Compositions and methods for treating disorders ameliorated by muscarinic receptor activation

Abstract

The present disclosure provides compositions and methods for treating disorders ameliorated by muscarinic receptor activation. In particular, the disclosure relates to oral pharmaceutical compositions of xanthene or a salt thereof and a trospchloramine salt formulated in different matrices. The disclosure also relates to the use of said composition as a medicament for the treatment of disorders ameliorated by muscarinic receptor activation in a human or animal subject.

Description

This application is a divisional of patent application with the application date of September 27, 2019, application number 201980064585.4, and the title of “Compositions and methods for treating disorders alleviated by muscarinic receptor activation.”

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

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

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

[0004] Existing schizophrenia treatments rely on dopamine and serotonin receptors, as was the case with the first antipsychotic drug, chloφromazine, discovered in 1952. For over 60 years, the same basic pharmacology has been the standard of care for schizophrenia. Current antipsychotic drugs are only effective against positive symptoms, and not against negative and cognitive symptoms. Alzheimer’s disease is another therapeutic area in which it has proven extremely difficult to develop new therapies, with a success rate of only 0.4% of molecules entering clinical development and gaining market approval. Patients in these areas are in desperate need of new treatments, but despite the tremendous efforts of scientists and drug developers from around the world, development remains extremely difficult.

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

[0006] In a double-blind placebo-controlled trial of schizophrenic patients using xanomeline, which is a muscarinic cholinergic receptor agonist with preferential activity at the Ml and M4 subtypes of receptors, schizophrenia was reduced. However, because xanomeline also binds to muscarinic receptors outside the brain, it resulted in a number of serious side effects, including GI side effects, cardiac side effects, and hypersalivation. Dose-limited adverse events were problematic and resulted in a high rate of discontinuation (56% in a 26-week Alzheimer's study), and ultimately led to the discontinuation of xanomeline development. Despite early promise, xanomeline development stalled for over 15 years. Many companies have attempted to develop muscarinic receptor agonists for CNS disorders that avoid these unacceptable side effects, but none have made it to market. Past development efforts have focused on medicinal chemistry to develop more tolerable molecules, often by selecting for Ml and M4 subtypes over M2 and M3 muscarinic receptor subtypes. However, activation of Ml and / or M4 outside the brain can still result in muscarinic-related intolerance. Little progress has been made in mitigating the adverse effects resulting from activation of peripheral muscarinic receptors.

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

[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 xanomeline beads is 0.425 mm to 1.18 mm. In certain embodiments, the size of the xanomeline beads is 0.6 mm and 0.85 mm. In certain embodiments, the size of the trospium beads is 0.425 mm to 1.18 mm. In certain embodiments, the size of the trospium beads is 0.6 mm to 0.85 mm.

[0010] In certain embodiments, the xanomeline contained in the xanomeline beads is about 2.5 times the amount of trospium chloride contained in the trospium beads.

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

[0012] In certain embodiments, the oral pharmaceutical composition provides a mean Cmax of 7850 ± 3360 pg / mL of trospium when administered to a patient as 20 mg trospium twice a day for at least 7 days 最 In certain embodiments, the oral pharmaceutical composition provides a mean AUC of 41900 ± 15500 hr»pg / mL of trospium when administered to a patient as 20 mg trospium twice a day for at least 7 days 0-12 .

[0013] In certain embodiments, the xinafoate salt is xinafoate. In certain embodiments, the xinafoate bead comprises 30 wt.% to 80 wt.% xinafoate, for example 66 wt.% xinafoate. In certain embodiments, the xinafoate bead comprises 15 wt.% to 65 wt.% microcrystalline cellulose, for example 33.5 wt.% microcrystalline cellulose. In certain embodiments, the xinafoate bead comprises 0 wt.% to 2 wt.% talc, for example 0.5 wt.% talc. In certain embodiments, the xinafoate bead comprises 30 wt.% to 80 wt.% xinafoate, 15 wt.% to 65 wt.% microcrystalline cellulose, and 0 wt.% to 2 wt.% talc. In certain embodiments, the xinafoate bead comprises 66 wt.% xinafoate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc.

[0014] In certain embodiments, the trospium salt is trospium chloride. In certain embodiments, the trospium bead comprises 8 wt.% to 35 wt.% trospium chloride, for example 17.7 wt.% trospium chloride. In certain embodiments, the trospium bead comprises 25 wt.% to 80 wt.% microcrystalline cellulose, for example 46.8 wt.% microcrystalline cellulose. In certain embodiments, the trospium bead comprises 15 wt.% to 70 wt.% lactose monohydrate, for example 35 wt.% lactose monohydrate. In certain embodiments, the trospium bead comprises 0 wt.% to 2 wt.% talc, for example 0.5 wt.% talc. In certain embodiments, the trospium bead comprises 8 wt.% to 35 wt.% trospium chloride, 25 wt.% to 80 wt.% microcrystalline cellulose, 15 wt.% to 70 wt.% lactose monohydrate, and 0 wt.% to 2 wt.% talc. In certain embodiments, the trospium bead comprises 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% 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 dosage strength of the capsule is 50 mg xanomeline free base and 20 mg trospium chloride. In certain embodiments, the dosage strength of the capsule is 50 mg xanomeline free base and 10 mg trospium chloride. In certain embodiments, the dosage strength of the capsule is 75 mg xanomeline free base and 20 mg trospium chloride. In certain embodiments, the dosage strength of the capsule is 75 mg xanomeline free base and 10 mg trospium chloride. In certain embodiments, the dosage strength of the capsule is 125 mg xanomeline free base and 30 mg trospium chloride. In certain embodiments, the dosage strength of the capsule is 125 mg xanomeline free base and 40 mg trospium chloride.

[0016] The present disclosure also provides an oral pharmaceutical composition comprising: a plurality of xanomeline beads having a size of 0.425 mm to 1.18 mm and a core comprising 30 wt.% to 80 wt.% xanomeline tartrate, 15 wt.% to 65 wt.% microcrystalline cellulose, and 0.2 wt.% to 2 wt.% talc; and a plurality of trospium beads having a size of 0.425 mm to 1.18 mm and a core comprising 8 wt.% to 35 wt.% trospium, 25 wt.% to 80 wt.% microcrystalline cellulose, 15 wt.% to 70 wt.% lactose monohydrate, and 0.2 wt.% to 2 wt.% talc; a dissolution rate of the plurality of xanomeline beads and the plurality of trospium beads greater than about 95% within about the first 45 minutes after the dosage form is placed in aqueous solution; and wherein the mean Cmax of trospium provided is 7850 ± 3360 pg / mL, the mean AUC 最大 is 41900 ± 15500 hr- pg / mL. 0-12 is 41900 ± 15500 hr- pg / mL.

[0017] The present disclosure also provides an oral pharmaceutical composition comprising: a capsule comprising a plurality of xanomeline beads and a plurality of trospium beads; the plurality of xanomeline beads having a size of 0.6 mm to 0.85 mm, and a core comprising 66 wt.% xanomeline tartrate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc; and the plurality of trospium beads having a size of 0.6 mm to 0.85 mm, and a core comprising 17.7 wt.% trospium chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate, and 0.5 wt.% talc; the plurality of xanomeline beads and the plurality of trospium beads having a dissolution rate greater than about 95% within about the first 20 minutes after the dosage form is placed in aqueous solution; and wherein the mean Cmax of trospium provided is 7850 ± 3360 pg / mL, the mean AUC 最大 is 41900 ± 15500 hr»pg / mL. 0-12 is 41900 ± 15500 hr»pg / mL.

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

[0019] Also provided is a method of treating a disorder ameliorated by activation of muscarinic receptors in a subject in need thereof, the method comprising administering to a patient in need thereof any of the oral pharmaceutical compositions described herein. In certain embodiments, the subject is a human. In certain embodiments, the disorder is selected from schizophrenia, Alzheimer’s disease, Parkinson’s disease, depression, dyskinesia, pain, drug addiction, tauopathies, and synucleinopathies.

[0020] Also provided is a method of treating a disorder ameliorated by activation of muscarinic receptors in a subject in need thereof, the method comprising administering sequentially or co-administering any of the oral pharmaceutical compositions 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 wt.% 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-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 wt.% 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-ium; and a plurality of trospium beads comprising a trospium salt.

[0022] The present disclosure also provides an oral pharmaceutical composition comprising xanomeline and / or a salt thereof and trospium chloride for use in treating a muscarinic disorder in a patient in need thereof, wherein when administered to a patient in need thereof, the composition is sufficient to provide an in vivo plasma profile comprising a median T 最大 of 2 hours for xanomeline, and a median T 最大 of 1 hour for trospium chloride. In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized C 最大 of 48.5 pg / mL / mg to 121.3 pg / mL / mg for xanomeline, and a mean dose-normalized C 最大 of 156 pg / mL / mg to 375 pg / mL / mg for trospium chloride. In certain embodiments, the in vivo plasma profile further comprises a mean dose-normalized AUC 0-12 of 263 hr-pg / mL / mg to 577 hr-pg / mL / mg for xanomeline, and a mean dose-normalized AUC 0-12 of 881 hr-pg / mL / mg to 2024 hr-pg / mL / mg for trospium chloride.

[0023] Other aspects and advantages will become apparent to those of ordinary skill in the art upon reading the following detailed description, including the specific embodiments described herein. While the dosage forms, methods of manufacture, and methods of treatment can have various embodiments, the following description includes specific embodiments with the understanding that the present disclosure is illustrative and is not intended to limit the disclosure to the particular embodiments described herein. BRIEF DESCRIPTION OF DRAWINGS

[0024] The present disclosure can be readily understood by reading the following detailed description, including the specific embodiments described herein, with the accompanying drawings. The drawings provide example embodiments or aspects of the present disclosure and do not limit the scope of the present disclosure.

[0025] Figure 1 A stability schedule and protocol for xanomeline / trospium chloride capsules is shown.

[0026] Figure 2 is a scanning electron microscope (SEM) image of xanomeline tartrate 66% beads at 30x magnification showing the bead size for xanomeline / trospium chloride capsules is 0.6 mm to 0.85 mm.

[0027] Figure 3 is a SEM image of trospium chloride 17.7% beads at 30x magnification showing the bead size for xanomeline / trospium chloride capsules is 0.6 mm to 0.85 mm.

[0028] Figure 4is the dissolution profile of xinafoate / tiotropium Cl 50 / 20 mg capsules comprising xinafoate beads and tiotropium Cl beads and measured at time 0, 1 month, 2 months, 3 months and 6 months after storage at 40°C / 75% RH and 3 months after storage at 25°C / 60% RH.

[0029] Figure 5 is the dissolution profile of xinafoate / tiotropium Cl 50 / 10 mg capsules comprising xinafoate beads and tiotropium Cl beads and measured at time 0, 1 month, 2 months and 3 months after storage at 40°C / 75% RH and 3 months after storage at 25°C / 60% RH.

[0030] Figure 6 shows the stability data of xinafoate / tiotropium Cl 50 / 10 mg capsules stored at 25°C / 60% RH and measured at time 0, 3 months, 6 months and 9 months.

[0031] Figure 7 shows the stability data of xinafoate / tiotropium Cl 50 / 10 mg capsules stored at 30°C / 65% RH and measured at time 0, 3 months and 6 months.

[0032] Figure 8 shows the stability data of xinafoate / tiotropium Cl 50 / 10 mg capsules stored at 40°C / 75% RH and measured at time 0, 3 months and 6 months.

[0033] Figure 9 is the dissolution of xinafoate / tiotropium Cl 50 / 10 mg capsules stored at 25°C / 60% RH and measured at time 0, 3 months, 6 months and 9 months.

[0034] Figure 10 is the dissolution profile of xinafoate / tiotropium Cl 50 / 10 mg capsules stored at 30°C / 65% RH and measured at time 0, 3 months and 6 months.

[0035] Figure 11 is the dissolution profile of xinafoate / tiotropium Cl 50 / 10 mg capsules stored at 40°C / 75% RH and measured at time 0, 3 months and 6 months.

[0036] Figure 12 is the related substances profile of xinafoate / tiotropium Cl 50 / 10 mg capsules measured at time 0, 3 months, 6 months and 9 months related to the xinafoate active pharmaceutical ingredient.

[0037] Figure 13is the spectrum of related substances associated with the xinafoate active pharmaceutical ingredient for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl measured at 0, 3 months, and 6 months.

[0038] Figure 14 is the detailed specification for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl.

[0039] Figure 15 shows the stability data for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl stored at 25 °C / 60% RH and measured at 0, 3 months, and 6 months.

[0040] Figure 16 shows the stability data for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl stored at 30 °C / 65% RH and measured at 0 and 6 months.

[0041] Figure 17 shows the stability data for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl stored at 40 °C / 75% RH and measured at 0, 3 months, and 6 months.

[0042] Figure 18 is the dissolution for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl stored at 25 °C / 60% RH and measured at 0, 3 months, 6 months, and 9 months.

[0043] Figure 19 is the dissolution spectrum for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl stored at 30 °C / 65% RH and measured at 0 and 6 months.

[0044] Figure 20 is the dissolution spectrum for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl stored at 40 °C / 75% RH and measured at 0, 3 months, and 6 months.

[0045] Figure 21 is the spectrum of related substances associated with the xinafoate active pharmaceutical ingredient for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl measured at 0, 3 months, and 6 months.

[0046] Figure 22 is the spectrum of related substances associated with the xinafoate active pharmaceutical ingredient for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl measured at 0, 3 months, and 6 months.

[0047] Figure 23 is the detailed specification for XANOMELT® 50 / 20 mg capsules of xinafoate / tiotropium chloride Cl.

[0048] Figure 24 Stability data for Xanomeline / Trozami ne CI 75 / 10 mg capsules stored at 25°C / 60% RH and measured at 0, 3 months and 6 months time.

[0049] Figure 25 Stability data for Xanomeline / Trozami ne CI 75 / 10 mg capsules stored at 30°C / 65% RH and measured at 0 and 6 months time.

[0050] Figure 26 Stability data for Xanomeline / Trozami ne CI 75 / 10 mg capsules stored at 40°C / 75% RH and measured at 0, 3 months and 6 months time.

[0051] Figure 27 Dissolution of Xanomeline / Trozami ne CI 75 / 10 mg capsules stored at 25°C / 60% RH and measured at 0, 3 months and 6 months time.

[0052] Figure 28 Dissolution profile of Xanomeline / Trozami ne CI 75 / 10 mg capsules stored at 30°C / 65% RH and measured at 0 and 6 months time.

[0053] Figure 29 Dissolution profile of Xanomeline / Trozami ne CI 75 / 10 mg capsules stored at 40°C / 75% RH and measured at 0, 3 months and 6 months time.

[0054] Figure 30 Related Substance Profile of Xanomeline / Trozami ne CI 75 / 10 mg capsules measured at 0, 3 months and 6 months time related to the Xanomeline active pharmaceutical ingredient.

[0055] Figure 31 Related Substance Profile of Xanomeline / Trozami ne CI 75 / 10 mg capsules measured at 0, 3 months and 6 months time related to the Trozami ne chloride active pharmaceutical ingredient.

[0056] Figure 32 Detailed description of Xanomeline / Trozami ne CI 75 / 10 mg capsules.

[0057] Figure 33 Dissolution of Xanomeline / Trozami ne CI 75 / 20 mg capsules stored at 25°C / 60% RH and measured at 0, 3 months and 6 months time.

[0058] Figure 34Dissolution of Xanomeline / Trospium Cl 75 / 20 mg capsules stored at 30°C / 65% RH and measured at 0 and 6 months.

[0059] Figure 35 Stability data for Xanomeline / Trospium Cl 75 / 20 mg capsules stored at 40°C / 75% RH and measured at 0, 3 months, and 6 months is shown.

[0060] Figure 36 Dissolution of Xanomeline / Trospium Cl 75 / 20 mg capsules stored at 25°C / 60% RH and measured at 0, 3 months, and 6 months.

[0061] 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.

[0062] Figure 38 Dissolution profile of Xanomeline / Trospium Cl 75 / 20 mg capsules stored at 40°C / 75% RH and measured at 0, 3 months, and 6 months.

[0063] Figure 39 Xanomeline / Trospium Cl 75 / 20 mg capsule related substances profile associated with the xanomeline active pharmaceutical ingredient measured at 0, 3 months, and 6 months.

[0064] Figure 40 Xanomeline / Trospium Cl 75 / 20 mg capsule related substances profile associated with the trospium chloride active pharmaceutical ingredient measured at 0, 3 months, and 6 months.

[0065] Figure 41 Xanomeline / Trospium Cl 75 / 20 mg capsule details.

[0066] Figure 42 Depicts the mean (± standard deviation) xanomeline pharmacokinetic concentration on Day 1 for the group of all KAR-003 pharmacokinetic populations treated with KarXT 50 / 20 twice daily.

[0067] Figure 43 Depicts the mean (± standard deviation) xanomeline pharmacokinetic concentration on Day 3 for the group of all KAR-003 pharmacokinetic populations treated with KarXT 50 / 20 twice daily.

[0068] Figure 44Depicts the mean (± standard deviation) xylometazoline pharmacokinetic concentration on Day 7 for the group of all KAR-003 pharmacokinetic populations by twice daily KarXT 50 / 20 treatment.

[0069] Figure 45 Depicts the mean (± standard deviation) xylometazoline pharmacokinetic concentration by treatment and follow-up for the KAR-003 pharmacokinetic population.

[0070] Figure 46 Depicts the mean (± standard deviation) xylometazoline pharmacokinetic trough concentration by treatment for the KAR-003 pharmacokinetic population.

[0071] Figure 47 Depicts the mean (± standard deviation) trospium pharmacokinetic concentration on Day 1 for the group of all KAR-003 pharmacokinetic populations by twice daily KarXT 50 / 20 treatment.

[0072] Figure 48 Depicts the mean (± standard deviation) trospium pharmacokinetic concentration on Day 3 by treatment for the KAR-003 pharmacokinetic population.

[0073] Figure 49 Depicts the mean (± standard deviation) trospium pharmacokinetic concentration on Day 7 by treatment for the KAR-003 pharmacokinetic population.

[0074] Figure 50 Depicts the mean (± standard deviation) trospium pharmacokinetic concentration by treatment and follow-up for the KAR-003 pharmacokinetic population.

[0075] Figure 51 Depicts the mean (± standard deviation) trospium pharmacokinetic trough concentration by treatment and follow-up for the KAR-003 pharmacokinetic population. DETAILED DESCRIPTION

[0076] The articles "a" and "an" are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0077] The terms "comprise" and "comprising" are used herein in their inclusive sense, meaning that they can include additional elements.

[0078] The term "consisting of is used herein to limit the claim to the specified materials or steps and to exclude addition of unrecited materials or steps. The term "consisting essentially of is used herein to limit the claim to the specified materials or steps and to exclude addition of unrecited materials or steps except for innocuous materials or steps that do not materially affect the character of the claim.

[0079] The term "consisting essentially of shall limit the elements to those specified, and those that do not materially affect the basic and novel characteristic(s) of the material or process.

[0080] All ranges expressed herein include all possible sub-ranges within the range and any combination of such sub-ranges, unless otherwise stated. Defaults are to the lower end of the range, unless otherwise noted. In providing a range of values, the upper and lower limits of the range are inclusive, unless otherwise stated, and each intermediate value and any other stated or intervening value within that range is contemplated to be included in the disclosure. The upper and lower limits of these smaller ranges can independently be included in the smaller ranges and are also encompassed within the disclosure, subject to any explicitly excluded limit in the stated range. Where the range includes one or both of the limits, ranges excluding either or both of those included limits are also contemplated to be included in the disclosure.

[0081] The term wt.% is a weight percent of, for example, the core, enteric coating, or total bead, based on the total weight, as described by context. Unless otherwise specified, wt.% is intended to describe a weight percent on a dry weight basis (e.g., for a dried core).

[0082] 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. The release kinetics of a controlled release formulation can result in measurable serum levels of the drug for a longer period of time than might be possible following intravenous injection or following administration of an immediate release oral dosage form. Controlled release, slow release, sustained release, extended release, time release, and delayed release have the same definition herein.

[0083] The term "comprising" means "including, but not limited to" The terms "comprising" and "including" are used interchangeably.

[0084] The term "mammal" is known in the art. Exemplary mammals include humans, primates, cows, pigs, dogs, cats, and rodents (e.g., mice and rats).

[0085] The terms "parenteral administration" and "parenterally administered" are art-recognized and refer to modes of administration other than oral and topical administration, usually by injection. These modes of administration include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinally, and intrasternal injection and infusion.

[0086] A "patient," "subject," or "host" treated by the subject methods refers to either a human or a non-human mammal.

[0087] 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, involved in carrying or transporting any subject composition or component thereof from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the subject composition and its components and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethylene glycol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations.

[0088] The term "pharmaceutically acceptable salt" is art-recognized, and refers to a salt of a relatively non-toxic acid or base, which includes inorganic and organic acids and bases, including those included in the compositions of the present disclosure. Suitable non-toxic acids include inorganic and organic acids such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, itaconic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like.

[0089] The term "treatment" is art-recognized, and refers to curing as well as ameliorating at least one symptom of any condition or disorder.

[0090] In jurisdictions where the patenting of a process for the administration of a composition to the human body is prohibited, the meaning of "administering" a composition to a human subject shall be limited to prescribing a controlled substance to a human subject who will self-administer by any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). The broadest reasonable interpretation in compliance with the law or regulation defining patentable subject matter is intended. In jurisdictions where the patenting of a process for the administration of a composition to the human body is not prohibited, "administering" a composition includes both a process for the administration of a composition to the human body and the aforementioned activity.

[0091] 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, drugs; vitamins; mineral supplements; substances used in the treatment, prevention, diagnosis, cure, or mitigation of a disease or condition; substances that affect the structure or function of the body, or prodrugs that become biologically active or more active upon being placed in a physiological environment.

[0092] The term“psychotherapy” refers to non-pharmacological therapies in which a person skilled in the art uses a variety of techniques (these techniques involve verbal and other interactions with the patient) to achieve a positive therapeutic outcome. Such techniques include, but are not limited to, behavioral therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling, art therapy, music therapy, occupational therapy, humanistic therapy, existential therapy, transpersonal therapy, client-centered therapy (also known as person-centered therapy), Gestalt therapy, biofeedback therapy, rational emotive behavior therapy, reality therapy, response-based therapy, sandplay therapy, state dynamic therapy, hypnosis, and verifiable therapy. Psychotherapy can involve a combination of two or more techniques. The therapist can select and adjust the techniques according to the needs of each patient and the patient’s response.

[0093] The term“muscarinic disorder” refers to any disease or condition that is improved by activation of the muscarinic system. Such diseases include diseases in which direct activation of muscarinic receptors themselves or inhibition of cholinesterase has produced a therapeutic effect.

[0094] The terms“disease related to schizophrenia” and“disorder related to schizophrenia” include, but are not limited to, schizoaffective disorder, psychosis, delusional disorder, psychosis related to Alzheimer’s disease, psychosis related to Parkinson’s disease, psychotic depression, bipolar disorder, psychotic bipolar disorder, Huntington’s disease, Lewy body dementia, or any other disease with psychotic features.

[0095] The term“movement disorder” includes, but is not limited to, Gilles de la Tourette syndrome, Friederich ataxia, Huntington’s chorea, restless leg syndrome, and other diseases or disorders whose symptoms include excessive movement, itching, and cramping.

[0096] The term "mood disorder" includes major depressive disorder, dysthymia, recurrent brief depression, minor depressive disorder, bipolar disorder, mania, and anxiety.

[0097] The term "cognitive disorder" refers to a disease or disorder characterized by cognitive deficits (e.g., having abnormal working memory, problem-solving abilities, 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, Lewy body-related dementia, and idiopathic dementia), Pick's disease, tauopathies, synucleinopathies, confusion, fatigue-related cognitive deficits, learning disorders, brain trauma, autism, age-related cognitive decline, and Cushing's Disease (cognitive disorders associated with autoimmune diseases).

[0098] The term "attention disorder" refers to a disease or condition characterized by abnormal or reduced attention span. Diseases include, but are not limited to, attention deficit and hyperactivity disorder (ADHD), attention deficit disorder (ADD), Dubowitz Syndrome, FG syndrome, Down's syndrome, growth retardation due to insulin-like growth factor I (IGF1) deficiency, hepatencephalopathy syndrome, and Strauss Syndrome.

[0099] The term "addictive disorder" refers to a disease or condition characterized by addiction or drug dependence as defined by the Diagnostic & Statistical Manual V (DSM-5). Such disorders are characterized by physical dependence, withdrawal, and tolerance to substances. These substances include, but are not limited to, alcohol, cocaine, amphetamines, opioids, benzodiazepines, inhalants, nicotine, barbiturates, cocaine, and cannabis. Addictive disorders also include behaviors that patients force or persist in despite clear negative consequences. For example, gambling addiction (gambling addiction or compulsive gambling) is recognized by those skilled in the art as an addictive behavior that often has devastating consequences. In certain embodiments, the addictive behavior can be internet gaming disorder (gaming addiction) as defined in the DSM-5.

[0100] The term "pain" refers to physical distress or discomfort caused by disease or injury. Pain is a subjective experience and the perception of pain is part of the central nervous system (CNS). Often, noxious (peripheral) stimuli are transmitted to the CNS in advance, but pain is not always associated with nociception. There is a wide variety of clinical pain that originates from different underlying pathophysiological mechanisms and requires different treatment approaches. Three major types of clinical pain have been characterized: acute pain, chronic pain, and neuropathic pain.

[0101] Acute clinical pain can be caused by inflammation or soft tissue injury. This type of pain is adaptive and has a biologically relevant alarm function and allows healing and repair of the already damaged body part undisturbed. The protective function is achieved by making the injured or inflamed area and the surrounding tissue highly sensitive to all stimuli so that contact with any external stimuli can be avoided. The neuronal mechanisms of this type of clinical pain are well known and pharmacological control of acute clinical pain is effective, e.g. by non-steroidal anti-inflammatory drugs (NSAIDs) up to opioids, depending on the type and extent of the pain sensation.

[0102] Chronic clinical pain manifests as persistent allodynia, which is caused by persistent peripheral lesions, e.g. cancer or chronic inflammation, e.g. arthritis, or it can be independent of such triggers. Chronic pain independent of triggers is maladaptive, has no survival advantage and is usually not effectively treatable.

[0103] Neuropathic pain can be peripheral or central. Peripheral neuropathic pain is caused by injury or infection of peripheral sensory nerves, while central neuropathic pain is caused by injury to the CNS or / and the spinal cord. Both peripheral and central neuropathic pain can occur without an obvious initial nerve injury.

[0104] 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.

[0105] The term "inhibitor" refers to a molecule described as an antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, allosteric antagonist, or a molecule that directly or indirectly decreases receptor activity or signaling.

[0106] The term "maximum tolerated dose" refers to the largest 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.

[0107] The term "muscarinic receptor" refers to a G protein-linked receptor that binds the neurotransmitter acetylcholine. Five subtypes of muscarinic receptors have been identified to date. "M1" refers to subtype one muscarinic receptor. "M2" refers to subtype two muscarinic receptor. "M3" refers to subtype three muscarinic receptor. "M4" refers to subtype four muscarinic receptor. "M5" refers to subtype five muscarinic receptor.

[0108] The term "antipsychotic" refers to a drug that reduces psychosis, hallucinations, or delusions. Antipsychotics include, but are not limited to, haloperidol, droperidol, chloφromazine, fluphenazine, peφhenazine, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, piperacetazine, promazine, triflupromazine, levomepromazine, promethazine, pipotiazine, chlorprothixene, thiothixene, flupenthixol, zuclopenthixol, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride, asenapine, paliperidone, zotepine, aripiprazole, blonanserin, and

[0109] The term "anxiolytic" refers to a drug that reduces anxiety, fear, panic, or related feelings. Such drugs include, but are not limited to, benzodiazepines (e.g., alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), and hydroxyzine.

[0110] The term "antidepressant" refers to a drug that reduces depression and related conditions (e.g., mood disorders). Such drugs include, but are not limited to, selective serotonin reuptake inhibitors (SSRIs, e.g., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), serotonin norepinephrine reuptake inhibitors (SNRIs, e.g., desvenlafaxine, duloxetine, milnacipram, venlafaxine), mianserin, mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindol, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, tricyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, protriptyline, nortriptyline), and monoamine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine).

[0111] The term "sedative" or "tranquilizer" refers to a drug that induces sleepiness, promotes tiredness or the desire to sleep, or promotes unconsciousness. Such drugs include, but are not limited to, benzodiazepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital), eszopiclone, zaleplon, Zolpidem, and zopiclone. Pharmaceutical compositions

[0112] 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 dissolution kinetics that have more effective therapeutic effects for both active ingredients, enhanced pharmacokinetics for the chloroquine tridihexethyl, and greater dose compliance. The present disclosure also provides dosage forms with different strengths and / or different ratios of the two active ingredients.

[0113] Provided herein is an oral pharmaceutical composition comprising a plurality of xanomeline beads comprising xanomeline or a salt thereof; and a plurality of tridihexethyl beads comprising a tridihexethyl salt. In certain embodiments, the plurality of xanomeline beads have a core comprising xanomeline or a salt thereof. In certain embodiments, the plurality of tridihexethyl beads have a core comprising a tridihexethyl salt.

[0114] In certain embodiments, separate populations of drug beads comprising either xanomeline tartrate or chloroquine tridihexethyl are contained within a capsule shell comprising hydroxypropyl methylcellulose (HPMC), wherein the drug beads are of comparable size and rapidly release the active ingredients at substantially similar rates. Upon dissolution of the capsule shell in the stomach, the drug beads can dissolve in the stomach and / or pass intact or partially intact through the pyloric valve into the duodenum, but the ratio of the two drugs, whether in dissolved or undissolved form, remains relatively constant in the gastrointestinal tract until the drugs are absorbed.

[0115] The formulation of each drug bead allows for substantially similar performance to be achieved from the two active ingredients over a range of different doses, wherein the active ingredients are released into the serum at substantially similar rates and / or achieve substantially similar T 最大 In certain embodiments, a capsule comprising 50 mg of xanomeline as a tartrate salt; and 10 mg of chloroquine tridihexethyl. Because 50 mg of xanomeline free base is equivalent to about 76 mg of xanomeline tartrate, the ratio of active ingredients in this formulation is about 7.6 to 1.

[0116] The variation in the number of beads in the capsule increases the likelihood that the proportion of beads will not remain substantially constant after the beads are released and dispersed. Thus, in certain embodiments, the trospium beads are formulated with a lower drug loading such that an effective dose of trospium and xanomeline are contained in approximately an equal number of beads. In certain embodiments, the trospium and xanomeline beads release at approximately similar rates despite the variation in drug loading. For example, if the dissolution of the capsule is evaluated using a United States Pharmacopeia (USP) dissolution apparatus, the percentage of dissolved xanomeline is substantially equal to the percentage of dissolved trospium chloride, for example, at 10 minutes, 20 minutes, or 30 minutes.

[0117] The drug can also include one or more pharmaceutically acceptable salts. The drug can include one or more pharmaceutically acceptable carriers. The drug can be administered orally. The drug can be delivered orally using tablets, lozenges, liquids, emulsions, suspensions, drops, capsules, caplets, or other oral administration methods known to one of skill in the art.

[0118] The drug can be in a dosage form that is an immediate release drug. In another embodiment, the drug can have a controlled release dosage form.

[0119] The drug can be in a dosage form using other controlled release formulation methods known to one of skill in the art.

[0120] In another embodiment, the drug is used in combination with one or more therapies, including psychotherapies and drugs. Therapeutic agents include, but are not limited to, antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers, analgesics, and other pharmacological interventions known to one of skill in the art. A therapeutic agent can belong to a class of more than one drug. For example, benzodiazepines can be considered anxiolytics, sedatives, and tranquilizers. Bead / core excipient

[0121] The beads and / or cores can include one or more excipients. In one embodiment, the excipients include one or more fillers, binders, and surfactants. Other optional ingredients include, but are not limited to, glidants, lubricants, disintegrants, swelling agents, and antioxidants. Xanomeline or a pharmaceutically acceptable salt thereof and trospium salt can be in different matrices within the same drug.

[0122] The amount of xanomeline free base in the core can be at least 10 wt.%, or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.% or at least 30 wt.%. For example, the amount of xanomeline tartrate can be at least 50 wt.% of the core, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% for example, in a range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%. It will be appreciated that all ranges including these values as endpoints are contemplated, for example, at least about 15 wt.% to about 90 wt.%, about 20 wt.% to about 85 wt.%, about 30 wt.% to about 85 wt.%, or about 50 wt.% to about 90 wt.%. In certain embodiments, the xanomeline bead comprises 30 wt.% to 80 wt.% xanomeline tartrate, for example, 66 wt.% xanomeline tartrate.

[0123] The amount of salt of trospium in the core can be at least 10 wt.%, or at least 15 wt.%, or at least 20 wt.%, or at least 25 wt.% or at least 30 wt.%. For example, the amount of trospium chloride can be at least 50 wt.% of the core, or at least 55 wt.%, or at least 60 wt.%, or at least 65 wt.%, or at least 70 wt.%, or at least 75 wt.%, or at least 80 wt.%, or at least 85 wt.% for example, in a range of about 60 wt.% to about 90 wt.% or about 65 wt.% to about 85 wt.%. It will be appreciated that all ranges including these values as endpoints are contemplated, for example, at least about 15 wt.% to about 90 wt.%, about 20 wt.% to about 85 wt.%, about 30 wt.% to about 85 wt.%, or about 50 wt.% to about 90 wt.%. In certain embodiments, the trospium is trospium chloride. In certain embodiments, the trospium bead comprises 8 wt.% to 35 wt.% trospium chloride, for example, 17.7 wt.% trospium chloride.

[0124] In another embodiment, the matrix comprises a polymer, for example, to modify the release profile of the active ingredient in the matrix. In another embodiment, the polymer comprises a water-soluble polymer. In another embodiment, the water-soluble polymer is selected from the group consisting of Eudragit® TM RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, and mixtures thereof. In another embodiment, the polymer comprises a water-insoluble polymer. In another embodiment, the water-insoluble polymer is selected from the group consisting of Eudragit® TMRS, ethyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), poly(ethylene), low density poly(ethylene), high density poly(ethylene), poly(propylene), poly(ethylene terephthalate), poly(vinyl butyral), poly(vinyl acetate), poly(vinyl chloride), polyurethane, and mixtures thereof.

[0125] Fillers include, but are not limited to, lactose, sucrose, glucose, starch, microcrystalline cellulose, super fine cellulose, mannitol, sorbitol, dibasic calcium phosphate, aluminum silicate, amorphous silicon dioxide, and sodium chloride, starch and dibasic calcium phosphate dihydrate. In one embodiment, the filler is water absorbent but not water soluble. In one embodiment, the filler is a spheronization aid. The spheronization aid can include one or more of crospovidone, carrageenan, chitosan, pectic acid, glyceryl esters, beta-cyclodextrin (beta-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose, polyplasdone crospovidone, and polyethylene oxide. In one embodiment, the filler includes microcrystalline cellulose.

[0126] The amount of filler in the xanomeline core is not particularly limited. In embodiments, the amount of filler (e.g., microcrystalline cellulose) can be in the range of about 10 wt.% to about 70 wt.%, or about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, e.g., about 20 wt.%. In certain embodiments, the xanomeline bead comprises 15 wt.% to 65 wt.% microcrystalline cellulose, e.g., about 15 wt.% to 20 wt.%, about 20 wt.% to 25 wt.%, about 25 wt.% to 30 wt.%, about 30 wt.% to 35 wt.%, about 35 wt.% to 40 wt.%, about 40 wt.% to 45 wt.%, about 45 wt.% to 50 wt.%, about 50 wt.% to 55 wt.%, about 55 wt.% to 60 wt.% or about 60 wt.% to 65 wt.%. In certain embodiments, the xanomeline bead comprises 33.5 wt.% microcrystalline cellulose.

[0127] There is no particular limitation on the amount of filler in the troxylamine core. In examples, the amount of filler (e.g., microcrystalline cellulose or lactose) may range from about 10 wt.% to about 80 wt.%, or from about 16 wt.% to about 23 wt.%, or at least 19 wt.% or at least 19.5 wt.%, for example, about 20 wt.%. In some embodiments, troxylamine beads comprise 25 wt.% to 80 wt.% of microcrystalline cellulose, such as about 25 wt.% to 30 wt.%, about 30 wt.% to 35 wt.%, about 35 wt.% to 40 wt.%, about 40 wt.% to 45 wt.%, about 45 wt.% to 50 wt.%, about 50 wt.% to 55 wt.%, about 55 wt.% to 60 wt.%, about 60 wt.% to 65 wt.%, about 65 wt.% to 70 wt.%, about 70 wt.% to 75 wt.%, or about 75 wt.% to 80 wt.%. In some embodiments, troxylamine beads comprise 46.8 wt.% of microcrystalline cellulose.

[0128] In some embodiments, troxylamine beads contain 15 wt.% to 70 wt.% lactose monohydrate, such as about 15 wt.% to 20 wt.%, about 20 wt.% to 25 wt.%, about 25 wt.% to 30 wt.%, about 30 wt.% to 35 wt.%, about 35 wt.% to 40 wt.%, about 40 wt.% to 45 wt.%, about 45 wt.% to 50 wt.%, about 50 wt.% to 55 wt.%, about 55 wt.% to 60 wt.%, about 60 wt.% to 65 wt.%, or about 65 wt.% to 70 wt.%. In some embodiments, troxylamine beads contain 35 wt.% lactose monohydrate.

[0129] Adhesives include, but are not limited to, cellulose ethers, methylcellulose, ethylcellulose, hydroxyethylcellulose, propylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and hydroxypropyl methylcellulose (hydroxypropyl methylcellulose, such as hydroxypropyl methylcellulose 2910, Methocel). TM E), carboxymethyl cellulose, starch, pregelatinized starch, gum arabic, astragalus gum, gelatin, polyvinylpyrrolidone (polyvinyl ketone), croscarmellose, sodium alginate, microcrystalline cellulose, and lower alkyl-substituted hydroxypropyl cellulose. In one embodiment, the adhesive is selected from wet adhesives. In one embodiment, the adhesive is selected from cellulose ethers, such as hydroxypropyl methylcellulose.

[0130] There is no particular limitation on the amount of binder in the cyclophosphamide core. In embodiments, the amount of binder (e.g., hydroxypropyl methylcellulose) can range from about 1 wt.% to about 10 wt.%, about 2 wt.% to about 8 wt.%, or about 4 wt.% to about 6 wt.%, for example, about 5 wt.%.

[0131] The amount of binder in the tiotropium core is not particularly limited. In embodiments, the amount of binder (e.g., hydroxypropyl methylcellulose) can be in the range of about 1 wt.% to about 10 wt.%, about 2 wt.% to about 8 wt.%, or about 4 wt.% to about 6 wt.%, e.g., about 5 wt.%.

[0132] Surfactants include, but are not limited to, anionic surfactants including sodium lauryl sulfate, sodium deoxycholate, sodium dioctyl sulfosuccinate, and sodium stearyl fumarate, non-ionic surfactants including polyoxyethylene ethers and polysorbate 80, and cationic surfactants including quaternary ammonium compounds. In one embodiment, the surfactant is selected from anionic surfactants, e.g., sodium lauryl sulfate.

[0133] The amount of surfactant in the xanomeline core, e.g., as a processing aid, is not particularly limited. In embodiments, the amount of surfactant (e.g., microcrystalline cellulose) can be in the range of about 0.1 wt.% to about 1 wt.%, about 0.2 wt.% to about 0.8 wt.%, or about 0.4 wt.% to about 0.6 wt.%, e.g., about 0.5 wt.%.

[0134] The amount of surfactant in the tiotropium core, e.g., as a processing aid, is not particularly limited. In embodiments, the amount of surfactant (e.g., sodium lauryl sulfate) can be in the range of about 0.1 wt.% to about 1 wt.%, about 0.2 wt.% to about 0.8 wt.%, or about 0.4 wt.% to about 0.6 wt.%, e.g., about 0.5 wt.%.

[0135] Disintegrants include, but are not limited to, starch, sodium croscarmellose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, and sodium starch glycolate, low-substituted hydroxypropylcellulose, and hydroxypropyl starch.

[0136] Glidants include, but are not limited to, polyethylene glycol of various molecular weights, magnesium stearate, calcium stearate, calcium silicate, fumed silica, magnesium carbonate, magnesium lauryl sulfate, aluminum stearate, stearic acid, palmitic acid, cetyl alcohol, stearyl alcohol, and talc.

[0137] Lubricants include, but are not limited to, stearic acid, magnesium stearate, calcium stearate, aluminum stearate, and silicified talc. In certain embodiments, the xanomeline bead comprises 0 wt.% to 2 wt.% talc, e.g., 0.5 wt.% talc. In certain embodiments, the tiotropium bead comprises 0 wt.% to 2 wt.% talc, e.g., 0.5 wt.% talc.

[0138] In certain embodiments, the formulation further comprises one or more antioxidants. Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. In certain embodiments, the formulation comprises less than 1 wt.% of an antioxidant, such as 0.9 wt.%, 0.8 wt.%, 0.7 wt.%, 0.6 wt.%, 0.5 wt.%, 0.4 wt.%, 0.3 wt.%, 0.2 wt.%, 0.1 wt.%, 0.09 wt.%, 0.08 wt.%, 0.07 wt.%, 0.06 wt.%, 0.05 wt.%, 0.04 wt.%, 0.03 wt.%, 0.02 wt.%, or 0.01 wt.%. In certain embodiments, the formulation comprises about 0.05 wt.% of BHT or 0.5 wt.% of ascorbic acid. In certain embodiments, the antioxidant is present in the xanomeline core or the xanomeline bead.

[0139] In certain embodiments, the xanomeline bead comprises 30 wt.% to 80 wt.% of xanomeline tartrate, 15 wt.% to 65 wt.% of microcrystalline cellulose, and 0 wt.% to 2 wt.% of talc. In certain embodiments, the trospium chloride bead comprises 0.2 wt.% to 2 wt.% of talc, such as 0.5 wt.% of talc. In certain embodiments, the trospium chloride bead comprises 8 wt% to 35 wt.% of trospium chloride, 25 wt.% to 80 wt.% of microcrystalline cellulose, 15 wt.% to 70 wt.% of lactose monohydrate, and 0.2 wt.% to 2 wt.% of talc.

[0140] In certain embodiments, the xanomeline tartrate bead comprises 66 wt.% of xanomeline tartrate, 33.5 wt.% of microcrystalline cellulose, and 0.5 wt.% of talc. In certain embodiments, the trospium chloride bead comprises 17.7 wt.% of trospium chloride, 46.8 wt.% of microcrystalline cellulose, 35 wt.% of lactose monohydrate, and 0.5 wt.% of talc. In this example, the amount of xanomeline contained in the xanomeline tartrate bead is about 2.5 times the amount of trospium chloride contained in the trospium chloride bead.

[0141] Capsules can be prepared with different amounts of xanomeline tartrate beads and trospium chloride beads depending on the dosage requirements. In various embodiments, the capsules contain 50 mg xanomeline and 10 mg trospium chloride, 50 mg xanomeline and 20 mg trospium chloride, 75 mg xanomeline and 10 mg trospium chloride, 75 mg xanomeline and 20 mg trospium chloride, 125 mg xanomeline and 30 mg trospium chloride, or 125 mg xanomeline and 40 mg trospium chloride. In certain embodiments, the capsules contain 25 mg xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsules contain 50 mg xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsules contain 50 mg xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsules contain 75 mg xanomeline tartrate and 10 mg trospium chloride. In certain embodiments, the capsules contain 75 mg xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsules contain 125 mg xanomeline tartrate and 20 mg trospium chloride. In certain embodiments, the capsules contain 125 mg xanomeline tartrate and 40 mg trospium chloride.

[0142] In another embodiment, the medicament contains 5 mg to 700 mg of xanomeline. In one embodiment, the medicament contains 25 mg to 300 mg of xanomeline.

[0143] In another embodiment, the medicament contains 1 mg to 400 mg of trospium chloride. In one embodiment, the medicament contains 6.5 mg to 200 mg of trospium chloride.

[0144] In one embodiment, trospium chloride extended release agent is used as the trospium chloride in the medicament. In another embodiment, the medicament contains 1 mg to 400 mg of trospium chloride extended release agent. In one embodiment, the medicament contains 6.5 mg to 200 mg of trospium chloride extended release agent.

[0145] In one embodiment, the medicament contains 75 mg or 225 mg of xanomeline and the same medicament contains 20 mg or 40 mg of trospium chloride. In another embodiment, the medicament contains 75 mg or 225 mg of xanomeline and a different medicament to be co-administered contains 20 mg or 40 mg of trospium chloride. Bead coating

[0146] In other embodiments, the beads may be coated with functional or non-functional coatings for aesthetic, processability, or stability purposes. In some embodiments, the beads may be coated with a pH-sensitive coating so that they do not dissolve in the low pH of the stomach. Non-functional coatings may be used to maintain chemical separation between the beads or for decorative reasons.

[0147] In another embodiment, the controlled-release formulation comprises a semi-permeable coating. Zanomeprazole and trexylamine in the same formulation may be in different coatings. In another embodiment, zanomeprazole and trexylamine may be in different coatings in different formulations or delivery vehicles. In another embodiment, the semi-permeable coating comprises a polymer. In another embodiment, the controlled-release formulation comprises a matrix suspending zanomeprazole and trexylamine.

[0148] In some embodiments, the coating thickness distribution may be stated as an increase in the weight 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%.

[0149] For example, the difference in coating thickness from bead to bead can range from + / - 1% to 7% based on the total weight of the coated beads. Based on the weight of the coated beads, the distribution of coating thickness can be from about 2% to about 14%, for example, 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%.

[0150] In one embodiment, the absorption (area under the curve, AUC) of the dosage form is advantageously increased when orally administered compared to other dosage forms of xamometrine or chlorpromazine. Without being bound by any theory, the increase in absorption is influenced by dosage forms exhibiting a pseudo-extended release profile. This pseudo-extended release profile is influenced by one or more factors, including the distribution of coating thickness (when present), the distribution of bead size, and the presence of beads with irregular bead shapes. For example, in embodiments where the beads have a coating thickness distribution, for beads with a relatively thin coating, the coating dissolves relatively quickly and completely at the trigger pH, releasing the xamometrine and / or chlorpromazine composition, while for beads with a relatively thick coating, the coating takes longer to dissolve completely and release the xamometrine and / or chlorpromazine composition. In embodiments where the beads have a particle size distribution and / or irregular bead shapes, the intestinal transit time of the beads can vary due to bead size and / or shape, making the transit time until the coating dissolution pH is reached variable, thus contributing to the pseudo-extended release profile. In another embodiment, when administered orally, either in a capsule shell or without a capsule shell, the dosage form exhibits substantially equivalent (e.g., bioequivalent) C 最大 And / or AUC characteristics.

[0151] In some embodiments, the dosage form provides a stepwise and predictable absorption profile. In one embodiment, when administered orally, the dosage form's T0... 最大 More stable on a dose-to-dose basis because the beads are individually coated. Predictable, consistent T. 最大 This facilitates more consistent and sustained therapeutic effects. For example, process-related variations in coating thickness or other effects on coating dissolution only affect a portion of the dosage forms of xaprometrine and chlorpromazine, and tend to lead to pseudo-prolonged release behavior. In contrast, coated capsules containing xaprometrine and chlorpromazine microspheres exhibit significant variability in absorption time between capsules.

[0152] In some embodiments, the oral pharmaceutical composition comprises xaprometrine and / or its salts, as well as trastrazolium chloride, for the treatment of muscarinic disorders in patients in need, wherein, when administered to said patients in need, the composition is sufficient to provide an in vivo plasma profile containing a 2-hour median T value for xaprometrine. 最大 And the median T value of 1 hour of trastoxetine 最大 In some embodiments, the in vivo plasma profile further comprises a mean dose-normalized Cmax of 48.5 to 121.3 pg / mL / mg. In some embodiments, the in vivo plasma profile further comprises a mean dose-normalized Cmax of trexylchloramine of 156 pg / mL / mg to 375 pg / mL / mg. 最大In some embodiments, the in vivo plasma profile further includes a mean dose-normalized AUC of 263 to 577 hr·pg / mL / mg for xanoxetine. 0-12 In some embodiments, the in vivo plasma profile further includes the mean dose-normalized AUC of troxetine from 881 hr·pg / mL / mg to 2024 hr·pg / mL / mg. 0-12 In some embodiments, the in vivo plasma profile further includes a mean C0.05 of trexylchloramine at 7850 ± 3360 pg / mL. 最大 In some embodiments, the in vivo plasma profile further includes an average AUC of 41900 ± 15500 hr·pg / mL. 0-12 .

[0153] In another embodiment, the dosage form exhibits favorable storage stability, for example, as measured by the amount of xamometrine and / or the total amount of related substances present after storage. Storage stability can be assessed after storage under typical environmental conditions (e.g., 25°C and 60% relative humidity) or under accelerated stabilization conditions involving increased temperature and / or humidity.

[0154] Unless otherwise stated, the anticipated dosage forms and methods include embodiments of one or more combinations of any of the additional optional elements, features, and steps (including those shown in the figures and examples) further described below. References to beads and their properties also apply to collections of beads (e.g., multiple such beads). Similarly, references to cores and their properties also apply to collections of cores (e.g., multiple such cores).

[0155] Enteric (anti-gastric) coating materials, such as polymers, can be polymers that dissolve in intestinal fluids at pH levels higher than those of the stomach, such as pH greater than 4.5 (e.g., in the small intestine), thus allowing the active substance to be released in the small intestinal region and substantially not released in the upper GI tract. In one embodiment, the enteric material begins to dissolve in an aqueous solution at a pH of about 4.5 to about 5.5. In another embodiment, the enteric material dissolves rapidly in an aqueous solution at a pH of about 5. In yet another embodiment, the enteric material dissolves rapidly in an aqueous solution at a pH of about 5.5.

[0156] For example, pH-sensitive materials do not dissolve significantly until the dosage form is emptied from the stomach. The pH of the small intestine gradually increases from about 4.5 to about 6.5 in the duodenal bulb, and then to about 7.2 in the distal small intestine (ileum). To provide predictable dissolution corresponding to a small intestinal transit time of about 3 hours (e.g., 2–3 hours) and to allow for reproducible release therein, the coating should begin to dissolve within the pH range of the duodenum and continue to dissolve within the pH range of the small intestine. Therefore, the amount (thickness) of the enteric coating should be sufficient to dissolve substantially in the small intestine (e.g., the proximal and mid-small intestine) within a transit time of about three hours.

[0157] Suitable enteric-coated (anti-gastric) materials include, but are not limited to, cross-linked polyvinylpyrrolidone; non-cross-linked polyvinylpyrrolidone; hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate succinate; cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate; starch acetate phthalate; polyvinyl acetate phthalate; carboxymethyl cellulose; methylcellulose phthalate; methylcellulose succinate; methylcellulose succinate; methylcellulose phthalate succinate; methylcellulose phthalate half-ester; ethyl... Cellulose succinate; carboxymethyl amide; potassium divinylbenzene copolymer of methacrylate; polyvinyl alcohol; polyethylene glycol; polyethylene glycol; sodium alginate; galactomannan; carboxylated polymethylene; sodium carboxymethyl starch; copolymers of acrylic acid and / or methacrylic acid with monomers selected from: methyl methacrylate, ethyl methacrylate, ethyl acrylate, butyl methacrylate, hexyl methacrylate, decyl methacrylate, lauryl methacrylate, phenyl methacrylate, methyl acrylate, isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate (e.g., Eudragit). TM The -L and -S series, including L100-55, L 30D-55, L 100, S100, L 12.5, and S12.5, are available from Evonik Industries; polyvinyl acetate; fats; oils; waxes; fatty alcohols; shellac; corn gluten; gluten; ethyl acrylate-maleic anhydride copolymer; maleic anhydride-vinyl methyl ether copolymer; styrene-maleic acid copolymer; 2-ethylhexyl acrylate-maleic anhydride; crotonic acid-vinyl acetate copolymer; glutamic acid / glutamate copolymer; carboxymethyl ethyl cellulose glycerol monooctanoate; polyarginine; poly(ethylene); poly(propylene); poly(ethylene oxide); poly(ethylene terephthalate); poly(vinyl isobutyl ether); poly(vinyl chloride); and polyurethane. Combinations of enteric materials may also be used. In one embodiment, the enteric material dissolves rapidly at pH 5.5 and higher to provide rapid dissolution in the upper intestine. For example, enteric materials can be selected from copolymers of methacrylic acid and methyl methacrylate, and copolymers of methacrylic acid and ethyl acrylate. For instance, the enteric polymer is poly(ethyl methacrylate) 1:1 (Eudragit... TM L 30D-55 and Eudragit TM L 100-55).

[0158] Other suitable examples of multiple enteric coatings include beeswax and glyceryl monostearate; beeswax, shellac, and cellulose; and cetyl alcohol, mastic, and shellac, as well as shellac and stearic acid; polyvinyl acetate and ethyl cellulose; and neutral copolymers of polymethyl methacrylate (Eudragit). TM L 30D); copolymers of methacrylic acid and methyl methacrylate, or neutral copolymers of polymethacrylates containing metal stearates. Such coatings include mixtures of fats and fatty acids, shellac and shellac derivatives, and phthalates of cellulosic acid, such as those with free carboxyl groups.

[0159] As is known in the art, one or more plasticizers can be added to enteric polymers to improve their flexibility and reduce brittleness. Suitable plasticizers include, for example, butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, polyethylene glycol (PEG, such as PEG 6000), triethyl acetate citrate, and triacetin. In one embodiment, the plasticizer is triethyl citrate. Although some enteric materials are flexible and do not require plasticizers, more brittle polymers (such as Eudragit) may require additional plasticizers. TM L / S type, Eudragit TM RL / RS and Eudragit TM FS 30D benefits from plasticizers, for example, ranging from 5 wt.% to 30 wt.% and from about 8 wt.% to about 12 wt.% of triethyl citrate to poly(ethyl methacrylate) in a 1:1 ratio, based on dry polymer mass.

[0160] In some embodiments, as is known in the art, the enteric coating includes one or more anti-adhesive agents to reduce film stickiness and prevent clumping. Suitable anti-adhesive agents include, but are not limited to, talc, glyceryl monostearate, and fumed silica (e.g., Aerosil). TM 200), precipitated silica (e.g., Sipernat) TM PQ) and magnesium stearate. The anti-sticking agent can be used in any suitable amount, for example, ranging from about 10 wt.% to 100 wt.%, from about 10 wt.% to about 50 wt.%, from about 10 wt.% to about 30 wt.%, or from about 15 wt.% to about 30 wt.% based on the dry polymer mass. For example, in one embodiment, the range is from 15 wt.% to about 30 wt.% based on the dry polymer mass.

[0161] As is known in the art, one or more surfactants may be added to the enteric coating mixture to improve the wettability of the substrate and / or stabilize the suspension. Surfactants include polysorbate 80, sorbitan monooleate, and sodium dodecyl sulfate, as well as other surfactants described herein.

[0162] Enteric coatings can be formed by any suitable method. Coating methods include, for example, pan coating, fluidized bed coating, and dry coating (e.g., thermal dry coating and electrostatic dry coating). Pan coating and fluidized bed coating using solvents are recognized methods. In liquid coating, the enteric material and optional excipients (e.g., pigments, plasticizers, anti-sticking agents) are mixed in an organic solvent or water to form a solution or dispersion. The coating solution or dispersion is sprayed into a solid dosage form in a pan coating machine or fluidized bed dryer and dried by hot air. For example, in the Wurster fluidized bed coating method, the coating fluid is sprayed from the bottom of the fluidized bed apparatus. Alternatively, the coating fluid is applied by top spraying. In some embodiments, tangential spraying is applied.

[0163] The amount of enteric material is sufficient to achieve the desired acid resistance and release characteristics. For example, in one embodiment, the amount of enteric coating meets the USP for a delayed-release formulation. <711> The requirement (USP 36-NF 31) is to release less than 10.0 wt.% of the drug after 2 hours in 0.1N HCl. In some embodiments, the formulation is prepared in a pH 6.8 buffer solution within 20 minutes, for example using USP 36-NF 31. <711> The dissolution method of the section releases at least 80% of the active ingredients.

[0164] In one embodiment, the amount of enteric coating present ranges from about 10% to 40%, or from 25% to about 35% (as measured by weight increase compared to uncoated particle cores), or based on the weight of uncoated particle cores, ranges from about 25% to about 31% weight increase, about 27% to about 31% weight increase, or about 28.5% to about 31% weight increase.

[0165] The formulation may include a capsule shell in which beads are placed. Soft capsule shells and hard capsule shells are known. In one embodiment, the capsule shell is a hard capsule shell, such as a gelatin capsule shell or a plant-based hard capsule shell. In some embodiments, the capsule shell comprises one or more enteric coatings as described herein. Gelatin capsules may collapse during accelerated storage. Therefore, in some embodiments, the formulation may comprise a hydroxypropyl methylcellulose capsule shell.

[0166] Therefore, for example, one embodiment combining the various features described above includes a pharmaceutical dosage form comprising a plurality of zenomeprazole beads, each bead comprising a core (the core comprising zenomeprazole tartrate, a filler (optionally microcrystalline cellulose), and a binder (optionally hydroxypropyl methylcellulose)) and an enteric coating (optionally Eudragit) surrounding the core. TML 30D-55), wherein the particle size distribution of the plurality of beads ranges from about 0.7 mm to about 2.5 mm, wherein the enteric coating ranges from about 20% to about 40% based on the weight of the plant core, and wherein the beads are located in a capsule shell. Size and shape of beads

[0167] The plurality of beads have a particle size distribution. The plurality of beads have a bead shape. When present, the plurality of beads have a coating thickness distribution.

[0168] Beads with a specific particle size distribution exhibit favorable pharmacokinetic properties. Without being bound by any theory, it can be expected that pharmacokinetic properties are influenced by multiple beads with a core size distribution.

[0169] In one embodiment, the bead size ranges from about 0.4 mm to about 1.2 mm, for example, 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 some embodiments, the size of the xapromine beads is from about 0.425 mm to about 1.18 mm. In some embodiments, the size of the xapromine beads is from about 0.6 mm to about 0.85 mm. In some embodiments, the size of the troxetine beads is from about 0.425 mm to about 1.18 mm. In some embodiments, the size of the troxetine beads is from about 0.6 mm to about 0.85 mm.

[0170] The beads or bead mixtures can be used, for example, as a suspension, filled into capsules, compressed into tablets, or filled into sachets. One or more types of modified release beads can be mixed together and encapsulated, or sprinkled onto the subject's food for use. In some embodiments, the oral solid dosage form can be any of these forms. In some embodiments, the dosage form is a capsule.

[0171] As bead size becomes too small, the variability in active ingredient content increases. As particle size becomes too large, the beads become so large that the drug cannot be labeled for administration by spillage (on applesauce or other soft foods, such as jelly) and swallowing without chewing, or by administration via an enteral feeding tube. Similarly, as particle size increases, larger particles are coated more than smaller particles, resulting in a lower relative assay compared to smaller particles. To compensate, a relatively larger number of beads are needed to meet the label strength for each capsule. Filling capsule shells with sufficiently large beads to meet the label strength for each capsule becomes difficult or impossible (e.g., filling a size 0 capsule with the free base strength of 75 mg xanofemort).

[0172] In one embodiment, for example, beads are encapsulated using an encapsulation machine. Various capsule sizes can be adapted to the strength and fill weight of the target formulation. For fill weights ranging from about 15 mg to about 630 mg, capsule sizes range from 0.00 to 5.

[0173] The beads can be sorted (e.g., by sieving) to a desired particle size. In some embodiments, the particle size range is any of the particle size ranges or combinations thereof described above regarding the core. In one embodiment, the particle size range is the same as the particle size range of the uncoated core. For example, the beads can be sieved such that 5% or less of the bead cores by weight remain on a #12 sieve (1.68 mm) and 10% or less by weight pass through a #20 sieve (0.84 mm). Preparation method

[0174] A method for preparing an oral pharmaceutical composition is provided, the method comprising mixing a plurality of xuanomelein beads containing a pharmaceutically acceptable salt thereof with a plurality of trastamide beads containing a trastamide salt such as trastamide chloride. In some embodiments, the method further comprises formulating the mixed beads into capsules.

[0175] This document also discloses a method for preparing a dosage form, the method comprising coating a core containing xaprometin or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form an enteric coating, and coating a core containing trastril chloride or a pharmaceutically acceptable salt thereof and an excipient with an enteric polymer to form an enteric coating. Optionally, the core may be formed by wet granulation. Optionally, before and optionally after enteric coating, the beads are sorted (e.g., by sieving) to a desired particle size range.

[0176] These beads can be made by various methods, including but not limited to spheroidizing extruded wet material and coating it with inert core spheres in a fluidized bed. In some embodiments, the beads are prepared by extrusion and spheroidization.

[0177] The beads are formulated to be free-flowing and compatible with modern encapsulation devices. In some embodiments, the beads are blended together to form a homogeneous mixture, which can be filled into capsules in a single stage. In other embodiments, a two-stage capsule filler is used to fill the beads into capsules separately.

[0178] A core comprising xaprometrine or a pharmaceutically acceptable salt thereof can be formed by any suitable method. In one embodiment, the core is formed by granulating and grinding a mixture of xaprometrine or a pharmaceutically acceptable salt thereof with an excipient to a desired particle size range. In another embodiment, the core can be formed by extruding and rounding a mixture of xaprometrine or a pharmaceutically acceptable salt thereof with an excipient.

[0179] A core comprising chlorpromazine chlorate or a pharmaceutically acceptable salt thereof can be formed by any suitable method. In one embodiment, the core is formed by granulating and grinding a mixture of chlorpromazine chlorate or a pharmaceutically acceptable salt thereof with an excipient to a desired particle size range. In another embodiment, the core can be formed by extruding and rounding a mixture of chlorpromazine chlorate or a pharmaceutically acceptable salt thereof with an excipient.

[0180] Granulation methods can include, for example, fluidized bed granulation, wet granulation, hot melt granulation, and spray condensation. Other methods include slugging and roll forming. The mixture to be granulated is first dry-mixed. The dry components of the dry mix can be mixed with water before extrusion.

[0181] Extruding and spheronizing a mixture of zenomeprazole or a pharmaceutically acceptable salt thereof with trastoxylamine chloride and excipients can provide a desired core having the particle size distribution described herein and one or more other desired properties. In some embodiments, shorter processing times 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 (when wet and / or before packaging) can also reduce oxidation. On the other hand, rapid processing by extrusion and spheronization can result in a product of poor quality, for example, causing most of the bead cores to fall outside the desired particle size range. Moisture absorbed by the spheronization aid (which varies over time) can affect the spheronization properties of the beads.

[0182] Accordingly, in one embodiment, the moisture content of the granulation mixture prior to drying ranges from about 20 wt.% to about 40 wt.%, for example, 25 wt.% to about 35 wt.%, about 28 wt.% to about 32 wt.%, at least about 28 wt.%, at least about 28.5 wt.%, about 20 wt.% to about 40 wt.%, about 25 wt.% to about 35 wt.%, about 27 wt.% to about 31 wt.%, or about 28.5 wt.% to about 31 wt.%.

[0183] In some embodiments, the wet material may be held prior to extrusion, for example, to allow the spheroidizing aid to swell together with the granulation fluid. The holding time may be at least 15 minutes, such as at least 30 minutes, at least 45 minutes, or at least 60 minutes. In some embodiments, the holding time ranges from about 15 minutes to about 120 minutes, such as about 30 minutes to 100 minutes, or 60 minutes to 90 minutes.

[0184] As described above regarding the core, the method may include the following steps: sorting the core (e.g., by sieving) prior to optional coating to retain particles within a predetermined size range, such as a size range of about 0.7 mm to about 2.8 mm, for example, about 0.7 mm to about 2.5 mm, about 0.8 mm to about 1.7 mm, or any range described herein.

[0185] As described above regarding beads, the method may include the steps of sorting the beads (e.g., by sieving) after optional coating to retain particles within a size range, such as a size range of about 0.7 mm to about 2.8 mm, for example about 0.7 mm to about 2.5 mm, or about 0.8 mm to about 1.7 mm, or any range described herein.

[0186] In the extrusion and spheronization methods, the following optional features may be used alone or in combination. Water may be a granulating agent. Microcrystalline cellulose may be included in the core as a spheronization aid. Hydroxypropyl methylcellulose may be included in the core as a binder. The extrusion screen size may be 1.0 mm. The friction plate of the spheronization machine may be cross-diagonally lined. The friction plate of the spheronization machine may be cross-diagonally lined with a grid of at least about 3 mm, or greater than about 3 mm, or at least about 4 mm, or greater than about 4 mm, or ranging from about 3 mm to about 7 mm, or about 5 mm. The spheronization time may be less than about 5 minutes, or less than about 4 minutes, or less than about 3 minutes, or less than about 2 minutes, or up to 1 minute. The spheronized particles may include non-spherical particles (i.e., irregular shapes), for example, a large portion of which may be at least about 20 wt.%, at least about 30 wt.%, at least about 40 wt.%, at least about 50 wt.%, at least about 60 wt.%, or at least about 70 wt.%.

[0187] In some embodiments, the pharmaceutical composition is stored with a desiccant, such as pharmaceutical-grade silica gel, crystalline sodium silicate, potassium aluminosilicate or calcium aluminosilicate, colloidal silica, anhydrous calcium sulfate, etc.

[0188] In some embodiments, the pharmaceutical composition is stored together with an oxygen absorber.

[0189] In some embodiments, the pharmaceutical composition is stored under a dry inert gas such as nitrogen, helium, argon, neon, xenon, krypton, or a mixture thereof.

[0190] In some embodiments, the pharmaceutical composition is stored under reduced pressure compared to ambient air.

[0191] In some embodiments, the pharmaceutical composition is stored at a reduced temperature (e.g., at a refrigerated temperature, such as 2°C to 8°C). In some embodiments, the pharmaceutical composition is stored with fewer impurities (e.g., impurity A) compared to storage at 25°C.

[0192] In some embodiments, the oral pharmaceutical composition is stored by the manufacturer, distributor, pharmacy, or hospital at a temperature of about 2°C to about 8°C before being dispensed to a subject. In some embodiments, the oral pharmaceutical composition is stored at a temperature of about 20°C to about 25°C after being dispensed to a subject.

[0193] A method for stabilizing the pharmaceutical dosage form or composition described herein is also provided, the method comprising storing the dosage form at a temperature of about 2°C to about 8°C.

[0194] In some embodiments, a method for preparing a pharmaceutical dosage form comprising sennametrine includes forming a wet material comprising sennametrine tartrate and an excipient (optionally microcrystalline cellulose) (with a moisture content ranging from about 20 wt.% to about 40 wt.%), extruding and spheroidizing the wet material comprising sennametrine tartrate and the excipient to form a core, sorting the core to a target particle size range (optionally about 0.7 mm to about 2.5 mm), coating the sorted core with a polymer to form beads comprising the core and the coating, and sorting the bead particles to a target particle size range (optionally about 0.7 mm to about 2.5 mm).

[0195] In some embodiments, a method for preparing a pharmaceutical dosage form comprising trastrilamide includes forming a wet material comprising trastrilamide chloride and an excipient (optionally microcrystalline cellulose) (with a moisture content ranging from about 20 wt.% to about 40 wt.%), extruding, rounding, and drying the wet material comprising trastrilamide chloride and the excipient to form a core, sorting the core to a target particle size range (optionally about 0.7 mm to about 2.5 mm), coating the sorted core with a polymer to form beads comprising the core and the coating, and sorting the bead particles to a target particle size range (optionally about 0.7 mm to about 2.5 mm). purity

[0196] The compound 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridine-1-onium is also provided.

[0197] A pharmaceutical composition is also provided comprising xamethonium and / or its salts and less than 0.5 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-onthium (impurity A). In some embodiments, the pharmaceutical composition comprises less than 0.30 wt.% of impurity A, for example less than 0.25 wt.%, less than 0.20 wt.%, less than 0.15 wt.%, less than 0.14 wt.%, or less than 0.1 wt.%. A pharmaceutical composition is also provided comprising xamethonium and / or its salts and less than 0.15 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-onthium (impurity A).

[0198] An oral pharmaceutical composition is also provided comprising a plurality of sennamidin beads, said plurality of sennamidin beads comprising sennamidin or a salt thereof and less than 0.5 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-onthium; and a plurality of trocechloramine beads comprising trocechloramine salt. An oral pharmaceutical composition is also provided comprising a plurality of sennamidin beads, said plurality of sennamidin beads comprising sennamidin or a salt thereof and less than 0.15 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-onthium; and a plurality of trocechloramine beads comprising trocechloramine salt.

[0199] In some embodiments, after the pharmaceutical composition has been stored at 40°C and 75% relative humidity for at least 3 months, the pharmaceutical composition contains less than 0.5 wt.% of impurity A.

[0200] In some embodiments, the total impurities in the pharmaceutical compositions provided herein are no more than about 5% by weight, no more than about 4% by weight, no more than about 3% by weight, no more than about 2.5% by weight, no more than about 2% by weight, no more than about 1.5% by weight, no more than about 1% by weight, no more than about 0.5% by weight, or no more than about 0.1% by weight. Treatment

[0201] A method for activating muscarinic receptors in a biological sample is further provided, the method comprising contacting the biological sample with any of the oral pharmaceutical compositions described herein. A method for treating a disorder improved by activation of muscarinic receptors in a subject of need is also provided, the method comprising administering any of the oral pharmaceutical compositions described herein to the subject of need.

[0202] While M1 and M4 muscarinic receptor activators are considered effective treatments for schizophrenia, the activation of muscarinic receptors located outside the brain leads to side effects that prevent the clinical use of xaprometin. For example, in Phase I and subsequent trials, the muscarinic agonist xaprometin exhibited unacceptable glycation end syndrome (GI) and other side effects related to the binding of muscarinic receptors in peripheral regions of the body. By combining xaprometin with chlorpromazine, the desired therapeutic effect can be achieved while reducing or eliminating the side effects associated with the activation of muscarinic receptors located outside the brain.

[0203] Tolerability of the muscarinic activator xaprometrine can be improved by co-administration with the muscarinic antagonist trastux chloramine. The most common adverse events observed with xaprometrine administration are nausea, vomiting, diarrhea, excessive sweating, and excessive salivation (so-called cholinergic adverse events). The disclosed composition reduces the incidence of these adverse events in humans, thus demonstrating improved xaprometrine tolerability.

[0204] In one embodiment, xaprometrine is combined with traxolamine to treat muscarinic disorders, relieving symptoms of muscarinic activation in response to xaprometrine-induced changes in living tissue found outside the brain. In one embodiment, such diseases or disorders include schizophrenia and schizophrenia-related disorders, cognitive impairment in neurodegenerative diseases such as Alzheimer's disease, and pain such as nociceptive pain or neuropathic pain. The combination of xaprometrine and traxolamine is a safer approach for treating diseases that respond to activation of muscarinic receptors.

[0205] In another embodiment, xaprometrine and chlorpromazine treat mood disorders. In another embodiment, xaprometrine and chlorpromazine treat motor disorders. In another embodiment, xaprometrine and chlorpromazine treat cognitive disorders, including enhancing cognitive function unrelated to a specific pathology. In another embodiment, xaprometrine and chlorpromazine treat attention disorders. In another embodiment, xaprometrine and chlorpromazine treat pain. Beyond disease treatment, enhanced attention can accelerate learning and reduce fatigue caused by sleep deprivation and circadian rhythm disruption (e.g., jet lag). In another embodiment, xaprometrine and chlorpromazine treat addiction disorders.

[0206] In one embodiment, xaprometrine is combined with chlorpromazine to treat an animal. In another embodiment, the animal is a mammal. In one embodiment, the mammal is a human.

[0207] In one embodiment, trexylchloride reduces the side effects associated with xaprometrine. These side effects include, but are not limited to, GI side effects, cardiac side effects, excessive sweating, and excessive salivation. When xaprometrine is not clinically usable due to its side effects, the use of trexylchloride in combination with xaprometrine allows for its clinical use. In another embodiment, the use of trexylchloride in combination with xaprometrine allows for a higher maximum tolerated dose of xaprometrine than would otherwise be achievable with xaprometrine.

[0208] Various time- and resource-intensive methods have demonstrated the efficacy of the combination of xaprometin and chlorpromazine. For example, animal models have demonstrated the efficacy of the new therapeutic agent against schizophrenia, including pharmacological models (e.g., ketamine models) and genetic models (e.g., DISC1 mice). Similarly, animal models (including rodents, dogs, and non-human primates) have demonstrated the spectrum of side effects of the pharmacological action. Animal models are alternatives to human experiments but may have limitations in terms of physiological differences between humans and animals, and therefore their predictive power for human experiments (especially for central nervous system disorders) may be limited. Alternatively, the disclosed combination can be tried in controlled clinical trials in humans. Standard measures based on patient self-reports can be used by those skilled in the art to assess various side effects, such as GI discomfort. As another example, those skilled in the art can use objective physiological measurements (e.g., EKG). A set of standard measures for assessing symptoms of schizophrenia has also been developed, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), and the Clinical Global Impression (CGI). Typically, clinical trials are double-blind, with one group of patients receiving an ineffective placebo and another group receiving an active intervention.

[0209] Before administering the combination of drugs requiring protection, patients may have a lead-in period of one to fourteen days, during which chlorpromazine is administered alone. In one embodiment, chlorpromazine is administered for one or more dose cycles before administration of xanthiprol to accumulate chlorpromazine in the body, or to bring chlorpromazine to or near steady-state exposure levels. This accumulation or higher exposure levels of chlorpromazine increase the blockade of extracerebral muscarinic receptors and reduce adverse events when taking xanthiprol. In another embodiment, chlorpromazine is administered one or more days before xanthiprol.

[0210] In one embodiment, xapromide and chlorpromazine are administered to the patient six times during a 24-hour cycle. In another embodiment, xapromide and chlorpromazine are administered to the patient five times during a 24-hour cycle. In another embodiment, xapromide and chlorpromazine are administered to the patient four times during a 24-hour cycle. In one embodiment, xapromide and chlorpromazine are administered to the patient three times during a 24-hour cycle. In another embodiment, xapromide and chlorpromazine are administered to the patient twice during a 24-hour cycle. In yet another embodiment, xapromide and chlorpromazine are administered to the patient once during a 24-hour cycle.

[0211] In one embodiment, the extended-release formulation of chlorpromazine is used in combination with xanthiprol. In another embodiment, the extended-release formulation of chlorpromazine is administered to the patient one to five times over a 24-hour cycle. In one embodiment, the extended-release formulation of chlorpromazine is administered one to three times over a 24-hour cycle. In another embodiment, a dose of chlorpromazine from 5 mg to 400 mg is used over a 24-hour cycle. In one embodiment, a dose of chlorpromazine from 20 mg to 200 mg is used over a 24-hour cycle.

[0212] In one embodiment, 225 mg of xaprometrine and 40 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 100 mg of xaprometrine and 20 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 125 mg of xaprometrine and 20 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 125 mg of xaprometrine and 30 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 125 mg of xaprometrine and 40 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 200 mg of xaprometrine and 40 mg of trastoxamine are administered to the patient during a 24-hour cycle. In yet another embodiment, 200 mg of xaprometrine and 80 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 250 mg of zanomeline and 60 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 250 mg of zanomeline and 80 mg of trastoxamine are administered to the patient during a 24-hour cycle. In another embodiment, 300 mg of zanomeline and 40 mg of trastoxamine are administered to the patient during a 24-hour cycle. In yet another embodiment, 300 mg of zanomeline and 80 mg of trastoxamine are administered to the patient during a 24-hour cycle.

[0213] Treatment can begin with a small dose. Thereafter, the dose can be increased in small increments until a balance is reached between therapeutic effect and side effects. When treating subjects, patient health can be monitored by measuring one or more relevant parameters at predetermined times during treatment. Treatment can be adjusted based on this monitoring, including composition, dosage, administration time, and formulation. Patients can be periodically reassessed to determine improvement by measuring the same parameters. The administered composition and, if possible, the administration time can be adjusted based on these reassessments. Examples

[0214] The following examples are provided for illustration and are not intended to limit the scope of this disclosure. Example 1 - Immediately Release Beads

[0215] Beads containing senna tartrate (Table 1) and trastoxamine chloride (Table 2) were prepared. Table 1: Zanomelide (66%) tartrate beads, talc-free Ingredients % w / w (dry basis) g / batch Xanomeline tartrate 66 99 Microcrystalline cellulose 34 51 Purified water (30) (45) Total: 100 150 *Removed during the drying process. Table 2: Traxamine Chloride (17.7%) Beads, Talc-Free Ingredients % w / w (dry basis) g / batch Xanomeline tartrate 17.7 17.7 Microcrystalline cellulose 35 35 Lactose monohydrate 47.3 47.3 Purified water (45) (45) Total: 100 100 *Removed during the drying process.

[0216] The powder was sieved at 1625 rpm using a Quadro Comil 197 equipped with a 457 μm round mesh sieve and 0.2-inch pads, and then mixed at a constant speed of 60 rpm for 2 minutes in a Hobart low-shear mixer / granulator (N-50 type). The dry mixing step is optional, as the homogeneity of the mixture is driven by the subsequent wet granulation. Beads were sieved by hand through a 40-mesh (425 μm) sieve.

[0217] Wetting was performed in Hobart. Water was added using a Cole-Parmer peristaltic pump. The water addition rate (water volume / dosage time) is a process variable.

[0218] Wet material is extruded through a multi-mesh screen (dome configuration) single-screw extruder at 30 rpm (shaft speed) using an LCI Multi Granulator MG-55. The wet material is extruded directly after wetting. Holding time, shaft speed, and extrusion rate (load) are process variables.

[0219] The extrudate is fed into an LCI Marumerizer (rounding machine) QJ-230T equipped with a 2.0mm friction plate. The extrudate is rounded at different plate speeds for a total of no more than 4 minutes. Rounding speed and time are process variables.

[0220] Using Aeromatic TM The Strea-1 fluidized bed dries beads at an inlet temperature of 60°C until the obtained moisture content does not exceed 3%. Since the beads melt after a few minutes at 60°C, they are then dried at 30°C.

[0221] The water content was assessed by weight using a Mettler Toledo HR83 halogen moisture analyzer via loss on drying (LOD). The beads were heated at 105°C until the weight loss rate decreased to less than or equal to 0.0% within 60 seconds. Table 3: Parameters for Extrusion / Spheronization Methods Example 2 - Expanding Immediate Release Bead Formulation

[0222] The beads from Example 1, with and without talc, were enlarged (Tables 4-7). The extrusion / spheronization method parameters are shown in Table 8. Table 4: Xanomeprazole tartrate (66%), talc-free Ingredients % w / w (dry basis) g / batch Xanomeline tartrate 66 660 Microcrystalline cellulose 34 340 Purified water (24) (240) Total: 100 1000 *Removed during the drying process. Table 5: Zanomeprazole tartrate (66%), containing talc Abbreviations: Ph.Eur = European Pharmacopoeia, USP = United States Pharmacopoeia *Evaporation occurs during processing and is therefore not included in the total weight. Table 6: Traxamine Chloride (17.7%) Beads, Talc-Free Ingredients % w / w (dry basis) g / batch Xanomeline tartrate 17.7 88.7 Microcrystalline cellulose 35 175.0 Lactose monohydrate 47.3 236.3 Purified water (59) (295) Total: 100 500 *Removed during the drying process. Table 7: Trax chloramine (17.7%) beads, containing talc Abbreviations: NF = National Formulary, Ph.Eur = European Pharmacopoeia, USP = United States Pharmacopeia. *- Evaporation during processing Table 8: Parameters for Extrusion / Spheronization Methods Example 3 - Capsule stability and dissolution test

[0223] Capsules are produced by weighing beads and manually filling them into HPMC capsules. Accofil is used. TM The capsule filling machine manually fills the capsules with beads, which are premixed with talc (0.5%) and filled one by one, as shown in Table 9. Table 9: Composition of Xanomeprazole / Traxolamine Chloride Capsules. Ingredients are listed in mg / capsule.

[0224] After drying, the beads were sieved through 16-mesh (1.18 mm) and 40-mesh (0.425 mm) sieves by shaking for 5 minutes. Beads with sizes between 1.18 mm and 0.425 mm on the sieves were retained for further analysis.

[0225] Using a JSM-6010LV InTouchScope with a backscattered electron detector (BES) TM (JEOL Ltd., Tokyo, Japan) The morphology and surface properties of beads were examined using a scanning electron microscope (SEM). The sample was placed on a metal post using a double-sided carbon conductive tape. Images were acquired at a low vacuum (60 Pa) and 30x magnification with an accelerating voltage of 20 kV.

[0226] Using a bulk density tester (JV 1000, Copley Scientific), with USP <616> Method 1 determines volume and bulk density in duplicate. The bulk density is measured from the volume of a powder sample of known mass in a graduated cylinder. The bulk density is measured by mechanically tapping the graduated cylinder until the volume no longer changes.

[0227] The flow properties of the powder were assessed using Carr's Compressibility Index (CI) and Hausner ratio, both derived from measurements of volumetric and bulk density. The CI was calculated using volumetric and bulk density data when fitted to the following equation: Compressibility Index = (Bulk Density - Bulk Density) / Bulk Density × 100%. The Hausner ratio (H) was calculated as the ratio of bulk density to volumetric density. The capsules were analyzed for appearance, determinations, related substances, water content, and solubility. Figure 1 The stability timeline and protocol for cyclophosphamide / trischloramine capsules are shown.

[0228] The beads further ranged in size from 0.6 mm to 0.85 mm. Some beads exhibited similar morphological properties. Modifications in other beads reduced their density and resulted in a rougher surface and a loss of sphericity. Zanomelide tartrate 66% beads ( Figure 2 ) and 17.7% benzyl chloride () Figure 3Scanning electron microscopy (SEM) images at 30x magnification show that the size of these beads ranges from 0.6 mm to 0.85 mm. These beads are used in xaprometrine / trastuxamine capsules. The particle size distribution (PSD) of the beads was determined by mechanical sieving. As shown in Table 10, the majority of beads for both APIs are between 0.425 mm and 1.18 mm in size. Table 10: Particle size distribution of beads after mechanical sieving

[0229] Table 11 shows the density and flow properties of beads collected between 0.425 mm and 1.18 mm sieves. Xanomelein tartrate and trastoxamine IR beads exhibit different density and flow properties, which may be crucial when mixing bead systems. Table 11: Density and flow properties of beads ranging from 0.425mm to 1.18mm

[0230] The analysis in Table 12 shows the following favorable results: determination and related substances, and moisture content of 50 mg xanoximeline and 20 mg chlorpromazine capsules. Data in Table 13 indicate that these properties were retained during the storage stability studies. Similar data are provided in Table 14 for 50 mg xanoximeline capsules and 10 mg chlorpromazine capsules. Solubility data for both dosage forms are provided in Tables 15 and 16. Figure 6-41 Other tables are shown, which illustrate the stability of the fenofibrate / traxolamine formulation. Table 12: Analysis Results Table 13: Stability of KarXT 50 / 20 Table 14: Dissolution of KarXT 50 / 20 Table 15: Determination of KarXT 50 / 10 and related substances Table 16: Dissolution of KarXT 50 / 10

[0231] Subsequent testing showed that KarXT 50 / 10, 50 / 20, and 75 / 20 in hard-shell capsules were stable for at least 12 months at 25°C / 60% RH. Based on available data, a shelf life of 15 months at 25°C / 60% RH is recommended.

[0232] Dissolution results indicated that both compounds were released rapidly, which may enhance their bioavailability. Despite significant differences in composition between the two bead formulations, they also released at comparable rates. Zanomeprazole and trastrazine both have low bioavailability, and rapid release can increase bioavailability by overwhelming saturable processes that limit absorption into the macrocycle.

[0233] During stability studies of the combination drug products, an unknown xametrine impurity was observed, with a relative retention time of approximately 1.09. The impurity was first observed at the three-month time point for the 50 mg xametrine / 10 mg trastrilamine chloride product and at the initial time point for the other three combination products, occurring simultaneously. The impurity peak increased with both time and storage temperature. This impurity had not been observed prior to this study.

[0234] Preliminary studies indicate that the impurity in RRT 1.09 is 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridin-1-onium (C 14 H 20 N3O2S + , MW=294.1271Da):

[0235] RRT 1.09 impurity is the hydroxylated form of compound V (C). 14 H 20 N3OS + (MW = 278.1322 Da), it is the penultimate intermediate with negative mutagenic potential in the synthesis of fenofibrate:

[0236] To reduce the presence of impurities, the storage temperature of the pharmaceutical product was lowered. During the packaging process, the bottles were rinsed with argon gas to minimize oxygen in the headspace. In some embodiments, the xametrine formulation was formulated with an antioxidant (e.g., 0.5 wt.% ascorbic acid or 0.05 wt.% BHT). Example 4 - KAR-001 Phase I Study of the Combination of Xanomeprazole and Traxol Chloride

[0237] In healthy volunteers, a phase I, double-blind, randomized, multiple-dose pilot study of xapromide monotherapy was conducted, comparing it with xapromide and trexylchloride monotherapy. The primary objectives of this study were (1) to assess the safety and tolerability of 225 mg xapromide daily plus 40 mg trexylchloride daily for 7 days, compared with 225 mg xapromide daily alone for 7 days; and (2) to determine whether adding 40 mg trexylchloride daily (20 mg BID) to 225 mg xapromide daily (75 mg TID) for 7 days significantly reduced peripheral cholinergic side effects (nausea, diarrhea, vomiting, sweating, excessive salivation) compared with 225 mg xapromide daily alone. Table 17 lists the parameters of this study. Table 17: Parameters of the KAR-001 study

[0238] Seventy study participants were randomly assigned to groups, and 68 of them underwent at least one assessment on day 3 (the first day of cyclophosphamide administration). Table 18 lists the demographics of the study participants. Table 18: Demographics of the participants in the KAR-001 study

[0239] The most common adverse events associated with the use of xaprometrine are so-called cholinergic adverse events, including nausea, vomiting, diarrhea, excessive sweating, and excessive salivation. In this study, co-administration of xaprometrine with chlorotroxylchloride resulted in a 43% reduction in the incidence of cholinergic adverse events compared to co-administration of xaprometrine with placebo (statistically significant, p = 0.016). In the xaprometrine + placebo group, 63% of participants reported at least one cholinergic adverse event, compared to only 34% in the xaprometrine + chlorotroxylchloride group.

[0240] Furthermore, in the study, the incidence of each type of individual cholinergic adverse event was also reduced in subjects receiving xametrine plus trastrazine compared to those receiving xametrine plus placebo. The reduction in the incidence of sweating was statistically significant, with an incidence of 20.0% in the xametrine plus trastrazine group and 48.5% in the xametrine plus placebo group, a reduction of 59% (p = 0.013).

[0241] The overall cholinergic adverse event rate in the xamotilium + traxol group in this study was very similar to the 32% reported in subjects using placebo + placebo during the two-day adjustment period. Although these two data points did not appear at different times in the study, the fact that the incidence of cholinergic adverse events was comparable to that of placebo suggests that the 43% reduction in adverse events achieved with traxol may be close to the maximum possible reduction in this study.

[0242] Table 19 shows the incidence and number of cholinergic adverse events in the evaluable population of this study, where all p-values ​​are based on chi-square tests, except those marked with *, which are based on Fisher's exact test. Table 19: Cholinergic Adverse Events

[0243] In addition to assessing whether the addition of chlorpromazine chlorate could improve the tolerability of xapromazine, this study also provided data on the overall safety and tolerability of xapromazine + chlorpromazine chlorate. Table 20 shows that the combination was generally well tolerable, with no serious or critical adverse events, and most adverse events were mild. Table 20: Tolerability

[0244] The tolerance spectrum discovered in this study allows for future research into combinations of fenpropathrin and trastox chloramine. Example 5 - Phase I study of KarXT (a combination of fenpropathrin and trexylchloramine) using the KAR-003 formulation.

[0245] This study was a phase 1, randomized, multi-dose, adaptively designed inpatient study to evaluate the safety and tolerability of KarXT in healthy volunteers aged 18 to 60 years. Participants signed informed consent forms and underwent screening assessments on days -21 to -1. Upon successful completion of all screening assessments, participants returned to the study clinic on day 0 for baseline safety assessments and were enrolled in the study, randomly assigned in a 3:1 ratio to one of two treatment groups: KarXT or placebo. Participants were assigned to one of four cohorts (cohort 1, 2, 3, or 4).

[0246] The study drug was administered by BID on days 1 through 7. A combination dose formulation of xaprometin and troxetine was used in all cohorts. All cohorts began with a 2-day induction of KarXT 50 / 20 BID (for subjects randomized to receive active treatment); after the 2-day induction period, a non-blinded pharmacist dispensed the study drug to each subject according to their randomization for a designated cohort dosing period of 5 days, for a total of 7 days of treatment. A matched placebo was administered throughout the study to maintain blinding. For cohorts 2 through 4, a sentinel group was introduced into the study and safety and tolerability were monitored by the Data Safety Evaluation Group (DSEG) so that approximately 30% of the recommended cohorts had been treated and safety assessed before dosing the remaining subjects in the cohorts. Subjects and study clinic staff were blinded to the treatment. The Dose Selection Committee (DSC) was non-blinded to determine the dose for subsequent treatment groups.

[0247] Blood samples were drawn serially on days 1, 3, and 7 for pharmacokinetic (PK) assessment of shammetrine and trocechloramide. Additional blood samples were collected at regular intervals to monitor trough concentrations of shammetrine and trocechloramide and for clinical laboratory assessments. Saliva volumes were collected twice on day 1. Saliva volumes were measured on day 1 prior to administration and then daily (afternoon) at approximately the same time each day from day 1 to day 7 to avoid diurnal variation. Other assessments included pupillary size measurement and Bristol stool scale evaluation. Subjects remained in the study clinic throughout the 7-day treatment period. Subjects were discharged from the study clinic after a safety assessment on day 8 and were asked to return approximately 14 days after administration of the study drug for a final safety assessment.

[0248] During the study, after 2 days of KarXT 50 / 20 BID (for subjects randomized to receive aggressive treatment) in each cohort, subjects were administered the following: • In Cohort 1, subjects completed either KarXT 100 / 20BID (200 mg of xaprometin plus 40 mg of trocechloramide total daily dose (TDD)) or placebo on days 3 through 7. • In cohort 2, the sentinel group (group 2a) discontinued dosing after the morning dose on day 4. Subjects in cohort 2 were dosed KarXT 150 / 20BID (300 mg xanoxetine plus 40 mg trocechloramide TDD) or placebo. Dosing in cohort 2 was discontinued (based on the DSEG decision regarding observed tolerability issues). Because the DSC determined that further dosing in cohort 2 with KarXT 150 / 20BID was unlikely to be well tolerated to a sufficient degree to warrant further development of this dose combination for the clinical population, the study proceeded to dosing in cohort 3, the sentinel group (group 3a). • In cohort 3, the sentinel group (group 3a) completed days 3 through 7 with either KarXT 150 / 40 BID (300 mg xanthiprol plus 80 mg trocechloramide TDD) or placebo. Group 2 in cohort 3 (group 3b) discontinued administration after the morning dose on day 5. • In cohort 4, the sentinel group (group 4a), group 2 (group 4b), and the remaining groups (group 4c) completed days 3 through 7 of KarXT 125 / 40BID (250 mg xanthiprol plus 80 mg trocechloramide TDD) or placebo.

[0249] Ninety-six participants were planned, 248 were screened, 69 were randomly assigned, 51 completed the study, and 18 withdrew. The population consisted of healthy male and female participants aged 18 to 60 years with a body mass index (BMI) of 18 to 40 kg / m². 2 Subjects with a history of irritable bowel syndrome or severe constipation requiring treatment within the 6 months prior to screening were excluded from the study. Subjects with a history of or presence of any medical condition or disorder, including psychosis or neurological disorders (which the investigator deems potentially detrimental to subject safety or the validity of study results), were also excluded. Table 21 summarizes the demographic and baseline characteristics by treatment group. Demographic and baseline characteristics were consistent between the safety and PK groups. Table 21: Summary of Demographic and Baseline Characteristics by Treatment Group - Safety Population

[0250] Serial blood samples were collected from all subjects in each cohort on days 1, 3, and 7 prior to the morning dose, and on days 1, 2, 3, 4, 6, 8, 10, and 12 after the morning dose to assess the pharmacokinetic (PK) of xaprometrine and trocechloramide. The PK parameters listed below were calculated from individual xaprometrine and trocechloramide concentration-time curves using standard non-compartmental methods. Dose-normalized parameters, including C-maximum and area under the concentration-time curve (AUC), were calculated. Additional blood samples were collected during the study period on days 2, 4, 5, and 6 prior to the morning dose, and on day 8 before discharge, to monitor trough concentrations of xaprometrine and trocechloramide.

[0251] Safety assessments included spontaneously reported adverse events, ECG, laboratory evaluations, vital signs, saliva volume assessment, Bristol stool scale, pupil size, and physical examination. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) summarized continuous data by treatment group. Geometric mean (GM), geometric percentage coefficient of variation (CV%), quartiles, or box plots were generated. Although no formal statistics were performed, counts and frequencies were listed for categorical measures.

[0252] Unless otherwise stated, the treatment group summaries are as follows: KarXT 50 / 20 BID (for adverse events and Day 1 PK summary only), KarXT 100 / 20 BID, KarXT 125 / 40 BID, KarXT 150 / 20 BID, KarXT 150 / 40 BID, and placebo (empty) Add capsules and (All cohorts were combined with placebo groups). Safety assessments were based on spontaneously reported adverse events, ECG, laboratory assessments, and vital signs. Exploratory analyses were also performed on saliva volume, Bristol stool scale, and pupillary size.

[0253] Following oral administration of the KAR-003 formulation at all doses, xaprometin was well absorbed into systemic circulation. Peak concentrations of xaprometin were observed at a median time of 2 hours across all treatment groups and study days.

[0254] The median t-value of xaprometrine was between treatment groups and throughout the study day. 1 / 2 The values ​​are similar, which indicates that t 1 / 2 It is not dose-dependent. (Median t) 1 / 2 The range is 3.4 to 5.8 hours.

[0255] On day 3, GM xanomelide exposure was not proportional to the dose increased from 100 to 150 mg (when xanomelide was administered with 20 mg trocechloramide) or from 125 to 150 mg (when trocechloramide was administered with 40 mg trocechloramide). Lower xanomelide exposure was observed after treatment with KarXT 150 / 40 compared to KarXT 125 / 40. GM xanomelide exposure on day 3 was highest (Cmax, AUC) when a 150 mg dose of xanomelide was administered with 20 mg and 40 mg trocechloramide. 0- Finally, and AUC 0-12hr Similar. On day 7, when genometrine was used in combination with 40 mg trocechloramine, the increase in GM genometrine exposure was slightly more proportional to the dose from 125 mg to 150 mg.

[0256] On days 3 through 7 following treatment with KarXT 100 / 20 BID and KarXT 125 / 40 BID, minimal to no zeaxanthin accumulation was observed in the plasma; however, accumulation was observed in 3 of the 4 subjects who completed the study after administration of KarXT 150 / 40 BID. The mean accumulation rate in the KarXT 150 / 40 BID group was RAUC 366.2%, RC 最大 It is 445.4%. Example 6 - Pharmacokinetics of KAR-003 compared to KAR-001 (Xanomalylin)

[0257] Comparison of genobarbital (GM) exposure between KAR-001 (75 mg xanoximelin TID ± 20 mg trocetylchloramine BID) and the KarXT100 / 20 BID group from KAR-003 indicated that C 最 Largest value and AUC 0-6hr (KAR-003) or AUC 0-tau The (KAR-001) values ​​were greater in KAR-003 (days 3 and 7) than the corresponding exposures from KAR-001 (days 3 and 9). Median T values ​​were observed at 2 hours in both studies and over both days (days 3 and 9 for KAR-001, and days 3 and 7 for KAR-003). 最大 These data indicate that KarXT formulations enhance xanthipes exposure.

[0258] Following oral administration of the KarXT formulation at all doses, trocechloramide was absorbed into systemic circulation. Peak concentrations of trocechloramide were observed at a median time of 1.0 hour across all treatment groups and study days.

[0259] On day 3, the median t of trocechloramine between treatment groups 1 / 2 The values ​​were similar, with a range of 4.1 to 4.8 hours. On day 7, the median t-values ​​for treatments with KarXT 100 / 20 BID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) were similar. 1 / 2 Similar, but slightly longer for the KarXT 150 / 40BID group (7.1 hours).

[0260] When administered with 150 mg of cyclophosphamide, the increase in GM troxetine exposure on day 3 was slightly less than that proportional to the dose from 20 mg to 40 mg. When a 20 mg BID dose of troxetine was administered with a 100 mg BID dose of cyclophosphamide, the GM troxetine exposure on day 3 was greater compared to a 150 mg BID dose of cyclophosphamide (C). 最大 AUC 0-最后 and AUC 0-12hrWhen 40 mg trozechloramine BID was administered together with 125 mg xanthiprol BID and 150 mg xanthiprol BID, the GM trozechloramine exposure on day 3 was similar.

[0261] Following administration of KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID, trocechloramine did not accumulate in plasma from day 3 to day 7. In the KarXT 100 / 20 BID group, trocechloramine accumulated in plasma from day 1 to day 7. The mean day 7 / day 1 accumulation ratio was 348.7% (RAUC) and 379.9% (RC). 最大 ).

[0262] Comparison of trocetylchloramine GM exposure between KAR-001 and the KarXT 100 / 20BID group from KAR-003 showed that C from KAR-003 最大 and AUC 0-12hr The values ​​for trocechloramine were greater over two days (days 3 and 9 for KAR-001, and days 3 and 7 for KAR-003) than the corresponding exposure from KAR-001. In both studies, a median T value for trocechloramine was observed over two days. 最大 It is 1.0 hour. These data indicate that KarXT formulations enhance trox chloramine exposure.

[0263] All cohorts of KAR-003 began with a 2-day induction period of KarXT 50 / 20 BID (for subjects randomized to receive KarXT). Figure 42 Mean (±SD) cyclophosphamide PK concentrations are shown, and Table 22 summarizes the cyclophosphamide PK parameters for all cohorts of the PK population on day 1 of KarXT 50 / 20BID treatment. Samples collected prior to administration of the first dose of cyclophosphamide on day 1 did not show measurable cyclophosphamide concentrations. Cyclophosphamide concentrations were quantifiable (>50 pg / mL) at all time points from morning dose administration on day 1 up to 12 hours later. Table 22: KarXT 50 / 20BID PK parameters for Xanometra on Day 1 (All Queues)

[0264] Figure 43The mean (±SD) xuannomilin PK concentrations generated by treatment in the PK population on day 3 are shown in Table 23, which summarizes these parameters. For all cohorts, xuannomilin concentrations were quantifiable in samples at all time points, prior to administration of the morning dose of the study drug on day 3 and up to 12 hours after administration, except for one subject whose plasma xuannomilin concentration at 12 hours post-administration was <50.0 pg / mL. The range of variability among subjects across the four treatment groups for T... 最大 It ranges from 23.7% to 58.2% (CV%) for C. 最大 It is 79.8% to 136.3% (geometric CV%), for t 1 / 2 It is 21.6% to 26.3% (CV%) for AUC 0-12hr The percentage ranged from 77.1% to 96.1% (geometric CV%). For the KarXT 100 / 20BID, KarXT 125 / 40BID, KarXT 150 / 20BID, and KarXT 150 / 40BID groups, the median T value of cyclophosphamide on day 3 was... 最大 It's 2 hours. Spanning four treatment groups, a single T... 最大 The values ​​ranged from 1.0 to 6.0 hours. Compared to previous studies on KAR-001 (where the elimination phase was not well characterized), t 1 / 2 The median t-value of xanoxetine on day 3 was estimated in 51 out of 53 subjects. This was achieved across four treatment groups. 1 / 2 They are numerically similar. The median t 1 / 2 The range was 3.4 to 4.3 hours. Spanning four treatment groups, a single t... 1 / 2 The value ranges from 2.4 to 8.6 hours. Table 23: PK parameters of fenpropathrin produced on day 3 after treatment

[0265] When KarXT was administered via BID, the dose-normalized GM exposure (dose-normalized GM C) for xaprometrine on day 3 was increased from 100 mg (cohort 1) to 150 mg (cohort 2) without changing the troxetine dose (20 mg). 最大 and dose-normalized GM AUC 0-最后 and AUC 0-12hrThe dose-normalized GM exposure on day 3 for xaprometrine was slightly reduced when the dose of xaprometrine was increased from 125 mg (cohort 4) to 150 mg (cohort 3) without changing the dose of trocechloramide (40 mg). (i.e., lower xaprometrine exposure after treatment with KarXT 150 / 40 BID compared to treatment with KarXT 125 / 40 BID). Comparison of xaprometrine exposure after administration of 150 mg xaprometrine BID with 20 mg or 40 mg trocechloramide BID showed that GM and C on day 3 for xaprometrine were lower. 最大 AUC 0-最后 and AUC 0-12hr resemblance.

[0266] Figure 44 The mean (±SD) xametrine PK concentrations generated by treatment in the PK population on day 7 are shown in Table 24, which summarizes these parameters. For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID groups, xametrine concentrations were quantifiable in samples collected at all time points, including before administration of the morning dose of the study drug on day 7 and up to 12 hours after the morning dose on day 7. The range of variability between subjects across the KarXT 100 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 40 BID groups for T... 最大 It is 38.3% to 47.9% (CV%), for C 最大 It is 81.4% to 106.8% (geometric CV%), for t 1 / 2 It ranges from 15.4% to 42.1% (CV%) for AUC. 0-12hr The percentages ranged from 45.2% to 71.2% (geometric CV%). For the KarXT 100 / 20BID, KarXT 125 / 40BID, and KarXT 150 / 40BID groups, the median T value of cyclophosphamide on day 7 was... 最大 It is 2.0 hours. Across KarXT 100 / 20BID, KarXT 150 / 40BID, and KarXT 125 / 40BID groups, a single T... 最大 The values ​​range from 0.0 to 6.0 hours. For the KarXT 100 / 20BID, KarXT 125 / 40BID, and KarXT 150 / 40BID groups, the median t of xamometrine on day 7 was... 1 / 2 They are numerically similar. The median t of fenofibrate is... 1 / 2 The range is 4.6 to 5.8 hours. Across KarXT 100 / 20BID, KarXT 150 / 40BID, and KarXT 125 / 40BID groups, a single t 1 / 2The value ranges from 3.6 to 14.0 hours. Table 24: PK parameters of fenpropathrin produced on day 7 after treatment

[0267] When KarXT was administered via BID, the dose-normalized GM exposure (dose-normalized GM C) for xaprometrine on day 7 was significantly reduced by increasing the xaprometrine dose from 125 mg (cohort 4) to 150 mg (cohort 3) without changing the troxetine dose (40 mg). 最大 AUC 0-最后 and AUC 0-12hr )Increase.

[0268] Table 25 summarizes the cyclophosphamide PK accumulation rates (day 7 / day 3) in patients treated with PK. Based on the mean cyclophosphamide accumulation rates after treatment with KarXT 100 / 20 BID (cohort 1) and KarXT 125 / 40 BID (cohort 4), there was minimal to no cyclophosphamide accumulation in plasma from day 3 to day 7. The mean accumulation rate in the KarXT 100 / 20 BID group was 133.4% for RAUC and for RC 最大 The mean accumulation rate for the KarXT 125 / 40BID group is 130.5%, while for the RC group it is 143.9%. 最大 The rate was 151.0%. Compared to day 3, only one subject in the KarXT 100 / 20 BID group showed lower exposure on day 7. In contrast, three of the four subjects who completed the study in the KarXT 150 / 40 BID group showed mild accumulation of xaproline. Another subject in the KarXT 150 / 40 BID group showed similar exposure on days 3 and 7. The mean accumulation rates in the KarXT 150 / 40 BID group were 366.2% (RAUC) and 445.4% (RC). 最 big). Table 25: Accumulated PK ratio of xanthiprol produced by treatment (Day 7 / Day 3)

[0269] Figure 45 The mean (±SD) PK concentration-time curves of xaprometin were compared between the treatment and visit (days) in the PK group. Figure 46 The mean (±SD) trough concentration of xaproline PK is shown by PK population treatment. Steady-state attainment was not assessed.

[0270] Comparison of genotoxic methylphenidate (GM) exposure between KAR-001 (75 mg xanoximelin TID ± 20 mg trozepine chlorpheniramine BID) (Table 23) and the KarXT 100 / 20 BID group from KAR-003 (Table 21) showed that the KarXT 100 / 20 BID group (KAR-003) had lower GM exposure on day 3. 最大 Value and AUC 0-6hr (KAR-003) or AUC 0-tau The AUC (KAR-001) value from 0 to 6 hours was 2.3 to 2.6 times greater than the corresponding exposure from KAR-001 on day 3.

[0271] Comparison of day 7 GM exposure from the KarXT 100 / 20BID group (KAR-003) with day 9 GM exposure from xaprometrine alone and day 9 GM exposure from xaprometrine + troxetine from KAR-001 (Table 23) showed that the day 7 value for the KarXT100 / 20BID group (KAR-003) was approximately 1.4 to 1.8 times higher than the corresponding day 9 exposure from KAR-001. The median T values ​​for day 3 and 7 of KAR-003 (Table 22) and day 3 and 9 of KAR-001 (Table 23) were... 最大 It is 2.0 hours. These data indicate that the KAR-003 formulation provides sufficient exposure and PK properties.

[0272] Table 26 summarizes a subset of the KAR-003 xenometrine PK parameters for the PK population in the KarXT 100 / 20BID group on days 3 and 7. Table 27 presents a summary of the KAR-001 xenometrine PK parameters for the PK population in the KAR-001 group on days 3 and 9. Table 26: Subsets of phosphomoresin PK parameters for KarXT 100 / 20BID on Day 3 and Day 7 Table 27: Subsets of phenylephrine PK parameters of KAR-001 on days 3 and 9

[0273] Figure 47 The mean (±SD) trocechloramide PK concentrations on day 1 for the PK population treated with KarXT 50 / 20 BID (all cohorts) are presented, and these parameters are summarized in Table 28. Samples collected prior to administration of the first dose of trocechloramide on day 1 did not show measurable trocechloramide concentrations. Trocechloramide concentrations were quantifiable (>20 pg / mL) at all time points from the morning dose administration on day 1 up to 12 hours later. Table 28: KarXT 50 / 20BID Tris-Chloramine PK Parameters on Day 1 (All Cohorts)

[0274] Figure 48 The mean (±SD) trocechloramine PK concentrations generated by treatment in the PK population on day 3 are shown in Table 29, which summarizes these parameters. For all treatment groups, trocechloramine concentrations were quantifiable in samples collected at all time points, including before administration of the morning dose of the study drug on day 3 and up to 12 hours after administration of the morning dose on day 3, except for one subject whose plasma trocechloramine concentration at 12 hours post-administration was <20.0 pg / mL. The range of variability among subjects across the four treatment groups for T... 最大 It ranges from 0.0% to 83.0% (CV%) for C. 最大 It is 54.8% to 80.7% (geometric CV%), for t 1 / 2 It ranges from 9.1% to 34.0% (CV%) for AUC. 0-12hr It is 59.0% to 67.6% (geometric CV%). Table 29: PK parameters of troxylchloramine produced on day 3 after treatment

[0275] For the KarXT 100 / 20 BID, KarXT 125 / 40 BID, KarXT 150 / 20 BID, and KarXT 150 / 40 BID groups, the median T value of trocechloramine on day 3 was... 最大 It is 1.0 hour. Spanning 4 treatment groups, single T 最大 The values ​​ranged from 1.0 to 6.0 hours. The median t-value for trocechloramine on day 3 was [value missing] across the four treatment groups. 1 / 2 Numerically similar; median t 1 / 2 The range was 4.1 to 4.8 hours. Spanning 4 treatment groups, a single t... 1 / 2 The value ranges from 2.8 to 9.0 hours.

[0276] When KarXT was administered via BID, the dose-normalized GM exposure for trocechloramide increased on day 3 due to increasing the dose from 20 mg (cohort 2) to 40 mg (cohort 3) without changing the dose of xanomeprazole (150 mg). Comparison of trocechloramide exposure on day 3 after administration of 20 mg trocechloramide BID and 100 mg (cohort 1) or 150 mg (cohort 2) xanomeprazole BID showed that the GM C of trocechloramide was higher when the 20 mg BID dose of trocechloramide was administered together with the 100 mg xanomeprazole BID compared to the 150 mg xanomeprazole BID. 最大 AUC 0-最后 and AUC 0-12hr Larger.

[0277] Similarly, comparing tracetamol BID with 40 mg tracetamol BID and 125 mg (cohort 4) or 150 mg (cohort 3) xanofemulin BID showed that tracetamol BID had a lower GM C when administered on day 3 in combination with 125 and 150 mg xanofemulin BID. 最大 AUC 0-最后 and AUC 0-12hr They are largely similar.

[0278] Figure 49 The mean (±SD) troxylchloramine PK concentrations generated by treatment in the PK population on day 7 are shown in Table 30, which summarizes the parameters. For the KarXT 100 / 20BID, KarXT 125 / 40BID, and KarXT 150 / 40BID groups, troxylchloramine concentrations were quantifiable in samples collected at all time points, including before administration of the morning dose of the study drug on day 7 and up to 12 hours after the morning dose on day 7. The range of variability between subjects across the KarXT 100 / 20BID, KarXT 150 / 40BID, and KarXT 125 / 40BID groups for T... 最大 It ranges from 0.0% to 86.3% (CV%) for C. 最大 It is 51.2% to 93.8% (geometric CV%), for t 1 / 2 It ranges from 23.0% to 44.5% (CV%) for AUC. 0-12hr It is 59.4% to 76.7% (geometric CV%). Table 30: PK parameters of troxylchloramine produced on day 7 after treatment

[0279] For treatment with KarXT 100 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 40 BID, the median T value of trocechloramine on day 7 was... 最大It is 1.0 hour. Across KarXT 100 / 20BID, KarXT 150 / 40BID, and KarXT 125 / 40BID groups, a single T... 最大 The value ranges from 0.0 to 6.0 hours.

[0280] For the KarXT 100 / 20 BID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) groups, the median t-day of trocechloramine on day 7 was... 1 / 2 Similar. Median t of the KarXT 150 / 40BID group 1 / 2 It is 7.1 hours. Across KarXT 100 / 20BID, KarXT150 / 40BID, and KarXT 125 / 40BID groups, a single t 1 / 2 The value ranges from 3.1 to 11.9 hours.

[0281] As observed on day 3, comparisons of day 7 trocechloramide exposure following administration of 40 mg trocechloramide BID and 125 mg (cohort 4) or 150 mg (cohort 3) xanofemulin BID indicated that trocechloramide GMC was lower when administered with 125 and 150 mg xanofemulin BID. 最大 AUC0- 最后 and AUC 0-12hr resemblance.

[0282] Table 31 summarizes the trocechloramine PK accumulation rates (day 7 / day 3; day 7 / day 1) across the PK populations. Based on the mean trocechloramine PK accumulation rate, the least trocechloramine accumulation in plasma was observed from day 3 to day 7 after administration of KarXT 100 / 20 BID (cohort 1), with little or no accumulation after administration of KarXT 125 / 40 BID (cohort 4) and KarXT 150 / 40 BID (cohort 3). Both subjects showed lower exposure on day 7 compared to day 3 in the KarXT 100 / 20 BID group.

[0283] The accumulation rate varied considerably between days 3 and 7 between the KarXT 125 / 40 BID and KarXT 150 / 20 BID groups. The mean accumulation rate ranged from 108.6% to 141.4% for RAUC and for RC 最大 The percentages ranged from 111.0% to 135.8%. In the KarXT 100 / 20 BID group, mild accumulation of trocechloramine in plasma occurred from day 1 to day 7. Compared to day 1, all but one subject showed higher trocechloramine exposure on day 7. The mean accumulation rate was 348.7% for RAUC and for RC... 最大It is 379.9%. The possible effect of increasing the dose of xaprometrine (from 50 mg BID to 100 mg BID starting on day 3) on PK and troxetine bioavailability cannot be ruled out, as this would lead to increased exposure from day 1 to day 7. Table 31: PK accumulation ratio of trocechloramine produced by treatment (Day 7 / Day 3; Day 7 / Day 1)

[0284] Figure 50 The mean (±SD) trocechloramine PK concentration-time curves were compared between the treatment and visit (days) in the PK group. Figure 51 The mean (±SD) trough concentration of troxetine PK is shown by the number of days treated and visited in the PK population. Steady state was not assessed. Example 7 - Pharmacokinetics of trocechloramine in KAR-003 compared to KAR-001

[0285] Comparing day 1 trocechloramide exposure in KAR-001 (Table 33) (first dose of trocechloramide alone without any prior treatment) and day 1 in KAR-003 (Table 32) (first dose of xaprometin + trocechloramide without prior treatment) showed that trocechloramide exposure from KAR-003 was approximately 2.1 to 2.5 times higher than that from KAR-001. Although the comparison of day 3 GM exposure between studies was not a true head-to-head comparison (xaprometin administration was started on day 3 in the KAR-003 study), the number of trocechloramide doses administered to subjects and the daily dose were the same. Day 3 GM trocechloramide exposure in KAR-003 (Table 32) was also approximately 2.4 to 3.3 times higher than that from KAR-001 (Table 33). Comparing the day 7 GM exposure of the KarXT100 / 20BID cohort (cohort 1) from KAR-003 (Table 32) with the day 9 GM exposure of the xamometrine + trocechloramine group from KAR-001 (Table 33) again showed that the exposure obtained from KAR-001 was much higher (approximately 3.5-4.3 times higher).

[0286] For KAR-003, the KarXT 100 / 20BID group had median trexate levels on days 3 and 7, and for KAR-001, the xanthipyl + trexate group had median trexate levels on days 3 and 9. 最大 It is 1.0 hour. The median T value of trexylchloramine on day 1 in the KarXT 50 / 20BID group (KAR-003) 最大 Lower (1.0 hour), compared to the group with only trocechloramide (KAR-001) with a median trocechloramide T on day 1. 最大It takes 3.0 hours.

[0287] Table 32 summarizes subsets of KAR-003 trocechloramide PK parameters for the PK population, including KarXT 50 / 20 BID treatment (all cohorts) on day 1 and KarXT 100 / 20 BID treatment on days 3 and 7. Table 33 summarizes subsets of KAR-001 trocechloramide PK parameters for the PK population, including trocechloramide alone on day 1 and xaprometrine + trocechloramide treatment on days 3 and 9. Table 32: Subset of KAR-003 troxylchloramine PK parameters for KarXT 50 / 20BID (all queues) on day 1 and for KarXT 100 / 20BID on days 3 and 7. Table 33: Subsets of trocechloramine PK parameters of KAR-001 on days 1, 3, and 9

[0288] Table 34 lists the incidence of cholinergic TEAEs and preferred safety profiles for the KAR-001 study population by system organ category (SOC). The overall incidence of cholinergic TEAEs was similar among subjects in the KAR-001 group in the xamopine + troxetine group (12 [34.3%] subjects), the KarXT 100 / 20 BID group (7 [38.9%] subjects), and the KarXT 125 / 40 BID group (6 [33.3%] subjects). Table 34: KAR-001 Cholinergic Therapy - Incidence of Emergency Adverse Events (by System Organ Class) and Preferred Qualifications - Safety Population

[0289] Compared to the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups, the incidence of excessive salivation, hyperhidrosis, and diarrhea was higher in the KAR-001 xenometrine + trocechloramide group. Excessive salivation occurred in 25.7% of subjects in the KAR-001 xenometrine + trocechloramide group, 5.6% of subjects in the KarXT 100 / 20 BID group, and none of subjects in the KarXT 125 / 40 BID group. Hyperhidrosis occurred in 20.0% of subjects in the KAR-001 xenometrine + trocechloramide group, 5.6% of subjects in the KarXT 100 / 20 BID group, and 11.1% of subjects in the KarXT 125 / 40 BID group. Diarrhea occurred in 5.7% of subjects in the KAR-001 cyclophosphamide + trocetylcholine group, while no subjects in the KarXT 100 / 20 BID or KarXT 125 / 40 BID groups experienced diarrhea.

[0290] Regarding nausea and vomiting, no other significant trends were observed in the xaprometrine + trocechloramide group of KAR-001 compared to the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups. Nausea occurred in 17.1% of subjects in the xaprometrine + trocechloramide group of KAR-001 and in 22.2% of subjects in each of the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups. Vomiting occurred in 5.7% of subjects in the xaprometrine + trocechloramide group of KAR-001, in 27.8% of subjects in the KarXT 100 / 20 BID group, and in 5.6% of subjects in the KarXT 125 / 40 BID group.

[0291] Following oral administration of the KAR-003 formulation at all doses, xaprometin and trocechloramide were well absorbed into systemic circulation. PK results indicated that neither xaprometin nor trocechloramide significantly affected the PK behavior of the other drug. Compared to KAR-001, in which the two compounds were administered separately, the KAR-003 formulation provided enhanced blood levels of both xaprometin and trocechloramide.

[0292] No new safety signals were reported with KarXT preparations. All TEAEs were mild to moderate in severity, with no SAEs or deaths. The incidence of excessive salivation, hyperhidrosis, and diarrhea was higher in the xamometrine + troxetine group in KAR-001 compared to the KarXT 100 / 20 BID and KarXT 125 / 40 BID groups in KAR-003.

[0293] The foregoing description is provided for clarity only and should not be construed as limiting in any way, as modifications within the scope of this disclosure will be readily 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 also consist substantially of or comprise any combination of the listed components or materials, unless otherwise stated. Similarly, when a method is described as comprising steps, it is contemplated that the method may also consist substantially of or comprise any combination of the listed steps, unless otherwise stated. This disclosure, which is illustratively disclosed herein, may be practiced appropriately in the absence of any element or step not specifically disclosed herein.

[0294] The methods disclosed herein and their individual steps can be performed manually and / or with the aid of automation provided by electronic devices. Although the methods have been described with reference to embodiments, those skilled in the art will readily understand that other ways of performing the actions associated with the methods can be used. For example, unless otherwise stated, the order of the individual steps can be changed without departing from the scope or spirit of the methods. Additionally, some individual steps can be combined, omitted, or further subdivided into other steps.

[0295] It should be understood that certain features of the invention described in the context of individual embodiments for clarity may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of individual embodiments may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups represented by variables included in the general chemical formula described herein are expressly covered by the invention as if each combination were individually and expressly stated, to the extent that such combinations comprise stable compounds (i.e., compounds whose biological activity can be isolated, characterized, and tested). In addition, all sub-combinations of chemical groups listed in embodiments describing such variables, as well as all sub-combinations of uses and medical indications described herein, are specifically described in the invention as if each sub-combination of chemical groups and sub-combinations of uses and medical indications were individually and expressly stated herein.

[0296] All patents, publications, and references cited herein are incorporated herein by reference in their entirety. In the event of any conflict between this disclosure and the incorporated patents, publications, and references, this disclosure shall prevail. This disclosure relates to the following implementation plan: 1. An oral pharmaceutical composition comprising: Multiple xanomilin beads containing xanomilin or its salts; and Multiple trox chloramine beads containing trox chloramine salt. 2. The oral pharmaceutical composition of claim 1, wherein the plurality of xuanometrine beads have a core comprising the xuanometrine or a salt thereof. 3. The oral pharmaceutical composition of claim 1 or 2, wherein the plurality of trocechloramine beads have a core comprising the trocechloramine salt. 4. The oral pharmaceutical composition of any one of claims 1 to 3, wherein the size of the fenofibrate beads is from 0.425 mm to 1.18 mm. 5. The oral pharmaceutical composition of claim 4, wherein the size of the zenomeprazole is from 0.6 mm to 0.85 mm. 6. The oral pharmaceutical composition of any one of claims 1 to 5, wherein the size of the trastuzumab beads is from 0.425 mm to 1.18 mm. 7. The oral pharmaceutical composition of claim 6, wherein the size of the trastamide beads is from 0.6 mm to 0.85 mm. 8. The oral pharmaceutical composition of any one of claims 1 to 7, wherein the amount of xuanomelin contained in the xuanomelin beads is about 2.5 times that of the trastocine salt contained in the trastocine beads. 9. The oral pharmaceutical composition of any one of claims 1 to 8, wherein the solubility of the plurality of zebucil and the plurality of tromethamine beads is greater than about 95% within about 45 minutes after the dosage form is dispensed into the aqueous solution. 10. The oral pharmaceutical composition as described in item 9 has a solubility of more than about 95% within about 20 minutes after the dosage form is introduced into an aqueous solution. 11. The oral pharmaceutical composition of any one of items 1 to 10, when administered to a patient at a dose of 20 mg trocechloramide twice daily for at least 7 days, provides an average C0.05 of trocechloramide. 最大 It was 7850±3360 pg / mL. 12. The oral pharmaceutical composition of any one of items 1 to 11, when administered to a patient at a dose of 20 mg trocechloramide twice daily for at least 7 days, provides the mean AUC 0-12 It was 41900±15500hr·pg / mL. 13. The oral pharmaceutical composition of any one of claims 1 to 12, wherein the xuanomeline is xuanomeline tartrate. 14. The oral pharmaceutical composition of claim 13, wherein the zebuline contains 30 wt.% to 80 wt.% of zebuline tartrate. 15. The oral pharmaceutical composition of claim 14, wherein the zebuline contains 66 wt.% zebuline tartrate. 16. The oral pharmaceutical composition of any one of claims 1 to 15, wherein the cyclophosphamide comprises 15 wt.% to 65 wt.% microcrystalline cellulose. 17. The oral pharmaceutical composition of claim 14, wherein the cyclophosphamide comprises 33.5 wt.% microcrystalline cellulose. 18. The oral pharmaceutical composition of any one of claims 1 to 17, wherein the cyclophosphamide comprises 0 wt.% to 2 wt.% talc. 19. The oral pharmaceutical composition of claim 18, wherein the cyclophosphamide contains 0.5 wt.% talc. 20. The oral pharmaceutical composition of any one of claims 1 to 12, wherein the zenomeline comprises 30 wt.% to 80 wt.% zenomeline tartrate, 15 wt.% to 65 wt.% microcrystalline cellulose and 0 wt.% to 2 wt.% talc. 21. The oral pharmaceutical composition of claim 20, wherein the zenomeline comprises 66 wt.% zenomeline tartrate, 33.5 wt.% microcrystalline cellulose and 0.5 wt.% talc. 22. The oral pharmaceutical composition of any one of claims 1 to 21, wherein the trastrilamine salt is trastrilamine chloride. 23. The oral pharmaceutical composition of claim 22, wherein the trastrilamide beads comprise 8 wt.% to 35 wt.% trastrilamide chloride. 24. The oral pharmaceutical composition of claim 23, wherein the trastrilamide beads comprise 17.7 wt.% trastrilamide chloride. 25. The oral pharmaceutical composition of any one of claims 1 to 24, wherein the trastuzumab contains 25 wt.% to 80 wt.% microcrystalline cellulose. 26. The oral pharmaceutical composition of claim 25, wherein the trastuzumab contains 46.8 wt.% microcrystalline cellulose. 27. The oral pharmaceutical composition of any one of claims 1 or 26, wherein the trastuzumab contains 15 wt.% to 70 wt.% lactose monohydrate. 28. The oral pharmaceutical composition of claim 27, wherein the trastuzumab contains 35 wt.% lactose monohydrate. 29. The oral pharmaceutical composition of any one of claims 1 to 28, wherein the trastuzumab contains 0 wt.% to 2 wt.% talc. 30. The oral pharmaceutical composition of claim 29, wherein the trastuzumab contains 0.5 wt.% talc. 31. The oral pharmaceutical composition of claims 1 to 21, wherein the trastuzumab beads comprise 8 wt% to 35 wt.% trastuzumab chloride, 25 wt.% to 80 wt.% microcrystalline cellulose, 15 wt.% to 70 wt.% lactose monohydrate and 0 wt.% to 2 wt.% talc. 32. The oral pharmaceutical composition of claim 31, wherein the trastuzumab beads comprise 17.7 wt.% trastuzumab chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate and 0.5 wt.% talc. 33. The oral pharmaceutical composition of any one of claims 1 to 32, wherein the oral pharmaceutical composition further comprises a capsule comprising the plurality of fenofibrate beads and the plurality of trocetylchloramine beads. 34. An oral pharmaceutical composition comprising: Multiple xanomylene beads having a size of 0.425 mm to 1.18 mm, and a core comprising 30 wt.% to 80 wt.% xanomylene tartrate, 15 wt.% to 65 wt.% microcrystalline cellulose, and 0 wt.% to 2 wt.% talc; and Multiple trast chloramine beads having a size of 0.425 mm to 1.18 mm, and a core comprising 8 wt.% to 35 wt.% chlorinated trast chloramine, 25 wt.% to 80 wt.% microcrystalline cellulose, 15 wt.% to 70 wt.% lactose monohydrate and 0 wt.% to 2 wt.% talc; Within approximately 45 minutes of the dosage form being incorporated into the aqueous solution, the dissolution rate of the plurality of zanofemort beads and the plurality of trocechloramide beads is greater than approximately 95%; and wherein, when 20 mg of trocechloramide is administered to a patient twice daily for at least 7 days, the average C0 of trocechloramide provided is [missing value]. 最大 It was 7850±3360 pg / mL, with an average AUC of 0-12 It was 41900±15500hr·pg / mL. 35. The oral pharmaceutical composition of claim 34, wherein the size of the fenofibrate beads is from 0.6 mm to 0.85 mm. 36. The oral pharmaceutical composition of claim 34 or 35, wherein the size of the trastamide beads is from 0.6 mm to 0.85 mm. 37. The oral pharmaceutical composition of any one of claims 34 to 36, wherein the amount of xuanomelin contained in the xuanomelin beads is about 2.5 times that of the traspinochloramine contained in the traspinochloramine beads. 38. The oral pharmaceutical composition of any one of items 34 to 37, wherein the solubility of the fenofibrate and the trocechloramine is greater than about 95% within about 20 minutes after the dosage form is dispensed into the aqueous solution. 39. The oral pharmaceutical composition of any one of claims 34 to 38, wherein the zenomeline comprises 66 wt.% zenomeline tartrate, 33.5 wt.% microcrystalline cellulose and 0.5 wt.% talc. 40. The oral pharmaceutical composition of any one of claims 34 to 39, wherein the trastuzumab beads comprise 17.7 wt.% trastuzumab chloride, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate and 0.5 wt.% talc. 41. The oral pharmaceutical composition of any one of claims 34 to 40, wherein the oral pharmaceutical composition further comprises a capsule comprising the plurality of fenofibrate beads and the plurality of trexylamine beads. 42. An oral pharmaceutical composition comprising: The capsule contains multiple fenofibrate beads and multiple trexylamine beads; The plurality of xuanomelein beads have a size of 0.6 mm to 0.85 mm and a core comprising 66 wt.% xuanomelein tartrate, 33.5 wt.% microcrystalline cellulose, and 0.5 wt.% talc; and The plurality of trex chloramine beads have a size of 0.6 mm to 0.85 mm and a core comprising 17.7 wt.% chlorinated trex chloramine, 46.8 wt.% microcrystalline cellulose, 35 wt.% lactose monohydrate and 0.5 wt.% talc. Within approximately the first 20 minutes after the dosage form is added to the aqueous solution, the solubility of the plurality of xanofemort beads and the plurality of trox chloramine beads is greater than approximately 95%; and When 20 mg trocechloramide was administered to patients twice daily for at least 7 days, the average C of trocechloramide provided was [missing information]. 最大 It was 7850±3360 pg / mL, with an average AUC of 0-12 It was 41900±15500hr·pg / mL. 43. The oral pharmaceutical composition of any one of claims 1 to 42, wherein the dosage strength of the capsule is 25 mg of fenofibrate free base and 10 mg of trastox chloramine. 44. The oral pharmaceutical composition of any one of claims 1 to 42, wherein the dosage strength of the capsule is 50 mg of zenomeline free base and 20 mg of trastox chloramine. 45. The oral pharmaceutical composition of claims 1 to 42, wherein the dosage strength of the capsule is 50 mg of zenomeprazole free base and 10 mg of trastox chloramine. 46. ​​The oral pharmaceutical composition of claims 1 to 42, wherein the dosage strength of the capsule is 75 mg of zenomeprazole free base and 10 mg of trastox chloramine. 47. The oral pharmaceutical composition of claims 1 to 42, wherein the dosage strength of the capsule is 75 mg of fenofibrate free base and 20 mg of trastox chloramine. 48. The oral pharmaceutical composition of claims 1 to 42, wherein the dosage strength of the capsule is 125 mg of fenofibrate free base and 20 mg of trastox chloramine. 49. The oral pharmaceutical composition of claims 1 to 42, wherein the dosage strength of the capsule is 125 mg of fenofibrate free base and 30 mg of trastox chloramine. 50. The oral pharmaceutical composition of claims 1 to 42, wherein the dosage strength of the capsule is 125 mg of fenofibrate free base and 40 mg of trastox chloramine. 51. The oral pharmaceutical composition of any one of the preceding claims, wherein the cyclophosphamide contains less than 0.5 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridine-1-onium. 52. An oral pharmaceutical composition comprising xaprometrine and / or a salt thereof and trastril chloride for treating muscarinic disorders in patients in need, wherein, when administered to said patients in need, it is sufficient to provide an in vivo plasma profile containing a 2-hour median T value of xaprometrine. 最大 And the median T value of 1 hour of trastoxetine 最大 . 53. The oral pharmaceutical composition of claim 52, wherein the in vivo plasma profile further comprises a mean dose-normalized C0 of 48.5 pg / mL / mg to 121.3 pg / mL / mg. 最大 and the mean dose normalization C of trastuzumab from 156 pg / mL / mg to 375 pg / mL / mg 最大 . 54. The oral pharmaceutical composition of claim 52 or 53, wherein the in vivo plasma profile further comprises a mean dose-normalized AUC of fenpropathrin ranging from 263 hr·pg / mL / mg to 577 hr·pg / mL / mg. 0-12 The mean dose-normalized AUC of trocechloramide ranged from 881 hr·pg / mL / mg to 2024 hr·pg / mL / mg. 0-12 . 55. A method for activating muscarinic receptors in a biological sample, the method comprising contacting the biological sample with an oral pharmaceutical composition as described in any one of items 1 to 55. 56. A method of treating a disorder improved by activating muscarinic receptors in a subject in need, the method comprising administering to the patient in need an oral pharmaceutical composition as described in any one of items 1 to 55. 57. A method of treating a disorder improved by activating muscarinic receptors in a subject in need, the method comprising sequential or co-administration of an oral pharmaceutical composition as described in any one of items 1 to 55; and a second therapeutic agent. 58. The method of any one of items 55 to 57, wherein the subject is a human. 59. The method of any one of claims 55 to 57, wherein the disorder is selected from schizophrenia, Alzheimer's disease, Parkinson's disease, depression, movement disorder, pain, drug addiction, tau protein disease, and synucleoprotein disease. 60. The method of any one of claims 55 to 57, wherein the disorder is a neurodegenerative disease. 61. The method of any one of items 55 to 57, wherein the disorder is a central nervous system disease. 62. Compound 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridine-1-onium. 63. An oral pharmaceutical composition comprising sennametrine and / or its salt and less than 0.5 wt.% of 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy-1-methylpyridine-1-onium. 64. A method for preparing an oral pharmaceutical composition as described in any one of claims 1 to 55, the method comprising mixing a plurality of xuanomelin beads containing a pharmaceutically acceptable salt thereof with a plurality of trocechloramine beads containing a trocechloramine salt. 65. The method of claim 64, wherein the plurality of beads containing zenomeprazole or a pharmaceutically acceptable salt thereof contains an antioxidant. 66. The method of claim 64 or 65, the method further comprising: formulating the mixed beads into a capsule. 67. The method of any one of claims 64 to 66, the method further comprising storing the oral pharmaceutical composition at a temperature of about 2°C to about 8°C before dispensing the oral pharmaceutical composition to the subject. 68. The method of claim 67, wherein after dispensing the oral pharmaceutical composition to the subject, the method further comprises storing the oral pharmaceutical composition at a temperature of about 20°C to about 25°C.

Claims

1. A pharmaceutical composition comprising xaprometrine or a salt thereof and troxetine salt, The cyclophosphamide or its salt and the troxylamine salt are formulated in different matrices of the pharmaceutical composition.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a plurality of xaprometrine beads comprising the xaprometrine or a salt thereof and a plurality of trastacylamine beads comprising the trastacylamine salt.

3. The pharmaceutical composition according to claim 1 or claim 2, wherein the pharmaceutical composition is an oral pharmaceutical composition.

4. The pharmaceutical composition of claim 1 or claim 2, wherein the zenomeline or its salt is zenomeline tartrate and the trastamide salt is trastamide chloride.

5. The pharmaceutical composition of claim 1 or claim 2, wherein the composition is formulated in a single capsule.

6. The pharmaceutical composition of claim 1 or claim 2, wherein the matrix comprising the sennamidrin or a salt thereof, or the plurality of sennamidrin beads, comprises 30 wt.% to 80 wt.% of sennamidrin tartrate.

7. The pharmaceutical composition of claim 6, wherein the matrix comprising the xuanomeline or a salt thereof, or the plurality of xuanomeline beads comprising 66 wt.% xuanomeline tartrate.

8. The pharmaceutical composition of claim 1 or claim 2, wherein the matrix comprising the sennamidrin or a salt thereof or the plurality of sennamidrin beads comprises 30 wt.% to 80 wt.% of sennamidrin tartrate, 15 wt.% to 65 wt.% of microcrystalline cellulose and 0 wt.% to 2 wt.% of talc.

9. The pharmaceutical composition of claim 1 or claim 2, wherein the matrix comprising the trast chloramine salt or the plurality of trast chloramine beads comprises 8 wt.% to 35 wt.% trast chloramine chloride.

10. The pharmaceutical composition of claim 9, wherein the matrix comprising the trast chloramine salt or the plurality of trast chloramine beads comprises 17.7 wt.% trast chloramine chloride.

11. The pharmaceutical composition of claim 1 or claim 2, wherein the matrix comprising the trast chloramine salt or the plurality of trast chloramine beads comprises 8 wt.% to 35 wt.% trast chloramine chloride, 25 wt.% to 80 wt.% microcrystalline cellulose, 15 wt.% to 70 wt.% lactose monohydrate and 0 wt.% to 2 wt.% talc.

12. The pharmaceutical composition of claim 1 or claim 2, wherein the different matrix or each of the zebuline and trastuzumab further comprises an antioxidant.

13. The pharmaceutical composition of claim 12, wherein the antioxidant is ascorbic acid or butylated hydroxytoluene (BHT).

14. The pharmaceutical composition of claim 13, wherein the different matrix or the zenomelin and trocechloramine beads each independently comprise 0.2 wt.% to 1.0 wt.% of ascorbic acid or 0.01 wt.% to 1.0 wt.% of BHT.

15. The pharmaceutical composition of claim 1 or claim 2, wherein the composition is a capsule comprising a dose intensity equal to the following: (a) 25 mg of fenofibrate free base and 10 mg of trexyl chloride; (b) 50 mg of fenofibrate free base and 20 mg of trexyl chloride; (c) 75 mg of cyclophosphamide free base and 20 mg of trastoxetine chloride; (d) 100 mg of fenpropathrin free base and 20 mg of trexyl chlorpheniramine chloride; or (e) 125 mg of cyclophosphamide free base and 30 mg of trastoxamine chloride.

16. The pharmaceutical composition of claim 2, wherein the composition is a capsule comprising a dose intensity equal to the following: (a) 50 mg of fenofibrate free base and 20 mg of trexyl chloride; (b) 100 mg of cyclophosphamide free base and 20 mg of trastoxetine chloride; or (c) 125 mg of cyclophosphamide free base and 30 mg of trastoxamine chloride.

17. The pharmaceutical composition of claim 16, wherein the capsule comprises a plurality of zenomeline beads containing zenomeline tartrate and a plurality of trastamide beads containing trastamide chloride.

Images