Composition for treating neurological disorders

Abstract

This document describes a combination composition of compound 1 and fesoterodine for treating neurological disorders (e.g., schizophrenia, Alzheimer's disease psychosis, Parkinson's disease psychosis, cognitive impairment in Alzheimer's disease, psychosis in Lewy body dementia, bipolar disorder, and dyskinesia).

Description

Technical Field

[0001] Cross - References to Related Applications This application claims the benefit of priority and priority to U.S. Provisional Patent Application No. 63 / 504,306, filed May 25, 2023; U.S. Provisional Patent Application No. 63 / 578,804, filed Aug. 25, 2023; U.S. Provisional Patent Application No. 63 / 540,277, filed Sep. 25, 2023; and U.S. Provisional Patent Application No. 63 / 556,028, filed Feb. 21, 2024, the disclosures of each of which are incorporated herein by reference in their entirety for all purposes.

Background Art

[0002] Neurological disorders are now a major cause of disability worldwide. There is a need for new compositions and strategies for treating neurological disorders such as schizophrenia, Alzheimer's disease psychosis, Parkinson's disease psychosis, cognitive impairment in Alzheimer's disease, psychosis in Lewy body dementia, bipolar disorder, and dyskinesia (including levodopa - induced dyskinesia and tardive dyskinesia).

[0003] This disclosure provides a composition containing an M1 / M4 muscarinic agonist (Compound 1) co - formulated with a peripherally acting muscarinic receptor antagonist (fesoterodine fumarate), and a method for treating neurological disorders such as schizophrenia, Alzheimer's disease psychosis, Parkinson's disease psychosis, cognitive impairment in Alzheimer's disease, psychosis in Lewy body dementia, bipolar disorder, and dyskinesia (including levodopa - induced dyskinesia and tardive dyskinesia).

Summary of the Invention

[0004] This disclosure provides compositions and methods for treating neurological disorders such as schizophrenia and Alzheimer's disease psychosis.

[0005] In an embodiment, this disclosure provides (a) from about 10 mg to about 500 mg of Compound 1

[0006] [Chemical] or a pharmaceutically acceptable salt thereof; and (b) a composition comprising about 2 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof is provided; after administration of the composition, the t of Compound 1 by oral administration of the composition to a patient who needs it max is about 0.1 hour to about 8 hours, and the t of desfesoterodine (also called 5-hydroxymethyltoltorodine or 5-HMT) max is about 0.1 hour to about 8 hours.

[0007] In an embodiment, the present disclosure provides a composition comprising (a) about 10 mg to about 500 mg of Compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof; after administration of the composition, the t of Compound 1 by oral administration of the composition to a patient who needs it max is about 0.1 hour to about 8 hours, and the t of desfesoterodine max is about 0.1 hour to about 8 hours.

[0008] In an embodiment, the t of Compound 1 by administration of the composition of the present disclosure max is about 0.5 hour to about 4 hours after administration of the composition. In an embodiment, the t of desfesoterodine by oral administration of the composition max is about 0.5 hour to about 4 hours after administration of the composition.

[0009] In an embodiment, the C of Compound 1 by oral administration of the composition max,ss is about 200 ng / mL to about 5,000 ng / mL after administration of the composition. In an embodiment, the C of desfesoterodine by oral administration of the composition max,ss is about 2 ng / mL to about 60 ng / mL after administration of the composition.

[0010] In an embodiment, the AUC of Compound 1 by oral administration of the composition 0-24h,ssThe AUC of desfesoterodine becomes approximately 4,000 ng·h / mL to approximately 40,000 ng·h / mL after administration of the composition. In the embodiment, the AUC of desfesoterodine after oral administration of the composition is 0-24h,ss The C1:1 ratio of compound 1 to desfesoterodine after oral administration of the composition is approximately 20 ng·h / mL to approximately 600 ng·h / mL. In the embodiment, the plasma concentration ratio of compound 1 to desfesoterodine after oral administration of the composition is approximately 10:1 to approximately 200:1. In the embodiment, the plasma concentration ratio of compound 1 to desfesoterodine after oral administration of the composition is approximately 10:1 to approximately 800:1. In the embodiment, the C1:1 ratio of compound 1 to desfesoterodine after oral administration of the composition is approximately 20 ng·h / mL to approximately 600 ng·h / mL. max The ratio is approximately 50:1 to approximately 250:1. In the embodiment, oral administration of the composition is performed, with a ratio of 1 part compound to 1 part desfesoterodine. max The ratio will be approximately 50:1 to 600:1.

[0011] In embodiments, the Disclosure provides a composition comprising (a) about 40 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 1 mg to about 10 mg or about 3 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof; the composition, when tested for elution at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 12 hours; and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.2 to 8 hours. In embodiments, the Disclosure provides a composition comprising (a) about 40 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 1 mg to about 10 mg or about 3 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof; the composition, when tested for elution at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 18 hours; and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.2 to 8 hours.

[0012] In embodiments, the present disclosure provides a composition comprising (a) about 40 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof; the composition, when tested for elution at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 12 hours; and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.2 to 12 hours. In embodiments, the Disclosure provides a composition comprising (a) about 40 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof; the composition, when tested for elution at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 18 hours; and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.2 to 12 hours.

[0013] In embodiments, the composition contains about 50 mg to about 600 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 100 mg to about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 150 mg to about 350 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 200 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 100 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 100 mg to about 200 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 250 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 105 mg, about 165 mg, or about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0014] In embodiments, the composition contains about 3 mg to about 12 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 1.5 mg to about 3 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 3 mg to about 9 mg of fesoterodine or a pharmaceutically acceptable salt thereof.

[0015] In the embodiments, the composition contains fesoterodine fumarate. In the embodiments, the weight percentage ratio of compound 1 to fesoterodine in the composition is about 40:1 to about 90:1. In the embodiments, the weight percentage ratio of compound 1 to fesoterodine in the composition is about 20:1 to about 40:1 (wt.%). In the embodiments, the weight percentage ratio of compound 1 to fesoterodine in the composition is about 46:1, or about 55:1, or about 70:1 (wt.%).

[0016] In embodiments, the compositions of the present disclosure are formulated as tablets. In embodiments, the tablets comprise a sustained-release (ER) moiety containing compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the tablets comprise a sustained-release (ER) moiety containing fesoterodine or a pharmaceutically acceptable salt thereof.

[0017] In embodiments, the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof and a sustained-release (ER) portion containing fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the tablet of the present disclosure comprises (a) a first ER portion containing compound 1 or a pharmaceutically acceptable salt thereof; or (b) a second ER portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the first and second portions constitute a bilayer tablet. In embodiments, when the tablet is tested for dissolution at 37°C in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), it releases approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 12 hours, and approximately 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 1 to 7 hours or 5 to 12 hours. In the embodiment, when the tablets were tested for dissolution in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer at 37°C using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), they released approximately 80% of compound 1 or a pharmaceutically acceptable salt within 2 to 18 hours, and approximately 80% of fesoterodine or a pharmaceutically acceptable salt within 1 to 7 hours or 5 to 12 hours.

[0018] In embodiments, the tablet comprises an immediate-release (IR) portion containing fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the tablet of the present disclosure comprises (a) an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof; or (b) an IR portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion constitute a bilayer tablet. In embodiments, when the tablet is tested for dissolution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, it releases approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 10 hours, and approximately 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.1 to 1 hour.

[0019] In the embodiment, the tablet further comprises a stabilizer, a controlled-release excipient, a lubricant, a diluent, or a mixture thereof.

[0020] In embodiments, the stabilizer is xylitol, sorbitol, polydextrose, isomalt, dextrose, microcrystalline cellulose (MCC), fructose, or a mixture thereof. In embodiments, the stabilizer is xylitol, fructose, or a mixture thereof. In embodiments, the weight % ratio of fesoterodine or its pharmaceutically acceptable salt to the stabilizer is about 1:20 to about 1:1 in the tablet. In embodiments, the weight % ratio of fesoterodine or its pharmaceutically acceptable salt to xylitol or fructose is about 1:9 to about 1:1 in the tablet. In embodiments, the weight % ratio of fesoterodine or its pharmaceutically acceptable salt to xylitol or fructose is about 1:50 to about 1:1 in the tablet. In embodiments, the weight % ratio of fesoterodine or its pharmaceutically acceptable salt to xylitol or fructose is about 1:39 in the tablet. In the embodiment, the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt thereof to xylitol or fructose is approximately 18:1 in the tablet.

[0021] In the embodiment, the lubricant is talc, silicon dioxide, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof. In the embodiment, the lubricant is talc, glyceryl behenate, silicon dioxide, magnesium stearate, or a mixture thereof.

[0022] In the embodiments, the controlled-release excipient is polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, or a mixture thereof.

[0023] In the embodiment, the diluent is microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, or a mixture thereof.

[0024] In embodiments, the tablets of the present disclosure further comprise lactose, sodium starch glycolate, croscarmellose sodium, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or a mixture thereof.

[0025] In embodiments, the tablets of the present disclosure comprise a portion comprising compound 1 or a pharmaceutically acceptable salt thereof, the portion comprising about 20 wt.% to about 55 wt.% hydroxypropyl methylcellulose (HPMC); about 4 wt.% to about 50 wt.% microcrystalline cellulose; about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc. In embodiments, the portion comprises about 20 wt.% to about 55 wt.% hydroxypropyl methylcellulose (HPMC); about 4 wt.% to about 50 wt.% microcrystalline cellulose; about 2 wt.% to about 6 wt.% glyceryl behenate; about 1 wt.% to about 4 wt.% talc; and optionally about 4 wt.% to about 50 wt.% xylitol. In embodiments, the tablets of the present disclosure comprise a portion comprising compound 1 or a pharmaceutically acceptable salt thereof, the portion comprising about 40 wt.% to about 60 wt.% HPMC; about 20 wt.% to about 25 wt.% microcrystalline cellulose; about 5 wt.% to about 20 wt.% xylitol; and about 0.1 wt.% to about 0.4 wt.% magnesium stearate.

[0026] In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 10 wt.% to about 50 wt.% xylitol; about 50 wt.% to about 80 wt.% 75% lactose / 25% microcrystalline cellulose; about 3 wt.% to about 8 wt.% sodium starch glycolate; about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0027] In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 10 wt.% to about 50 wt.% xylitol; about 50 wt.% to about 80 wt.% 75% lactose / 25% microcrystalline cellulose; about 3 wt.% to about 8 wt.% croscarmellose sodium; about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0028] In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 10 wt.% to about 50 wt.% xylitol; about 50 wt.% to about 80 wt.% 75% lactose / 25% microcrystalline cellulose; about 3 wt.% to about 8 wt.% polyvinylpyrrolidone (PVP); about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0029] In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 10 wt.% to about 50 wt.% xylitol; about 10 wt.% to about 50 wt.% 75% lactose / 25% microcrystalline cellulose; about 10 wt.% to about 40 wt.% hydroxypropyl methylcellulose (HPMC); about 1 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0030] In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 8 wt.% to about 50 wt.% xylitol; about 10 wt.% to about 50 wt.% 75% lactose / 25% microcrystalline cellulose; about 20 wt.% to about 50 wt.% cellulose ether; about 1 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc. In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 8 wt.% to about 50 wt.% xylitol; about 10 wt.% to about 50 wt.% 75% lactose / 25% microcrystalline cellulose; about 10 wt.% to about 40 wt.% 80% polyvinyl acetate (PVA) / 19% povidone; about 1 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc. In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 10 wt.% to about 50 wt.% xylitol; about 10 wt.% to about 40 wt.% 75% lactose / 25% microcrystalline cellulose; about 20 wt.% to about 40 wt.% HPMC; about 1 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc. In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising approximately 10 wt.% to approximately 50 wt.% xylitol; approximately 20 wt.% to approximately 40 wt.% MCC; approximately 20 wt.% to approximately 40 wt.% HPMC; approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and approximately 1 wt.% to approximately 4 wt.% talc. In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 8 wt.% to about 20 wt.% xylitol; about 10 wt.% to about 40 wt.% 75% lactose / 25% microcrystalline cellulose; about 10 wt.% to about 30 wt.% lactose; about 10 wt.% to about 40 wt.% HPMC; about 1 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.In embodiments, the tablets of the present disclosure comprise a portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the portion comprising about 10 wt.% to about 40 wt.% xylitol; about 10 wt.% to about 20 wt.% lactose; about 10 wt.% to about 40 wt.% MCC; about 20 wt.% to about 40 wt.% HPMC; about 1 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0031] In embodiments, the disclosure comprises a sustained-release (ER) moiety containing compound 1 or a pharmaceutically acceptable salt thereof; and an immediate-release (IR) coating containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on the ER moiety. In embodiments, the IR coating comprises HPMC, triacetin, titanium dioxide, xanthan gum, lecithin, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate, methacrylate copolymer, talc, or mixtures thereof.

[0032] In embodiments, the IR coating comprises (a) polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate 80, and talc; (b) HPMC, triacetin, and talc; (c) PVA, xylitol, PEG, polysorbate 80, and talc; (d) PVA, fructose, PEG, polysorbate 80, and talc; (e) a copolymer of PVA and PEG in a weight percentage ratio of 3:1; (f) HPMC; (g) HPMC and xylitol; or (h) HPMC and fructose.

[0033] In the embodiment, the IR coating consists of (a) about 40 wt.% to about 60 wt.% polyvinyl alcohol (PVA), about 10 wt.% to about 20 wt.% polyethylene glycol (PEG), about 1 wt.% to about 5 wt.% polysorbate 80, and about 20 wt.% to about 40 wt.% talc; (b) about 70 wt.% to about 85 wt.% HP (c) MC, approximately 5 wt.% to approximately 10 wt.% triacetin, and approximately 5 wt.% to approximately 10 wt.% talc; (c) approximately 25 wt.% to approximately 50 wt.% PVA, approximately 10 wt.% to approximately 40 wt.% xylitol, approximately 5 wt.% to approximately 20 wt.% PEG, approximately 1 wt.% to approximately 5 wt.% polysorbate 80, and approximately 10 wt.% to approximately 30 wt.% (d) Talc; (e) Approximately 20 wt.% to 40 wt.% of PVA, approximately 30 wt.% to 40 wt.% of fructose, approximately 5 wt.% to 15 wt.% of PEG, approximately 1 wt.% to 3 wt.% of polysorbate 80, and approximately 10 wt.% to 25 wt.% of talc; (f) Polyvinyl alcohol and polyethylene in a 3:1 wt.% ratio in the coating. (f) a glycol copolymer of approximately 85 wt.% to 95 wt.%; (g) approximately 65 wt.% to 95 wt.% HPMC; (h) approximately 40 wt.% to 60 wt.% HPMC and approximately 30 wt.% to 45 wt.% xylitol; or (h) approximately 40 wt.% to 60 wt.% HPMC and approximately 30 wt.% to 45 wt.% fructose.

[0034] In the embodiment, when the IR coating was tested at 37°C in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer using a US Pharmacopeia apparatus II (paddle speed 50 rpm), it released 80% of the fesoterodine within 0.5 to 2 hours.

[0035] In embodiments, the present disclosure provides a method for treating dyskinesia in a patient requiring treatment for dyskinesia, the method comprising administering a therapeutically effective amount of the composition of the present disclosure to the patient requiring treatment. In embodiments, the dyskinesia is levodopa-induced dyskinesia. In embodiments, the patient has been diagnosed with Parkinson's disease. In embodiments, the dyskinesia is tardive dyskinesia.

[0036] In embodiments, the present disclosure provides a method for treating schizophrenia in a patient requiring treatment for schizophrenia, the method comprising administering a therapeutically effective amount of the composition of the present disclosure to the patient requiring treatment.

[0037] In embodiments, the present disclosure provides a method for treating Alzheimer's disease in a patient requiring treatment for Alzheimer's disease, the method comprising administering a therapeutically effective amount of the composition of the present disclosure to the patient requiring treatment. [Brief explanation of the drawing]

[0038] [Figure 1A] The observed and predicted Cmax values ​​after administration of 1 mg, 3 mg, 10 mg, 20 mg, 40 mg, and 60 mg of Compound 1, as described in Example 1, are shown. [Figure 1B] The observed and predicted AUCinf values ​​are shown after administration of 1 mg, 3 mg, 10 mg, 20 mg, 40 mg, and 60 mg of Compound 1, as described in Example 1. [Figure 2] The Cmax and AUC0-8 curves after administering compound 1 as described in Example 1 are shown. [Figure 3A] The mean plasma concentration (ng / mL) of compound 1 after administering 20 mg of compound 1 as described in Example 1 is shown. [Figure 3B] The mean plasma concentration (ng / mL) of compound 1 after administering 40 mg of compound 1 as described in Example 1 is shown. [Figure 3C] The mean plasma concentration (ng / mL) of compound 1 after administering 60 mg of compound 1 as described in Example 1 is shown. [Figure 4A] The mean plasma concentrations (ng / mL) of compound 1 after administration of compound 1 and 8 mg of fesoterodine (immediate-release) as described in Example 1 are shown. [Figure 4B] The mean plasma concentration (ng / mL) of 5-hydroxymethyltolterodine (5-HMT) after administration of fesoterodine, as described in Example 1, is shown. [Figure 4C]The mean plasma concentrations (ng / mL) of 5-HMT after administration of fesoterodine and compound 1, as described in Example 1, are shown. [Figure 5A] The mean plasma concentration (ng / mL) of 5-HMT after administration of fesoterodine as described in Example 1 is shown. [Figure 5B] The mean plasma concentrations (ng / mL) of 5-HMT after co-administration of 40 mg of compound 1 and 1 mg of fesoterodine as described in Example 1 are shown. [Figure 6A] The mean plasma concentrations (ng / mL) of compound 1 and 5-HMT after administration of 135 mg of compound 1 and 9 mg of fesoterodine as described in Example 1 are shown. [Figure 6B] The mean plasma concentrations (ng / mL) of compound 1 and 5-HMT after administration of 135 mg of compound 1 and 9 mg of fesoterodine, as described in Example 1, are shown. [Figure 7A] The mean plasma concentrations (ng / mL) of compound 1 and 5-HMT after administration of 90 mg of compound 1 and 6 mg of fesoterodine as described in Example 1 are shown. [Figure 7B] The mean plasma concentrations (ng / mL) of compound 1 and 5-HMT after administration of 60 mg of compound 1 and 6 mg of fesoterodine as described in Example 1 are shown. [Figure 8A] The predicted mean plasma concentration (ng / mL) of compound 1 after administering 200 mg of compound 1 and 12 mg of fesoterodine as described in Example 1 is shown. [Figure 8B] The predicted required and target mean plasma concentrations (ng / mL) of Compound 1 after administration of 300 mg and 436 mg of Compound 1 BID as described in Example 1 are shown. [Figure 9A] The predicted mean plasma concentrations (ng / mL) of compound 1(C1) and 5-HMT after administration of 300 mg of compound 1 (sustained-release) and 3 mg of fesoterodine (immediate-release) BID as described in Example 1 are shown. [Figure 9B]The predicted mean plasma concentrations (ng / mL) of compound 1(C1) and 5-HMT after administration of 250 mg of compound 1 and 6 mg of fesoterodine (12-hour sustained-release) BID as described in Example 1 are shown. [Figure 9C] The predicted mean plasma concentrations (ng / mL) of compound 1(C1) and 5-HMT after administration of 436 mg of compound 1 and 9.9 mg of fesoterodine (8-hour sustained-release) as described in Example 1 are shown. [Figure 10A] This shows the elution rate (%) of compound 1 over time for a specific test composition. Test composition: Compound 1 composition containing 50% HPMC; 50% PEO; or 25% HPMC / 25% PEO. [Figure 10B] This shows the elution rate (%) of compound 1 over time for a specific test composition. Test composition: A compound 1 composition containing 40 mg of compound 1 or 250 mg of compound 1. [Figure 10C] This shows the time course (%) of dissolution rate (%) of compound 1 for a specific test composition. Test composition: Compound 1 composition containing 50% HPMC in a 1000 mg tablet; 50% HPMC in an 1100 mg tablet; or 50% HPMC in a 1300 mg tablet. [Figure 10D] This shows the elution rate (%) of compound 1 over time for a specific test composition. Test compositions: Compound 1 composition containing 50% HPMC, no xylitol; 50% HPMC and 15% xylitol; or 50% HPMC and 25% xylitol. [Figure 10E] This shows the elution rate (%) of compound 1 over time for a specific test composition. Test composition: 50% HPMC and microcrystalline cellulose; or d: a compound 1 composition containing 50% HPMC and dicalcium phosphate. [Figure 10F] This shows the time course (%) of compound 1 for a specific test composition. Test compositions: 1000 mg tablets containing 50% PEO; 1100 mg tablets containing 50% PEO; and 1300 mg tablets containing 50% PEO. [Figure 10G]This shows the elution rate (%) of compound 1 over time for a specific test composition. Test composition: compound 1 composition containing 50% PEO, no xylitol; or 50% PEO and 23% xylitol. [Figure 11] The typical manufacturing process for compound 1 sustained-release tablets (40 mg and 125 mg) is shown. [Figure 12] Figure 11 shows the dissolution rate (%) of the tablets over time. [Figure 13A] Figure 11 shows the dissolution rate (%) of one 40 mg tablet of compound measured by USP2 and USP3 methods. [Figure 13B] Figure 11 shows the dissolution rate (%) of one 125 mg tablet of compound measured by USP2 and USP3 methods. [Figure 14A] This shows the time course (%) of dissolution of compound 1 from compound 1 / fesoterodine ER / IR bilayer tablet formulations. [Figure 14B] Table 5 in Example 4 shows the elution rates (%) of Compound 1 and fesoterodine released from the ER / ER formulation. [Figure 15] The plasma concentration ratio of compound 1 to 5-HMT after oral administration of a composition containing 135 mg of compound 1 and 6 mg of fesoterodine, as described in Example 1, is shown. [Figure 16A] As described in Example 7, the mean distance traveled in a 30-minute open-field exercise test in amphetamine-treated mice after administration of compound 1 at 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg is shown. p<0.0001, one-way ANOVA. [Figure 16B] As described in Example 7, the changes in distance traveled in amphetamine-treated mice, measured by open-field exercise tests at 5-minute intervals after administration of compound 1 at 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg, are shown. p<0.0001, one-way ANOVA. [Figure 17A]As described in Example 8, the mean distance traveled in a 30-minute open-field exercise test in phencyclidine-treated mice after administration of compound 1 at 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg is shown. p<0.0001, one-way ANOVA. [Figure 17B] As described in Example 8, the changes in distance traveled in phencyclidine-treated mice, measured by open-field exercise tests at 5-minute intervals after administration of compound 1 at 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg, are shown. p<0.0001, one-way ANOVA. [Modes for carrying out the invention]

[0039] definition Throughout this disclosure, various patents, patent applications, and publications (including non-patent publications) are referenced. The disclosures of these patents, patent applications, and publications are incorporated into this disclosure by reference for any purpose to more fully illustrate the highest standards known to those skilled in the art as of the date of this disclosure. In the event of any inconsistency between the cited patents, patent applications, and publications and this disclosure, this disclosure shall prevail.

[0040] For convenience, certain terms used in this specification, examples, and claims are summarized here. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains.

[0041] The term “approximately” preceding a number means a range (e.g., ±10% of that value). For example, unless the context of this disclosure indicates otherwise, or unless such interpretation is inconsistent, “approximately 50” could mean 45–55, and “approximately 25,000” could mean 22,500–27,500. For example, in a list of numbers, e.g., “approximately 49, approximately 50, approximately 55,…”, “approximately 50” means a range that extends less than half the interval(s) between the preceding and succeeding values, e.g., greater than 49.5 and less than 52.5. Furthermore, expressions “approximately” “less than” a value or “approximately” “greater than” a value should be understood in light of the definition of the term “approximately” provided herein. Similarly, when the term “approximately” precedes a series of numbers or ranges of values ​​(e.g., “approximately 10, 20, 30” or “approximately 10–30”), it refers to all the values ​​in the series or the end point of the range, respectively.

[0042] As used herein, the term "compound 1" refers to the following structural formula:

[0043] [ka] This refers to 1-(3-methyl-[1,2,4]oxadiazole-5-yl)-(1R,5R)-3-azabicyclo[3.1.0]hexane having the following properties: In embodiments, this disclosure describes compound 1 or any pharmaceutically acceptable salt thereof.

[0044] As used herein, “fesoterodine” refers to 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenylisobutyrate, R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylisobutyrate, or R-(+)-isobutyrate 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester. In embodiments, this disclosure describes fesoterodine or any pharmaceutically acceptable salt thereof, e.g., fesoterodine fumarate, which is described in U.S. Patent Publications US2013 / 0287847A1 and US2010 / 0130606A1, which are incorporated herein by reference in their entirety.

[0045] As used herein, the term “pharmaceutically acceptable” means a compound, substance, composition, and / or dosage form that is suitable for use in contact with human and animal tissues, within the bounds of sound medical judgment, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit-to-risk ratio.

[0046] The term "part" refers to a region of the composition of this disclosure. In embodiments, a part is a layer, fragment, segment, granule, particle, or matrix. In embodiments, a part is a layer comprising compound 1 or a pharmaceutically acceptable salt thereof, or fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, a part is a matrix comprising compound 1 or a pharmaceutically acceptable salt thereof, or fesoterodine or a pharmaceutically acceptable salt thereof.

[0047] The term "therapeutic dose" refers to an amount of the compound or pharmaceutical composition described herein that is sufficient to affect the intended use, including but not limited to disease treatment, as exemplified below.

[0048] Where used herein in reference to a patient, the term “to treat” means to improve at least one symptom of the patient’s disorder (e.g., schizophrenia or Alzheimer’s disease psychosis). Treating may mean improving the disorder or achieving at least partial remission.

[0049] composition In embodiments, the present disclosure provides compositions comprising compound 1 or a pharmaceutically acceptable salt thereof and fesoterodine or a pharmaceutically acceptable salt thereof.

[0050] In embodiments, the composition of the present disclosure contains about 10 mg to about 800 mg of compound 1 or a pharmaceutically acceptable salt thereof, for example, about 10 mg, about 12 mg, about 14 mg, about 16 mg, about 18 mg, about 20 mg, about 22 mg, about 24 mg, about 26 mg, about 28 mg, about 30 mg, about 32 mg, about 34 mg, about 36 mg, about 38 mg, about 40 mg, about 42 mg, about 44 mg, about 46 mg, about 48 mg, about 50 mg, about 52 mg, about 54 mg, about 56 mg, about 58 mg, about 60 mg, about 62 mg, about 64 mg, about 66 mg, about 68 mg, about 70 mg, about 72 mg, about 74 mg mg, approx. 76 mg, approx. 78 mg, approx. 80 mg, approx. 82 mg, approx. 84 mg, approx. 86 mg, approx. 88 mg, approx. 90 mg, approx. 92 mg, approx. 94 mg, approx. 96 mg, approx. About 112mg, about 114mg, about 116mg, about 118mg, about 120mg, about 122mg, about 124mg, about 126mg, about 128mg, about 130mg, about 132mg, about 134mg, about 136mg, about 138mg, about 140mg, about 142mg, about 144mg, about 146mg Approximately 148mg, approximately 150mg, approximately 152mg, approximately 154mg, approximately 156mg, approximately 158mg, approximately 160mg, approximately 162mg, approximately 164mg, approximately 165mg, approximately 166mg, approximately 168mg, approximately 170mg, approximately 172mg, approximately 174mg, approximately 176mg, approximately 178mg, approximately 180mg, approximately 182mg, approximately 184mg, approximately 186mg, approximately 188mg, approximately 190mg, approximately 192mg, approximately 194mg, approximately 196mg, approximately 198mg, approximately 200mg, approximately 201mg, approximately 202mg, approximately 204mg, approximately 206mg, approximately 208mg, approximately 210mg, approximately 212mg, approximately 21 4mg, approx. 216mg, approx. 218mg, approx. 220mg, approx. 222mg, approx. 224mg, approx. 226mg, approx. 228mg, approx. 230mg, approx. 232mg, approx. 250mg, about 252mg, about 254mg, about 256mg, about 258mg, about 260mg, about 262mg, about 264mg, about 266mg, about 268mg, about 270mg, about 272mg, about 274mg, about 276mg, about 278mg, about 280mg, about 290mg, about 300mg,About 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 4 40mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570m g contains approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, or approximately 800 mg (including any value or range in between). In embodiments, the composition contains approximately 10 mg to approximately 500 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains approximately 10 mg to approximately 200 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0051] In embodiments, the composition contains about 105 mg, about 165 mg, or about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 105 mg, about 135 mg, about 165 mg, or about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 105 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 135 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 270 mg of compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 330 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0052] In embodiments, the composition of the present disclosure contains about 1 mg to about 50 mg of fesoterodine or a pharmaceutically acceptable salt thereof, for example, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, The composition contains approximately 19 mg, approximately 20 mg, approximately 21 mg, approximately 22 mg, approximately 23 mg, approximately 24 mg, approximately 25 mg, approximately 26 mg, approximately 27 mg, approximately 28 mg, approximately 29 mg, approximately 30 mg, approximately 31 mg, approximately 32 mg, approximately 33 mg, approximately 34 mg, approximately 35 mg, approximately 36 mg, approximately 37 mg, approximately 38 mg, approximately 39 mg, approximately 40 mg, 41 mg, approximately 42 mg, approximately 43 mg, approximately 44 mg, approximately 45 mg, approximately 46 mg, approximately 47 mg, approximately 48 mg, approximately 49 mg, or approximately 50 mg (including any value or range in between). In embodiments, the composition contains approximately 1 mg to approximately 30 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains approximately 1 mg to approximately 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 1.5 mg to about 3 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 1.5 mg, about 3 mg, or about 4.5 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 1.5 mg, about 3 mg, about 4.5 mg, or about 6 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 1.5 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 3 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition contains about 6 mg of fesoterodine or a pharmaceutically acceptable salt thereof.

[0053] In embodiments, the composition of the present disclosure comprises about 10 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and about 2 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 40 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and about 3 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof.

[0054] In some embodiments, the composition contains about 50 mg to about 600 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 100 mg to about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 150 mg to about 350 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 200 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 250 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0055] In embodiments, the composition of the present disclosure comprises about 100 mg to about 200 mg of compound 1 or a pharmaceutically acceptable salt thereof; and about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof. The composition of the present disclosure comprises about 100 mg to about 200 mg of compound 1 or a pharmaceutically acceptable salt thereof; and about 1 mg to about 5 mg of fesoterodine or a pharmaceutically acceptable salt thereof.

[0056] In embodiments, the composition of the present disclosure comprises about 3 mg to about 8 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 3 mg to about 12 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 1 mg to about 5 mg of fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises fesoterodine fumarate.

[0057] In embodiments, the compositions of the present disclosure contain compound 1 and fesoterodine in a ratio of about 5:1 to about 100:1, for example, about 5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 12:1, about 14:1, about 16:1, about 18:1, about 20:1, about 22:1, about 24:1, about 26:1, about 28:1, about 30:1, about 32:1, about 34:1, about 36:1, about 38:1, about 40:1, about 42:1, about 44:1, about 46:1, about 48 It is included in weight % ratios of 1:1, approximately 50:1, approximately 52:1, approximately 54:1, approximately 56:1, approximately 58:1, approximately 60:1, approximately 62:1, approximately 64:1, approximately 66:1, approximately 68:1, approximately 70:1, approximately 72:1, approximately 74:1, approximately 76:1, approximately 78:1, approximately 80:1, approximately 82:1, approximately 84:1, approximately 86:1, approximately 88:1, approximately 90:1, approximately 92:1, approximately 94:1, approximately 96:1, approximately 98:1, or approximately 100:1 (including any value or range in between). In embodiments, the weight % ratio of compound 1 to fesoterodine in the composition is approximately 40:1 to approximately 90:1. In embodiments, the weight % ratio of compound 1 to fesoterodine in the composition is approximately 20:1 to approximately 40:1. In the embodiments, the weight percentage ratio of compound 1 to fesoterodine in the composition is about 5:1 to about 15:1. In the embodiments, the weight percentage ratio of compound 1 to fesoterodine in the composition is about 55:1 to about 70:1. In the embodiments, the weight percentage ratio of compound 1 to fesoterodine in the composition is about 46:1 to about 70:1.

[0058] In embodiments, oral administration of the compositions disclosed herein results in substantially the same T with respect to desfesoterodine and compound 1. max In embodiments, the composition of the present disclosure comprises about 10 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and about 2 mg to about 20 mg or about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof, wherein oral administration of the composition results in the t maxThis ranges from approximately 0.1 hours to approximately 18 hours (for example, approximately 0.1 hours to approximately 12 hours), for example, approximately 0.1 hours, approximately 0.2 hours, approximately 0.3 hours, approximately 0.4 hours, approximately 0.5 hours, approximately 0.6 hours, approximately 0.7 hours, approximately 0.8 hours, approximately 0.9 hours, approximately 1.0 hours, approximately 1.2 hours, approximately 1.4 hours, approximately 1.6 hours, approximately 1.8 hours, approximately 2.0 hours, approximately 2.2 hours, approximately 2.4 hours, approximately 2.6 hours, approximately 2.8 hours, approximately 3.0 hours, approximately 3.2 hours, approximately 3.4 hours, and approximately 3.6 hours. Approximately 3.8 hours, approximately 4.0 hours, approximately 4.2 hours, approximately 4.4 hours, approximately 4.6 hours, approximately 4.8 hours, approximately 5.0 hours, approximately 5.2 hours, approximately 5.4 hours, approximately 5.6 hours, approximately 5.8 hours, approximately 6.0 hours, approximately 6.2 hours, approximately 6.4 hours, approximately 6.6 hours, approximately 6.8 hours, approximately 7.0 hours, approximately 7.2 hours, approximately 7.4 hours, approximately 7.6 hours, approximately 7.8 hours, approximately 8.0 hours, approximately 8.2 hours, approximately 8.4 hours, approximately 8.6 hours, approximately 8.8 hours, approximately 9.0 hours, approximately 9.2 hours. Approximately 9.4 hours, approximately 9.6 hours, approximately 9.8 hours, approximately 10.0 hours, approximately 10.2 hours, approximately 10.4 hours, approximately 10.6 hours, approximately 10.8 hours, approximately 11.0 hours, approximately 11.2 hours, approximately 11.4 hours, approximately 11.6 hours, approximately 11.8 hours, approximately 12.0 hours, approximately 12.2 hours, approximately 12.4 hours, approximately 12.6 hours, approximately 12.8 hours, approximately 13.0 hours, approximately 13.2 hours, approximately 13.4 hours, approximately 13.6 hours, approximately 13.8 hours, approximately 14.0 hours, approximately 14.2 hours, Approximately 14.4 hours, approximately 14.6 hours, approximately 14.8 hours, approximately 15.0 hours, approximately 15.2 hours, approximately 15.4 hours, approximately 15.6 hours, approximately 15.8 hours, approximately 16.0 hours, approximately 16.2 hours, approximately 16.4 hours, approximately 16.6 hours, approximately 16.8 hours, approximately 17.0 hours, approximately 17.2 hours, approximately 17.4 hours, approximately 17.6 hours, approximately 17.8 hours, or approximately 18.0 hours (including any value or range in between), and the t of desfesoterodine (i.e., 5-HMT). maxThis ranges from approximately 0.1 hours to approximately 12 hours, for example, approximately 0.1 hours, approximately 0.2 hours, approximately 0.3 hours, approximately 0.4 hours, approximately 0.5 hours, approximately 0.6 hours, approximately 0.7 hours, approximately 0.8 hours, approximately 0.9 hours, approximately 1.0 hours, approximately 1.2 hours, approximately 1.4 hours, approximately 1.6 hours, approximately 1.8 hours, approximately 2.0 hours, approximately 2.2 hours, approximately 2.4 hours, approximately 2.6 hours, approximately 2.8 hours, approximately 3.0 hours, approximately 3.2 hours, approximately 3.4 hours, approximately 3.6 hours, approximately 3.8 hours, approximately 4.0 hours, approximately 4.2 hours, approximately 4.4 hours, approximately 4.6 hours, approximately 4.8 hours, approximately 5.0 hours, approximately 5.2 hours, approximately 5.4 hours, approximately 5.6 hours, approximately 5.8 The time will be approximately 6.0 hours, 6.2 hours, 6.4 hours, 6.6 hours, 6.8 hours, 7.0 hours, 7.2 hours, 7.4 hours, 7.6 hours, 7.8 hours, 8.0 hours, 8.2 hours, 8.4 hours, 8.6 hours, 8.8 hours, 9.0 hours, 9.2 hours, 9.4 hours, 9.6 hours, 9.8 hours, 10.0 hours, 10.2 hours, 10.4 hours, 10.6 hours, 10.8 hours, 11.0 hours, 11.2 hours, 11.4 hours, 11.6 hours, 11.8 hours, or 12.0 hours (including any value or range in between).

[0059] In the embodiment, the t of compound 1 is obtained by oral administration of the composition. max This occurs approximately 0.5 hours to approximately 4 hours after administration of the composition. In the embodiment, the t of compound 1 is obtained by oral administration of the composition. max The time intervals after administration of the composition are approximately 0.5 hours to 10 hours, 1 hour to 10 hours, 1.5 hours to 10 hours, 1.5 hours to 8 hours, 2 hours to 8 hours, 3 hours to 6 hours, or 3 hours to 4 hours.

[0060] In this embodiment, the oral administration of the composition results in the t of desfesoterodine. max This occurs approximately 0.5 hours to 4 hours after administration of the composition. In the embodiment, the t of desfesoterodine is obtained by oral administration of the composition. max The time intervals after administration of the composition are approximately 0.1 hours to 10 hours, 0.5 hours to 10 hours, 1 hour to 10 hours, 1 hour to 8 hours, 2 hours to 6 hours, 3 hours to 6 hours, or 3 hours to 4 hours.

[0061] In the embodiment, the C of compound 1 is obtained by oral administration of the composition. max,ss After administration of the composition, the glycemic index (NG) ranges from approximately 200 ng / mL to approximately 5,000 ng / mL, for example, approximately 200 ng / mL, approximately 250 ng / mL, approximately 300 ng / mL, approximately 350 ng / mL, approximately 400 ng / mL, approximately 450 ng / mL, approximately 500 ng / mL, approximately 550 ng / mL, approximately 600 ng / mL, approximately 650 ng / mL, approximately 700 ng / mL, approximately 750 ng / mL, approximately 800 ng / mL, and so on. 850ng / mL, approximately 900ng / mL, approximately 950ng / mL, approximately 1000ng / mL, approximately 1100ng / mL, approximately 1200ng / mL, approximately 1300ng / mL, approximately 1400ng / mL, Approx. 1500ng / mL, approx. 1600ng / mL, approx. 1700ng / mL, approx. 1800ng / mL, approx. 1900ng / mL, approx. 2000ng / mL, approx. 2100ng / mL, approx. 2200ng / mL, approx. 2300ng / mL, approx. 2400ng / mL, approx. 2500ng / mL, approx. 2600ng / mL, approx. 2700ng / mL, approx. 2800ng / mL, approx. 2900ng / mL, approx. 30 00ng / mL, approximately 3100ng / mL, approximately 3200ng / mL, approximately 3300ng / mL, approximately 3400ng / mL, approximately 3500ng / mL, approximately 3600ng / mL, approximately 3700ng / mL The C2000 ng / mL of the composition is approximately 3800 ng / mL, approximately 3900 ng / mL, approximately 4000 ng / mL, approximately 4100 ng / mL, approximately 4200 ng / mL, approximately 4300 ng / mL, approximately 4400 ng / mL, approximately 4500 ng / mL, approximately 4600 ng / mL, approximately 4700 ng / mL, approximately 4800 ng / mL, approximately 4900 ng / mL, or approximately 5000 ng / mL (including any value or range in between). In the embodiment, oral administration of the composition results in C2000 ng / mL of desfesoterodine. max,ssAfter administration of the composition, the concentration ranges from approximately 2 ng / mL to approximately 60 ng / mL, for example, approximately 2 ng / mL, approximately 3 mg / mL, approximately 4 ng / mL, approximately 5 mg / mL, approximately 6 ng / mL, 7 ng / mL, approximately 8 ng / mL, approximately 9 mg / mL, approximately 10 ng / mL, approximately 11 mg / mL, approximately 12 ng / mL, approximately 13 mg / mL, approximately 14 ng / mL, approximately 15 mg / mL, approximately 16 ng / mL, 17 ng / mL, approximately 18 ng / mL, approximately 19 mg / mL, approximately 20 ng / mL, approximately 22 mg / mL This can be approximately mL, 24 ng / mL, 26 mg / mL, 28 ng / mL, 30 mg / mL, 32 mg / mL, 34 ng / mL, 36 mg / mL, 38 ng / mL, 40 mg / mL, 42 mg / mL, 44 ng / mL, 46 mg / mL, 48 ng / mL, 50 mg / mL, 52 mg / mL, 54 ng / mL, 56 mg / mL, 58 ng / mL, or 60 mg / mL (including any value or range in between).

[0062] In this embodiment, the steady state C of compound 1 is reached by oral administration of the composition. min (C min,ss ) is present over approximately 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, or 18 hours after administration of the composition, ranging from approximately 50 ng / mL to approximately 1,000 ng / mL, for example, approximately 50 ng / mL, approximately 60 ng / mL, approximately 80 ng / mL, approximately 100 ng / mL, approximately 120 ng / mL, approximately 140 ng / mL, approximately 150 ng / mL, approximately 160 ng / mL, approximately 180 ng / mL, approximately 200 ng / mL, approximately 250 ng / mL. This can be g / mL, approximately 300 ng / mL, approximately 350 ng / mL, approximately 400 ng / mL, approximately 450 ng / mL, approximately 500 ng / mL, approximately 550 ng / mL, approximately 600 ng / mL, approximately 650 ng / mL, approximately 700 ng / mL, approximately 750 ng / mL, approximately 800 ng / mL, approximately 850 ng / mL, approximately 900 ng / mL, approximately 950 ng / mL, or approximately 1000 ng / mL (including any value or range in between).

[0063] In the embodiment, the AUC of compound 1 after oral administration of the composition is 0-24h,ssAfter administration of the composition, the blood glucose level ranges from approximately 4,000 ng·h / mL to approximately 80,000 ng·h / mL, for example, approximately 4,000 ng·h / mL, approximately 5,000 ng·h / mL, approximately 6,000 ng·h / mL, approximately 7,000 ng·h / mL, approximately 8,000 ng·h / mL, approximately 9,000 ng·h / mL, approximately 10,000 ng·h / mL, approximately 11,000 ng·h / mL, approximately 12,000 ng·h / mL, approximately 13,000 ng·h / mL. Approximately 14,000ng·h / mL, Approximately 15,000ng·h / mL, 16,000ng·h / mL, Approximately 17,000ng·h / mL, Approximately 18,000ng·h / mL, Approximately 19,000ng·h / mL, Approximately 20,000ng·h / mL, approximately 21,000ng·h / mL, approximately 22,000ng·h / mL, approximately 23,000ng·h / mL, approximately 24,000ng·h / mL, approximately 25,000ng·h / mL, 26 ,000ng·h / mL, approximately 27,000ng·h / mL, approximately 28,000ng·h / mL, approximately 29,000ng·h / mL, approximately 30,000ng·h / mL, 31,000ng·h / mL, approximately 32, 000ng·h / mL, approximately 33,000ng·h / mL, approximately 34,000ng·h / mL, approximately 35,000ng·h / mL, 36,000ng·h / mL, approximately 37,000ng·h / mL, approximately 38,00 The values ​​are 0 ng·h / mL, approximately 39,000 ng·h / mL, approximately 40,000 ng·h / mL, 45,000 ng·h / mL, approximately 50,000 ng·h / mL, approximately 55,000 ng·h / mL, approximately 60,000 ng·h / mL, approximately 65,000 ng·h / mL, 70,000 ng·h / mL, approximately 75,000 ng·h / mL, or approximately 80,000 ng·h / mL (including any value or range in between). In embodiments, the AUC of compound 1 after oral administration of the composition is measured. 0-24h,ss The concentration becomes approximately 4,000 ng·h / mL to approximately 40,000 ng·h / mL after administration of the composition.

[0064] In one embodiment, the AUC of desfesoterodine after oral administration of the composition. 0-24h,ssAfter administration of the composition, the concentration ranges from approximately 20 ng·h / mL to approximately 1000 ng·h / mL, for example, approximately 20 ng·h / mL, approximately 30 ng·h / mL, approximately 40 ng·h / mL, approximately 50 ng·h / mL, approximately 60 ng·h / mL, approximately 70 ng·h / mL, approximately 80 ng·h / mL, approximately 90 ng·h / mL, approximately 100 ng·h / mL, approximately 120 ng·h / mL, approximately 140 ng·h / mL, approximately 160 ng·h / mL, and approximately 180ng·h / mL, approximately 200ng·h / mL, approximately 220ng·h / mL, approximately 240ng·h / mL, approximately 260ng·h / mL, approximately 280ng·h / mL, approximately 300ng·h / mL, approximately 320n g h / mL, approx. 340 ng h / mL, approx. 360 ng h / mL, approx. 380 ng h / mL, approx. 400 ng h / mL, approx. 420 ng h / mL, approx. 440 ng h / mL, approx. 460 ng h / mL, approx. 480ng h / mL, approx. 500ng h / mL, approx. 520 ng h / mL, approx. 540 ng h / mL, approx. 560 ng h / mL, approx. 580 ng h / mL, approx. 600 ng h / mL, approx. 620ng·h / mL, approximately 640ng·h / mL, approximately 660ng·h / mL, approximately 680ng·h / mL, approximately 700ng·h / mL, approximately 720ng·h / mL, approximately 740ng·h / mL, approximately 760n This can be g·h / mL, approximately 780 ng·h / mL, approximately 800 ng·h / mL, approximately 820 ng·h / mL, approximately 840 ng·h / mL, approximately 860 ng·h / mL, approximately 880 ng·h / mL, approximately 900 ng·h / mL, approximately 920 ng·h / mL, approximately 940 ng·h / mL, approximately 960 ng·h / mL, approximately 980 ng·h / mL, or approximately 1000 ng·h / mL (including any value or range in between).

[0065] In the embodiment, the plasma concentration ratio of compound 1 to desfesoterodine after oral administration is approximately 10:1 to approximately 1000:1, for example, approximately 10:1, approximately 11:1, approximately 12:1, approximately 13:1, approximately 14:1, approximately 15:1, approximately 16:1, approximately 17:1, approximately 18:1, approximately 19:1, approximately 20:1, approximately 21:1, approximately 22:1, approximately 23:1, approximately 24:1, approximately 25:1, approximately 26:1, approximately 27:1, approximately 28:1, approximately 29:1, approximately 30:1, approximately 31:1, approximately 32:1, approximately 33:1, approximately 34:1, approximately 35:1, approximately 36:1, approximately 37:1, approximately 38:1, approximately 39:1, approximately 40:1, approximately 4 1:1, approximately 42:1, approximately 43:1, approximately 44:1, approximately 45:1, approximately 46:1, approximately 47:1, approximately 48:1, approximately 49:1, approximately 50:1, approximately 51:1, approximately 52:1, approximately 53:1, approximately 54:1, approximately 55:1, approximately 56:1, approximately 57:1, approximately 58:1, approximately 59:1, approximately 60:1, approximately 61: 1, approximately 62:1, approximately 63:1, approximately 64:1, approximately 65:1, approximately 66:1, approximately 67:1, approximately 68:1, approximately 69:1, approximately 70:1, approximately 71:1, approximately 72:1, approximately 73:1, approximately 74:1, approximately 75:1, approximately 76:1, approximately 77:1, approximately 78:1, approximately 79:1, approximately 80:1, approximately 81:1, approximately 82:1, approximately 83:1, approximately 84:1, approximately 85:1, approximately 86:1, approximately 87:1, approximately 88:1, approximately 89:1, approximately 90:1, approximately 91:1, approximately 92:1, approximately 93:1, approximately 94:1, approximately 95:1, approximately 96:1, approximately 97:1, approximately 98:1, approximately 99:1, approximately 100:1, approximately 110:1, approximately 120:1, approximately 130:1, approximately 140:1, approximately 150:1, approximately 160:1, approximately 170:1, approximately 180:1, approximately 190:1, approximately 200:1, approximately 210:1, approximately 220:1, approximately 230:1, approximately 240:1, approximately 250:1, approximately 260:1, approximately 270:1, approximately 280:1, approximately 290 :1, approximately 300:1, approximately 310:1, approximately 320:1, approximately 330:1, approximately 340:1, approximately 350:1, approximately 360:1, approximately 370:1, approximately 380:1, approximately 390:1, approximately 400:1, approximately 410:1, approximately 420:1, approximately 430:1, approximately 440:1, approximately 450:1, approximately 460:1, approximately 470:1, approximately 480:1, approximately 490:1, approximately 500:1, approximately 550:1, approximately 600:1, approximately 650:1, approximately 700:1, approximately 750:1, approximately 800:1, approximately 850:1, approximately 900:1, approximately 950:1, or approximately 1000:1 (including all values ​​and ranges in between).In the embodiment, the plasma concentration ratio of compound 1 to desfesoterodine after administration is approximately 10:1 to approximately 200:1. In the embodiment, the plasma concentration ratio of compound 1 to desfesoterodine after administration is approximately 100:1 to approximately 250:1. In the embodiment, the plasma concentration ratio of compound 1 to desfesoterodine after administration is approximately 100:1 to approximately 800:1. In the embodiment, the plasma concentration ratio of compound 1 to desfesoterodine after administration is approximately 100:1 to approximately 600:1.

[0066] In the embodiment, the C of compound 1 to desfesoterodine is administered. maxThe ratio is approximately 20:1 to 800:1 or 20:1 to 500:1, for example, approximately 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1, 31:1, 32:1, 33:1, 34:1 , approximately 35:1, approximately 36:1, approximately 37:1, approximately 38:1, approximately 39:1, approximately 40:1, approximately 41:1, approximately 42:1, approximately 43:1, approximately 44:1, approximately 45:1, approximately 46:1, approximately 47:1, approximately 48:1, approximately 49:1, approximately 50:1, approximately 51:1, approximately 52:1, approximately 53:1, approximately 54:1, approximately 55: 1, approximately 56:1, approximately 57:1, approximately 58:1, approximately 59:1, approximately 60:1, approximately 61:1, approximately 62:1, approximately 63:1, approximately 64:1, approximately 65:1, approximately 66:1, approximately 67:1, approximately 68:1, approximately 69:1, approximately 70:1, approximately 71:1, approximately 72:1, approximately 73:1, approximately 74:1, approximately 75:1, approximately 76 :1, approximately 77:1, approximately 78:1, approximately 79:1, approximately 80:1, approximately 81:1, approximately 82:1, approximately 83:1, approximately 84:1, approximately 85:1, approximately 86:1, approximately 87:1, approximately 88:1, approximately 89:1, approximately 90:1, approximately 91:1, approximately 92:1, approximately 93:1, approximately 94:1, approximately 95:1, approximately 96:1, approximately 9 7:1, approximately 98:1, approximately 99:1, approximately 100:1, approximately 110:1, approximately 120:1, approximately 130:1, approximately 140:1, approximately 150:1, approximately 160:1, approximately 170:1, approximately 180:1, approximately 190:1, approximately 200:1, approximately 210:1, approximately 220:1, approximately 230:1, approximately 240:1, approximately 25 0:1, approximately 260:1, approximately 270:1, approximately 280:1, approximately 290:1, approximately 300:1, approximately 310:1, approximately 320:1, approximately 330:1, approximately 340:1, approximately 350:1, approximately 360:1, approximately 370:1, approximately 380:1, approximately 390:1, approximately 400:1, approximately 410:1, approximately 420:1, approximately 4 30:1, approximately 440:1, approximately 450:1, approximately 460:1, approximately 470:1, approximately 480:1, approximately 490:1, approximately 500:1, approximately 510:1, approximately 520:1, approximately 530:1, approximately 540:1, approximately 550:1, approximately 560:1, approximately 570:1, approximately 580:1, approximately 590:1, approximately 600:1, approximately 610:1, approximately 620:1, approximately 630:1, approximately 640:1, approximately 650:1, approximately 660:1, approximately 670:1, approximately 680:1, approximately 690:1, approximately 700:1, approximately 710:1, approximately 720:1, approximately 730:1, approximately 740:1, approximately 750:1, approximately 760:1, approximately 770:1, approximately 780:1,The ratio is approximately 790:1, or approximately 800:1 (including all values ​​and ranges in between). In the embodiment, the ratio of compound 1 to desfesoterodine C, max The ratio is approximately 50:1 to approximately 250:1. In the embodiment, oral administration of the composition is performed, with a ratio of 1 part compound to 1 part desfesoterodine. max The ratio is approximately 50:1 to approximately 800:1. In the embodiment, oral administration of the composition is performed, and the ratio of compound 1 to desfesoterodine C max The ratio will be approximately 50:1 to 500:1.

[0067] In embodiments, the composition of the present disclosure comprises about 40 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and about 3 mg to about 20 mg or about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof; the composition is prepared by discharging 900 mL of 0.1N using a United States Pharmacopeia apparatus II (paddle speed 50 rpm). When elution is tested in HCl or pH 6.8 phosphate buffer at 37°C, approximately 80% of compound 1 or its pharmaceutically acceptable salt is released within 2 to 20 hours, 2 to 18 hours, or 2 to 12 hours (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 hours (including any value or range in between)), and approximately 80% of fesoterodine or its pharmaceutically acceptable salt is released within 0.2 to 8 hours (e.g., 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, or 8 hours (including any value or range in between)).

[0068] In embodiments, the compositions of the present disclosure are formulated as tablets. In embodiments, the tablets comprise a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof. In embodiments, the tablets comprise a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof and a sustained-release (ER) portion containing fesoterodine or a pharmaceutically acceptable salt thereof. In embodiments, the tablets of the present disclosure comprise a first ER portion containing compound 1 or a pharmaceutically acceptable salt thereof; and a second ER portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the first and second portions constitute a bilayer tablet.

[0069] In the embodiment, the ER / ER tablet releases fesoterodine or a pharmaceutically acceptable salt thereof (an anticholinergic agent) into the peripheral system before or simultaneously with the release of compound 1, thereby reducing the peripheral cholinergic effect of compound 1. In the embodiment, when the tablet is tested for dissolution at 37°C in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer using a US Pharmacopeia apparatus II (paddle speed 50 rpm), approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof is released within 2 to 20 hours, 2 to 18 hours, 2 to 12 hours, or 5 to 18 hours (for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, or 20 hours (any value in between)). In embodiments, the ER / ER tablet releases fesoterodine or a pharmaceutically acceptable salt thereof (an anticholinergic agent) into the peripheral system before or simultaneously with the release of compound 1, thereby reducing the peripheral cholinergic effect of compound 1.

[0070] In the embodiment, when the tablets were tested for dissolution in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer at 37°C using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), they released approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 5 to 18 hours, and approximately 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 5 to 12 hours.

[0071] In the embodiment, the tablet comprises a sustained-release (ER) moiety containing compound 1 or a pharmaceutically acceptable salt thereof. In the embodiment, the tablet comprises an immediate-release (IR) moiety containing fesoterodine or a pharmaceutically acceptable salt thereof.

[0072] In the embodiment, the ER / IR tablet immediately releases fesoterodine or a pharmaceutically acceptable salt thereof (an anticholinergic agent) into the peripheral system before the release of compound 1, thereby reducing the peripheral cholinergic effect of compound 1. In the embodiment, the tablet comprises an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof, and an IR portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion constitute a two-layer tablet. In the embodiment, when the tablets are tested for dissolution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, they release about 80% of compound 1 or a pharmaceutically acceptable salt within 2 to 18 hours, or 2 to 10 hours (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 hours (including any value or range in between)), and about 80% of fesoterodine or a pharmaceutically acceptable salt within 0.1 to 1 hour (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 hour (including any value or range in between)).

[0073] In embodiments, the tablets of the present disclosure further comprise stabilizers, controlled-release excipients, lubricants, diluents, or mixtures thereof.

[0074] In embodiments, the stabilizer is xylitol, sorbitol, polydextrose, isomalt, dextrose, microcrystalline cellulose, fructose, or a mixture thereof. In embodiments, the stabilizer is xylitol, fructose, or a mixture thereof. In embodiments, the weight % ratio of fesoterodine or its pharmaceutically acceptable salt to the stabilizer is about 1:20 to about 1:1 in the tablet. In the embodiment, the weight % ratio of fesoterodine or its pharmaceutically acceptable salt to stabilizer is about 1:50 to about 1:1 in the tablet, for example, about 1:50, about 1:49, about 1:48, about 1:47, about 1:46, about 1:45, about 1:44, about 1:43, about 1:42, about 1:41, about 1:40, about 1:39, about 1:38, about 1:37, about 1:36, about 1:35, about 1:34, about 1:33, about 1:32, about 1:31, about 1:30, about 1 The ratios are approximately 1:29, 1:28, 1:27, 1:26, 1:25, 1:24, 1:23, 1:22, 1:21, 1:20, 1:19, 1:18, 1:17, 1:16, 1:15, 1:14, 1:13, 1:12, 1:11, 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, or 1:1 (including any values ​​or ranges in between). In embodiments, the weight % ratio of fesoterodine or its pharmaceutically acceptable salt to stabilizer is approximately 1:9 to approximately 1:1 in the tablet. In embodiments, the weight percentage ratio of fesoterodine or its pharmaceutically acceptable salt to the stabilizer is about 1:1 to about 1:50, about 1:5 to about 1:45, about 1:10 to about 1:40, or about 1:18 to about 1:40 in the tablet. In embodiments, the weight percentage ratio of fesoterodine or its pharmaceutically acceptable salt to xylitol, sorbitol, or fructose is about 1:9 to about 1:1 in the tablet. In embodiments, the weight percentage ratio of fesoterodine or its pharmaceutically acceptable salt to xylitol, sorbitol, or fructose is about 1:1 to about 1:50, about 1:5 to about 1:45, about 1:10 to about 1:40, or about 1:18 to about 1:40 in the tablet. In embodiments, the weight percentage ratio of fesoterodine or its pharmaceutically acceptable salt to xylitol is about 1:9 to about 1:1 in the tablet.In embodiments, the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt to xylitol in the tablet is approximately 1:1 to approximately 1:50, approximately 1:5 to approximately 1:45, approximately 1:10 to approximately 1:40, or approximately 1:18 to approximately 1:40. In embodiments, the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt to xylitol in the tablet is approximately 1:9. In embodiments, the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt to xylitol in the tablet is approximately 1:19. In embodiments, the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt to xylitol in the tablet is approximately 1:39.

[0075] In embodiments, the tablets of the present disclosure are formulated by a wet granulation process. In embodiments, fesoterodine or a pharmaceutically acceptable salt thereof is mixed or combined with a stabilizer selected from the group consisting of xylitol, fructose, sorbitol, polydextrose, isomalt, dextrose, or a combination thereof, in the presence of water, the resulting granules are dried, and combined with one or more pharmaceutically acceptable excipients to form the tablets of the present disclosure. In embodiments, the tablets are formulated by dry granulation.

[0076] In embodiments, the tablets of the present disclosure further comprise a lubricant. In embodiments, the lubricant is talc, silicon dioxide, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof. In embodiments, the lubricant is talc, glyceryl behenate, glyceryl dibehenate, silicon dioxide, magnesium stearate, or a mixture thereof. In embodiments, the lubricant is talc, glyceryl behenate, or a mixture thereof.

[0077] In embodiments, the tablets of the present disclosure further comprise a fluidizing agent. In embodiments, the fluidizing agent is colloidal silicon dioxide.

[0078] In embodiments, the tablets of the present disclosure further comprise a controlled-release excipient. In embodiments, the controlled-release excipient is polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, or a mixture thereof.

[0079] In embodiments, the tablets of the present disclosure further comprise a diluent. In embodiments, the diluent is microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, or a mixture thereof.

[0080] In the embodiment, the tablet further comprises lactose, sodium starch glycolate, croscarmellose sodium, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or a mixture thereof.

[0081] In embodiments, the tablets of the present disclosure comprise an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof, and include HPMC, microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, silicon dioxide, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogol, glyceryl behenate, corn starch, magnesium stearate, polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, sodium starch glycolate, sodium croscarmellose, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or any combination thereof.

[0082] In embodiments, the tablets of the present disclosure comprise an ER moiety containing compound 1 or a pharmaceutically acceptable salt thereof, and further comprising HPMC, xylitol, MCC, and magnesium stearate. In embodiments, the tablets of the present disclosure further comprise about 0.01 wt.% to about 0.05 wt.% of a coloring agent (e.g., a pink pigment blend of iron oxides).

[0083] In embodiments, the ER portion containing compound 1 or a pharmaceutically acceptable salt thereof comprises about 30 wt.% to about 55 wt.% hydroxypropyl methylcellulose (HPMC); about 10 wt.% to about 30 wt.% microcrystalline cellulose; about 5 wt.% to about 20 wt.% xylitol; about 0.1 wt.% to about 0.3 wt.% magnesium stearate; and about 0.02 wt.% colorant.

[0084] In embodiments, the tablets of the present disclosure comprise a portion comprising compound 1 or a pharmaceutically acceptable salt thereof, the portion comprising about 40 wt.% to about 60 wt.% HPMC; about 20 wt.% to about 25 wt.% microcrystalline cellulose; and about 0.1 wt.% to about 0.4 wt.% magnesium stearate.

[0085] In embodiments, the tablets of the present disclosure comprise an ER moiety containing compound 1 or a pharmaceutically acceptable salt thereof, and further comprises hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, glyceryl behenate, and talc. In embodiments, the tablets of the present disclosure comprise an ER moiety containing compound 1 or a pharmaceutically acceptable salt thereof, and further comprises hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, glyceryl behenate, xylitol, and talc. In embodiments, the tablets of the present disclosure comprise an ER moiety containing compound 1 or a pharmaceutically acceptable salt thereof, and further comprises about 10 wt.% to about 60 wt.% (e.g., about 10 wt.%, about 11 wt.%, about 12 wt.%, about 13 wt.%, about 14 wt.%, about 15 wt.%, about 16 wt.%, about 17 wt.%, about 17 wt.%, about 18 wt.%, about 19wt.%, approx. 20wt.%, approx. 21wt.%, approx. 22wt.%, approx. 23wt.%, approx. 24wt.%, approx. 25wt.%, approx. 26wt.%, approx. 27wt.%, approx. 2 8wt.%, approx. 29wt.%, approx. 30wt.%, approx. 31wt.%, approx. 32wt.%, approx. 33wt.%, approx. 34wt.%, approx. 35wt.%, approx. 36wt.%, approx. 37 wt.%, approx. 38wt.%, approx. 39wt.%, approx. 40wt.%, approx. 41wt.%, approx. 42wt.%, approx. 43wt.%, approx. 44wt.%, approx. 45wt.%, approx. 46w t.%, approx. 47wt.%, approx. 48wt.%, approx. 49wt.%, approx. 50wt.%, approx. 51wt.%, approx. 52wt.%, approx. 53wt.%, approx. 54wt.%, approx. 55wt Hydroxypropyl methylcellulose (HPMC) in 0% (including any value or range in between), approximately 56 wt.%, approximately 57 wt.%, approximately 58 wt.%, approximately 59 wt.%, or approximately 60 wt.%, or approximately 20 wt.% to approximately 60 wt.%, or approximately 20 wt.% to approximately 55 wt.%, or approximately 30 wt.% to approximately 55 wt.% (including any value or range in between); Approximately 2 wt.% to approximately 50 wt.% (for example, approximately 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, 3 Microcrystalline cellulose in the following proportions: 0 wt.%, approximately 31 wt.%, approximately 32 wt.%, approximately 33 wt.%, approximately 34 wt.%, approximately 35 wt.%, approximately 36 wt.%, approximately 37 wt.%, approximately 38 wt.%, approximately 39 wt.%, approximately 40 wt.%, approximately 41 wt.%, approximately 42 wt.%, approximately 43 wt.%, approximately 44 wt.%, approximately 45 wt.%, approximately 46 wt.%, approximately 47 wt.%, approximately 48 wt.%, approximately 49 wt.%, approximately 50 wt.%, or approximately 4 wt.% to approximately 9 wt.%, or approximately 2 wt.% to approximately 10 wt.%, or approximately 4 wt.% to approximately 50 wt.% (including any values ​​or ranges in between); Glyceryl behenate in amounts of approximately 2 wt.% to approximately 10 wt.% (for example, approximately 2 wt.%, approximately 3 wt.%, approximately 4 wt.%, approximately 5 wt.%, approximately 6 wt.%, approximately 7 wt.%, approximately 8 wt.%, approximately 9 wt.%, or approximately 10 wt.%, or approximately 2 wt.% to approximately 6 wt.% (including any value or range in between)); and Contains approximately 1 wt.% to 8 wt.% of talc (for example, approximately 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, or approximately 1 wt.% to 4 wt.% (including any value or range in between)). In this embodiment, the portion is approximately 4 wt.% to approximately 50 wt.% (for example, approximately 4 wt.%, approximately 5 wt.%, approximately 6 wt.%, approximately 7 wt.%, approximately 8 wt.%, approximately 9 wt.%, approximately 10 wt.%, approximately 11 wt.%, approximately 12 wt.%, approximately 13 wt.%, approximately 14 wt.%, approximately 15 wt.%, approximately 16 wt.%, approximately 17 wt.%, approximately 17 wt.%, approximately 18 wt.%, approximately 19 wt.%, approximately 20 wt.%, approximately 21 wt.%, approximately 22 wt.%, approximately 23 wt.%, approximately 24 wt.%, approximately 25 wt.%, approximately 26 wt.%, approximately 27 wt.%, approximately 28 wt.%) Further containing xylitol in amounts of t.%, approximately 29 wt.%, approximately 30 wt.%, approximately 31 wt.%, approximately 32 wt.%, approximately 33 wt.%, approximately 34 wt.%, approximately 35 wt.%, approximately 36 wt.%, approximately 37 wt.%, approximately 38 wt.%, approximately 39 wt.%, approximately 40 wt.%, approximately 41 wt.%, approximately 42 wt.%, approximately 43 wt.%, approximately 44 wt.%, approximately 45 wt.%, approximately 46 wt.%, approximately 47 wt.%, approximately 48 wt.%, approximately 49 wt.%, approximately 50 wt.%, or approximately 4 wt.% to approximately 50 wt.% (including any value or range in between).

[0086] In embodiments, the portion containing compound 1 or a pharmaceutically acceptable salt thereof comprises about 30 wt.% to about 55 wt.% hydroxypropyl methylcellulose (HPMC); about 4 wt.% to about 9 wt.% microcrystalline cellulose; about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0087] In embodiments, the portion containing compound 1 or a pharmaceutically acceptable salt thereof comprises about 20 wt.% to about 55 wt.% hydroxypropyl methylcellulose (HPMC); about 4 wt.% to about 50 wt.% microcrystalline cellulose; about 2 wt.% to about 6 wt.% glyceryl behenate; about 4 wt.% to about 50 wt.% xylitol; and about 1 wt.% to about 4 wt.% talc.

[0088] In embodiments, the tablets of the present disclosure comprise an IR portion containing fesoterodine or a pharmaceutically acceptable salt thereof, the IR portion comprising xylitol, lactose, microcrystalline cellulose, sodium starch glycolate, glyceryl behenate, and talc. In embodiments, the tablets of the present disclosure comprise an IR portion containing fesoterodine or a pharmaceutically acceptable salt thereof, Approximately 5 wt.% to 60 wt.% xylitol (for example, approximately 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, 30 wt.%, 31 wt.%, 32 wt.%) t.%, approximately 33 wt.%, approximately 34 wt.%, approximately 35 wt.%, approximately 36 wt.%, approximately 37 wt.%, approximately 38 wt.%, approximately 39 wt.%, approximately 40 wt.%, approximately 41 wt.%, approximately 42 wt.%, approximately 43 wt.%, approximately 44 wt.%, approximately 45 wt.%, approximately 46 wt.%, approximately 47 wt.%, approximately 48 wt.%, approximately 49 wt.%, approximately 50 wt.%, approximately 51 wt.%, approximately 52 wt.%, approximately 53 wt.%, approximately 54 wt.%, approximately 55 wt.%, approximately 56 wt.%, approximately 57 wt.%, approximately 58 wt.%, approximately 59 wt.%, or approximately 60 wt.% (including any value or range in between)); Approximately 40 wt.% to 90 wt.% (for example, approximately 40 wt.%, 41 wt.%, 42 wt.%, 43 wt.%, 44 wt.%, 45 wt.%, 46 wt.%, 47 wt.%, 48 wt.%, 49 wt.%, 50 wt.%, 51 wt.%, 52 wt.%, 53 wt.%, 54 wt.%, 55 wt.%, 56 wt.%, 57 wt.%, 58 wt.%, 59 wt.%, or approximately 60 wt.%, 61 wt.%, 62 wt.%, 63 wt.%, 64 wt.%, 65 wt.%, 66 wt.%). 75% lactose / 25% microcrystalline cellulose in the range of approximately 67 wt.%, 68 wt.%, 69 wt.%, 70 wt.%, 71 wt.%, 72 wt.%, 73 wt.%, 74 wt.%, 75 wt.%, 76 wt.%, 77 wt.%, 78 wt.%, 79 wt.%, 80 wt.%, 81 wt.%, 82 wt.%, 83 wt.%, 84 wt.%, 85 wt.%, 86 wt.%, 87 wt.%, 88 wt.%, 89 wt.%, or 90 wt.% (including any value or range in between); Sodium starch glycolate in amounts ranging from approximately 2 wt.% to approximately 10 wt.% (for example, approximately 2 wt.%, approximately 3 wt.%, approximately 4 wt.%, approximately 5 wt.%, approximately 6 wt.%, approximately 7 wt.%, approximately 8 wt.%, approximately 9 wt.%, or approximately 10 wt.% (including any value or range in between)); Glyceryl behenate in amounts of approximately 2 wt.% to approximately 10 wt.% (for example, approximately 2 wt.%, approximately 3 wt.%, approximately 4 wt.%, approximately 5 wt.%, approximately 6 wt.%, approximately 7 wt.%, approximately 8 wt.%, approximately 9 wt.%, or approximately 10 wt.% (including any value or range in between)); and Contains approximately 1 wt.% to 10 wt.% of talc (for example, approximately 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, or 10 wt.% (including any value or range in between)).

[0089] In embodiments, the tablets of the present disclosure comprise an immediate-release portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the IR portion comprising a) about 10 wt.% to about 50 wt.% xylitol; about 50 wt.% to about 80 wt.% 75% lactose / 25% microcrystalline cellulose; about 3 wt.% to about 8 wt.% sodium starch glycolate; about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0090] In embodiments, the tablets of the present disclosure comprise an IR portion containing fesoterodine or a pharmaceutically acceptable salt thereof, the IR portion comprising about 10 wt.% to about 50 wt.% xylitol; about 50 wt.% to about 80 wt.% 75% lactose / 25% microcrystalline cellulose; about 2 wt.% to about 10 wt.% (e.g., about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, or about 10 wt.%, or about 3 wt.% to about 8 wt.% (including any value or range in between)) croscarmellose sodium; about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0091] In embodiments, the tablets of the present disclosure comprise an immediate-release portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the IR portion comprising about 10 wt.% to about 50 wt.% xylitol; about 50 wt.% to about 80 wt.% 75% lactose / 25% microcrystalline cellulose; about 2 wt.% to about 10 wt.% (e.g., about 2 wt.%, about 3 wt.%, about 4 wt.%, about 5 wt.%, about 6 wt.%, about 7 wt.%, about 8 wt.%, about 9 wt.%, or about 10 wt.%, or about 3 wt.% to about 8 wt.% (including any value or range in between)) polyvinylpyrrolidone (PVP); about 2 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0092] In embodiments, the tablets of the present disclosure comprise an ER portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the ER portion comprising about 10 wt.% to about 40 wt.% xylitol; about 10 wt.% to about 20 wt.% lactose; about 10 wt.% to about 30 wt.% MCC; about 20 wt.% to about 40 wt.% HPMC; about 2 wt.% to about 5 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc. In embodiments, the tablets of the present disclosure comprise an ER portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the ER portion comprising about 10 wt.% to about 40 wt.% xylitol; about 10 wt.% to about 25 wt.% lactose; about 10 wt.% to about 30 wt.% MCC; about 20 wt.% to about 40 wt.% HPMC; about 2 wt.% to about 5 wt.% glyceryl behenate; about 0.2 wt.% to about 1 wt.% colloidal silicon dioxide; and about 1 wt.% to about 4 wt.% talc.

[0093] In embodiments, the tablets of the present disclosure comprise an ER portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the ER portion Approximately 10 wt.% to 50 wt.% xylitol; Approximately 10 wt.% to approximately 50 wt.% (for example, approximately 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, 30 wt.%, 31 wt.%) 75% lactose / 25% microcrystalline cellulose in wt.%, approximately 32 wt.%, approximately 33 wt.%, approximately 34 wt.%, approximately 35 wt.%, approximately 36 wt.%, approximately 37 wt.%, approximately 38 wt.%, approximately 39 wt.%, approximately 40 wt.%, approximately 41 wt.%, approximately 42 wt.%, approximately 43 wt.%, approximately 44 wt.%, approximately 45 wt.%, approximately 46 wt.%, approximately 47 wt.%, approximately 48 wt.%, approximately 49 wt.%, or approximately 50 wt.% (including any value or range in between); Approximately 10 wt.% to approximately 60 wt.% (for example, approximately 10 wt.%, approximately 11 wt.%, approximately 12 wt.%, approximately 13 wt.%, approximately 14 wt.%, approximately 15 wt.%, approximately 16 wt.%, approximately 17 wt.%, approximately 17 wt.%, approximately 18 wt.%, approximately 19 wt.%, approximately 20 wt.%, approximately 21 wt.%, approximately 22wt.%, approx. 23wt.%, approx. 24wt.%, approx. 25wt.%, approx. 26wt.%, approx. 27wt.%, approx. 28wt.%, approx. 29wt.%, Approx. 30wt.%, approx. 31wt.%, approx. 32wt.%, approx. 33wt.%, approx. 34wt.%, approx. 35wt.%, approx. 36wt.%, approx. 37wt.% Hydroxypropyl methylcellulose (HPMC) in amounts of approximately 38 wt.%, 39 wt.%, 40 wt.%, 41 wt.%, 42 wt.%, 43 wt.%, 44 wt.%, 45 wt.%, 46 wt.%, 47 wt.%, 48 wt.%, 49 wt.%, 50 wt.%, 51 wt.%, 52 wt.%, 53 wt.%, 54 wt.%, 55 wt.%, 56 wt.%, 57 wt.%, 58 wt.%, 59 wt.%, or 60 wt.%, or approximately 10 wt.% to 40 wt.% (including any value or range in between); Glyceryl behenate in amounts of approximately 1 wt.% to approximately 10 wt.% (for example, approximately 1 wt.%, approximately 2 wt.%, approximately 3 wt.%, approximately 4 wt.%, approximately 5 wt.%, approximately 6 wt.%, approximately 7 wt.%, approximately 8 wt.%, approximately 9 wt.%, or approximately 10 wt.%, or approximately 1 wt.% to approximately 6 wt.% (including any value or range in between)); and Contains approximately 1 wt.% to 10 wt.% of talc (for example, approximately 1 wt.%, 2 wt.%, 3 wt.%, 4 wt.%, 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, or 10 wt.%, or approximately 1 wt.% to 4 wt.% (including any value or range in between)).

[0094] In embodiments, the ER moiety comprising fesoterodine or a pharmaceutically acceptable salt thereof further comprises about 0.1 wt.% to about 1 wt.% (e.g., about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, or about 1 wt.%, or about 0.2 wt.% to about 1 wt.% (including any value or range in between)) colloidal silicon dioxide.

[0095] In embodiments, the tablets of the present disclosure comprise an ER portion comprising fesoterodine or a pharmaceutically acceptable salt thereof, the ER portion comprising about 10 wt.% to about 50 wt.% xylitol; about 10 wt.% to about 50 wt.% 75% lactose / 25% microcrystalline cellulose; about 10 wt.% to about 40 wt.% hydroxypropyl methylcellulose (HPMC); about 1 wt.% to about 6 wt.% glyceryl behenate; and about 1 wt.% to about 4 wt.% talc.

[0096] In the embodiment, the HPMC used in the tablet has a viscosity of about 4,000 mPas to about 100,000 mPas (e.g., about 4,000 mPas, about 6,000 mPas, about 8,000 mPas, about 10,000 mPas, about 20,000 mPas, about 30,000 mPas, about 40,000 mPas, about 50,000 mPas, about 60,000 mPas, about 70,000 mPas, about 80,000 mPas, about 90,000 mPas, or about 100,000 mPas (including any value or range in between)) when dissolved at a rate of about 2% by weight in water.

[0097] In embodiments, the portion containing fesoterodine or a pharmaceutically acceptable salt thereof is approximately 8 wt.% to approximately 50 wt.% xylitol; approximately 10 wt.% to approximately 50 wt.% 75% lactose / 25% microcrystalline cellulose; approximately 10 wt.% to approximately 50 wt.% (e.g., approximately 10 wt.%, approximately 11 wt.%, approximately 12 wt.%, approximately 13 wt.%, approximately 14 wt.%, approximately 15 wt.%, approximately 16 wt.%, approximately 17 wt.%, approximately 17 wt.%, approximately 18 wt.%, approximately 19 wt.%, approximately 20 wt.%, approximately 21 wt.%, approximately 22 wt.%, approximately 23 wt.%, approximately 24 wt.%, approximately 25 wt.%, approximately 26 wt.%, approximately 27 wt.%, approximately 28 wt.%) Approx. 29wt.%, approx. 30wt.%, approx. 31wt.%, approx. 32wt.%, approx. 33wt.%, approx. 34wt.%, approx. 35wt.%, approx. 36wt.%, approx. 37w t.%, approx. 38wt.%, approx. 39wt.%, approx. 40wt.%, approx. 41wt.%, approx. 42wt.%, approx. 43wt.%, approx. 44wt.%, approx. 45wt.%, approx. It contains 46 wt.%, approximately 47 wt.%, approximately 48 wt.%, approximately 49 wt.%, or approximately 50 wt.%, or approximately 10 wt.% to approximately 40 wt.% (including any value or range in between) of cellulose ether; approximately 1 wt.% to approximately 6 wt.% of glyceryl behenate; and approximately 1 wt.% to approximately 4 wt.% of talc.

[0098] In embodiments, the portion containing fesoterodine or a pharmaceutically acceptable salt thereof is approximately 8 wt.% to approximately 50 wt.% xylitol; approximately 10 wt.% to approximately 50 wt.% 75% lactose / 25% microcrystalline cellulose; and approximately 10 wt.% to approximately 50 wt.% (e.g., approximately 10 wt.%, approximately 11 wt.%, approximately 12 wt.%, approximately 1 3wt.%, approx. 14wt.%, approx. 15wt.%, approx. 16wt.%, approx. 17wt.%, approx. 17wt.%, approx. 18wt.%, approx. 19wt.%, approx. 20wt.%, approx. 21wt.%, about 22wt.%, about 23wt.%, about 24wt.%, about 25wt.%, about 26wt.%, about 27wt.%, about 28wt.%, about 29wt.%, Approx. 30wt.%, approx. 31wt.%, approx. 32wt.%, approx. 33wt.%, approx. 34wt.%, approx. 35wt.%, approx. 36wt.%, approx. 37wt.%, approx. 38wt.% , about 39wt.%, about 40wt.%, about 41wt.%, about 42wt.%, about 43wt.%, about 44wt.%, about 45wt.%, about 46wt.%, about 47wt. Contains 80% polyvinyl acetate (PVA) / 19% povidone in %, approximately 48 wt.%, approximately 49 wt.%, or approximately 50 wt.%, or approximately 10 wt.% to approximately 40 wt.% (including any value or range in between); approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and approximately 1 wt.% to approximately 4 wt.% talc.

[0099] In embodiments, the ER / ER or ER / IR tablets of the present disclosure further include a cosmetic coating.

[0100] In embodiments, the disclosure comprises a sustained-release (ER) moiety containing compound 1 or a pharmaceutically acceptable salt thereof; and an immediate-release (IR) coating containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on the ER moiety. In embodiments, the IR coating comprises HPMC, triacetin, titanium dioxide, xanthan gum, lecithin, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate, methacrylate copolymer, talc, or mixtures thereof.

[0101] In this embodiment, the IR coating comprises polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate 80, and talc.

[0102] In this embodiment, the IR coating is Polyvinyl alcohol (PVA) in an amount of approximately 40 wt.% to approximately 60 wt.% (for example, approximately 40 wt.%, 41 wt.%, 42 wt.%, 43 wt.%, 44 wt.%, 45 wt.%, 46 wt.%, 47 wt.%, 48 wt.%, 49 wt.%, 50 wt.%, 51 wt.%, 52 wt.%, 53 wt.%, 54 wt.%, 55 wt.%, 56 wt.%, 57 wt.%, 58 wt.%, 59 wt.%, or approximately 60 wt.% (including any value or range in between)); Polyethylene glycol (PEG) in amounts of approximately 10 wt.% to 20 wt.% (for example, approximately 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, or 20 wt.% (including any value or range in between)); Polysorbate 80 in amounts of approximately 1 wt.% to approximately 5 wt.% (for example, approximately 1 wt.%, approximately 2 wt.%, approximately 3 wt.%, approximately 4 wt.%, or approximately 5 wt.% (including any value or range in between)); and Contains approximately 20 wt.% to 40 wt.% of talc (for example, approximately 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, 30 wt.%, 31 wt.%, 32 wt.%, 33 wt.%, 34 wt.%, 35 wt.%, 36 wt.%, 37 wt.%, 38 wt.%, 39 wt.%, or 40 wt.% (including any value or range in between)).

[0103] In the embodiment, the IR coating comprises HPMC, triacetin, and talc.

[0104] In this embodiment, the IR coating is HPMC in the range of approximately 70 wt.% to 85 wt.% (for example, approximately 70 wt.%, 71 wt.%, 72 wt.%, 73 wt.%, 74 wt.%, 75 wt.%, 76 wt.%, 77 wt.%, 78 wt.%, 79 wt.%, 80 wt.%, 81 wt.%, 82 wt.%, 83 wt.%, 84 wt.%, or 85 wt.% (including any value or range in between)); Triacetin in amounts of approximately 5 wt.% to approximately 10 wt.% (for example, approximately 5 wt.%, approximately 6 wt.%, approximately 7 wt.%, approximately 8 wt.%, approximately 9 wt.%, or approximately 10 wt.% (including any value or range in between)); and Contains approximately 5 wt.% to 10 wt.% of talc (for example, approximately 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, or 10 wt.% (including any value or range in between)).

[0105] In the embodiment, the IR coating comprises PVA, xylitol, PEG, polysorbate 80, and talc.

[0106] In this embodiment, the IR coating is PVA in the range of approximately 25 wt.% to approximately 50 wt.% (for example, approximately 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, 30 wt.%, 31 wt.%, 32 wt.%, 33 wt.%, 34 wt.%, 35 wt.%, 36 wt.%, 37 wt.%, 38 wt.%, 39 wt.%, 40 wt.%, 41 wt.%, 42 wt.%, 43 wt.%, 44 wt.%, 45 wt.%, 46 wt.%, 47 wt.%, 48 wt.%, 49 wt.%, or approximately 50 wt.% (including any value or range in between)); Approximately 10 wt.% to approximately 40 wt.% (for example, approximately 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%) Xylitol in amounts of t.%, approximately 26 wt.%, approximately 27 wt.%, approximately 28 wt.%, approximately 29 wt.%, approximately 30 wt.%, approximately 31 wt.%, approximately 32 wt.%, approximately 33 wt.%, approximately 34 wt.%, approximately 35 wt.%, approximately 36 wt.%, approximately 37 wt.%, approximately 38 wt.%, approximately 39 wt.%, or approximately 40 wt.% (including any value or range in between); PEG in the range of approximately 5 wt.% to 20 wt.% (for example, approximately 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, or 20 wt.% (including any value or range in between)); Polysorbate 80 in amounts of approximately 1 wt.% to approximately 5 wt.% (for example, approximately 1 wt.%, approximately 2 wt.%, approximately 3 wt.%, approximately 4 wt.%, or approximately 5 wt.% (including any value or range in between)); and Contains approximately 10 wt.% to 30 wt.% of talc (for example, approximately 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, or 30 wt.% (including any value or range in between)).

[0107] In the embodiment, the IR coating comprises PVA, fructose, PEG, polysorbate 80, and talc.

[0108] In this embodiment, the IR coating is PVA in the range of approximately 20 wt.% to 40 wt.% (for example, approximately 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, 25 wt.%, 26 wt.%, 27 wt.%, 28 wt.%, 29 wt.%, 30 wt.%, 31 wt.%, 32 wt.%, 33 wt.%, 34 wt.%, 35 wt.%, 36 wt.%, 37 wt.%, 38 wt.%, 39 wt.%, or 40 wt.% (including any value or range in between)); Fructose in amounts of approximately 30 wt.% to 40 wt.% (for example, approximately 30 wt.%, 31 wt.%, 32 wt.%, 33 wt.%, 34 wt.%, 35 wt.%, 36 wt.%, 37 wt.%, 38 wt.%, 39 wt.%, or 40 wt.% (including any value or range in between)); PEG in amounts of approximately 5 wt.% to 15 wt.% (for example, approximately 5 wt.%, 6 wt.%, 7 wt.%, 8 wt.%, 9 wt.%, 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, or 15 wt.% (including any value or range in between)); Polysorbate 80 in amounts of approximately 1 wt.% to approximately 3 wt.% (e.g., approximately 1.0 wt.%, 1.2 wt.%, 1.4 wt.%, 1.6 wt.%, 1.8 wt.%, 2.0 wt.%, 2.2 wt.%, 2.4 wt.%, 2.6 wt.%, 2.8 wt.%, or approximately 3 wt.% (including any value or range in between)); and Contains approximately 10 wt.% to 25 wt.% of talc (for example, approximately 10 wt.%, 11 wt.%, 12 wt.%, 13 wt.%, 14 wt.%, 15 wt.%, 16 wt.%, 17 wt.%, 17 wt.%, 18 wt.%, 19 wt.%, 20 wt.%, 21 wt.%, 22 wt.%, 23 wt.%, 24 wt.%, or 25 wt.% (including any value or range in between)).

[0109] In the embodiment, the IR coating comprises a copolymer of PVA and PEG in a 3:1 wt% ratio. In the embodiment, the IR coating comprises about 85 wt.% to about 95 wt.% copolymer of polyvinyl alcohol and polyethylene glycol in a 3:1 wt% ratio.

[0110] In the embodiment, the IR coating contains HPMC. In the embodiment, the IR coating contains about 65 wt.% to about 95 wt.% HPMC.

[0111] In this embodiment, the IR coating comprises HPMC and xylitol.

[0112] In this embodiment, the IR coating is HPMC in the range of approximately 40 wt.% to approximately 60 wt.% (for example, approximately 40 wt.%, 41 wt.%, 42 wt.%, 43 wt.%, 44 wt.%, 45 wt.%, 46 wt.%, 47 wt.%, 48 wt.%, 49 wt.%, 50 wt.%, 51 wt.%, 52 wt.%, 53 wt.%, 54 wt.%, 55 wt.%, 56 wt.%, 57 wt.%, 58 wt.%, 59 wt.%, or approximately 60 wt.% (including any value or range in between)); and Contains approximately 30 wt.% to 45 wt.% of xylitol (for example, approximately 30 wt.%, 31 wt.%, 32 wt.%, 33 wt.%, 34 wt.%, 35 wt.%, 36 wt.%, 37 wt.%, 38 wt.%, 39 wt.%, 40 wt.%, 41 wt.%, 42 wt.%, 43 wt.%, 44 wt.%, or 45 wt.% (including any value or range in between)).

[0113] In the embodiment, the IR coating comprises HPMC and fructose.

[0114] In this embodiment, the IR coating is HPMC in the range of approximately 40 wt.% to approximately 60 wt.% (for example, approximately 40 wt.%, 41 wt.%, 42 wt.%, 43 wt.%, 44 wt.%, 45 wt.%, 46 wt.%, 47 wt.%, 48 wt.%, 49 wt.%, 50 wt.%, 51 wt.%, 52 wt.%, 53 wt.%, 54 wt.%, 55 wt.%, 56 wt.%, 57 wt.%, 58 wt.%, 59 wt.%, or approximately 60 wt.% (including any value or range in between)); and Contains approximately 30 wt.% to 45 wt.% of fructose (for example, approximately 30 wt.%, 31 wt.%, 32 wt.%, 33 wt.%, 34 wt.%, 35 wt.%, 36 wt.%, 37 wt.%, 38 wt.%, 39 wt.%, or 40 wt.% (including any value or range in between)).

[0115] In embodiments, the tablets contain (i) about 60 wt.% to about 70 wt.% of polyvinyl alcohol (PVA), about 15 wt.% to about 25 wt.% of talc, about 1 wt.% to about 5 wt.% of lecithin, and about 0.1 wt.% to about 1.5 wt.% of xanthan gum (e.g., about 0.1 wt.%, about 0.2 wt.%, about 0.3 wt.%, about 0.4 wt.%, about 0.5 wt.%, about 0.6 wt.%, about 0.7 wt.%, about 0.8 wt.%, about 0.9 wt.%, about 1.0 wt.%, about 1.1 wt.%, about 1.2 wt.%, about 1.4 wt.%, or about 1.5 wt.% (including any value or range in between)).

[0116] In the embodiment, the IR coating, when tested at 37°C in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), releases 80% of fesoterodine within 0.5 to 2 hours (e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 hours (including any value or range in between)).

[0117] In embodiments, the compositions of the present disclosure are formulated as osmotic tablets. In embodiments, when the osmotic tablets are tested for dissolution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, they release about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 4 to 16 hours (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 hours (including any value or range in between)) and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 4 to 16 hours (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 hours (including any value or range in between)).

[0118] In embodiments, the compositions of the present disclosure are formulated as multiparticle formulations. In embodiments, the multiparticle formulations release about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 8 hours (e.g., 2, 3, 4, 5, 6, 7, or 8 hours (including any value or range in between)) and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 4 to 12 hours (e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12 hours (including any value or range in between)) when elution is tested using a United States Pharmacopeia II apparatus (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C.

[0119] Treatment methods for nerve damage In embodiments, the present disclosure provides a method for treating neurological disorders (e.g., schizophrenia or Alzheimer's disease psychosis) by reducing peripheral cholinergic activity by administering one or more compositions of the present disclosure (i.e., co-formulations of Compound 1 or a pharmaceutically acceptable salt thereof, in combination with the peripherally acting anticholinergic agent fesoterodine or a pharmaceutically acceptable salt thereof) to a patient in need.

[0120] In embodiments, the neurological disorder is schizophrenia. In embodiments, the patient is treated for acute schizophrenia. In embodiments, the patient is treated for chronic schizophrenia. In embodiments, this disclosure provides a method for treating cognitive impairment in schizophrenia.

[0121] In the embodiment, the neurological disorder is Alzheimer's disease. In the embodiment, the neurological disorder is Alzheimer's psychosis. In the embodiment, the patient is treated with respect to the cognition of Alzheimer's disease. In the embodiment, the treatment improves or maintains the cognitive function of the patient with Alzheimer's disease.

[0122] In the embodiment, the neurological disorder is dyskinesia. In the embodiment, the dyskinesia is levodopa-induced dyskinesia. In the embodiment, the patient is diagnosed with Parkinson's disease. In the embodiment, the dyskinesia is tardive dyskinesia.

[0123] In the embodiment, the neurological disorder is psychosis. In the embodiment, the neurological disorder is Parkinson's disease psychosis, dementia-associated psychosis, short-term psychotic disorder, Lewy body dementia with psychosis, or acute delirium.

[0124] In embodiments, this disclosure provides methods for treating agitation in Alzheimer's disease dementia, Lewy body dementia with psychosis, Lewy body dementia, bipolar manic episodes, bipolar mixed episodes, bipolar maintenance phase (bipolar type 1 and / or type 2), bipolar depression, or cognitive impairment in bipolar type 1 and / or type 2 disorder.

[0125] In embodiments, the present disclosure provides a method for treating neurological disorders as described in International Application No. PCT / US2022 / 080429 (which is incorporated herein by reference in its entirety for all purposes).

[0126] In embodiments, the present application provides a method for treating neurological disorders by orally administering a pharmaceutical composition comprising about 10 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 1 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof to a patient in need. In embodiments, the method comprises orally administering a composition comprising about 100 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof to a patient in need.

[0127] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg, based on the free base content of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg, based on the free base content of fesoterodine) or a pharmaceutically acceptable salt thereof, wherein the administration of compound 1 max The t of desfesoterodine lasts for approximately 0.1 to 8 hours. max This ranges from approximately 0.1 hours to approximately 10 hours.

[0128] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the administration of compound 1 results in max The t of desfesoterodine lasts for approximately 1.5 to 8 hours. max This will take approximately 1 to 8 hours.

[0129] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the administration brings compound 1 to a steady state C max (C max,ss ) is approximately 200 ng / mL to approximately 5,000 ng / mL, and the C of desfesoterodine max,ss This ranges from approximately 2 ng / mL to approximately 60 ng / mL.

[0130] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the administration of compound 1 results in the C max,ss This is 600 ng / mL to approximately 4,000 ng / mL, and the C content of desfesoterodine. max,ss This ranges from approximately 1 ng / mL to approximately 20 ng / mL.

[0131] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the AUC of compound 1 obtained by such administration 0-24h,ss The AUC of desfesoterodine is approximately 4,000 ng·h / mL to approximately 40,000 ng·h / mL.0-24h,ss This ranges from approximately 5 ng·h / mL to approximately 600 ng·h / mL.

[0132] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the AUC of compound 1 obtained by such administration 0-24h,ss The AUC of desfesoterodine is approximately 4,000 ng·h / mL to approximately 40,000 ng·h / mL. 0-24h,ss This ranges from approximately 20 ng·h / mL to approximately 200 ng·h / mL.

[0133] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the plasma concentration ratio of compound 1 to desfesoterodine after such administration is about 10:1 to about 400:1.

[0134] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the plasma concentration ratio of compound 1 to desfesoterodine after such administration is about 10:1 to about 200:1.

[0135] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the administration results in a C ratio of compound 1 to desfesoterodine. max The ratio will be approximately 50:1 to 600:1.

[0136] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein the administration results in a C ratio of compound 1 to desfesoterodine. max The ratio will be approximately 50:1 to 250:1.

[0137] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 40 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 20 mg or about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof; when elution is tested at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), the composition releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 18 hours; and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.2 to 18 hours.

[0138] In embodiments, the method of the present disclosure comprises orally administering a pharmaceutical composition comprising about 40 mg to about 500 mg of compound 1 (e.g., compound 1 with a free base amount of 105 mg, 135 mg, 165 mg, 210 mg, 270 mg, 330 mg, 405 mg, or 495 mg) or a pharmaceutically acceptable salt thereof and about 1 mg to about 20 mg or about 1 mg to about 10 mg of fesoterodine (e.g., fesoterodine with a free base amount of 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof; when elution is tested at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), the composition releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 12 hours; and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.2 to 12 hours.

[0139] In embodiments, the method of this disclosure includes orally administering one or more pharmaceutical compositions listed in Tables 5 to 5d.

[0140] In the embodiment, the administered pharmaceutical composition is a tablet. In the embodiment, the administered tablet comprises a sustained-release (ER) moiety containing compound 1 or a pharmaceutically acceptable salt thereof and a sustained-release (ER) moiety containing fesoterodine or a pharmaceutically acceptable salt thereof. In the embodiment, the weight % ratio of compound 1 to fesoterodine in the administered composition is about 40:1 to about 90:1.

[0141] In embodiments, the compositions of the Disclosure are administered once daily. In embodiments, one composition of the Disclosure is administered once daily (for example, one tablet containing 165 mg of Compound 1 and 3 mg of fesoterodine is administered once daily). In embodiments, two or more compositions of the Disclosure are administered once daily (for example, two tablets containing 165 mg of Compound 1 and 3 mg of fesoterodine are administered once daily).

[0142] In embodiments, the method of the present disclosure includes orally administering to a patient about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of fesoterodine or a pharmaceutically acceptable salt thereof once daily. In embodiments, the method of the present disclosure includes orally administering to a patient about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of fesoterodine or a pharmaceutically acceptable salt thereof once daily. In embodiments, the method of the present disclosure includes orally administering to a patient about 270 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 6 mg of fesoterodine or a pharmaceutically acceptable salt thereof once daily. In embodiments, the method of the present disclosure includes orally administering to a patient about 330 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 6 mg of fesoterodine or a pharmaceutically acceptable salt thereof once daily. In embodiments, the method of the present disclosure comprises orally administering to a patient about 495 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 9 mg of fesoterodine or a pharmaceutically acceptable salt thereof once daily. In embodiments, the method of the present disclosure comprises orally administering to a patient about 495 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 6 mg of fesoterodine or a pharmaceutically acceptable salt thereof once daily.

[0143] In one embodiment, the average steady-state plasma concentration of compound 1 after once-daily oral administration is at least approximately 50 ng / mL, at least approximately 100 ng / mL, at least approximately 150 ng / mL, at least approximately 200 ng / mL, at least approximately 250 ng / mL, at least approximately 300 ng / mL, at least approximately 350 ng / mL, or at least approximately 400 ng / mL over at least approximately 12 hours, at least approximately 16 hours, at least approximately 18 hours, at least approximately 20 hours, at least approximately 22 hours, or at least approximately 24 hours after administration. In another embodiment, the average steady-state plasma concentration of compound 1 after once-daily oral administration is at least approximately 100 ng / mL over at least approximately 18 hours, at least approximately 20 hours, at least approximately 22 hours, or at least approximately 24 hours after administration. In yet another embodiment, the average steady-state plasma concentration of compound 1 after once-daily oral administration is at least approximately 200 ng / mL over at least approximately 20 hours after administration.

[0144] In some embodiments, the compositions of the Disclosure are administered twice daily. In embodiments, one composition of the Disclosure is administered twice daily (for example, one tablet containing 165 mg of Compound 1 and 3 mg of fesoterodine is administered twice daily). In embodiments, two or more compositions of the Disclosure are administered twice daily (for example, two tablets containing 165 mg of Compound 1 and 3 mg of fesoterodine are administered twice daily).

[0145] In embodiments, the method of the present disclosure comprises administering to a patient about 105 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 1.5 mg of fesoterodine or a pharmaceutically acceptable salt thereof twice daily (i.e., a total daily dose of 210 mg of compound 1 and 3 mg of fesoterodine). In embodiments, the method of the present disclosure comprises administering to a patient about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of fesoterodine or a pharmaceutically acceptable salt thereof twice daily (i.e., a total daily dose of 330 mg of compound 1 and 6 mg of fesoterodine). In embodiments, the method of the present disclosure comprises administering to a patient about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of fesoterodine or a pharmaceutically acceptable salt thereof twice daily (i.e., a total daily dose of 420 mg of compound 1 and 6 mg of fesoterodine).

[0146] In one embodiment, the mean steady-state plasma concentration of compound 1 after administration twice daily is at least about 50 ng / mL, at least about 100 ng / mL, at least about 150 ng / mL, at least about 200 ng / mL, at least about 250 ng / mL, at least about 300 ng / mL, at least about 350 ng / mL, or at least about 400 ng / mL over a period of at least about 12 hours, at least about 16 hours, at least about 18 hours, at least about 20 hours, at least about 22 hours, at least about 24 hours, at least about 26 hours, at least about 28 hours, at least about 30 hours, at least about 32 hours, at least about 34 hours, or at least about 36 hours after administration. In this embodiment, the mean steady-state plasma concentration of compound 1, after administration twice daily, is at least approximately 200 ng / mL for at least approximately 24 hours after administration.

[0147] In the embodiments, the composition of the present disclosure is administered three times a day.

[0148] In the embodiment, the administered composition contains the hydrochloride salt of compound 1. In the embodiment, the administered composition contains fesoterodine fumarate.

[0149] In the embodiment, compound 1, or a pharmaceutically acceptable salt thereof, is administered to the patient in amounts ranging from approximately 0.05 mg / kg to approximately 8 mg / kg, for example, approximately 0.05 mg / kg, approximately 0.10 mg / kg, approximately 0.15 mg / kg, approximately 0.20 mg / kg, approximately 0.25 mg / kg, approximately 0.30 mg / kg, approximately 0.35 mg / kg, approximately 0.40 mg / kg, approximately 0.45 mg / kg, approximately 0.50 mg / kg, Approx. 0.55mg / kg, approx. 0.60mg / kg, approx. 0.65mg / kg, approx. 0.70mg / kg, approx. 0.75mg / kg, approx. 0.80mg / kg, approx. 0.85mg / kg, approx. 0.90mg / k g, about 0.95mg / kg, about 1.00mg / kg, about 1.20mg / kg, about 1.40mg / kg, about 1.60mg / kg, about 1.80mg / kg, about 2.00mg / kg, about 2.20mg / kg, about 2.40mg / kg, about 2.60mg / kg, about 2.80mg / kg, about 3.00mg / kg, about 3.20mg / kg, about 3.40mg / kg, about 3.60mg / kg, about 3.80 mg / kg, approximately 4.00 mg / kg, approximately 4.20 mg / kg, approximately 4.40 mg / kg, approximately 4.60 mg / kg, approximately 4.80 mg / kg, approximately 5.00 mg / kg, approximately 5.20 mg / kg, approximately 5. 40 mg / kg, approximately 5.60 mg / kg, approximately 5.80 mg / kg, approximately 6.00 mg / kg, approximately 6.20 mg / kg, approximately 6.40 mg / kg, approximately 6.60 mg / kg, approximately 6.80 mg / kg, approximately 7.00 mg / kg, approximately 7.20 mg / kg, approximately 7.40 mg / kg, approximately 7.60 mg / kg, approximately 7.80 mg / kg, or approximately 8.00 mg / kg (including all values ​​and ranges in between).

[0150] In the embodiment, approximately 0.01 mg / kg to approximately 0.602 mg / kg of fesoterodine, or a pharmaceutically acceptable salt thereof, is administered to the patient, for example, approximately 0.010 mg / kg, approximately 0.011 mg / kg, approximately 0.012 mg / kg, approximately 0.013 mg / kg, approximately 0.015 mg / kg, approximately 0.016 mg / kg, approximately 0.018 mg / kg, approximately 0.019 mg / kg, approximately 0.021 mg / kg, approximately 0.024 mg / kg, approximately 0.026 mg / kg, approximately 0.029 mg / kg, approximately 0.031 mg / kg, approximately 0.035 mg / kg, approximately 0.038 mg / kg, approximately 0.042 mg / kg, approximately 0.046 mg / kg, approximately 0.051 mg / kg, approximately 0.056 mg / kg, and approximately 0.061 mg / kg. , about 0.067mg / kg, about 0.074mg / kg, about 0.081mg / kg, about 0.090mg / kg, about 0.098mg / kg, about 0.108mg / kg, about 0. 119mg / kg, approx. 0.131mg / kg, approx. 0.144mg / kg, approx. 0.159mg / kg, approx. 0.174mg / kg, approx. 0.192mg / kg, approx. 0.211mg / kg, approximately 0.232 mg / kg, approximately 0.255 mg / kg, approximately 0.281 mg / kg, approximately 0.309 mg / kg, approximately 0.340 mg / kg, approximately 0.374 mg / kg, approximately 0.411 mg / kg, approximately 0.453 mg / kg, approximately 0.498 mg / kg, approximately 0.548 mg / kg, approximately 0.602 mg / kg (including all values ​​and ranges in between).

[0151] Numbering implementation 1. (a) Compound 1 in an amount of approximately 10 mg to 500 mg

[0152] [ka] or a pharmaceutically acceptable salt thereof; and (b) A composition comprising approximately 2 mg to approximately 20 mg, approximately 1 mg to approximately 20 mg, or 1 mg to approximately 10 mg of fesoterodine or a pharmaceutically acceptable salt thereof; After administration of the composition, the oral administration of the composition results in the t of compound 1. max However, the t of desfesoterodine lasts for approximately 0.1 hours to approximately 8 hours. maxHowever, the above composition has a shelf life of approximately 0.1 hours to approximately 8 hours.

[0153] 2. Oral administration of the above composition results in the t of compound 1. max However, the composition according to Embodiment 1, wherein the time after administration of the composition is approximately 0.5 hours to approximately 4 hours.

[0154] 3. Oral administration of the above composition results in the t of desfesoterodine. max The composition according to Embodiment 1 or 2, wherein the time after administration of the composition is approximately 0.5 hours to approximately 4 hours.

[0155] 4. Oral administration of the above composition results in the C of compound 1. max,ss However, the composition according to any one of Embodiments 1 to 3, wherein the concentration becomes approximately 200 ng / mL to approximately 5,000 ng / mL after administration of the composition.

[0156] 5. Oral administration of the above composition results in the C of desfesoterodine max,ss However, the composition according to any one of Embodiments 1 to 4, wherein the concentration becomes approximately 2 ng / mL to approximately 60 ng / mL after administration of the composition.

[0157] 6. AUC of Compound 1 after oral administration of the composition. 0-24h,ss The composition according to any one of Embodiments 1 to 5, wherein after administration of the composition, the concentration becomes approximately 4,000 ng·h / mL to approximately 40,000 ng·h / mL.

[0158] 7. AUC of desfesoterodine after oral administration of the above composition. 0-24h,ss However, the composition according to any one of Embodiments 1 to 6, wherein after administration of the composition, the concentration becomes approximately 20 ng·h / mL to approximately 600 ng·h / mL.

[0159] 7a. Steady state C of compound 1 after oral administration of the composition. avg A composition according to any one of Embodiments 1 to 6, wherein the concentration exceeds 100 ng / mL for at least 8 hours after administration.

[0160] 7b. Steady state C of compound 1 after oral administration of the composition. avg A composition according to any one of Embodiments 1 to 6, wherein the concentration exceeds 100 ng / mL for at least 12 hours after administration.

[0161] 7c. Steady state C of compound 1 after oral administration of the composition. avg A composition according to any one of Embodiments 1 to 6, wherein the concentration is greater than 100 ng / mL for at least 24 hours after administration.

[0162] 7d. Steady state C of compound 1 after oral administration of the composition. avg The composition according to any one of Embodiments 1 to 6, wherein the concentration is approximately 350 ng / mL to approximately 850 ng / mL for at least 8 hours after administration.

[0163] 7e. Steady state C of compound 1 after oral administration of the composition. avg The composition according to any one of Embodiments 1 to 6, wherein the concentration is approximately 350 ng / mL to approximately 850 ng / mL for at least 12 hours after administration.

[0164] 7f. Steady state C of compound 1 after oral administration of the composition. avg The composition according to any one of Embodiments 1 to 6, wherein the concentration is approximately 350 ng / mL to approximately 850 ng / mL for at least 24 hours after administration.

[0165] 8. The composition according to any one of Embodiments 1 to 7, wherein the plasma concentration ratio of compound 1 to desfesoterodine after oral administration of the composition is approximately 10:1 to approximately 200:1.

[0166] 9. Oral administration of the above composition results in a ratio of compound 1 to desfesoterodine C max A composition according to any one of Embodiments 1 to 8, wherein the ratio is approximately 50:1 to approximately 250:1.

[0167] 10. (a) Compound 1 or a pharmaceutically acceptable salt thereof in an amount of approximately 40 mg to approximately 500 mg; and (b) containing approximately 1 mg to 10 mg, approximately 1 mg to 20 mg, or approximately 3 mg to 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof, When the composition was tested for elution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, Approximately 80% of the compound 1 or its pharmaceutically acceptable salt within 2 to 12 hours; and Approximately 80% of the fesoterodine or a pharmaceutically acceptable salt thereof is released within 0.2 to 8 hours or 0.2 to 12 hours. The aforementioned composition.

[0168] 11. The composition according to any one of the prior embodiments, wherein the composition comprises about 50 mg to about 600 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0169] 12. The composition according to any one of the prior embodiments, wherein the composition comprises about 100 mg to about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0170] 13. The composition according to any one of the prior embodiments, wherein the composition comprises about 150 mg to about 350 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0171] 13a. The composition according to any one of the prior embodiments, wherein the composition comprises about 100 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0172] 14. The composition according to any one of the prior embodiments, wherein the composition comprises about 200 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0173] 14a. The composition according to any one of the prior embodiments, wherein the composition comprises about 100 mg to about 200 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0174] 15. The composition according to any one of the prior embodiments, wherein the composition comprises about 105 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0175] 15a. The composition according to any one of the prior embodiments, wherein the composition comprises about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0176] 15b. The composition according to any one of the prior embodiments, wherein the composition comprises about 250 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0177] 16. The composition according to any one of the prior embodiments, wherein the composition comprises about 1 mg to about 12 mg of fesoterodine or a pharmaceutically acceptable salt thereof.

[0178] 16a. The composition according to any one of the prior embodiments, wherein the composition comprises about 3 mg to about 12 mg of fesoterodine or a pharmaceutically acceptable salt thereof.

[0179] 17. The composition according to any one of the prior embodiments, wherein the composition comprises fesoterodine fumarate.

[0180] 18. The composition according to any one of the prior embodiments, wherein the weight percentage ratio of the compound to fesoterodine in the composition is about 40:1 to about 90:1.

[0181] 19. The composition according to any one of the prior embodiments, wherein the weight percentage ratio of the compound to fesoterodine in the composition is about 20:1 to about 40:1, about 46:1 to about 70:1, or about 55:1 to about 70:1.

[0182] 20. The composition according to any one of the prior embodiments, wherein the composition is a tablet.

[0183] 21. The tablet according to Embodiment 20, wherein the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof.

[0184] 22. The tablet according to Embodiment 20 or 21, wherein the tablet comprises a sustained-release (ER) portion containing fesoterodine or a pharmaceutically acceptable salt thereof.

[0185] 23. The tablet according to any one of Embodiments 20 to 22, wherein the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof and a sustained-release (ER) portion containing fesoterodine or a pharmaceutically acceptable salt thereof.

[0186] twenty four. (a) A first ER portion comprising compound 1 or a pharmaceutically acceptable salt thereof; and (b) The tablet according to Embodiment 23, comprising a second ER portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the first portion and the second portion constitute a two-layer tablet.

[0187] 25. The tablet according to Embodiment 21, wherein the tablet comprises an immediate-release (IR) portion containing fesoterodine or a pharmaceutically acceptable salt thereof.

[0188] 26. (a) an ER moiety comprising compound 1 or a pharmaceutically acceptable salt thereof; and (b) The tablet according to Embodiment 25, comprising an IR portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion are formed in a two-layer tablet.

[0189] 27. The tablet according to any one of embodiments 20 to 26, wherein the tablet further comprises a stabilizer, a controlled-release excipient, a lubricant, a diluent, or a mixture thereof.

[0190] 28. The tablet according to Embodiment 27, wherein the stabilizer is xylitol, sorbitol, polydextrose, isomalt, dextrose, microcrystalline cellulose, fructose, or a mixture thereof.

[0191] 29. The tablet according to Embodiment 27 or 28, wherein the stabilizer is xylitol, fructose, or a mixture thereof.

[0192] 30. The tablet according to any one of Embodiments 27 to 29, wherein the weight percentage ratio of the fesoterodine or a pharmaceutically acceptable salt thereof to the stabilizer is about 1:20 to about 1:1 or about 1:10 to about 1:50 in the tablet.

[0193] 31. The tablet according to Embodiment 30, wherein the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt thereof to xylitol or fructose is about 1:9 to about 1:1 or about 1:18 to about 1:39 in the tablet.

[0194] 32. The tablet according to Embodiment 27, wherein the lubricant is talc, silicon dioxide, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof.

[0195] 33. The tablet according to Embodiment 32, wherein the lubricant is talc, glyceryl behenate, silicon dioxide, magnesium stearate, or a mixture thereof.

[0196] 34. The tablet according to Embodiment 33, wherein the lubricant is talc, glyceryl behenate, or a mixture thereof.

[0197] 35. The tablet according to Embodiment 27, wherein the controlled-release excipient is polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, or a mixture thereof.

[0198] 36. The tablet according to Embodiment 27, wherein the diluent is microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, or a mixture thereof.

[0199] 37. The tablet according to any one of Embodiments 20 to 36, wherein the tablet further comprises lactose, sodium starch glycolate, croscarmellose sodium, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or a mixture thereof.

[0200] 38. The portion comprising compound 1 or a pharmaceutically acceptable salt thereof Approximately 20 wt.% to 55 wt.% hydroxypropyl methylcellulose (HPMC); Approximately 4 wt.% to 50 wt.% of microcrystalline cellulose; Approximately 2 wt.% to 6 wt.% glyceryl behenate; Approximately 1 wt.% to approximately 4 wt.% of talc; and A tablet according to any one of Embodiments 21 to 37, optionally containing approximately 4 wt.% to approximately 50 wt.% of xylitol.

[0201] 39. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 50 wt.% to 80 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 3 wt.% to 8 wt.% sodium starch glycolate; Approximately 2 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of embodiments 25 to 38, containing approximately 1 wt.% to approximately 4 wt.% of talc.

[0202] 40. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 50 wt.% to 80 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 3 wt.% to 8 wt.% croscarmellose sodium; Approximately 2 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of embodiments 25 to 38, containing approximately 1 wt.% to approximately 4 wt.% of talc.

[0203] 41. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 50 wt.% to 80 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 3 wt.% to 8 wt.% of polyvinylpyrrolidone (PVP); Approximately 2 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of embodiments 25 to 38, containing approximately 1 wt.% to approximately 4 wt.% of talc.

[0204] 42. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 10 wt.% to 50 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 10 wt.% to 40 wt.% hydroxypropyl methylcellulose (HPMC); Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of embodiments 22-24 and 27-38, containing approximately 1 wt.% to approximately 4 wt.% of talc.

[0205] 43. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 8 wt.% to 50 wt.% xylitol; Approximately 10 wt.% to 50 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 20 wt.% to 50 wt.% cellulose ether; Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of embodiments 22-24 and 27-38, containing approximately 1 wt.% to approximately 4 wt.% of talc.

[0206] 44. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 8 wt.% to 50 wt.% xylitol; Approximately 10 wt.% to 50 wt.% of 75% lactose / 25% microcrystalline cellulose; 80% polyvinyl acetate (PVA) / 19% povidone, ranging from 10 wt.% to approximately 40 wt.%. Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of embodiments 22-24 and 27-38, containing approximately 1 wt.% to approximately 4 wt.% of talc.

[0207] 45. The tablet according to any one of Embodiments 25 to 41, wherein, when the tablet is tested for dissolution in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), it releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 10 hours, and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.1 to 1 hour.

[0208] 46. ​​The tablet according to any one of embodiments 22-24, 27-38, and 42-44, wherein when the tablet is tested for dissolution in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), it releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 12 hours, and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 1 to 7 hours or 5 to 12 hours.

[0209] 47. The composition is A sustained-release (ER) moiety comprising compound 1 or a pharmaceutically acceptable salt thereof; and An immediate-release (IR) coating containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on top of the ER portion, the tablet according to Embodiment 20 or 21.

[0210] 48. The tablet according to Embodiment 47, wherein the IR coating contains HPMC, triacetin, titanium dioxide, xanthan gum, lecithin, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate, methacrylate copolymer, talc, or a mixture thereof.

[0211] 49. The IR coating is (a) polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate 80, and talc; (b) HPMC, triacetin, and talc; (c) PVA, xylitol, PEG, polysorbate 80, and talc; (d) PVA, fructose, PEG, polysorbate 80, and talc; (e) a copolymer of PVA and PEG in a weight ratio of 3:1; (f) HPMC; (g) HPMC and xylitol; or (h) HPMC and fructose, the tablet according to Embodiment 47 or 48.

[0212] 50. The IR coating is (a) about 40 wt.% to about 60 wt.% of polyvinyl alcohol (PVA), about 10 wt.% to about 20 wt.% of polyethylene glycol (PEG), about 1 wt.% to about 5 wt.% of polysorbate 80, and about 20 wt.% to about 40 wt.% of talc; (b) about 70 wt.% to about 85 wt.% of HPMC, about 5 wt.% to about 10 wt.% of triacetin, and about 5 wt.% to about 10 wt.% of talc; (c) Approximately 25 wt.% to 50 wt.% of PVA, approximately 10 wt.% to 40 wt.% of xylitol, approximately 5 wt.% to 20 wt.% of PEG, approximately 1 wt.% to 5 wt.% of polysorbate 80, and approximately 10 wt.% to 30 wt.% of talc; (d) Approximately 20 wt.% to 40 wt.% of PVA, approximately 30 wt.% to 40 wt.% of fructose, approximately 5 wt.% to 15 wt.% of PEG, approximately 1 wt.% to 3 wt.% of polysorbate 80, and approximately 10 wt.% to 25 wt.% of talc; (e) A copolymer of polyvinyl alcohol and polyethylene glycol in a 3:1 wt.% to approximately 95 wt.% ratio in the coating; (f) HPMC of approximately 65 wt.% to 95 wt.%; (g) Approximately 40 wt.% to 60 wt.% HPMC and approximately 30 wt.% to 45 wt.% xylitol; or (h) A tablet according to Embodiment 49, comprising approximately 40 wt.% to approximately 60 wt.% HPMC and approximately 30 wt.% to approximately 45 wt.% fructose.

[0213] 51. The aforementioned tablets (i) A tablet according to any one of Embodiments 47 to 50, further comprising approximately 60 wt.% to approximately 70 wt.% of polyvinyl alcohol (PVA), approximately 15 wt.% to approximately 25 wt.% of talc, approximately 1 wt.% to approximately 5 wt.% of lecithin, and approximately 0.1 wt.% to approximately 1.5 wt.% of xanthan gum.

[0214] 52. A tablet according to any one of Embodiments 47 to 51, wherein the IR coating releases 80% of the fesoterodine within 0.5 to 2 hours when tested at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm).

[0215] 53. The composition according to any one of Embodiments 1 to 19, wherein the composition is an osmotic tablet.

[0216] 54. When the tablets were tested for dissolution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, approximately 80% of compound 1 or its pharmaceutically acceptable salt was dissolved within 4 to 16 hours, and An osmotic tablet according to Embodiment 53, which releases approximately 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 4 to 16 hours.

[0217] 55. The composition according to any one of Embodiments 1 to 19, wherein the composition is a multi-particle formulation.

[0218] 56. When the formulation was tested for elution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, approximately 80% of compound 1 or its pharmaceutically acceptable salt was eluted within 2 to 8 hours, and A multi-particle formulation according to Embodiment 55, which releases approximately 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 4 to 12 hours.

[0219] 57. A method for treating dyskinesia in a patient requiring treatment of dyskinesia, comprising administering a therapeutically effective amount of a composition according to any one of embodiments 1 to 20 and 53 to 56, or a tablet according to any one of embodiments 21 to 52.

[0220] 58. The method according to Embodiment 57, wherein the dyskinesia is levodopa-induced dyskinesia.

[0221] 58a. The method according to Embodiment 57, wherein the dyskinesia is slow-onset dyskinesia.

[0222] 59. The method according to embodiment 57 or 58, wherein the patient has been diagnosed with Parkinson's disease.

[0223] 60. A method for treating schizophrenia in a patient requiring treatment for schizophrenia, comprising administering a composition according to any one of embodiments 1 to 19 and 53 to 56, or a tablet according to any one of embodiments 20 to 52, in a therapeutically effective amount, said method.

[0224] 61. A method for treating Alzheimer's disease psychosis in a patient requiring treatment for Alzheimer's disease psychosis, comprising administering a composition according to any one of embodiments 1 to 19 and 53 to 56, or a tablet according to any one of embodiments 20 to 52, in a therapeutically effective amount, said method.

[0225] 62. A method for treating neuropathy in a patient requiring treatment for neuropathy, comprising administering a composition according to any one of embodiments 1 to 19 and 53 to 56, or a tablet according to any one of embodiments 20 to 52, in a therapeutically effective amount, wherein said neuropathy is excitement in Alzheimer's dementia, Lewy body disease with psychosis, Lewy body type dementia, bipolar manic episode, bipolar mixed episode, bipolar maintenance phase (bipolar type 1 and / or type 2), bipolar depression, or cognitive dysfunction in bipolar type 1 and / or type 2 disorder, said method.

[0226] 63. The method according to any one of embodiments 57 to 62, wherein the composition is administered once a day.

[0227] 63a. The method according to any one of embodiments 57 to 62, wherein one composition is administered once a day.

[0228] 63b. The method according to any one of embodiments 57 to 62, wherein two compositions are administered once a day.

[0229] 64. The method according to any one of embodiments 57 to 61, wherein the composition is administered twice a day.

[0230] 64a. The method according to any one of embodiments 57 to 61, wherein one composition is administered twice a day.

[0231] 64b. The method according to any one of embodiments 57 to 61, wherein the two compositions are administered twice daily.

[0232] 65a. Steady state C of compound 1 after oral administration as described above. avg The method according to any one of embodiments 57 to 64, wherein the concentration is greater than 100 ng / mL for at least 8 hours after administration.

[0233] 65b. Steady state C of compound 1 after oral administration as described above. avg The method according to any one of embodiments 57 to 64, wherein the concentration is greater than 100 ng / mL for at least 12 hours after administration.

[0234] 65c. Steady state C of compound 1 after oral administration as described above. avg The method according to any one of embodiments 57 to 64, wherein the concentration is greater than 100 ng / mL for at least 24 hours after administration.

[0235] 65d. Steady state C of compound 1 after oral administration. avg The method according to any one of embodiments 57 to 64, wherein the concentration is approximately 350 ng / mL to approximately 850 ng / mL for at least 8 hours after administration.

[0236] 65e. Steady state C of compound 1 after oral administration. avg The method according to any one of embodiments 57 to 64, wherein the concentration is approximately 350 ng / mL to approximately 850 ng / mL for at least 12 hours after administration.

[0237] 65f. Steady state C of compound 1 after oral administration as described above. avg The method according to any one of embodiments 57 to 64, wherein the concentration is approximately 350 ng / mL to approximately 850 ng / mL for at least 24 hours after administration.

[0238] 65 g. The method according to any one of Embodiments 57 to 64, wherein the plasma concentration ratio of compound 1 to desfesoterodine after oral administration is approximately 10:1 to approximately 200:1.

[0239] 65h. The C of compound 1 to desfesoterodine after oral administration as described above. max The method according to any one of embodiments 57 to 64, wherein the ratio is approximately 50:1 to approximately 250:1.

[0240] 66. D of compound 1 50 However, the composition according to any one of Embodiments 1 to 19 and 53 to 56, or the tablet according to any one of Embodiments 20 to 52, having a particle size of approximately 40 μm to approximately 50 μm.

[0241] 67. D of compound 1 90 However, the composition according to any one of Embodiments 1 to 19 and 53 to 56, or the tablet according to any one of Embodiments 20 to 52, having a particle size of approximately 200 μm to approximately 300 μm.

[0242] 68. The aforementioned tablets Approximately 20 wt.% to 40 wt.% of microcrystalline cellulose; Approximately 5 wt.% to 25 wt.% xylitol; Approximately 40 wt.% to approximately 60 wt.% hypromellose; and A tablet according to Embodiment 20, containing approximately 0.25 wt.% to approximately 0.75 wt.% magnesium stearate.

[0243] 69. The aforementioned tablets Approximately 5 wt.% to 15 wt.% lactose; Approximately 3 wt.% to 20 wt.% of microcrystalline cellulose; Approximately 0.1 wt.% to 0.6 wt.% sodium starch glycolate; Approximately 0.04 wt.% to 0.2 wt.% magnesium stearate; Approximately 0.5 wt.% to approximately 8 wt.% xylitol; and A tablet according to Embodiment 20, containing approximately 2 wt.% to approximately 8 wt.% of fructose. [Examples]

[0244] The present invention will be further described by reference to the following examples. These examples are illustrative and should not be construed as limiting the scope of the present invention in any way.

[0245] Example 1. Pharmacokinetics of Compound 1 and Fesoterodine Preparations The pharmacokinetics of compound 1 and the fesoterodine-containing formulation were evaluated. The C12C2 of compound 1 was evaluated after administration of compound 1 formulation (without fesoterodine) at various doses. max and AUC inf The observed and predicted values ​​(based on the power model) are shown in Figures 1A-B, 2, and 3A-C.

[0246] The mean plasma concentrations of compound 1 and 5-hydroxymethyltolterodine (5-HMT) were measured after administration of compound 1, fesoterodine, or compound 1 in combination with fesoterodine (fesoterodine was administered 30 minutes prior to compound 1) (Figures 4A-C).

[0247] The mean plasma concentrations of 5-HMT and compound 1 after administration of fesoterodine alone and in combination with fesoterodine and compound 1 are shown in Figures 5A-B. Figures 6A-B and 7A-B provide exposure corrections for exemplary compound 1 and 5-HMT metabolites in different subjects after administration of 60 mg, 90 mg, or 135 mg of compound 1 and 6 mg or 9 mg of fesoterodine.

[0248] As shown in Figure 15, after administration of 135 mg of compound 1 and 6 mg of fesoterodine, the concentration ratio of compound 1 and 5-HMT in plasma was consistently maintained over time.

[0249] Based on PK modeling, the plasma C of compound 1 max The concentration exceeded 3000 ng / mL, reaching 328 ng / mL in CSF. The target plasma concentration of compound 1 is 300 ng / mL, and the tolerable CSF level was predicted to be 10 times higher than the minimum effective exposure concentration level.max This enables BID administration using the formulation of the present disclosure (Figure 8A). Simulations based on Phase 1 SAD / MAD data show that to maintain compound 1 at or above therapeutic levels for 12 hours, a C concentration of 1200 ng / mL or higher is required. max It was predicted that this would be necessary. Based on efficacy data from multiple animal studies, the plasma C of compound 1 min It was predicted to be 300 ng / mL (and 25 ng / mL in CSF) (Figure 8B).

[0250] Figures 9A-C show the predicted exposure levels of compound 1 and 5-HMT after administration of compound 1 (ER) and fesoterodine (IR, 12-hour ER, or 8-hour ER) formulations.

[0251] Example 2. Compound 1 sustained-release core Polymer matrix formulations of compound 1 were prepared. The target in vitro release (IVR) profile was to release 80% of compound 1 within 8 hours using a USP instrument type 2, 0.1N HCl acidic solution (or pH 6.8 phosphate buffer), and a paddle speed of 50 rpm. Formulations were prepared containing different polymer types (e.g., high molecular weight HPMC, PEO, and mixtures thereof); fillers (soluble / insoluble fillers); tablet sizes (1000-1300 mg); and dose strengths (40 mg-250 mg of compound 1). The dissolution test results of the test formulations are shown in Figures 10A-G.

[0252] Based on these data, 40 mg and 125 mg sustained-release (ER) tablets (Compound 1) were prepared for clinical trials (Table 1). The manufacturing processes for these formulations are shown in Figure 11.

[0253] [Table 1]

[0254] The test results for these formulations are summarized in Table 2. The results from the dissolution test are shown in Figure 12.

[0255] [Table 2] As shown in Figures 13A-B, the robustness of these formulations to stirring conditions was tested using a USP3 dissolution device at 30 dpm. The dissolution profile obtained using the USP3 method at 30 dpm was the same as that obtained using the USP2 dissolution test.

[0256] Example 3. Sustained-release compound 1 and immediate-release fesoterodine composition (two-layer tablet) Four bilayer tablet formulations, some with and some without stabilizers, were prepared and subjected to accelerated stability testing. The compositions of the formulations are shown in Table 3.

[0257] [Table 3]

[0258] Figure 14A compares the elution profiles of formulations containing xylitol as a stabilizer and formulations without a stabilizer, measured using a USP instrument type 2, pH 6.8 phosphate buffer, and a paddle speed of 50 rpm. No significant differences were observed in the release profiles of fesoterodine and compound 1 for these formulations.

[0259] The formulations shown in Table 4 were prepared. Xylitol and fesoterodine fumarate were used in a 9:1 weight ratio in these formulations (wet granulation). The compound 1 blend was prepared via direct tableting.

[0260] [Table 4]

[0261] Example 4. Sustained-release compound 1 and sustained-release fesoterodine composition (two-layer tablet) The formulations shown in Table 5 were prepared. The in vitro release (IVR) target for these formulations was to release 80% of fesoterodine within 2-8 hours and 80% of compound 1 within 2-12 hours, using a USP instrument type 2 with pH 6.8 phosphate buffer and a paddle speed of 50 rpm (Figure 14B).

[0262] As shown in Tables 5a-d, additional formulations were prepared.

[0263] [Table 5]

[0264] [Table 6-1] [Table 6-2]

[0265] [Table 7]

[0266] [Table 8]

[0267] [Table 9]

[0268] Example 5. Sustained-release (ER) compound 1 and immediate-release (IR) fesoterodine coated formulations Tablets containing an immediate-release fesoterodine coating on a sustained-release (ER) compound 1 core were prepared.

[0269] Tables 6a and 6b show the composition of exemplary IR fesoterodine coated compound 1 (ER) tablets.

[0270] [Table 10-1] [Table 10-2]

[0271] [Table 11-1] [Table 11-2]

[0272] Example 6. Osmotic tablets and multi-particle PK test Osmotic tablets and multi-particle formulations containing compound 1 and fesoterodine will be prepared.

[0273] The release profile for the osmotic tablets is as follows: Determined using a USP instrument type 2, pH 6.8 phosphate buffer, and a paddle speed of 50 rpm, 80% of both fesoterodine and compound 1 are released over 4 to 16 hours (zero-order release).

[0274] The release profile for the multi-particle formulation is as follows: Determined using a USP instrument type 2, pH 6.8 phosphate buffer, and a paddle speed of 50 rpm, 80% of fesoterodine is released in 2-8 hours, and 80% of compound 1 is released in 4-12 hours.

[0275] Example 7. Effect of Compound 1 on amphetamine-induced hyperactivity (AIH) The effect of compound 1 in a mouse model of amphetamine-induced hyperactivity (AIH) was evaluated.

[0276] Compound 1 dose-dependently reduced AIH, showing significant effects at 0.3, 0.6, and 1 mg / kg when measured in a 30-minute open-field exercise test (p<0.0001, one-way ANOVA) (Figures 16A-B). These results demonstrate that Compound 1 reverses hyperdopaminergic-mediated motor behavior in a dose-dependent manner. These data provide evidence of the treatment potential of Compound 1 for psychotic disorders, such as schizophrenia, Alzheimer's disease, and Parkinson's disease, as well as levodopa-induced dyskinesia.

[0277] The effect of co-administration of compound 1 and fesoterodine on AIH was also evaluated. Co-administration of compound 1 alone at 1.0 mg / kg, as well as co-administration with fesoterodine at 0.3 mg and 1.0 mg / kg, inhibited AIH to a similar degree, demonstrating that co-administration of fesoterodine does not have a significant inhibitory effect on the activity of compound 1 in the CNS.

[0278] Example 8. Effect of Compound 1 on phencyclidine-induced hyperactivity The effect of compound 1 on phencyclidine (PCP)-induced hyperdopaminergic motor behavior was evaluated.

[0279] Mice were acclimatized to the behavioral testing chamber for at least 30 minutes prior to the test. Lighting of 50 ± 20 LUX was maintained during the test. Mice were weighed, administered intravenously with either 0.3, 0.6, or 1 mg / kg of compound 1, and rapidly and sequentially administered 5 mg / kg of PCP subcutaneously. Immediately afterward, they were placed in an open field arena (44 cm × 44 cm × 20 cm) where they were allowed to freely explore the space. Their position and distance traveled were monitored for 30 minutes using an automated video tracking system.

[0280] Spontaneous motor behavior was measured using an automated video tracking system (Noldus EthoVision v15). Data were presented over time and summarized as the average total distance traveled after treatment. Statistical significance was tested using one-way ANOVA followed by Dunnett's multiple comparison test, n=16 / group.

[0281] As shown in Figures 17A and 17B, compound 1 dose-dependently reduced PCP-induced hyperactivity, showing significant effects at 0.3, 0.6, and 1 mg / kg in 30-minute measurements (p<0.0001, one-way ANOVA).

[0282] Example 9. Effect of Compound 1 on Alzheimer's disease The effect of compound 1 on resident intruder aggression was evaluated in a Tg2576 mouse model of Alzheimer's disease. Compound 1, at 0.5 mg / kg, reduced both the number and duration of attacks in Tg2576 mice (p<0.05, paired t-test), supporting the conclusion that compound 1 has anti-aggression activity.

[0283] Example 10: Effect of Compound 1 on MPTP-induced dyskinesia The effect of compound 1 on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dyskinesia was evaluated.

[0284] The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was discovered as an impurity in heroin and identified as a compound that selectively induces degeneration of dopaminergic neurons in the substantia nigra when users present with clinical symptoms indistinguishable from Parkinson's disease (PD). Currently, it is used in non-human primates to model the phenotype of major Parkinson's disease motor symptoms and subsequent responses to treatments such as L-DOPA, including dyskinesia, and can therefore be used as a foundational model for LID. See Huat 2012. (Huot P, Johnston TH, Koprich JB, Fox SH, Brotchie JM. L-DOPA pharmacokinetics in the MPTP-lesioned macaque model of Parkinson's disease. Neuropharmacology. 2012 Oct;63(5):829-36). Because it possesses both face validity and construct validity, the MPTP non-human primate model is considered the animal model of PD motor symptoms with the highest translational relevance.

[0285] The study was conducted in seven female cynomolgus monkeys with MPTP lesions. These monkeys were chronically treated with L-dopa, inducing stable and reproducible dyskinesia with choreiform and dystonic characteristics. In each test animal, a single dose of 1 mg / kg of compound 1 or vehicle was administered in combination with a high dose of L-dopa (Madopar®) adjusted according to the LID symptoms, and the monkeys' behavior was evaluated. The "on-time" therapeutic effect and abnormal LID movements were evaluated over a 6-hour period after L-dopa administration. At the start of behavioral observation, a single oral dose of 1 mg / kg of compound 1 or vehicle was administered simultaneously with L-dopa. All animals received all treatments in a crossover design, with a minimum interval of 72 hours between repeated treatments in each animal. Treatment behaviors and LID behaviors were scored in a blinded manner by trained evaluators supervised by neurologists, using high-definition video recordings and the Non-Human Primate Dyskinesia Rating Scale. See Fox 2012. (Fox SH, Johnston TH, Li Q, Brotchie J, Bezard EA critique of available scales and presentation of the Non-Human Primate Dyskinesia Rating Scale. Mov Disord. 2012 Sep 15;27(11):1373-8).

[0286] Compound 1 (1 mg / kg, PO) demonstrated a significant anti-dyskinesia effect, reducing the median dyskinesia level by 91% during the 0–1 hour period (median level 11 vs. 1, vehicle vs. compound 1, p<0.001). A substantial reduction in LID was observed in 6 out of 7 animals included in the final analysis. Cumulatively over 0–2 hours, the median dyskinesia level decreased by 42%, becoming non-disruptive (median level 33 vs. 19; vehicle vs. compound 1, P=0.0156). This significant reduction in peak-effect dyskinesia was further demonstrated by a beneficial reduction (41%) in the duration of “poor” on-time (on-time with disruptive dyskinesia) and a significant increase (143%) in the duration of “good” on-time (on-time without dyskinesia or with only non-disruptive dyskinesia). Compound 1 did not reduce the anti-Parkinsonian benefit of L-DOPA or the overall duration of the on-time associated with L-DOPA.

[0287] These results from the MPTP-induced dyskinesia cynomolgus monkey study provide strong evidence that compound 1 has therapeutic potential for dyskinesia, such as LID, in PD patients.

[0288] Example 11. Effect of Compound 1 on late-onset dyskinesia The effect of compound 1 on tardive dyskinesia in a chronic haloperidol mouse model was evaluated.

[0289] Tardive dyskinesia (TD) can be a side effect of treatment with atypical antipsychotics. Chronic haloperidol treatment induces symptoms of TD in mice. These symptoms include venous mastication (VCM), which consists of micromanagement, frequent jaw / oral tremors, and purposeless vertical opening of the mouth, with or without tongue protrusion.

[0290] Compound 1 at 0.5 mg / kg significantly reduced VCM in a chronic haloperidol mouse model of TD (p<0.001, one-sided paired t-test).

[0291] Example 12. Comparative PK study of oral administration of one compound with and without fesoterodine in healthy adults. This study is an open-label, comparative PK / bioavailability study of oral administration of a compound with or without fesoterodine in healthy adults under fed or fasting conditions.

[0292] The objectives of this study are to evaluate the single-dose and multi-dose pharmacokinetics (PK) of compound 1, fesoterodine, and its active metabolite desfesoterodine in plasma and cerebrospinal fluid (CSF); to evaluate the safety and tolerability of compound 1 formulations with or without fesoterodine; and to evaluate the effect of fesoterodine on the PK of compound 1. The evaluation items of this study are the measurement of non-compartment PK parameters of compound 1, fesoterodine, and its bioactive metabolite desfesoterodine, including the area under the concentration-time curve (AUC) and the maximum observed concentration (C). max ) and C max Arrival time (T max ) is included.

[0293] Dosage: Administer a solution containing 32 mg of compound 1. For orally disintegrating tablets (ODTs), administer a maximum dose of 32 mg of compound 1 (e.g., 8 mg, 16 mg, 24 mg, and 32 mg). For sustained-release formulations, administer a starting dose of 40 mg of compound 1, and the dose can be increased up to a maximum of 375 mg (e.g., 80 mg, 125 mg, 165 mg, and 375 mg). When compound 1 is co-administered with fesoterodine, administer 3 mg of fesoterodine.

[0294] Example 13. Clinical observation and pharmacokinetics of orally administered compound 1 / fesoterodine preparation. Studies were conducted to characterize the pharmacokinetic (PK), safety, and tolerability profiles of compound 1 and fesoterodine fumarate in healthy adult human subjects. Subjects were administered single doses of compound 1 HCl and fesoterodine fumarate (ER / ER tablets, F25-F28, Example 4) in dose-intensity combinations selected from Table 7. The once-daily (QD) cohort received 165 mg / 3 mg, 210 mg / 3 mg, 270 mg / 6 mg, and 330 mg / 6 mg. The twice-daily (BID) cohort received 105 mg / 1.5 mg, 165 mg / 3 mg, and 210 mg / 3 mg.

[0295] [Table 12]

[0296] Results: Steady-state PK data for seven drug cohorts (165 mg / 3 mg QD, 210 mg / 3 mg QD, 270 mg / 6 mg QD, 330 mg / 6 mg QD, 105 mg / 1.5 mg BID, 165 mg / 3 mg BID, and 210 mg / 3 mg BID) are summarized in Tables 8A-B. In all cohorts, therapeutically effective target plasma compound 1 concentrations of 100 ng / mL or higher were maintained for 24 hours post-administration (steady-state C). avg (Range levels of 350 ng / mL to 850 ng / mL were observed). All doses were well-tolerated, and no serious, treatment-induced adverse events (TEAEs) were reported.

[0297] [Table 13]

[0298] [Table 14]

[0299] Built-in by reference All references, articles, publications, patents, patent gazettes, and patent applications cited herein are incorporated by reference in their entirety for all purposes. However, nothing in the references, articles, publications, patents, patent gazettes, and patent applications cited herein should be construed as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of common general knowledge in any country of the world.

Claims

1. (a) Compound 1 in an amount of approximately 10 mg to approximately 500 mg 【Chemistry 1】 or a pharmaceutically acceptable salt thereof; and (b) A composition comprising about 1 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof; After administration of the composition, oral administration of the composition to patients who require it results in the t of compound 1. ｍａｘ However, the t of desfesoterodine lasts for approximately 0.1 to 10 hours. ｍａｘ However, the composition has a shelf life of approximately 0.1 hours to approximately 10 hours.

2. Oral administration of the above composition results in the t of compound 1. ｍａｘ The composition according to claim 1, wherein the period after administration of the composition is approximately 1.5 hours to approximately 8 hours.

3. Oral administration of the above composition results in the t of desfesoterodine. ｍａｘ The composition according to claim 1 or 2, wherein the period after administration of the composition is approximately 1 hour to approximately 8 hours.

4. Oral administration of the above composition results in the C of compound 1. ｍａｘ，ｓｓ The composition according to any one of claims 1 to 3, wherein, after administration of the composition, the concentration becomes approximately 200 ng / mL to approximately 5,000 ng / mL.

5. Oral administration of the above composition results in the C of desfesoterodine. ｍａｘ，ｓｓ The composition according to any one of claims 1 to 4, wherein the concentration becomes approximately 2 ng / mL to approximately 60 ng / mL after administration of the composition.

6. AUC of compound 1 upon oral administration of the composition ０－２４ｈ，ｓｓ The composition according to any one of claims 1 to 5, wherein, after administration of the composition, the concentration becomes approximately 4,000 ng·h / mL to approximately 40,000 ng·h / mL.

7. AUC of desfesoterodine upon oral administration of the above composition ０－２４ｈ，ｓｓ The composition according to any one of claims 1 to 6, wherein, after administration of the composition, the concentration becomes approximately 5 ng·h / mL to approximately 600 ng·h / mL.

8. The composition according to any one of claims 1 to 7, wherein the plasma concentration ratio of compound 1 to desfesoterodine after oral administration of the composition is about 10:1 to about 400:

1.

9. The composition according to any one of claims 1 to 8, wherein the C ｍａｘ ratio of compound 1 to desfesoterodine upon oral administration of the composition is from about 50:1 to about 600:

1. ｍａｘ ​

10. (a) about 40 mg to about 500 mg of compound 1 or a pharmaceutically acceptable salt thereof; and (b) A composition comprising about 1 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof; When the composition was tested for elution in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), Approximately 80% of the compound 1 or its pharmaceutically acceptable salt within 2 to 12 hours; and Approximately 80% of the fesoterodine or a pharmaceutically acceptable salt thereof is released within 0.2 to 12 hours. The aforementioned composition.

11. The composition according to any one of the prior claims, wherein the composition comprises about 50 mg to about 600 mg of compound 1 or a pharmaceutically acceptable salt thereof.

12. The composition according to any one of the prior claims, wherein the composition comprises about 100 mg to about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof.

13. The composition according to any one of the prior claims, wherein the composition comprises about 100 mg to about 350 mg of compound 1 or a pharmaceutically acceptable salt thereof.

14. The composition according to any one of the prior claims, wherein the composition comprises about 100 mg to about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof.

15. The composition according to any one of the prior claims, wherein the composition comprises about 105 mg, about 165 mg, about 210 mg, about 270 mg, or 330 mg of compound 1 or a pharmaceutically acceptable salt thereof.

16. The composition according to any one of the prior claims, wherein the composition comprises about 1.5 mg to about 12 mg of fesoterodine or a pharmaceutically acceptable salt thereof.

17. The composition according to any one of the prior claims, wherein the composition comprises fesoterodine fumarate.

18. The composition according to any one of the prior claims, wherein the weight percentage ratio of the compound to fesoterodine in the composition is about 40:1 to about 90:

1.

19. The composition according to any one of the prior claims, wherein the weight percentage ratio of the compound to fesoterodine in the composition is about 46:1 to about 70:

1.

20. The composition according to any one of the prior claims, wherein the composition is a tablet.

21. The tablet according to claim 20, wherein the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof.

22. The tablet according to claim 20 or 21, wherein the tablet comprises a sustained-release (ER) portion containing fesoterodine or a pharmaceutically acceptable salt thereof.

23. The tablet according to any one of claims 20 to 22, wherein the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof and a sustained-release (ER) portion containing fesoterodine or a pharmaceutically acceptable salt thereof.

24. (a) A first ER portion comprising compound 1 or a pharmaceutically acceptable salt thereof; and (b) The tablet according to claim 23, comprising a second ER portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the first portion and the second portion constitute a two-layer tablet.

25. The tablet according to claim 21, wherein the tablet comprises an immediate-release (IR) portion containing fesoterodine or a pharmaceutically acceptable salt thereof.

26. (a) an ER portion comprising compound 1 or a pharmaceutically acceptable salt thereof; and (b) The tablet according to claim 25, comprising an IR portion containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion are formed in a two-layer tablet.

27. The tablet according to any one of claims 20 to 26, further comprising a stabilizer, a controlled-release excipient, a lubricant, a diluent, or a mixture thereof.

28. The tablet according to claim 27, wherein the stabilizer is xylitol, sorbitol, polydextrose, isomalt, dextrose, microcrystalline cellulose, fructose, or a mixture thereof.

29. The tablet according to claim 27 or 28, wherein the stabilizer is xylitol, fructose, or a mixture thereof.

30. The tablet according to any one of claims 27 to 29, wherein the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt thereof to the stabilizer is about 1:20 to about 1:1 in the tablet.

31. The tablet according to claim 30, wherein the weight percentage ratio of fesoterodine or a pharmaceutically acceptable salt thereof to xylitol or fructose is about 1:18 to about 1:39 in the tablet.

32. The tablet according to claim 27, wherein the lubricant is talc, silicon dioxide, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof.

33. The tablet according to claim 32, wherein the lubricant is talc, glyceryl behenate, silicon dioxide, magnesium stearate, or a mixture thereof.

34. The tablet according to claim 33, wherein the lubricant is talc, glyceryl behenate, or a mixture thereof.

35. The tablet according to claim 27, wherein the controlled-release excipient is polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropylcellulose (HPC), sodium carboxymethylcellulose, or a mixture thereof.

36. The tablet according to claim 27, wherein the diluent is microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, or a mixture thereof.

37. The tablet according to any one of claims 20 to 36, wherein the tablet further comprises lactose, sodium starch glycolate, croscarmellose sodium, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or a mixture thereof.

38. The portion comprising the compound 1 or a pharmaceutically acceptable salt thereof Approximately 20 wt.% to approximately 55 wt.% hydroxypropyl methylcellulose (HPMC); Microcrystalline cellulose in a concentration of approximately 4 wt.% to 50 wt.%; Approximately 2 wt.% to 6 wt.% glyceryl behenate; Approximately 1 wt.% to approximately 4 wt.% talc; and A tablet according to any one of claims 21 to 37, optionally containing approximately 4 wt.% to approximately 50 wt.% of xylitol.

39. The portion comprising the compound 1 or a pharmaceutically acceptable salt thereof HPMC of approximately 40 wt.% to 60 wt.% Approximately 20 wt.% to 25 wt.% microcrystalline cellulose; Approximately 5 wt.% to approximately 20 wt.% xylitol; and A tablet according to any one of claims 21 to 37, comprising approximately 0.1 wt.% to approximately 0.4 wt.% of magnesium stearate.

40. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 50 wt.% to 80 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 3 wt.% to approximately 8 wt.% sodium starch glycolate; Approximately 2 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 25 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

41. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 50 wt.% to 80 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 3 wt.% to approximately 8 wt.% croscarmellose sodium; Approximately 2 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 25 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

42. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 50 wt.% to 80 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 3 wt.% to 8 wt.% polyvinylpyrrolidone (PVP); Approximately 2 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 25 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

43. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 10 wt.% to 50 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 10 wt.% to approximately 40 wt.% hydroxypropyl methylcellulose (HPMC); Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 22 to 24 and 27 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

44. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 8 wt.% to approximately 50 wt.% xylitol; Approximately 10 wt.% to 50 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 20 wt.% to 50 wt.% cellulose ether; Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 22 to 24 and 27 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

45. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 8 wt.% to approximately 50 wt.% xylitol; Approximately 10 wt.% to 50 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 10 wt.% to 40 wt.% of 80% polyvinyl acetate (PVA) / 19% povidone; Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 22 to 24 and 27 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

46. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; Approximately 10 wt.% to 40 wt.% of 75% lactose / 25% microcrystalline cellulose; HPMC of approximately 20 wt.% to 40 wt.%; Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 22 to 24 and 27 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

47. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 50 wt.% xylitol; MCC of approximately 20 wt.% to 40 wt.%; HPMC of approximately 20 wt.% to 40 wt.%; Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 22 to 24 and 27 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

48. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 8 wt.% to 20 wt.% xylitol; Approximately 10 wt.% to 40 wt.% of 75% lactose / 25% microcrystalline cellulose; Approximately 10 wt.% to 30 wt.% lactose; HPMC in a quantity of approximately 10 wt.% to 40 wt.%; Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 22 to 24 and 27 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

49. The portion comprising fesoterodine or a pharmaceutically acceptable salt thereof Approximately 10 wt.% to 40 wt.% xylitol; Approximately 10 wt.% to 20 wt.% lactose; MCC of approximately 10 wt.% to approximately 40 wt.%; HPMC of approximately 20 wt.% to 40 wt.%; Approximately 1 wt.% to approximately 6 wt.% glyceryl behenate; and A tablet according to any one of claims 22 to 24 and 27 to 39, comprising approximately 1 wt.% to approximately 4 wt.% of talc.

50. When the tablets were tested for dissolution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, approximately 80% of compound 1 or its pharmaceutically acceptable salt was dissolved within 2 to 10 hours, and A tablet according to any one of claims 25 to 42, which releases about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 0.1 to 1 hour.

51. The tablet according to any one of claims 22-24, 27-38, and 43-49, wherein when the tablet is tested for dissolution in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C using a United States Pharmacopeia apparatus II (paddle speed 50 rpm), it releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 12 hours, and about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 1 to 7 hours or 5 to 12 hours.

52. The composition is A sustained-release (ER) moiety comprising compound 1 or a pharmaceutically acceptable salt thereof; and A tablet according to claim 20 or 21, comprising an immediate-release (IR) coating containing fesoterodine or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on the ER portion.

53. The tablet according to claim 52, wherein the IR coating comprises HPMC, triacetin, titanium dioxide, xanthan gum, lecithin, polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate, methacrylate copolymer, talc, or a mixture thereof.

54. The aforementioned IR coating (a) Polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate 80, and talc; (b) HPMC, triacetin, and talc; (c) PVA, xylitol, PEG, polysorbate 80, and talc; (d) PVA, fructose, PEG, polysorbate 80, and talc; (e) A copolymer of PVA and PEG in a 3:1 weight percentage ratio; (f) HPMC; (g) HPMC and xylitol; or (h) The tablet according to claim 52 or 53, comprising HPMC and fructose.

55. The aforementioned IR coating (a) Approximately 40 wt.% to 60 wt.% polyvinyl alcohol (PVA), approximately 10 wt.% to 20 wt.% polyethylene glycol (PEG), approximately 1 wt.% to 5 wt.% polysorbate 80, and approximately 20 wt.% to 40 wt.% talc; (b) Approximately 70 wt.% to 85 wt.% HPMC, approximately 5 wt.% to 10 wt.% triacetin, and approximately 5 wt.% to 10 wt.% talc; (c) Approximately 25 wt.% to 50 wt.% of PVA, approximately 10 wt.% to 40 wt.% of xylitol, approximately 5 wt.% to 20 wt.% of PEG, approximately 1 wt.% to 5 wt.% of polysorbate 80, and approximately 10 wt.% to 30 wt.% of talc; (d) Approximately 20 wt.% to 40 wt.% of PVA, approximately 30 wt.% to 40 wt.% of fructose, approximately 5 wt.% to 15 wt.% of PEG, approximately 1 wt.% to 3 wt.% of polysorbate 80, and approximately 10 wt.% to 25 wt.% of talc; (e) A copolymer of polyvinyl alcohol and polyethylene glycol in a 3:1 wt.% ratio, approximately 85 wt.% to approximately 95 wt.% in the coating; (f) HPMC of approximately 65 wt.% to approximately 95 wt.%; (g) Approximately 40 wt.% to 60 wt.% HPMC and approximately 30 wt.% to 45 wt.% xylitol; or (h) The tablet according to claim 54, comprising approximately 40 wt.% to approximately 60 wt.% HPMC and approximately 30 wt.% to approximately 45 wt.% fructose.

56. The aforementioned tablet, (i) A tablet according to any one of claims 52 to 55, further comprising approximately 60 wt.% to approximately 70 wt.% of polyvinyl alcohol (PVA), approximately 15 wt.% to approximately 25 wt.% of talc, approximately 1 wt.% to approximately 5 wt.% of lecithin, and approximately 0.1 wt.% to approximately 1.5 wt.% of xanthan gum.

57. The tablet according to any one of claims 52 to 56, wherein the IR coating releases 80% of the fesoterodine within 0.5 to 2 hours when tested at 37°C in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (paddle speed 50 rpm).

58. The composition according to any one of claims 1 to 19, wherein the composition is an osmotic tablet.

59. When the tablets were tested for dissolution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, approximately 80% of compound 1 or its pharmaceutically acceptable salt was dissolved within 4 to 16 hours, and The osmotic tablet according to claim 58, which releases about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 4 to 16 hours.

60. The composition according to any one of claims 1 to 19, wherein the composition is a multi-particle formulation.

61. When the formulation was tested for elution using a United States Pharmacopeia apparatus II (paddle speed 50 rpm) in 900 mL of 0.1 N HCl or pH 6.8 phosphate buffer at 37°C, approximately 80% of compound 1 or its pharmaceutically acceptable salt was eluted within 2 to 8 hours, and The multi-particle formulation according to claim 60, which releases about 80% of fesoterodine or a pharmaceutically acceptable salt thereof within 4 to 12 hours.

62. A method for treating dyskinesia in a patient requiring treatment for dyskinesia, comprising administering a therapeutically effective amount of the composition according to any one of claims 1 to 19 and 58 to 61, or a tablet according to any one of claims 20 to 57.

63. The method according to claim 62, wherein the dyskinesia is levodopa-induced dyskinesia or tardive dyskinesia.

64. The method according to claim 62 or 63, wherein the patient has been diagnosed with Parkinson's disease.

65. A method for treating Parkinson's disease psychosis in a patient requiring treatment for Parkinson's disease psychosis, comprising administering a therapeutically effective amount of the composition according to any one of claims 1 to 19 and 58 to 61, or a tablet according to any one of claims 20 to 57.

66. A method for treating schizophrenia in a patient requiring treatment for schizophrenia, comprising administering a therapeutically effective amount of the composition according to any one of claims 1 to 19 and 58 to 61, or a tablet according to any one of claims 20 to 57.

67. A method for treating Alzheimer's disease in a patient requiring treatment for Alzheimer's disease, comprising administering a therapeutically effective amount of the composition according to any one of claims 1 to 19 and 58 to 61, or a tablet according to any one of claims 20 to 57.

68. The method according to any one of claims 62 to 66, wherein the composition is administered once a day.

69. The method according to any one of claims 62 to 66, wherein the composition is administered twice a day.

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