Compositions and methods for treating disorders ameliorated by muscarinic receptor activation - Patents.com

Abstract

To provide a pharmaceutical composition with increased tolerability for xanomeline, especially useful to treat cognitive and psychotic disorders, and a method for preparing the same.SOLUTION: An oral pharmaceutical composition comprises xanomeline and / or a salt thereof and trospium chloride for treating a muscarinic disorder in a patient in need thereof, the oral pharmaceutical composition being sufficient to provide an in-vivo plasma profile comprising a median Tmax for xanomeline of 2 hours and a median Tmax for trospium of 1 hour, when administered to the patient in need thereof. A method for preparing an oral pharmaceutical composition includes mixing beads comprising a plurality of xanomeline beads comprising xanomeline or a pharmaceutically acceptable salt thereof with a plurality of trospium beads comprising a salt of trospium.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] This application is a continuation of U.S. Provisional Patent Application No. 62 / 738,333, filed September 28, 2018. No. 6,313,625, filed on Oct. 13, 2006, and claims the benefit of priority to the present application, the disclosure of which is incorporated by reference in its entirety for all purposes. Be absorbed.

[0002] The present disclosure provides a method for improving the function of the muscarinic receptors in a human or animal subject by activating the muscarinic receptors. The present invention relates to compositions for treating disorders such as rheumatoid arthritis and their application as medicaments. [Background technology]

[0003] Schizophrenia affects approximately 0.5-1% of the population. The disease is characterized by positive symptoms (e.g. hallucinations, symptoms (e.g., delusional thoughts, etc.), negative symptoms (e.g., social isolation, anhedonia, etc.), and cognitive symptoms (e.g., It is characterized by a set of symptoms that can be divided into four categories (e.g., inability to process information, poor working memory, etc.). Patients with schizophrenia experience a significant decline in their quality of life and many other side effects, including an increased suicide rate. Many factors increase the risk of death for people with schizophrenia. People who are incarcerated or homeless are at higher risk. The cost of schizophrenia to society is high because people with schizophrenia are much more likely to be depressed or unemployed. stomach.

[0004] Existing treatments for schizophrenia include chlorpromazine, the first antipsychotic drug discovered in 1952. Like the serotonin receptors, the drug relies on dopamine and serotonin receptors. The same basic pharmacology has become the standard of care for schizophrenia. Current antipsychotics target the positive symptoms. It is effective only for the symptomatic symptoms, leaving the negative and cognitive symptoms untreated. Cancer is another therapeutic area where developing new treatments has proven extremely difficult. As a result, the success rate of molecules entering clinical development and receiving marketing approval is only 0.4%. Patients in this field desperately need new treatments, but scientists and drug developers around the world Despite great efforts, development has been extremely difficult.

[0005] Activation of the muscarinic system through muscarinic agonists has been shown to be effective in treating schizophrenia, Alzheimer's disease, and other conditions. Parkinson's disease, depression, movement disorders, drug addiction, pain, and tauopathy or syndromic syndrome It may be possible to treat some diseases such as neurodegenerative disorders such as neuropathy. The cholinergic receptors are G protein receptors with five different receptor subtypes (M1 to M5). are receptor-coupled, and each of the receptor subtypes is found in the CNS with different tissue distributions The M1 and M4 subtypes are of interest as therapeutic targets for various diseases, e.g., bipolar disorder. The mood stabilizers lithium and valproate used to treat depression act on the muscarinic system. They may exert their effects via the M4 subtype receptor, in particular. Genetic evidence supports the notion that , directly linking the muscarinic system to alcoholism.

[0006] Muscarinic cholinergic receptor agonist with preferential activity at M1 and M4 subtype receptors In a double-blind, placebo-controlled study of the drug xanomeline in patients with schizophrenia, However, xanomeline also binds to muscarinic receptors outside the brain. This combination caused a number of serious side effects, including GI side effects, cardiac side effects, and excessive salivation. Dose-limiting adverse events were problematic, with very high discontinuation rates (2.5% in patients with Alzheimer's disease). (including a 56% dropout rate in a 6-week trial), ultimately resulting in the halting of xanomeline development. Despite early promise, development of xanomeline has stalled for over 15 years. Many companies have sought to avoid these unacceptable side effects by developing muscarin for CNS disorders. Attempts have been made to develop cholinergic receptor agonists and failed, but such agonists have not yet reached the market. Development efforts to date have typically targeted M2 and M3 muscarinic receptor subtypes. By selecting M1 and M4 subtypes over type, we have been able to identify better tolerated molecules. However, the focus of the current study was on medicinal chemistry to develop and develop M1 and / or M4 activation may still lead to muscarinic intolerance. Little progress has been made to mitigate the adverse effects of phosphoreceptor activation. Summary of the Invention [Problem to be solved by the invention]

[0007] The art provides pharmaceutical compositions with increased tolerance to xanomeline, particularly for treating cognitive impairment and There remains a need for pharmaceutical compositions for treating psychiatric disorders. The embodiments are meant to be exemplary and illustrative, and are not intended to be limiting in scope. In various embodiments, one or more of the above problems are addressed using a method and method. have been reduced or eliminated, while other embodiments are directed to other improvements. [Means for solving the problem]

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

[0009] In certain embodiments, the size of the xanomelin beads is between 0.425 mm and 1.18 mm. In a particular embodiment, the size of the xanomelin beads is between 0.6 mm and 0.85 mm. In certain embodiments, the size of the trospium beads is between 0.425 mm and 1. In a particular embodiment, the size of the trospium beads is 0.6 mm to 0.18 mm. It is .85mm.

[0010] In certain embodiments, the xanomelin beads are trospium chloride beads. Contains approximately 2.5 times the amount of xanomeline as when

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

[0012] In certain embodiments, patients are administered 20 mg of trospium twice daily for at least 7 days. When administered, the oral pharmaceutical composition provided a mean trospium concentration of 7850±3360 pg / mL C max In certain embodiments, at least 20 mg of trospium twice daily is provided. When administered to patients for 7 days, the oral pharmaceutical composition had a mean blood glucose level of 41,900 ± 15,500 pg / kg. Mean AUC / mL 0-12 to provide.

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

[0014] In certain embodiments, the trospium salt is trospium chloride. Trospium beads contain 8% to 35% by weight of trospium chloride, e.g. 17.7 In a particular embodiment, the trospium beads contain 25% by weight trospium chloride. % by weight, e.g., 46.8% by weight of microcrystalline cellulose. In certain embodiments, the trospium beads contain between 15% and 70% by weight lactose monohydrate, e.g. For example, 35% by weight lactose monohydrate. In a particular embodiment, the trospium beads contain 0. % to 2% by weight of talc, for example 0.5% by weight of talc. Trospium beads are 8% to 35% by weight of trospium chloride, 25% to 80% by weight of % microcrystalline cellulose, 15% to 70% lactose monohydrate, and 0% to 20% lactose monohydrate. In a particular embodiment, the trospium beads contain 17.7% by weight salt. trospium chloride, 46.8% by weight microcrystalline cellulose, 35% by weight lactose monohydrate, and Contains 0.5% by weight of talc.

[0015] In certain embodiments, the oral pharmaceutical composition comprises a plurality of xanomeline beads and a plurality of tros In a particular embodiment, the capsule further comprises 50 mg of pium beads. Dosage strengths of 10 mg xanomeline free base and 20 mg trospium chloride In a particular embodiment, the capsule contains 50 mg of xanomeline. In certain embodiments, the dosage strengths are 10 mg of trospium chloride and 10 mg of free base. The capsule contains a dosage strength of 75 mg xanomeline free base and 20 mg trospium chloride. In a particular embodiment, the capsule contains 75 mg of xanomeline free base and 10 In a particular embodiment, the capsules have a dosage strength of 125 mg of trospium chloride. mg of xanomeline free base and 30 mg of trospium chloride. In one embodiment, the capsule contains 125 mg of xanomeline free base and 40 mg of trichloroethylene. Has the dosage strength of rospium.

[0016] The present disclosure also provides a method for producing ... and 30% to 80% by weight of xanomeline tartrate, 15% to 65% by weight of fine powder. A core containing crystalline cellulose and 0.2% by weight to 2% by weight of talc, and A number of trospium beads with a size of .18 mm and 8% to 35% trospium by weight Spium, 25% to 80% microcrystalline cellulose, 15% to 70% lactose monohydrate, and a core comprising 0.2% to 2% by weight of talc, The trospium beads and multiple trospium beads were approximately 100% effective within the first 45 minutes after the dosage form was placed in aqueous solution. A dissolution rate of >95% and 20 mg of trospium twice daily for at least 7 days , the mean C of trospium when administered to patients was 7850 ± 3360 pg / mL. max , and mean AUC of 41,900 ± 15,500 pg / mL over time. 0-12 An oral pharmaceutical A composition is provided.

[0017] The present disclosure also provides a capsule comprising a plurality of xanomeline beads and a plurality of trospium beads. The oral pharmaceutical composition includes a plurality of xanomeline beads, the plurality of xanomeline beads being 0.6 mm to 0.85 mm in diameter. mm in size, 66% by weight of xanomeline tartrate, 33.5% by weight of microcrystalline cellulose and a core comprising 0.5% by weight talc, the plurality of trospium beads comprising 0.6 Size: 0.85mm to 17.7% trospium chloride, 46.8% A core comprising microcrystalline cellulose, 35% by weight lactose monohydrate, and 0.5% by weight talc. and the plurality of xanomeline and the plurality of trospium beads are and has a dissolution rate of greater than about 95% within about the first 20 minutes of administration of 20 mg of trospium in 1 When administered to patients twice daily for at least 7 days, the thorax was 7850 ± 3360 pg / mL. Average C of Spium max and mean AUC of 41,900 ± 15,500 pg / mL over time. 0-1 Provide 2.

[0018] Additionally, the biological sample is contacted with any of the oral pharmaceutical compositions described herein. In accordance with another aspect of the present invention, there is provided a method for activating a muscarinic receptor in a biological sample, comprising:

[0019] Administering any of the oral pharmaceutical compositions described herein to a patient in need of treatment for a disorder. Activating muscarinic receptors in a subject in need of treatment for a disorder, including Also provided are methods for treating disorders ameliorated by In certain embodiments, the disorder is schizophrenia, Alzheimer's disease, Parkinson's disease, or Son's disease, depression, movement disorders, pain, drug addiction, tauopathy, and synucleinopathy are selected.

[0020] Additionally, any of the oral pharmaceutical compositions described herein; and a second therapeutic agent administered sequentially or The present invention relates to a method for the treatment of a muscarinic disorder comprising administering to a subject a therapeutically effective amount of a muscarinic receptor antagonist in a subject in need of treatment for a muscarinic disorder, the method comprising administering to a subject a therapeutically effective amount of a muscarinic receptor antagonist in a subject in need of treatment for ... The present invention provides a method for treating a disorder in which the disorder is ameliorated by administering

[0021] The present disclosure also provides a method for the preparation of a compound comprising administering to a subject a compound comprising administering to said subject a compound having a formula (I) of xanomeline and / or a salt thereof and less than 0.5% by weight of 3-[(4-hexyl)-2-phenylpropanediol.

[0024] -1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methyloxy and xanomeline or a salt thereof. and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2,5-thiadiazole- Multiple xanome containing [3-yl]-5-hydroxyl-1-methylpyridin-1-ium Oral pharmaceutical compositions comprising lin beads; and a plurality of trospium beads containing a salt of trospium - Patent Application 20070229333 Items are also provided.

[0022] The present invention further provides a method for treating a muscarinic disorder in a subject in need of treatment for the disorder. The present invention provides an oral pharmaceutical composition comprising xanomeline and / or a salt thereof and trospium chloride for the treatment of and the composition, when administered to a subject in need of treatment for the disorder, exhibits a 2-hour response to xanomeline. Median T max and median T for trospium at 1 hourmax Including In certain embodiments, the in vivo plasma profile is sufficient to provide a The profile showed a mean dose-normalized C of 48.5 to 121.3 pg / mL / mg. max , and Mean dose-normalized C of trospium between 156 and 375 pg / mL / mg max Also includes In certain embodiments, the in vivo plasma profile is between 263 and 577 pg / mL / hr. Mean dose-normalized AUC of xanomeline in mg 0-12 , and 881-2024 hours pg / Mean Dose-Normalized AUC of Trospium in mL / mg 0-12 Further includes:

[0023] Further aspects and advantages will become apparent to those skilled in the art upon consideration of the following detailed description. The dosage forms, methods of preparation and methods of treatment will be amenable to various forms of embodiment. However, the following description is illustrative and is not intended to limit the scope of the present disclosure to the specific embodiments described herein. It is understood that the invention is not intended to be limited to the specific embodiments described herein.

[0024] The present disclosure is described in detail below in conjunction with the accompanying drawings, in which like reference numerals indicate like structural elements, and in which: The drawings are illustrative of exemplary embodiments or aspects of the present disclosure. It is provided without limiting the scope of the present disclosure. [Brief description of the drawings]

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

[0026] The articles "a" and "an" refer to one or to more than one (i.e., at least one) article. For example, "an element" can mean one element or more than one element. .

[0027] The terms "comprise" and "comprising" have an inclusive and open meaning and may include additional elements. This means that it is okay to

[0028] The term "consisting of" refers to an element that is specified, except for impurities that normally accompany the element. is limited to.

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

[0030] All ranges set forth herein include all possible subsets of ranges, and any such subsets. Contains any combination of subset ranges. By default, ranges are When a range of values ​​is provided, each value between the upper and lower limits of that range is inclusive of the stated endpoints. Intervening values, and any other stated or intervening values ​​within the stated ranges, are not intended to be limiting unless otherwise stated within this disclosure. The upper and lower limits of these smaller ranges may independently be any smaller number. may be included in the range, subject to any specifically excluded limitations in the stated range. Any limit not included in the stated range is included within the present disclosure. Ranges excluding either or both of these limits are also considered to be part of the disclosure. do.

[0031] The term "wt. %" refers to the weight percent of the active ingredient, e.g., the core, or the enteric coating, or is the weight percent based on the total weight of all beads. Unless otherwise noted, weight percent is on a dry basis. It is intended to state weight percentages based on weight (e.g., for dried cores). can be.

[0032] The term "controlled release" refers to the administration of one or more drugs such that the drug is released over a period of time. A controlled release formulation is defined as an extended release pattern. The ability to measure drug for a longer period of time than is possible after injection or administration of an immediate release oral dosage form. The drug has release kinetics that result in acceptable serum levels. Ended release, prolonged release, and delayed release are used herein. has the same definition.

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

[0034] The term "mammal" is known in the art. Exemplary mammals include humans, spirits, and the like. These include protozoa, cattle, pigs, dogs, cats, and rodents (e.g., mice and rats). do.

[0035] The terms "parenteral administration" and "parenterally administered" are art-recognized and Refers to modes of administration other than enteral and local administration, usually by injection. These modes include intravenous Intramuscular, intraarterial, intrathecal, intravesical, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, superficial These include, but are not limited to, subcutaneous, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions. However, the present invention is not limited to the above.

[0036] The "patient," "subject," or "host" treated by the present method may be a human or non-human mammal. It means any of the things.

[0037] The term "pharmaceutically acceptable carrier" is art-recognized and refers to a liquid or solid carrier. Pharmaceutically acceptable carriers, such as fillers, diluents, excipients, solvents or encapsulating materials. Refers to a material, composition, or vehicle, which is any composition of interest or its components, contained in a single container. Involved in conveying or transporting from one organ or part of the body to another. The body must be "acceptable" in the sense that the subject composition and its components are compatible and not harmful to the patient. Some examples of materials that can function as pharma- ceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; corn starch and potato starches such as moder starch; carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; cellulose and its derivatives; powdered tragacanth; malt; gelatin; talc; Excipients such as cocoa butter and suppository wax; peanut oil, cottonseed oil, safflower oil, sesame oil oils such as 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; magnesium hydroxide and Buffers such as aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; phosphorus Gel solutions; ethyl alcohol; phosphate buffer solutions; and other non-toxic conforming materials used in pharmaceutical preparations. Contains sexual substances.

[0038] The term "pharmaceutically acceptable salt" is art-recognized and is used herein for purposes of illustration only. Relatively non-toxic, including inorganic and organic acids and bases, including those contained in the composition. Suitable non-toxic acids include acetic acid, benzenesulfonyl chloride, and ethyl acetate. Sulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethylenesulfonic acid, fumaric acid, Gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, phosphorus Gonic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid , succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and Examples of the acids include inorganic acids such as sulfuric acid and organic acids.

[0039] The term "treating" is art-recognized and refers to at least one of the following: Both refer to the cure or improvement of a single symptom.

[0040] In jurisdictions that prohibit patents on methods administered to the human body, "Administering" means administering to a human subject any technique (e.g., orally, by inhalation, topical application, injection, "(a) The prescription for a controlled substance to be administered by a pharmacy, hospital, or other facility (including a pharmacy) shall be limited to prescribing controlled substances to be self-administered (by injection, etc.) or to administering to a patient." The broadest reasonable interpretation is intended, consistent with any statute or regulation defining patentable subject matter. In jurisdictions that do not prohibit the patenting of methods administered to the human body, "administration" of a composition refers to administration of a composition to the human body. This includes both the methods and activities described above.

[0041] The term "therapeutic agent" is art-recognized and refers to a therapeutic agent that acts locally or systemically in a subject. "The term 'chemical moiety' refers to any chemical moiety that is a biologically, physiologically, or pharmacologically active substance that has a therapeutic or therapeutic effect." Examples of therapeutic agents, also called "drugs," are listed in the Merck Index (14th ed.), Physicians' Guide to Drugs, 1999, ed. ians' Desk Reference (64th ed.), and The Pharmac Publicizing the Theological Basis of Therapeutics (12th Edition) These therapeutic agents include drugs; vitamins; mineral supplements; substances used to treat, prevent, diagnose, cure or mitigate a disease or illness; Substances that affect structure or function, or that become biologically active or more active after being placed in a physiological environment. These include, but are not limited to, prodrugs that become active when

[0042] The term "psychotherapy" refers to the verbal and physical interactions that a person skilled in the art has with a patient to affect a positive therapeutic outcome. This refers to non-pharmacological therapies that use a variety of techniques, including drug and other interactions. , behavioral therapy, cognitive therapy, psychodynamic therapy, psychoanalytic therapy, group therapy, family counseling therapy, art therapy, music therapy, occupational therapy, humanistic therapy, existential therapy, transpersonal therapy , client-centered therapy (also called person-centered therapy), Gestalt therapy, biophysics Back therapy, rational emotive behavior therapy, reality therapy, response-based therapy d therapy, sandplay therapy, status dynamics therapy These include, but are not limited to, amics therapy, hypnosis and validation therapy. Psychotherapy may involve the combination of two or more techniques. The therapist Techniques can be selected and adjusted based on the needs of the patient and their response.

[0043] The term "muscarinic disorder" refers to any disorder that is improved by activating the muscarinic system. Such diseases include those caused by the direct activation of the muscarinic receptor itself. These include those in which activation or inhibition of the cholinesterase enzyme has a therapeutic effect.

[0044] The terms "schizophrenia-related disease" and "schizophrenia-related disorder" include disorders related to schizophrenia. Affective disorders, psychosis, delusional disorders, Alzheimer's-related psychoses, and Parkinson's disease Associated psychoses, psychotic depression, bipolar disorder, bipolar disorder with psychosis, Huntington's This includes, but is not limited to, dementia with cerebrospinal fluid (CSF), dementia with Lewy bodies, or any other disorder with psychotic features. However, the present invention is not limited to the above.

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

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

[0047] The term "cognitive disorder" refers to a condition that is characterized by a cognitive deficit (e.g., abnormal working memory, problem-solving ability, etc.). The term refers to a disease or disorder characterized by the following: Alzheimer's disease, Parkinson's disease, cognitive impairment, and Dementia (AIDS-related dementia, vascular dementia, age-related dementia, dementia associated with Lewy bodies) , and idiopathic dementia), Pick's disease, tauopathy, syncytial dementia, Raynopathies, confusion, fatigue-related cognitive deficits, learning disabilities, traumatic brain injury, autism, aging These include cognitive decline associated with glaucoma and Cushing's disease, which is cognitive impairment associated with autoimmune diseases. Not limited to these.

[0048] The term "attention deficit" refers to a disorder or condition characterized by having an abnormal or reduced attention span. Refers to a condition. Diseases include Attention Deficit Hyperactivity Disorder (ADHD), Attention Deficit Disorder (ADD), , Dubowitz syndrome, FG syndrome, Down syndrome, insulin-like growth factor I (IGF 1) Deficiency-related symptoms include growth retardation, hepatic encephalopathy syndrome, and Strauss syndrome. Not limited to.

[0049] The term "addictive disorder" is defined in the Diagnostic & Statistical Manual of Clinical Trials. A disease or condition characterized by addiction or substance dependence as defined by the DSM-5. Such disorders are characterized by physical dependence, withdrawal, and tolerance to the substance. Such substances include alcohol, cocaine, amphetamines, opioids, and benzodiazepines. These include, but are not limited to, pinpoints, inhalants, nicotine, barbiturates, cocaine and cannabis. Addiction disorders are also characterized by a compulsive or obsessive behavior in which the patient has an obsession with something despite apparent negative consequences. It includes behaviors that are repeated over and over. For example, gambling mania (addictive gambling or compulsive gambling) Addictions to drugs are recognized by those skilled in the art as addictive behaviors that often have devastating consequences. In certain embodiments, the addictive behavior is Internet Gaming Disorder as defined by DSM-5 ( It may also be gaming addiction.

[0050] The term "pain" refers to physical suffering or discomfort caused by illness or injury. Pain is a subjective experience and the perception of pain is carried out in parts of the central nervous system (CNS). Normally, noxious (peripheral) stimuli are transmitted to the CNS beforehand, but pain is not necessarily associated with nociception. There is no single common denominator. Different underlying pathophysiological mechanisms lead to different treatment approaches. There are many different types of clinical pain that require treatment. There are three main types of clinical pain: acute pain , chronic pain, and neuropathic pain have been characterized.

[0051] Acute clinical pain can result, for example, from inflammation or soft tissue injury. This type of pain is , adaptive, biologically relevant, warning, and healing of already damaged body parts. Allow healing and repair to occur unhindered. Avoid contact with any external stimuli. To sensitize the damaged or inflamed area and surrounding tissue to all stimuli so that The neural mechanisms underlying this type of clinical pain are well understood. It is well understood that, for example, depending on the type and severity of pain sensation, Pharmacological control of acute clinical pain with nonsteroidal anti-inflammatory drugs (NSAIDs) is available. It is possible and effective.

[0052] Chronic clinical pain is due to ongoing peripheral pathology such as cancer or chronic inflammation (e.g., arthritis). It may manifest as a persistent paresthesia that recurs or may be unrelated to such an initiating trigger. Chronic pain that is unrelated to the initiating trigger is maladaptive, confers no survival advantage, and requires effective treatment. Very often there is no law.

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

[0054] The term "activator" refers to an agonist, partial agonist, coagonist, physiological agonist, potentiator, , stimulants, allosteric enhancers, positive allosteric modulators, allosteric Molecules described as agonists, or those that directly or It means a molecule that indirectly increases

[0055] The term "inhibitor" refers to an antagonist, partial antagonist, competitive antagonist, noncompetitive antagonist, uncompetitive antagonist, or antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible Antagonists, inhibitors, reversible inhibitors, irreversible inhibitors, negative allosteric modulators, Molecules described as allosteric antagonists or antagonists that inhibit receptor activity or signal transduction By this is meant a molecule that directly or indirectly decreases

[0056] The term "maximum tolerated dose" refers to the maximum dose of a drug or treatment that a patient can take without experiencing intolerable side effects. The maximum tolerated dose is typically determined empirically in clinical trials. can be.

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

[0058] The term "antipsychotic" refers to a drug that reduces psychosis, hallucinations, or delusions. haloperidol, droperidol, chlorpromazine, fluphenazine, perphenazine azide, prochlorperazine, thioridazine, trifluoperazine, mesoridazine, pericycline Azine, Promazine, Triflupromazine, Levomepromazine, Promethazine, Pimozide , Chlorprothixene, Flupentixol, Thiothixene, Zuclopenthixol, Chlorprothixene, Rosapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride , asenapine, paliperidone, zotepine, aripiprazole, bifeprunox, and tetanus. These include, but are not limited to, travenadin.

[0059] The term "anxiolytic" refers to a drug that reduces anxiety, fear, panic, or related feelings. Such drugs include benzodiazepines (e.g., alprazolam, chlordiazepoxide, Cid, clonazepam, clorazepate, diazepam, lorazepam), buspirone, barbiturates Barbiturates (e.g., amobarbital, pentobarbital, secobarbital, phenobarbital, These include phenobarbitol, and hydroxyzine. However, the present invention is not limited to the above.

[0060] The term "antidepressant" refers to a drug that relieves depression and related conditions (e.g., dysthymia). Such drugs include selective serotonin reuptake inhibitors (SSRIs, e.g., Citalopram, fluoxetine, fluvoxamine, paroxetine, sertra phosphate), serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g., desbenzamide, Lafaxine, duloxetine, milnacipram, venlafaxine), mianserin, Mirtazapine, norepinephrine reuptake inhibitors (e.g., atomoxetine, mazindo valproate, reboxetine, viloxazine), bupropion, tianeptine, agomelatine, trimethoprim, Cyclic antidepressants (e.g., amitriptyline, clomipramine, doxepin, imipramine , trimipramine, desipramine, nortriptyline, protriptyline), and monoazapramine. amine oxidase inhibitors (e.g., isocarboxazid, moclobemide, phenelzine, These include, but are not limited to, selegiline, tranylcypromine.

[0061] The term "sedative" or "tranquilizer" refers to a drug that induces drowsiness and reduces the feeling of tiredness or the desire to sleep. These drugs include benzodiazepines, benzodiazepines, and benzodiazepines. Azepines, barbiturates (e.g., amobarbital, pentobarbital, secobarbital, Bital, phenobarbitol, eszopiclone, These include, but are not limited to, Replon, Zolpidem, and Zopiclone.

[0062] Pharmaceutical Compositions Early development of the muscarinic receptor agonist xanomeline as monotherapy has demonstrated that it The present disclosure provides a more effective treatment for both active ingredients. Therapeutic efficacy, enhanced pharmacokinetics for trospium chloride, and higher dosing compliance The present disclosure also provides dosage forms having dissolution kinetics with different strengths and / or different The present invention provides a dosage form having the two active substances in a ratio such that

[0063] Provided herein are multiple xanomeline compositions that include xanomeline or a salt thereof. and a plurality of trospium beads containing a salt of trospium. In certain embodiments, the plurality of xanomeline beads comprises xanomeline or a salt thereof. In certain embodiments, the plurality of trospium beads has a core comprising a trospium salt. The core comprises:

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

[0065] The formulation for each drug bead is such that the active agent is released into serum at substantially the same rate, and and / or substantially similar T max from two active substances in different dose ranges to achieve In certain embodiments, the tartrate salt is 50% or more. A capsule containing 10 mg of xanomeline and 10 mg of trospium chloride as the free base. 50 mg of xanomeline is equivalent to approximately 76 mg of xanomeline tartrate. The ratio of active ingredients in such formulations is approximately 7.6 to 1.

[0066] The discrepancy in the number of drug beads in the capsules may be due to the drug bead count being increased after the beads are released and dispersed. This increases the probability that the ratio of the number of samples will not remain substantially constant. Trospium beads contain approximately the same effective dose of trospium and xanomeline. In certain embodiments, the difference in drug loading is Nevertheless, trospium and xanomelin beads released at approximately the same rate. For example, the United States Pharmacopeia When the dissolution of the capsules was evaluated using a USP dissolution apparatus, the percentage of dissolved xanomeline The percentage is substantially equivalent to the percentage of dissolved trospium chloride, e.g. For example, 10 minutes, 20 minutes, or 30 minutes.

[0067] The agent may also include one or more pharma- ceutically acceptable salts. The drug may be administered orally. The drug may be administered by tablet. tablet, troche, liquid, emulsion, suspension, drop, capsule, caplet or gel It may be delivered orally using a cup and other oral administration methods known to those skilled in the art.

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

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

[0070] In another embodiment, the agent is combined with one or more therapies including psychotherapy and medication. Therapeutic agents include antipsychotics, anxiolytics, antidepressants, sedatives, tranquilizers, analgesics, and These include, but are not limited to, other pharmacological interventions known to those of skill in the art. For example, benzodiazepines are used as an anxiolytic, sedative, It can be considered a sedative and tranquilizer.

[0071] Bead / Core Excipients The beads and / or cores may include one or more excipients. The vehicle may include one or more of a filler, a binder, and a surfactant. Other optional ingredients include: These include, but are not limited to, flow agents, lubricants, disintegrants, swelling agents, and antioxidants. Xanomeline or a pharma- ceutically acceptable salt thereof and a salt of trospium may be used in the same drug. They may be in separate matrices.

[0072] The amount of xanomeline free base in the core is at least 10% by weight, or at least 15% by weight. %, or at least 20%, or at least 25%, or at least 30% by weight For example, the amount of xanomeline tartrate may be at least 50% by weight of the core, or At least 55% by weight, or at least 60% by weight, or at least 65% by weight, or At least 70% by weight, or at least 75% by weight, or at least 80% by weight, or less At least 85% by weight, for example, about 60% to about 90% by weight, or about 65% to about 85% by weight. All ranges including these values ​​as endpoints can be, for example, a range of at least About 15% to about 90% by weight, about 20% to about 85% by weight, about 30% to about 85% by weight %, or from about 50% to about 90% by weight are contemplated. The xanomeline beads are made of 30% to 80% by weight of xanomeline tartrate, e.g., 6 Contains 6% by weight of xanomeline tartrate.

[0073] The amount of trospium salt in the core is at least 10% by weight, or at least 15% by weight, Or at least 20%, or at least 25%, or at least 30% by weight. For example, the amount of trospium chloride may be at least 50% by weight of the core, or at least or at least 55% by weight, or at least 60% by weight, or at least 65% by weight, or at least 70% by weight, or at least 75% by weight, or at least 80% by weight, or at least 8 5% by weight, for example, about 60% by weight to about 90% by weight, or about 65% by weight to about 85% by weight. All ranges including these values ​​as endpoints may, for example, include at least about 15 ranges. % to about 90% by weight, about 20% to about 85% by weight, about 30% to about 85% by weight, or It is understood that about 50% to about 90% by weight is contemplated. Trospium is trospium chloride. In a particular embodiment, the trospium beads are % to 35% by weight of trospium chloride, for example 17.7% by weight of trospium chloride nothing.

[0074] In further embodiments, the matrix may be, for example, a polymeric material that is capable of inhibiting the release of an active agent in the matrix. In a further embodiment, the polymer is included to modify the exit profile. In a further embodiment, the water soluble polymer is Eudrag it® RL, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, Polyethylene In a further embodiment, the polymer is selected from water, In a further embodiment, the water insoluble polymer is Eudragit RS, Ethyl Cellulose, Cellulose Acetate, Cellulose Propionate, Acetic Acid Cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate Poly(methyl methacrylate), Poly(ethyl methacrylate), Poly(methacrylic acid butyl), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(meth isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate) ), poly(methyl acrylate), poly(isopropyl acrylate), poly(isopropyl acrylate) isobutyl), Poly(octadecyl acrylate), Poly(ethylene), Poly(ethylene) low Density, Poly(ethylene) High Density, Poly(propylene), Poly(ethylene terephthalate) , poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride), poly urethanes, and mixtures thereof.

[0075] Fillers include lactose, sucrose, glucose, starch, and microcrystalline cellulose. cellulose, mannitol, sorbitol, calcium hydrogen phosphate, aluminum silicate aluminum, amorphous silica, sodium chloride, starch, and dibasic calcium phosphate In one embodiment, the filler is a water soluble sucrose dihydrate. In one embodiment, the filler is a spheronization aid. Spheronization aids include crospovidone, carrageenan, chitosan, pectic acid, glycerides, β -Cyclodextrin (β-CD), cellulose derivatives, microcrystalline cellulose, powdered cellulose Polypropylene, crospovidone, and polyethylene oxide. In one embodiment, the filler comprises microcrystalline cellulose.

[0076] The amount of filler in the xanomelin core is not particularly limited. In an embodiment, the filler ( For example, the amount of microcrystalline cellulose is about 10% by weight to about 70% by weight, or about 16% by weight. % to about 23% by weight, or at least 19% by weight or at least 19.5% by weight, e.g. For example, it may be about 20% by weight. In a particular embodiment, the xanomelin beads may be about 15% by weight. % to 65% by weight, for example, about 15% to 20% by weight, about 20% to 25% by weight, about 2 5wt%~30wt%, approx. 30wt%~35wt%, approx. 35wt%~40wt%, approx. 40 Weight% ~ 45% by weight, approx. 45% ~ 50% by weight, approx. 50% ~ 55% by weight, approx. 55% by weight % to 60% by weight, or about 60% to 65% by weight of microcrystalline cellulose. In an embodiment, the xanomeline beads comprise 33.5% by weight microcrystalline cellulose.

[0077] The amount of filler in the trospium core is not particularly limited. In an embodiment, the filler ( For example, the amount of microcrystalline cellulose or lactose is about 10% by weight to about 80% by weight, or or in the range of about 16% to about 23% by weight, or at least 19% by weight, or at least 19% by weight 0.5% by weight, for example, about 20% by weight. The amount of the cellulose is 25% by weight to 80% by weight, for example, about 25% by weight to 30% by weight, about 30% by weight to 3 5% by weight, about 35% to 40% by weight, about 40% to 45% by weight, about 45% to 50% by weight Weight%, approx. 50wt%~55wt%, approx. 55wt%~60wt%, approx. 60wt%~65wt %, about 65% to 70% by weight, about 70% to 75% by weight, or about 75% to 80% by weight % by weight of microcrystalline cellulose. In a particular embodiment, the trospium beads contain 46. Contains 8% by weight of microcrystalline cellulose.

[0078] In certain embodiments, the trospium beads are 15% to 70% by weight, for example about 15% Weight%~20wt%, approx. 20wt%~25wt%, approx. 25wt%~30wt%, approx. 30wt Amount%~35wt%, approx. 35wt%~40wt%, approx. 40wt%~45wt%, approx. 45wt %~50wt%, approx. 50wt%~55wt%, approx. 55wt%~60wt%, approx. 60wt% In certain embodiments, the lactose monohydrate content is about 65% to about 70% by weight. Trospium beads contain 35% by weight lactose monohydrate.

[0079] Binders include cellulose ethers, methylcellulose, ethylcellulose, hydroxycellulose, Ethyl cellulose, propyl cellulose, hydroxypropyl cellulose, low-substituted hydroxy Hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose, e.g. For example, hypromellose 2910, Methocel E, carboxymethyl cellulose starch, pregelatinized starch, acacia, tragacanth, gelatin, polyvinyl Pyrrolidone (Povidone), Cross-linked Polyvinylpyrrolidone, Sodium Alginate, Microcrystalline Ce cellulose, and lower alkyl-substituted hydroxypropyl cellulose. In one embodiment, the binder is selected from wet binders. The binder is selected from cellulose ethers, such as hypromellose.

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

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

[0082] Surfactants include sodium lauryl sulfate, sodium deoxycholate, and sulfosuccinate. Anionic surfactants including dioctyl sodium acrylate and sodium stearyl fumarate non-ionic surfactants, including polyoxyethylene ethers and polysorbate 80 , as well as cationic surfactants containing quaternary ammonium compounds, In one embodiment, the surfactant is an anionic surfactant, such as lauryl sulfate. Sodium sulfate is selected from the group consisting of:

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

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

[0085] Disintegrants include starch, sodium cross-linked carboxymethylcellulose, and carmellol. sodium carmellose, calcium carmellose, cross-linked polyvinylpyrrolidone, and starch glycol Sodium cholate, low-substituted hydroxypropyl cellulose, and hydroxypropyl de Examples of suitable saccharides include, but are not limited to, starch.

[0086] The flow agents include polyethylene glycols of various molecular weights, magnesium stearate, Calcium stearate, calcium silicate, fumed silicon dioxide, magnesium carbonate Sodium, Magnesium Lauryl Sulfate, Aluminum Stearate, Stearic Acid, Palmitic Acid These include, but are not limited to, acetic acid, cetanol, stearol, and talc. .

[0087] Lubricants include stearic acid, magnesium stearate, and calcium stearate. , aluminum stearate, and silicone-treated talc. In certain embodiments, the xanomelin beads contain 0% to 2% by weight of talc, e.g. For example, 0.5% by weight of talc. In a particular embodiment, the trospium beads contain 0% by weight of talc. % talc, such as 0.5% talc.

[0088] In certain embodiments, the formulation further comprises one or more antioxidants. Examples of antioxidants that can be used include: (1) ascorbic acid, cysteine ​​hydrochloride, and sodium bisulfate. (2) Water-soluble antioxidants such as sodium metabisulfite and sodium sulfite; (3) palmitic acid Ascorbyl, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, and other oil-soluble antioxidants; (3) Citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphorus In certain embodiments, the formulation contains less than 1% by weight, e.g., For example, 0.9% by weight, 0.8% by weight, 0.7% by weight, 0.6% by weight, 0.5% by weight, 0.4% by weight, Weight%, 0.3% by weight, 0.2% by weight, 0.1% by weight, 0.09% by weight, 0.08% by weight , 0.07% by weight, 0.06% by weight, 0.05% by weight, 0.04% by weight, 0.03% by weight , 0.02% by weight, or 0.01% by weight of an antioxidant. In certain embodiments, the formulation comprises , about 0.05% by weight BHT or 0.5% by weight ascorbic acid. In the present invention, the antioxidant is present in the xanomelin core or in the xanomelin beads.

[0089] In certain embodiments, the xanomelin beads contain 30% to 80% by weight xanomelin tartrate. phosphorus, 15% to 65% by weight of microcrystalline cellulose, and 0% to 2% by weight of talc In certain embodiments, the trospium beads contain 0.2% to 2% by weight of talc, e.g. For example, 0.5% by weight of talc. In a particular embodiment, the trospium beads contain 8% by weight of talc. ~35% by weight trospium chloride, 25% to 80% by weight microcrystalline cellulose, 15% by weight The composition comprises 0.2% to 2% by weight of lactose monohydrate, and 0.2% to 70% by weight of talc.

[0090] In certain embodiments, the xanomeline tartrate drug beads are 66% by weight xanomeline tartrate. % by weight of talc, 33.5% by weight of microcrystalline cellulose, and 0.5% by weight of talc. In an embodiment, the trospium chloride beads are 17.7% by weight trospium chloride, 46.8% by weight % by weight of microcrystalline cellulose, 35% by weight of lactose monohydrate, and 0.5% by weight of talc. In this example, the xanomeline tartrate beads are mixed with trospium chloride beads. It contains approximately 2.5 times the amount of xanomeline as when it contains nicotine.

[0091] Depending on the dosing requirement, the capsules contain different amounts of xanomeline tartrate and trospium chloride. In various embodiments, the capsules may be prepared using beads. of xanomeline and 10 mg of trospium chloride, 50 mg of xanomeline and 20 mg of of trospium chloride, 75 mg of xanomeline and 10 mg of trospium chloride, 75 mg g of xanomeline and 20 mg of trospium chloride, 125 mg of xanomeline and 30 mg trospium chloride, or 125 mg xanomeline and 40 mg trospium chloride In a particular embodiment, the capsule contains 25 mg of xanomeline tartrate. Nomeline, and 10 mg of trospium chloride. In a particular embodiment, the capsule contains: 50 mg of xanomeline tartrate and 10 mg of trospium chloride In a particular embodiment, the capsule contains 50 mg of xanomeline tartrate. In a particular embodiment, the capsule contains tartaric acid, phosphorus, and 20 mg of trospium chloride. Contains 75 mg of xanomeline acid and 10 mg of trospium chloride In a particular embodiment, the capsule contains 75 mg of xanomeline as xanomeline tartrate. In a particular embodiment, the capsule contains 20 mg of trospium chloride. Sanomelin contains 125 mg of xanomeline and 20 mg of trospium chloride. In a particular embodiment, the capsule contains 125 mg of xanomeline as xanomeline tartrate. , and 40 mg of trospium chloride.

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

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

[0094] In one embodiment, trospium chloride extended release is used as trospium chloride in the drug. In another embodiment, the drug comprises 1 milligram to 400 milligrams of trospirus chloride. In one embodiment, the drug comprises 6.5 milligrams to 200 milligrams of salt. Includes trospium chloride extended release.

[0095] In one embodiment, the medicament contains 75 mg or 225 mg of xanomeline, and this same medicament The formulation contains 20 mg or 40 mg of trospium chloride. The drug contains 5 mg or 225 mg of xanomeline, and different drugs administered simultaneously are 20 mg or contains 40 mg of trospium chloride.

[0096] Bead Coating In other embodiments, the beads may be provided with functionality or other properties, e.g., for aesthetics, handling, or stability. may be coated with a non-functional coating. In certain embodiments, the beads are It may be coated with a pH-sensitive coating so that it does not dissolve in the low pH of the stomach. Non-functional coatings are used to maintain chemical separation between beads or for aesthetic reasons. It can be used for this purpose.

[0097] In a further embodiment, the controlled release formulation comprises a semi-permeable coating. Phosphorus and trospium chloride may be present in different coatings of the same formulation. In an embodiment, xanomeline and trospium chloride are administered in different formulations or administration vehicles. In a further embodiment, the semi-permeable coating may be present in a coating comprising In a further embodiment, the controlled release formulation comprises xanomeline and trochlore. It contains a matrix that suspends the spium.

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

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

[0100] In one embodiment, the absorption (area under the curve, AUC) of the dosage form when administered orally is The efficacy of trospium chloride in treating pulmonary hypertension is favorably increased compared to other dosage forms of melin or trospium chloride. Although not intended to be bound, the increased absorption indicates a pseudo-extended release profile. The pseudo-extended release profile is influenced by the dosage form, if any, in the coating. including beads having a distribution of thicknesses, a distribution of bead particle sizes, and irregular bead shapes. It is influenced by one or more factors. For example, the beads have a distribution of coating thickness. In an embodiment, for beads having a relatively thin coating, the coating is triaxially dispersed. The xanomeline and / or trospium chloride components dissolve relatively rapidly and completely at pH 6. For beads with a relatively thick coating, the coating It may take some time to completely dissolve and release the xanomeline and / or trospium chloride composition. It takes a long time. The beads have an irregular particle size distribution and / or bead shape. In an embodiment, the gastrointestinal transit time of the beads varies depending on the size and / or shape of the beads. This changes the transit time to reach the coating dissolution pH, thus resulting in pseudo-extended release. In another embodiment, the dosage form can contribute to the release profile within the capsule shell. When administered orally in the form of a capsule or without a capsule shell, the results are substantially equivalent (e.g. For example, bioequivalent C max and / or AUC characteristics.

[0101] In certain embodiments, the dosage form provides a gradual and predictable absorption curve. So, what is the dosage form of T when administered orally? max Because the beads are individually coated, , more stable on a dose-by-dose basis. Predictable and consistent T max More consistent retention It is advantageous to achieve a sustained therapeutic effect. Dissolution-related variations or other effects on the dissolution of the coating may be due to the presence of xanomeline and salts in the dosage form. This tends to affect only a portion of the trospium chloride, resulting in pseudo-extended release behavior. In contrast, a coated capsule containing xanomeline and trospium chloride microspheres was The capsules show significant variability in absorption time from capsule to capsule.

[0102] In certain embodiments, the oral pharmaceutical composition is administered to a patient in need of treatment for a muscarinic disorder. Xanomeline and / or its salts and trochlore for treating muscarinic disorders in and the composition, when administered to a patient in need thereof, provides a 2-hour xanthoma therapy. Melin's Median T max and median trospium T at 1 hour max In vivo plasma containing In certain embodiments, the in vivo plasma profile is sufficient to provide a The mean dose-normalized C ranged from 48.5 to 121.3 pg / mL / mg. max Further includes: In certain embodiments, the in vivo plasma profile is between 156 and 375 pg / mL / mg. Trospium mean dose normalized C max In certain embodiments, the in vivo blood The plasma profile was consistent with a mean dose-normal response of xanomeline ranging from 263 to 577 pg / mL / mg. AUC 0-12 In certain embodiments, the in vivo plasma profile further comprises: Mean dose-normalized AUC of trospium from 81 to 20 pg / mL / mg over 24 hours 0-12 of In certain embodiments, the in vivo plasma profile is 7850±3360p Mean C of trospium in g / mL max In certain embodiments, the in vivo blood The plasma profile showed a mean AUC of 41,900 ± 15,500 pg / mL over time. 0-12 Further Included.

[0103] In another embodiment, the dosage form may be modified, for example, by controlling the amount and / or relationship of xanomeline present after storage. The storage stability is favorable as measured by the total amount of associated substances. Stable at accelerated conditions (e.g., 25°C and 60% relative humidity) or at elevated temperatures and / or humidity The results can be evaluated after storage at environmental conditions.

[0104] Formulations and methods are further described below (as illustrated in the Figures and Examples) unless otherwise indicated. Any combination of one or more of the additional optional elements, features, and steps (including those described herein) Reference to beads and their properties is intended to include embodiments of a collection of beads. The same applies to the core and its properties. The references apply equally to a collection of cores (eg, a plurality of such cores).

[0105] Enteric (gastro-resistant) coating materials, e.g., polymers, are designed to resist the effects of acidification at pH levels higher than those of the stomach. At pH levels above 4.5, for example, in the small intestine, the drug dissolves in the intestinal fluid and thus region, but not substantially 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 between about 5. In this embodiment, the enteric material dissolves rapidly in aqueous solutions at a pH between about 5.5.

[0106] For example, pH-sensitive materials do not dissolve significantly until the dosage form is emptied from the stomach. It gradually increases from about 4.5 to about 6.5 in the duodenal bulb and then to about 6.5 in the distal small intestine (ileum). 7.2, corresponding to a small intestinal transit time of approximately 3 hours (e.g., 2–3 hours). The coating should be sufficiently thick to provide adequate dissolution and allow for reproducible release therein. It should begin to dissolve within the pH range of the bidenum and continue to dissolve within the pH range of the small intestine. The amount (thickness) of the enteric coating is about 3 hours in the small intestine (e.g., proximal and mid-small intestine). The time required for the passage of the polymer should be sufficient to cause substantial dissolution.

[0107] Suitable enteric (gastro-resistant) materials include cross-linked polyvinylpyrrolidone; non-cross-linked polyvinylpyrrolidone. Don; Hydroxypropyl methylcellulose phthalate, Hydroxypropyl acetate succinate Methyl cellulose; Cellulose acetate succinate; Cellulose acetate phthalate; Cellulose acetate succinate Hydroxypropyl methylcellulose, Cellulose acetate trimellitate, Dendritic acetate phthalate Polyvinyl acetate phthalate; Carboxymethyl cellulose; Methyl cellulose phthalate methyl cellulose succinate; methyl cellulose phthalate; methyl cellulose phthalate Cellulose half ester; ethyl cellulose succinate; carboxymethyl amide; potassium methyl ester Acrylate divinylbenzene copolymer; Polyvinyl alcohol; Polyoxyethylene glycol;polyethylene glycol;sodium alginate;galactomannan;cal carboxypolymethylene; sodium carboxymethyl starch; acrylic acid and / or methacrylic acid Copolymers of acrylic acid and a monomer selected from the following: methyl methacrylate, methacrylate Ethyl acrylate, Ethyl acrylate, Butyl methacrylate, Hexyl methacrylate, Methacrylate decyl acrylate; lauryl methacrylate; phenyl methacrylate; methyl acrylate; isopropyl acrylate, isobutyl acrylate, or octadecyl acrylate, for example Ev Eudragit™-L and -S available from Onik Industries Series (L 100-55, L 30 D-55, L 100, S 100, L 12 .5 and S12.5);polyvinyl acetate;fats;oils;waxes;fatty alcohols; Shellac;Zein;Gluten;Ethyl acrylate-maleic anhydride copolymer;Maleic 2-Methyl-2-propanol-vinyl methyl ether copolymer;styrene-maleic acid copolymer; -Ethyl-hexyl-acrylate maleic anhydride; Crotonic acid-vinyl acetate copolymer Glutamic acid / glutamic acid ester copolymer;Carboxymethylcellulose glycol Cerol monooctanoate;Polyarginine;Poly(ethylene);Poly(propylene) Poly(ethylene oxide); Poly(ethylene terephthalate); Poly(vinyl isobutene) Poly(vinyl chloride); and polyurethanes. A combination of enteric materials may also be used. In one embodiment, the enteric material is Rapid dissolution at pH 5.5 or above provides rapid dissolution in the upper intestine. The materials are copolymers of methacrylic acid and methyl methacrylate, and copolymers of methacrylic acid and acrylic acid. For example, the enteric polymer may be selected from poly(ethyl acrylate and copolymers thereof). Methacrylic acid co-ethyl acrylate) 1:1 (Eudragit® L 30 D- 55 and Eudragit® L 100-55).

[0108] Other suitable examples of enteric coatings include beeswax and glyceryl monostearate; Waxes, shellac and cellulose; and cetyl alcohol, mastics and shellac; shellac and stearic acid; polyvinyl acetate and ethyl cellulose; and polymethacrylamide. Neutral copolymer of acrylic acid esters (Eudragit® L 30D); copolymer of methacrylic acid and methyl ester of methacrylic acid, or a polymer containing a metal stearate Neutral copolymers of acrylic acid esters are also included. Such coatings include fats and Fatty acids, shellac and shellac derivatives, and cellulose acid phthalates, e.g., free carboxylates. Includes mixtures of those having carboxyl content.

[0109] As is known in the art, one or more plasticizers may be added to the enteric polymer to improve its Suitable plasticizers include, for example, , butyl citrate, triethyl citrate, diethyl phthalate, dibutyl sebacate, poly Ethylene glycol (PEG such as PEG 6000), acetyl triethyl citrate, and and triacetin. In one embodiment, the plasticizer is triethyl citrate. Some enteric materials are flexible and do not require plasticizers, but more brittle polymers (e.g. For example, Eudragit® L / S type, Eudragit® RL / RS, and Eudragit® FS 30 D) is, for example, 5 based on the dry polymer weight. % to 30% by weight of the plasticizer, poly(methacrylic acid-co-ethyl acetate) 1:1. The composition may benefit from about 8% to about 12% by weight of triethyl citrate.

[0110] In certain embodiments, the enteric coating is a filler coating, as known in the art. Contains one or more anti-adhesive agents to reduce the stickiness of the gel and prevent clumping. Suitable anti-adhesive agents include talc, glyceryl monostearate, and fumed silica. silica (e.g., Aerosil® 200), precipitated silica (e.g., Sipernat (trademark) PQ), and magnesium stearate. The anti-blocking agent may be present in any suitable amount, for example, from about 10% by weight to about 10% by weight based on the dry polymer weight. 100% by weight, about 10% to about 50% by weight, about 10% to about 30% by weight, or about 15% by weight In one embodiment, the amount of the dry polysaccharide may range from about 10% to about 30% by weight. It can be used in the range of 15% by weight to about 30% by weight based on the polymer mass.

[0111] One or more surfactants may be added to the enteric coating mixture to provide a coating composition that is suitable for use in the preparation of enteric coatings, as known in the art. It may also increase the wettability of the substrate and / or stabilize the suspension so that the Surfactants include polysorbate 80, sorbitan monooleate, and sodium dodecyl sulfate. and other surfactants as described herein.

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

[0113] The amount of enteric material applied is sufficient to achieve the desired acid resistance and release characteristics. For example, in one embodiment, the amount of enteric coating is within the USP <71 for delayed release dosage forms. 1> Meets the requirements (USP 36-NF 31) and therefore in 0.1N HCl does not release 10.0% by weight of the drug after 2 hours. In certain embodiments, the formulation comprises, e.g., USP 36-NF 31 Section <711> Using the dissolution method, pH 6.8 buffer solution was used. It releases at least 80% of the active substance in buffer solution after 20 minutes.

[0114] In one embodiment, the enteric coating has a About 10% to 40%, or 25% to about 35%, or coating, as measured by weight gain. From about 25% to about 31%, from about 27% to about 31%, based on the weight of the unfilled particle core. %, or from about 28.5% to about 31% weight gain.

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

[0116] Thus, for example, one embodiment combining various features described above includes multiple xanomelines. The pharmaceutical dosage form includes beads, the beads being comprised of xanomeline tartrate, a filler (optionally microcrystalline crystalline cellulose), a binder (optionally hypromellose), and an enteric coating ( A plurality of beads, each of which optionally comprises a core comprising Eudragit® L 30 D-55. has a particle size distribution ranging from about 0.7 mm to about 2.5 mm, and the enteric coating The range is about 20% to about 40% based on the weight of the bead core, and the beads are capsule shells. The device is placed in a well.

[0117] Bead Size and Shape The plurality of beads has a distribution of particle sizes.The plurality of beads has a bead shape. The beads, if present, have a distribution of coating thicknesses.

[0118] Beads with a particle size distribution have been shown to exhibit favorable pharmacokinetics. Without intending to be bound by theory, pharmacokinetics may have a distribution of core sizes. It is expected that the effect of multiple beads on the luminance distribution will be significant.

[0119] In one embodiment, the particle size of the beads is from about 0.4 mm to about 1.2 mm, for example about 0. 4mm~approx. 0.5mm, approx. 0.5mm~approx. 0.6mm, approx. 0.6mm~approx. 0.7mm, approx. 0.7mm~0.8mm, 0.8mm~0.9mm, 0.9mm~1.0mm , about 1.0 mm to about 1.1 mm, or about 1.1 mm to about 1.2 mm. In an embodiment, the size of the xanomelin beads is about 0.425 mm to about 1.18 mm. In certain embodiments, the size of the xanomelin beads is from about 0.6 mm to about 0.85 mm. In certain embodiments, the size of the trospium beads is from about 0.425 mm to about In a particular embodiment, the size of the trospium beads is about 0.6 mm. m ~ about 0.85 mm.

[0120] The beads or bead mixtures may be, for example, in a suspension, filled into capsules and compressed into tablets. One or more types of modified release beads may be used in one Mixed together and encapsulated or used as a sprinkle on the food of interest. In certain embodiments, the oral solid dosage form may be in any of these forms. In an embodiment, the dosage form is a capsule.

[0121] If the particle size of the beads becomes too small, the variability of the active substance content increases. If the particle size becomes too large, the beads will be too large and the labeled drug will disperse (e.g. , on applesauce or other soft foods such as jelly) and without chewing. It cannot be administered by swallowing or through an enteral feeding tube and the particle size increases. As the amount of added water increases, the larger particles become more coated than the smaller particles, resulting in a more This results in a lower relative assay compared to smaller particles. To compensate, A relatively large number of beads are required to achieve a labeling intensity of 1000 mg / capsule. It has become difficult or impossible to fill capsule shells with particles large enough to meet the requirements. (e.g., filling size 0 capsules to 75 mg strength of xanomeline free base) thing).

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

[0123] The beads can be sorted (e.g., by sieving) to a desired particle size. In certain embodiments, the particle size range is any of the particle size ranges described above for the core. or a combination thereof. In one embodiment, the particle size range is The particle size range of the bead core is the same as that of the untreated core. For example, no more than 5% by weight of the bead core is #1 2 mesh (1.68 mm) screen, with no more than 10% by weight being #20 mesh The beads can be sieved to pass through a (0.84 mm) screen.

[0124] Manufacturing method A plurality of xanomeline beads comprising xanomeline or a pharma- ceutically acceptable salt thereof. The beads are mixed with multiple trospium beads containing a salt of trospium, such as trospium chloride. In certain embodiments, a method for preparing an oral pharmaceutical composition is provided, comprising combining Now, the method further comprises formulating the mixed beads into a capsule.

[0125] Also, a core containing xanomeline or a pharma- ceutical acceptable salt thereof and an excipient may be coated with an enteric polymer. The drug is coated with trospium chloride or its pharmacopoietin to form an enteric coating. The core containing acceptable salts and excipients is coated with an enteric polymer to form an enteric coating. Disclosed herein are methods for preparing a dosage form comprising forming a capsule. The cores can be formed by wet granulation. Optionally, the drug beads can be enteric coated. before enteric coating, and optionally again after enteric coating, to a desired particle size range (e.g. They are then separated (by sieving, for example).

[0126] The drug beads are prepared by spheronizing the extruded wet mass and forming inert core spheres in a fluidized bed. These are made by different processes, including but not limited to coating In certain embodiments, the beads are prepared by extrusion and spheronization.

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

[0128] The core comprising xanomeline or a pharma- ceutically acceptable salt thereof may be subjected to any suitable process. In one embodiment, the core can be formed by xanomeline or a pharma- ceutical thereof. By granulating a mixture of acceptable salts and excipients and milling to the desired particle size range. In another embodiment, the core is formed from xanomeline or a pharma- ceutically acceptable salt thereof. The tablet can be formed by extrusion and spheronization of a mixture of the salt and excipients.

[0129] The core containing trospium chloride or a pharma- ceutically acceptable salt thereof may be prepared by any suitable process. In one embodiment, the core may be formed by trospium chloride or its The mixture of pharma- ceutically acceptable salt and excipients is granulated and milled to the desired particle size range. In another embodiment, the core is formed by The pharmaceutical composition may be formed by extrusion and spheronization of a mixture of a commercially acceptable salt and excipients.

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

[0131] A mixture of xanomeline or a pharma- ceutically acceptable salt thereof and trospium chloride with an excipient. The extrusion and spheronization of the mixture may result in a particle size distribution and one or more of the following: It provides a desirable core with other desirable properties. In certain embodiments, it provides a fast processing time. For example, reducing spheroidization can result in a more stable product. Reduce the time the product is exposed to air (when wet and Rapid processing by extrusion and spheronization (either before or after packaging) also reduces oxidation. Poor processing can result in poor quality, for example, in that a large proportion of the bead cores are outside the desired particle size range. This can result in a poor quality product. Moisture absorbed by the spheronization aid (which (which occurs over time) affects the spheronization properties of the beads.

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

[0133] In certain embodiments, the wet mass is extruded, e.g., to allow the spheronization aid to swell with the granulation fluid. The holding time may be at least 15 minutes, for example at least 30 minutes. In certain embodiments, the holding time may be at least 45 minutes, or at least 60 minutes. The time is about 15 minutes to about 120 minutes, for example, about 30 minutes to 100 minutes, or about 60 minutes to 90 minutes. It is.

[0134] As noted above with respect to the cores, the method includes screening (e.g., For example, by sieving, the particles are separated into a predetermined size range, for example, 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 The present invention can include maintaining the size, or any range described herein.

[0135] As described above in relation to the beads, the method further comprises sorting the beads after any coating. (e.g., by sieving) to separate the particles into a size range, e.g., from about 0.7 mm to about 2. 8 mm, for example, in the range of about 0.7 mm to about 2.5 mm, or about 0.8 mm to about 1.7 mm or any range described herein.

[0136] In the extrusion and spheronization process, any of the following characteristics may be used individually or in combination with one or more of them: They can be used in combination. Water can be a granulating agent. Microcrystalline cellulose can be Hypromellose may be present in the core as a spheronization aid. The size of the extrusion screen may be 1.0 mm. The friction plates of the spheronizer may be cross-hatched. The friction plates of the spheronizer may be at least about 3 mm, or greater than about 3 mm, or at least about 4 mm, or greater than about 4 mm, or Cross-hatching can be done in the range of about 3mm to about 7mm, or with a square pitch of about 5mm. The spheronization time is less than about 5 minutes, or less than about 4 minutes, or less than about 3 minutes, or less than about 2 minutes. The spheronized particles may be, for example, at least about 20% by weight, at least at least about 30% by weight, at least about 40% by weight, at least about 50% by weight, at least about 60% by weight %, or a substantial fraction thereof, such as at least about 70% by weight, of non-spherical particles (i.e., irregular The shape may include a

[0137] In certain embodiments, the pharmaceutical composition may further comprise a desiccant, e.g., pharmaceutical grade silica gel, Crystalline sodium, potassium or calcium aluminosilicate, colloidal silica, anhydrous It is preserved with calcium sulfate, etc.

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

[0139] In certain embodiments, the pharmaceutical composition comprises nitrogen, helium, argon, neon, xenon, The materials are stored under a dry inert gas such as krypton, or a mixture thereof.

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

[0141] In certain embodiments, the pharmaceutical composition can be stored at low temperatures, e.g., refrigerated temperatures (e.g., 2°C to 8°C). In certain embodiments, the pharmaceutical composition is stored at a concentration of less impurities than when stored at 25° C. It is stored so that there are few impurities such as substance A.

[0142] In certain embodiments, the pharmaceutical composition is prepared by dispensing the oral pharmaceutical composition into a pharmaceutical composition containing a 50% or more 50% glycerol (GlcNAc) from the manufacturer prior to dispensing the oral pharmaceutical composition into a subject. The product is stored at a temperature of about 2° C. to about 8° C. by the distributor, pharmacy, or hospital. In this embodiment, after the oral pharmaceutical composition is delivered to a subject, the pharmaceutical composition is stored at a temperature of about 20° C. to about 25° C. is stored in degrees.

[0143] The pharmaceutical dosage form or formulation described herein, including storing the dosage form at a temperature of about 2° C. to about 8° C. Also provided is a method for stabilizing a composition.

[0144] In certain embodiments, the method for preparing a pharmaceutical dosage form comprising xanomeline beads comprises the steps of: The composition contains xanomeline stearate and an excipient, and optionally microcrystalline cellulose, and is about 20% by weight to about 40% by weight. forming a wet mass having a moisture content in the range of 0.1% by weight of xanomeline tartrate and excipients; A wet mass containing the agent is extruded and spheronized to prepare a core, and the core is arbitrarily cut to a size of about 0.7 mm. The selected cores are then sorted into the target particle size range of 100 to 2.5 mm, and the sorted cores are then coated with a polymer. coating the bead particles to form beads comprising a core and a coating; and optionally screening to a target particle size range of about 0.7 mm to about 2.5 mm.

[0145] In certain embodiments, the method for preparing a pharmaceutical dosage form comprising trospium beads comprises the steps of: Trospium chloride and an excipient, optionally microcrystalline cellulose, about 20% by weight to about 40% by weight %, and forming a wet mass comprising trospium chloride and excipients. the wet mass is extruded, spheronized, and dried to produce a core; and the core is optionally cut to a size of about 0.7 mm. The target particle size range is selected from 100 to 2.5 mm, and the selected core is coated with a polymer. coating the bead particles to form beads comprising a core and a coating; This involves screening the particles to a target particle size range of about 0.7 mm to about 2.5 mm.

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

[0147] Xanomeline and / or its salts and less than 0.5% by weight of 3-[(4-hexyloxy)- 1,2,5-Thiadiazol-3-yl]-5-hydroxyl-1-methylpyridine-1 Also provided is a pharmaceutical composition comprising: The substance is less than 0.30% by weight, for example less than 0.25% by weight, less than 0.20% by weight, less than 0.15% by weight, %, less than 0.14%, or less than 0.1% by weight of impurity A. and / or its salts and less than 0.15% by weight of 3-[(4-hexyloxy)-1,2,5 -Thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium ( Also provided is a pharmaceutical composition comprising impurity A).

[0148] Xanomeline or its salts and less than 0.5% by weight of 3-[(4-hexyloxy)-1,2 ,5-Thiadiazol-3-yl]-5-hydroxyl-1-methylpyridine-1-sulfur a plurality of xanomelin beads containing a salt of trospium; and a plurality of trospium beads containing a salt of trospium. Also provided is an oral pharmaceutical composition comprising xanomeline or a salt thereof and less than 0.15% by weight of xanomeline or a salt thereof. 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxy A plurality of xanomeline beads containing hydroxyl-1-methylpyridin-1-ium and and a plurality of trospium beads containing a salt of trospium. Also provided is an oral pharmaceutical composition comprising the

[0149] In certain embodiments, the pharmaceutical composition has a shelf life of at least 10 years at 40° C. and 75% relative humidity. Both contain less than 0.5% by weight of impurity A after storage for 3 months.

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

[0151] Treatment Further provided is a method of activating a muscarinic receptor in a biological sample, comprising: and contacting a target sample with any of the oral pharmaceutical compositions described herein. Any of the oral pharmaceutical compositions described herein may be administered to a subject in need of treatment for a disorder. Activating muscarinic receptors in a subject in need of treatment for a disorder, including Also provided are methods for treating disorders ameliorated by

[0152] Activators of M1 and M4 muscarinic receptors have been shown to be effective treatments for schizophrenia. However, activating muscarinic receptors outside the brain can cause side effects. This resulted in the exclusion of oxanomeline from clinical trials. In both cases, the muscarinic agonist xanomeline inhibits muscarinic receptors in the periphery of the body. There were unacceptable GI and other side effects related to binding to the cholinergic receptor. Combined with trospium chloride, it blocks muscarinic receptors located outside the brain. The desired therapeutic effect is achieved while reducing or eliminating side effects associated with activation of the

[0153] The tolerability of the muscarinic activator xanomeline was comparable to that of the muscarinic antagonist This is augmented by the coadministration of trospium chloride, which is a potent anti-inflammatory drug. The most common adverse events were nausea, vomiting, diarrhea, excessive sweating, and excessive salivation (also known as coagulation syndrome). The disclosed compositions reduce the incidence of these adverse events in humans. The results showed that xanomeline was more resistant to erythropoietin and reduced survival and demonstrated increased tolerance to xanomeline.

[0154] In one embodiment, xanomeline is administered in the presence of trosidine chloride to treat a muscarinic disorder. Combined with xanomeline, it has been shown to inhibit mutagenesis in tissues found outside the brain. In one embodiment, the present invention provides a method for treating such a disease or disorder, comprising administering to the patient a therapeutically effective amount of a medicament for the treatment of a disease or disorder, the method ... in schizophrenia and related disorders, as well as neurodegenerative diseases such as Alzheimer's. These include cognitive impairment caused by pain, as well as pain such as nociceptive or neuropathic pain. The combination of tropium and trospium chloride has been shown to respond to muscarinic receptor activation. This represents a safer way to treat these diseases.

[0155] In another embodiment, xanomeline and trospium chloride treat a mood disorder. In an embodiment, xanomeline and trospium chloride treat a movement disorder. In these conditions, xanomeline and trospium chloride enhance cognitive function not related to a specific pathology. In another embodiment, the xanomeline and trospium chloride are In another embodiment, xanomeline and trospium chloride are used to treat pain, Besides treating diseases, enhancing attention can also accelerate learning and improve the relief of sleep deprivation and jet lag. In another embodiment, xanomeline reduces fatigue due to both circadian rhythm disorders such as bronchitis and cardiovascular disease. and trospium chloride to treat addictive disorders.

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

[0157] In one embodiment, trospium chloride reduces the side effects associated with xanomeline. These side effects include GI side effects, cardiac side effects, excessive sweating, and hypersalivation. These include, but are not limited to, the use of trospium with xanomeline. Therefore, when xanomeline is not used clinically due to its side effects, In another embodiment, trospium chloride may be used in conjunction with xanomeline. By virtue of this, xanomeline provides a higher solubility than would otherwise be achieved. This makes it possible to achieve a maximum tolerated dose that is not too high.

[0158] Various time- and resource-intensive methods have been used to evaluate the efficacy and safety of the combination of xanomeline and trospium chloride. For example, animal models have demonstrated efficacy, as have pharmacological models (e.g., ketamine models). Novel therapeutic approaches for schizophrenia, including both therapeutic and genetic models (e.g., DISC1 mice) Similarly, animal models, including rodents, dogs, and non-human primates, DEL demonstrates the side effect profile of pharmacological agents. Animal models are an alternative to human experiments. However, due to the physiological differences between humans and animals, there may be flaws, so human experiments, especially Alternatively, the disclosed combinations may have limited predictive power for central nervous system disorders. can be attempted in controlled clinical trials in people. Those skilled in the art can also assess the efficacy of self-reported patient outcomes. Various side effects, such as GI discomfort, can be assessed using a standard scale based on the GI tract. As another example, objective physiological measures (e.g., EKG) are used by those skilled in the art. In addition, the Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PAN) A set of standards for assessing schizophrenia symptoms, including the Clinical Global Impression (CGI), Clinical trials are typically double-blind, with one patient group being unresponsive and the other being blinded. One group will receive a sexual placebo, while the other group will receive the active intervention.

[0159] Prior to administering the claimed combination, patients may have a lead-in period of 1 to 14 days. During this induction period, trospium chloride is given alone. Trospium is used to accumulate trospium chloride in the body before administering xanomeline. One or more doses of trospium chloride must be administered to reach or approach steady-state exposure levels. This accumulation, or higher exposure, of trospium chloride occurs over a period of time. increases blockade of muscarinic receptors outside the brain, reducing adverse events when xanomeline is administered. In another embodiment, trospium chloride is administered one or more days prior to xanomeline. will be done.

[0160] In one embodiment, the xanomeline and trospium chloride are administered to a patient six times over a 24 hour period. In another embodiment, the xanomeline and trospium chloride are administered to the patient over a 24 hour period. In another embodiment, the xanomeline and trospium chloride are administered 24 hours a day to a subject. In one embodiment, xanomeline and trospium chloride are administered to the patient four times. In another embodiment, xanomeline and trochlore are administered to a patient three times over a 24 hour period. In another embodiment, xanomeline and Trospium chloride is administered to the patient once over a 24-hour period.

[0161] In one embodiment, an extended release formulation of trospium chloride is combined with xanomeline. In another embodiment, the extended release of trospium chloride is administered once every 24 hours. In one embodiment, the extended release of trospium chloride is administered to a patient for 24 hours. In another embodiment, 5 milligrams to 400 milligrams of trichloroethylene are administered 1 to 3 times. Rospium extended release is used for 24 hours. In one embodiment, 20 milligrams to 200 milligrams of trospium chloride extended release is used over a 24 hour period.

[0162] In one embodiment, 225 mg of xanomeline and 40 mg of trospium chloride are administered in a 24 In another embodiment, 100 mg of xanomeline and 20 mg of xanomeline are administered to a patient over a period of time. g of trospium chloride is administered to the patient over a 24 hour period. mg of xanomeline and 20 mg of trospium chloride were administered to the patient over a 24-hour period. In another embodiment, 125 mg of xanomeline and 30 mg of trospium chloride are In another embodiment, 125 mg of xanomeline and 4 mg of cefotaxime are administered to the patient over a 24 hour period. In another embodiment, 2.0 mg of trospium chloride is administered to the patient over a 24 hour period. 00 mg of xanomeline and 40 mg of trospium chloride were administered to the patient over a 24-hour period. In another embodiment, 200 mg of xanomeline and 80 mg of trospium chloride. are administered to the patient over a 24 hour period. and 60 mg of trospium chloride are administered to the patient over a 24 hour period. 250 mg of xanomeline and 80 mg of trospium chloride were administered to the patient over a 24-hour period. In another embodiment, 300 mg of xanomeline and 40 mg of trospiracela chloride are administered. In another embodiment, 300 mg of xanthene is administered to the patient over a 24 hour period. The patient is administered 80 mg of trospium chloride and 80 mg of tetracycline over a 24 hour period.

[0163] Treatment can be initiated with lower dosages, after which dosages can be adjusted to determine therapeutic efficacy and side effects. The dose may be increased in small increments until a balance between efficacy and safety is achieved. , the patient's health is monitored by measuring one or more relevant indicators at predetermined times during the treatment period. Treatments, including compositions, amounts, administration times and formulations, may be monitored in accordance with such monitoring. The patient can adjust the parameters for each monitoring session by measuring the same parameters. Periodically, reassessments can be made to determine improvement. Based on these reassessments, the treatment being administered can be adjusted. Adjustments can be made to the compositions shown, and possibly to the times of administration. EXAMPLES

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

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

[0166] [Table 1]

[0167] [Table 2]

[0168] Quadro Comi with 457μm round hole screen, 0.2 inch spacer The powder was screened using a Model 197 at 1625 rpm and a Hobar Mix in a low shear mixer / granulator (model N-50) at a fixed speed of 60 rpm for 2 minutes. Blend uniformity is driven by subsequent wet granulation, so the dry blending step Optional. Hand screen the beads through a 40 mesh (425 μm) sieve. did.

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

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

[0171] The extrudate was passed through an LCI Marumerizer (Spherona) equipped with a 2.0 mm friction plate. The extrudates were spheronized at different plate speeds for a total of 4 minutes. The rate and time of crystallization are process variables.

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

[0173] Moisture content was measured using a Mettler Toledo Halogen Moisture Analyzer, Model HR83. The weight loss was evaluated gravimetrically by loss on drying (LOD). The weight loss rate was 0.0 within 60 seconds. The beads were heated at 105° C. until the solubility decreased to below 5%.

[0174] [Table 3]

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

[0176] [Table 4]

[0177] [Table 5]

[0178] [Table 6]

[0179] [Table 7]

[0180] [Table 8]

[0181] Example 3 - Capsule stability and dissolution testing Capsules were produced by weighing the beads and manually filling them into HPMC capsules. As shown in Table 9, beads premixed with talc (0.5%) were individually / subjected to capsules. The beads were manually encapsulated using an Accofil™ capsule filling machine, which was individually filled. It has become.

[0182] [Table 9]

[0183] After drying, the beads were separated into 16 mesh (1.18 mm) and 40 mesh (0.425 mm) sieves. ) screen by shaking for 5 minutes. Sieve 1.18 Beads with sizes between 0.425 mm and 0.5 mm were retained for further analysis.

[0184] The morphology and surface properties of the beads were characterized using a JSM-601 equipped with a backscattered electron detector (BES). 0LV InTouchScope (trademark) (JEOL Ltd, Tokyo, JP) The samples were examined by scanning electron microscopy (SEM) using a double-sided carbon conductive film. The specimen was placed on a metal stub using adhesive tape. Images were taken at low vacuum (60 Pa) and 30x magnification. The results were obtained at an accelerating voltage of 20 kV.

[0185] The bulk density and tap density were measured using a tap density tester (JV 1000, Copley Sc ientific) using USP <616> The bulk density was measured twice using the method. Tap density was measured by the volume of a powder sample of known mass in a cylinder. The measuring cylinder was mechanically tapped until there was no further change.

[0186] The powder flow characteristics were evaluated using the Carr compressibility index and the Hausner ratio. Both were derived using bulk and tapped density measurements. Carr's Compressibility Index (CI) is Using the data on bulk density and tapped density, the compressibility index is calculated as follows: (tapped density - bulk density) / tapped density The Hausner ratio (H) was calculated by fitting the density to the equation of density x 100%. The capsules were analyzed for appearance, assay, related substances, moisture content, and other properties. The stability and dissolution of the xanomeline / trospium capsules were analyzed. The modules and protocols are shown.

[0187] The beads also ranged in size from 0.6 mm to 0.85 mm. Some beads were , which showed similar morphological characteristics. Several other bead modifications were performed to increase the density of the beads. The results were a rough surface and loss of sphericity. Scanning electron microscopy of 66% tetracycline beads (Figure 2) and 17.7% trospium chloride beads (Figure 3) Scanning electron microscopy (SEM) images showed that the beads were 0.6 mm to 0.85 mm in size. These beads were used in xanomeline / trospium capsules. Particle size distribution of the beads The PSD (Protein Saturation Density) was measured by mechanical sieving. As shown in Table 10, both APIs had Most of the beads ranged in size from 0.425 to 1.18 mm.

[0188] [Table 10]

[0189] Table 11 shows the density and mass of beads collected between the 0.425 mm and 1.18 mm sieves. The flow characteristics of xanomeline tartrate and trospium chloride IR beads are shown in Fig. 1. and flow properties, which can be important in mixing bead systems.

[0190] [Table 11]

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

[0192] [Table 12]

[0193] [Table 13]

[0194] [Table 14]

[0195] [Table 15]

[0196] [Table 16]

[0197] [Table 17]

[0198] [Table 18]

[0199] Subsequent studies have examined KarXT 50 / 10, 50 / 20, and and 75 / 20 have been shown to be stable at 25°C / 60% RH for at least 12 months. Based on available data, a shelf life of 15 months at 25°C / 60% RH is proposed.

[0200] The dissolution results showed that the two compounds were rapidly released, which may explain their bioavailability. This can increase the irritability of the beads, despite the substantial difference in composition between the two bead formulations. Both xanomeline and trospium chloride were released at similar rates regardless of the dosage. It has low bioavailability and rapid release reduces pressures that limit absorption into the systemic circulation. The bioavailability can be increased by inverse saturable processes.

[0201] During stability testing of the combination drug, an unknown xanthene derivative with a relative retention time of approximately 1.09 was The impurity was observed in the form of xanomeline at 50 mg / 10 mg trichloroethylene during the study. At the 3-month mark, the rospium drug showed the highest mean mean mean of 1.1% for the other three combination drugs. The impurity peaks increased with time and both occurred simultaneously. It increased with increasing storage temperature. Impurities had not been observed prior to this study.

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

[0203] The RRT 1.09 impurity is compound V(C 14 H 20 N3OS + , MW=278.13 22 Da), which is a hydroxylated form of xanome, which has negative mutation potential. It is the penultimate intermediate in the synthesis of phosphorus. [ka]

[0204] The storage temperature of pharmaceutical products has been reduced to reduce the presence of impurities. Headspace in packaging The bottle was flushed with argon to minimize oxygen in the solution. Sanomelin Beads formulation contains 0.5% by weight of ascorbic acid or 0.05% by weight of BHT, etc. Formulated with antioxidants.

[0205] Example 4 - KAR-001 Phase I Trial of Combination of Xanomeline and Trospium Chloride Experience In healthy volunteers, xanomeline administered with trospium chloride was A Phase I double-blind, randomized, multiple-dose pilot study was conducted with Nomelin alone. The primary objective of this study was to (1) administer 225 mg of xanomeline together with 40 mg of trospium chloride; daily for 7 days vs. xanomeline 225 mg alone daily for 7 days (2) To evaluate the safety and tolerability of xanomeline 225 mg daily alone for 7 days; Compared with xanomeline 225 mg daily (75 mg TID) for 7 days, days plus trospium 40 mg daily (20 mg BID). Significantly reduced peripheral cholinergic side effects (nausea, diarrhea, vomiting, sweating, hypersalivation) The objective of this study was to determine whether or not the IL-16 receptor agonist (IL-16 receptor agonist) was associated with a decreased risk of developing IL-16 receptor agonist (IL-16 receptor agonist) in the absence of a median IL-16 receptor agonist (AL-16 receptor agonist). Table 17 lists the parameters of this study.

[0206] [Table 19]

[0207] [Table 20]

[0208] A total of 70 study subjects were randomized, of which 68 received xanomeline. All participants underwent at least one assessment on the first day of treatment, Day 3. Demographics of the study subjects are shown in Table 18. vinegar.

[0209] [Table 21]

[0210] The most common adverse events with xanomeline were nausea, vomiting, diarrhea, excessive sweating, and saliva. This is a so-called cholinergic adverse event, which is excessive secretion of fluid. Concomitant administration of xanomeline increased the cholinergic response compared with xanomeline administered concomitantly with placebo. This resulted in a statistically significant (p=0.016) 43% reduction in the incidence of motor adverse events. In the xanomeline plus placebo arm of the study, 63% of subjects had at least one cholinergic event. reported adverse events, whereas the xanomeline plus trospium chloride arm of the study reported no such events. Only 34% of subjects reported events.

[0211] In addition, the study also examined the individual cholinergic adverse events of each type in the xanomeline plus placebo group. The incidence of bronchitis in subjects receiving xanomeline plus trospium chloride was compared with that in subjects receiving bronchodilator The incidence of sweating was reduced in subjects who had been exposed to the condition. The reduction in the incidence of sweating was statistically significant in itself. The rate was 20.0% in the xanomeline + trospium chloride group and 10.0% in the xanomeline + placebo group. This was down from 48.5% in the previous study, a 59% decrease (p=0.013).

[0212] Overall cholinergic adverse events in the xanomeline + trospium chloride arm of the study Incidence rates were reported during the 2-day run-in period for placebo + placebo subjects. These two data points occurred during different periods of the study. Although no significant difference was observed between placebo and placebo, the incidence of cholinergic adverse events was similar to that of placebo. The 43% reduction in adverse events with trospium chloride was close to the maximum reduction possible in the study This suggests the possibility.

[0213] Table 19 shows the incidence and number of cholinergic adverse events in the evaluable population of this study: All p-values ​​are based on Fisher's exact test. * Excluding those with Based on chi-square test.

[0214] [Table 22]

[0215] To evaluate whether the addition of trospium chloride increases the tolerability of xanomeline. In addition, the study assessed the overall safety and tolerability of xanomeline plus trospium chloride. Table 20 shows that the combination was generally well tolerated, with no serious adverse events. There were no morbidities or serious adverse events, indicating that most adverse events were mild. .

[0216] [Table 23]

[0217] The tolerability profile found in this study supports the combination of xanomeline and trospium chloride. This makes it possible to proceed with future trials of the combination.

[0218] Example 5 - KarXT, a xanomeline + trospium combination formulation, KAR-003 Phase I The study evaluated the safety and tolerability of KarXT in healthy volunteers aged 18 to 60 years. This was a phase 1 randomized, multiple-dose, adaptive design, inpatient study to evaluate the efficacy and safety of cerebrospinal fluid in patients with cerebrospinal fluid (C-TEF) in the treatment of cerebrospinal fluid-resistant cerebrospinal fluid (C-TEF)-associated ... They signed informed consent and underwent screening evaluations on days -21 to -1. Upon successful completion of all screening assessments, subjects were assessed for baseline safety and efficacy. Patients returned to the study clinic on Day 0 for sex assessment and enrollment in the study. were randomly assigned to one of two treatment arms: KarXT or placebo. Subjects were assigned to one of four cohorts (cohort 1, 2, 3, or 4). Ta.

[0219] The study drugs were administered BID on days 1 to 7. All cohorts received xanomeline and thrombin timepoints. Both combination formulations of KarXT 5 and rospium were used. All cohorts were Beginning with a 2-day run-in of 0 / 20 BID (for subjects randomized to active treatment) After a 2-day run-in period, an unblinded pharmacist assigned subjects Each subject was assigned a specific cohort dose for 5 days, for a total of 7 days of treatment. To maintain the efficacy of the treatment, participants received a matching placebo throughout the study. The sentinel group was introduced into the study and safety was assessed by the Data Safety Evaluation Group (DSEG). and tolerability will be monitored, with the result that approximately 30% of the proposed cohort will The subjects were treated and evaluated for safety before receiving the drug. Staff were blinded to treatment. A Dose Selection Committee (DSC) determined the dose distribution of subsequent treatment arms. The subjects were not blinded to the dosing decision for treatment.

[0220] Serial blood samples for PK evaluation of xanomeline and trospium were collected on days 1, 3, and 7. Monitoring of trough concentrations of xanomeline and trospium and laboratory evaluation More blood was sampled at routine intervals for the purpose of determining the saliva volume. Saliva volume was measured before dosing on day 1, and then daily (afternoon) on days 1-7. The saliva volume was measured at approximately the same time each day to avoid diurnal variation. Other evaluations included pupil size and The subjects were followed up throughout the treatment period (7 After the safety evaluation on Day 8, subjects were discharged from the study clinic. Patients were discharged from the hospital and asked to return approximately 14 days after study drug administration for a final safety evaluation. I was asked to do so.

[0221] During the study, each cohort was randomized to KarXT 50 / 20 BID (active treatment) After a 2-day induction period (for subjects who were immunized), subjects were dosed as follows: In cohort 1, subjects received KarXT 100 / 20 BID (200 mg xanthene The subjects were administered 40 mg trospium plus 40 mg total daily dose (TDD) or placebo for 3 to 7 days. Completed to the eye. In cohort 2, the Sentinel group (group 2a) discontinued treatment after the morning dose on day 4. The dose for subjects in cohort 2 was KarXT 150 / 20 BID (300 mg / kg). The cohort 2 doses were either sanomelin + 40mg trospium TDD or placebo. The study was discontinued (DSEG decision based on observed tolerability concerns). , and further administration of KarXT 150 / 20 BID in cohort 2 will be performed in the clinical population. This dose combination is unlikely to be well tolerated to justify further development. Therefore, we proceeded to administration of the sentinel group of cohort 3 (group 3a). In cohort 3, the sentinel group (group 3a) received KarXT 150 / 40 BID (TDD of 300mg xanomeline + 80mg trospium) or placebo for 3 days The second group of cohort 3 (group 3b) completed the study after the morning dose on day 5. Administration was discontinued. In cohort 4, the sentinel group (group 4a), the second group (group 4b), and the remaining Group 4c received KarXT 125 / 40 BID (250 mg xanomeline + Patients completed treatment with 80 mg trospium TDD or placebo on days 3 through 7.

[0222] 96 subjects were planned, 248 subjects were screened, and 69 subjects were randomized. The study was randomized to 18 subjects, 51 of whom completed the study and 18 of whom discontinued. ~40kg / m 2 Men and women aged 18-60 years at screening with a body mass index of The study included healthy subjects of either sex. Subjects were randomly assigned to receive the immunization for irritable bowel syndrome (IBS) within 6 months prior to screening. Patients were excluded if they had a medical history of severe constipation requiring treatment. Psychiatric or neurological disorders which, in the opinion of the FDA, may jeopardize the safety of the subject or the validity of the study. Subjects were also excluded from the study if they had a history or presence of any disease or condition, including Demographic and baseline characteristics are summarized by treatment group in Table 21. Line characteristics were consistent between the safety and PK populations.

[0223] [Table 24]

[0224] [Table 25]

[0225] Serial blood samples to assess the PK of xanomeline and trospium were collected on days 1, 3, and 4. On the 7th day, before the morning dose and 1, 2, 3, 4, 6, 8, 10, and 12 hours after the morning dose, PK parameters were collected from all subjects in the cohort. The individual xanomeline and trospium concentration-time profiles were determined by compartmental methods. The dose-normalized parameters were calculated from the max and the area under the concentration-time curve (A During the study, UC values ​​were calculated before the morning administration on days 2, 4, 5, and 6 and at discharge on day 8. Prior to the study, additional blood samples were collected to monitor trough concentrations of xanomeline and trospium. A sample was taken.

[0226] Safety evaluations included spontaneously reported adverse events, ECGs, clinical laboratory evaluations, and vital signs. Tests included assessment of saliva flow, Bristol stool scale, pupil size, and physical examination. Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) were calculated for each treatment group. Data were summarized as geometric mean (GM), geometric coefficient of variation (CV%), quartiles, and mean mean (M). No formal statistics were performed, but counts and frequencies were used to determine the Category measurements were tabulated.

[0227] Unless otherwise stated, treatment groups were summarized as follows: KarXT 50 / 20 BI D (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 Vcaps® Plus capsules) and Capsugel®; all cohorts combined (placebo group). Safety Assessment The values ​​were based on spontaneously reported adverse events, ECGs, clinical laboratory evaluations, and vital signs. Exploratory analyses of saliva volume, Bristol stool scale, and pupil size were also conducted.

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

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

[0230] Exposure to GM xanomeline was administered on the third day with 20 mg of xanomeline and 20 mg of trospium. When administered, it was increased from 100 mg to 150 mg with 40 mg of trospium. In the case of KarXT 125, the dose was not proportionally increased from 125 mg to 150 mg. Lower xanomeline exposure after treatment with KarXT 150 / 40 compared with KarXT 150 / 40 A dose of 150 mg xanomeline was administered with 20 and 40 mg trospium. When administered, the GM xanomelin exposure on the third day (C max , AUC 0-last and AU C 0-12hr On day 7, exposure to GM xanomeline was similar to that of xanomeline. When given with 40 mg of trospium, dose proportionality was 125 mg to 150 mg. The increase was slightly higher than expected.

[0231] After treatment with KarXT 100 / 20 BID and KarXT 125 / 40 BID Accumulation of xanomeline in plasma was minimal to nonexistent from days 3 to 7, but the study was completed Three of four subjects had accumulation after administration of KarXT 150 / 40 BID. The mean accumulation rate in the KarXT 150 / 40 BID group was 366.2% in RAUC and 36.2% in RC. max The rate was 445.4%.

[0232] Example 6 - Xanomeline Pharmacokinetics of KAR-003 Compared to KAR-001 KAR-001 (75 mg xanomeline TID ± 20 mg trospium BID) and KA Compare xanomeline GM exposure between the KarXT 100 / 20 BID group of R-003 The results showed that the 3 days of exposure to KAR-003 (3 days) were significantly higher than the 3 and 9 days of exposure to KAR-001 (corresponding to the corresponding exposures). Day 1 and Day 7) max Value and AUC 0-6hr (KAR-003) or AUC 0-tau (KAR-001) values ​​were shown to be large. Median T max Both trials The results were observed at 2 hours on both days (days 3 and 9 for KAR-001). day 1 for KAR-003 and day 3 and day 7 for KAR-003). enhances xanomeline exposure.

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

[0234] Median t of trospium 1 / 2 was similar between treatment groups on day 3, with values ​​ranging from 4.1 to 4. On day 7, the median t 1 / 2 Value is KarXT 100 / 20 B ID (4.9 hours) and KarXT 125 / 40 BID (4.5 hours) treatment The mean mean time to recovery was similar, but slightly longer for the KarXT 150 / 40 BID group ( 7.1 hours).

[0235] GM trospium exposure was 1.0% on day 3 of dosing when administered with 150 mg xanomeline. , slightly less than dose proportional from 20 to 40 mg. GM trospium on day 3 Exposure (C max , AUC 0-last and AUC 0-12hr ) is 150mg BID trospium at 100 mg BID compared with xanomeline at 20 mg BID The effect was greater when GM trospium was administered with xanomeline on day 3. The patient was given 40 mg trospium BID, 125 mg xanomeline BID, and 150 mg quinolones. When given with sanomelin BID, the results were similar.

[0236] Trospium is available in KarXT 100 / 20 BID and KarXT 125 / 40 BID. Accumulation in plasma from day 3 to day 7 after administration of ID and KarXT 150 / 40 BID Trospium was administered on days 1 to 7 in the KarXT 100 / 20 BID group. The mean day 7 / day 1 accumulation ratio was 348.7% (RAUC) and 3 79.9% (RC max ) was.

[0237] Trough between KAR-001 and KAR-003 KarXT 100 / 20 BID groups When comparing exposure to GM, C of KAR-003 max and AUC 0-12hr Both The exposures were greater than those of the corresponding KAR-001 on both days (3 (Days 3 and 7 for KAR-003 and Days 9 for KAR-003). T max was observed at 1.0 hours in both studies and on both days. These data have shown that the KarXT formulation enhances trospium exposure.

[0238] All cohorts of KAR-003 were randomized to KarXT. Patients were started with a 2-day induction period of KarXT 50 / 20 BID. D) Xanomeline PK concentrations. Table 22 shows the KarX concentration for the entire cohort for the PK population. Summarize xanomeline PK parameters on day 1 for T 50 / 20 BID treatment. Samples collected before the first dose of xanomeline on day 1 showed no measurable xanomeline. Xanomeline concentrations were not shown. Xanomeline concentrations were measured over the entire 12-hour period following the morning dose on Day 1. was quantifiable (>50 pg / mL) at time point.

[0239] [Table 26]

[0240] FIG. 43 shows the mean (±SD) xanomeline PK concentrations by treatment on day 3 for the PK population. Table 23 summarizes these parameters. Xanomeline concentrations were All cohorts except for one subject in whom plasma concentrations of xanomeline were <50.0 pg / mL were For both groups, quantification was possible at all time points over 12 hours following the morning administration of study drug on Day 3. Intersubject variability was 0.01 across the four treatment groups. max 23.7-58.2% (CV% ), C max 79.8-136.3% (geometric CV%), t 1 / 2 So 21.6~26 .3% (CV%) and AUC 0-12hr The geometric CV% was 77.1-96.1%. The median T value of xanomeline on day 3 was max KarXT 100 / 20 BID , KarXT 125 / 40 BID, KarXT 150 / 20 BID, and Kar The time was 2 hours in the XT 150 / 40 BID group. max Values ​​are for all four treatment groups. The range is 1.0 to 6.0 hours in the body. 1 / 2 The elimination phase was not well characterized. In contrast to the previous study, KAR-001, which showed that Median t of xanomeline 1 / 2 was numerically similar among the four treatment groups; median 1 / 2 The individual t 1 / 2 The value was 2.4 across the four treatment groups. The range was ~8.6 hours.

[0241] [Table 27]

[0242] When KarXT was administered BID, the dose of trospium (20 mg) was unchanged and the dose of xanthelasma was When the melin dose was increased from 100 mg (cohort 1) to 150 mg (cohort 2), Dose-normalized GM exposure to sanomelin on day 3 (dose-normalized GM C max and dosage Normalized GM AUC 0-last and AUC 0-12hr ) has decreased. The dose of xanomeline was increased from 125 mg (cohort 4) to 125 mg (cohort 5) without changing the dose of rifampin (40 mg). When increased to 150 mg (cohort 3), day 3 dose-normalized GM for xanomeline Exposure was slightly decreased (i.e., xanomeline exposure was greater in the KarXT 125 / 40 Lower after treatment with KarXT 150 / 40 BID compared with BID The 150 mg oxaliplatin was administered with either 20 mg or 40 mg trospium BID. Comparing xanomeline exposure after BID administration of xanomeline, the G M.C. max , AUC 0-last , and AUC 0-12hr It has been shown that It was.

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

[0244] [Table 28]

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

[0246] Table 25 shows the xanomeline PK accumulation ratio (day 7 / day 3) by treatment for the PK population. KarXT 100 / 20 BID (cohort 1) and KarXT 125 Based on the mean accumulation ratio of xanomeline after treatment with 100 mg / 40 BID (cohort 4), 3 Accumulation of xanomeline in plasma from day 1 to day 7 was minimal to nonexistent. The mean accumulation rate in the 00 / 20 BID group was 133.4% in RAUC and 133.4% in RC. max That's 130. 5%, and in the KarXT 125 / 40 BID group, RAUC was 143.9%, and RC was 143.9%. max in Only one subject in the KarXT 100 / 20 BID group had a 3-day In contrast, the KarXT 150 / 4 patients who completed the study had lower exposure on day 7 compared to the control group. 0 Moderate accumulation of xanomeline occurred in 3 of 4 subjects in the BID group. KarXT 1 Other subjects in the 50 / 40 BID group had similar exposures on days 3 and 7. The mean accumulation ratios in the 150 / 40 BID group were 366.2% (RAUC) and 445.4%. (RC max ) was.

[0247] [Table 29]

[0248] FIG. 45 shows the mean (±SD) xanomeline by treatment and visit (day) for the PK population. The PK concentration-time profiles were compared. The mean (±SD) xanomeline PK trough concentrations per dose are shown. Attainment of steady state was assessed. There wasn't.

[0249] Exposure to xanomeline GM was compared with KAR-001 (75 mg xanomeline TID ± 20 mg tro Spium BID) (Table 23) and KAR-003 KarXT 100 / 20 BID group ( When compared between the KarXT 100 / 20 BID group (KAR-003) and C on the third day max Value and AUC 0-6hr (KAR-003) or AUC 0-tau ( AUC) values ​​from time 0 to 6 hours (KAR-001) are the corresponding KAR-001 values ​​on day 3. The exposure was approximately 2.3 to 2.6 times greater than that of

[0250] 7 of the KarXT 100 / 20 BID group of xanomeline in KAR-003 (Table 22) GM exposure on the day was compared between KAR-001 (Table 23) xanomeline alone and xanomeline + Compared with the 9th day exposure in the rospium group, the KarXT 100 / 20 BID group (KA R-003) were approximately 10% lower than the corresponding exposure for KAR-001 on day 9. The median T max is KAR-003 (Table 22) In KAR-001 (Table 23), the mean values ​​were 2.0 on the 3rd and 7th days, and 2.0 on the 3rd and 9th days. These data indicate that the KAR-003 formulation provides adequate exposure and PK characteristics. This indicates that

[0251] Table 26 shows the KA of the KarXT 100 / 20 BID group on days 3 and 7 in the PK population. A subset of R-003 xanomeline PK parameters are summarized. Table 27 shows the PK population KAR-001 xanomeline PK parameters on days 3 and 9 of KAR-001 treatment A summary of a subset of the models is shown below.

[0252] [Table 30]

[0253] [Table 31]

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

[0255] [Table 32]

[0256] FIG. 48 shows the mean (±SD) trospium PK concentrations by treatment on day 3 for the PK population. The levels of trospium in all treatment groups are shown in Table 29, and these parameters are summarized. Before the morning administration of the study drug on Day 3 and at all time points up to 12 hours after the morning administration on Day 3 The collected samples were quantifiable (plasma trospium concentrations at 12 hours post-dose were < Except for one subject with a T of 20.0 pg / mL. Inter-subject variability was observed across the four treatment groups. max 0.0-83.0% (CV%), C max 54.8-80.7% (CV%), t 1 / 2 9.1-34.0% (CV%), AUC 0-12hr So 59.0~67.6 % (CV%).

[0257] [Table 33]

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

[0259] When KarXT was administered BID, the dose of xanomeline (150 mg) was unchanged. When the dose of thrombin was increased from 20 mg (cohort 2) to 40 mg (cohort 3), Dose-normalized GM exposure on day 3 of trospium was increased. 00 mg (Cohort 1) or 150 mg (Cohort 2) of xanomeline BID When comparing trospium exposure on day 3 after coadministration, the 20 mg BI of trospium was When dose D is administered with 100 mg xanomeline BID, 150 mg xanomeline B Compared with ID, trospium GM C max , AUC 0-last and AUC 0-1 2hr was shown to be larger.

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

[0261] FIG. 49 shows the mean (±SD) trospium PK concentrations by treatment on day 7 for the PK population. The concentration of trospium is shown in Table 30, and the parameters are summarized in Table 31. 00 / 20 BID, KarXT 125 / 40 BID, and KarXT 150 / 4 0 For the BID group, before the morning administration of the study drug on Day 7 and 12 hours after the morning administration on Day 7 The intersubject variability was quantifiable in samples taken at all time points. 00 / 20 BID, KarXT 150 / 40 BID, and KarXT 125 / 4 0 BID group overall, T max 0.0% to 86.3% (CV%), C max So 51 .2%~93.8%(geometric CV%), t 1 / 2 23.0% to 44.5% (CV%), and AUC 0-12hr The geometric CV% ranged from 59.4% to 76.7%.

[0262] [Table 34]

[0263] Median trospium T on day 7 max KarXT 100 / 20 BID, Ka 1 for rXT 125 / 40 BID and KarXT 150 / 40 BID treatments .0 hours. max Values ​​are KarXT 100 / 20 BID, KarX T 150 / 40 BID and KarXT 125 / 40 BID groups were 0.0 to 6 The range was .0 hours.

[0264] Median trospium dose on day 7 1 / 2 KarXT 100 / 20 BID(4. The results were similar for the KarXT 125 / 40 BID (4.5 h) and KarXT 125 / 40 BID (4.5 h) groups. Median t 1 / 2 The mean time to death was 7.1 hours in the KarXT 150 / 40 BID group. t 1 / 2 Values ​​are KarXT 100 / 20 BID, KarXT 150 / 40 BI The mean time to presentation ranged from 3.1 to 11.9 hours for all groups. Ta.

[0265] As observed on day 3, 40 mg trospium BID to 125 mg (cohort 4) or 150 mg (Cohort 3) xanomeline BID on day 7 When comparing trospium exposure in When administered with trospium BID, max , AUC 0-last and AUC 0-12hr were shown to be similar.

[0266] Table 31 shows the trospium PK accumulation ratios by treatment for the PK population (day 7 / day 3; day 7 / day Based on the mean trospium PK accumulation ratio, trospium Almost no plasma levels were detected from day 3 to day 7 after administration of XT 100 / 20 BID (cohort 1). KarXT 125 / 40 BID (cohort 4) and KarXT 150 There was little to no accumulation after 40 / BID (cohort 3). , exposure was lower on day 7 compared with day 3 in the KarXT 100 / 20 BID group.

[0267] The accumulation ratio from day 3 to day 7 was 1.0% in the KarXT 125 / 40 BID group and 1.0% in the KarXT The mean accumulation ratios were 10 for RAUC and 10 for 150 / 20 BID. 8.6%~141.4%, RC max The range was 111.0% to 135.8%. In the KarXT 100 / 20 BID group, moderate levels of uracil were detected in plasma from days 1 to 7. All but one subject had higher trospium exposure on day 7 compared with day 1. The average accumulation ratio was 348.7% for RAUC and 348.7% for RC. max The rate was 379.9%. The effect of increasing doses of xanomeline on the PK and bioavailability of trospium The potential effect of 50 mg BID to 100 mg BID starting on day 3 was It cannot be ruled out that this may contribute to increased exposure from the 1st to 7th days.

[0268] [Table 35]

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

[0270] Example 7 - Trospium Pharmacokinetics of KAR-003 Compared to KAR-001 Trospium on day 1 of KAR-001 (first dose of trospium alone without pretreatment ) (Table 33) and Day 1 of KAR-003 (xanomeline + trospium without pretreatment When comparing the GM exposure of the two groups (Table 32), the trospium exposure of KAR-003 was , which is approximately 2.1-2.5 times higher than that obtained from KAR-001. The comparison of day 3 GM exposure in the KAR-003 study is not really a direct comparison (though (xanomeline administration was not initiated until day 3), and subjects were administered trospium The number of doses and daily doses were the same. KAR-003 GM trospium exposure on day 3 (Table 32) are also approximately 2.4-3.3 times higher than those obtained from KAR-001 (Table 3 3) The KarXT 100 / 20 BID cohort of KAR-003 (Table 32) 7-day GM exposure to trospium in (T1) and xanomeline + in KAR-001 (Table 33) Compared with the trospium group's exposure on day 9, exposure was It was again shown that the concentrations were higher (approximately 3.5 to 4.3 times) than those of the control.

[0271] Median T of Trospium max KarXT 100 / 20 BI of KAR-003 In group D, KAR-001 xanomeline + trospium was administered for 1.0 hour on the 3rd and 7th days. In the 100 mg / kg group, the median T max Trospium alone Median T on Day 1 in Group (KAR-001) max (Compared to 3.0 hours, KarXT It was low (1.0 hour) on day 1 in the 50 / 20 BID group (KAR-003).

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

[0273] [Table 36]

[0274] [Table 37]

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

[0276] [Table 38]

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

[0278] The xanomeline + trospium arm of KAR-001 showed a statistically significant improvement in nausea and vomiting compared with KarX Compared with the T 100 / 20 BID group and the KarXT 125 / 40 BID group, No clear trends were observed. 17.1%, KarXT 100 / 20 BID and KarXT 125 / 40 BI Nausea occurred in 22.2% of subjects in each of the D groups. 5.7% of subjects in the rituximab + trospium group and 2.0% of subjects in the KarXT 100 / 20 BID group It occurred in 7.8% of subjects in the KarXT 125 / 40 BID group and 5.6% of subjects in the KarXT 125 / 40 BID group.

[0279] Xanomeline and trospium were significantly associated with overall toxicity following oral administration of the KAR-003 formulation at all doses. The PK results showed that neither xanomeline nor trospium was more effective than the PK of the other drug. The results suggest that the KAR-003 formulation did not meaningfully affect behavior in either Compared with KAR-001, which was administered with either compound separately, elevated blood levels.

[0280] No new safety signals were reported with the KarXT formulation. Symptoms were mild or moderate, and there were no SAEs or deaths. The incidence of diarrhea was 100% in the KAR-003 group compared with the KarXT 100 / 20 BID and Kar Compared with the XT 125 / 40 BID group, KAR-001 xanomeline + trospiu The levels were higher in the ham group.

[0281] The preceding description has been given for clarity of understanding only and is intended to provide a general understanding of the present disclosure. Modifications may be apparent to those skilled in the art, and no unnecessary limitations should be understood therefrom. Throughout this specification, when a composition is described as including an ingredient or material, Unless otherwise stated, the composition consists essentially of any combination of the listed components or materials. It is contemplated that the method may also comprise or consist of the steps. When described as a method, unless otherwise indicated, the method may include any combination of the recited steps. It is contemplated that the composition may consist essentially of or consist of the combination of the above. The disclosure illustratively disclosed in is not intended to limit the scope of any element or step not specifically disclosed herein. The method may be suitably carried out in the absence of

[0282] The methods disclosed herein, and their individual steps, may be performed manually and / or electronically. The process can be carried out with the aid of automation provided by the Although described with reference to an embodiment, those skilled in the art may use other ways of performing the acts associated with the method. For example, the order of the various steps is as follows, unless otherwise indicated: Modifications may be made without departing from the scope or spirit of the process. Some may be combined, omitted, or further subdivided into additional steps. do.

[0283] For clarity, certain features of the invention which are described in the context of separate embodiments may also be incorporated herein by reference in a single embodiment. It will be appreciated that in an embodiment, combinations may be provided. Conversely, for the sake of brevity, Therefore, various features of the invention that are described in the context of a single embodiment may also be used separately or in any suitable combination. The general formulas given herein may be used in any suitable subcombination. All combinations of the embodiments relating to the chemical groups represented by the variables included are contemplated. Such combinations are suitable for producing stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). To the extent that each and every combination is expressly intended to encompass any compound that can be used in combination with any of the compounds described herein, each and every combination is expressly intended to encompass any compound that can be used in combination with any of the compounds described herein. are specifically encompassed by the present invention as if they were set forth in All subcombinations of chemical groups listed in the embodiments described herein, as well as any combination of the chemical groups described herein. All subcombinations of the uses and medical indications described herein are also intended to be used with respect to each of the chemical groups, and all subcombinations, and subcombinations for use and medical indications are specifically encompassed by the present invention as if individually and expressly recited herein.

[0284] All patents, publications and references cited herein are hereby incorporated by reference in their entirety. Any inconsistencies between this disclosure and the incorporated patents, publications and references are hereby incorporated by reference. In such cases, this disclosure shall take precedence.

Claims

1. Xanomeline or a pharma- ceutically acceptable salt thereof Trospium chloride, 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium, Including, Pharmaceutical compositions.

2. The 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium is present in the pharmaceutical composition in an amount of less than 0.25% by weight. The pharmaceutical composition of claim 1.

3. The 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium is present in the pharmaceutical composition in an amount of less than 0.2% by weight. The pharmaceutical composition of claim 1.

4. said 3-[(4-hexyloxy)-1,2,5-thiadiazol-3-yl]-5-hydroxyl-1-methylpyridin-1-ium is present in said pharmaceutical composition in an amount of less than 0.5% by weight after said pharmaceutical composition has been stored at 40° C. and 75% relative humidity for at least 3 months; The pharmaceutical composition of claim 1.

5. The xanomeline is xanomeline tartrate. The pharmaceutical composition of claim 1.

6. The xanomeline or a pharma- ceutically acceptable salt thereof is formulated as a first component; The trospium chloride is formulated as the second component. A pharmaceutical composition according to any one of claims 1 to 5.

7. The first component further comprises a first excipient; The second component further comprises a second excipient. The pharmaceutical composition according to claim 6.

8. The first component further comprises microcrystalline cellulose; The second component further comprises microcrystalline cellulose, lactose, or a combination thereof. The pharmaceutical composition according to claim 6.

9. the first component is a plurality of first beads; the second component is a plurality of second beads; The pharmaceutical composition according to claim 6.

10. Further comprising an antioxidant, A pharmaceutical composition according to any one of claims 1 to 5.

11. The antioxidant is ascorbic acid. The pharmaceutical composition according to claim 10.

12. the antioxidant and the xanomeline or a pharma- ceutically acceptable salt thereof are formulated as a first component; The trospium chloride is formulated as the second component. The pharmaceutical composition according to claim 10.

13. The first component further comprises a first excipient; The second component further comprises a second excipient.

13. The pharmaceutical composition of claim 12.

14. The first component further comprises microcrystalline cellulose; The second component further comprises microcrystalline cellulose, lactose, or a combination thereof.

13. The pharmaceutical composition of claim 12.

15. the first component is a plurality of first beads; the second component is a plurality of second beads; 13. The pharmaceutical composition of claim 12.

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