, randomized, repeated-dose, adaptive-design, inpatient trial to evaluate the safety and tolerability of KarXT in healthy volunteers aged 18 to 60 years. Subjects signed informed consent and underwent screening assessments on days -21 to -1. Upon successful completion of all screening assessments, subjects returned to the study clinic on day 0 for baseline safety assessments and enrollment in the study. They were randomly assigned to one of two treatment arms: KarXT or placebo, in a 3:1 ratio within each cohort. Subjects were assigned to one of four cohorts (Cohorts 1, 2, 3, or 4).

[0219] The study drug was administered BID on days 1 through 7. All cohorts used a combination formulation of both xanomeline and trospium. All cohorts began with a 2-day run-in of KarXT 50 / 20 BID (for subjects randomized to active treatment). After the 2-day run-in period, an unblinded pharmacist distributed study drug to each subject according to their randomization assignment, providing a specific cohort dose for 5 days, for a total of 7 days of treatment. To maintain blinding, a matching placebo was administered throughout the study. A sentinel group was enrolled in cohorts 2 through 4 and monitored for safety and tolerability by the Data Safety Evaluation Group (DSEG). As a result, approximately 30% of the proposed cohort was treated and evaluated for safety before the remaining cohorts were dosed. Subjects and study clinic staff were blinded to treatment. A dose selection committee (DSC) was not blinded to determine dosing for subsequent treatment groups.

[0220] Serial blood samples for PK assessment of xanomeline and trospium were collected on Days 1, 3, and 7. Larger blood samples were collected at routine intervals for monitoring trough concentrations of xanomeline and trospium and for clinical laboratory evaluation. On Day 1, saliva volume was collected twice. Saliva volume was measured pre-dose on Day 1 and then daily (afternoon) on Days 1–7 at approximately the same time to avoid diurnal variation. Other assessments included pupil size measurement and Bristol stool scale assessment. Subjects remained in the study clinic for the entire treatment period (7 days). After the safety assessment on Day 8, subjects were discharged from the study clinic and asked to return approximately 14 days after study drug administration for a final safety assessment.

[0221] During the study, after a 2-day lead-in of KarXT 50 / 20 BID in each cohort (for subjects randomized to active treatment), subjects received the following: In Cohort 1, subjects completed KarXT 100 / 20 BID (200 mg xanomeline + 40 mg trospium total daily dose (TDD)) or placebo on days 3-7. In Cohort 2, the Sentinel group (Group 2a) discontinued dosing after the morning dose on Day 4. Subjects in Cohort 2 received KarXT 150 / 20 BID (TDD of 300 mg xanomeline + 40 mg trospium) or placebo. Dosing in Cohort 2 was discontinued (DSEG decision based on observed tolerability concerns). The study progressed to dosing the Sentinel group in Cohort 3 (Group 3a) because the DSC determined that further dosing of KarXT 150 / 20 BID in Cohort 2 was unlikely to be sufficiently tolerated to warrant further development of this dose combination in the clinical population. In Cohort 3, the Sentinel group (Group 3a) completed KarXT 150 / 40 BID (300 mg xanomeline + 80 mg trospium TDD) or placebo on Days 3 through 7. The second group of Cohort 3 (Group 3b) discontinued treatment after the morning dose on Day 5. In Cohort 4, the Sentinel group (Group 4a), Group 2 (Group 4b), and the remaining group (Group 4c) completed KarXT 125 / 40 BID (250 mg xanomeline + 80 mg trospium TDD) or placebo on days 3-7.

[0222] 96 subjects were planned, 248 subjects were screened, 69 subjects were randomized, 51 subjects completed the study, and 18 subjects discontinued the study. The population consisted of subjects with a blood pressure of 18–40 kg / m 2The study included healthy male and female subjects aged 18 to 60 years at screening with a body mass index of 0.01 or greater. Subjects were excluded if they had a history of irritable bowel syndrome or severe constipation requiring treatment within the six months prior to screening. Subjects were also excluded from the study if they had a history or presence of any disease or condition, including psychiatric or neurological disorders, that, in the investigator's opinion, would compromise the subject's safety or the validity of the study. Table 21 summarizes demographic and baseline characteristics by treatment group. Demographic and baseline characteristics were consistent between the safety and PK populations.

[0223] [Table 24]

[0224] [Table 25]

[0225] Serial blood samples to assess the PK of xanomeline and trospium were collected from all subjects in each cohort before the morning dose and 1, 2, 3, 4, 6, 8, 10, and 12 hours after the morning dose on days 1, 3, and 7. The PK parameters listed below were calculated from the individual xanomeline and trospium concentration-time profiles by standard non-compartmental methods. Dose-normalized parameters were calculated using C max and area under the concentration-time curve (AUC) values were calculated. During the study, additional blood samples were collected to monitor trough concentrations of xanomeline and trospium before the morning dose on days 2, 4, 5, and 6 and before discharge on day 8.

[0226] Safety assessments included spontaneously reported adverse events, ECG, clinical laboratory assessments, vital signs, salivary flow assessment, Bristol stool scale, pupil size, and physical examination. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) summarized continuous data by treatment group. Geometric mean (GM), geometric percent coefficient of variation (CV%), quartiles, or box plots were generated. No formal statistics were performed, but categorical measures were tabulated by count and frequency.

[0227] Unless otherwise specified, treatment groups were summarized as follows: KarXT 50 / 20 BID (for adverse events and Day 1 PK summaries only), KarXT 100 / 20 BID, KarXT 125 / 40 BID, KarXT 150 / 20 BID, KarXT 150 / 40 BID, and placebo (empty Vcaps® Plus capsules and Capsugel®; all cohorts were combined). Safety assessments were based on spontaneously reported adverse events, ECGs, clinical laboratory assessments, and vital signs. Exploratory analyses of saliva flow, Bristol stool scale, and pupil size were also performed.

[0228] Xanomeline was well absorbed into the systemic circulation at all doses following oral administration of the KAR-003 formulation, with peak concentrations of xanomeline observed at a median of 2 hours across all treatment groups and study days.

[0229] Median t of xanomeline 1 / 2 was similar across treatment groups and study days, and t 1 / 2 was not shown to be dose-dependent. Median t 1 / 2 The time was 3.4 to 5.8 hours.

[0230] GM xanomeline exposure did not increase dose-proportionally on day 3, from 100 mg to 150 mg when xanomeline was administered with 20 mg trospium, or from 125 mg to 150 mg when xanomeline was administered with 40 mg trospium. Lower xanomeline exposure was observed after treatment with KarXT 150 / 40 compared with KarXT 125 / 40. GM xanomeline exposure (C) on day 3 was significantly higher when the 150 mg xanomeline dose was administered with 20 and 40 mg trospium. max , AUC 0-last and AUC 0-12hr On day 7, GM xanomeline exposure increased slightly more than dose-proportionally from 125 mg to 150 mg when xanomeline was administered with 40 mg trospium.

[0231] After treatment with KarXT 100 / 20 BID and KarXT 125 / 40 BID, plasma accumulation of xanomeline was minimal to absent from days 3 to 7, but accumulation occurred after administration of KarXT 150 / 40 BID in 3 of 4 subjects who completed the study. The mean accumulation rates in the KarXT 150 / 40 BID group were 366.2% for RAUC and 366.2% for RC. max The rate was 445.4%.

[0232] Example 6 - Xanomeline Pharmacokinetics of KAR-003 Compared to KAR-001 Comparing xanomeline GM exposure between KAR-001 (75 mg xanomeline TID ± 20 mg trospium BID) and the KarXT 100 / 20 BID group of KAR-003, C was significantly higher in KAR-003 (days 3 and 7) than in the corresponding exposure in KAR-001 (days 3 and 9). max Value and AUC 0-6hr (KAR-003) or AUC 0-tau (KAR-001) showed a large median T maxwas observed at 2 hours in both studies and on both days (days 3 and 9 for KAR-001, and days 3 and 7 for KAR-003). These data indicate that the KarXT formulation enhances xanomeline exposure.

[0233] Trospium was absorbed into the systemic circulation after oral administration of the KarXT formulation at all doses. Peak trospium concentrations were observed at a median of 1.0 hour across all treatment groups and study days.

[0234] Median trospium t 1 / 2 was similar between treatment groups on day 3, with values ranging from 4.1 to 4.8 hours. On day 7, the median t 1 / 2 Values were similar for the KarXT 100 / 20 BID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) treatments, but slightly longer for the KarXT 150 / 40 BID group (7.1 hours).

[0235] GM trospium exposure decreased slightly less than dose-proportional from 20 to 40 mg on day 3 when administered with 150 mg xanomeline. Day 3 GM trospium exposure (C max , AUC 0-last and AUC 0-12hr ) was greater when a 20 mg BID dose of trospium was given with 100 mg BID xanomeline compared with 150 mg BID xanomeline. Day 3 GM trospium exposure was similar when 40 mg BID trospium was given with 125 mg BID and 150 mg BID xanomeline.

[0236] Trospium did not accumulate in plasma from days 3 to 7 after administration of KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID. Trospium accumulated in plasma from days 1 to 7 in the KarXT 100 / 20 BID group. The mean day 7 / day 1 accumulation rates were 348.7% (RAUC) and 379.9% (RC). max) was.

[0237] When comparing trospium GM exposure between the KarXT 100 / 20 BID groups of KAR-001 and KAR-003, C max and AUC 0-12hr was greater than the corresponding KAR-001 exposure on both days (days 3 and 9 for KAR-001, and days 3 and 7 for KAR-003). max was observed at 1.0 hour in both studies and on both days. These data indicate that the KarXT formulation enhances trospium exposure.

[0238] All cohorts in KAR-003 began with a 2-day run-in period of KarXT 50 / 20 BID for subjects randomized to KarXT. Figure 42 shows the mean (±SD) xanomeline PK concentrations, and Table 22 summarizes the xanomeline PK parameters on Day 1 for KarXT 50 / 20 BID treatment for all cohorts for the PK population. Samples collected prior to the first dose of xanomeline on Day 1 did not display measurable xanomeline concentrations. Xanomeline concentrations were quantifiable (>50 pg / mL) at all time points for 12 hours following the morning dose on Day 1.

[0239] [Table 26]

[0240] Figure 43 shows the mean (±SD) xanomeline PK concentrations by treatment on day 3 for the PK population. Table 23 summarizes these parameters. Xanomeline concentrations were measured 12 hours after administration. All subjects had plasma concentrations of xanomeline <50.0 pg / mL except for one subject. For each study group, quantification was possible at all time points within 12 hours following the morning administration of study drug on Day 3. Inter-subject variability was observed across the four treatment groups. max 23.7-58.2% (CV% ), C max 79.8-136.3% (geometric CV%), t 1 / 2 So 21.6~26 0.3% (CV%) and AUC 0-12hr The geometric CV is 77.1-96.1%. The median T value of xanomeline on day 3 was max KarXT 100 / 20 BID , KarXT 125 / 40 BID, KarXT 150 / 20 BID, and Kar The time was 2 hours in the XT 150 / 40 BID group. max Values are for all four treatment groups. The range is 1.0 to 6.0 hours in the body. 1 / 2 The elimination phase was not well characterized. In contrast to the previous study, KAR-001, the median time to peritoneal xanomeline on day 3 was estimated in 51 of 53 subjects. 1 / 2 was numerically similar among the four treatment groups. Median 1 / 2 The individual t 1 / 2 Values ranged from 2.4 to 8.6 hours across the four treatment groups.

[0241] [Table 27]

[0242] When KarXT was administered BID, the trospium dose (20 mg) was unchanged and the xanthate When the melin dose was increased from 100 mg (cohort 1) to 150 mg (cohort 2), Dose-normalized GM exposure to sanomelin on day 3 (dose-normalized GM C max and dosage Normalized GM AUC 0-last and AUC 0-12hr ) has decreased. The dose of xanomeline was increased from 125 mg (Cohort 4) without changing the dose of riboflavin (40 mg). When increased to 150 mg (Cohort 3), the dose-normalized GM on day 3 for xanomeline Exposure was slightly reduced (i.e., xanomeline exposure was significantly greater in KarXT 125 / 40 Lower after treatment with KarXT 150 / 40 BID compared with treatment with BID 150 mg oxaliplatin with either 20 mg or 40 mg trospium BID When comparing xanomeline exposure after BID administration, the G M.C. max , AUC 0-last , and AUC 0-12hr are shown to be similar It was.

[0243] Figure 44 shows the mean (±SD) xanomeline PK concentrations by treatment on day 7 for the PK population. The concentrations of xanomeline are shown in Table 24, and these parameters are summarized in Table 24. XT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 1 For the 50 / 40 BID group, the subjects were administered the investigational drug before the morning administration on the 7th day and after the morning administration on the 7th day. The intersubject variability was quantifiable in samples collected at all time points from Kar XT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 1 In the 25 / 40 BID group overall, T max 38.3% to 47.9% (CV%), C ma x 81.4% to 106.8% (geometric CV%), t 1 / 2 15.4% to 42.1% (CV%), AUC 0-12hr The geometric CV% ranged from 45.2% to 71.2%. Median T on day 7 of xanomeline max KarXT 100 / 20 BID, Kar XT 125 / 40 BID and KarXT 150 / 40 BID groups in 2.0 hours There was. Individual T max Values are KarXT 100 / 20 BID, KarXT 150 / 40 BID and KarXT 125 / 40 BID groups were 0.0 to 6.0 hours The median t value of xanomeline on day 7 was 1 / 2 KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID The median t 1 / 2 ranges from 4.6 to 5.8 hours Individual t 1 / 2 Values are KarXT 100 / 20 BID, KarXT 15 0 / 40 BID and KarXT 125 / 40 BID groups: 3.6 to 14.0 hours The range was between

[0244] [Table 28]

[0245] When KarXT was administered BID, the dose of trospium (40 mg) was unchanged and the dose of xanthate was When the Melin dose was increased from 125 mg (Cohort 4) to 150 mg (Cohort 3), Dose-normalized GM exposure to sanomelin on day 7 (dose-normalized GM C max , AUC0 -last and AUC 0-12hr ) increased.

[0246] Table 25 shows the xanomeline PK accumulation ratio (Day 7 / Day 3) by treatment for the PK population. Based on the mean accumulation ratios of xanomeline after treatment with KarXT 100 / 20 BID (Cohort 1) and KarXT 125 / 40 BID (Cohort 4), plasma accumulation of xanomeline from days 3 to 7 was minimal to nonexistent. The mean accumulation rates in the KarXT 100 / 20 BID group were 133.4% for RAUC and 125.4% for RC. max In the KarXT 125 / 40 BID group, RAUC was 143.9% and RC was 130.5%. max The mean accumulation ratios for the KarXT 150 / 40 BID group were 151.0%. Only one subject in the KarXT 100 / 20 BID group had lower exposure on Day 7 compared to Day 3. In contrast, three of four subjects in the KarXT 150 / 40 BID group who completed the study experienced moderate accumulation of xanomeline. The other subjects in the KarXT 150 / 40 BID group had similar exposure on Days 3 and 7. The mean accumulation ratios for the KarXT 150 / 40 BID group were 366.2% (RAUC) and 445.4% (RC). max ) was.

[0247] [Table 29]

[0248] Figure 45 compares the mean (±SD) xanomeline PK concentration-time profiles by treatment and visit (day) for the PK population. Figure 46 shows the mean (±SD) xanomeline PK trough concentrations by treatment for the PK population. Attainment of steady state was not assessed.

[0249] When comparing xanomeline GM exposure between KAR-001 (75 mg xanomeline TID ± 20 mg trospium BID) (Table 23) and the KarXT 100 / 20 BID group of KAR-003 (Table 21), the C on day 3 in the KarXT 100 / 20 BID group (KAR-003) was significantly higher. max Value and AUC 0-6hr (KAR-003) or AUC 0-tau The (AUC from time 0 to 6 hours) values (KAR-001) were shown to be approximately 2.3 to 2.6 times greater than the corresponding KAR-001 exposure on day 3.

[0250] Comparing the GM exposure of xanomeline on day 7 for the KarXT 100 / 20 BID group in KAR-003 (Table 22) with the exposure on day 9 for the xanomeline alone and xanomeline + trospium groups in KAR-001 (Table 23) showed that the day 7 values for the KarXT 100 / 20 BID group (KAR-003) were approximately 1.4-1.8 times greater than the corresponding exposure for KAR-001 on day 9. Median T max was 2.0 hours on days 3 and 7 for KAR-003 (Table 22) and 2.0 hours on days 3 and 9 for KAR-001 (Table 23). These data indicate that the KAR-003 formulation provided adequate exposure and PK characteristics.

[0251] Table 26 summarizes a subset of KAR-003 xanomeline PK parameters for the KarXT 100 / 20 BID group on days 3 and 7 of the PK population. Table 27 shows a summary of a subset of KAR-001 xanomeline PK parameters for the KAR-001 treatment on days 3 and 9 of the PK population.

[0252] [Table 30]

[0253] [Table 31]

[0254] Figure 47 shows the KarXT 50 / 20 BID treatment in the PK population (all cohorts). The mean (±SD) trospium PK concentrations on Day 1 are shown, and Table 28 shows the correlation between these parameters. Summarize the data collected before the first dose of trospium on Day 1. Samples did not show measurable concentrations of trospium. Trospium concentrations were quantifiable (>20 pg / mL) at all time points over the 12-hour period following administration of the morning dose on Day 1.

[0255] [Table 32]

[0256] Figure 48 shows the mean (±SD) trospium PK concentrations by treatment on Day 3 for the PK population, and Table 29 summarizes these parameters. Trospium concentrations were quantifiable in samples collected at all time points before and 12 hours after the morning Day 3 dose of study drug for all treatment groups (except for one subject who had a trospium plasma concentration <20.0 pg / mL at 12 hours post-dose). Inter-subject variability was <0.0 pg / mL across the four treatment groups. max 0.0 to 83.0% (CV%), C max 54.8-80.7% (CV%), t 1 / 2 9.1-34.0% (CV%), AUC 0-12hr The CV% ranged from 59.0 to 67.6%.

[0257] [Table 33]

[0258] Median trospium T on day 3 max KarXT 100 / 20 BID, Ka rXT 125 / 40 BID, KarXT 150 / 20 BID, and KarXT The 150 / 40 BID group had a mean of 1.0 hour. max Values are across all four treatment groups The median trospium dose on day 3 ranged from 1.0 to 6.0 hours. 1 / 2 There are four were numerically similar between treatment groups, with median t 1 / 2 The range is 4.1 to 4.8 hours. Individual t 1 / 2 ranged from 2.8 to 9.0 hours across the four treatment groups.

[0259] When KarXT was administered BID, the dose of xanomeline (150 mg) was unchanged. When the dose of spironolactone was increased from 20 mg (Cohort 2) to 40 mg (Cohort 3), Dose-normalized GM exposure on day 3 of trospium was increased. and either 100 mg (Cohort 1) or 150 mg (Cohort 2) xanomeline BID. When comparing trospium exposure on day 3 after coadministration, the 20 mg BI of trospium When dose D is administered with 100 mg xanomeline BID, 150 mg xanomeline B Compared with ID, trospium GM C max , AUC 0-last and AUC 0-1 2hr was shown to be larger.

[0260] Similarly, 40 mg trospium BID was administered at 125 mg (Cohort 4) or 150 mg (Cohort 5). Horoscope 3) Compare trospium exposure after co-administration with either xanomeline or On day 3, trospium was administered with 125 mg and 150 mg xanomeline BID. If trospium GM C max , AUC 0-last and AUC 0-12h were shown to be generally similar.

[0261] Figure 49 shows the mean (±SD) trospium PK concentrations by treatment at day 7 for the PK population. The concentrations of trospium are shown in Table 30, and the parameters are summarized in Table 30. 00 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 4 0 For the BID group, before the morning administration of the study drug on Day 7 and 12 hours after the morning administration on Day 7 Inter-subject variability was quantifiable in samples taken at all time points. 00 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 4 0 BID group overall, T max 0.0% to 86.3% (CV%), C max So 51 .2%~93.8%(geometric CV%), t 1 / 2 23.0% to 44.5% (CV%) and AUC 0-12hr The geometric CV% ranged from 59.4% to 76.7%.

[0262] [Table 34]

[0263] Median trospium T on day 7 max was 1.0 hour for the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID treatments. max Values ranged from 0.0 to 6.0 hours across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups.

[0264] Median trospium dose on day 7 1 / 2 was similar for the KarXT 100 / 20 BID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) groups. Median t 1 / 2 The mean time to death was 7.1 hours in the KarXT 150 / 40 BID group. 1 / 2 Values ranged from 3.1 to 11.9 hours across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups.

[0265] As observed on day 3, comparing trospium exposure on day 7 after administration of 40 mg trospium twice daily with either 125 mg (Cohort 4) or 150 mg (Cohort 3) xanomeline twice daily, trospium GM C was significantly lower when trospium was administered with 125 mg and 150 mg xanomeline twice daily. max , AUC 0-last and AUC 0-12hr were shown to be similar.

[0266] Table 31 summarizes the trospium PK accumulation ratios (Day 7 / Day 3; Day 7 / Day 1) by treatment for the PK population. Based on the mean trospium PK accumulation ratios, trospium accumulated little in plasma from Day 3 to Day 7 after administration of KarXT 100 / 20 BID (Cohort 1), and little to no accumulation after administration of KarXT 125 / 40 BID (Cohort 4) and KarXT 150 / 40 BID (Cohort 3). Two subjects had lower exposure on Day 7 compared to Day 3 in the KarXT 100 / 20 BID group.

[0267] The accumulation ratios from days 3 to 7 differed significantly between subjects in the KarXT 125 / 40 BID group and the KarXT 150 / 20 BID group. The mean accumulation ratios were 108.6% to 141.4% for RAUC and 141.4% for RC. max Trospium moderately accumulated in plasma from days 1 to 7 in the KarXT 100 / 20 BID group. All but one subject showed higher trospium exposure on day 7 compared with day 1. The mean accumulation ratios were 348.7% for RAUC and 348.7% for RC. max The potential effect of increasing the xanomeline dose (from 50 mg BID to 100 mg BID starting on Day 3) on trospium PK and bioavailability cannot be ruled out as contributing to the increased exposure from Days 1 to 7.

[0268] [Table 35]

[0269] Figure 50 shows the mean (±SD) trospium by treatment and visit (day) for the PK population. PK concentration-time profiles were compared. Figure 51 shows the treatment-dependent PK population. Mean (±SD) trospium PK trough concentrations by visit (day) are shown. Reach was not assessed.

[0270] Example 7 - Trospium Pharmacokinetics of KAR-003 Compared to KAR-001 Trospium on Day 1 of KAR-001 (first dose of trospium alone without pretreatment) ) (Table 33) and Day 1 of KAR-003 (xanomeline + trospium without pretreatment) When comparing the trospium exposure of KAR-003 with that of the control group (first dose) (Table 32), the trospium exposure of KAR-003 was , which are approximately 2.1-2.5 times higher than those obtained from KAR-001. While the comparison of day 3 GM exposure between studies is not actually a direct comparison (in the KAR-003 study, xanomeline administration did not begin until day 3), the number of doses and daily dose of trospium administered to subjects were the same. Day 3 GM trospium exposure in KAR-003 (Table 32) is also approximately 2.4-3.3 times higher than those obtained from KAR-001 (Table 33). Comparing the day 7 GM exposure of trospium in the KarXT 100 / 20 BID cohort (Cohort 1) in KAR-003 (Table 32) with the day 9 exposure in the xanomeline + trospium group in KAR-001 (Table 33) shows that exposure was again higher (approximately 3.5-4.3 times) than that obtained from KAR-001.

[0271] Trospium median T max The median T of trospium was 1.0 hour on days 3 and 7 in the KarXT 100 / 20 BID group of KAR-003 and 3 and 9 in the xanomeline + trospium group of KAR-001. max is the median T on day 1 in the trospium-only group (KAR-001). maxThe mean ...

[0272] Table 32 summarizes a subset of KAR-003 trospium PK parameters for the PK population, KarXT 50 / 20 BID treatment on Day 1 (all cohorts) and KarXT 100 / 20 BID treatment on Days 3 and 7. Table 33 summarizes a subset of KAR-001 trospium PK parameters for the PK population, trospium alone treatment on Day 1 and xanomeline + trospium treatment on Days 3 and 9.

[0273] [Table 36]

[0274] [Table 37]

[0275] Table 34 shows the system organ classes (SOCs) of the safety analysis population in Study KAR-001. The incidence of cholinergic TEAEs by preferred term is listed. The overall incidence was in the xanomeline + trospium group of KAR-001 (12 subjects [34. 3%]), KarXT 100 / 20 BID group (7 subjects [38.9%]), and Kar The results were similar in the XT 125 / 40 BID group (6 subjects [33.3%]).

[0276] [Table 38]

[0277] In the xanomeline + trospium arm of KAR-001, KarXT 100 / 20 B Compared with the ID and KarXT 125 / 40 BID groups, there was no significant difference in salivary secretion, hyperhidrosis, and laxative function. The incidence of diarrhea was high in subjects. Hypersalivation was also observed in patients receiving KAR-001 xanomeline plus trospiraceta. The incidence of rheumatoid arthritis was 25.7% in the KarXT 100 / 20 BID group and 5.6% in the KarXT 100 / 20 BID group. Hyperhidrosis was not observed in the XT 125 / 40 BID group. 20.0% of subjects in the Melin + Trospium group and 20.0% of subjects in the KarXT 100 / 20 BID group This occurred in 5.6% of subjects in the KarXT 125 / 40 BID group and 11.1% of subjects in the KarXT 125 / 40 BID group. Diarrhea occurred in 5.7% of subjects in the xanomeline plus trospium arm of KAR-001, No expression was observed in the rXT 100 / 20 BID group or the KarXT 125 / 40 BID group. It was.

[0278] The xanomeline + trospium arm of KAR-001 showed a significant improvement in nausea and vomiting compared with KarX T 100 / 20 BID group and KarXT 125 / 40 BID group compared with other No clear trends were observed. Nausea occurred in 17.1% of subjects in the KAR-001 xanomeline + trospium group and 22.2% of subjects in each of the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups. Vomiting occurred in 5.7% of subjects in the KAR-001 xanomeline + trospium group, 27.8% of subjects in the KarXT 100 / 20 BID group, and 5.6% of subjects in the KarXT 125 / 40 BID group.

[0279] Xanomeline and trospium were absorbed into the systemic circulation after oral administration of the KAR-003 formulation at all doses. PK results suggest that neither xanomeline nor trospium significantly affected the PK behavior of the other drug. The KAR-003 formulation increased the blood levels of xanomeline and trospium compared with KAR-001, which administered both compounds separately.

[0280] No new safety signals were reported with the KarXT formulation. All TEAEs were mild or moderate in severity, and there were no SAEs or deaths. The incidence of subject hypersalivation, hyperhidrosis, and diarrhea was higher in the xanomeline + trospium arm of KAR-001 compared with the KarXT 100 / 20 BID and KarXT 125 / 40 BID arms of KAR-003.

[0281] The foregoing description is given for clarity of understanding only, and no unnecessary limitations should be understood therefrom, as modifications within the scope of the present disclosure may be apparent to those skilled in the art. Throughout this specification, when a composition is described as comprising components or materials, it is contemplated that the composition may consist essentially of, or consist of, any combination of the listed components or materials, unless otherwise specified. Similarly, when a method is described as comprising steps, it is contemplated that the method may consist essentially of, or consist of, any combination of the listed steps, unless otherwise specified. The disclosure illustratively disclosed herein may suitably be practiced in the absence of any element or step not specifically disclosed herein.

[0282] The implementation of the methods disclosed herein, and their individual steps, can be performed manually and / or with the aid of automation provided by electronic devices. While the processes have been described with reference to embodiments, those skilled in the art will readily recognize that other ways of performing the operations associated with the methods can be used. For example, the order of various steps can be changed without departing from the scope or spirit of the methods, unless otherwise noted. Furthermore, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0283] It is recognized that certain features of the invention that are described, for clarity, in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention that are described in the context of a single embodiment may also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables contained in the general chemical formulas described herein, to the extent that such combinations encompass stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), are specifically encompassed by the present invention, as if each and every combination were individually and explicitly set forth. Furthermore, all subcombinations of chemical groups listed in embodiments describing such variables, and all subcombinations of uses and medical indications described herein, are also specifically encompassed by the present invention, as if each and every subcombination of chemical groups and subcombinations of uses and medical indications were individually and explicitly set forth herein.

[0284] All patents, publications, and references cited herein are hereby incorporated by reference in their entirety. In the event of a conflict between the present disclosure and the incorporated patents, publications, and references, the present disclosure shall control.

Claims

1. 1. An oral pharmaceutical composition comprising xanomeline and / or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, wherein the oral pharmaceutical composition reduces the median Tmax of xanomeline at 2 hours when administered to a patient in need thereof. ｍａｘ and median trospium T at 1 hour ｍａｘ an oral pharmaceutical composition sufficient to provide an in vivo plasma profile comprising:

2. The in vivo plasma profile has a mean dose-normalized C of 48.5 to 121.3 pg / mL / mg. ｍａｘ and mean dose-normalized C of trospium from 156 to 375 pg / mL / mg. ｍａｘ 10. The oral pharmaceutical composition of claim 1, further comprising:

3. The in vivo plasma profile shows a mean dose-normalized AUC of xanomeline from 263 to 577 pg / mL / mg. ０－１２ and mean dose-normalized AUC of trospium from 881 to 2024 pg / mL / mg. ０－１２ 3. The oral pharmaceutical composition of claim 1 or 2, further comprising:

4. Use of an oral pharmaceutical composition according to any one of claims 1 to 3 for activating muscarinic receptors in a biological sample.

5. 4. Use of an oral pharmaceutical composition according to any one of claims 1 to 3 for treating a disorder ameliorated by activating muscarinic receptors in a subject in need thereof.

6. 10. Use of an oral pharmaceutical composition according to any one of claims 1 to 3 and a second therapeutic agent to treat a disorder ameliorated by activating muscarinic receptors in a subject in need of such treatment.

7. 7. The use according to claim 5 or 6, wherein the disorder is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy.

8. 7. The use according to claim 5 or 6, wherein the disorder is a neurodegenerative disease.

9. 7. The use according to claim 5 or 6, wherein the disorder is a central nervous system disease.

10. The compound 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium.

11. An oral pharmaceutical composition comprising xanomeline and / or a salt thereof and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium.

12. 4. A method for preparing an oral pharmaceutical composition according to any one of claims 1 to 3, comprising mixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads comprising a salt of trospium.

13. 13. The method of claim 12, wherein the plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof comprises an antioxidant.

14. 14. The method of claim 12 or 13, further comprising formulating the mixed beads into a capsule.

15. 15. The method of any one of claims 12-14, further comprising storing the oral pharmaceutical composition at a temperature of about 2°C to about 8°C prior to distributing the oral pharmaceutical composition to the subject.

16. 16. The method of claim 15, wherein the method further comprises storing the oral pharmaceutical composition at a temperature of about 20°C to about 25°C after the oral pharmaceutical composition has been dispensed to the subject.

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