Compositions for treating neurological disorders

Abstract

Combination compositions of Compound 1 and fesoterodine for use in the treatment of neurological disorders, such as schizophrenia, Alzheimer's disease psychosis, Parkinson's disease psychosis, cognitive in Alzheimer's disease, psychosis in Lewy body dementia, bipolar disorder, and dyskinesia, are described.

Description

Cross Reference to Related Applications

[0001] This application claims the priority benefit of and priority to U.S. Provisional Application No. 63 / 504,306, filed May 25, 2023, U.S. Provisional Application No. 63 / 578,804, filed August 25, 2023, U.S. Provisional Application No. 63 / 540,277, filed September 25, 2023, and U.S. Provisional Application No. 63 / 556,028, filed February 21, 2024, the disclosure of each of which is hereby incorporated by reference in its entirety for all purposes. BACKGROUND

[0002] Neurological disorders are now the leading 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, cognition in Alzheimer’s disease, psychosis in Lewy Body Dementia, bipolar disorder, and movement disorders including levodopa-induced dyskinesia and tardive dyskinesia.

[0003] The present disclosure provides compositions comprising an M1 / M4 muscarinic agonist (Compound 1) co-formulated with a peripherally active muscarinic receptor antagonist (fesoterodine fumarate) and methods for treating neurological disorders such as schizophrenia, Alzheimer’s disease psychosis, Parkinson’s Disease psychosis, cognition in Alzheimer’s disease, psychosis in Lewy Body Dementia, bipolar disorder, and movement disorders including levodopa-induced dyskinesia and tardive dyskinesia. SUMMARY

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

[0005] In embodiments, the present disclosure provides a composition comprising: (a) about 10 mg to about 500 mg of Compound 1 Compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 2 mg to about 20 mg of fesoterodine or a pharmaceutically acceptable salt thereof; wherein oral administration of the composition to a patient in need thereof provides a t max of Compound 1 of about 0.1 h to about 8 h and a t max of about 0.1 h to about 8 h of fesoterodine (also known as 5-hydroxymethyl tolterodine or 5-HMT) after administration of the composition.

[0006] In embodiments, 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 desloratadine, or a pharmaceutically acceptable salt thereof; wherein oral administration of the composition to a patient in need thereof provides a t max of Compound 1 of about 0.1 h to about 8 h and a t max of desloratadine of about 0.1 h to about 8 h after administration of the composition.

[0007] In embodiments, administration of the composition of the present disclosure provides a t max of Compound 1 of about 0.5 h to about 4 h and a t max of desloratadine of about 0.5 h to about 4 h after administration of the composition.

[0008] In embodiments, oral administration of the composition provides a C max,ss of Compound 1 of about 200 ng / mL to about 5,000 ng / mL and a C max,ss of desloratadine of about 2 ng / mL to about 60 ng / mL after administration of the composition.

[0009] In embodiments, oral administration of the composition provides an AUC 0-24h,ss of Compound 1 of about 4,000 ng·h / mL to about 40,000 ng·h / mL and an AUC 0-24h,ss of desloratadine of about 20 ng·h / mL to about 600 ng·h / mL after administration of the composition. max In embodiments, oral administration of the composition provides a plasma concentration ratio of Compound 1 to desloratadine of about 10: 1 to about 800: 1. In embodiments, oral administration of the composition provides a plasma concentration ratio of Compound 1 to desloratadine of about 50: 1 to about 250: 1. max In embodiments, oral administration of the composition provides a plasma concentration ratio of Compound 1 to desloratadine of about 50: 1 to about 600: 1. 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 or about 3 mg to about 20 mg of fesoxodine or a pharmaceutically acceptable salt thereof; wherein the composition releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 12 h; and about 80% of fesoxodine, or a pharmaceutically acceptable salt thereof, within 0.2 h to 8 h, the release tested for dissolution using a USP Apparatus II (paddle, 50 rpm) in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer at 37 °C. 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 or about 3 mg to about 20 mg of fesoxodine or a pharmaceutically acceptable salt thereof; wherein the composition releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 18 h; and about 80% of fesoxodine, or a pharmaceutically acceptable salt thereof, within 0.2 h to 8 h, the release tested for dissolution using a USP Apparatus II (paddle, 50 rpm) in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer at 37 °C.

[0010] 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 fesoxodine or a pharmaceutically acceptable salt thereof; wherein the composition releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 12 h; and about 80% of fesoxodine, or a pharmaceutically acceptable salt thereof, within 0.2 h to 12 h, the release tested for dissolution using a USP Apparatus II (paddle, 50 rpm) in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer at 37 °C. 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 fesoxodine or a pharmaceutically acceptable salt thereof; wherein the composition releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 18 h; and about 80% of fesoxodine, or a pharmaceutically acceptable salt thereof, within 0.2 h to 12 h, the release tested for dissolution using a USP Apparatus II (paddle, 50 rpm) in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer at 37 °C.

[0011] In embodiments, the composition comprises about 50 mg to about 600 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 100 mg to about 400 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 150 mg to about 350 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 200 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 100 mg to about 300 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 100 mg to about 200 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 250 mg of Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 105 mg, about 165 mg, or about 210 mg of Compound 1, or a pharmaceutically acceptable salt thereof.

[0012] In embodiments, the composition comprises about 3 mg to about 12 mg of

[0013] In embodiments, the composition comprises Compound 1 and furosemide. In embodiments, the weight % ratio of Compound 1 to furosemide in the composition is about 40:1 to about 90:1. In embodiments, the weight % ratio of Compound 1 and furosemide in the composition is about 20:1 to about 40:1 (weight %). In embodiments, the weight % ratio of Compound 1 and furosemide in the composition is about 46:1 or about 55:1, or about 70:1 (weight %).

[0014] In embodiments, the composition of the present disclosure is formulated as a tablet. In embodiments, the tablet comprises an extended release (ER) portion comprising Compound 1, or a pharmaceutically acceptable salt thereof. In embodiments, the tablet comprises an extended release (ER) portion comprising furosemide, or a pharmaceutically acceptable salt thereof.

[0015] In embodiments, the tablet comprises an extended release (ER) portion comprising Compound 1, or a pharmaceutically acceptable salt thereof, and an extended release (ER) portion comprising Fesoterodine, or a pharmaceutically acceptable salt thereof. In embodiments, the tablet of the present disclosure comprises (a) a first ER portion comprising Compound 1, or a pharmaceutically acceptable salt thereof; or (b) a second ER portion comprising Fesoterodine, or a pharmaceutically acceptable salt thereof, wherein the first portion and the second portion are configured in a bilayer tablet. In embodiments, the tablet releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 12 h and about 80% of Fesoterodine, or a pharmaceutically acceptable salt thereof, within 1 h to 7 h or 5 h to 12 h, the release being tested for dissolution at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle at 50 rpm). In embodiments, the tablet releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 18 h and about 80% of Fesoterodine, or a pharmaceutically acceptable salt thereof, within 1 h to 7 h or 5 h to 12 h, the release being tested for dissolution at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle at 50 rpm).

[0016] In embodiments, the tablet comprises an immediate release (IR) portion comprising Fesoterodine, or a pharmaceutically acceptable salt thereof. In embodiments, the tablet of the present disclosure comprises (a) an ER portion comprising Compound 1, or a pharmaceutically acceptable salt thereof; or (b) an IR portion comprising Fesoterodine, or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion are configured in a bilayer tablet. In embodiments, the tablet releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 10 h and about 80% of Fesoterodine, or a pharmaceutically acceptable salt thereof, within 0.1 h to 1 h, the release being tested for dissolution at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle at 50 rpm).

[0017] In embodiments, the tablet further comprises a stabilizer, a controlled release excipient, a lubricant, a diluent, or a mixture thereof.

[0018] 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 ratio of the weight % of fesoxodine or a pharmaceutically acceptable salt thereof to the stabilizer in the tablet is about 1 :20 to about 1 : 1. In embodiments, the ratio of the weight % of fesoxodine or a pharmaceutically acceptable salt thereof to xylitol or fructose in the tablet is about 1 :9 to about 1 : 1. In embodiments, the ratio of the weight % of fesoxodine or a pharmaceutically acceptable salt thereof to xylitol or fructose in the tablet is about 1 :50 to about 1 : 1. In embodiments, the ratio of the weight % of fesoxodine or a pharmaceutically acceptable salt thereof to xylitol or fructose in the tablet is about 1 :39. In embodiments, the ratio of the weight % of fesoxodine or a pharmaceutically acceptable salt thereof to xylitol or fructose in the tablet is about 18: 1.

[0019] In embodiments, the lubricant is talc, silicon dioxide, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, polyethylene glycol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof. In embodiments, the lubricant is talc, glyceryl behenate, silicon dioxide, magnesium stearate, or a mixture thereof.

[0020] In embodiments, the controlled release excipient is polyethylene oxide (PEO), methyl cellulose (MC), ethyl cellulose, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, or a mixture thereof.

[0021] In embodiments, the diluent is microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, or a mixture thereof.

[0022] In embodiments, the tablet of the present disclosure further comprises lactose, sodium carboxymethyl starch, sodium croscarmellose, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or a mixture thereof.

[0023] In embodiments, the tablets of the present disclosure comprise a portion comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the portion comprises: about 20% to about 55% by weight of hydroxypropyl methylcellulose (HPMC); about 4% to about 50% by weight of microcrystalline cellulose, about 2% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc. In embodiments, the portion comprises: about 20% to about 55% by weight of hydroxypropyl methylcellulose (HPMC); about 4% to about 50% by weight of microcrystalline cellulose, about 2% to about 6% by weight of glyceryl behenate; about 1% to about 4% by weight of talc; and optionally about 4% to about 50% by weight of xylitol. In embodiments, the tablets of the present disclosure comprise a portion comprising Compound 1, or a pharmaceutically acceptable salt thereof, wherein the portion comprises: about 40% to about 60% by weight of HPMC; about 20% to about 25% by weight of microcrystalline cellulose; about 5% to about 20% by weight of xylitol; and about 0.1% to about 0.4% by weight of magnesium stearate.

[0024] In embodiments, the tablets of the present disclosure comprise a portion comprising Fexofenadine, or a pharmaceutically acceptable salt thereof, wherein the portion comprises: about 10% to about 50% by weight of xylitol; about 50% to about 80% by weight of 75% lactose / 25% microcrystalline cellulose; about 3% to about 8% by weight of sodium starch glycolate; about 2% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc.

[0025] In embodiments, the tablets of the present disclosure comprise a portion comprising Fexofenadine, or a pharmaceutically acceptable salt thereof, wherein the portion comprises: about 10% to about 50% by weight of xylitol; about 50% to about 80% by weight of 75% lactose / 25% microcrystalline cellulose; about 3% to about 8% by weight of croscarmellose sodium; about 2% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc.

[0026] In embodiments, the tablets of the present disclosure comprise a portion comprising Fexofenadine, or a pharmaceutically acceptable salt thereof, wherein the portion comprises: about 10% to about 50% by weight of xylitol; about 50% to about 80% by weight of 75% lactose / 25% microcrystalline cellulose; about 3% to about 8% by weight of polyvinylpyrrolidone (PVP); about 2% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc.

[0027] In embodiments, a tablet of the present disclosure comprises a portion comprising non- opioid analgesic, wherein the portion comprises: about 10% to about 50% by weight of mannitol; about 10% to about 50% by weight of 75% lactose / 25% microcrystalline cellulose; about 10% to about 40% by weight of hydroxypropyl methylcellulose (HPMC); about 1% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc.

[0028] In an embodiment, the tablets of this disclosure comprise a portion containing nonsorodine or a pharmaceutically acceptable salt thereof, said portion comprising: about 8% to about 50% by weight xylitol; about 10% to about 50% by weight 75% lactose / 25% microcrystalline cellulose; about 20% to about 50% by weight cellulose ether; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc. In an embodiment, the tablets of this disclosure comprise a portion containing nonsorodine or a pharmaceutically acceptable salt thereof, said portion comprising: about 8% to about 50% by weight xylitol; about 10% to about 50% by weight 75% lactose / 25% microcrystalline cellulose; about 10% to about 40% by weight 80% polyvinyl acetate (PVA) / 19% povidone; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc. In an embodiment, the tablets of this disclosure comprise a portion containing nonsorodine or a pharmaceutically acceptable salt thereof, said portion comprising: about 10% to about 50% by weight xylitol; about 10% to about 40% by weight 75% lactose / 25% microcrystalline cellulose; about 20% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc. In an embodiment, the tablets of this disclosure comprise a portion containing nonsorodine or a pharmaceutically acceptable salt thereof, said portion comprising: about 10% to about 50% by weight xylitol; about 20% to about 40% by weight MCC; about 20% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc. In an embodiment, the tablets of this disclosure comprise a portion containing nonsorodine or a pharmaceutically acceptable salt thereof, said portion comprising: about 8% to about 20% by weight xylitol; about 10% to about 40% by weight 75% lactose / 25% microcrystalline cellulose; about 10% to about 30% by weight lactose; about 10% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc. In an embodiment, the tablets of this disclosure comprise a portion containing nonsorodine or a pharmaceutically acceptable salt thereof, said portion comprising: about 10% to about 40% by weight xylitol; about 10% to about 20% by weight lactose; about 10% to about 40% by weight MCC; about 20% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

[0029] In embodiments, the present disclosure provides a composition comprising: an extended release (ER) portion comprising Compound 1, or a pharmaceutically acceptable salt thereof; and an immediate release (IR) coating comprising Fesoterodine, or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on the ER portion. In embodiments, 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.

[0030] 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 % ratio of 3: 1; (f) HPMC; (g) HPMC and xylitol; or (h) HPMC and fructose.

[0031] In embodiments, the IR coating comprises (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% HPMC, about 5 wt% to about 10 wt% triacetin, and about 5 wt% to about 10 wt% talc; (c) about 25 wt% to about 50 wt% PVA, about 10 wt% to about 40 wt% xylitol, about 5 wt% to about 20 wt% PEG, about 1 wt% to about 5 wt% polysorbate 80, and about 10 wt% to about 30 wt% talc; (d) about 20 wt% to about 40 wt% PVA, about 30 wt% to about 40 wt% fructose, about 5 wt% to about 15 wt% PEG, about 1 wt% to about 3 wt% polysorbate 80, and about 10 wt% to about 25 wt% talc; (e) about 85 wt% to about 95 wt% a copolymer of polyvinyl alcohol and polyethylene glycol in a weight % ratio of 3: 1 in the coating; (f) about 65 wt% to about 95 wt% HPMC; (g) about 40 wt% to about 60 wt% HPMC and about 30 wt% to about 45 wt% xylitol; or (h) about 40 wt% to about 60 wt% HPMC and about 30 wt% to about 45 wt% fructose.

[0032] In embodiments, the IR coating releases 80% of the fesoterodine within 0.5 h to 2 h, the release being tested at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle speed 50 rpm).

[0033] In embodiments, the present disclosure provides a method of treating a movement disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a therapeutically effective amount of a composition of the present disclosure. In embodiments, the movement disorder is levodopa-induced dyskinesia. In embodiments, the patient is diagnosed with Parkinson’s disease. In embodiments, the movement disorder is tardive dyskinesia.

[0034] In embodiments, the present disclosure provides a method of treating schizophrenia in a patient in need thereof, the method comprising administering to the patient in need thereof a therapeutically effective amount of a composition of the present disclosure.

[0035] In embodiments, the present disclosure provides a method of treating Alzheimer’s disease in a patient in need thereof, the method comprising administering to the patient in need thereof a therapeutically effective amount of a composition of the present disclosure. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1A Observed and predicted C max values following administration of 1 mg, 3 mg, 10 mg, 20 mg, 40 mg, and 60 mg of Compound 1 as described in Example 1.

[0037] Figure 1B Observed and predicted AUC inf values following administration of 1 mg, 3 mg, 10 mg, 20 mg, 40 mg, and 60 mg of Compound 1 as described in Example 1.

[0038] Figure 2 C max and AUC 0-8 curves following administration of Compound 1 as described in Example 1.

[0039] Figure 3A Mean plasma concentration (ng / mL) of Compound 1 following administration of 20 mg of Compound 1 as described in Example 1 is shown.

[0040] Figure 3B Mean plasma concentration (ng / mL) of Compound 1 following administration of 40 mg of Compound 1 as described in Example 1 is shown.

[0041] Figure 3CMean plasma concentrations of Compound 1 (ng / mL) following administration of 60 mg of Compound 1 are shown as described in Example 1.

[0042] Figure 4A Mean plasma concentrations of Compound 1 (ng / mL) following administration of Compound 1 and 8 mg of Furosemide (immediate release) are shown as described in Example 1.

[0043] Figure 4B Mean plasma concentrations of 5-hydroxymethyl tolteridine (5-HMT) following administration of Furosemide are shown as described in Example 1 (ng / mL).

[0044] Figure 4C Mean plasma concentrations of 5-HMT following administration of Furosemide and Compound 1 are shown as described in Example 1 (ng / mL).

[0045] Figure 5A Mean plasma concentrations of 5-HMT following administration of Furosemide are shown as described in Example 1 (ng / mL).

[0046] Figure 5B Mean plasma concentrations of 5-HMT following co-administration of 40 mg of Compound 1 and 1 mg of Furosemide are shown as described in Example 1 (ng / mL).

[0047] Figure 6A Mean plasma concentrations of Compound 1 and 5-HMT following administration of 135 mg of Compound 1 and 9 mg of Furosemide are shown as described in Example 1 (ng / mL).

[0048] Figure 6B Mean plasma concentrations of Compound 1 and 5-HMT following administration of 135 mg of Compound 1 and 9 mg of Furosemide are shown as described in Example 1 (ng / mL).

[0049] Figure 7A Mean plasma concentrations of Compound 1 and 5-HMT following administration of 90 mg of Compound 1 and 6 mg of Furosemide are shown as described in Example 1 (ng / mL).

[0050] Figure 7B Mean plasma concentrations of Compound 1 and 5-HMT following administration of 60 mg of Compound 1 and 6 mg of Furosemide are shown as described in Example 1 (ng / mL).

[0051] Figure 8A Mean plasma concentrations of Compound 1 (ng / mL) following administration of 200 mg of Compound 1 and 12 mg of Furosemide are shown as described in Example 1.

[0052] Figure 8B Predicted mean and target average plasma concentrations (ng / mL) of Compound 1 following administration of 300 mg of Compound 1 BID and 436 mg of Compound 1 BID as described in Example 1 are shown.

[0053] Figure 9A Predicted mean plasma concentrations (ng / mL) of Compound 1 (C1) and 5-HMT following administration of 300 mg of Compound 1 (extended release) and 3 mg of Fesoterodine (immediate release) BID as described in Example 1 are shown.

[0054] Figure 9B Predicted mean plasma concentrations (ng / mL) of Compound 1 (C1) and 5-HMT following administration of 250 mg of Compound 1 and 6 mg of Fesoterodine (12 hour extended release) BID as described in Example 1 are shown.

[0055] Figure 9C Predicted mean plasma concentrations (ng / mL) of Compound 1 (C1) and 5-HMT following administration of 436 mg of Compound 1 and 9.9 mg of Fesoterodine (8 hour extended release) as described in Example 1 are shown.

[0056] Figures 10A-10G % Solubility of Compound 1 over time for certain tested compositions of Compound 1 is shown. Tested compositions: Compound 1 compositions containing 50% HPMC; 50% PEO; or 25% HPMC / 25% PEO ( Figure 10A ); Compound 1 compositions containing 40 mg of Compound 1; or 250 mg of Compound 1 ( Figure 10B ); Compound 1 compositions containing 1000 mg tablets containing 50% HPMC; 1100 mg tablets containing 50% HPMC; or 1300 mg tablets containing 50% HPMC ( Figure 10C ); Compound 1 compositions containing 50% HPMC but no xylitol; 50% HPMC and 15% xylitol; or 50% HPMC and 25% xylitol ( Figure 10D ); Compound 1 compositions containing 50% HPMC and microcrystalline cellulose; or 50% HPMC and dicalcium phosphate ( Figure 10E ); 1000 mg tablets containing 50% PEO; 1100 mg tablets containing 50% PEO; and 1300 mg tablets containing 50% PEO ( Figure 10F ); Compound 1 compositions containing 50% PEO but no xylitol; or 50% PEO and 23% xylitol ( Figure 10G ).

[0057] Figure 11 A representative manufacturing process for Compound 1 extended release tablets (40 mg and 125 mg) is shown.

[0058] Figure 12 Dissolution of tablets of Figure 11 over time is shown.

[0059] Figure 13A Dissolution of 40 mg Compound 1 tablets of Figure 11 measured by the USP 2 and USP 3 methods is shown.

[0060] Figure 13B Dissolution of 125 mg Compound 1 tablets of Figure 11 measured by the USP 2 and USP 3 methods is shown.

[0061] Figure 14A Dissolution of Compound 1 over time from Compound 1 / fesoxodol ER / IR bilayer tablet formulations is shown.

[0062] Figure 14B Dissolution of Compound 1 and fesoxodol from the ER / ER formulations of Table 5 in Example 4 is shown.

[0063] Figure 15 Plasma concentration ratios of Compound 1 to 5-HMT following oral administration of a composition containing 135 mg of Compound 1 and 6 mg of fesoxodol as described in Example 1 are shown.

[0064] Figure 16A Average distance traveled in 30 minutes in the Open Field locomotor activity test following 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg Compound 1 administration in amphetamine-treated mice as described in Example 7 is shown. p < 0.0001, one-way ANOVA.

[0065] Figure 16B Change in distance traveled measured by the Open Field locomotor activity test at 5 minute intervals following 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg Compound 1 administration in amphetamine-treated mice as described in Example 7 is shown. p < 0.0001, one-way ANOVA.

[0066] Figure 17A Average distance traveled in 30 minutes in the Open Field locomotor activity test following 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg Compound 1 administration in phencyclidine-treated mice as described in Example 8 is shown. p < 0.0001, one-way ANOVA.

[0067] Figure 17B The change in distance traveled as measured by the Open Field Test of locomotor ability at 5 minute intervals following 0.3 mg / kg, 0.6 mg / kg, and 1 mg / kg Compound 1 administration in phencyclidine treated mice as described in Example 8 is shown. p < 0.0001, one-way ANOVA. DETAILED DESCRIPTION

[0068] Definitions Throughout this disclosure, various patents, patent applications, and publications (including non-patent publications) are referenced by author and year of publication. The disclosures of these patents, patent applications, and publications in their entireties are hereby incorporated by reference for all purposes to more fully describe the state of the art as of the date of the disclosure. In the event of any inconsistencies between the disclosures in the referenced patents, patent applications, and publications and the disclosure contained herein, the disclosure contained herein is to be considered the most accurate and authentic.

[0069] For convenience, certain terms used in the specification, examples, and claims are collected here. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0070] The term “about” when immediately preceding a numerical value means a range (e.g., the value plus or minus 10%). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless otherwise stated in the context of the disclosure, or inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55...”, “about 50” means a range extending to less than half the interval between the preceding and following values, e.g., greater than 49.5 to less than 52.5. Further, the phrase “less than about” a value or “greater than about” a value shall be interpreted in accordance with the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) means all values in the series or endpoints of the range, respectively.

[0071] As used herein, the term “Compound 1” refers to 1-(3-methyl-[1,2,4]oxadiazol-5-yl)-(1 R ,5 R )-3-aza-bicyclo[3.1.0]hexane: .

[0072] In embodiments, the disclosure describes Compound 1, or any pharmaceutically acceptable salt thereof.

[0073] As used herein, “fesorodine” refers to 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl isobutyrate, R-(+)-2-(3-(diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl isobutyrate, or R-(+)-isobutyric acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester. In embodiments, this disclosure describes fesorodine or any pharmaceutically acceptable salt thereof, including fesorodine fumarate, as described in U.S. Patent Publications US 2013 / 0287847 A1 and US 2010 / 0130606 A1, which are incorporated herein by reference in their entirety.

[0074] As used herein, the phrase “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, those compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with tissues of humans and animals without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0075] The term "part" refers to a region of the compositions disclosed herein. In embodiments, a part is a layer, segment, section, particle, particle, or matrix. In embodiments, a part is a layer comprising compound 1 or a pharmaceutically acceptable salt thereof, or nonsorodine or a pharmaceutically acceptable salt thereof. In embodiments, a part is a matrix comprising compound 1 or a pharmaceutically acceptable salt thereof, and nonsorodine or a pharmaceutically acceptable salt thereof.

[0076] The term “therapeutic effective amount” refers to the amount of a compound or pharmaceutical composition described herein that is sufficient to achieve the intended application (including, but not limited to, the treatment of diseases described below).

[0077] As used in this article with respect to patients, the term "treatment" refers to the improvement of at least one symptom of a patient's condition (e.g., schizophrenia or Alzheimer's disease). Treatment can improve or at least partially alleviate the symptoms.

[0078] Compositions In embodiments, this disclosure provides compositions comprising compound 1 or a pharmaceutically acceptable salt thereof and nonsorodine or a pharmaceutically acceptable salt thereof.

[0079] In embodiments, the compositions of this disclosure comprise about 10 mg to about 800 mg of compound 1 or a pharmaceutically acceptable salt thereof, such as 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, about 76 mg, about 78 mg, about 80 mg, about 82 mg, about 84 mg, about 86 mg, about 88 mg, about 90 mg, about 92 mg, about 94 mg, about 96 ... mg, approximately 98 mg, approximately 100 mg, approximately 102 mg, approximately 104 mg, approximately 105 mg, approximately 106 mg, approximately 108 mg, approximately 110 mg, approximately 112 mg, approximately 114 mg, approximately 116 mg, approximately 118 mg, approximately 120 mg, approximately 122 mg, approximately 124 mg, approximately 126 mg, approximately 128 mg, approximately 130 mg, approximately 132 mg, approximately 134 mg, approximately 136 mg, approximately 138 mg, approximately 140 mg, approximately 142 mg, approximately 144 mg, approximately 146 mg, approximately 148 mg, approximately 150 mg, approximately 152 mg, approximately 154 mg, approximately 156 mg, approximately 158 mg, approximately 160 mg, approximately 162 mg, approximately 164 mg, approximately 165 mg, approximately 166 mg, approximately 168 mg, approximately 170 mg, approximately 172 mg, approximately 174 mg, approximately 174 mg, approximately 174 mg, approximately 175 mg, approximately 166 mg, approximately 168 mg, approximately 170 mg, approximately 172 ...5 mg, approximately 166 mg, approximately 168 mg, approximately 170 mg, approximately 172 mg, approximately 174 mg, approximately 175 mg, approximately 166 mg, approximately 168 mg, approximately 170 mg, approximately 172 mg, approximately 174 mg, approximately 175 mg, approximately 174 mg, approximately 175 mg, approximately 166 mg, approximately 168 mg mg, approximately 176 mg, approximately 178 mg, approximately 180 mg, approximately 182 mg, approximately 184 mg, approximately 186 mg, approximately 188 mg, approximately 190 mg, approximately 192 mg, approximately 194 mg, approximately 196 mg, approximately 198 mg, approximately 200 mg, approximately 201 mg, approximately 202 mg, approximately 204 mg, approximately 206 mg, approximately 208 mg, approximately 210 mg, approximately 212 mg, approximately 214 mg, approximately 216 mg, approximately 218 mg, approximately 220 mg, approximately 222 mg, approximately 224 mg, approximately 226 mg, approximately 228 mg, approximately 230 mg, approximately 232 mg, approximately 234 mg, approximately 236 mg, approximately 238 mg, approximately 240 mg, approximately 242 mg, approximately 244 mg, approximately 246 mg, approximately 248 mg, approximately 250 mg, approximately 252 mgmg, approximately 254 mg, approximately 256 mg, approximately 258 mg, approximately 260 mg, approximately 262 mg, approximately 264 mg, approximately 266 mg, approximately 268 mg, approximately 270 mg, approximately 272 mg, approximately 274 mg, approximately 276 mg, approximately 278 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg The values ​​or ranges are approximately 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, or 800 mg, including any values ​​or ranges therebetween. In one embodiment, the composition comprises approximately 10 mg to approximately 500 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises approximately 10 mg to approximately 200 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0080] In one embodiment, the composition comprises about 105 mg, about 165 mg, or about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 105 mg, about 135 mg, about 165 mg, or about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 105 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 135 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 270 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 330 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0081] In embodiments, the compositions of this disclosure comprise about 1 mg to about 50 mg of nonsorodine or a pharmaceutically acceptable salt thereof, such as 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, about 19 mg, about 20 mg, about 21 mg, about 22 mg, about 23 mg, about 24 mg, about 25 mg, about 26 mg, about 27 mg, about 28 mg, about 29 mg, about 30 mg, about 31 mg, about 32 mg, about 33 mg, about 34 mg, about 35 mg, etc. The composition contains approximately 1 mg to approximately 30 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In one embodiment, the composition contains approximately 1 mg to approximately 20 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition contains approximately 1 mg to approximately 3 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition contains approximately 1 mg to approximately 3 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition contains approximately 1.5 mg to approximately 3 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition contains approximately 1.5 mg, approximately 3 mg, or approximately 4.5 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition contains approximately 1.5 mg, approximately 3 mg, approximately 4.5 mg, or approximately 6 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In one embodiment, the composition comprises about 1.5 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 3 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition comprises about 6 mg of nonsorodine or a pharmaceutically acceptable salt thereof.

[0082] In one embodiment, the composition disclosed herein 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 nonsorodine or a pharmaceutically acceptable salt thereof. In another embodiment, 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 nonsorodine or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the composition comprises about 50 mg to about 600 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 100 mg to about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 150 mg to about 350 mg of compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 200 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition comprises about 250 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0084] In embodiments, the compositions disclosed herein comprise 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 nonsorodine or a pharmaceutically acceptable salt thereof. In embodiments, the compositions disclosed herein comprise 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 nonsorodine or a pharmaceutically acceptable salt thereof.

[0085] In one embodiment, the composition disclosed herein comprises about 3 mg to about 8 mg of fesosteroidine or a pharmaceutically acceptable salt thereof. In another embodiment, the composition comprises about 3 mg to about 12 mg of fesosteroidine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition comprises about 1 mg to about 5 mg of fesosteroidine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the composition comprises fesosteroidine fumarate.

[0086] In embodiments, the compositions of this disclosure comprise a weight percentage of about 5:1 to about 100:1, such as 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. The composition contains compound 1 and nonsorodine in ratios of approximately 46:1, 48:1, 50:1, 52:1, 54:1, 56:1, 58:1, 60:1, 62:1, 64:1, 66:1, 68:1, 70:1, 72:1, 74:1, 76:1, 78:1, 80:1, 82:1, 84:1, 86:1, 88:1, 90:1, 92:1, 94:1, 96:1, 98:1, or 100:1 (inclusive of any values ​​or ranges therebetween). In one embodiment, the weight percentage ratio of compound 1 to nonsorodine in the composition is approximately 40:1 to approximately 90:1. In another embodiment, the weight percentage ratio of compound 1 to nonsorodine in the composition is approximately 20:1 to approximately 40:1. In one embodiment, the weight percentage ratio of compound 1 and non-sodrodin in the composition is from about 5:1 to about 15:1. In another embodiment, the weight percentage ratio of compound 1 and non-sodrodin in the composition is from about 55:1 to about 70:1. In yet another embodiment, the weight percentage ratio of compound 1 and non-sodrodin in the composition is from about 46:1 to about 70:1.

[0087] In the embodiments, oral administration of the compositions disclosed herein provides substantially the same T for defensodrone and compound 1. maxIn embodiments, the compositions of this disclosure comprise 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 nonsorodine or a pharmaceutically acceptable salt thereof, wherein oral administration of the composition provides about 0.1 h to about 18 h (such as about 0.1 h to about 12 h), for example about 0.1 h, about 0.2 h, about 0.3 h, about 0.4 h, about 0.5 h, about 0.6 h, about 0.7 h, about 0.8 h, about 0.9 h, about 1.0 h, about 1.2 h, about 1.4 h, about 1.6 h, about 1.8 h, about 2.0 h, about 2.2 h, about 2.4 h, about 2.6 h, about 2.8 h, about 3.0 h, about 3.2 h, about 3.4 h, about 3.6 h, about 3.8 h, about 4.0 h, about 4.2 h, about 4.4 h. h, approximately 4.6 h, approximately 4.8 h, approximately 5.0 h, approximately 5.2 h, approximately 5.4 h, approximately 5.6 h, approximately 5.8 h, approximately 6.0 h, approximately 6.2 h, approximately 6.4 h, approximately 6.6 h, approximately 6.8 h, approximately 7.0 h, approximately 7.2 h, approximately 7.4 h, approximately 7.6 h, approximately 7.8 h, approximately 8.0 h, approximately 8.2 h, approximately 8.4 h, approximately 8.6 h, approximately 8.8 h, approximately 9.0 h, approximately 9.2 h, approximately 9.4 h, approximately 9.6 h, approximately 9.8 h, approximately 10.0 h, approximately 10.2 h, approximately 10.4 h, approximately 10.6 h, approximately 10.8 h, approximately 11.0 h, approximately 11.2 h, approximately 11.4 h, approximately 11.6 h, approximately 11.8 h, approximately 12.0 h, approximately 12.2 h The t of compound 1 at approximately 12.4 h, approximately 12.6 h, approximately 12.8 h, approximately 13.0 h, approximately 13.2 h, approximately 13.4 h, approximately 13.6 h, approximately 13.8 h, approximately 14.0 h, approximately 14.2 h, approximately 14.4 h, approximately 14.6 h, approximately 14.8 h, approximately 15.0 h, approximately 15.2 h, approximately 15.4 h, approximately 15.6 h, approximately 15.8 h, approximately 16.0 h, approximately 16.2 h, approximately 16.4 h, approximately 16.6 h, approximately 16.8 h, approximately 17.0 h, approximately 17.2 h, approximately 17.4 h, approximately 17.6 h, approximately 17.8 h, or approximately 18.0 h (inclusive of any value or range therein) maxand approximately 0.1 h to approximately 12 h, for example, approximately 0.1 h, approximately 0.2 h, approximately 0.3 h, approximately 0.4 h, approximately 0.5 h, approximately 0.6 h, approximately 0.7 h, approximately 0.8 h, approximately 0.9 h, approximately 1.0 h, approximately 1.2 h, approximately 1.4 h, approximately 1.6 h, approximately 1.8 h, approximately 2.0 h, approximately 2.2 h, approximately 2.4 h, approximately 2.6 h, approximately 2.8 h, approximately 3.0 h, approximately 3.2 h, approximately 3.4 h, approximately 3.6 h, approximately 3.8 h, approximately 4.0 h, approximately 4.2 h, approximately 4.4 h, approximately 4.6 h, approximately 4.8 h, approximately 5.0 h, approximately 5.2 h, approximately 5.4 h, approximately 5.6 h, approximately 5.8 h, approximately 6.0 h, approximately 6.2 h, approximately 6.4 h, approximately 6.6 h, approximately 6.8 h. The t values ​​of non-soradiline (i.e., 5-HMT) at approximately 10.0 h, 7.0 h, 7.2 h, 7.4 h, 7.6 h, 7.8 h, 8.0 h, 8.2 h, 8.4 h, 8.6 h, 8.8 h, 9.0 h, 9.2 h, 9.4 h, 9.6 h, 9.8 h, 10.0 h, 10.2 h, 10.4 h, 10.6 h, 10.8 h, 11.0 h, 11.2 h, 11.4 h, 11.6 h, 11.8 h, or 12.0 h (inclusive of any value or range therein) are as follows: max .

[0088] In the embodiments, the oral administration composition provides about 0.5 h to about 4 h of compound 1 after administration of the composition. max In the embodiments, the oral administration composition provides, after administration, a dose of compound 1 for about 0.5 h to about 10 h, about 1 h to about 10 h, about 1.5 h to about 10 h, about 1.5 h to about 8 h, about 2 h to about 8 h, about 3 h to about 6 h, or about 3 h to about 4 h. max .

[0089] In the implementation scheme, the oral administration composition provides about 0.5 h to about 4 h of defensodrone after administration of the composition. max In the embodiments, the oral administration composition provides about 0.1 h to about 10 h, about 0.5 h to about 10 h, about 1 h to about 10 h, about 1 h to about 8 h, about 2 h to about 6 h, about 3 h to about 6 h, or about 3 h to about 4 h of defensodrone after administration of the composition. max .

[0090] In the embodiments, the oral administration composition provides about 200 ng / mL to about 5,000 ng / mL after administration, for example about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, about 1000 ng / mL, about 1100 ng / mL, about 1200 ng / mL, about 1300 ng / mL, about 1400 ng / mL, about 1500 ng / mL, about 1600 ng / mL, etc. ng / mL, approximately 1700 ng / mL, approximately 1800 ng / mL, approximately 1900 ng / mL, approximately 2000 ng / mL, approximately 2100 ng / mL, approximately 2200 ng / mL, approximately 2300 ng / mL, approximately 2400 ng / mL, approximately 2500 ng / mL, approximately 2600 ng / mL, approximately 2700 ng / mL, approximately 2800 ng / mL, approximately 2900 ng / mL, approximately 3000 ng / mL, approximately 3100 ng / mL, approximately 3200 ng / mL, approximately 3300 ng / mL, approximately 3400 ng / mL, approximately 3500 ng / mL, approximately 3600 ng / mL, approximately 3700 ng / mL, approximately 3800 ng / mL, approximately 3900 ng / mL, approximately 4000 ng / mL The C1 concentration of compound 1 is 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 (inclusive of any value or range therebetween). max,ss. In the embodiments, the oral administration composition provides about 2 ng / mL to about 60 ng / mL after administration of the composition, for example about 2 ng / mL, about 3 mg / mL, about 4 ng / mL, about 5 mg / mL, about 6 ng / mL, 7 ng / mL, about 8 ng / mL, about 9 mg / mL, about 10 ng / mL, about 11 mg / mL, about 12 ng / mL, about 13 mg / mL, about 14 ng / mL, about 15 mg / mL, about 16 ng / mL, 17 ng / mL, about 18 ng / mL, about 19 mg / mL, about 20 ng / mL, about 22 mg / mL, about 24 ng / mL, about 26 mg / mL, about 28 ng / mL, about 30 mg / mL, about 32 mg / mL, about 34 ng / mL, about 36 mg / mL, about 38 ng / mL, about 40 mg / mL, about 42 mg / mL, about 4 ... C60 of defensoroid at concentrations of approximately 46 mg / mL, 48 mg / mL, 50 mg / mL, 52 mg / mL, 54 mg / mL, 56 mg / mL, 58 mg / mL, or 60 mg / mL (inclusive of any value or range therebetween). max,ss .

[0091] In the embodiments, the oral administration composition provides about 50 ng / mL to about 1,000 ng / mL within about 8 h, about 10 h, about 12 h, about 14 h, about 16 h, or about 18 h after administration of the composition, for example about 50 ng / mL, about 60 ng / mL, about 80 ng / mL, about 100 ng / mL, about 120 ng / mL, about 140 ng / mL, about 150 ng / mL, about 160 ng / mL, about 180 ng / mL, about 200 ng / mL, about 250 ng / mL, about 300 ng / mL, about 350 ng / mL, about 400 ng / mL, about 450 ng / mL, about 500 ng / mL, about 550 ng / mL, about 600 ng / mL, about 650 ng / mL, about 700 ng / mL, about 750 ng / mL. The steady-state C of compound 1 at ng / mL, about 800 ng / mL, about 850 ng / mL, about 900 ng / mL, about 950 ng / mL, or about 1000 ng / mL (inclusive of any value or range therebetween). min (C min,ss ).

[0092] In the embodiments, the orally administered composition provides approximately 4000 ng·h / mL to approximately 80,000 ng·h / mL after administration, for example, approximately 4000 ng·h / mL, approximately 5000 ng·h / mL, approximately 6000 ng·h / mL, approximately 7000 ng·h / mL, approximately 8000 ng·h / mL, approximately 9000 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 14,000 ng·h / mL, approximately 15,000 ng·h / mL, 16,000 ng·h / mL, approximately 17,000 ng·h / mL, approximately 18,000 ng·h / mL, and approximately 19,000 ng·h / mL. ng·h / mL, about 20,000 ng·h / mL, about 21,000 ng·h / mL, about 22,000 ng·h / mL, about 23,000 ng·h / mL, about 24,000 ng·h / mL, about 25,000 ng·h / mL, 26,000 ng·h / mL, about 27,000 ng·h / mL, about 28,000 ng·h / mL, about 29,000 ng·h / mL, about 30,000 ng·h / mL, 31,000 ng·h / mL, about 32,000 ng·h / mL, about 33,000ng·h / mL, about 34,000 ng·h / mL, about 35,000 ng·h / mL、36,000 The AUC of compound 1 at approximately 37,000 ng·h / mL, approximately 38,000 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 (inclusive of any value or range therebetween). 0-24h,ss In an embodiment, the oral administration composition provides an AUC of about 4000 ng·h / mL to about 40,000 ng·h / mL of compound 1 after administration of the composition. 0-24h,ss .

[0093] In the embodiments, the oral administration composition provides about 20 ng·h / mL to about 1000 ng·h / mL after administration, for example about 20 ng·h / mL, about 30 ng·h / mL, about 40 ng·h / mL, about 50 ng·h / mL, about 60 ng·h / mL, about 70 ng·h / mL, about 80 ng·h / mL, about 90 ng·h / mL, about 100 ng·h / mL, about 120 ng·h / mL, about 140 ng·h / mL, about 160 ng·h / mL, about 180 ng·h / mL, about 200 ng·h / mL, about 220 ng·h / mL, about 240 ng·h / mL, about 260 ng·h / mL, about 280 ng·h / mL, about 300 ng·h / mL, about 320 ng·h / mL, etc. ng·h / mL, about 340 ng·h / mL, about 360 ng·h / mL, about 380 ng·h / mL, about 400 ng·h / mL, about 420 ng·h / mL, about 440 ng·h / mL, about 460 ng·h / mL, about 480 ng·h / mL, about 500 ng·h / mL, about 520 ng·h / mL, about 540 ng·h / mL, about 560 ng·h / mL, about 580 ng·h / mL, about 600 ng·h / mL, about 620 ng·h / mL, about 640 ng·h / mL, about 660 ng·h / mL, about 680 ng·h / mL, about 700 ng·h / mL, about 720 ng·h / mL, about 740 ng·h / mL, about 760 AUC of defensodrone at concentrations of 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 (inclusive of any value or range therebetween). 0-24h,ss .

[0094] In the implementation plan, oral administration provides a ratio of 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 41:1, approximately 42:1, approximately 43:1, approximately 43:1, approximately 42:1, approximately 43:1, approximately 43:1, approximately 44:1, 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 8 2:1, 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, 290:1, 300:1, 310:1, 320:1, 330:1, 340:1, 350:1, 360:1, 370:1, 380:1, 390:1, 400:1, 410:1, 420:1, 430:1, 440:1, 450:1, 460:1, 470:1, 480:1, 490:1, 500:1, 550:1, 600:1, 650:1, 700:1, 750:1, 800:1, 850:1, 900:1, 950:1, or 1000:1 The plasma concentration ratio of compound 1 to defensodrone (including all values ​​or ranges therein) is specified. In an embodiment, administration provides a plasma concentration ratio of compound 1 to defensodrone of about 10:1 to about 200:1.In one embodiment, the plasma concentration ratio of compound 1 to defensorondine is provided at a ratio of approximately 100:1 to approximately 250:1. In another embodiment, the plasma concentration ratio of compound 1 to defensorondine is provided at a ratio of approximately 100:1 to approximately 800:1. In yet another embodiment, the plasma concentration ratio of compound 1 to defensorondine is provided at a ratio of approximately 100:1 to approximately 600:1.

[0095] In the implementation scheme, the application provides a ratio of approximately 20:1 to approximately 800:1 or approximately 20:1 to approximately 500:1, for example, 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 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. John 55:1, John 56:1, John 57:1, John 58:1, John 59:1, John 60:1, John 61:1, John 62:1, John 63:1, John 64:1, John 65:1, John 66:1, John 67:1, John 68:1, John 69:1, John 70:1, John 71:1, John 72:1, John 73:1, John 74:1, John 75 :1, 76:1, 77:1, 78:1, 79:1, 80:1, 81:1, 82:1, 83:1, 84:1, 85:1, 86:1, 87:1, 88:1, 89:1, 90:1, 91:1, 92:1, 93:1, 94:1, 95:1, 9 6:1, 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 42 0:1, 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 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 770:1Compound 1 with a ratio of approximately 780:1, 790:1, or 800:1 (inclusive of all values ​​and ranges in between) and the C-value of devisodrone max The ratio. In the implementation scheme, compound 1 is applied to provide a ratio of approximately 50:1 to approximately 250:1 with C of difenosine. max The ratio. In the embodiments, the oral administration composition provides compound 1 in a ratio of about 50:1 to about 800:1 with C of difenosine. max The ratio. In the embodiments, the oral administration composition provides compound 1 in a ratio of about 50:1 to about 500:1 with C of difenosine. max ratio.

[0096] In embodiments, the compositions of this disclosure comprise 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 nonsorodine or a pharmaceutically acceptable salt thereof; wherein the compositions release about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 20 h, 2 h to 18 h, or 2 h to 12 h (e.g., 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, or 20 h, including any value or range therebetween) and within 0.2 h to 8 h (e.g., 0.2 h, 0.3 h, 0.4 h, 0.5 h, 0.6 h, 0.7 h, 0.8 h, 0.9 h, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, or 8 h). Release of approximately 80% of nonsorodine or its pharmaceutically acceptable salt within h (including any value or range therein), the release being tested for dissolution at 37°C in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer using United States Pharmacopeia Equipment II (paddle speed 50 rpm).

[0097] In one embodiment, the compositions of this disclosure are formulated into tablets. In another embodiment, the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof. In yet another embodiment, the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof and a sustained-release (ER) portion containing nonsorodine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the tablets of this disclosure comprise a first ER portion containing compound 1 or a pharmaceutically acceptable salt thereof; and a second ER portion containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the first and second portions are constructed in a bilayer tablet form.

[0098] In the implementation scheme, the ER / ER tablet releases nonsorodine 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 implementation scheme, the tablet releases approximately 80% of compound 1 or its pharmaceutically acceptable salt within 2 to 20 hours, 2 to 18 hours, 2 to 12 hours, or 5 to 18 hours (e.g., within 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, including any value or range therebetween) and within 1 to 20 hours, 1 to 18 hours, 1 to 12 hours, 1 to 7 hours, or 5 to 12 hours (e.g., within 1 hour, 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). The release of approximately 80% of nonsorodine or a pharmaceutically acceptable salt thereof (including any values ​​or ranges thereof) is performed at 37°C while dissolution is tested in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer using a United States Pharmacopeia apparatus II (slurry at 50 rpm). In the embodiment, the ER / ER tablet releases nonsorodine 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.

[0099] In the implementation scheme, the tablet releases approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 5 h to 18 h and approximately 80% of nonsorodine or a pharmaceutically acceptable salt thereof within 5 h to 12 h, the release being 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 at 50 rpm).

[0100] In one embodiment, the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof. In another embodiment, the tablet comprises an immediate-release (IR) portion containing nonsorodine or a pharmaceutically acceptable salt thereof.

[0101] In the embodiments, the ER / IR tablet releases fesorodine or a pharmaceutically acceptable salt thereof (an anticholinergic agent) into the peripheral system immediately before releasing compound 1, thereby reducing the peripheral cholinergic effect of compound 1. In the embodiments, the tablet comprises an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof; and an IR portion containing fesorodine or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion are constructed in a bilayer tablet form. In the implementation scheme, the tablet releases approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 18 hours or 2 to 10 hours (e.g., 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, including any value or range therebetween) and approximately 80% of nonsorodine or a pharmaceutically acceptable salt thereof within 0.1 h to 1 hour (e.g., 0.1 h, 0.2 h, 0.3 h, 0.4 h, 0.5 h, 0.6 h, 0.7 h, 0.8 h, 0.9 h, or 1 hour, including any value or range therebetween), said release being 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 at 50 rpm).

[0102] In the embodiments, the tablets of this disclosure further comprise stabilizers, controlled-release excipients, lubricants, diluents, or mixtures thereof.

[0103] In the embodiments, the stabilizer is xylitol, sorbitol, polydextrose, isomaltitol, glucose, microcrystalline cellulose, fructose, or a mixture thereof. In the embodiments, the stabilizer is xylitol, fructose, or a mixture thereof. In the embodiments, the weight percentage ratio of fesorodine or a pharmaceutically acceptable salt thereof to the stabilizer in the tablet is about 1:20 to about 1:1. In the embodiments, the weight percentage ratio of fesorodine or a pharmaceutically acceptable salt thereof to the stabilizer in the tablet is about 1:50 to about 1:1, 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... The ratio of 1:29, about 1:28, about 1:27, about 1:26, about 1:25, about 1:24, about 1:23, about 1:22, about 1:21, about 1:20, about 1:19, about 1:18, about 1:17, about 1:16, about 1:15, about 1:14, about 1:13, about 1:12, about 1:11, about 1:10, about 1:9, about 1:8, about 1:7, about 1:6, about 1:5, about 1:4, about 1:3, about 1:2, or about 1:1, including any value or range therebetween. In the embodiment, the weight % ratio of nonsorodine or its pharmaceutically acceptable salt to the stabilizer in the tablet is about 1:9 to about 1:1. In the embodiments, the weight percentage ratio of fesorodine or its pharmaceutically acceptable salt to the stabilizer in the tablets 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 embodiments, the weight percentage ratio of fesorodine or its pharmaceutically acceptable salt to xylitol, sorbitol, or fructose in the tablets is about 1:9 to about 1:1. In the embodiments, the weight percentage ratio of fesorodine or its pharmaceutically acceptable salt to xylitol, sorbitol, or fructose in the tablets 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 embodiments, the weight percentage ratio of fesorodine or its pharmaceutically acceptable salt to xylitol in the tablets is about 1:9 to about 1:1. In one embodiment, the weight percentage ratio of fesotropin or its pharmaceutically acceptable salt to xylitol in the tablet 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 another embodiment, the weight percentage ratio of fesotropin or its pharmaceutically acceptable salt to xylitol in the tablet is about 1:9. In yet another embodiment, the weight percentage ratio of fesotropin or its pharmaceutically acceptable salt to xylitol in the tablet is about 1:19. In yet another embodiment, the weight percentage ratio of fesotropin or its pharmaceutically acceptable salt to xylitol in the tablet is about 1:39.

[0104] In one embodiment, the tablets of this disclosure are formulated using a wet granulation process. In another embodiment, fesotropin or a pharmaceutically acceptable salt thereof and a stabilizer selected from the group consisting of xylitol, fructose, sorbitol, polydextrose, isomaltitol, glucose, or combinations thereof are mixed or combined in the presence of water, and the resulting granules are dried and combined with one or more pharmaceutically acceptable excipients to form the tablets of this disclosure. In yet another embodiment, the tablets are formulated using a dry granulation process.

[0105] In some embodiments, the tablets of this disclosure further comprise a lubricant. In some embodiments, the lubricant is talc, silica, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearate fumarate, polyethylene glycol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof. In some embodiments, the lubricant is talc, glyceryl behenate, glyceryl dibehenate, silica, magnesium stearate, or a mixture thereof. In some embodiments, the lubricant is talc, glyceryl behenate, or a mixture thereof.

[0106] In some embodiments, the tablets of this disclosure further comprise a flow aid. In some embodiments, the flow aid is colloidal silica.

[0107] In the embodiments, the tablets of this disclosure further comprise a controlled-release excipient. In the embodiments, the controlled-release excipient is polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, or a mixture thereof.

[0108] In embodiments, the tablets of this disclosure further comprise a diluent. In embodiments, the diluent is microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, or a mixture thereof.

[0109] In the implementation scheme, the tablets also contain lactose, sodium carboxymethyl starch, sodium croscarmellose, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or a mixture thereof.

[0110] In the embodiments, the tablets of this disclosure comprise an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof, comprising 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 stearate fumarate, polyethylene glycol, glyceryl behenate, corn starch, magnesium stearate, polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or any combination thereof.

[0111] In embodiments, the tablets of this disclosure comprise an ER moiety containing compound 1 or a pharmaceutically acceptable salt thereof, including HPMC, xylitol, MCC, and magnesium stearate. In embodiments, the tablets of this disclosure further comprise about 0.01% by weight to about 0.05% by weight of a colorant (e.g., an iron oxide pink pigment blend).

[0112] In the embodiments, the ER portion comprising compound 1 or a pharmaceutically acceptable salt thereof comprises: about 30% to about 55% by weight of hydroxypropyl methylcellulose (HPMC); about 10% to about 30% by weight of microcrystalline cellulose; about 5% to about 20% by weight of xylitol; about 0.1% to about 0.3% by weight of magnesium stearate and about 0.02% by weight of colorant.

[0113] In an embodiment, the tablet of this disclosure comprises a portion containing compound 1 or a pharmaceutically acceptable salt thereof, wherein said portion comprises: about 40% to about 60% by weight of HPMC; about 20% to about 25% by weight of microcrystalline cellulose; and about 0.1% to about 0.4% by weight of magnesium stearate.

[0114] In one embodiment, the tablet of this disclosure comprises an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof, comprising hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, glyceryl behenate, and talc. In another embodiment, the tablet of this disclosure comprises an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof, comprising hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, glyceryl behenate, xylitol, and talc. In yet another embodiment, the tablet of this disclosure comprises an ER portion containing compound 1 or a pharmaceutically acceptable salt thereof, comprising: about 10% by weight to about 60% by weight. (For example, approximately 10% by weight, approximately 11% by weight, approximately 12% by weight, approximately 13% by weight, approximately 14% by weight, approximately 15% by weight, approximately 16% by weight, approximately 17% by weight, approximately 17% by weight, approximately 18% by weight, approximately 19% by weight, approximately 20% by weight, approximately 21% by weight, approximately 22% by weight, approximately 23% by weight, approximately 24% by weight, approximately 25% by weight, approximately 26% by weight, approximately 27% by weight, approximately 28% by weight, approximately 29% by weight, approximately 30% by weight, approximately 31% by weight, approximately 32% by weight, approximately 33% by weight, approximately 34% by weight, approximately 35% by weight, approximately 36% by weight, approximately 37% by weight, approximately 38% by weight, approximately 39% by weight) Hydroxypropyl methylcellulose (HPMC) of about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, or about 60% by weight, or about 20% by weight to about 60% by weight, or about 20% by weight to about 55% by weight, or about 30% by weight to about 55% by weight, including any values ​​or ranges therein; From about 2% by weight to about 50% by weight (e.g., about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight). Microcrystalline cellulose (by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, or about 4% by weight to about 9% by weight, or about 2% by weight to about 10% by weight, or about 4% by weight to about 50% by weight, including any value or range therein); Glyceryl behenate esters: about 2% to about 10% by weight (e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, or about 2% to about 6% by weight, including any values ​​or ranges therein); and Talc comprises about 1% to about 8% by weight (e.g., about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, or about 1% by weight to about 4% by weight, including any value or range therebetween). In an embodiment, the portion further comprises about 4% to about 50% by weight (e.g., about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 2... Xylitol of about 9 wt%, about 30 wt%, about 31 wt%, about 32 wt%, about 33 wt%, about 34 wt%, about 35 wt%, about 36 wt%, about 37 wt%, about 38 wt%, about 39 wt%, about 40 wt%, about 41 wt%, about 42 wt%, about 43 wt%, about 44 wt%, about 45 wt%, about 46 wt%, about 47 wt%, about 48 wt%, about 49 wt%, about 50 wt%, about 4 wt% to about 50 wt%, including any value or range therein.

[0115] In the embodiments, the portion comprising compound 1 or a pharmaceutically acceptable salt thereof comprises: about 30% to about 55% by weight of hydroxypropyl methylcellulose (HPMC); about 4% to about 9% by weight of microcrystalline cellulose; about 2% to about 6% by weight of behenate glyceride; and about 1% to about 4% by weight of talc.

[0116] In the embodiments, the portion comprising compound 1 or a pharmaceutically acceptable salt thereof comprises: about 20% to about 55% by weight of hydroxypropyl methylcellulose (HPMC); about 4% to about 50% by weight of microcrystalline cellulose; about 2% to about 6% by weight of behenate glyceride; about 4% to about 50% by weight of xylitol; and about 1% to about 4% by weight of talc.

[0117] In embodiments, the tablets of this disclosure comprise an IR portion containing nonsorodine or a pharmaceutically acceptable salt thereof, said IR portion comprising xylitol, lactose, microcrystalline cellulose, sodium carboxymethyl starch, glyceryl behenate, and talc. In embodiments, the tablets of this disclosure comprise an IR portion containing nonsorodine or a pharmaceutically acceptable salt thereof, comprising: From about 5% by weight to about 60% by weight xylitol (e.g., about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 3% by weight) 2% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight or about 60% by weight, including any value or range therein; From about 40% by weight to about 90% by weight (e.g., about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, or about 60% by weight, about 61% by weight, about 62% by weight, about 63% by weight, about 64% by weight, about 65% by weight, about 66% by weight, about 67% by weight, approximately 68% by weight, approximately 69% by weight, approximately 70% by weight, approximately 71% by weight, approximately 72% by weight, approximately 73% by weight, approximately 74% by weight, approximately 75% by weight, approximately 76% by weight, approximately 77% by weight, approximately 78% by weight, approximately 79% by weight, approximately 80% by weight, approximately 81% by weight, approximately 82% by weight, approximately 83% by weight, approximately 84% by weight, approximately 85% by weight, approximately 86% by weight, approximately 87% by weight, approximately 88% by weight, approximately 89% by weight or approximately 90% by weight (including any value or range therein) of 75% lactose / 25% microcrystalline cellulose; Sodium carboxymethyl starch from about 2% to about 10% by weight (e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% or about 10% by weight, including any value or range therein). Glyceryl behenate esters: about 2% by weight to about 10% by weight (e.g., about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight, including any value or range therein); and Talc from about 1% to about 10% by weight (e.g., about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight or about 10% by weight, including any value or range therein).

[0118] In an embodiment, the tablets of this disclosure comprise an immediate-release fraction containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the IR fraction comprises a) about 10% to about 50% by weight xylitol; about 50% to about 80% by weight 75% lactose / 25% microcrystalline cellulose; about 3% to about 8% by weight sodium carboxymethyl starch; about 2% to about 6% by weight behenate glyceride; and about 1% to about 4% by weight talc.

[0119] In an embodiment, the tablets of this disclosure comprise an IR portion containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the IR portion comprises: about 10% to about 50% xylitol; about 50% to about 80% 75% lactose / 25% microcrystalline cellulose; about 2% to about 10% (e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, or about 3% to about 8%, including any values ​​or ranges therein) sodium croscarmellose; about 2% to about 6% behenate glycerides; and about 1% to about 4% talc.

[0120] In embodiments, the tablets of this disclosure comprise an immediate-release fraction containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the IR fraction comprises: about 10% to about 50% xylitol; about 50% to about 80% 75% lactose / 25% microcrystalline cellulose; about 2% to about 10% (e.g., about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, or about 3% to about 8%, including any value or range therebetween) polyvinylpyrrolidone (PVP); about 2% to about 6% behenate glycerides; and about 1% to about 4% talc.

[0121] In an embodiment, the tablet of this disclosure comprises an ER portion containing fesorodine or a pharmaceutically acceptable salt thereof, wherein the ER portion comprises about 10% to about 40% by weight xylitol; about 10% to about 20% by weight lactose; about 10% to about 30% by weight MCC; about 20% to about 40% by weight HPMC; about 2% to about 5% by weight behenate glyceride; and about 1% to about 4% by weight talc. In an embodiment, the tablet of this disclosure comprises an ER portion containing fesorodine or a pharmaceutically acceptable salt thereof, wherein the ER portion comprises about 10% to about 40% by weight xylitol; about 10% to about 25% by weight lactose; about 10% to about 30% by weight MCC; about 20% to about 40% by weight HPMC; about 2% to about 5% by weight behenate glyceride; about 0.2% to about 1% by weight colloidal silica; and about 1% to about 4% by weight talc.

[0122] In embodiments, the tablets of this disclosure comprise an ER portion containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the ER portion comprises: From about 10% by weight to about 50% by weight of xylitol; From about 10% by weight to about 50% by weight (e.g., about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight or about 50% by weight, including any value or range therein) 75% lactose / 25% microcrystalline cellulose; From about 10% by weight to about 60% by weight (e.g., about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight). Hydroxypropyl methylcellulose (HPMC) of approximately 38% by weight, approximately 39% by weight, approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, approximately 50% by weight, approximately 51% by weight, approximately 52% by weight, approximately 53% by weight, approximately 54% by weight, approximately 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, or approximately 60% by weight, or approximately 10% by weight to approximately 40% by weight, including any value or range therebetween. Glyceryl behenate from about 1% to about 10% by weight (e.g., about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%, or about 1% to about 6%, including any value or range therein); and Talc from about 1% to about 10% by weight (e.g., about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight, or about 1% by weight to about 4% by weight, including any value or range therein).

[0123] In the embodiments, the ER portion comprising nonsorodine 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 values ​​or ranges therein) of colloidal silica.

[0124] In an embodiment, the tablets of this disclosure comprise an ER portion containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the ER portion comprises: about 10% to about 50% by weight xylitol; about 10% to about 50% by weight 75% lactose / 25% microcrystalline cellulose; about 10% to about 40% by weight hydroxypropyl methylcellulose (HPMC); about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

[0125] In the embodiments, the HPMC used in the tablets 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 therebetween) when dissolved in about 2% by weight in water.

[0126] In the embodiment, the portion comprising nonsorodine or a pharmaceutically acceptable salt thereof comprises about 8% to about 50% xylitol; about 10% to about 50% 75% lactose / 25% microcrystalline cellulose; and about 10% to about 50% (e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%). Cellulose ethers of about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, or about 50% by weight, or about 10% by weight to about 40% by weight (inclusive of any value or range therein); glyceryl behenate of about 1% by weight to about 6% by weight; and talc of about 1% by weight to about 4% by weight.

[0127] In the embodiment, the portion comprising nonsorodine or a pharmaceutically acceptable salt thereof comprises about 8% to about 50% xylitol; about 10% to about 50% 75% lactose / 25% microcrystalline cellulose; and about 10% to about 50% (e.g., about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%). 80% polyvinyl acetate (PVA) / 19% povidone (approximately 36% by weight, approximately 37% by weight, approximately 38% by weight, approximately 39% by weight, approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, or approximately 50% by weight, or approximately 10% by weight to approximately 40% by weight, including any value or range therein); approximately 1% by weight to approximately 6% by weight of glyceryl behenate; and approximately 1% by weight to approximately 4% by weight of talc.

[0128] In the embodiments, the ER / ER or ER / IR tablets of this disclosure also include an aesthetic coating.

[0129] In embodiments, this disclosure provides a composition comprising a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof; and an immediate-release (IR) coating containing fesotropin or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on the ER portion. 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.

[0130] In the implementation scheme, the IR coating comprises polyvinyl alcohol (PVA), polyethylene glycol (PEG), polysorbate 80, and talc.

[0131] In the implementation scheme, the IR coating includes: Polyvinyl alcohol (PVA) of about 40% to about 60% by weight (e.g., about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight, about 50% by weight, about 51% by weight, about 52% by weight, about 53% by weight, about 54% by weight, about 55% by weight, about 56% by weight, about 57% by weight, about 58% by weight, about 59% by weight, or about 60% by weight, including any value or range therebetween). About 10% by weight to about 20% by weight (e.g., about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight or about 20% by weight, including any value or range therein). Polysorbate 80: about 1% to about 5% by weight (e.g., about 1%, about 2%, about 3%, about 4%, or about 5%, including any value or range therein); and Talc of about 20% to about 40% by weight (e.g., about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight or about 40% by weight, including any value or range therebetween).

[0132] In the implementation scheme, the IR coating comprises HPMC, triacetin, and talc.

[0133] In the implementation scheme, the IR coating includes: HPMC of about 70% to about 85% by weight (e.g., about 70% by weight, about 71% by weight, about 72% by weight, about 73% by weight, about 74% by weight, about 75% by weight, about 76% by weight, about 77% by weight, about 78% by weight, about 79% by weight, about 80% by weight, about 81% by weight, about 82% by weight, about 83% by weight, about 84% by weight or about 85% by weight, including any value or range therebetween); Triacetin, approximately 5% by weight to approximately 10% by weight (e.g., approximately 5% by weight, approximately 6% by weight, approximately 7% by weight, approximately 8% by weight, approximately 9% by weight, or approximately 10% by weight, including any value or range therein); and Talc of about 5% to about 10% by weight (e.g., about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight or about 10% by weight, including any value or range therebetween).

[0134] In the implementation scheme, the IR coating comprises PVA, xylitol, PEG, polysorbate 80, and talc.

[0135] In the implementation scheme, the IR coating includes: PVA of about 25% by weight to about 50% by weight (e.g., about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight, about 40% by weight, about 41% by weight, about 42% by weight, about 43% by weight, about 44% by weight, about 45% by weight, about 46% by weight, about 47% by weight, about 48% by weight, about 49% by weight or about 50% by weight, including any value or range therebetween); From about 10% by weight to about 40% by weight (e.g., about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight or about 40% by weight, including any value or range therebetween); PEG of about 5% to about 20% by weight (e.g., about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight or about 20% by weight, including any value or range therebetween); Polysorbate 80: about 1% to about 5% by weight (e.g., about 1%, about 2%, about 3%, about 4%, or about 5%, including any value or range therein); and Talc from about 10% to about 30% by weight (e.g., about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, or about 30% by weight, including any value or range therebetween).

[0136] In the implementation scheme, the IR coating comprises PVA, fructose, PEG, polysorbate 80, and talc.

[0137] In the implementation scheme, the IR coating includes: PVA of about 20% to about 40% by weight (e.g., about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% by weight, about 29% by weight, about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight or about 40% by weight, including any value or range therebetween); Fructose of about 30% to about 40% by weight (e.g., about 30% by weight, about 31% by weight, about 32% by weight, about 33% by weight, about 34% by weight, about 35% by weight, about 36% by weight, about 37% by weight, about 38% by weight, about 39% by weight or about 40% by weight, including any value or range therein); PEG of about 5% to about 15% by weight (e.g., about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14% or about 15%, including any value or range therein); Polysorbate 80, about 1% by weight to about 3% by weight (e.g., about 1.0% by weight, about 1.2% by weight, about 1.4% by weight, about 1.6% by weight, about 1.8% by weight, about 2.0% by weight, about 2.2% by weight, about 2.4% by weight, about 2.6% by weight, about 2.8% by weight, or about 3% by weight, including any value or range therein); and Talc from about 10% to about 25% by weight (e.g., about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 17% by weight, about 18% by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight or about 25% by weight, including any value or range therebetween).

[0138] In one embodiment, the IR coating comprises a copolymer of PVA and PEG in a weight ratio of 3:1. In another embodiment, the IR coating comprises approximately 85% to approximately 95% by weight of a copolymer of polyvinyl alcohol and polyethylene glycol in a weight ratio of 3:1 in the coating.

[0139] In one embodiment, the IR coating comprises HPMC. In another embodiment, the IR coating comprises approximately 65% ​​to approximately 95% by weight of HPMC.

[0140] In the implementation scheme, the IR coating comprises HPMC and xylitol.

[0141] In the implementation scheme, the IR coating includes: HPMC of approximately 40% to approximately 60% by weight (e.g., approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, approximately 50% by weight, approximately 51% by weight, approximately 52% by weight, approximately 53% by weight, approximately 54% by weight, approximately 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, or approximately 60% by weight, including any value or range therebetween); and Xylitol of about 30% to about 45% by weight (e.g., about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44% or about 45%, including any value or range therebetween).

[0142] In the implementation scheme, the IR coating contains HPMC and fructose.

[0143] In the implementation scheme, the IR coating includes: HPMC of approximately 40% to approximately 60% by weight (e.g., approximately 40% by weight, approximately 41% by weight, approximately 42% by weight, approximately 43% by weight, approximately 44% by weight, approximately 45% by weight, approximately 46% by weight, approximately 47% by weight, approximately 48% by weight, approximately 49% by weight, approximately 50% by weight, approximately 51% by weight, approximately 52% by weight, approximately 53% by weight, approximately 54% by weight, approximately 55% by weight, approximately 56% by weight, approximately 57% by weight, approximately 58% by weight, approximately 59% by weight, or approximately 60% by weight, including any value or range therebetween); and Fructose of about 30% to about 45% by weight (e.g., about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, or about 40%, including any value or range therein).

[0144] In the embodiments, the tablets comprise: (i) about 60% to about 70% by weight of polyvinyl alcohol (PVA), about 15% to about 25% by weight of talc, about 1% to about 5% by weight of lecithin, and about 0.1% to about 1.5% by weight (e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.4%, or about 1.5%, including any values ​​or ranges therein).

[0145] In the implementation scheme, the IR coating releases 80% of nonsorodine within 0.5 h to 2 h (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 h, including any value or range therein), said release is 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 at 50 rpm).

[0146] In an embodiment, the compositions of this disclosure are formulated into permeation tablets. In an embodiment, the permeation tablets release approximately 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 therebetween) and approximately 80% of nonsorodine 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 therebetween), said release being 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 at 50 rpm).

[0147] In an embodiment, the compositions of this disclosure are formulated into a multiplying formulation. In an embodiment, the multiplying formulation releases approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 8 h (e.g., 2, 3, 4, 5, 6, 7, or 8 h, including any value or range therebetween) and approximately 80% of nonsorodine or a pharmaceutically acceptable salt thereof within 4 h to 12 h (e.g., 4, 5, 6, 7, 8, 9, 10, 11, or 12 h, including any value or range therebetween), said release being 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 at 50 rpm).

[0148] Methods of treating neurological disorders In its implementation, this disclosure provides a method of treating neurological disorders (such as schizophrenia or Alzheimer's disease psychosis) with reduced peripheral cholinergic effects by administering one or more compositions of this disclosure (i.e., a combination formulation compound 1 or a pharmaceutically acceptable salt thereof in combination with the peripherally acting anticholinergic agent fesorodine or a pharmaceutically acceptable salt thereof) to a patient in need.

[0149] In the implementation scheme, the neurological disorder is schizophrenia. In the implementation scheme, acute schizophrenia is treated in a patient. In the implementation scheme, chronic schizophrenia is treated in a patient. In the implementation scheme, this disclosure provides a method for treating cognitive impairment in schizophrenia.

[0150] In the implementation plan, the neurological disorder is Alzheimer's disease. In the implementation plan, the neurological disorder is Alzheimer's psychosis. In the implementation plan, the patient's Alzheimer's cognition is treated. In the implementation plan, treatment aims to improve or maintain the cognitive function of Alzheimer's patients.

[0151] In this implementation plan, the neurological disorder is a motor disorder. In this implementation plan, the motor disorder is a levodopa-induced motor disorder. In this implementation plan, the patient is diagnosed with Parkinson's disease. In this implementation plan, the motor disorder is a tardive dyskinesia.

[0152] In the implementation plan, neurological disorders are defined as mental illnesses. Specifically, neurological diseases include Parkinson's disease-related psychosis, dementia-related psychosis, transient psychotic disorders, Lewy body disease with psychosis, or acute delirium.

[0153] In its implementation, this disclosure provides a method for treating agitation in cognitive impairments of Alzheimer's disease dementia, Lewy body disease with psychosis, Lewy body dementia, bipolar manic episodes, bipolar mixed episodes, bipolar maintenance (bipolar type 1 and / or type 2), bipolar depression, or bipolar type 1 and / or type 2 disorders.

[0154] In its implementation, this 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.

[0155] In its embodiments, this application provides a method for treating neurological disorders by orally administering to a patient in need 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 fesosteroidine or a pharmaceutically acceptable salt thereof. In its embodiments, the method comprises orally administering to a patient in need 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 fesosteroidine or a pharmaceutically acceptable salt thereof.

[0156] In embodiments, the method of this disclosure includes oral administration of a pharmaceutical composition comprising about 100 mg to about 500 mg of compound 1 (e.g., based on the amount of free base of compound 1, 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 fesorodine (e.g., based on the amount of free base of fesorodine, 1.5 mg, 3 mg, 6 mg, or 9 mg) or a pharmaceutically acceptable salt thereof, wherein administration provides about 0.1 h to about 8 h of compound 1. max and the t of defensorodine from about 0.1 h to about 10 h max .

[0157] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesorodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of fesorodine) or a pharmaceutically acceptable salt thereof, wherein administration provides about 1.5 h to about 8 h of compound 1. max and the t of defensorodine from about 1 hour to about 8 hours max .

[0158] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesorodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of fesorodine) or a pharmaceutically acceptable salt thereof, wherein administration provides a steady-state C2 solution of compound 1 providing about 200 ng / mL to about 5,000 ng / mL. max (C max,ss ) and C of devisodrone at approximately 2 ng / mL to approximately 60 ng / mL max,ss .

[0159] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesorodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of fesorodine) or a pharmaceutically acceptable salt thereof, wherein administration provides 600 ng / mL to about 4,000 ng / mL of compound 1 in C max,ss and C of difenosine at approximately 1 ng / mL to approximately 20 ng / mL max,ss .

[0160] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesorodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of fesorodine) or a pharmaceutically acceptable salt thereof, wherein administration provides an AUC of about 4000 ng·h / mL to about 40,000 ng·h / mL of compound 1. 0-24h,ss The AUC of devisodrone was approximately 5 ng·h / mL to approximately 600 ng·h / mL. 0-24h,ss .

[0161] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesorodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of fesorodine) or a pharmaceutically acceptable salt thereof, wherein administration provides an AUC of about 4000 ng·h / mL to about 40,000 ng·h / mL of compound 1. 0-24h,ss The AUC of difenosonin at approximately 20 ng·h / mL to approximately 200 ng·h / mL 0-24h,ss .

[0162] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of desofosine (e.g., 1.5 mg, 3 mg, 6 mg or 9 mg of free base of desofosine) or a pharmaceutically acceptable salt thereof, wherein the administration provides a plasma concentration ratio of compound 1 to desofosine of about 10:1 to about 400:1.

[0163] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of desofosine (e.g., 1.5 mg, 3 mg, 6 mg or 9 mg of free base of desofosine) or a pharmaceutically acceptable salt thereof, wherein the administration provides a plasma concentration ratio of compound 1 to desofosine of about 10:1 to about 200:1.

[0164] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of fesotropin (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of fesotropin) or a pharmaceutically acceptable salt thereof, wherein the administration provides a ratio of compound 1 to fesotropin of about 50:1 to about 600:1. max ratio.

[0165] In embodiments, the method of this disclosure includes oral administration of 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 10 mg of desofosine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of desofosine) or a pharmaceutically acceptable salt thereof, wherein the administration provides a ratio of compound 1 to desofosine of about 50:1 to about 250:1. max ratio.

[0166] In embodiments, the method of this disclosure includes oral administration of a pharmaceutical composition comprising about 40 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 20 mg or about 1 mg to about 10 mg of nonsorodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of nonsorodine) or a pharmaceutically acceptable salt thereof; wherein the composition releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 18 h; and releases about 80% of nonsorodine or a pharmaceutically acceptable salt thereof within 0.2 h to 18 h, the release being 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 at 50 rpm).

[0167] In embodiments, the method of this disclosure includes oral administration of a pharmaceutical composition comprising about 40 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 of free base of compound 1) or a pharmaceutically acceptable salt thereof and about 1 mg to about 20 mg or about 1 mg to about 10 mg of nonsorodine (e.g., 1.5 mg, 3 mg, 6 mg, or 9 mg of free base of nonsorodine) or a pharmaceutically acceptable salt thereof; wherein the composition releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 12 h; and releases about 80% of nonsorodine or a pharmaceutically acceptable salt thereof within 0.2 h to 12 h, the release being 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 at 50 rpm).

[0168] In embodiments, the methods of this disclosure include oral administration of one or more pharmaceutical compositions described in Tables 5-5d.

[0169] In one embodiment, the administered pharmaceutical composition is a tablet. In another embodiment, the administered tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof and a sustained-release (ER) portion containing fesorodine or a pharmaceutically acceptable salt thereof. In another embodiment, the weight % ratio of compound 1 to fesorodine in the administered composition is from about 40:1 to about 90:1.

[0170] In one embodiment, the compositions of this disclosure are administered once daily. In another embodiment, one composition of this disclosure is administered once daily (e.g., one tablet containing 165 mg of compound 1 and 3 mg of nonsorodine is administered once daily). In yet another embodiment, two or more compositions of this disclosure are administered once daily (e.g., two tablets containing 165 mg of compound 1 and 3 mg of nonsorodine are administered once daily).

[0171] In one embodiment, the method of this disclosure includes orally administering to a patient once daily about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In another embodiment, the method of this disclosure includes orally administering to a patient once daily about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the method of this disclosure includes orally administering to a patient once daily about 270 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 6 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the method of this disclosure includes orally administering to a patient once daily about 330 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 6 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In yet another embodiment, the method of this disclosure includes orally administering to a patient once daily about 495 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 9 mg of nonsorodine or a pharmaceutically acceptable salt thereof. In the implementation scheme, the method of this disclosure includes oral administration of about 495 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 6 mg of nonsorodine or a pharmaceutically acceptable salt thereof to a patient once daily.

[0172] In one embodiment, once-daily oral administration provides a mean steady-state plasma concentration of compound 1 of 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 within at least about 12 h, at least about 16 h, at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h after administration. In another embodiment, once-daily oral administration provides a mean steady-state plasma concentration of compound 1 of at least about 100 ng / mL within at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h after administration. In yet another embodiment, once-daily oral administration provides a mean steady-state plasma concentration of compound 1 of at least about 200 ng / mL within at least about 20 h after administration.

[0173] In one embodiment, the compositions of this disclosure are administered twice daily. In another embodiment, one composition of this disclosure is administered twice daily (e.g., one tablet containing 165 mg of compound 1 and 3 mg of nonsorodine is administered twice daily). In yet another embodiment, two or more compositions of this disclosure are administered twice daily (e.g., two tablets containing 165 mg of compound 1 and 3 mg of nonsorodine are administered twice daily).

[0174] In one embodiment, the method of this disclosure comprises administering to a patient twice daily about 105 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 1.5 mg of fesorodine or a pharmaceutically acceptable salt thereof (i.e., a total daily dose of 210 mg of compound 1 and 3 mg of fesorodine). In another embodiment, the method of this disclosure comprises administering to a patient twice daily about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of fesorodine or a pharmaceutically acceptable salt thereof (i.e., a total daily dose of 330 mg of compound 1 and 6 mg of fesorodine). In yet another embodiment, the method of this disclosure comprises administering to a patient twice daily about 210 mg of compound 1 or a pharmaceutically acceptable salt thereof and about 3 mg of fesorodine or a pharmaceutically acceptable salt thereof (i.e., a total daily dose of 420 mg of compound 1 and 6 mg of fesorodine).

[0175] In the implementation scheme, twice-daily administration provides an average steady-state plasma concentration of compound 1 of 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 for at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h after administration. In the implementation scheme, twice-daily administration provides an average steady-state plasma concentration of compound 1 of at least about 100 ng / mL for at least about 18 h, at least about 20 h, at least about 22 h, or at least about 24 h after administration. In the implementation plan, twice-daily administration provides an average steady-state plasma concentration of at least about 200 ng / mL of compound 1 within at least about 24 hours after administration.

[0176] In the implementation scheme, the composition of this disclosure is applied three times daily. In one embodiment, the applied composition comprises compound 1 hydrochloride. In another embodiment, the applied composition comprises fesorodine fumarate.

[0177] In the implementation scheme, the patient is administered compound 1 or a pharmaceutically acceptable salt thereof at a dose of about 0.05 mg / kg to about 8 mg / kg, for example, about 0.05 mg / kg, about 0.10 mg / kg, about 0.15 mg / kg, about 0.20 mg / kg, about 0.25 mg / kg, about 0.30 mg / kg, about 0.35 mg / kg, about 0.40 mg / kg, about 0.45 mg / kg, about 0.50 mg / kg, about 0.55 mg / kg, about 0.60 mg / kg, about 0.65 mg / kg, about 0.70 mg / kg, about 0.75 mg / kg, about 0.80 mg / kg, about 0.85 mg / kg, about 0.90 mg / kg, about 0.95 mg / kg, about 1.00 mg / kg, about 1.20 mg / kg, about 1.40 mg / kg, about 1.60 mg / kg, about 1.80 mg / kg. mg / kg, approximately 2.00 mg / kg, approximately 2.20 mg / kg, approximately 2.40 mg / kg, approximately 2.60 mg / kg, approximately 2.80 mg / kg, approximately 3.00 mg / kg, approximately 3.20 mg / kg, approximately 3.40 mg / kg, approximately 3.60 mg / kg, approximately 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.

[0178] In the implementation plan, the patient is administered about 0.01 mg / kg to about 0.602 mg / kg of fesorodine or a pharmaceutically acceptable salt thereof, for example, about 0.010 mg / kg, about 0.011 mg / kg, about 0.012 mg / kg, about 0.013 mg / kg, about 0.015 mg / kg, about 0.016 mg / kg, about 0.018 mg / kg, about 0.019 mg / kg, about 0.021 mg / kg, about 0.024 mg / kg, about 0.026 mg / kg, about 0.029 mg / kg, about 0.031 mg / kg, about 0.035 mg / kg, about 0.038 mg / kg, about 0.042 mg / kg, about 0.046 mg / kg, about 0.051 mg / kg, about 0.056 mg / kg, about 0.061 mg / kg, or about 0.061 mg / kg. mg / kg, approximately 0.067 mg / kg, approximately 0.074 mg / kg, approximately 0.081 mg / kg, approximately 0.090 mg / kg, approximately 0.098 mg / kg, approximately 0.108 mg / kg, approximately 0.119 mg / kg, approximately 0.131 mg / kg, approximately 0.144 mg / kg, approximately 0.159 mg / kg, approximately 0.174 mg / kg, approximately 0.192 mg / kg, approximately 0.211 mg / 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 therein.

[0179] Implementation plan with numbering 1. A composition comprising: (a) Compound 1 in amounts of approximately 10 mg to approximately 500 mg Compound 1 or its pharmaceutically acceptable salt; and (b) about 2 mg to about 20 mg, about 1 mg to about 20 mg or 1 mg to about 10 mg of nonsorodine or a pharmaceutically acceptable salt thereof; The oral administration of the composition provides approximately 0.1 h to approximately 8 h of the t of compound 1 after administration of the composition. max and the t of defensorodine from about 0.1 h to about 8 h max .

[0180] 2. The composition as described in embodiment 1, wherein oral administration of the composition provides a t of compound 1 for about 0.5 h to about 4 h after administration of the composition. max .

[0181] 3. The composition as described in embodiment 1 or 2, wherein oral administration of the composition provides about 0.5 h to about 4 h of defensodrone after administration of the composition. max .

[0182] 4. The composition according to any one of embodiments 1 to 3, wherein oral administration of the composition provides, after administration of the composition, about 200 ng / mL to about 5,000 ng / mL of C1 of compound 1. max,ss .

[0183] 5. The composition according to any one of embodiments 1 to 4, wherein oral administration of the composition provides about 2 ng / mL to about 60 ng / mL of defensodrone C10 after administration of the composition. max,ss .

[0184] 6. The composition according to any one of embodiments 1 to 5, wherein oral administration of the composition provides an AUC of about 4000 ng·h / mL to about 40,000 ng·h / mL of compound 1 after administration of the composition. 0-24h,ss .

[0185] 7. The composition according to any one of embodiments 1 to 6, wherein oral administration of the composition provides an AUC of about 20 ng·h / mL to about 600 ng·h / mL of defensodrone after administration of the composition. 0-24h,ss .

[0186] 7a. The composition according to any one of embodiments 1 to 6, wherein oral administration of the composition provides a steady-state C of greater than 100 ng / mL of compound 1 for at least 8 h after administration. avg concentration.

[0187] 7b. The composition according to any one of embodiments 1 to 6, wherein oral administration of the composition provides a steady-state C of greater than 100 ng / mL of compound 1 for at least 12 h after administration. avg concentration.

[0188] 7c. The composition according to any one of embodiments 1 to 6, wherein oral administration of the composition provides a steady-state C of greater than 100 ng / mL of compound 1 for at least 24 h after administration. avg concentration.

[0189] 7d. The composition as described in any one of embodiments 1 to 6, wherein oral administration of the composition provides a steady-state C1 of compound 1 at a rate of about 350 ng / mL to about 850 ng / mL for at least 8 h after administration. avg concentration.

[0190] 7e. The composition according to any one of embodiments 1 to 6, wherein oral administration of the composition provides a steady-state C of about 350 ng / mL to about 850 ng / mL of compound 1 for at least 12 h after administration. avg concentration.

[0191] 7f. The composition as described in any one of embodiments 1 to 6, wherein oral administration of the composition provides a steady-state C1 of compound 1 at a rate of about 350 ng / mL to about 850 ng / mL for at least 24 h after administration. avg concentration.

[0192] 8. The composition according to any one of embodiments 1 to 7, wherein oral administration of the composition provides a plasma concentration ratio of compound 1 to defensodrone of about 10:1 to about 200:1.

[0193] 9. The composition according to any one of embodiments 1 to 8, wherein oral administration of the composition provides a ratio of compound 1 to difenosonine C in a ratio of about 50:1 to about 250:1. max ratio.

[0194] 10. 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, about 1 mg to about 20 mg, or about 3 mg to about 20 mg of nonsorodine or a pharmaceutically acceptable salt thereof; The composition thereon: Approximately 80% of compound 1 or its pharmaceutically acceptable salt is released within 2 to 12 hours; and Releases approximately 80% of the said nonsorodine or its pharmaceutically acceptable salt within 0.2 h to 8 h or 0.2 h to 12 h. The release was tested at 37°C using a United States Pharmacopeia Instrument II (paddle at 50 rpm) to test dissolution in 900 mL of 0.1N HCl or pH 6.8 phosphate buffer.

[0195] 11. The composition according to any one of the foregoing embodiments, wherein the composition comprises about 50 mg to about 600 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0196] 12. The composition as described in any of the preceding embodiments, wherein the composition comprises about 100 mg to about 400 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0197] 13. The composition as described in any of the preceding embodiments, wherein the composition comprises about 150 mg to about 350 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0198] 13a. The composition as described in any of the preceding embodiments, wherein the composition comprises about 100 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0199] 14. The composition as described in any of the preceding embodiments, wherein the composition comprises about 200 mg to about 300 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0200] 14a. The composition as described in any of the preceding embodiments, wherein the composition comprises about 100 mg to about 200 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0201] 15. The composition as described in any of the preceding embodiments, wherein the composition comprises about 105 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0202] 15a. The composition as described in any of the preceding embodiments, wherein the composition comprises about 165 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0203] 15b. The composition as described in any of the preceding embodiments, wherein the composition comprises about 250 mg of compound 1 or a pharmaceutically acceptable salt thereof.

[0204] 16. The composition of any one of the foregoing embodiments, wherein the composition comprises about 1 mg to about 12 mg of nonsodrone or a pharmaceutically acceptable salt thereof.

[0205] 16a. The composition as described in any of the preceding embodiments, wherein the composition comprises about 3 mg to about 12 mg of nonsolodine or a pharmaceutically acceptable salt thereof.

[0206] 17. The composition of any one of the foregoing embodiments, wherein the composition comprises fesorodine fumarate.

[0207] 18. The composition of any one of the foregoing embodiments, wherein the weight % ratio of compound 1 to nonsodrone in the composition is about 40:1 to about 90:1.

[0208] 19. The composition of any one of the foregoing embodiments, wherein the weight % ratio of compound 1 and nonsorodine 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.

[0209] 20. The composition as described in any of the foregoing embodiments, wherein the composition is a tablet.

[0210] 21. The tablet of embodiment 20, wherein the tablet comprises a sustained-release (ER) portion containing compound 1 or a pharmaceutically acceptable salt thereof.

[0211] 22. The tablet as described in embodiment 20 or 21, wherein the tablet comprises a sustained-release (ER) portion containing nonsorodine or a pharmaceutically acceptable salt thereof.

[0212] 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 nonsodrone or a pharmaceutically acceptable salt thereof.

[0213] 24. The tablet as described in embodiment 23, comprising: (a) The first ER portion containing compound 1 or a pharmaceutically acceptable salt thereof; and (b) A second ER portion containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the first and second portions are constructed in the form of a bilayer tablet.

[0214] 25. The tablet of claim 21, wherein the tablet comprises an immediate-release (IR) portion containing nonsodrone or a pharmaceutically acceptable salt thereof.

[0215] 26. The tablet as described in embodiment 25, comprising: (a) An ER moiety containing compound 1 or a pharmaceutically acceptable salt thereof; and (b) An IR portion containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion are constructed in the form of a bilayer tablet.

[0216] 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.

[0217] 28. The tablet as described in embodiment 27, wherein the stabilizer is xylitol, sorbitol, polydextrose, isomaltitol, glucose, microcrystalline cellulose, fructose, or a mixture thereof.

[0218] 29. The tablet as described in embodiment 27 or 28, wherein the stabilizer is xylitol, fructose, or a mixture thereof.

[0219] 30. The tablet of any one of embodiments 27 to 29, wherein the weight % ratio of the nonsorodine or a pharmaceutically acceptable salt thereof to the stabilizer in the tablet is about 1:20 to about 1:1 or about 1:10 to about 1:50.

[0220] 31. The tablet of embodiment 30, wherein the weight % ratio of the nonsorodine or its pharmaceutically acceptable salt to xylitol or fructose in the tablet is from about 1:9 to about 1:1 or from about 1:18 to about 1:39.

[0221] 32. The tablet as described in embodiment 27, wherein the lubricant is talc, silica, stearic acid, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearate fumarate, polyethylene glycol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof.

[0222] 33. The tablet as described in embodiment 32, wherein the lubricant is talc, glyceryl behenate, silica, magnesium stearate, or a mixture thereof.

[0223] 34. The tablet as described in embodiment 33, wherein the lubricant is talc, glyceryl behenate, or a mixture thereof.

[0224] 35. The tablet of embodiment 27, wherein the controlled-release excipient is polyethylene oxide (PEO), methylcellulose (MC), ethylcellulose, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), sodium carboxymethyl cellulose, or a mixture thereof.

[0225] 36. The tablet as described in embodiment 27, wherein the diluent is microcrystalline cellulose (MCC), mannitol, lactose, dicalcium phosphate, xylitol, or a mixture thereof.

[0226] 37. The tablet according to any one of embodiments 20 to 36, wherein the tablet further comprises lactose, sodium carboxymethyl starch, sodium croscarmellose, polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), glyceryl behenate, talc, or a mixture thereof.

[0227] 38. A tablet as described in any one of embodiments 21 to 37, wherein the portion comprising said compound 1 or a pharmaceutically acceptable salt thereof comprises: Hydroxypropyl methylcellulose (HPMC) of about 20% to about 55% by weight; From about 4% to about 50% by weight of microcrystalline cellulose; From about 2% to about 6% by weight of behenate glycerides; Talc from about 1% to about 4% by weight; and Optional xylitol, from about 4% to about 50% by weight.

[0228] 39. A tablet as described in any one of embodiments 25 to 38, wherein the portion comprising the nonsorodine or a pharmaceutically acceptable salt thereof comprises: From about 10% by weight to about 50% by weight of xylitol; Approximately 50% to approximately 80% by weight of 75% lactose / 25% microcrystalline cellulose; Sodium carboxymethyl starch, approximately 3% to approximately 8% by weight; About 2% by weight to about 6% by weight of behenate glycerides; and Talc, approximately 1% to approximately 4% by weight.

[0229] 40. A tablet as described in any one of embodiments 25 to 38, wherein the portion comprising the nonsorodine or a pharmaceutically acceptable salt thereof comprises: From about 10% by weight to about 50% by weight of xylitol; Approximately 50% to approximately 80% by weight of 75% lactose / 25% microcrystalline cellulose; Approximately 3% to approximately 8% by weight of croscarmellose sodium; About 2% by weight to about 6% by weight of behenate glycerides; and Talc, approximately 1% to approximately 4% by weight.

[0230] 41. The tablet of any one of embodiments 25 to 38, wherein the portion comprising the nonsorodine or a pharmaceutically acceptable salt thereof comprises: From about 10% by weight to about 50% by weight of xylitol; Approximately 50% to approximately 80% by weight of 75% lactose / 25% microcrystalline cellulose; From about 3% to about 8% by weight of polyvinylpyrrolidone (PVP); About 2% by weight to about 6% by weight of behenate glycerides; and Talc, approximately 1% to approximately 4% by weight.

[0231] 42. The tablet according to any one of embodiments 22 to 24 and 27 to 38, wherein the portion comprising nonsorodine or a pharmaceutically acceptable salt thereof comprises: From about 10% by weight to about 50% by weight of xylitol; Approximately 10% by weight to approximately 50% by weight of 75% lactose / 25% microcrystalline cellulose; Hydroxypropyl methylcellulose (HPMC) of about 10% to about 40% by weight; About 1% to about 6% by weight of behenate glycerides; and Talc, approximately 1% to approximately 4% by weight.

[0232] 43. The tablet according to any one of embodiments 22 to 24 and 27 to 38, wherein the portion comprising nonsorodine or a pharmaceutically acceptable salt thereof comprises: From about 8% by weight to about 50% by weight of xylitol; Approximately 10% by weight to approximately 50% by weight of 75% lactose / 25% microcrystalline cellulose; About 20% by weight to about 50% by weight of cellulose ether; About 1% to about 6% by weight of behenate glycerides; and Talc, approximately 1% to approximately 4% by weight.

[0233] 44. The tablet of any one of embodiments 22 to 24 and 27 to 38, wherein the portion comprising nonsorodine or a pharmaceutically acceptable salt thereof comprises: From about 8% by weight to about 50% by weight of xylitol; Approximately 10% by weight to approximately 50% by weight of 75% lactose / 25% microcrystalline cellulose; 10% by weight to about 40% by weight of 80% polyvinyl acetate (PVA) / 19% polyvinyl ketone; About 1% to about 6% by weight of behenate glycerides; and Talc, approximately 1% to approximately 4% by weight.

[0234] 45. A tablet according to any one of embodiments 25 to 41, wherein the tablet releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 10 h and about 80% of nonsorodine or a pharmaceutically acceptable salt thereof within 0.1 h to 1 h, wherein the release 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 at 50 rpm).

[0235] 46. ​​A tablet as described in any one of embodiments 22 to 24, 27 to 38, and 42 to 44, wherein the tablet releases about 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 12 hours and about 80% of nonsorodine or a pharmaceutically acceptable salt thereof within 1 to 7 hours or 5 to 12 hours, wherein the release 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 at 50 rpm).

[0236] 47. The tablet as described in embodiment 20 or 21, wherein the composition comprises: Containing a sustained-release (ER) portion of compound 1 or a pharmaceutically acceptable salt thereof; and An immediate-release (IR) coating containing nonsorodine or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on the ER portion.

[0237] 48. The tablet of embodiment 47, 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.

[0238] 49. The tablet as described in embodiment 47 or 48, wherein 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 % ratio of 3:1; (f) HPMC; (g) HPMC and xylitol; or (h) HPMC and fructose.

[0239] 50. The tablet of claim 49, wherein the IR coating comprises: (a) about 40% to about 60% by weight of polyvinyl alcohol (PVA), about 10% to about 20% by weight of polyethylene glycol (PEG), about 1% to about 5% by weight of polysorbate 80 and about 20% to about 40% by weight of talc; (b) about 70% to about 85% HPMC, about 5% to about 10% triacetin and about 5% to about 10% talc; (c) about 25% to about 50% PVA, about 10% to about 40% xylitol, about 5% to about 20% PEG, about 1% to about 5% polysorbate 80 and about 10% to about 30% talc. (d) about 20% to about 40% PVA, about 30% to about 40% fructose, about 5% to about 15% PEG, about 1% to about 3% polysorbate 80 and about 10% to about 25% talc. (e) about 85% by weight to about 95% by weight of a copolymer of polyvinyl alcohol and polyethylene glycol in a weight ratio of 3:1 in the coating; (f) HPMC of about 65% to about 95% by weight; (g) about 40% to about 60% by weight of HPMC and about 30% to about 45% by weight of xylitol; or (h) about 40% to about 60% HPMC and about 30% to about 45% fructose.

[0240] 51. The tablet according to any one of embodiments 47 to 50, wherein the tablet further comprises: (i) about 60% to about 70% by weight of polyvinyl alcohol (PVA), about 15% to about 25% by weight of talc, about 1% to about 5% by weight of lecithin and about 0.1% to about 1.5% by weight of xanthan gum.

[0241] 52. The tablet according to any one of embodiments 47 to 51, wherein the IR coating releases 80% of the nonsorodine within 0.5 h to 2 h, the release being 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 at 50 rpm).

[0242] 53. The composition as described in any one of embodiments 1 to 19, wherein the composition is a permeation tablet.

[0243] 54. The permeation tablet as described in embodiment 53, wherein the tablet releases approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 4 to 16 hours. The release of approximately 80% of nonsorodine or its pharmaceutically acceptable salts was achieved within 4 to 16 hours, with the release 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 at 50 rpm).

[0244] 55. The composition of any one of embodiments 1 to 19, wherein the composition is a multi-particulate formulation.

[0245] 56. A multi-particle formulation as described in embodiment 55, wherein the formulation releases approximately 80% of compound 1 or a pharmaceutically acceptable salt thereof within 2 to 8 hours. The release of approximately 80% of nonsorodine or its pharmaceutically acceptable salts was achieved within 4 to 12 hours, with the release tested at 37°C using 900 mL of 0.1N HCl or pH 6.8 phosphate buffer via a United States Pharmacopeia Equipment II (paddle at 50 rpm).

[0246] 57. A method for treating a patient with a motor disorder, the method comprising administering a therapeutically effective amount of a composition as described in any one of embodiments 1 to 20 and 53 to 56, or a tablet as described in any one of embodiments 21 to 52.

[0247] 58. The method of embodiment 57, wherein the dyskinesia is a levodopa-induced dyskinesia.

[0248] 58a. The method as described in embodiment 57, wherein the movement disorder is a tardive movement disorder.

[0249] 59. The method as described in embodiment 57 or 58, wherein the patient is diagnosed with Parkinson's disease.

[0250] 60. A method of treating schizophrenia in a patient in need, the method comprising administering a therapeutically effective amount of a composition as described in any one of embodiments 1 to 19 and 53 to 56, or a tablet as described in any one of embodiments 20 to 52.

[0251] 61. A method for treating Alzheimer's disease psychosis in patients in need, the method comprising administering a therapeutically effective amount of a composition as described in any one of embodiments 1 to 19 and 53 to 56 or a tablet as described in any one of embodiments 20 to 52.

[0252] 62. A method for treating a neurological disorder in a patient in need, the method comprising administering a therapeutically effective amount of a composition as described in any one of embodiments 1 to 19 and 53 to 56 or a tablet as described in any one of embodiments 20 to 52, wherein the neurological disorder is Alzheimer's dementia, Lewy body disease with psychosis, Lewy body dementia, bipolar manic episode, bipolar mixed episode, bipolar maintenance (bipolar type 1 and / or type 2), bipolar depression, or agitation in cognitive impairment of bipolar type 1 and / or type 2 disorder.

[0253] 63. The method of any one of embodiments 57 to 62, wherein the composition is applied once daily.

[0254] 63a. The method as described in any one of embodiments 57 to 62, wherein one of the compositions is applied once daily.

[0255] 63b. The method as described in any one of embodiments 57 to 62, wherein the two compositions are applied once daily.

[0256] 64. The method of any one of embodiments 57 to 61, wherein the composition is applied twice daily.

[0257] 64a. The method as described in any one of embodiments 57 to 61, wherein one of the compositions is applied twice daily.

[0258] 64b. The method as described in any one of embodiments 57 to 61, wherein the two compositions are applied twice daily.

[0259] 65a. The method of any one of embodiments 57 to 64, wherein the oral administration provides a steady-state C of compound 1 greater than 100 ng / mL for at least 8 hours after administration. avg concentration.

[0260] 65b. The method of any one of embodiments 57 to 64, wherein the oral administration provides a steady-state C of compound 1 greater than 100 ng / mL for at least 12 h after administration. avg concentration.

[0261] 65c. The method of any one of embodiments 57 to 64, wherein the oral administration provides a steady-state C of compound 1 greater than 100 ng / mL for at least 24 h after administration. avg concentration.

[0262] 65d. The method as described in any one of embodiments 57 to 64, wherein the oral administration provides a steady-state C1 of compound 1 at a rate of about 350 ng / mL to about 850 ng / mL for at least 8 hours after administration. avg concentration.

[0263] 65e. The method of any one of embodiments 57 to 64, wherein the oral administration provides a steady-state C1 of compound 1 at a rate of about 350 ng / mL to about 850 ng / mL for at least 12 h after administration. avg concentration.

[0264] 65f. The method of any one of embodiments 57 to 64, wherein the oral administration provides a steady-state C1 of compound 1 at a rate of about 350 ng / mL to about 850 ng / mL for at least 24 h after administration. avg concentration.

[0265] 65g. The method as described in any one of embodiments 57 to 64, wherein the oral administration provides a plasma concentration ratio of compound 1 to defensodrone of about 10:1 to about 200:1.

[0266] 65h. The method as described in any one of embodiments 57 to 64, wherein the oral administration provides a ratio of compound 1 of about 50:1 to about 250:1 with C of difenosine. max ratio.

[0267] 66. The composition as described in any one of embodiments 1 to 19 and 53 to 56, or the tablet as described in any one of embodiments 20 to 52, wherein the D of said compound 1 50 It is approximately 40 µm to approximately 50 µm.

[0268] 67. The composition as described in any one of embodiments 1 to 19 and 53 to 56, or the tablet as described in any one of embodiments 20 to 52, wherein the D of said compound 1 90 It is approximately 200 µm to approximately 300 µm.

[0269] 68. The tablet as described in embodiment 20, wherein the tablet comprises: Approximately 20% to approximately 40% by weight of microcrystalline cellulose; From about 5% by weight to about 25% by weight of xylitol; About 40% by weight to about 60% by weight of hydroxypropyl methylcellulose; and Magnesium stearate, about 0.25% by weight to about 0.75% by weight.

[0270] 69. The tablet according to any embodiment 20, wherein the tablet comprises: Approximately 5% by weight to approximately 15% by weight of lactose; From about 3% to about 20% by weight of microcrystalline cellulose; Sodium carboxymethyl starch, approximately 0.1% to approximately 0.6% by weight; Magnesium stearate, approximately 0.04% by weight to approximately 0.2% by weight; about 0.5% by weight to about 8% by weight of xylitol; and Fructose: about 2% to about 8% by weight.

[0271] Example The invention is further illustrated by referring to the following embodiments. These embodiments are illustrative and should not be construed as limiting the scope of the invention in any way.

[0272] Example 1. Pharmacokinetics of Compound 1 and Non-Soroform Derivative Evaluate the pharmacokinetics of formulations containing compound 1 and non-soxodine. Figures 1A-1B , Figure 2 and Figures 3A-3C The figure shows the observed and (by power model) predicted C values ​​of compound 1 after administration of different doses of the compound 1 formulation (without fensodrone). max and AUC inf value.

[0273] The mean plasma concentrations of compound 1 and 5-hydroxymethyl tolterodine (5-HMT) were measured after administration of compound 1, nonsodrone, or a combination of compound 1 and nonsodrone (with nonsodrone administered 30 min prior to compound 1). Figures 4A-4C ).

[0274] Figures 5A-5B The mean plasma concentrations of 5-HMT and compound 1 are shown in the figures for both nonsorodine alone and concurrent administration of nonsorodine and compound 1. Figures 6A-6B and Figures 7A-7B Exemplary corrections for compound 1 and 5-HMT metabolite exposure are provided in different subjects following administration of 60 mg, 90 mg, or 135 mg of compound 1 and 6 mg or 9 mg of nonsorodine.

[0275] like Figure 15 As shown, after administration of 135 mg of compound 1 and 6 mg of nonsodrone, the concentration ratio of compound 1 and 5-HMT in plasma remained consistent over time.

[0276] Based on PK modeling, plasma C of compound 1 max At CSF levels, concentrations exceeded 3000 ng / mL and 328 ng / mL. The target plasma concentration for compound 1 was 300 ng / mL, and the tolerable CSF level was predicted to be 10 times higher than the minimum effective exposure level. max This will enable the formulation disclosed herein to be administered via BID (Binary Intake). Figure 8A Based on simulations using Phase 1 SAD / MAD data, a C10 concentration of 1200 ng / mL or higher is required.max To maintain compound 1 at or above therapeutic levels for 12 hours. Based on efficacy data from multiple animal studies, the plasma C of compound 1... min The predicted value was 300 ng / mL (and 25 ng / mL in CSF). Figure 8B ).

[0277] Figures 9A-9C The predicted exposure concentration levels of compound 1 and 5-HMT after administration of compound 1 (ER) and non-sorodin (IR, 12-hour ER, or 8-hour ER) formulations are shown.

[0278] Example 2. Compound 1 sustained-release tablet core Prepare polymer matrix formulations of compound 1. Using a Type 2 USP apparatus, 0.1 N HCl acidic solution (or pH 6.8 phosphate buffer), paddle speed 50 rpm, target in vitro release (IVR) curves show 80% release of compound 1 over 8 hours. Prepare formulations containing different polymer types (e.g., high molecular weight HPMC, PEO, and mixtures thereof); fillers (soluble / insoluble fillers), tablet sizes (1000 to 1300 mg), and dose intensities (40 mg to 250 mg of compound 1). Figures 10A-10G The results of the solubility test of the test formulation are shown in the figure.

[0279] Based on these data, 40 mg and 125 mg extended-release (ER) tablets (compound 1) were prepared for clinical testing (Table 1). Figure 11 The manufacturing process of these formulations is shown in the figure.

[0280] Table 1. 40 mg and 125 mg ER formulation compositions

[0281] The test results for these formulations are summarized in Table 2. Figure 12 The results from the dissolution test are shown in the figure.

[0282] Table 2. Release tests of 40 mg and 125 mg ER tablets

[0283] like Figures 13A-13B As shown, the robustness of these formulations to stirring conditions was tested using a USP 3 dissolution apparatus at 30 dpm. The USP 3 method at 30 dpm provides the same dissolution profile as obtained using the USP 2 dissolution test.

[0284] Example 3. Combination of sustained-release compound 1 and immediate-release fesotropin (bilayer tablet) Four bilayer tablet formulations, one with and one without stabilizers, were prepared and accelerated stability studies were conducted. The composition of the formulations is shown in Table 3.

[0285] Table 3. Compound 1 sustained-release and nonsorodine immediate-release bilayer tablets

[0286] * 6.41 mg of fesorodine fumarate (salt) is equivalent to 5.0 mg of fesorodine (free base). Figure 14A Release profiles of formulations containing xylitol as a stabilizer were compared with those without stabilizer, measured using a Type 2 USP apparatus, pH 6.8 phosphate buffer, and a paddle speed of 50 rpm. No significant differences were observed in the release profiles of nonsorodine and compound 1 between these formulations.

[0287] The formulations described in Table 4 were prepared. In these formulations, xylitol and fesorodine fumarate were used in a 9:1 weight ratio (wet granulation). The compound 1 blend was prepared via a direct compression process.

[0288] Table 4. Compound 1 sustained-release and non-solodine immediate-release bilayer tablets

[0289] Example 4. Composition of sustained-release compound 1 and sustained-release fesorodine (bilayer tablet) The formulations shown in Table 5 were prepared. The in vitro release (IVR) target for these formulations was the release of 80% of nonsorodine within 2 to 8 hours and 80% of compound 1 within 2 to 12 hours, as tested using a Type 2 USP apparatus at pH 6.8 phosphate buffer and a paddle speed of 50 rpm. Figure 14B ).

[0290] Prepare other formulations as shown in Tables 5a-5d.

[0291] Table 5. ER / ER tablet formulations

[0292] Table 5a. ER / ER formulations

[0293] Table 5b. ER / ER formulations

[0294] Table 5c. ER / ER formulations

[0295] Table 5d. ER / ER formulations

[0296] Example 5. Extended-release (ER) compound 1 and immediate-release (IR) nonsodrone coated formulations A tablet containing an immediate-release fenosine coating on the core portion of a sustained-release (ER) compound 1 was prepared.

[0297] Tables 6a and 6b show the composition of an exemplary IR-coated compound 1 (ER) tablet.

[0298] Table 6a. Compound 1 (ER) tablets coated with IR-coated nonsorodine

[0299] Table 6b. IR-coated compound 1 (ER) tablets containing nonsorodine

[0300] Example 6. PK Study of Permeable Tablets and Multiparticles The plan is to prepare penetrating tablets and multi-particle formulations containing compound 1 and non-sodrodin.

[0301] The release profiles of the permeation tablets will be as follows: measured using a Type 2 USP device, pH 6.8 phosphate buffer, paddle speed = 50 rpm, releasing 80% of nonsorodine and compound 1 (zero-order release) over 4 to 16 hours.

[0302] The release profiles for the multi-particle formulation are as follows: measured using a Type 2 USP apparatus, pH 6.8 phosphate buffer, and a paddle speed of 50 rpm, 80% of nonsorodine is released in 2 to 8 hours and 80% of compound 1 is released in 4 to 12 hours.

[0303] Example 7. Effect of Compound 1 on amphetamine-induced hyperkinesis (AIH) To evaluate the role of compound 1 in an amphetamine-induced hyperactivity (AIH) mouse model.

[0304] Compound 1 reduced AIH in a dose-dependent manner, with significant effects at 0.3, 0.6, and 1 mg / kg, as measured in a 30-minute open-field exercise capacity test (p < 0.0001, one-way ANOVA). Figures 16A-16B The results showed that compound 1 reversed hyperdopaminergic-mediated motor behavior in a dose-dependent manner. These data provide evidence for the therapeutic potential of compound 1 for psychotic disorders such as schizophrenia, Alzheimer's disease, and Parkinson's disease, as well as levodopa-induced motor disorders.

[0305] The effects of compound 1 and co-administration of nonsodrone on AIH were also evaluated. Alone administration of 1.0 mg / kg compound 1, as well as co-administration with 0.3 and 1.0 mg / kg nonsodrone, inhibited AIH to similar degrees, indicating that co-administration of nonsodrone did not significantly inhibit the activity of compound 1 in the CNS.

[0306] Example 8. Effect of Compound 1 on benzylpyridin-induced hyperkinesis To evaluate the role of compound 1 in phencyclidine (PCP)-induced hyperdopaminergic motor behavior.

[0307] Prior to testing, mice were acclimatized to the behavioral testing room for at least 30 minutes. Illumination was maintained at 50 ± 20 LUX during testing. Mice were weighed and administered the medium, 0.3, 0.6, or 1 mg / kg of compound 1 via intraperitoneal injection, followed by rapid, continuous subcutaneous administration of 5 mg / kg of PCP. Immediately afterward, mice were placed in an open area (44 cm x 44 cm x 20 cm) and allowed to freely explore the space while an automated video tracking system monitored their position and distance traveled for 30 minutes.

[0308] Motor behavior was measured using an automated video tracking system (Noldus EthoVision v15). Data were presented in time-series format and summarized as the mean total distance traveled after treatment. Statistical significance was tested using univariate ANOVA followed by Dunnett's multiple comparisons test, n=16 / group.

[0309] like Figures 17A-17B As shown, compound 1 dose-dependently reduced excessive movement induced by 5 mg / kg PCP, as measured over a 30-minute period at 0.3, 0.6, and 1 mg / kg, with significant effects (p<0.0001, one-way ANOVA test).

[0310] Example 9. Effect of Compound 1 on Alzheimer's Disease To evaluate the effect of compound 1 on resident intruder aggression in a Tg2576 mouse model of Alzheimer's disease. Compound 1 reduced the number and duration of attacks in Tg2576 mice at 0.5 mg / kg (p<0.05, paired t-test), thus supporting the conclusion that compound 1 has anti-attack activity.

[0311] Example 10: Effect of compound 1 on MPTP-induced dyskinesia To evaluate the role of compound 1 in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dyskinesia.

[0312] The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been identified as a compound that selectively induces the degeneration of dopaminergic neurons in the substantia nigra when it is found as a contaminant in heroin and when users present with clinical symptoms that are difficult to distinguish from PD. This neurotoxin is now being used in non-human primates to mimic the motor symptom phenotype of primary Parkinson's disease and subsequent response to therapies including motor disorders, such as levodopa, and thus it can be used as a basal model of 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. Oct 2012;63(5):829-36). With both face validity and construct validity, the MPTP non-human primate model is considered to be the animal model of motor symptoms of PD with the highest conversion relevance.

[0313] A study was conducted in seven female cynomolgus monkeys with MPTP injury who received chronic, repetitive treatment with levodopa and exhibited stable and repetitive dyskinesia (LID) in response. Behavior was assessed in the monkeys following a single 1 mg / kg dose of compound 1 or its carrier in combination with a high dose of levodopa delivered in Madopar™ form, titrated against LID symptoms in each test animal. Treatment efficacy and abnormal LID dyskinesia were assessed within 6 hours of levodopa administration. A single oral dose of compound 1 or its carrier at 1 mg / kg was administered concurrently with levodopa at the start of behavioral observation. All animals received all treatments in a crossover design with a minimum 72-hour interval between repeated treatments per animal. Treatment and LID behavior were assessed in a blinded manner using high-definition video recordings and the Nonhuman Primate Dyskinesia Rating Scale by trained raters supervised by neurologists. See Fox 2012. (Fox SH, Johnston TH, Li Q, Brotchie J, Bezard E. A critique of available scales and presentation of the Non-Human Primate Dyskinesia Rating Scale. Mov Disord. 2012 Sep 15;27(11):1373-8).

[0314] Compound 1 (1 mg / kg, PO) provided a significant anti-motor dyskinesia effect, reducing the median level of motor dysfunction by 91% during the 0–1 h period (median level 11 vs. 1; mediator vs. compound 1, P<0.001). A potent reduction in LID was evident in six of the seven animals included in the final analysis. Accumulated over the 0–2 h period, the median level of motor dysfunction was reduced by 42%, resulting in a non-disabling level (median level 33 vs. 19; mediator vs. compound 1, P=0.0156). This peak-effect reduction in motor dysfunction was further demonstrated by a beneficial reduction (41%) in the duration of 'unfavorable' onset (onset associated with disabling motor dysfunction) and a significant increase (143%) in the duration of 'favorable' onset (onset associated with absence or only non-disabling motor dysfunction). Compound 1 did not produce an anti-Parkinson's disease benefit of L-DOPA or a reduction in the total onset duration associated with L-DOPA.

[0315] These results from the MPTP-induced movement disorder study in macaques provide strong evidence for the therapeutic potential of compound 1 for movement disorders such as LID in patients with PD.

[0316] Example 11. The role of compound 1 in tardive dyskinesia To evaluate the role of compound 1 in a long-term haloperidol mouse model of tardive dyskinesia.

[0317] Tardive dyskinesia (TD) may be a side effect of treatment with atypical antipsychotic drugs. Long-term haloperidol treatment induced TD symptoms in mice. These symptoms included fine chewing movements, high-frequency jaw / mouth tremors, and aimless mouth openings (VCM) on the vertical plane with or without tongue protrusion.

[0318] Compound 1 at 0.5 mg / kg significantly reduced VCM in the long-term haloperidol mouse model of TD (p<0.001, one-tailed paired t-test).

[0319] Example 12. Comparative pharmacokinetic study of oral administration of compound 1 with or without fesoroid in healthy adult subjects. This study is an open-label, comparative pharmacokinetic / bioavailability study of compound 1 administered orally with or without fesodrodin in healthy adult subjects under both eating and fasting conditions.

[0320] The aim of this study was to evaluate the single- or multiple-dose pharmacokinetic (PK) profiles of compound 1, fexordine, and its active metabolite defexordine in plasma and cerebrospinal fluid (CSF); to assess the safety and tolerability of compound 1 formulations with or without fexordine; and to evaluate the PK effect of fexordine on compound 1. The endpoint of this study was the measurement of non-compartmental PK parameters of compound 1, fexordine, and its bioactive metabolite defexordine, including the area under the concentration-time curve (AUC) and the maximum observed concentration (C). max ) and reaching C max Time (T) max ).

[0321] Doses A solution of 32 mg of compound 1 will be administered. In orally disintegrating tablets (ODT), a dose of up to 32 mg of compound 1 will be administered (e.g., 8 mg, 16 mg, 24 mg, and 32 mg). In extended-release formulations, a starting dose of 40 mg of compound 1 will be administered, and the dose may be increased up to 375 mg (including 80 mg, 125 mg, 165 mg, and 375 mg). When compound 1 is co-administered with fesorodine, 3 mg of fesorodine will be administered.

[0322] Example 13. Clinical observation results and pharmacokinetics of orally administered compound 1 / fesoro customized formulation A study was conducted to characterize the pharmacokinetic (PK), safety, and tolerability profiles of compound 1 and fexordine fumarate in healthy adult subjects. Subjects received a single dose of compound 1 HCl and fexordine fumarate (ER / ER tablets, F25-F28, Example 4) at dose strength combinations selected from Table 7. The once-daily (QD) dosing cohort received 165 mg / 3 mg, 210 mg / 3 mg, 270 mg / 6 mg, and 330 mg / 6 mg. The twice-daily (BID) dosing cohort received 105 mg / 1.5 mg, 165 mg / 3 mg, and 210 mg / 3 mg.

[0323] Table 7. Dosage Intensity Combinations

[0324] Dosage is based on the amount of free base of compound 1 and non-sodrodin.

[0325] Results: Steady-state PK data for the seven dosing 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-8B. In all cohorts, therapeutically effective target plasma concentrations of the target compound 1 (observed steady-state concentrations) remained greater than 100 ng / mL for 24 hours after administration. avg (350 ng / mL to 850 ng / mL). All doses were well tolerated, and no serious treatment-emergent adverse events (TEAEs) were reported.

[0326] Table 8A. Steady-state PK of Compound 1

[0327] PK parameter values ​​are presented in the form of median (minimum, maximum). Table 8B. Steady-state PK of 5-HMT

[0328] PK parameter values ​​are presented in the form of median (minimum, maximum). Incorporated by reference All references, articles, publications, patents, patent publications, and patent and patent application cited herein are incorporated herein by reference in their entirety for all purposes. However, any mention of any reference, article, publication, patent, patent publication, and patent application cited herein does not and should not be construed as an admission or in any way an implication that they constitute valid prior art or form part of common general knowledge in any country of the world.

Claims

1. A composition comprising: (a) about 10 mg to about 500 mg of Compound 1 Compound 1 or a pharmaceutically acceptable salt thereof; and (b) about 1 mg to about 20 mg of fesoxodine or a pharmaceutically acceptable salt thereof; wherein oral administration of the composition to a patient in need provides a t max of about 0.1 h to about 10 h of Compound 1 max of about 0.1 h to about 10 h of Compound 1 max of about 0.1 h to about 10 h of Compound 1 max of about 0.1 h to about 10 h of Compound 1 max of about 0.1 h to about 10 h of Compound 1 max of about 0.1 h to about 10 2. The composition of claim 1, wherein oral administration of the composition provides a t max . of Compound 1 from about 1.5 h to about 8 h after administration of the composition.

3. The composition of claim 1 or 2, wherein orally administering the composition provides a t of about 1 h to about 8 h of desloratadine after administration of the composition. max .

4. The composition of any one of claims 1 to 3, wherein oral administration of the composition provides a Cmaxof Compound 1 of about 200 ng / mL to about 5,000 ng / mL after administration of the composition. max,ss .

5. The composition of any one of claims 1 to 4, wherein oral administration of the composition provides a C max,ss .

6. The composition of any one of claims 1 to 5, wherein oral administration of the composition provides an AUC of compound 1 of about 4000 ng-h / mL to about 40,000 ng-h / mL after administration of the composition. 0-24h,ss .

7. The composition of any one of claims 1 to 6, wherein oral administration of the composition provides an AUC of between about 5 ng-h / mL and about 600 ng-h / mL of desiropridex after administration of the composition. 0-24h,ss .

8. The composition of any one of claims 1 to 7, wherein oral administration of the composition provides a plasma concentration ratio of Compound 1 to fesoxodine of about 10: 1 to about 400:

1.

9. The composition of any one of claims 1 to 8, wherein oral administration of the composition provides a ratio of compound 1 to difenosonine of about 50:1 to about 600:

1. max ratio.

10. 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 20 mg of fesoxodine or a pharmaceutically acceptable salt thereof; wherein the composition: releases about 80% of the Compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 12 h; and releases about 80% of the fesoxodine or a pharmaceutically acceptable salt thereof within 0.2 h to 12 h the release is tested for dissolution using USP Apparatus II (paddle at 50 rpm) in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer at 37 °C.

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

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

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

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

15. The composition of any one of the preceding 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 of any one of the preceding claims, wherein the composition comprises about 1.5 mg to about 12 mg of fesoxodine or a pharmaceutically acceptable salt thereof.

17. The composition of any one of the preceding claims, wherein the composition comprises fesoxodine fumarate.

18. The composition of any one of the preceding claims, wherein the weight % ratio of Compound 1 to fesoxodine in the composition is about 40: 1 to about 90:

1.

19. The composition of any one of the preceding claims, wherein the weight % ratio of Compound 1 and fesoxodine in the composition is about 46: 1 to about 70:

1.

20. The composition of any one of the preceding claims, wherein the composition is a tablet.

21. The tablet of claim 20, wherein the tablet comprises a sustained release (ER) portion comprising Compound 1, or a pharmaceutically acceptable salt thereof.

22. The tablet of claim 20 or 21, wherein the tablet comprises a sustained release (ER) portion comprising Fesoxodine, or a pharmaceutically acceptable salt thereof.

23. The tablet of any one of claims 20 to 22, wherein the tablet comprises a sustained release (ER) portion comprising Compound 1, or a pharmaceutically acceptable salt thereof, and a sustained release (ER) portion comprising Fesoxodine, or a pharmaceutically acceptable salt thereof.

24. The tablet of claim 23, comprising: (a) a first ER portion comprising Compound 1, or a pharmaceutically acceptable salt thereof; and (b) a second ER portion comprising Fesoxodine, or a pharmaceutically acceptable salt thereof, wherein the first portion and the second portion are configured in a bilayer tablet.

25. The tablet of claim 21, wherein the tablet comprises an immediate release (IR) portion comprising Fesoxodine, or a pharmaceutically acceptable salt thereof.

26. The tablet of claim 25, comprising: (a) an ER portion comprising Compound 1, or a pharmaceutically acceptable salt thereof; and (b) an IR portion comprising Fesoxodine, or a pharmaceutically acceptable salt thereof, wherein the ER portion and the IR portion are configured in a bilayer tablet.

27. The tablet of any one of claims 20 to 26, wherein the tablet further comprises a stabilizer, a controlled release excipient, a lubricant, a diluent, or a mixture thereof.

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

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

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

1.

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

39.

32. The tablet of 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, polyethylene glycol, glyceryl behenate, corn starch, magnesium stearate, or a mixture thereof.

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

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

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

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

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

38. The tablet of any one of claims 21 to 37, wherein the portion comprising the Compound 1, or a pharmaceutically acceptable salt thereof, comprises: about 20% to about 55% by weight of hydroxypropyl methylcellulose (HPMC); about 4% to about 50% by weight of microcrystalline cellulose; about 2% to about 6% by weight of glyceryl behenate; about 1% to about 4% by weight of talc; and optionally about 4% to about 50% by weight of xylitol.

39. The tablet of any one of claims 21 to 37, wherein the portion comprising the Compound 1, or a pharmaceutically acceptable salt thereof, comprises: about 40% to about 60% by weight of HPMC about 20% to about 25% by weight of microcrystalline cellulose; about 5% to about 20% by weight of xylitol; and about 0.1% to about 0.4% by weight of magnesium stearate.

40. The tablet of any one of claims 25 to 39, wherein the portion comprising the fexofenadine, or a pharmaceutically acceptable salt thereof, comprises: about 10% to about 50% by weight of xylitol; about 50% to about 80% by weight of 75% lactose / 25% microcrystalline cellulose; about 3% to about 8% by weight of sodium carboxymethyl starch; about 2% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc.

41. The tablet of any one of claims 25 to 39, wherein the portion comprising the fexofenadine, or a pharmaceutically acceptable salt thereof, comprises: about 10% to about 50% by weight of xylitol; about 50% to about 80% by weight of 75% lactose / 25% microcrystalline cellulose; about 3% to about 8% by weight of sodium croscarmellose; about 2% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc.

42. The tablet of any one of claims 25 to 39, wherein the portion comprising the fexofenadine, or a pharmaceutically acceptable salt thereof, comprises: about 10% to about 50% by weight of xylitol; about 50% to about 80% by weight of 75% lactose / 25% microcrystalline cellulose; about 3% to about 8% by weight of polyvinylpyrrolidone (PVP); about 2% to about 6% by weight of glyceryl behenate; and about 1% to about 4% by weight of talc.

43. The tablet of any one of Claims 22 to 24 and 27 to 39, wherein the portion comprising fesoterodine or a pharmaceutically acceptable salt thereof comprises: about 10% to about 50% by weight xylitol; about 10% to about 50% by weight 75% lactose / 25% microcrystalline cellulose; about 10% to about 40% by weight hydroxypropyl methylcellulose (HPMC); about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

44. The tablet of any one of Claims 22 to 24 and 27 to 39, wherein the portion comprising fesoterodine or a pharmaceutically acceptable salt thereof comprises: about 8% to about 50% by weight xylitol; about 10% to about 50% by weight 75% lactose / 25% microcrystalline cellulose; about 20% to about 50% by weight cellulose ether; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

45. The tablet of any one of Claims 22 to 24 and 27 to 39, wherein the portion comprising fesoterodine or a pharmaceutically acceptable salt thereof comprises: about 8% to about 50% by weight xylitol; about 10% to about 50% by weight 75% lactose / 25% microcrystalline cellulose; about 10% to about 40% by weight 80% polyvinyl acetate (PVA) / 19% povidone; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

46. The tablet of any one of Claims 22 to 24 and 27 to 39, wherein the portion comprising fesoterodine or a pharmaceutically acceptable salt thereof comprises: about 10% to about 50% by weight xylitol; about 10% to about 40% by weight 75% lactose / 25% microcrystalline cellulose; about 20% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

47. The tablet of any one of Claims 22 to 24 and 27 to 39, wherein the portion comprising fesoterodine or a pharmaceutically acceptable salt thereof comprises: about 10% to about 50% by weight xylitol; about 20% to about 40% by weight MCC; about 20% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

48. The tablet of any one of Claims 22 to 24 and 27 to 39, wherein the portion comprising fesoterodine or a pharmaceutically acceptable salt thereof comprises: about 8% to about 20% by weight xylitol; about 10% to about 40% by weight 75% lactose / 25% microcrystalline cellulose; about 10% to about 30% by weight lactose; about 10% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl behenate; and about 1% to about 4% by weight talc.

49. The tablet of any one of Claims 22 to 24 and 27 to 39, wherein the portion comprising fisibocin or a pharmaceutically acceptable salt thereof comprises: about 10% to about 40% by weight xylitol; about 10% to about 20% by weight lactose; about 10% to about 40% by weight MCC; about 20% to about 40% by weight HPMC; about 1% to about 6% by weight glyceryl monostearate; and about 1% to about 4% by weight talc.

50. The tablet of any one of Claims 25 to 42, wherein the tablet releases about 80% of Compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 10 h and about 80% of fisibocin or a pharmaceutically acceptable salt thereof within 0.1 h to 1 h, the release tested for dissolution at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle at 50 rpm).

51. The tablet of any one of Claims 22 to 24, 27 to 38, and 43 to 49, wherein the tablet releases about 80% of Compound 1 or a pharmaceutically acceptable salt thereof within 2 h to 12 h and about 80% of fisibocin or a pharmaceutically acceptable salt thereof within 1 h to 7 h or 5 h to 12 h, the release tested for dissolution at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle at 50 rpm).

52. The tablet of Claim 20 or 21, wherein the composition comprises: an extended release (ER) portion comprising Compound 1 or a pharmaceutically acceptable salt thereof; and an immediate release (IR) coating comprising fisibocin or a pharmaceutically acceptable salt thereof, wherein the IR coating is disposed on the ER portion.

53. The tablet of 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 tablet of Claim 52 or 53, wherein 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 ratio of 3: 1; (f) HPMC; (g) HPMC and xylitol; or (h) HPMC and fructose.

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

56. The tablet of any one of claims 52 to 55, wherein the tablet further comprises: (i) about 60 wt% to about 70 wt% polyvinyl alcohol (PVA), about 15 wt% to about 25 wt% talc, about 1 wt% to about 5 wt% lecithin, and about 0.1 wt% to about 1.5 wt xanthan gum.

57. The tablet of any one of claims 52 to 56, wherein the IR coating releases 80% of the fesoxodine within 0.5 h to 2 h, the release tested at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle at 50 rpm).

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

59. The osmotic tablet of claim 58, wherein the tablet releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 4 h to 16 h and about 80% of fesoxodine, or a pharmaceutically acceptable salt thereof, within 4 h to 16 h, the release tested for dissolution at 37°C in 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer using USP Apparatus II (paddle at 50 rpm).

60. The composition of any one of claims 1 to 19, wherein the composition is a multiparticulate formulation.

61. The multiparticulate formulation of claim 60, wherein the formulation releases about 80% of Compound 1, or a pharmaceutically acceptable salt thereof, within 2 h to 8 h and about 80% of solifenacin, or a pharmaceutically acceptable salt thereof, within 4 h to 12 h, the release tested for dissolution using USP Apparatus II (paddle at 50 rpm) 900 mL of 0.1 N HC1 or pH 6.8 phosphate buffer at 37 °C.

62. A method of treating a movement disorder in a patient in need thereof, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 19 and 58 to 61 or the tablet of any one of claims 20 to 57.

63. The method of claim 62, wherein the movement disorder is levodopa-induced dyskinesia or tardive dyskinesia.

64. The method of claim 62 or 63, wherein the patient is diagnosed with Parkinson’s disease.

65. A method of treating parkinsonian psychosis in a patient in need thereof, the method comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 19 and 58 to 61 or the tablet of any one of claims 20 to 57.

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

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

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

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

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