Combination of latrepirdine and a pharmacokinetic stabilizer

Abstract

The present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and an effective amount of a PK stabilizer. The PK stabilizer may be selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof. The PK stabilizer in the composition results in improved pharmacokinetic profile and enhanced therapeutic effect of latrepirdine. The disclosure further relates to treatment of disorders associated with noradrenergic hyperarousal using the pharmaceutical composition.

Description

Agent Reference No.: BXTI-060 / 01WO (332712-2433) COMBINATION OF LATREPIRDINE AND A PHARMACOKINETIC STABILIZER CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Provisional Application No. 63 / 608,676, filed December 11, 2023, the contents of which are hereby incorporated in their entirety as set forth herein. INCORPORATION BY REFERENCE

[0002] The contents of PCT / US2023 / 031731 filed August 31, 2023 and the contents of PCT / US2022 / 017963 filed February 25, 2022 are hereby incorporated in their entirety as if set forth herein. FIELD

[0003] The present disclosure relates to pharmaceutical compositions comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and an effective amount of a pharmacokinetic (PK) stabilizer, wherein the PK stabilizer is administered in a sub-therapeutic dose. The PK stabilizer may be selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof. The PK stabilizer in the composition results in improved pharmacokinetic profile and enhanced therapeutic effect of latrepirdine. The disclosure further relates to treatment of disorders associated with noradrenergic hyperarousal using said pharmaceutical composition. BACKGROUND

[0004] Latrepirdine has demonstrated a promising profile in clinical settings, showcasing safety in human trials and yielding preliminary proof of concept (POC) in preclinical studies. Latrepirdine appears to operate through multiple mechanisms of action, both blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels, modulating the action of AMPA and NMDA glutamate receptors, and may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores, which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process. Early evidence also indicates its potential efficacy in treating neuropsychiatric symptoms associated with dementia. The therapeutic actions of latrepirdine are closely linked to its inhibitory effect on the serotonin 5-HT7 receptor, as the beneficialAgent Reference No.: BXTI-060 / 01WO (332712-2433) effects have been observed at plasma concentrations that are known to activate this specific receptor pathway. The dual mechanism of latrepirdine's action includes reducing arousal within the locus coeruleus—a principal site for brain arousal regulation—and inhibiting post-synaptic 5-HT7 receptors. This dual functionality underscores its potential in managing neuropsychiatric conditions by modulating serotonergic signaling. However, the same mechanism poses additional challenges for pharmaceutical development, especially regarding the therapeutic window of plasma concentration.

[0005] Significant challenges in the clinical application of latrepirdine stem from the variability and fluctuations in plasma concentration levels among patients, which critically impacts the drug's efficacy and safety profile. To address this issue, maintaining a consistent plasma concentration of latrepirdine across the patient population and over the dosing interval is imperative for optimal therapeutic outcomes. While some publications have suggested that plasma concentration variation may be due to genetic differences in the cytochrome P4502D6 enzyme among the patient population, other studies indicate that the mechanism is more complex. The variability in plasma exposure previously limited the potential of latrepirdine as a viable therapeutic agent.

[0006] The present inventors developed a novel pharmaceutical composition that incorporates latrepirdine with a PK stabilizer. This composition substantially minimizes fluctuations in plasma concentration, ensuring a more consistent and reproducible distribution of latrepirdine's plasma levels among the patients. This breakthrough could significantly enhance the efficacy and safety profile of latrepirdine in clinical settings. SUMMARY

[0007] The present disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in sub-therapeutic dose.

[0008] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 200 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0009] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 180 mg of a PK stabilizer.

[0010] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 160 mg of a PK stabilizer, wherein the PK stabilizer is administered in a sub-therapeutic dose.

[0011] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 150 mg of a PK stabilizer.

[0012] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 140 mg of a PK stabilizer.

[0013] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 120 mg of a PK stabilizer.

[0014] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 100 mg of a PK stabilizer.

[0015] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 90 mg of a PK stabilizer.

[0016] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 80 mg of a PK stabilizer.

[0017] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 70 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0018] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0019] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0020] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0021] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0022] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.

[0023] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0024] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 20 mg of a PK stabilizer.

[0025] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 15 mg of a PK stabilizer.

[0026] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0027] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0028] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer.

[0029] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0030] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0031] In embodiments, the present disclosure a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0032] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0033] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0034] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of a PK stabilizer.

[0035] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0036] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of a PK stabilizer.

[0037] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0038] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0039] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0040] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0041] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0042] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0043] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0044] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 200 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0045] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 200 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0046] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 200 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0047] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 190 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0048] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 180 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0049] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 170 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0050] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 160 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0051] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 150 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0052] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 140 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0053] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 130 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0054] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 120 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0055] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 110 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0056] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 100 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0057] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 90 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0058] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 80 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0059] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 70 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0060] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0061] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0062] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0063] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0064] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0065] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0066] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0067] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0068] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0069] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0070] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0072] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0073] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0074] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0075] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0076] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0077] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0078] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg to about 60 mg of a PK stabilizer.

[0079] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg to about 10 mg of a PK stabilizer.

[0080] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg to about 60 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0081] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0082] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0083] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0084] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0085] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0086] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0087] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0088] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0089] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0090] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0091] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0092] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0093] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0094] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0095] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0096] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0097] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0098] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0099] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0100] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0101] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0102] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0103] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0104] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0105] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0106] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0107] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0108] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0109] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0110] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0111] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0112] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0113] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0114] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0115] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0116] In embodiments, the PK stabilizer is paroxetine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride).

[0117] In embodiments, the PK stabilizer is paroxetine and the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, theAgent Reference No.: BXTI-060 / 01WO (332712-2433) subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0118] In embodiments, the PK stabilizer is fluoxetine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride).

[0119] In embodiments, the PK stabilizer is fluoxetine and the subtherapeutic dose of fluoxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, the subtherapeutic dose of fluoxetine or a pharmaceutically acceptable salt thereof is about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0120] In embodiments, the PK stabilizer is quinidine or a pharmaceutically acceptable salt thereof (e.g. sulfate, gluconate).

[0121] In embodiments, the PK stabilizer is quinidine and the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 200 mg. In embodiments, the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 190 mg, about 185 mg, about 180 mg, about 175 mg, about 170mg, about 165 mg, about 160 mg, about 155 mg, about 150 mg, about 145 mg, about 140 mg, about 135 mg, about 130 mg, about 125 mg, about 115 mg, about 120 mg, about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, 35 mg, about 30 mg, about 25 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0122] In embodiments, the pharmaceutical composition is administered to a human subject and results in a plasma concentration of latrepirdine and wherein the plasma concentration of latrepirdine is between 1 and 20 ng / ml. In embodiments, the plasma concentration of latrepirdine is maintained above 2 ng / ml.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0123] I n embodiments, the plasma concentration of latrepirdine is maintained for at least 8 to 12 hours. In embodiments, the plasma concentration of latrepirdine is maintained for at least 8 hours. In embodiments, the plasma concentration of latrepirdine is maintained for at least 10 hours. In embodiments, the plasma concentration of latrepirdine is maintained for at least 12 hours. In embodiments, the plasma concentration of latrepirdine is maintained for 13 hours, 14 hours, 15 hours, 16 hours, 18 hours, 20 hours, 22 hours , 24 hours or more.

[0124] In embodiments, the plasma concentration of latrepirdine is between 2 and 15 ng / ml.

[0125] In embodiments, the plasma concentration of latrepirdine is between 3 and 15 ng / ml.

[0126] In embodiments, the plasma concentration of latrepirdine is between 4 and 10 ng / ml.

[0127] In embodiments, the plasma concentration of latrepirdine is between 4 and 7 ng / ml.

[0128] In embodiments, the plasma concentration of latrepirdine is 5 ng / ml. In embodiments, the plasma concentration of latrepirdine is 4 ng / ml. In embodiments, the plasma concentration of latrepirdine is 3 ng / ml. In embodiments, the plasma concentration of latrepirdine is 2 ng / ml.

[0129] In some embodiments, the plasma concentration of latrepirdine is about 50 ng / ml.

[0130] The present disclosure also provides methods of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub- therapeutic dose.

[0131] The present disclosure also provides methods of improving the pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub- therapeutic dose.Agent Reference No.: BXTI-060 / 01WO (332712-2433) BRIEF DESCRIPTION OF THE DRAWINGS

[0132] Figure 1: depicts metabolism of latrepirdine dihydrochloride hydrate (percent concentration remaining) in presence of specific enzyme inhibitors (i.e. Furafylline, clopidogrel, montelukast, sulfaphenazole, oxybutin oxybutynin, quinidine, ketoconazole, fluconazole, fluoxetine, fluvoxamine, bupropion, paroxetine, voriconazole, troleandomycin and itraconazole) at different time intervals in comparison to control.

[0133] Figure 2: depicts the comparison of potency of different CYP inhibitors (fluoxetine, paroxetine, quinidine, bupropion, fluvoxamine) w.r.t percent concentration remaining of latrepirdine dihydrochloride hydrate after 60 minutes of incubation in human liver microsomes (HLM).

[0134] Figure 3: depicts the comparison of potency of different CYP inhibitors (fluoxetine, paroxetine, quinidine, bupropion, fluvoxamine) w.r.t percent of latrepirdine dihydrochloride hydrate metabolized after 60 minutes of incubation in human liver microsomes (HLM).

[0135] Figure 4: depicts the effect of different concentrations (i.e. 0.1, 0.5, 1, 5 and 10 M) of different CYP inhibitors (fluoxetine, paroxetine, quinidine, bupropion, fluvoxamine) on mean half-life measurement (in minutes) of metabolism of latrepirdine dihydrochloride hydrate in human liver microsomes (HLM).

[0136] Figure 5: depicts the administration time points of latrepirdine dihydrochloride and vehicle in open space swim test (OSST) according to Example 8.

[0137] Figure 6: depicts the study design and administration schedule of different doses of latrepirdine dihydrochloride in open space swim test (OSST) according to Example 8.

[0138] Figure 7: depicts the effect of different doses of latrepirdine dihydrochloride hydrate on distance traveled (in centimeters) by mice in open space swim test (OSST) according to Example 8.

[0139] Figure 8: depicts the effect of different doses of latrepirdine dihydrochloride hydrate on duration of immobility (in seconds) by mice in open space swim test (OSST) according to Example 8.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0140] Figure 9: depicts the effect of different doses of latrepirdine dihydrochloride (BX-008) on time spent in periphery (in seconds) by mice in open space swim test according to Example 8.

[0141] Figure 10. depicts the effect of repeated daily administration of latrepirdine dihydrochloride hydrate (20 mg / kg) as compared to vehicle on behavior of mice over 26-day period.

[0142] Figure 11: depicts study design and administration schedule of different doses of latrepirdine dihydrochloride in marble burying test (MBT) according to Example 9.

[0143] Figure 12. depicts effect on compulsivity in terms of marbles buried after administration of different doses of latrepirdine dihydrochloride (1 mg / kg, 3 mg / kg, 10 mg / kg and 30 mg / kg) as compared to vehicle control and diazepam in mice.

[0144] Figure 13. depicts effect on REM sleep in terms of latency of sleep after administration of different doses of latrepirdine dihydrochloride hydrate (3 mg / kg and 10 mg / kg) as compared to vehicle control in mice. DETAILED DESCRIPTION Abbreviations:

[0145] AMPA: -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

[0146] ANOVA: analysis of variance

[0147] CCK-4: cholecystokinin-4

[0148] 5-HT:5-hydroxytryptamine

[0149] HLM: human liver microsomes

[0150] MBT: marble burying test

[0151] NMDA: N-methyl-D-aspartate

[0152] OCD: Obsessive compulsive disorder

[0153] ODT: Orally disintegrating tabletAgent Reference No.: BXTI-060 / 01WO (332712-2433)

[0154] OSST: Open space swim test

[0155] PMDD: pre-menstrual dysphoric disorder

[0156] PTSD: Post-traumatic stress disorders

[0157] PK: pharmacokinetic

[0158] POC: proof of concept

[0159] REM: rapid eye movement

[0160] SSRI: selective serotonin reuptake inhibitor

[0161] SWS: slow wave sleep

[0162] g: microgram

[0163] mg: milligram

[0164] wt%: Weight percentage

[0165] Definitions:

[0166] It will be understood that the terminology used herein is for the purpose of describing embodiments only and is not intended to be limiting. As used in this specification, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0167] In aspects, an active ingredient herein, such as latrepirdine, paroxetine, fluoxetine, or quinidine may optionally be present as pharmaceutically acceptable salts, or alternate solid forms, such as polymorphs, solvates, hydrates, etc. The active ingredient may be a tautomer. The active ingredient may also be deuterium-modified, such as deuterium-modified latrepirdine. In aspects, compositions disclosed herein may contain a pro-drug of the active ingredient; i.e., a chemical species that converts to an active ingredient or compound described herein under conditions in which the active ingredients or compounds are used as described herein.

[0168] As used herein, “about” or “approximately,” when used in connection with a numerical variable, generally refers to the value of the variable and to all values of the variable that areAgent Reference No.: BXTI-060 / 01WO (332712-2433) within the experimental error (e.g., within the 95% confidence interval for the mean) or within ±10% of the indicated value.

[0169] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range “between 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54- 76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).

[0170] The term “a” or “an” refers to one or more of that entity. In addition, reference to “an agent” by the indefinite article “a” or “an” does not necessarily exclude the possibility that more than one of the agents is present.

[0171] As used herein, the term “comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present disclosure may suitably “comprise”, “consist of”, or “consist essentially of”, the steps, elements, and / or reagents described in the claims.

[0172] As used herein, the term “subject” preferably refers to a human patient. In embodiments, the subject can be any animal, including non-human mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates.

[0173] As used herein, unless indicated otherwise, the terms “dosage form”, "pharmaceutical composition", "composition", "formulation" and "composition of the disclosure," are used interchangeably. Unless stated otherwise, the terms are meant to encompass, and are not limited to, dosage form containing drug substance.

[0174] As used herein, the term "therapeutically effective amount" is interchangeable with "therapeutically effective dose," and refers to an amount sufficient to produce the desired effect. A therapeutically effective amount is sufficient to cause an improvement in a clinically significant condition of the subject. A therapeutically effective amount can be administered in one or more administrations, applications, or dosages.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0175] As used herein, "pharmaceutically acceptable salt" refers to a salt known to be non- toxic and commonly used in pharmaceutical literature. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyl alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids may also be used. A preferred salt is hydrochloride (or dihydrochloride) salt.

[0176] The term “treatment” is used herein to mean to relieve or alleviate at least one symptom of a disease in a subject. Treatment may be measured as a reduction level by at least 10% or higher, preferably 20% or higher, more preferably 40% or higher, even more preferably 60% or higher, still more preferably 80% or higher, and 90% or higher, as compared to a control.

[0177] The term “improving the pharmacokinetics” means an improvement in at least one pharmacokinetic parameter of the therapeutic compound upon co-administration of an effective amount of the PK stabilizer compared to the value of the parameter when the same dosage regimen of latrepirdine is administered without the PK stabilizer. Non-limiting examples of improved pharmacokinetic (PK) parameters are increased half-life (t1 / 2), increased maximum concentration (Cmax), increased mean residence time (MRT), increased AUC between doses, decreased rate of clearance (CL) and reduced levels of potentially toxic metabolites in whole blood, plasma or serum. In mammals, these parameters are usually determined by measuring, using conventional analytical techniques, the concentration of the therapeutic compound, or its toxic metabolites, if applicable, in multiple whole blood, plasma or serum samples taken over a period of time. The improved pharmacokinetics achieved by the present invention usually results in elevating the blood plasma levels of latrepirdine at a given time point or maintaining a therapeutically effective blood plasma level for a longer time period, when compared to blood plasma levels of latrepirdine administered without the PK stabilizer.

[0178] The term “therapeutic” as used herein, may mean treatment and / or prophylaxis, depending on context.

[0179] The term “sub-therapeutic” as used herein refers to dose of a drug (such as PK stabilizer) which is too low to produce an intended therapeutic effect.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0180] The term “obsessive -compulsive disorder” or repetitive behavior as used herein refers to a mental health condition that causes people to have uncontrollable, recurring thoughts (obsessions) and repetitive behaviors (compulsions)

[0181] The term "pharmaceutically acceptable carrier" refers to a pharmacologically inert substance to be used as a carrier. As used herein, the phrase “carrier” and “excipients” are used interchangeably, except where otherwise clearly intended to have different meanings.

[0182] The term "disintegrate" refers to the breaking up of or loss of structural cohesion of the constituent particles comprising a solid formulation. This can occur in a number of different ways including breaking into smaller pieces and ultimately, fine and large particulates or, alternatively, eroding from the outside in until the dosage form has disappeared.

[0183] The terms “oral dosage form”, “oromucosal dosage form,” and “oral transmucosal dosage form,” may be used interchangeably herein and refer to a dosage form for use in practicing the present disclosure, which comprises pharmaceutical composition comprising an active agent (e.g., latrepirdine or a pharmaceutically acceptable salt thereof, a PK stabilizer, or latrepirdine or pharmaceutically acceptable salt thereof and a PK stabilizer). The disclosure covers that by controlling the formulation design of such oral dosage forms immediate, intermediate and sustained release of drugs can be achieved.

[0184] The term “orally disintegrating tablet” (ODT) refers to an oral dosage form composed of a tablet that is designed to disintegrate in the oral cavity without need for chewing or swallowing with liquids. Orally disintegrating tablets may have the characteristics set forth by the U.S. Food & Drug Administration in Guidance for Industry: Orally Disintegrating Tablets (Dept. of Health and Human Services, U.S. FDA Center for Drug Evaluation and Research, December 2008). The rate of disintegration of the solid pharmaceutical compositions of the present disclosure can be measured using various in vitro test methods, for example the USP <701> Disintegration Test. As explained in the foregoing section of the U.S Pharmacopoeia, the USP Disintegration Test is conducted by placing the dosage form to be tested in a basket rack assembly, immersing the assembly in a specified fluid at a temperature between 35° C. and 39° C. for a given time period, and raising and lowering the basket in the immersion fluid through a distance of about 5.5 cm at a frequency of about 30 cycles per minute. The dosageforms are visually inspected at specified times for complete disintegration, defined in Section 701 of USP 24-NF 19 as the state in which any residue of the dosage formAgent Reference No.: BXTI-060 / 01WO (332712-2433) remaining in the basket rack of the test apparatus is a “soft mass having no palpably firm core.” As such, it will be appreciated that the present dosage forms are optimal for disintegration in the mouth without the need to drink additional water. Adsorption may be through the oral mucosa.

[0185] The term “freeze-drying” or “lyophilization” refers to a process used in the creation of a stable preparation of a substance by freezing a fluid formulation containing the substance and substantially remove the frozen liquid under vacuum. The term "lyophilization" refers to the conventional, art-recognized procedure freeze-drying a composition. "Lyophilized" and "freeze-dried" are used herein as synonyms.

[0186] The term “unit dosage form,” as used herein, refers to a physically discrete unit, where each unit contains a quantity of active ingredient that produces a desired therapeutic effect, in association with one or more pharmaceutical carriers. Administering a unit dosage form to the subject provides a unit dosage to the subject.

[0187] It will be understood, however, that the total daily usage of the compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0188] As used herein, the term "granulation" refers to the process of agglomerating powder particles into larger agglomerates (i.e. granules) that contain the active agent. The term "granulation" includes dry and wet granulation techniques. The term "wet granulation" refers to any process comprising the steps of addition of a water comprising liquid, preferably water to the powder starting materials, preferably kneading, and drying to yield a solid dosage form. The term "dry granulation" refers to any process that comprises compacting the powder, usually either by slugging or with a roller compactor, and preferably milling the compacted powder to obtain the granules. No liquid is employed for the dry granulation. The compacted granulate or compacted granules are preferably prepared by dry granulation.

[0189] The term “direct compression” refers to a process which involves blending the ingredients and then compressing them into tablets. I. Active agents

[0190] LatrepirdineAgent Reference No.: BXTI-060 / 01WO (332712-2433)

[0191] Latrepirdine (also known as Dimebon) has the IUPAC name of 2,8-dimethyl-5-[2-(6- methylpyridin-3-yl)ethyl]-3,4-dihydro-1H-pyrido[4,3-b]indole. Latrepirdine may be used in any pharmaceutically acceptable form, including, solvates, hydrates, isomorphs, polymorphs, co-crystals, pseudomorphs, neutral forms, acid addition salt forms, and prodrugs. It may be present in a form of salts with pharmaceutically acceptable acids and in a form of quarternized derivatives. Pharmaceutically acceptable base addition salts can be prepared from inorganic and / or organic bases.

[0192] The pharmaceutically acceptable acid addition salts of latrepirdine may be prepared in a conventional manner by treating a solution or suspension of the free base with, for example, one or two chemical equivalents of a pharmaceutically acceptable acid. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, mesylic, tosylic, benzoic, cinnamic, fumaric, nitric, sulfuric, phosphoric, hydrochloric, dihydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic such as methanesulfonic, benzenesulfonic, and related acids. In embodiments, latrepirdine is present as a free base. In embodiments, latrepirdine is present as latrepirdine dihydrochloride. In embodiments, latrepirdine is present as latrepirdine hydrochloride. In embodiments, latrepirdine is present as latrepirdine dihydrochloride dihydrate. In embodiments, latrepirdine is present as latrepirdine dihydrochloride hydrate. II. PK stabilizers:

[0193] Paroxetine (also known as Paxil) is a selective serotonin reuptake inhibitor (SSRI). It is used to treat several diseases, including major depressive disorder, obsessive-compulsive disorder, social anxiety disorder, panic disorder, posttraumatic stress disorder, generalized anxiety disorder, and premenstrual dysphoric disorder. It has a half-life of 21-24 hours. It is available as tablets in dosages of 10, 20, 30 and 40 mg and as suspension 10 mg / 5 mL (equally bioavailable). Its recommended starting dose is 10-20 mg / day with potential to increase to 40- 60 mg / day. Steady state is achieved in about 10 days (it exhibits nonlinear PK due to enzyme saturation):30 mg / day - Cmax: 61.7 ng / mL (~0.2 umol / L); Tmax: 5.2 hours; Cmin: 30.7 ng / mL (~0.1 umol / L); T1 / 2: 21 hours. Common side effects include nausea / diarrhea, constipation, asthenia, drowsiness, insomnia, sexual dysfunction, dry mouth, anorexia, anxiety, sweating, dizziness, tremor, and weight gain. In embodiments, paroxetine is present as free base. In embodiments, paroxetine is present as paroxetine hydrochloride.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0194] Fluoxetine (Prozac) is a selective serotonin reuptake inhibitor (SSRI). It is used to treat depression, bipolar 1 depression (as olanzapine + fluoxetine), OCD, bulimia, panic disorder, PMDD (pre-menstrual dysphoric disorder). It has a long half-life [1-3 days for parent compound; 6 – 14 days for norfluoxetine (active metabolite)]. It is available as pulvules 10, 20, 40 mg; weekly dose 90 mg. Its recommended dose is 10-20 mg / day and may go up to 60 mg / day. Frequent side effects include nausea / vomiting, diarrhea, insomnia, headache, sexual dysfunction, dry mouth, anorexia, and anxiety.

[0195] In embodiments, fluoxetine is present as free base. In embodiments, fluoxetine is present as fluoxetine hydrochloride.

[0196] Quinidine is an anti-arrhythmic agent to treat heart rhythmic problems and also indicated in severe malaria infection; pseudobulbar affect (as dextromethorphan + quinidine). It is a sodium-channel blocker that depresses phase 0 depolarization of heart, prolongs cardiac action potential duration with a half-life of 6 – 8 hours and Tmax approx. 3 hours. The typical therapeutic range for quinidine is from 2-6 mg / L (6.2-18.5 umol / L). It prolongs QT interval, has anticholinergic activity, negative inotropic activity and acts peripherally as alpha- adrenergic antagonist (is a vasodilator). Its recommended dose is about 200 mg of base quinidine TID or 2 tablets BID.

[0197] In embodiments, quinidine is present as free base. In embodiments, quinidine is present as quinidine sulfate. In embodiments, quinidine is present as quinidine gluconate. III. Doses

[0198] In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of between about 0.5 mg to about 100 mg. Examples of suitable dosages include: about 0.5 mg to about 450 mg, about 0.5 mg to about 400 mg, about 0.5 mg to about 350 mg, about 0.5 mg to about 300 mg, about 0.5 mg to about 250 mg, about 0.5 mg to about 200 mg, about 0.5 mg to about 150 mg, about 0.5 mg to about 100 mg, about 1 mg to about 500 mg, about 1 mg to about 450 mg, about 1 mg to about 400 mg, about 1 mg to about 350 mg, about 1 mg to about 300 mg, about 1 mg to about 200 mg, about 1mg to about 150 mg, about 1 mg to about 100 mg, about 2 mg to about 500 mg, about 2 mg to about 450 mg, about 2 mg to about 400 mg, about 2 mg to about 350 mg, about 2 mg to about 300 mg, about 2 mg to about 250 mg, about 2 mg to about 200 mg, about 2 mg to about 150 mg, about 2 mg to about 100 mg, about 3 mg to about 500 mg, about 3 mg toAgent Reference No.: BXTI-060 / 01WO (332712-2433) about 450 mg, about 3 mg to about 400 mg, about 3 mg to about 350 mg, about 3mg to about 300 mg, about 3mg to about 250 mg, about 3 mg to about 200 mg, about 3 mg to about 150 mg, about 3 mg to about 100 mg, about 4 mg to about 500 mg, about 4 mg to about 450 mg, about 4 mg to about 400 mg, about 4 mg to about 350 mg, about 4 mg to about 300 mg, about 4 mg to about 250 mg, about 4 mg to about 200 mg, about 4 mg to about 150 mg, about 4 mg to about 100 mg, about 5 mg to about 500 mg, about 5 mg to about 450 mg, about 5 mg to about 400 mg, about 5 mg to about 350 mg, about 5 mg to about 300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, about 5 mg to about 90 mg, about 5 mg to about 80 mg, about 5 mg to about 70 mg, about 5 mg to about 60 mg, about 5 mg to about 50 mg, about 5 mg to about 40 mg, about 5 mg to about 30 mg, about 5 mg to about 20 mg or about 5 mg to about 10 mg. In embodiments, the daily dose of latrepirdine or a pharmaceutically acceptable salt thereof administered may conveniently be in the range of about 5 mg to about 60 mg, for example about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 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, about 36 mg, about 37 mg, about 38 mg, about 39 mg, about 40 mg, about 41 mg, about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg, or about 60 mg, including all values and ranges in between.

[0199] In embodiments, latrepirdine is administered in a dosage amount of about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, about 10 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg, or about 0.5 mg or about 0.1 mg, including all ranges and values in between.

[0200] In embodiments, latrepirdine is administered in a dosage amount of about 1 mg to about 100 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 10 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of aboutAgent Reference No.: BXTI-060 / 01WO (332712-2433) 25 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 40 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 50 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 60 mg once a day.

[0201] In embodiments, latrepirdine is administered in a dosage amount of about 20 mg twice a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg thrice a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 30 mg twice a day. In embodiments, latrepirdine is administered to the subject in a total daily dose of about 40 mg. In embodiments, latrepirdine is administered to the subject in a total daily dose of about 60 mg.

[0202] In embodiments, latrepirdine is administered in a dosage amount between 5 mg and 80 mg. In embodiments, latrepirdine is administered in a dosage amount between 5 mg and 60 mg. In embodiments, latrepirdine is administered in a dosage amount between 5 mg and 50 mg. In embodiments, latrepirdine is administered in a dosage amount between 5 mg and 40 mg. In embodiments, latrepirdine is administered in a dosage amount between 10 mg and 30 mg. In embodiments, latrepirdine is administered in a dosage amount between 15 mg and 25 mg. In embodiments, latrepirdine is administered in a dosage amount between 15 mg and 20 mg. In embodiments, latrepirdine is administered in a dosage amount between 20 mg and 25 mg. In embodiments, latrepirdine is administered in a dosage amount between 40 mg and 60 mg.

[0203] In embodiments, latrepirdine is administered in a dosage amount of about 20 mg. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg once a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg twice a day. In embodiments, latrepirdine is administered in a dosage amount of about 20 mg thrice a day.

[0204] In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 200 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 190 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 180 mg. In embodiments, the PK stabilizer is administered in a dosageAgent Reference No.: BXTI-060 / 01WO (332712-2433) amount of between 5 mg and 170 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 160 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 150 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 140 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 130 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 120 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 110 mg In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 100 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 90 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 80 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 70 mg.

[0205] In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 60 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 5 mg and 50 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 10 mg and 50 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 10 mg and 40 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 10 mg and 30 mg. In embodiments, the PK stabilizer is administered in a dosage amount of between 15 mg and 25 mg.

[0206] In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 20 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 25 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 30 mg.

[0207] In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 40 mg. In embodiments, PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 60 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 80 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 90 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 120 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) isAgent Reference No.: BXTI-060 / 01WO (332712-2433) administered in a dosage amount of about 160 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 180 mg. In embodiments, the PK stabilizer (e.g. paroxetine, fluoxetine or quinidine) is administered in a dosage amount of about 200 mg.

[0208] In embodiments, the PK stabilizer is administered in a dosage amount between 6 mg and 50 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 7 mg and 50 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 8 mg and 50 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 9 mg and 50 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 7 mg and 40 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 7 mg and 30 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 8 mg and 20 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 9 mg and 20 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 9 mg and 15 mg. In embodiments, the PK stabilizer is administered in a dosage amount between 10 mg and 15 mg.

[0209] In embodiments, the PK stabilizer is administered in a dosage amount of about 10 mg once a day. In embodiments, the PK stabilizer is administered in a dosage amount of about 20 mg once a day. In embodiments, the PK stabilizer is administered in a dosage amount of about 25 mg once a day. In embodiments, the PK stabilizer is administered in a dosage amount of about 30 mg once a day. In embodiments, the PK stabilizer is administered in a dosage amount of about 40 mg once a day. In embodiments, the PK stabilizer is administered in a dosage amount of about 50 mg once a day. In embodiments, the PK stabilizer is administered in a dosage amount of about 60 mg once a day.

[0210] The exemplary dosages of latrepirdine or a pharmaceutically acceptable salt thereof (e.g. dihydrochloride salt) and PK stabilizers (e.g. paroxetine, fluoxetine or quinidine) to be administered to a particular patient, will depend on the type and extent of the condition, the overall health status of the particular patient, the particular form of latrepirdine, PK stabilizer or pharmaceutically acceptable salts thereof being administered, and the particular formulation used to treat the patient. IV. DosagesAgent Reference No.: BXTI-060 / 01WO (332712-2433)

[0211] In embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer doses is a sub-therapeutic dose.

[0212] In embodiments, the PK stabilizer is paroxetine or a pharmaceutically acceptable salt thereof and the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0213] In embodiments, the PK stabilizer is fluoxetine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride).

[0214] In embodiments, the PK stabilizer is fluoxetine or a pharmaceutically acceptable salt thereof and the subtherapeutic dose of fluoxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, the subtherapeutic dose of fluoxetine or a pharmaceutically acceptable salt thereof is about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0215] In embodiments, the PK stabilizer is quinidine or a pharmaceutically acceptable salt thereof (e.g. sulfate, gluconate).

[0216] In embodiments, the PK stabilizer is quinidine or a pharmaceutically acceptable salt thereof and the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 200 mg. In embodiments, the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 190 mg, about 185 mg, about 180 mg, about 175 mg, about 170mg, about 165 mg, about 160 mg, about 155 mg, about 150 mg, about 145 mg, about 140 mg, about 135 mg, about 130 mg, about 125 mg, about 115 mg, about 120 mg, about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, aboutAgent Reference No.: BXTI-060 / 01WO (332712-2433) 40 mg, 35 mg, about 30 mg, about 25 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0217] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 200 mg of a PK stabilizer.

[0218] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 150 mg of a PK stabilizer.

[0219] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 120 mg of a PK stabilizer.

[0220] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 100 mg of a PK stabilizer.

[0221] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 90 mg of a PK stabilizer.

[0222] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 80 mg of a PK stabilizer.

[0223] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 70 mg of a PK stabilizer

[0224] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0225] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0226] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.

[0227] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0228] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 20 mg of a PK stabilizer.

[0229] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0230] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0231] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer.

[0232] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg to about 10 mg of a PK stabilizer.

[0233] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg to about 60 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0234] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of a PK stabilizer.

[0235] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of a PK stabilizer.

[0236] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of a PK stabilizer.

[0237] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of a PK stabilizer.

[0238] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of a PK stabilizer.

[0239] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of a PK stabilizer.

[0240] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of a PK stabilizer.

[0241] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of a PK stabilizer.

[0242] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0243] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of a PK stabilizer.

[0244] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of a PK stabilizer.

[0245] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of a PK stabilizer.

[0246] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of a PK stabilizer.

[0247] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of a PK stabilizer.

[0248] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg of a PK stabilizer.

[0249] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg of a PK stabilizer.

[0250] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0251] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of paroxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0252] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0253] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0254] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0255] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0256] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0257] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0258] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0259] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0260] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0261] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0262] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0263] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0264] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0265] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0266] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 10 mg of a PK stabilizer.

[0267] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0268] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 10 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0269] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 10 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0270] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0271] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0272] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 90 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0273] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 120 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0274] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 180 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0275] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 200 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0276] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0277] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0278] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 90 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0279] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 120 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0280] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 180 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0281] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 200 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0282] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0283] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0284] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0285] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 15 mg of a PK stabilizer.

[0286] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 15 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0287] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0288] In embodiments, the present disclosure provides a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and 15 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0289] In embodiments, the present disclosure provides a fixed dose composition comprising (i) latrepirdine or a pharmaceutically acceptable salt thereof in an amount of about 20 mg and (ii) a PK stabilizer or a pharmaceutically acceptable salt thereof in an amount of about 20 mg.

[0290] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a paroxetine or a pharmaceutically acceptable salt thereof.

[0291] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0292] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0293] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0294] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0295] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0296] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0297] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0298] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 30 mg of a PK stabilizer.

[0299] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0300] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0301] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer

[0302] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0303] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0304] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0305] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0306] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0307] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0308] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.

[0309] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0310] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 30 mg of a PK stabilizer.

[0311] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0312] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0313] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer.

[0314] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0315] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0316] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0317] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0318] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0319] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.

[0320] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0321] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 30 mg of a PK stabilizer.

[0322] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0323] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0324] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer

[0325] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0326] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0327] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0328] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0329] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0330] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.

[0331] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0332] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 30 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0333] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0334] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0335] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer

[0336] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0337] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0338] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0339] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0340] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0341] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0342] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0343] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 30 mg of a PK stabilizer.

[0344] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0345] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0346] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer

[0347] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0348] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0349] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0350] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0351] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0352] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.

[0353] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0354] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 30 mg of a PK stabilizer.

[0355] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0356] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0357] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer

[0358] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0359] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0360] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0361] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of a PK stabilizer.

[0362] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 4 mg and 50 mg of a PK stabilizer.

[0363] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 40 mg of a PK stabilizer.

[0364] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 6 mg and 30 mg of a PK stabilizer.

[0365] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 7 mg and 30 mg of a PK stabilizer.

[0366] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 8 mg and 20 mg of a PK stabilizer.

[0367] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 9 mg and 15 mg of a PK stabilizer.

[0368] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 15 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0369] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0370] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0371] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0372] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0373] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0374] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0375] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0376] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0377] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0378] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0379] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0380] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0381] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0382] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0383] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0384] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0385] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0386] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0387] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0388] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0389] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0390] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0391] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0392] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0393] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0394] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0395] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0396] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.

[0397] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0398] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0399] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0400] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0401] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0402] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0403] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 5 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0404] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0405] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0406] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0407] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0408] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0409] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0410] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0411] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0412] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0413] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0414] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0415] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0416] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0417] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof

[0419] . In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0420] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0421] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0422] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0423] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0424] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0425] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0426] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0427] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0428] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0429] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0430] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable saltAgent Reference No.: BXTI-060 / 01WO (332712-2433) thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0431] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of a PK stabilizer.

[0432] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0433] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0434] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 50 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0435] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0436] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0437] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0438] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0439] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0440] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0441] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0442] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0443] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0444] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0445] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable saltAgent Reference No.: BXTI-060 / 01WO (332712-2433) thereof and between 10 mg and 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0446] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0447] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0448] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0449] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0450] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0451] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0452] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of paroxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0453] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0454] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0455] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0456] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0457] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0458] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0459] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of a PK stabilizer.

[0460] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable saltAgent Reference No.: BXTI-060 / 01WO (332712-2433) thereof and between 10 mg and 40 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0461] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0462] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 40 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0463] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0464] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0465] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0466] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0467] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0468] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0469] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0470] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0471] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0472] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0473] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0474] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0475] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0476] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0477] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0478] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0479] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0480] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0481] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0482] In embodiments, the present disclosure a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0483] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0484] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof. In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0486] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0487] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0488] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0489] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0490] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable saltAgent Reference No.: BXTI-060 / 01WO (332712-2433) thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0491] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of a PK stabilizer.

[0492] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0493] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0494] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 10 mg and 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0495] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0496] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0497] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0498] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0499] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0500] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0501] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0502] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0503] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0504] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0505] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable saltAgent Reference No.: BXTI-060 / 01WO (332712-2433) thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0506] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 50 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0507] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0508] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0509] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0510] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 5 mg and 40 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0511] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0512] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0513] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0514] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 10 mg and 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0515] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0516] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0517] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0518] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0519] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0520] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable saltAgent Reference No.: BXTI-060 / 01WO (332712-2433) thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0521] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0522] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 15 mg and 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0523] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of a PK stabilizer.

[0524] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0525] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0526] In embodiments, the present disclosure provides a pharmaceutical composition comprising between 20 mg and 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof and between 15 mg and 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0527] In embodiments, the present disclosure provides an oral pharmaceutical composition comprising latrepirdine, a PK stabilizer or a pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients or carriers.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0528] In embodiments, the oral composition is a tablet, capsule, disc, patch or film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (solution, suspension or emulsion), spray, microspheres or nanospheres which can be formulated in accordance with methods that are standard in the art.

[0529] In embodiments, the oral composition is a tablet, with or without coating. In embodiments, the composition is orally disintegrating tablet. In embodiments, the composition is an immediate release tablet. In embodiments, the composition is a sustained release tablet. In embodiments, the composition is an extended-release tablet. In embodiments, the composition is a bilayer tablet. In embodiments, the composition is an oromucosal tablet (sublingual or buccal). In embodiments, the tablet is lyophilized.

[0530] In embodiments, the composition is a bilayer tablet containing (i) a first layer comprising latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a second layer comprising paroxetine or a pharmaceutically acceptable salt thereof and (iii) one or more pharmaceutically acceptable excipients or carriers.

[0531] In embodiments, the composition is a bilayer tablet containing (i) a first layer comprising latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a second layer comprising fluoxetine or a pharmaceutically acceptable salt thereof and (iii) one or more pharmaceutically acceptable excipients or carriers.

[0532] In embodiments, the composition is a bilayer tablet containing (i) a first layer comprising latrepirdine or a pharmaceutically acceptable salt thereof; (ii) a second layer comprising quinidine or a pharmaceutically acceptable salt thereof and (iii) one or more pharmaceutically acceptable excipients or carriers.

[0533] In embodiments, the PK stabilizer and latrepirdine are administered together as a single dose via a single dosage form.

[0534] In embodiments, the composition comprising latrepirdine and PK stabilizer or salts thereof is administered once daily, twice daily, thrice daily or four times, five times, six times a day, preferably once, twice or thrice daily.

[0535] In embodiments, the composition comprising latrepirdine and PK stabilizer or salts thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, atAgent Reference No.: BXTI-060 / 01WO (332712-2433) least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0536] In embodiments, the composition is an oral tablet. In embodiments, the oral tablet conveniently includes the active ingredient within a matrix. In embodiments, the matrix is composed of, for example, at least one filler and / or a lubricant. Fillers include, for example, lactose or mannitol, and suitable lubricants include, but are not limited to, magnesium stearate, silicon dioxide and talc. The matrix may also include one or more of: a binder (e.g. povidone, a sugar or carboxymethylcellulose), a disintegrant (e.g. croscarmellose sodium, crospovidone or sodium starch glycolate), a sweetening agent (e.g. sucralose) and the like. The tablet may conveniently have a friability of about 2% or less and a hardness of about 15 to about 50 Newtons.

[0537] In embodiments, the tablet dosages forms as used herein may be prepared by direct compression comprising mixing the active agents with one or more pharmaceutically acceptable excipients, lubricating the blend and directly compressing into a tablet.

[0538] The dosage form of the present disclosure may be administered to mammals, including humans, as well as non-human mammals (e.g., rats, cats and dogs) in need thereof.

[0539] In embodiments, the dosage form comprises a mucoadhesive agent to make the active agent or agents adhere to the oral mucosa. The mucoadhesive agent may possess properties to swell and expand in contact with water thus making tablet disintegrate when wetted with saliva. In embodiments, the dosage form comprises one or more mucoadhesive agents in an amount of about 0.5% to about 30% w / w. For example, the one or more mucoadhesive agents are present in an amount ranging from about 0.5% w / w to about 30% w / w, about 0.5% w / w to about 25% w / w, about 0.5% w / w to about 20% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, about 1% w / w to about 30% w / w, about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 3% w / w to about 30% w / w, about 3% w / w to about 20% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 5% w / w to about 30% w / w, about 5% w / w to about 20% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 30% w / w, about 10% w / w to about 20% w / w, about 10% w / w to about 15% w / w, about 15% w / w to about 30% w / w, about 15% w / w to about 20% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, or about 25% w / w toAgent Reference No.: BXTI-060 / 01WO (332712-2433) about 30% w / w. In embodiments, the mucoadhesive agent is present in an amount of about 1% w / w to about 5% w / w. In embodiments, the mucoadhesive agent is present in an amount of about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w, about 25% w / w, about 26% w / w, about 27% w / w, about 28% w / w, about 29% w / w, or about 30% w / w, including all ranges and values in between.

[0540] In embodiments, the mucoadhesive dosage forms have a mucoadhesive strength of at least about 50 dynes / cm2, e.g. about 50 dynes / cm2, about 75 dynes / cm2, about 100 dynes / cm2, about 150 dynes / cm2, about 200 dynes / cm2, about 250 dynes / cm2, about 300 dynes / cm2, about 350 dynes / cm2, about 400 dynes / cm2, about 450 dynes / cm2, about 500 dynes / cm2, about 550 dynes / cm2, about 600 dynes / cm2, about 650 dynes / cm2, about 700 dynes / cm2, about 750 dynes / cm2, about 800 dynes / cm2, about 850 dynes / cm2, about 900 dynes / cm2, about 950 dynes / cm2, or about 1000 dynes / cm2, including all ranges and values in between. In embodiments, the mucoadhesive dosage forms have a mucoadhesive strength greater than about 1000 dynes / cm2. In embodiments, the dosage form has a mucoadhesive peak force greater than about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500g, about 600g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g or about 1500 g. In embodiments, the dosage form has a mucoadhesive peak force of about 50 g, about 100 g, about 200 g, about 300 g, about 400 g, about 500g, about 600g, about 700 g, about 800 g, about 900 g, about 1000 g, about 1100 g, about 1200 g, about 1300 g, about 1400 g or about 1500 g, including all ranges and values in between.

[0541] In embodiments, suitable mucoadhesive agents as used in the present disclosure include but are not limited to polyacrylic acid polymers (such as carbomers (e.g. with low viscosity), polycarbophil etc.), methacrylic acid polymers, cellulose derivatives such as hydroxyethyl cellulose, (HEC), hydroxypropyl cellulose (HPC-such as lower viscosity grades of MW <150K daltons), ethyl hydroxyethyl cellulose, hydroxypropyl methylcellulose (HPMC-such as grades with lower viscosity like K100L or 4000cps or less), methyl cellulose, sodium carboxymethyl cellulose, thiolated carboxymethyl cellulose; polysaccharides (such as chitosan, pectin etc.); xanthan gum, karaya gum, tragacanth gum; propylene glycol, propylene glycol alginate,Agent Reference No.: BXTI-060 / 01WO (332712-2433) sodium alginate, polyethylene oxide (PEO), microcrystalline cellulose (Avicel), croscarmellose, poloxamers (i.e. nonionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene flanked by two hydrophilic chains of polyoxyethylene; e.g. Poloxamer 407) and mixtures thereof.

[0542] In embodiments, the excipients or carriers for inclusion in oromucosal dosages are selected from the group consisting of disintegrants, fillers / diluents (matrix forming agents), binders, glidants, lubricants, plasticizers, pH regulators, coloring agents, flavoring agents, taste masking agents, viscosity enhancers, sweetening agents and combinations thereof. Carriers which readily dissolve in saliva are preferred.

[0543] In embodiments, examples of suitable disintegrants as used in the present disclosure include but are not limited to cross-linked polyvinyl pyrrolidone, low-substituted hydroxypropyl cellulose, carboxymethyl starch, natural starch, carboxymethyl starch, sodium starch glycolate, pregelatinized starch, dextrins, and other modified starches (starches whose hydroxyl groups have been esterified, hydroxypropyl di-starch phosphate, an enzymatically modified starch, a pregelatinized di-starch phosphate, hydroxyethyl starch, hydroxypropyl starch, a pregelatinized acetylated di-starch phosphate and a pregelatinized purified starch); carboxymethylcellulose calcium, carboxymethylcellulose sodium (or croscarmellose sodium), microcrystalline cellulose, cellulose gum and mixtures thereof. In embodiments, the amount of disintegrant present in the dosage form may range from about 1% w / w to about 5% w / w. For example, the amount of disintegrant present in the dosage form may range from about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about about 3% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w or about 4% w / w to about 5% w / w. In embodiments, the disintegrant is present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, or about 5% w / w. In embodiments, the disintegrant is present in an amount of about 1% w / w. In embodiments, the disintegrant is present in an amount of about 2% w / w. In embodiments, the disintegrant is present in an amount of about 3% w / w. In embodiments, the disintegrant is present in an amount of about 4% w / w. In embodiments, the disintegrant is present in an amount of about 5% w / w.

[0544] In embodiments, examples of suitable diluents / fillers (also called as matrix forming agents) include but are not limited to materials derived from animal or vegetable proteins, such as mammalian gelatin, non-mammalian gelatins, fish gelatin (e.g. high molecular weightAgent Reference No.: BXTI-060 / 01WO (332712-2433) gelatin in which more than 50%, more than 60%, or more than 70% of the molecular weight distribution of the gelatin is greater than 30,000 daltons); a standard molecular weight gelatin in which more than substantially 50%, preferably more than 60% and most preferably more than 70% of the molecular weight distribution of the gelatin is below than 30,000 daltons and combinations may be formed wherein the ratio of high molecular weight gelatin to standard molecular weight gelatin (HMW:SMW) ranges substantially from 1:1 to 1:9), dextrins and soy, wheat and psyllium seed proteins; gums such as acacia, guar, agar, and xanthan; polysaccharides; alginates; carboxymethylcelluloses; carrageenans; dextrans; pectins; synthetic polymers such as polyvinylpyrrolidone; and polypeptide / protein or polysaccharide complexes such as gelatin-acacia complexes, starch, mannitol, dicalcium phosphate, potassium sulfate, microcrystalline cellulose, dextrose, lactose, galactose and trehalose; cyclic sugars such as cyclodextrin; inorganic salts such as sodium phosphate, sodium chloride and aluminum silicates; and amino acids having from 2 to 12 carbon atoms such as a glycine, L-alanine, L- aspartic acid, L-glutamic acid, L-hydroxyproline, L-isoleucine, L-leucine and L-phenylalanine and mixtures thereof. In embodiments, the diluents / fillers (or matrix forming agent) are present in a range from about 1% to about 50% w / w of the dosage form. For example, the amount of diluents / fillers present in the dosage form may range from about 1% w / w to about 50% w / w, about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 5% w / w to about 50% w / w, about 5% w / w to about 25% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 50% w / w, about 10% w / w to about 40% w / w, about 10% w / w to about 30% w / w, about 10% w / w to about 20% w / w, about 10% w / w to about 15% w / w, about 20% w / w to about 50% w / w, about 20% w / w to about 40% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, about 30% w / w to about 50% w / w, about 30% w / w to about 40% w / w, about 30% w / w to about 35% w / w, about 40% w / w to about 50% w / w, or about 40% w / w to about 45% w / w. In embodiments, the diluents / fillers are present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, or about 50% w / w, including all ranges and values in between.

[0545] In embodiments, examples of suitable binders include but are not limited to starch, pregelatinized starch, PVP (polyvinylpyrrolidone), polyethylene oxide, polyethylene glycol, acacia, alginic acid, tragacanth, sucrose, guar gum, bentonite, cellulose derivatives,Agent Reference No.: BXTI-060 / 01WO (332712-2433) such as hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC) and carboxymethyl cellulose (CMC) and their salts; and mixtures thereof. In embodiments, the binder is present in a range from about 0% to about 20% w / w of the dosage form. For example, the amount of binder present in the dosage form may range from about 1% w / w to about 20% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 5% w / w to about 20% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 20% w / w, or about 10% w / w to about 15% w / w. In embodiments, the binder is present in an amount of about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, or about 20% w / w, including all ranges and values in between.

[0546] In embodiments, examples of suitable glidants are selected from group comprising calcium phosphate, calcium silicate, powdered cellulose, magnesium silicate, magnesium trisilicate, talc, colloidal silicon dioxide, silica gel, precipitated silica and mixtures thereof. In embodiments, the glidant is present in a range from about 0% to about 5% w / w of the dosage form. For example, the amount of glidant present in the dosage form may range from about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w or about 4% w / w to about 5% w / w. In embodiments, the glidant is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, or about 5% w / w, including all ranges and values in between.

[0547] In embodiments, examples of suitable lubricants include but are not limited to magnesium stearate, calcium stearate, stearic acid, talc, sodium fumarate stearate, sucrose fatty acid esters, aluminum stearate, potassium sodium tartrate, light silicic anhydride, carnauba wax, carmellose calcium, carmellose sodium, hydrated silicon dioxide, hydrogenated oil, hydrogenated rapeseed oil, and mixtures thereof. In embodiments, the lubricant is present in aAgent Reference No.: BXTI-060 / 01WO (332712-2433) range from about 0% to about 3% w / w of the dosage form. For example, the amount of lubricant present in the dosage form may range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the lubricant is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w, including all ranges and values in between.

[0548] In embodiments, examples of suitable plasticizers include but are not limited to macrogol, triethyl citrate, acetylated monoglyceride, glycerin, monoacetin, diacetin triacetin, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate polysorbate 80, and propylene glycol, 1,2,3-propanetiol triacetate, hydrogenated starch hydrolysates, corn syrups, distilled acetylated monoglycerides, castor oil derivatives thereof sucrose acetate isobutyrate, and mixtures thereof. In embodiments, the plasticizer is present in a range from about 0% to about 10% w / w of the dosage form. For example, the amount of glidant present in the dosage form may range from about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 10% w / w, about 4% w / w to about 5% w / w, or about 5% w / w to about 10% w / w. In embodiments, the plasticizer is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w, including all ranges and values in between.

[0549] In embodiments, examples of suitable pH regulators include but are not limited to inorganic acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid), an inorganic base (e.g.,Agent Reference No.: BXTI-060 / 01WO (332712-2433) sodium hydroxide, potassium hydroxide, calcium hydroxide), an organic acid (e.g., citric acid, acetic acid, tartaric acid, succinic acid, boric acid, edetic acid, glucuronic acid, glutaric acid, malic acid, formic acid, gluconic acid, ascorbic acid or fatty acids), and / or an organic base (e.g., ethanolamine, triethanolamine) or mixtures thereof. In embodiments, the pH regulator is present in a range from about 0% to about 2% w / w of the dosage form. For example, the amount of pH regulator present in the dosage form may range from about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, or about 1% w / w to about 2% w / w. In embodiments, pH regulator is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, or about 2% w / w, including all ranges and values in between.

[0550] In embodiments, examples of suitable coloring agents include but are not limited to food, drug, and cosmetic (FD&C) dyes (FD&C blue, FD&C green, FD&C red, FD&C yellow, FD&C lake), ponceau, indigo drug & cosmetic (D&C) blue, indigo Carmine; iron oxides (e.g. red iron oxide, yellow, black), quinoline yellow, flame red, brilliant red (carmine), carmoisine, sunset yellow and mixtures thereof. In embodiments, the amount of coloring used ranges from about 0% to about 3 % w / w of the dosage form. For example, the amount of coloring agent present in the dosage form may range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the coloring agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w, including all ranges and values in between.

[0551] In embodiments, examples of suitable flavoring agents include but are not limited to strawberry, apple, pear, peach, plum, orange, pineapple, apricot, lemon, peppermint, black currant, banana, raspberry, raspberry aroma, wild berries, caramel, mint, licorice, grapefruit, caramel, vanilla, cherry and grape flavor, flavoring oils such as cinnamon oil, wintergreen oil, peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leave oil, nutmeg oil, sage oil, bitter almond oil and cassia oil and mixtures thereof. In embodiments, the amount of flavoring agent used ranges from about 0% to about 3 % w / w of the dosage form. ForAgent Reference No.: BXTI-060 / 01WO (332712-2433) example, the amount of flavoring agent present in the dosage form may range from about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 2% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, or about 2% w / w to about 3% w / w. In embodiments, the flavoring agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, or about 3% w / w, including all ranges and values in between.

[0552] In embodiments, suitable taste-masking agents include sodium bicarbonate, ion- exchange resins, cyclodextrin inclusion compounds, adsorbates or microencapsulated actives. In embodiments, the amount of taste-masking agent used ranges from about 0% to about 10 % w / w of the dosage form. For example, the amount of taste-masking agent present in the dosage form may range from about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 0.1% w / w to about 3% w / w, about 0.1% w / w to about 1% w / w, about 0.5% w / w to about 10% w / w, about 0.5% w / w to about 5% w / w, about 0.5% w / w to about 3% w / w, about 0.5% w / w to about 1% w / w, about 1% w / w to about 10% w / w, about 1% w / w to about 5% w / w, about 1% w / w to about 4% w / w, about 1% w / w to about 3% w / w, about 1% w / w to about 2% w / w, about 2% w / w to about 10% w / w, about 2% w / w to about 5% w / w, about 2% w / w to about 4% w / w, about 2% w / w to about 3% w / w, about 3% w / w to about 10% w / w, about 3% w / w to about 5% w / w, about 3% w / w to about 4% w / w, about 4% w / w to about 10% w / w, about 4% w / w to about 5% w / w, or about 5% w / w to about 10% w / w. In embodiments, the taste-masking agent is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, or about 10% w / w, including all ranges and values in between.

[0553] In embodiments, suitable viscosity enhancers include but are not limited to polymers, sugars, sugar alcohols, gums, clays, silicas, and the like. In embodiments, the amount of viscosity enhancers used ranges from about 0% to about 65% w / w of the dosage form. For example, the amount of viscosity enhancers present in the dosage form may range from about 0.1% w / w to about 65% w / w, about 0.1% w / w to about 50% w / w, about 0.1% w / w to about 20% w / w, about 0.1% w / w to about 10% w / w, about 0.1% w / w to about 5% w / w, about 5%Agent Reference No.: BXTI-060 / 01WO (332712-2433) w / w to about 65% w / w, about 5% w / w to about 50% w / w, about 5% w / w to about 25% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 65% w / w, about 10% w / w to about 50% w / w, about 10% w / w to about 40% w / w, about 10% w / w to about 30% w / w, about 10% w / w to about 20% w / w, about 10% w / w to about 15% w / w, about 20% w / w to about 65% w / w, about 20% w / w to about 50% w / w, about 20% w / w to about 40% w / w, about 20% w / w to about 30% w / w, about 20% w / w to about 25% w / w, about 30% w / w to about 65% w / w, about 30% w / w to about 50% w / w, about 30% w / w to about 40% w / w, about 30% w / w to about 35% w / w, about 40% w / w to about 65% w / w, about 40% w / w to about 50% w / w, about 40% w / w to about 45% w / w, about 50% w / w to about 65% w / w, about 50% w / w to about 60% w / w, or about 50% w / w to about 55% w / w. In embodiments, the viscosity enhancer is present in an amount of about 0% w / w, about 0.1% w / w, about 0.2% w / w, about 0.3% w / w, about 0.4% w / w, about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, about 2% w / w, about 3% w / w, about 4% w / w, about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 15% w / w, about 20% w / w, about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, or about 65% w / w, including all ranges and values in between.

[0554] In embodiments, examples of suitable sweetening agents include but are not limited to fructose, sucrose, glucose, maltose, sorbitol, erythritol, xylitol, aspartame, stevia extract, glycyrrhiza, mogroside, sodium cyclamate, saccharine, saccharine sodium, acesulfame, dextrose, sucralose, monosodium glycyrrhizinate, monoamonium glycyrrhizinate, isomalt, glycerine, dipotassium glycyrrhizinate, thaumatin and mixtures thereof. In embodiments, the amount of sweetening agent ranges from about 0.5 to about 2 % w / w of the dosage form. For example, the amount of sweetening agents present in the dosage form may range from about 0.5% w / w to about 2% w / w, about 0.5% w / w to about 1% w / w, or about 1% w / w to about 2% w / w. In embodiments, the sweetening agents are present in an amount of about 0.5% w / w, about 0.6% w / w, about 0.7% w / w, about 0.8% w / w, about 0.9% w / w, about 1% w / w, or about 2% w / w, including all ranges and values in between.

[0555] In embodiments, the dosage form is administered via a single dosage form.

[0556] In embodiments, the present disclosure provides an oromucosal (sublingual or buccal) lyophilized tablet comprising (i) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; (ii) an effective amount of PK stabilizer or aAgent Reference No.: BXTI-060 / 01WO (332712-2433) pharmaceutically acceptable salt thereof; (iii) sodium alginate, xanthan gum, carbomer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or polyethylene oxide; (iv) croscarmellose sodium or sodium starch glycolate; (v) sucralose; (vi) magnesium stearate and / or silicon dioxide; (vii) lactose or mannitol; and (viii) optionally other pharmaceutical acceptable excipients. In embodiments, the tablet disintegrates in not less than about 1 minute upon contact with an oral mucosa.

[0557] In embodiments, the pharmaceutical compositions of the present disclosure possess sufficient mechanical strength to resist attrition / chipping during packaging in blisters and bottles, storage and transportation for commercial distribution and end use.

[0558] In embodiments, the composition is a hard or compressed powdered sublingual, buccal or gingival tablet having a low grit component for an organoleptically pleasant mouth feel. In embodiments, the tablet (or particles thereof containing the active agent which can be compressed to form the tablet) comprises a protective outer coating e.g. any polymer conventionally used in the formation of microparticles and microcapsules. In embodiments, the dosage form is a sublingual (or buccal or gingival) tablet containing an effervescent agent. Sublingual compositions comprising effervescent agents are disclosed in US Patent No. 6,200,604, which is herein incorporated by reference in its entirety, for all purposes.

[0559] In embodiments, the oromucosal (sublingual, buccal or gingival) tablet disintegrates in about 5 seconds to about 10 minutes, about 5 seconds to about 5 minutes, about 5 seconds to about 1 minute, about 5 seconds to about 30 seconds, about 5 seconds to about 10 seconds, about 30 seconds to about 10 minutes, about 30 seconds to about 5 minutes, about 30 seconds to about 1 minute, about 1 minute to about 10 minutes, about 1 minute to about 5 minutes, about 1 minute to about 2 minutes, about 2 minutes to about 10 minutes, about 2 minutes to about 5 minutes, about 2 minutes to about 3 minutes, about 3 minutes to about 10 minutes, about 3 minutes to about 5 minutes, about 4 minutes to about 10 minutes, about 4 minutes to about 5 minutes, about 5 minutes to about 10 minutes, about 5 minutes to about 7 minutes, or about 7 minutes to about 10 minutes upon contact with an oral mucosa. In embodiments, the composition disintegrates in less than about 1 minute upon contact with an oral mucosa, e.g. about 5 seconds, about 10 seconds, about 15 seconds, about 20 seconds, about 25 seconds, about 30 seconds, about 35 seconds, about 40 seconds, about 45 seconds, about 50 seconds, about 55 seconds, or about 60 seconds, including all ranges and values in between. In embodiments, the composition does not disintegrate within 1 minute upon contact with an oralAgent Reference No.: BXTI-060 / 01WO (332712-2433) mucosa. In embodiments, the composition disintegrates in more than 1 minute upon contact with an oral mucosa, e.g. about 1 minute, about 2 minutes, about 3 minutes, about 4 minutes, about 5 minutes, about 6 minutes, about 7 minutes, about 8 minutes, about 9 minutes, or about 10 minutes. Thus, compositions produced in accordance with one of the embodiments of the present disclosure meet the disintegration time criteria of disintegration within about 5 seconds to about 10 minutes when tested by the <701> disintegration test method (see Guidance to Industry, herein incorporated by reference).

[0560] In embodiments, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98% or at least about 99% of the drug in a dosage form comprising a formulation of the disclosure is absorbed via the oral mucosa.

[0561] In embodiments, the oromucosal tablet is prepared by lyophilization (or freeze-drying). A suspension comprising active agent(s) may be prepared with appropriate excipients and the active agent suspension may be dispensed into blister packs and freeze-dried. An exemplary freeze-dried preparation platform is orally disintegrating table (ODT) is the ZYDIS® (Catalent, Somerset, NJ, USA) formulation. In particular, the excipients are blended and the active agents are separately milled to size and then mixed with the excipients. The solution / suspension then undergoes lyophilization by flash freezing and freeze drying. This aqueous solution / suspension must be chemically and morphologically stable throughout the dosing process. Gelatin may be used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows for immediate disintegration of the dosage form. Other alternatives such as fish gelatin and modified starches may be used. During processing, dosed solution / suspension is preferably frozen by passing through a gaseous medium. This serves to immobilize the solution / suspension rapidly, thereby improving the manufacture efficiency. Examples of oromucosal dosage forms includes orally disintegrating tablets disclosed in US Patent No. 6,509,040, US Patent No. 7,972,621, US Patent No. 1,054,8839, US Patent No.9,775,819, US Patent No.5,188,825, US Patent No.5,631,023, US Patent No. 6,297,240, US Patent No. 6,413,549, US Patent No. 5,976,577, US Patent No. 6, 156,339, US Patent No. 5,827,541, US Patent No. 5,729,958, US Patent No. 6,726,928, US Patent No. 9,192,580, US Patent No. 6,709,669, US Appl. Publication No. 20200138721, US Appl. Publication No. 20190276707, US Appl. Publication No. 20190314274, US Appl.Agent Reference No.: BXTI-060 / 01WO (332712-2433) Publication No. 20040156894, PCT Publication No. 1999038496, PCT Publication No. 2000044351, and US Appl. Publication No. 20090226522 and related patents / patent applications, which are herein incorporated by reference in their entirety, for all purposes.

[0562] Other methods of preparing dosages such as ODTs may be used without limitation, and detailed description of general methods thereof have been disclosed, for example, in US Patent No 5,837,287; US Patent No 6,149,938; US Patent No 6,212,791; US Patent No 6,284,270; US Patent No 6,316,029; US Patent No 6,465,010; US Patent No 6,471,992; US Patent No 6,471,992; US Patent No 6,814,978; US Patent No 6,908,626; US Patent No 6,908,626; US Patent No 6,982,251; US Patent No 7,282,217; US Patent No 7,425,341; US Patent No 7,939,105; US Patent No. 7,993.674; US Patent No. 8,048,449; US Patent No. 8,127,516; US Patent No. 8,158,152; US Patent No. 8,221,480; US Patent No. 8,256,233; US Patent No. 8,313,768, US Patent No. 5,039,540; US Patent No. 5,120,549; US Patent No. 5,330,763; US Patent No.4,760,093; US Patent No.4,760,094; and US Patent No.4,767,789, which are herein incorporated by reference in their entirety, for all purposes.

[0563] Different technologies that may be used to prepare oromucosal dosages of the disclosure include but not limited to Flash Dose, Orasolv, durasolv, wowtab technology, Flash Tab Technology, Oraquick Technology, Quick–Dis Technology, Nanocrystal Technology, Shearform Technology, Ceform Technology, Pharmaburst technology, Frosta technology, Ziplet technology, Humidity treatment, Sintering, Lyoc Technolog, Quicksolv Technology, Nanocrystal technology, Pharmafreeze, AdvaTab Technology, cotton-candy technology and the like.

[0564] In embodiments, the oromucosal dosages (e.g., sublingual or buccal or gingival tablet) of the present disclosure may be prepared by sublimation, nanonization, spray drying, granulation including wet granulation, dry granulation or direct compression and the like. U.S. Pat. Nos. 5,178,878, 6,269,615 and 6,221,392 disclose manufacturing friable orally disintegrating tablets by direct compression and packaging in specially designed dome-shaped blister package using a robot-controlled integrated tableting-packaging system; which are herein incorporated by reference in their entirety, for all purposes.

[0565] In embodiments, the dosage form is in the form of a patch or film (e.g. thin film). The patch may have adhesive qualities to prevent movement or swallowing of the patch. SuitableAgent Reference No.: BXTI-060 / 01WO (332712-2433) film compositions further comprising dexmedetomidine are disclosed in US Patent No. 10,792,246, which is incorporated herein by reference in its entirety for all purposes.

[0566] In embodiments, the oral dosage form is in the form of a paste, gel or ointment. The viscosity of the paste, gel or ointment can be adjusted to allow for retention under the tongue or near gums or cheeks or upper lip.

[0567] In embodiments, the oral dosage form is in a liquid form (e.g. as a solution, suspension or emulsion), and may be, for example, presented as a spray or as drops. In a particular embodiment of the disclosure, Latrepirdine and / or PK stabilizers (paroxetine, fluoxetine or quinidine) or pharmaceutically acceptable salts thereof are administered in liquid form, e.g. in a flavored or unflavored physiological saline solution. The liquid dosage form may conveniently be administered under the tongue or near the gums or cheeks or upper lip as drops or as a spray. The solutions include the active ingredient together with a diluent such as water, normal saline, sodium chloride solution, or any other suitable solvent such as propylene glycol, glycerol, ethyl alcohol and so on. The diluent for the solution may particularly be physiological saline solution or water.

[0568] The non-solid dosages of the disclosure may conveniently be administered by spraying, dripping, painting or squirting the composition under the tongue or near the gums or cheeks or upper lip. V. Methods and Administration

[0569] In embodiments, the present disclosure provides methods of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof to the subject, wherein the PK stabilizer is administered in a sub-therapeutic dose.

[0570] In embodiments, the present disclosure provides methods of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering orally a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptableAgent Reference No.: BXTI-060 / 01WO (332712-2433) salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof to the subject, wherein the PK stabilizer is administered in a sub-therapeutic dose.

[0571] In embodiments, the PK stabilizer is paroxetine or a pharmaceutically acceptable salt thereof and the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0572] In embodiments, the present disclosure provides methods of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof to the subject.

[0573] In embodiments, the PK stabilizer is fluoxetine or a pharmaceutically acceptable salt thereof (e.g. hydrochloride). In embodiments, the PK stabilizer is fluoxetine or a pharmaceutically acceptable salt thereof and the subtherapeutic dose of fluoxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, the subtherapeutic dose of fluoxetine or a pharmaceutically acceptable salt thereof is about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0574] In embodiments, the present disclosure provides methods of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof to the subject.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0575] In embodiments, the PK stabilizer is quinidine or a pharmaceutically acceptable salt thereof (e.g. sulfate, gluconate).

[0576] In embodiments, the PK stabilizer is quinidine or a pharmaceutically acceptable salt thereof and the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 200 mg. In embodiments, the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 190 mg, about 185 mg, about 180 mg, about 175 mg, about 170mg, about 165 mg, about 160 mg, about 155 mg, about 150 mg, about 145 mg, about 140 mg, about 135 mg, about 130 mg, about 125 mg, about 115 mg, about 120 mg, about 110 mg, about 105 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, 35 mg, about 30 mg, about 25 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg (including all values in between).

[0577] In embodiments, the present disclosure provides methods of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof to the subject.

[0578] In embodiments, the present disclosure provides methods of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub-therapeutic dose.

[0579] In embodiments, the present disclosure provides methods of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combinationAgent Reference No.: BXTI-060 / 01WO (332712-2433) with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub-therapeutic dose.

[0580] In embodiments, the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 15 mg. In embodiments, the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 10 mg.

[0581] In embodiments, the subtherapeutic dose of fluoxetine or a pharmaceutically acceptable salt thereof is about 20 mg. In embodiments, the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 15 mg. In embodiments, the subtherapeutic dose of paroxetine or a pharmaceutically acceptable salt thereof is about 10 mg.

[0582] In embodiments, the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 200 mg. In embodiments, the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 100 mg. In embodiments, the subtherapeutic dose of quinidine or a pharmaceutically acceptable salt thereof is about 50 mg.

[0583] In embodiments, the present disclosure provides methods of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0584] In embodiments, the present disclosure provides methods of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0585] In embodiments, the present disclosure provides methods of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0586] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the subject is a human subject.

[0587] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering orally a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof to the subject. In embodiments, the subject is a human subject.

[0588] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt to the subject.

[0589] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 20 mg of paroxetine or a pharmaceutically acceptable salt to the subject. In embodiments, the composition comprises about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof

[0590] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical compositionAgent Reference No.: BXTI-060 / 01WO (332712-2433) comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 20 mg of paroxetine or a pharmaceutically acceptable salt to the subject.

[0591] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 10 mg of paroxetine or a pharmaceutically acceptable salt to the subject.

[0592] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 10 mg of paroxetine or a pharmaceutically acceptable salt to the subject.

[0593] In embodiments, paroxetine is administered once a day.

[0594] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt to the subject.

[0595] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 20 mg of fluoxetine or a pharmaceutically acceptable salt to the subject. In embodiments, the composition comprises about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereofAgent Reference No.: BXTI-060 / 01WO (332712-2433)

[0596] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 20 mg of fluoxetine or a pharmaceutically acceptable salt to the subject.

[0597] In embodiments, fluoxetine is administered once a day.

[0598] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 15 mg to about 60 mg of quinidine or a pharmaceutically acceptable salt to the subject.

[0599] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 15 mg to about 60 mg of quinidine or a pharmaceutically acceptable salt to the subject.

[0600] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt to the subject.

[0601] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to 200 mg of quinidine or a pharmaceutically acceptable salt to the subject.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0602] In embodiments, the composition comprises about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof. In embodiments, the composition comprises about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof.

[0603] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to 200 mg of quinidine or a pharmaceutically acceptable salt to the subject.

[0604] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 10 mg of quinidine or a pharmaceutically acceptable salt to the subject.

[0605] In embodiments, the present disclosure provides methods of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 10 mg of quinidine or a pharmaceutically acceptable salt to the subject.

[0606] In embodiments, quinidine is administered once a day.

[0607] In embodiments, latrepirdine is administered once a day.

[0608] In embodiments, the method comprises measuring at least one pharmacokinetic parameter at one or more time points following the administration of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer and comparing the measured parameter to a target range for the pharmacokinetic parameter. In embodiments, the method further comprises adjusting the dose of the PK stabilizer administered with latrepirdine if the measured value does not fall within the target range.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0609] In embodiments, the method of the present disclosure includes measuring half-life (t1 / 2) and clearance (CL) in the blood of subject following the administration of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine. In embodiments, increase in half-life following the administration of said combination indicates improvement in pharmacokinetic profile of administered drug latrepirdine. In embodiments, decrease in clearance following the administration of said combination indicates improvement in pharmacokinetic profile of administered drug latrepirdine.

[0610] In embodiments, the administration of composition to the human subject results in a plasma concentration of latrepirdine and wherein the plasma concentration of latrepirdine is between 1 and 20 ng / ml (including all ranges and values in between). In embodiments, the plasma concentration of latrepirdine is maintained above 2 ng / ml.

[0611] In embodiments, the plasma concentration of latrepirdine is maintained for at least 8 to 12 hours. In embodiments, the plasma concentration of latrepirdine is maintained for at least 8 hours. In embodiments, the plasma concentration of latrepirdine is maintained for at least 10 hours. In embodiments, the plasma concentration of latrepirdine is maintained for at least 12 hours.

[0612] In embodiments, the plasma concentration of latrepirdine is between 2 and 20 ng / ml. In embodiments, the administration of composition to a human subject result in a plasma concentration of latrepirdine and wherein the plasma concentration of latrepirdine is between 2 and 15 ng / ml. In embodiments, the plasma concentration of latrepirdine is between 3 and 15 ng / ml. In embodiments, the plasma concentration of latrepirdine is about 4 ng / ml, 5 ng / ml, 6 ng / ml, 7 ng / ml, 8 ng / ml, 9 ng / ml, 10 ng / ml, 11 ng / ml, 12 ng / ml, 13 ng / ml, 14 ng / ml or 15 ng / ml.

[0613] In embodiments, the administration of composition to a human subject result in a plasma concentration of latrepirdine and wherein the plasma concentration of latrepirdine is between 4 and 10 ng / ml. In embodiments, the plasma concentration of latrepirdine is between 4 and 7 ng / ml. In embodiments, the administration of composition to a human subject result in a plasma concentration of latrepirdine and wherein the plasma concentration of latrepirdine is about 5 ng / ml. In embodiments, the plasma concentration of latrepirdine is maintained for at least 8 hours. In embodiments, the plasma concentration of latrepirdine is maintained for atAgent Reference No.: BXTI-060 / 01WO (332712-2433) least 10 hours. In embodiments, the plasma concentration of latrepirdine is maintained for at least 12 hours. In embodiments, the plasma concentration of latrepirdine is maintained for 16 hours, 20 hours, 24 hours or more.In some embodiments, the plasma concentration of latrepirdine is about 50 ng / ml.

[0614] In embodiments, there are provided methods of treating agitation in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0615] In embodiments, there are provided methods of treating agitation in a subject, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0616] In embodiments, there are provided methods of treating agitation in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt.

[0617] In embodiments, there are provided methods of treating agitation in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt.

[0618] In embodiments, there are provided methods of treating agitation in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt.

[0619] In embodiments, the agitation is caused by noradrenergic hyperarousal. In embodiments, the agitated subject also exhibits aggression. In embodiments, the agitation is chronic or acute.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0620] In embodiments, the agitation is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer’s disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post-traumatic stress disorder (PTSD), Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy and other related neurodegenerative disorders. In embodiments, the agitation is associated with sundown syndrome in Alzheimer’s disease / dementia. In embodiments, the Alzheimer’s disease agitation is chronic agitation.

[0621] In embodiments, the agitation is associated with a neuropsychiatric disease selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, obsessive- compulsive disorder (OCD), delirium, and depression. In embodiments, the agitation is associated with an alcohol and substance abuse withdrawal, for example, opioid withdrawal. In embodiments, the agitation is associated with an OPD / IPD procedure (e.g. MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedures).

[0622] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0623] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0624] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0625] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 5 mg to about 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 60 mg of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0626] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 5 mg to about 80 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg to about 30 mg of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0627] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 5 mg to about 60 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 15 mg to about 25 mg of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0628] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 5 mg to about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 15 mg to about 25 mg of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0629] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0630] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical compositionAgent Reference No.: BXTI-060 / 01WO (332712-2433) comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0631] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0632] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0633] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0634] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0635] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0636] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 25 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0637] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical compositionAgent Reference No.: BXTI-060 / 01WO (332712-2433) comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0638] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt.

[0639] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 5 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0640] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0641] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0642] In embodiments, there are provided methodsof treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0643] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0644] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical compositionAgent Reference No.: BXTI-060 / 01WO (332712-2433) comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0645] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0646] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0647] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0648] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt.

[0649] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0650] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0651] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical compositionAgent Reference No.: BXTI-060 / 01WO (332712-2433) comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0652] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0653] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0654] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0655] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0656] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 25 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0657] In embodiments, there are provided methods of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0658] In embodiments, there are provided methods of treating psychosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereofAgent Reference No.: BXTI-060 / 01WO (332712-2433) in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0659] In embodiments, there are provided methods of treating psychosis in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0660] In embodiments, there are provided methods of treating psychosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0661] In embodiments, there are provided methods of treating psychosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0662] In embodiments, there are provided methods of treating psychosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0663] In embodiments, the psychosis is acute. In embodiments, the psychosis is chronic. In embodiments, the psychosis is a single episode. In embodiments, the psychosis is recurring or includes recurrent episodes. In embodiments, the acute psychosis is associated with acute psychotic episodes and / or mixed episodes.

[0664] In embodiments, the psychosis is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, depression, dementia andAgent Reference No.: BXTI-060 / 01WO (332712-2433) bipolar disorder or another related neuropsychiatric disorder. In embodiments, the psychosis is associated with neurodegenerative disorders.

[0665] In embodiments, the psychosis is associated with diseased conditions such as substance abuse disorders (e.g., alcohol, opioid and other substance withdrawal).

[0666] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0667] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0668] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0669] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neuropsychiatric disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0670] In embodiments, the neuropsychiatric disorder is recurrent. In embodiments, the neuropsychiatric disorder is stress- mediated.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0671] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered daily. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered daily. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks or 6 weeks.

[0672] In embodiments, the repeated administration of latrepirdine or a pharmaceutically acceptable salt thereof does not produce desensitization. In embodiments, the repeated administration of latrepirdine or a pharmaceutically acceptable salt thereof does not produce rebound effect.

[0673] In embodiments, administration of latrepirdine or a pharmaceutically acceptable salt thereof provides reversible effect.

[0674] In embodiments, the neuropsychiatric disorder is selected from the group consisting of but not limited to schizophrenia, bipolar disorder, bipolar mania, delirium, depression, obsessive-compulsive disorder (OCD) / repetitive behavior and an alcohol and substance abuse withdrawal including opioid withdrawal.

[0675] In embodiments, the neuropsychiatric disorder is obsessive-compulsive disorder (OCD).

[0676] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0677] In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 50 mg to about 100 mg.

[0678] In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 20 mg to about 30 mg. In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 25 mg.

[0679] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceuticalAgent Reference No.: BXTI-060 / 01WO (332712-2433) composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0680] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 2.5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0681] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0682] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0683] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0684] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 5 mg of paroxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0685] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0686] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 5 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0687] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0688] In embodiments, there are provided methods of treatment of obsessive compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0689] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0690] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0691] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 30 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0692] In embodiments, there are provided methods of treatment of obsessive compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 60 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0693] In embodiments, there are provided methods of treatment of obsessive compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0694] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0695] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0696] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 2.5 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0697] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0698] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0699] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 20 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0700] In embodiments, there are provided methodsof treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 15 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0701] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0702] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 25 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 60 mg of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0703] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 15 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0704] In embodiments, there are provided methods of treatment of obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 30 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0705] In embodiments, there are provided methods of treatment of obsessive compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising about 30 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with 60 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0706] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0707] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neuropsychiatric disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0708] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0709] In embodiments, there are provided methods of treatment of behavioral and psychological symptoms in subjects with neuropsychiatric disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0710] The present disclosure also contemplates methods of treatment of diseases selected from Alzheimer's, schizophrenia, type-2 diabetes, neuronal death mediated ocular diseases, ALS, slowing the progression of Huntington's disease, cognitive Impairment, macular degeneration, autism, autism spectrum disorder, Asperger syndrome, Rett syndrome, an avulsion injury, a spinal cord injury, myasthenia gravis, Guillain-Barre syndrome, multiple sclerosis, neuropathy and a non-neuronal indication, acute and chronic disorders of cerebral circulation, anxiety, Chronic Pain, chronic visceral pain, chronic inflammatory pain, treating fibromyalgia syndrome, preventing headache pain, epilepsy, multiple sclerosis, cancer, Mitochondrial Disease, Excitotoxic Disorder, Disease associated with or caused by elevated human leptin receptor (LEPR) signaling, gut motility disorder or neuropathy in a subject, comprising administering effective amounts of latrepirdine and PK stabilizer (e.g. paroxetine, fluoxetine, quinidine) or pharmaceutically acceptable salts thereof.

[0711] The present disclosure also contemplates method of treatment of diseases selected from neuropsychiatric symptoms associated with neurological diseases such as Alzheimer’s Disease and Parkinson’s Disease. These symptoms include but are not limited to: agitation, aggression, hostility, irritability, anxiety, compulsive, appetite disorders, sleep disorders, apathy, delusions, hallucinations and psychosis. Other indications include symptoms associated with affective disorders (bipolar mania and major depression) and schizophrenia. Schizophrenia related symptoms include but are not limited to delusions, hallucinations, hypervigilance, hyperactivity, grandiosity, hostility, blunted affect, anxiety, panic, tension, depression, motor retardation, uncooperativeness, hostility, disorientation, deficits in attention, poor impulse control, and social avoidance. Depression related symptoms include but are not limited to: sadness and despair, depressed mood, despair, despondency, inner tension, panic, dread, sleep disturbances, appetite and eating disorders, concentration difficulty, lassitude, anhedonia, suicidal thoughts, anxiety, guilt, and agitation. Bipolar symptoms include but are not limited to: elevated mood, increased motor activity, sexual interest, sleep changes, irritability, thought disorder, disruptive behaviors aggression, agitation, anxiety, and paranoia. Other symptomsAgent Reference No.: BXTI-060 / 01WO (332712-2433) include: pain, discomfort, migraine, compulsivity, attention disorders, circadian rhythm changes, autism spectrum disorder related symptoms, ADHD related symptoms, symptoms related to stress including acute stress syndrome and post-traumatic stress, symptoms from injury such as traumatic brain injury, symptoms from illness such as viral infections, symptoms from substance use disorders such as alcohol, opioids or cocaine, or neuropsychiatric symptoms from genetic disorders such as familial dysautonomia.

[0712] In embodiments, the neuropsychiatric disorder is recurrent. In embodiments, the neuropsychiatric disorder is stress- mediated.

[0713] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered daily. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered daily. In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is administered for at least 1 week, 2 weeks, 3 weeks, 4 weeks or 6 weeks.

[0714] In embodiments, the repeated administration of latrepirdine or a pharmaceutically acceptable salt thereof does not produce desensitization. In embodiments, the repeated administration of latrepirdine or a pharmaceutically acceptable salt thereof does not produce rebound effect.

[0715] In embodiments, administration of latrepirdine or a pharmaceutically acceptable salt thereof provides reversible effect.

[0716] In embodiments, the treatment is effective with reduced or no side effects (e. g. cardiac or respiratory side effects). In embodiments, the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof is present in a dosage form. In embodiments, the effective amount of a PK stabilizer or a pharmaceutically acceptable salt thereof is present in a dosage form.

[0717] In embodiments, the effective amount of latrepirdine and PK stabilizer or a pharmaceutically acceptable salt thereof are present in the single dosage form. In embodiments, the single dosage form comprising effective amount of latrepirdine and PK stabilizer or a pharmaceutically acceptable salt thereof is an oral dosage form. In embodiments, the oral dosage form is a tablet, capsule, disc, patch or film, sachet, wafer, powder, minitablet or a pellet.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0718] In embodiments, the single oral dosage form is a tablet.

[0719] In embodiments, the composition comprising latrepirdine and PK stabilizer or salts thereof is administered once daily, twice daily, thrice daily or four times, five times, six times a day, preferably once, twice or thrice daily.

[0720] In embodiments, the composition comprising latrepirdine and PK stabilizer or salts thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer. VI. Medical Kits:

[0721] In embodiments, the present disclosure provides a kit of parts comprising a single dosage form comprising: (i) an effective amount of a PK stabilizer (selected from the group consisting of paroxetine, fluoxetine or quinidine) or a pharmaceutically acceptable salt thereof, (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and optionally (iii) instructions for the administration of the single dosage form to a subject in need thereof.

[0722] In embodiments, the present disclosure provides a kit of parts comprising a single dosage form comprising: (i) an effective amount of paroxetine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and optionally (iii) instructions for the administration of the single dosage form to a subject in need thereof.

[0723] In embodiments, the present disclosure provides a kit of parts comprising a single dosage comprising: (i) an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof,Agent Reference No.: BXTI-060 / 01WO (332712-2433) (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and optionally (iii) instructions for the administration of the single dosage form to a subject in need thereof.

[0724] In embodiments, the present disclosure provides a kit of parts comprising a single dosage form comprising: (i) an effective amount of quinidine or a pharmaceutically acceptable salt thereof, (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and optionally (iii) instructions for the administration of the single dosage form to a subject in need thereof.

[0725] In embodiments, latrepirdine or a pharmaceutically acceptable salt thereof is latrepirdine hydrochloride.

[0726] In embodiments, paroxetine or a pharmaceutically acceptable salt thereof is paroxetine hydrochloride. In embodiments, fluoxetine or a pharmaceutically acceptable salt thereof is fluoxetine hydrochloride.

[0727] In embodiments, quinidine or a pharmaceutically acceptable salt thereof is quinidine sulfate. In embodiments, quinidine or a pharmaceutically acceptable salt thereof is quinidine gluconate.

[0728] In embodiments, the single dosage form is an oral tablet. In embodiments, the tablet is lyophilized.

[0729] In embodiments, the single dosage form is a capsule, disc, patch or film, sachet, wafer, powder, minitablet or a pellet.

[0730] In embodiments, the kit comprises (i) latrepirdine or a pharmaceutically acceptable salt thereof in an amount between 5 mg and 80 mg; and (ii) PK stabilizer or a pharmaceutically acceptable salt thereof in an amount between 5 mg and 60 mg.

[0731] In embodiments, the kit comprises (i) latrepirdine or a pharmaceutically acceptable salt thereof in an amount of about 20 mg; and (ii) PK stabilizer or a pharmaceutically acceptable salt thereof in an amount of about 20 mg.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0732] In embodiments, the kit comprises (i) latrepirdine or a pharmaceutically acceptable salt thereof in an amount of about 20 mg; and (ii) PK stabilizer or a pharmaceutically acceptable salt thereof in an amount of about 10 mg.

[0733] In embodiments, the kit comprises (i) latrepirdine or a pharmaceutically acceptable salt thereof in an amount of about 20 mg; and (ii) PK stabilizer or a pharmaceutically acceptable salt thereof in an amount of about 200 mg. EXEMPLARY SPECIFIC EMBODIMENTS:

[0734] Embodiment 1. A pharmaceutical composition comprising: a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine, or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub-therapeutic dose.

[0735] Embodiment 2. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 80 mg of latrepirdine.

[0736] Embodiment 3. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 60 mg of latrepirdine.

[0737] Embodiment 4. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 50 mg of latrepirdine.

[0738] Embodiment 5. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 40 mg of latrepirdine.

[0739] Embodiment 6. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 10 mg and 30 mg of latrepirdine.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0740] Embodiment 7. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 15 mg and 25 mg of latrepirdine.

[0741] Embodiment 8. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 15 mg and 20 mg of latrepirdine.

[0742] Embodiment 9. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 20 mg and 25 mg of latrepirdine.

[0743] Embodiment 10. The pharmaceutical composition of embodiment 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is about 20 mg of latrepirdine.

[0744] Embodiment 11. The pharmaceutical composition of any one of embodiments 1 to 10, wherein the pharmaceutical composition is administered to a human subject and wherein the plasma concentration of latrepirdine is between 1 and 20 ng / ml and wherein the plasma concentration of latrepirdine is maintained for at least 8 to 12 hours.

[0745] Embodiment 12. The pharmaceutical composition of embodiment 11, wherein the plasma concentration of latrepirdine is between 2 and 15 ng / ml.

[0746] Embodiment 13. The pharmaceutical composition of embodiment 11, wherein the plasma concentration of latrepirdine is between 3 and 15 ng / ml.

[0747] Embodiment 14. The pharmaceutical composition of embodiment 11, wherein the plasma concentration of latrepirdine is between 4 and 10 ng / ml.

[0748] Embodiment 15. The pharmaceutical composition of embodiment 11, wherein the plasma concentration of latrepirdine is between 4 and 7 ng / ml.

[0749] Embodiment 16. The pharmaceutical composition of embodiment 11, wherein the plasma concentration of latrepirdine is about 5 ng / ml.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0750] Embodiment 17. The pharmaceutical composition of any one of embodiments 1 to 16, wherein the PK stabilizer is paroxetine and wherein the effective amount of the PK stabilizer is between 5 mg and 60 mg.

[0751] Embodiment 18. The pharmaceutical composition of embodiment 17, wherein the effective amount of the PK stabilizer is between 5 mg and 50 mg.

[0752] Embodiment 19. The pharmaceutical composition of embodiment 17, wherein the effective amount of the PK stabilizer is between 10 mg and 50 mg.

[0753] Embodiment 20. The pharmaceutical composition of embodiment 17, wherein the effective amount of the PK stabilizer is between 10 mg and 40 mg.

[0754] Embodiment 21. The pharmaceutical composition of embodiment 17, wherein the effective amount of the PK stabilizer is between 10 mg and 30 mg.

[0755] Embodiment 22. The pharmaceutical composition of embodiment 17, wherein the effective amount of the PK stabilizer is between 15 mg and 25 mg.

[0756] Embodiment 23. The pharmaceutical composition of embodiment 17, wherein the effective amount of the PK stabilizer is about 20 mg.

[0757] Embodiment 24. The pharmaceutical composition of any one of embodiments 1 to 23, wherein the PK stabilizer is fluoxetine and wherein the effective amount of the PK stabilizer is between 5 mg and 50 mg.

[0758] Embodiment 25. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is between 6 mg and 50 mg.

[0759] Embodiment 26. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is between 7 mg and 40 mg.

[0760] Embodiment 27. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is between 7 mg and 30 mg.

[0761] Embodiment 28. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is between 8 mg and 20 mg.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0762] Embodiment 29. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is between 9 mg and 20 mg.

[0763] Embodiment 30. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is between 9 mg and 15 mg.

[0764] Embodiment 31. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is between 10 mg and 15 mg.

[0765] Embodiment 32. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is about 10 mg.

[0766] Embodiment 33. The pharmaceutical composition of embodiment 24, wherein the effective amount of the PK stabilizer is about 15 mg.

[0767] Embodiment 34. The pharmaceutical composition of any one of embodiments 1 to 33, wherein the PK stabilizer is quinidine and wherein the effective amount of the PK stabilizer is between 4 mg and 50 mg.

[0768] Embodiment 35. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is between 4 mg and 50 mg.

[0769] Embodiment 36. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is between 5 mg and 40 mg.

[0770] Embodiment 37. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is between 6 mg and 30 mg.

[0771] Embodiment 38. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is between 7 mg and 20 mg.

[0772] Embodiment 39. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is between 8 mg and 20 mg.

[0773] Embodiment 40. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is between 9 mg and 15 mg.

[0774] Embodiment 41. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is between 10 mg and 15 mg.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0775] Embodiment 42. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is about 10 mg.

[0776] Embodiment 43. The pharmaceutical composition of embodiment 34, wherein the effective amount of the PK stabilizer is about 15 mg.

[0777] Embodiment 44. A method of treating agitation in a subject in need thereof comprising administrating to the subject the pharmaceutical composition in any one of embodiments 1 to 43, wherein the agitation is associated with a neuropsychiatric disease.

[0778] Embodiment 45. The method of embodiment 44, wherein the neuropsychiatric disease is selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, depression, obsessive-compulsive disorder (OCD) and an alcohol and substance abuse withdrawal including opioid withdrawal.

[0779] Embodiment 46. A kit of parts comprising a single dosage form comprising: (i) an effective amount of a PK stabilizer or a pharmaceutically acceptable salt thereof, (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and (iii) optionally instructions for the administration of the single dosage form to a subject in need thereof.

[0780] Embodiment 47. The kit of embodiment 46, wherein the PK stabilizer is selected from the group consisting of paroxetine, fluoxetine, and quinidine, or a pharmaceutically acceptable salt thereof.

[0781] Embodiment 48. The kit of embodiment 46, wherein the single dosage form is an oral tablet.

[0782] Embodiment 49. A kit of parts comprising a single dosage form comprising: (i) an effective amount of paroxetine or a pharmaceutically acceptable salt thereof; (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and optionally (iii) instructions for the administration of the single dosage form to a subject in need thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0783] Embodiment 50. A kit of parts comprising a single dosage form comprising: (i) an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof, (ii) therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and optionally (iii) instructions for the administration of the single dosage form to a subject in need thereof.

[0784] Embodiment 51. A kit of parts comprising a single dosage form comprising: (i) an effective amount of quinidine or a pharmaceutically acceptable salt thereof, (ii) a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof; and optionally (iii) instructions for the administration of the single dosage form to a subject in need thereof.

[0785] Embodiment 52. The kit of any of embodiments 46 to 51, wherein the single dosage form is an oral tablet.

[0786] Embodiment 53. The kit of embodiment 52, wherein the tablet is lyophilized.

[0787] Embodiment 54. The kit of embodiment 52 or 53, wherein the tablet is a bilayer tablet.

[0788] Embodiment 55. A method of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering orally a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof to the subject, wherein the PK stabilizer is administered in a sub-therapeutic dose..

[0789] Embodiment 56. A method of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising an effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof to the subject.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0790] Embodiment 57. A method of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof to the subject.

[0791] Embodiment 58. A method of enhancing the therapeutic efficacy (or bioavailability) of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof to the subject.

[0792] Embodiment 59. A method of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub- therapeutic dose..

[0793] Embodiment 60. A method of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0794] Embodiment 61. A method of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0795] Embodiment 62. A method of treating disorders associated with noradrenergic hyperarousal in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or aAgent Reference No.: BXTI-060 / 01WO (332712-2433) pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0796] Embodiment 63. A method of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof, comprising administering orally a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof to the subject, wherein the PK stabilizer is administered in a sub-therapeutic dose

[0797] Embodiment 64. A method of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof to the subject.

[0798] Embodiment 65. A method of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof to the subject.

[0799] Embodiment 66. A method of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof to the subject.

[0800] Embodiment 67. The method of any of embodiments 63 to 66, wherein the method comprises measuring at least one pharmacokinetic parameter at one or more time points following the administration of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer.

[0801] Embodiment 68. The method of embodiment 67, wherein the method further comprises comparing the measured parameter to a target range for the pharmacokinetic parameter.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0802] Embodiment 69. The method of embodiment 67 or 68, wherein the method further comprises adjusting the dose of the PK stabilizer administered with latrepirdine if the measured value does not fall within the target range.

[0803] Embodiment 70. The method of any of embodiments 63 to 69, wherein the method includes measuring half-life (t1 / 2) and clearance (CL) in the blood of subject following the administration of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer.

[0804] Embodiment 71. The method of embodiment 70, wherein an increase in half-life following the administration of said combination indicates improvement in pharmacokinetic profile of administered drug latrepirdine.

[0805] Embodiment 72. The method of embodiment 70, wherein a decrease in clearance following the administration of said combination indicates improvement in pharmacokinetic profile of administered drug latrepirdine.

[0806] Embodiment 73. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the PK stabilizer and latrepirdine are administered together in a single dosage form.

[0807] Embodiment 74. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the composition of PK stabilizer and latrepirdine or pharmaceutically acceptable salts thereof is a fixed dosage form.

[0808] Embodiment 75. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the composition comprising latrepirdine and PK stabilizer or salts thereof is administered once daily, twice daily, thrice daily or four times, five times, six times a day, preferably once, twice or thrice daily.

[0809] Embodiment 76. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the combination comprising latrepirdine and PK stabilizer or salts thereof is administered orally as tablet, capsule, disc, patch or film, sachet, wafer, powder, minitablet, pellet, paste, gel, ointment, cream, drops, liquid (solution, suspension or emulsion), spray, microspheres or nanospheres.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0810] Embodiment 77. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the composition comprising latrepirdine and PK stabilizer or salts thereof is administered orally in the form of a single tablet dosage form.

[0811] Embodiment 78. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the composition comprising latrepirdine and PK stabilizer or salts thereof is administered for at least 3 days, at least 5 days, at least 7 days, at least 10 days, at least 15 days, at least 30 days, at least 60 days, at least 90 days, at least 180 days, at least 365 days, or longer.

[0812] Embodiment 79. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the subject is a human subject.

[0813] Embodiments 80. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the latrepirdine or a pharmaceutically acceptable salt thereof is latrepirdine hydrochloride (or dihydrochloride).

[0814] Embodiments 81. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein the paroxetine or a pharmaceutically acceptable salt thereof is paroxetine hydrochloride.

[0815] Embodiment 82. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein fluoxetine or a pharmaceutically acceptable salt thereof is fluoxetine hydrochloride.

[0816] Embodiment 83. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein quinidine or a pharmaceutically acceptable salt thereof is quinidine sulfate.

[0817] Embodiment 84. The pharmaceutical composition, the methods or the kit of any of preceding embodiments, wherein quinidine or a pharmaceutically acceptable salt thereof is quinidine gluconate.

[0818] Embodiment 85. A method of treating agitation in a subject, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine,Agent Reference No.: BXTI-060 / 01WO (332712-2433) and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub-therapeutic dose..

[0819] Embodiment 86. A method of treating agitation in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0820] Embodiment 87. A method of treating agitation in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0821] Embodiment 88. A method of treating agitation in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0822] Embodiment 89. The method of any of embodiments 85 to 88, wherein the agitation is caused by noradrenergic hyperarousal.

[0823] Embodiment 90. The method of any of embodiments 85 to 88, wherein the agitation is chronic or acute.

[0824] Embodiment 91. The method of any of embodiments 85 to 88, wherein the agitation is associated with a neurodegenerative disorder selected from the group consisting of Alzheimer’s disease, frontotemporal dementia (FTD), dementia, dementia with Lewy bodies (DLB), post- traumatic stress disorder (PTSD), Parkinson's disease, vascular dementia, vascular cognitive impairment, Huntington's disease, multiple sclerosis, Creutzfeldt-Jakob disease, multiple system atrophy, progressive supranuclear palsy and other related neurodegenerative disorders.

[0825] Embodiment 92. The method of any of embodiments 85 to 88, wherein the agitation is associated with sundown syndrome in Alzheimer’s disease / dementia.

[0826] Embodiment 93. The method of any of embodiments 85 to 88, wherein the agitation is associated with a neuropsychiatric disease selected from the group consisting of schizophrenia,Agent Reference No.: BXTI-060 / 01WO (332712-2433) bipolar disorder, bipolar mania, delirium, depression, OCD, alcohol- and substance- abuse withdrawal, including opioid withdrawal.

[0827] Embodiment 94. The method of any of embodiments 85 to 88, wherein the agitation is associated with an OPD / IPD procedure (e.g. MRI, CT or CAT scan, lumbar puncture, bone marrow aspiration / biopsy, tooth extraction or other dental procedures).

[0828] Embodiment 95. A method of treating depression in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in a sub-therapeutic dose.

[0829] Embodiment 96. A method of treating depression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt.

[0830] Embodiment 97. A method of treating depression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt.

[0831] Embodiment 98. A method of treating depression in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0832] Embodiment 99. A method of treating psychosis in a subject in need thereof, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0833] Embodiment 100. A method of treating psychosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0834] Embodiment 101. A method of treating psychosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0835] Embodiment 102. A method of treating psychosis in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0836] Embodiment 103. The method of any of embodiments 99 to 102, wherein the psychosis is acute.

[0837] Embodiment 104. The method of any of embodiments 99 to 102, wherein the psychosis is chronic.

[0838] Embodiment 105. The method of any of embodiments 99 to 102, wherein the psychosis is a single episode.

[0839] Embodiment 106. The method of any of embodiments 99 to 102, wherein the psychosis is recurring or includes recurrent episodes.

[0840] Embodiment 107. The method of any of embodiments 99 to 102, wherein acute psychosis is associated with acute psychotic episodes and / or mixed episodes.

[0841] Embodiment 108. The method of any of embodiments 99 to 102, wherein the psychosis is associated with a neuropsychiatric disorder selected from the group consisting of schizophrenia, schizoaffective disorder, OCD, depression, dementia and bipolar disorder or another related neuropsychiatric disorder.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0842] Embodiment 109. The method of embodiment 99 to 102, wherein the psychosis is associated with neurodegenerative disorders.

[0843] Embodiment 110. The method of embodiment 99 to 102, wherein the psychosis is associated with diseased condition such as substance abuse disorders (e.g., alcohol, opioid and other substance withdrawal).

[0844] Embodiment 111. A method of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering orally to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine or a pharmaceutically acceptable salt thereof.

[0845] Embodiment 112. A method of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0846] Embodiment 113. A method of treatment of behavioral and psychological symptoms in subjects with neuropsychiatric disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of paroxetine or a pharmaceutically acceptable salt thereof.

[0847] Embodiment 114. A method of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0848] Embodiment 115. A method of treatment of behavioral and psychological symptoms in subjects with neuropsychiatric disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or aAgent Reference No.: BXTI-060 / 01WO (332712-2433) pharmaceutically acceptable salt thereof in combination with an effective amount of fluoxetine or a pharmaceutically acceptable salt thereof.

[0849] Embodiment 116. A method of treatment of behavioral and psychological symptoms in subjects with neurodegenerative disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0850] Embodiment 117. A method of treatment of behavioral and psychological symptoms in subjects with neuropsychiatric disorder, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof in combination with an effective amount of quinidine or a pharmaceutically acceptable salt thereof.

[0851] Embodiment 118. The method according to any of preceding embodiments, wherein the pharmaceutical composition is administered orally.

[0852] Embodiment 119. The method of embodiment 118, wherein the oral composition is a single dosage form.

[0853] Embodiment 120. The method of embodiment 119, wherein the dosage form is a tablet.

[0854] Embodiment 121. The method of any of preceding embodiments, wherein the subject is human.

[0855] Embodiment 122. A method of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 10 mg of paroxetine or a pharmaceutically acceptable salt to the subject.

[0856] Embodiment 123. A method of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 15 mg to about 60 mg of fluoxetine or a pharmaceutically acceptable salt to the subject.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0857] Embodiment 124. A method of improving the pharmacokinetics / pharmacokinetic profile of latrepirdine or a pharmaceutically acceptable salt thereof in a subject in need thereof, comprising administering a pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof in combination with about 2.5 mg to about 10 mg of quinidine or a pharmaceutically acceptable salt to the subject.

[0858] Embodiment 125. The method of any of embodiments 122 to 124, wherein latrepirdine is administered once a day.

[0859] Embodiment 126. The method of embodiment 122, wherein paroxetine is administered once a day.

[0860] Embodiment 127. The method of embodiment 123, wherein fluoxetine is administered once a day.

[0861] Embodiment 128. The method of embodiment 124, wherein quinidine is administered once a day.

[0862] Embodiment 129. A pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg to about 10 mg of a PK stabilizer.

[0863] Embodiment 130. A pharmaceutical composition comprising about 5 mg to about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg to about 60 mg of a PK stabilizer.

[0864] Embodiment 131. A pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0865] Embodiment 132. A pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0866] Embodiment 133. A pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0867] Embodiment 134. A pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of paroxetine or a pharmaceutically acceptable salt thereof.

[0868] Embodiment 135. A pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 2.5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0869] Embodiment 136. A pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 5 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0870] Embodiment 137. A pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 10 mg of quinidine or a pharmaceutically acceptable salt thereof.

[0871] Embodiment 138. A pharmaceutical composition comprising about 5 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 15 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0872] Embodiment 139. A pharmaceutical composition comprising about 10 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0873] Embodiment 140. A pharmaceutical composition comprising about 15 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 25 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0874] Embodiment 141. A pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0875] Embodiment 142. A pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 20 mg of fluoxetine or a pharmaceutically acceptable salt thereof.Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0876] Embodiment 143. A pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 30 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0877] Embodiment 144. A pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 40 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0878] Embodiment 145. A pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 50 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0879] Embodiment 146. A pharmaceutical composition comprising about 20 mg of latrepirdine or a pharmaceutically acceptable salt thereof and about 60 mg of fluoxetine or a pharmaceutically acceptable salt thereof.

[0880] Embodiment 147. A method of treatment of obsessive - compulsive disorder in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

[0881] Embodiment 148. The method of embodiment 147, wherein the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 50 mg to about 100 mg.

[0882] Embodiment 149. The method of embodiment 147, wherein the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 20 mg to about 30 mg.

[0883] Embodiment 150. The method of embodiment 149, wherein the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 25 mg.

[0884] Embodiment 151. The method of embodiment 147 to 150, wherein the composition is administered orally once or multiple times a day

[0885] Embodiment 152. embodiment 147 to 150, wherein latrepirdine or a pharmaceutically acceptable salt thereof is latrepirdine hydrochloride or latrepirdine dihydrochloride.Agent Reference No.: BXTI-060 / 01WO (332712-2433) The details of the disclosure, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations. EXAMPLES

[0886] Example 1: To determine the effect of specific expressed human enzymes on the metabolic stability of Latrepirdine dihydrochloride dihydrate using human liver microsomes assay.

[0887] Latrepirdine is rapidly metabolized. The ability to attain and maintain therapeutically effective concentrations in vivo may require improvements in the PK profile of latrepirdine. Such improvements may require the ability to reduce its rate of metabolism which could be achieved through the use of inhibitors to the enzymes responsible for metabolism. Thus, identification of specific metabolizing enzymes responsible for the metabolism of latrepirdine whose activity could be inhibited and reduced was the goal of this set of experiments.

[0888] Method: The effect of specific expressed human CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6 and CYP2E1) at 0.1 M concentration on overall metabolic stability of latrepirdine dihydrochloride hydrate in human liver microsomes was determined.

[0889] Experimental conditions: ADME-Tox: In-vitro metabolism

[0890] Assay: Clearance (liver microsomes- human)

[0891] Source: human liver microsomes (0.1 mg / mL)

[0892] Substrate: test compound (i.e latrepirdine dihydrochloride)

[0893] Incubation time: 0, 15, 30, 45, 60 min 37°C

[0894] Measured component: test compound (i.e latrepirdine dihydrochloride)

[0895] Detection method: HPLC-MS / MSn

[0896] Test compound: latrepirdine dihydrochloride (MW: 319.44) Stock solution: 1.E-02 M DMSOAgent Reference No.: BXTI-060 / 01WO (332712-2433)

[0897] Results: Table 1 shows that out of specific expressed enzymes, CYP2D6was capable of metabolizing latrepirdine as it completely metabolized the substrate very quickly. Whereas most of the other enzymes showed little potential to metabolize latrepirdine, the results also showed that CYP3A4 exhibited some potential to metabolize latrepirdine and perhaps CYP2C19 to a limited extent. Table 1. Latrepirdine metabolic stability: Specific expressed human enzymes (0.1 M)

[0898] Example 2: To compare the inhibition of metabolism of latrepirdine dihydrochloride hydrate by specific inhibitors (Furafylline, clopidogrel, montelukast, sulfaphenazole, oxybutynin, quinidine, ketoconazole, fluconazole, fluoxetine, fluvoxamine, bupropion, paroxetine, voriconazole, troleandomycin and itraconazole).Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0899] Method: The ability of various inhibitors to modify metabolism of latrepirdine dihydrochloride hydrate and thus act as PK stabilizers of latrepirdine was investigated. The inhibitors were Furafylline, clopidogrel, montelukast, sulfaphenazole, oxybutynin, quinidine, ketoconazole, fluconazole, fluoxetine, fluvoxamine, bupropion, paroxetine, voriconazole, troleandomycin and itraconazole. The effect was measured at 0.1 M at time intervals of 0, 15, 30, 45 and 60 minutes compared to control.

[0900] Specific inhibitors, namely Furafylline, clopidogrel, montelukast, sulfaphenazole, oxybutynin, quinidine, ketoconazole, fluconazole, fluoxetine, fluvoxamine, bupropion,paroxetine, voriconazole, troleandomycin and itraconazole were taken at 0.1 M concentrationand tested concurrently with latrepirdine. Metabolic stability of test compound latrepirdine in terms of percent remaining at incubation time up to 60 minutes were studied. Metabolic stability, expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming the first-order kinetics. The apparent clearance (CLint, in L / min / pmol, L / min / mg or L / min / Mcell) was calculated according to the following formula: CL= 0.693 / T1 / 2*(mg protein / L or million cells / L or pmol CYP isozyme / L)

[0901] Results: Using selective chemical inhibitors to specific human CYP enzymes, it was shown that some inhibitors demonstrated potential to inhibit the metabolism of latrepirdine in human liver microsomes. Specifically, quinidine, fluoxetine and paroxetine reduced the percentage of the substrate metabolized by the end of the incubation period (60 mins) as compared to control with ~80% of substrate left (paroxetine: 81.6%, fluoxetine: 87.84% and quinidine: 80.20%) compared to ~26% for the control incubation without any inhibitor. Most of the other inhibitors showed little or no activity at reducing the metabolism of latrepirdine except for some potential demonstrated by fluvoxamine (~48% substrate left at the end of the incubation ((Table 2, Figure 1).C A0308.3 4 8 553.7.4..20.)R10 13 TI 1 875438183 :3C;el42E68 4 4 3OoTzpsC U002 4 2 5 0. 615.6 4.9 3.1 0.028.4X:eL8 5 3 2 2 2O;O RF el RtaozPU )gC1 4 1 1 8 an BMnO04 1 6 0 . 4. e;u iTE01 .1. . . 4805820 8 42he1n.iK2 2 pa n0a f i(m lumax1sero RIti)NI 0 0888580 8. 0 S: ov 31U0Q1 .6.97.87 2.707852<1>AF ulFbi%(L:hntU inceUSO V B ic0 619772461. 7;.tsU frY0i1 .8.7.0.891 13akL ceX8 5 4 2 2u FePOle ;ptsnenyAbFL0032. 2627558. 3oit.M eU14. . . 3 x96673325 72 :omsS 2Euli T loNF:b EelaT7 0O XotN03.2. 49. 92. 0.18.MOzeO01484582919232 ;lUanomMerL egFcno ; ar idIdieltI:rP 0 0iO7pL01 . 930. 21. 421. 9. p o9266.33825 62olzaC A e C2C:nIocR rtal F P uT f A0 8lo R0 5. 85. 89. 32. 4.50.OFI;U10:niF 88462611322L C;OcCynoietnU moi lboirt 6illLdnhn04. 33. 32. 47. 3.28. yFano01681673623292fa;eelICruloor:F z T2 ) e):an:E lnirebt lo)F oam( em L pniA RcoO Te 051035406maL / Cnimm(2U teR / FK T mirTa / L1Pu(TAgent Reference No.: BXTI-060 / 01WO (332712-2433) Example 3 : To determine PK stability of latrepirdine dihydrochloride hydrate in presence of paroxetine with increasing concentrations (0.1 M, 0.5 M, 1 M, 5 M and 10 M) in human liver microsomes assay.

[0902] Experimental conditions: ADME-Tox: In-vitro metabolism

[0903] Assay: Clearance (liver microsomes- human)

[0904] Source: human liver microsomes (0.1 mg / mL)

[0905] Substrate: test compound (i.e latrepirdine dihydrochloride)

[0906] Incubation time: 0, 15, 30, 45, 60 min 37°C

[0907] Measured component: test compound (i.e latrepirdine dihydrochloride)

[0908] Detection method: HPLC-MS / MS

[0909] Test compound: latrepirdine dihydrochloride (MW: 319.44) Stock solution: 1.E-02 M DMSO

[0910] Reference compound: The reference compound, paroxetine, at concentrations of0.1 M, 0.5 M, 1 M, 5 M and 10 M was tested concurrently with latrepirdine, and the datawere compared with historical values determined at Eurofins. The experiment was accepted in accordance with Eurofins validation Standard Operating Procedure.

[0911] Clearance (microsomes, S9, cryopreserved hepatocytes, recombinant CYP, recombinant UGT)

[0912] Metabolic stability, expressed as percent of the parent compound remaining, was calculated by comparing the peak area of the compound at the time point relative to that at time-0. The half-life (T1 / 2) was estimated from the slope of the initial linear range of the logarithmic curve of compound remaining (%) vs. time, assuming the first-order kinetics. The apparent clearance (CL, in L / min / pmol, L / min / mg or L / min / Mcell) was calculated according to the following formula: CL= 0.693 / T1 / 2*(mg protein / L or million cells / L or pmol CYP isozyme / L)

[0913] Method:Agent Reference No.: BXTI-060 / 01WO (332712-2433)

[0914] The liver microsome according to the present invention was prepared from liver tissue materials. The microsomes were obtained from liver tissue material homogenates by differential centrifugation and resuspending the final fraction obtained as a precipitate.

[0915] In the presence of the co-factor NADPH, which initiates the reaction, the microsomes were incubated with the test compound at 37°C. The reaction was terminated by adding methanol containing an internal standard. After centrifugation, the supernatant was analyzed on LC-MS / MS. The disappearance of the test compound is monitored over 60 minutes. The peak area of the compound at respective times is compared to that at time zero and is plotted against time, and the gradient of the line was determined.

[0916] Final latrepirdine concentration was 0.1 M in the incubation reaction containing 0.1 mg / mL microsomes solution was dispensed to the assay plates designated for different time points (0, 15, 3...

Claims

Agent Reference No.: BXTI-060 / 01WO (332712-2433) CLAIMS:

1. A pharmaceutical composition comprising: a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof and an effective amount of a PK stabilizer selected from the group consisting of paroxetine, fluoxetine, and quinidine, or a pharmaceutically acceptable salt thereof, wherein the PK stabilizer is administered in sub-therapeutic dose.

2. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 80 mg of latrepirdine.

3. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 60 mg of latrepirdine.

4. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 50 mg of latrepirdine.

5. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 5 mg and 40 mg of latrepirdine.

6. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 10 mg and 30 mg of latrepirdine.

7. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 15 mg and 25 mg of latrepirdine.

8. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 15 mg and 20 mg of latrepirdine.

9. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is between 20 mg and 25 mg of latrepirdine.Agent Reference No.: BXTI-060 / 01WO (332712-2433) 10. The pharmaceutical composition of claim 1, wherein the therapeutically effective amount of latrepirdine or the pharmaceutically acceptable salt thereof is about 20 mg of latrepirdine.

11. The pharmaceutical composition of any one of claims 1 to 10, wherein the pharmaceutical composition is administered to a human subject,wherein the plasma concentration of latrepirdine is between 1 ng / ml and 20 ng / ml and wherein the plasma concentration of latrepirdine is maintained for at least 8 to 12 hours.

12. The pharmaceutical composition of claim 11, wherein the plasma concentration of latrepirdine is between 2 ng / ml and 15 ng / ml.

13. The pharmaceutical composition of claim 11, wherein the plasma concentration of latrepirdine is between 3 ng / ml and 15 ng / ml.

14. The pharmaceutical composition of claim 11, wherein the plasma concentration of latrepirdine is between 4 ng / ml and 10 ng / ml.

15. The pharmaceutical composition of claim 11, wherein the plasma concentration of latrepirdine is between 4 ng / ml and 7 ng / ml.

16. The pharmaceutical composition of claim 11, wherein the plasma concentration of latrepirdine is about 5 ng / ml.

17. The pharmaceutical composition of any one of claims 1 to 16, wherein the PK stabilizer is paroxetine and wherein the effective amount of the PK stabilizer is between 5 mg and 60 mg.

18. The pharmaceutical composition of claim 17, wherein the effective amount of the PK stabilizer is between 5 mg and 50 mg.

19. The pharmaceutical composition of claim 17, wherein the effective amount of the PK stabilizer is between 10 mg and 50 mg.

20. The pharmaceutical composition of claim 17, wherein the effective amount of the PK stabilizer is between 10 mg and 40 mg.

21. The pharmaceutical composition of claim 17, wherein the effective amount of the PK stabilizer is between 10 mg and 30 mg.

22. The pharmaceutical composition of claim 17, wherein the effective amount of the PK stabilizer is between 15 mg and 25 mg.Agent Reference No.: BXTI-060 / 01WO (332712-2433) 23. The pharmaceutical composition of claim 17, wherein the effective amount of the PK stabilizer is about 20 mg.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein the PK stabilizer is fluoxetine and wherein the effective amount of the PK stabilizer is between 5 mg and 50 mg.

25. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is between 6 mg and 50 mg.

26. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is between 7 mg and 40 mg.

27. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is between 7 mg and 30 mg.

28. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is between 8 mg and 20 mg.

29. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is between 9 mg and 20 mg.

30. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is between 9 mg and 15 mg.

31. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is between 10 mg and 15 mg.

32. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is about 10 mg.

33. The pharmaceutical composition of claim 24, wherein the effective amount of the PK stabilizer is about 15 mg.

34. The pharmaceutical composition of any one of claims 1 to 33, wherein the PK stabilizer is quinidine and wherein the effective amount of the PK stabilizer is between 4 mg and 50 mg.

35. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is between 4 mg and 50 mg.

36. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is between 5 mg and 40 mg.Agent Reference No.: BXTI-060 / 01WO (332712-2433) 37. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is between 6 mg and 30 mg.

38. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is between 7 mg and 20 mg.

39. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is between 8 mg and 20 mg.

40. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is between 9 mg and 15 mg.

41. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is between 10 mg and 15 mg.

42. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is about 10 mg.

43. The pharmaceutical composition of claim 34, wherein the effective amount of the PK stabilizer is about 15 mg.

44. A method of treating agitation in a subject in need thereof, comprising administrating to the subject the pharmaceutical composition of any one of claims 1 to 43, wherein the agitation is associated with a neuropsychiatric disease.

45. The method of claim 44, wherein the neuropsychiatric disease is selected from the group consisting of schizophrenia, bipolar disorder, bipolar mania, delirium, depression, obsessive-compulsive disorder (OCD) and an alcohol or substance abuse withdrawal optionally, opioid withdrawal.

46. A method of reducing noradrenergic hyperarousal in a subject, comprising administering to the subject the pharmaceutical composition of any one of claims 1 to 43.

47. The method of claim 46, wherein the plasma concentration of latrepirdine in the subject is between 1 ng / ml and 20 ng / ml, optionally between 4 ng / ml and 10 ng / ml, or between 7 ng / ml and 10 ng / ml and wherein the plasma concentration of latrepirdine is maintained for at least 12 hours.

48. The method of claim 46, wherein the subject has dementia, schizophrenia, bipolar disorder, bipolar mania, delirium, depression, psychosis, obsessive-compulsive disorder (OCD), alcohol abuse withdrawal, or substance abuse withdrawal.Agent Reference No.: BXTI-060 / 01WO (332712-2433) 49. The method of claim 48, wherein the subject has substance abuse withdrawal and the substance is an opioid.

50. The method of claim 46, wherein the subject has dementia and has chronic agitation.

51. A method of treating obsessive-compulsive disorder (OCD) in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein the therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 50 mg to about 100 mg.

53. The method of claim 51, wherein therapeutically effective amount of latrepirdine or a pharmaceutically acceptable salt is about 25 mg to about 50 mg.

54. The method of any one of claims 51 to 53, wherein the composition is administered orally once or multiple times a day 55. The method of any one of claims 51 to 54, wherein latrepirdine or a pharmaceutically acceptable salt thereof is latrepirdine hydrochloride or latrepirdine dihydrochloride.

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