Amorphous otenaproxesul for the treatment of acute pain

Abstract

The present application relates to methods of treating or preventing acute pain using amorphous otenaproxesul. In particular, the present application includes methods of treating or preventing acute pain using dosing regimens of amorphous solid dispersions comprising otenaproxesul and compositions comprising the amorphous solid dispersions. The present application further relates to pharmaceutical packages and kits comprising amorphous otenaproxesul. Formula (I) (Otenaproxesul)

Description

TITLE: AMORPHOUS OTENAPROXESUL FOR THE TREATMENT OF ACUTE PAINFIELD

[0001] The present application relates to methods of treating or preventing acute pain using amorphous otenaproxesul. In particular, the present application relates to methods of treating or preventing acute pain using dosing regimens of amorphous solid dispersions comprising otenaproxesul and compositions thereof.BACKGROUND

[0002] Otenaproxesul is chemically known as (S)-4-carbamothioylphenyl 2-(6- methoxynaphthalen-2-yl) propanoate or (S)-2-(6-methoxy-naphthalen-2-yl)-propionic acid 4- thiocarbamoyl-phenyl ester and is a hydrogen sulfide-releasing analogue of naproxen with a strikingly different safety and efficacy profile in humans than naproxen itself. US 8,541 ,398 discloses various non-steroidal anti-inflammatory drug (NSAID) derivatives covalently linked to H2S-releasing moieties including otenaproxesul, and found that the anti-inflammatory activity of a variety of NSAIDs is significantly enhanced when covalently linked to, or NSAID salts are formed with, an H2S-releasing moiety.

[0003] Hydrogen sulfide (H2S) has been shown to be produced in the Gl tract and to contribute to gastrointestinal mucosal defense and the healing of gastrointestinal ulcers. In the intestine, H2S modulates epithelial secretion and promotes resolution of colitis. H2S inhibits leukocyte adherence to the vascular endothelium and appears to play an important role in the regulation of systemic blood pressure. Endogenous H2S and H2S donors have also been reported to have a potential role in protecting against viral infections [Li H et al. J. Virol. 2015; 89:5557-5568, Bazhanov N et al. Sci. Rep. 2017; 7:41029, Yang G. Am. J. Physiol. Cell Physiol. 2020; 318:C244-C249, Citi V. et al. Brit. J. Pharmacol. 2020; 177:4931-4941 , Kim JZJ Et al. 2020, Journal of Translational Medicine, volume 18, Article number: 257257],

[0004] Otenaproxesul exhibits anti-inflammatory, analgesic, antinociceptive, immunomodulatory, and neuroprotective activities and was found to be effective at reducing pain in osteoarthritis patients with an efficacy similar to other NSAIDS such as naproxen or celecoxib in comparable osteoarthritis studies. Advantageously, linking an H2S-releasing moiety to naproxen also greatly reduces the gastrointestinal (Gl) damaging effects of this NSAID compared to naproxen as demonstrated in human clinical trials, including trial NCT03978208 listed on clinicaltrials.gov.

[0005] Processes for the synthesis of otenaproxesul disclosed in US 8,541 ,398 provide crystalline otenaproxesul.SUMMARY

[0006] The present application includes a method of treating or preventing acute pain in a subject in need thereof comprising: administering one or two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 14 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0007] In some embodiments, the method provides a plasma concentration of naproxen metabolite of about 10 pg / mL or greater or about 15 pg / mL or greater in about one hour or less.

[0008] In some embodiments, administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, comprises administering one or more first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more second oral maintenance doses comprising about 100 mg to about 350 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more third up to one or more eighth oral maintenance doses comprising about 25 mg to about 150 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the amorphous otenaproxesul, or pharmaceutically acceptable salt thereof is formulated into an amorphous solid dispersion.

[0010] In some embodiments, the amorphous otenaproxesul, or pharmaceutically acceptable salt thereof is formulated into an amorphous solid dispersion.

[0011] The present application includes a pharmaceutical package or kit comprising:one oral loading dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof of the application, and instructions for administration of the one oral loading dose of the amorphous otenaproxesul or the pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0012] In some embodiments, the pharmaceutical package or kit includes a second oral loading doses comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0013] The present application also includes a pharmaceutical package or kit comprising: one or two oral loading doses comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof of the application, and one or more oral maintenance doses amorphous otenaproxesul or a pharmaceutically acceptable salt thereof of the application.

[0014] The present application includes a pharmaceutical package or kit comprising: two or more oral maintenance doses comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof of the application, and instructions for administration of the two or more oral pharmaceutical compositions, to a subject in need thereof.

[0015] Other features and advantages of the present application will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating embodiments of the application, are given by way of illustration only and the scope of the claims should not be limited by these embodiments but should be given the broadest interpretation consistent with the description as a whole.DRAWINGS

[0016] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0017] Figure 1 shows levels in plasma of naproxen (a metabolite of otenaproxesul) after single ascending dose (SAD) otenaproxesul (ATB-346) oral administration in healthy subjects. The single dosage amounts of otenaproxesul were (from the top line to the bottom line) 2000 mg, 1500 mg, 1000 mg, 500 mg, 300 mg, 150 mg, 75 mg and 25 mg.

[0018] Figure 2 shows an XRPD of exemplary amorphous solid dispersion no.1 (bottom line), exemplary amorphous solid dispersion no. 2 (top line) and exemplaryamorphous solid dispersion no. 3 (middle line) after being kept at 40°C and 75% relative humidity (RH) under closed conditions for one month.

[0019] Figure 3 shows dissolution profiles of various exemplary amorphous solid dispersions on Day 1 (initial) and after 1 -month 40°C at 75% relative humidity under closed conditions. Data were obtained using an in vitro gastric to intestinal transfer test using 0.1 N HCI gastric media with an addition of intestinal media after 30 minutes for a final composition of 0.5% simulated intestinal fluid (SIF) in phosphate buffer saline (PBS) at pH.

[0020] Figure 4 is a graph showing the mean M25 plasma concentration-time pharmacokinetic profiles of the three treatment arms in human subjects as described in Table 23 using compositions comprising a 200 mg, 400 mg or 600 mg Day 1 loading dose (LD) of amorphous otenaproxesul in an amorphous solid dispersion.

[0021] Figure 5 is a graph showing M25 plasma concentrations within the first 4-hours post drug administration to human subjects of compositions comprising a 200 mg, 400 mg or 600 mg loading dose (LD) of amorphous otenaproxesul in an amorphous solid dispersion.

[0022] Figure 6 is a graph showing the pharmacokinetic profile of H2S concentration versus time (0 to 12 Hours) after administration to human subjects of compositions comprising a 200 mg, 400 mg or 600 mg loading dose (LD) of amorphous otenaproxesul in an amorphous solid dispersion.

[0023] Figure 7 is a graph showing the pharmacokinetic profile of H2S concentration versus time (0 to 120 Hours) after administration to human subjects of the three treatment arms described in Table 23 comprising administration of compositions comprising a 200 mg, 400 mg or 600 mg loading dose (LD) of amorphous otenaproxesul in an amorphous solid dispersion.

[0024] Figure 8 are graphs showing the comparative plasma H2S (top graph) and M25 (bottom graph) concentrations over the initial 12 hours post-administration to human subjects after administration of the three treatment arms described of Table 23 comprising administration of compositions comprising a 200 mg, 400 mg or 600 mg loading dose (LD) of amorphous otenaproxesul in an amorphous solid dispersion.

[0025] Figure 9 is a graph showing plasma H2S plots of fold increase over baseline for each of the three treatment arms in human subjects described in Table 23.

[0026] Figure 10 is a graph showing plasma concentrations of M25 and H2S over 72- hours following administration to human subjects of a composition comprising 600 mg amorphous solid dispersion of otenaproxesul loading dose (LD).DETAILED DESCRIPTIONI. Definitions

[0027] Unless otherwise indicated, the definitions and embodiments described in this, and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0028] All features disclosed in the specification, including the claims, abstract, and drawings, and all the steps in any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. Each feature disclosed in the specification, including the claims, abstract, and drawings, can be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0029] In understanding the scope of the present application, the term “comprising” and its derivatives, as used herein, are intended to be open-ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words having similar meanings such as the terms, “including”, “having” and their derivatives.

[0030] The term “amorphous solid dispersions of the application” and the like as used herein refers to solid dispersions comprising amorphous, i.e., non-crystalline, otenaproxesul, or pharmaceutically acceptable salt thereof, and a polymer as described herein.

[0031] The term “composition(s) of the application” and the like as used herein refers to a composition, such as a pharmaceutical composition, comprising an amorphous solid dispersion of the application as described herein.

[0032] The term “methods of the application” as used herein refers to methods for treating or preventing acute pain by administration or use of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof including amorphous solid dispersions and compositions thereof described herein.

[0033] The term “consisting” and its derivatives, as used herein, are intended to be closed terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0034] The term “consisting essentially of’, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps as wellas those that do not materially affect the basic and novel characteristic(s) of features, elements, components, groups, integers, and / or steps.

[0035] Terms of degree such as “substantially”, “about” and “approximately” as used herein mean a reasonable amount of deviation of the modified term such that the end-result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0036] As used in this application, the singular forms “a”, “an” and “the” include plural references unless the content clearly dictates otherwise.

[0037] In embodiments comprising an “additional” or “second” component, the second component as used herein is different from the other components or first component. A “third” component is different from the other, first, and second components, and further enumerated or “additional” components are similarly different.

[0038] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present.

[0039] The term “pharmaceutically acceptable salt” means either an acid addition salt or a base addition salt which is suitable for, or compatible with the treatment of subjects.

[0040] An acid addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic acid addition salt of any basic compound.

[0041] A base addition salt suitable for, or compatible with, the treatment of subjects is any non-toxic organic or inorganic base addition salt of any acidic compound.

[0042] The term "protecting group" or "PG" and the like as used herein refers to a chemical moiety which protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in "Protective Groups in Organic Chemistry" McOmie, J.F.W. Ed., Plenum Press, 1973, in Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic Synthesis", John Wiley & Sons, 3rdEdition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0043]

[0044] The term “administered” as used herein means administration of a therapeutically effective amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, or compositions comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof to a cell either in cell culture or in a subject.

[0045] The term “subject” as used herein includes all members of the animal kingdom, including mammals, and suitably refers to humans. In a clinical setting, a subject may also be referred to, interchangeably, as a patient.

[0046] The term “pharmaceutical composition” as used herein refers to a composition of matter for pharmaceutical use.

[0047] The term “pharmaceutically acceptable” means compatible with the treatment of subjects.

[0048] The term “parenteral” as used herein means taken into the body or administered in a manner other than through the gastrointestinal tract.

[0049] The term “oral” as used herein means taken into the body or administered in a manner that the compound or drug passes through the gastrointestinal tract.

[0050] The terms “to treat”, “treating” and “treatment” as used herein and as is well understood in the art, means an approach for obtaining beneficial or desired results, including clinical results. Examples of beneficial or desired clinical results include, but are not limited to diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, preventing spread of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “To treat”, “treating” and “treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. “To treat”, “treating” and “treatment” as used herein also includes prophylactic treatment.

[0051] The term “treatment period” as used herein refers to the total time period during which a subject is treated using a method of the application.

[0052] “Palliating” a disease, disorder or condition means that the extent and / or undesirable clinical manifestations of a disease, disorder or condition are lessened and / ortime course of the progression is slowed or lengthened, as compared to not treating the disease, disorder or condition.

[0053] The term “prevention” or “prophylaxis”, or synonym thereto, as used herein refers to a reduction in the risk or probability of a subject becoming afflicted with a disease, disorder or condition or manifesting a symptom associated with a disease, disorder or condition.

[0054] As used herein, the term “effective amount” or “therapeutically effective amount” means an amount of the one or more amorphous solid dispersions of the application or compositions of the application, that is effective, at dosages and for periods of time necessary to achieve a desired result.

[0055] The term “administered” as used herein means administration of a therapeutically effective amount of one or more amorphous solid dispersions of the application or one or more compositions of the application to a cell either in cell culture or in a subject.

[0056] When used in reference to a peak in the DSC thermogram, the term "about" means that the peak may vary by + / - 1 °0 of the subject value.

[0057] As used herein when referring to a diffractogram, spectrum and / or to data presented in a graph, the term "peak" refers to a feature that one skilled in the art would recognize as not attributing to background noise.

[0058] The term “enhanced bioavailability” as used herein refers to any detectable increase (e.g., plasma levels) of otenaproxesul or metabolite thereof following administration one or more amorphous solid dispersions of the application or one or more compositions of the application compared to the levels (e.g., plasma levels) of otenaproxesul or metabolite thereof following administration of crystalline otenaproxesul under otherwise identical conditions.

[0059] The term “treating acute pain” as used herein means any detectable reduction, for example, in the sensation or duration of acute pain after administration or use of a compound or composition, in this case amorphous otenaproxesul, compared to otherwise the same conditions except in the absence of administration or use of the compound or compositions, for example, amorphous otenaproxesul.

[0060] When used, for example, with respect to the methods of treatment, uses, compositions, packages and / or kits of the application, a subject, for example a subject “in need thereof’ is a subject experiencing or expected to experience acute pain or any subject that would benefit from administration of otenaproxesul, or a pharmaceutically acceptable salt thereof.

[0061] The term “otenaproxesul” as used herein refers to a compound having the chemical name: (S)-4-carbamothioylphenyl 2-(6-methoxynaphthalen-2-yl) propanoate, and having the structural formula:Otenaproxesul is also known as “ATB-346” and under the chemical name (S)-2-(6-methoxy- naphthalen-2-yl)-propionic acid 4-thiocarbamoyl-phenyl ester.

[0062] The term “otenaproxesul-amide” as used herein refers to a compound having the chemical name: 4-carbamoylphenyl (S)-2-(6-methoxynaphthalen-2-yl)propanoate and having the structural formula:

[0063] The term “alanine aminotransferase” or “ALT” as used herein refers to an enzyme that catalyzes the transfer of an amino group from L-alanine to a- ketoglutarate to produce pyruvate and L-glutamate.

[0064] The term “aspartate aminotransferase” or “AST” as used herein refers to an enzyme that catalyzes the transfer of an amino group from aspartate to a-ketoglutarate to produce oxaloacetate and glutamate.

[0065] The term "bilirubin” as used herein refers to a catabolite of heme that is cleared from the body by the liver.

[0066] The term “alkaline phosphatase” or “ALP” as used herein refers to an enzyme that hydrolyzes phosphate groups from various molecules and is present in the cells lining the biliary ducts of the liver.

[0067] The term “thromboxane B2” or “TXB2” as used herein refers to an inactive metabolite of thromboxane A2.

[0068] The term “thromboxane A2” as used herein refers to a type of thromboxane synthesized in platelets, via cyclo-oxygenase-1 , that causes blood clotting and constriction of blood vessels.

[0069] The term “AUC” as used herein refers to the area under the curve of a concentration versus time graph (a concentration-time curve) which represents levels of a compound in the blood (e.g., plasma levels) as a function of time following administration and can be determined by measuring plasma levels of the compound at various time points following administration.

[0070] The term "AUCo-iast” as used herein describes the area under the concentrationtime curve up to the last quantifiable time-point post-administration of a dose. AUCo-iast” is “AUCo-t” when time t is the last quantifiable time-point.

[0071] The term "AUCo-t” as used herein describes the area under the concentrationtime curve from time zero (e.g., dosing) to time “t” post-dosing.

[0072] The term “AUC0-inf” or “AUC0-co” as used herein means an estimate of area under the concentration-time curve from time zero (e.g., dosing) to infinity.

[0073] The term “Tmax” as used herein refers to the time which elapses after administration of a compound at which the concentration of the compound or metabolite thereof in the blood (e.g., plasma level) attains the maximum concentrations.

[0074] The term “Cmax” refers to the maximal concentration of a compound in the blood (e.g., plasma levels), and can be determined by measuring levels of the compound at various time points following administration.

[0075] The term “C60” refers to the concentration of a compound in the blood (e.g., plasma levels) at 60 minutes following administration of the compound.

[0076] The term “steady state” as used herein refers to a state in which the amount of the compound reaching the system is approximately the same as the amount of the compound leaving the system.

[0077] The term “naproxen” or “M25” as used herein refers to a compound having the IUPAC name: (2S)-2-(6-methoxynaphthalen-2-yl) propanoic acid, and having the chemical formula:and which is a metabolite of otenaproxesul.

[0078] The term “cumulative drug exposure” or “cumulative naproxen metabolite exposure” as used herein means the total amount of a compound or metabolite thereof in the blood (e.g., plasma levels) after administration of the compound which may be available for uptake by tissues over a specific time course. Cumulative drug exposure is measured in |j.g*hr / mL as a function of the concentration of drug times volume of a subject’s plasma, over time, and can be estimated using the formula:(AUCO-24 x T-1) + AUCo-infwherein T is the number of treatment days (e.g. “treatment period”). For example, the cumulative drug exposure resulting from a 7 day treatment period providing a daily steady state AUC0.24 Of 250 |j.g*hr / mL and a AUC0-inf on the last day of treatment of 400 |j.g*hr / mL is 1900 |jg*hr / mL (e.g., (250 |j.g*hr / mL X 6) + 400 |j.g*hr / mL).

[0079] The term “loading dose” as used herein refers to dose of a compound / drug which is given before, at the time of and / or shortly after the onset of the acute pain and is greaterthan the maintenance dose(s) if being used. There are either one ortwo loading doses and each may be the same or different but both are greater than any of the maintenance doses, if being used.

[0080] The term “maintenance dose” as used herein refers to a dose of a compound / drug that follows a loading dose and that is lower than the loading dose.

[0081] The term “tapering” or “tapered” as used herein with respect to doses means to gradually decrease the dosage amount of a compound / drug overtime. Therefore a tapered dose is a dose that is less than the previous dose.

[0082] The term “treatment period interval” or “interval of time between treatment periods” as used herein means the interval of time after administration of the last dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof in a treatment period and the first dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof in a subsequent treatment period during which no amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is administered.

[0083] The term “spray-dried dispersion” as used herein means a product of a spraydrying process wherein the product comprises a dispersion of one or more compounds and at least one other component, such as a polymer.

[0084] The term “solid dispersion” as used herein refers to a compound molecularly dispersed with a polymer.

[0085] The term “molecularly dispersed”, as used herein, refers to the random distribution of a compound with a polymer.

[0086] The term “amorphous solid dispersion” as used herein means that the solid dispersion contains the compound in a substantially amorphous solid state form.

[0087] As used herein, the term “amorphous” or “amorphous form” “amorphous solid state form” refers to a compound that is in a non-crystalline state. It is noted that the phrase “amorphous solid” is sometimes used in the art to refer to a crystal form with disorganized small crystals (typically resulting from rapid small scale drying). This latter meaning is not theintended usage in this application as such an amorphous solid comprises crystals and is not the substantially amorphous form of the invention.

[0088] The term “excipient” as used herein means a therapeutically non-active ingredient which facilitates aspects of manufacturing, stability, dissolution of tablets.

[0089] The term "HPMCAS" as used herein refers to the polymer hydroxypropylmethylcellulose acetate succinate which is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethylcellulose.

[0090] The term “PVPVA” or “PVPA / A” or “polyvinylpyrrolidone-vinyl acetate” as used herein refers to the polymer poly(1-vinylpyrrolidone-co-vinyl acetate).

[0091] The term “sustaining agent” as used herein means an agent that sustains the dissolution rate of the compound and may include a polymer.

[0092] The term “D50” as used herein refers the diameter value for the particles in a material at which about 50% of the particles have a diameter below the diameter value.

[0093] The term “D90” as used herein refers the diameter value for the particles in a material at which about 90% of the particles have a diameter below the diameter value.

[0094] The acronym "XRPD" means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the presence of a solid component. Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. Materials with similar unit cells will give powder patterns that are similar in position as measured in °20 (theta). The intensity of the reflections varies according to the electron density causing diffraction as well as sample, sample preparation, and instrument parameters. Analysis of XRPD data is based upon the general appearance of the measured powder pattern(s) with respect to the known response of the X-ray diffraction system used to collect the data. For diffraction peaks that may be present in the powder pattern, their positions, shapes, widths and relative intensity distributions can be used to characterize the type of solid state order in the powder sample. The position, shape and intensity of any broad diffuse scatter (halos) on top of the instrumental background can be used to characterize the level and type of solid state disorder. The combined interpretation of the solid state order and disorder present in a powder sample provides a qualitative measure of the macro-structure of the sample.II. Methods and uses of the application

[0095] Otenaproxesul is an analgesic and anti-inflammatory H2S-releasing analogue of naproxen which has been shown to have an enhanced ability to suppress cyclooxygenase- 2 (COX-2) activity and / or cyclooxygenase 1 (COX-1) activity and also an increased anti-inflammatory activity when compared to naproxen alone. Otenaproxesul also has greatly reduced gastrointestinal (Gl) damaging effects compared to naproxen.

[0096] Otenaproxesul was studied in a phase I escalating dose clinical trial wherein a single dose of crystalline otenaproxesul ranging from 25 mg to 2000 mg was administered orally. All dose levels were found to be very well tolerated and shown to be safe. Subsequent placebo-controlled phase 2 clinical dose-range finding efficacy studies in patients having osteoarthritis pain in the knee validated the efficacy of otenaproxesul in reducing osteoarthritis pain.

[0097] However, analysis of liver injury test results, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) observed during one of the phase 2 studies showed that while these tests were found to be normal for the majority of patients in the study, a dose-related liver transaminase elevation (LTE), for example, of ALT and AST levels, in approximately 10% of the patients, was observed after the patients had completed their full treatment course (e.g., at ten days or more after treatment with otenaproxesul had been completed.

[0098] After further analysis of the results of all clinical studies, it was found that the LTE’s are not detected after single dose administration of crystalline otenaproxesul of 25 mg to 2000 mg or after multiple dose administration of crystalline otenaproxesul at doses of 150 mg, 200 mg or 250 mg for treatment periods of 14 days or less, such as seven days or less. Additionally, analysis of the liver injury test results indicates that LTEs are not observed when the cumulative plasma drug exposure ofthe primary otenaproxesul metabolite, naproxen, over the prescribed treatment does not exceed about 4000 |j.g*hr / mL. Analysis of the naproxen metabolite plasma levels during the Phase 2 clinical trials also revealed that a naproxen metabolite plasma concentration of about >10 to about 15 pg / mL is associated with a therapeutic effect (i.e., pain relief), at least in association with the release of H2S from the parent compound otenaproxesul.

[0099] The Applicant has developed and investigated amorphous otenaproxesul, in particular amorphous otenaproxesul in amorphous solid dispersions, and has found that amorphous solid dispersions of otenaproxesul have an unexpectedly large increase in solubility in biologically relevant media as well as a faster release profile and enhanced bioavailability (for example, as measured using levels of naproxen metabolite) compared to crystalline otenaproxesul, even when the crystalline form was milled or micro-milled, Since the amorphous solid dispersions and compositions ofthe application have an increased solubility and provide a faster release profile and enhanced bioavailability compared to crystalline otenaproxesul, a lower amount of amorphous otenaproxesul comprised in an amorphous soliddispersion or composition of the application is needed to achieve a beneficial effect compared to a dose of crystalline otenaproxesul needed to achieve the same beneficial effect. This results in a lower risk of adverse events such as LTEs, a faster onset of action and a greater patient compliance by providing a reduced pill burden (e.g., lower number of oral compositions of the application required per day).

[0100] The Applicants have further found that although the amorphous solid dispersions of otenaproxesul demonstrate an enhanced absorption and initial plasma exposures on Day 1 of naproxen compared to crystalline otenaproxesul, the amorphous solid dispersions of otenaproxesul surprisingly demonstrated lower steady state (e.g, Day 4) exposures compared to crystalline otenaproxesul. With a lower overall cumulative naproxen and by extrapolation H2S exposure in plasma, concomitant lower liver exposure to exogenous H2S associated with otenaproxesul and in turn fewer liver-adverse events, would be expected with the use of amorphous solid dispersions of otenaproxesul compared to administration or use of crystalline otenaproxesul.

[0101] The Applicant has further investigated dosage regimens for treating acute pain using amorphous otenaproxesul formulated as amorphous solid dispersion. Dosage regimens were developed to provide levels of naproxen expected to be concomitant with pain relief within 60 to 90 minutes after administration, and sustained pain relief while advantageously mitigating the liver adverse events observed with sustained higher doses of otenaproxesul.

[0102] Initial dosage regimens were developed and investigated using amounts of otenaproxesul in amorphous solid dispersions and compositions thereof based on animal (rat and dog) pharmacokinetic studies previously described in Applicant’s co-pending PCT patent application no. PCT / CA2023 / 051347. These clinical investigations used a loading dose comprising up to 600 mg of otenaproxesul in an amorphous solid dispersion. Unexpectedly, when these dosage regimens were tested in human studies, it was found that the naproxen metabolite (M25) underwent faster plasma elimination resulting in lower overall AUC exposures than predicted from the animal studies. The faster elimination of naproxen metabolite decreases overall AUC exposure and therefore increases the safety factor of the dosage regimens. This advantageously suggested that dosing regimens comprising a loading dose with higher amounts of otenaproxesul in an amorphous solid dispersion than predicted from the animal studies (e.g. greater than 600 mg) can be administered without liver adverse events. Accordingly, the Applicants further investigated dosage regimens for treating or preventing acute pain using loading doses comprising greater than 600 mg amorphous otenaproxesul in amorphous solid dispersions and compositions thereof which would provide higher amounts of naproxen within 60 - 90 minutes or less after administration along withexpected improved levels of concomitant pain relief, and unexpectedly without liver adverse events.

[0103] Accordingly, the present application includes modified treatment protocols comprising amorphous otenaproxesul that are designed for the treatment of acute pain, for example, peri-operative pain, pain associated with trauma or injury, or pain associated with diseases, disorders or conditions, such as migraine or gout. In the modified treatment protocols the use or administration comprises dosage amounts of amorphous otenaproxesul and timings to provide a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0104] Therefore, the present application includes a method of treating or preventing acute pain in a subject in need thereof comprising: administering one or two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 14 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0105] The present application also includes a use of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof for treating or preventing acute pain, wherein the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for use in one or two oral loading doses independently comprising greater than 600 mg of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, optionally followed by one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for use for a treatment period of 14 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0106] The present application also includes a use of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof for preparation of a medicament for treating or preventing acute pain, wherein the amorphous otenaproxesul or a pharmaceuticallyacceptable salt thereof is for use in one or two oral loading doses independently comprising greater than 600 mg of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, optionally followed by one or more maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for use for a treatment period of 14 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0107] The present application also includes amorphous otenaproxesul or a pharmaceutically acceptable salt thereof for use to treat or prevent acute pain, wherein the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is used in a dosage regiment comprising: administration of one or two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administration of one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 14 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL

[0108] In some embodiments, the acute pain is pain that is expected to resolve in a short period of time, for example, 28 days or less, 21 days or less or 14 days or less.

[0109] In some embodiments, the methods and uses provide a plasma concentration of naproxen metabolite of about 10 pg / mL or greater, about 15 pg / mL or greater or about 20 pg / mL or greater, in about 30 minutes or less, or in about one hour or less. In some embodiments, the method provides a plasma concentration of naproxen metabolite of about 15 pg / mL or greater in about 30 minutes or less, or in about one hour or less. In some embodiments, the method provides a plasma concentration of naproxen metabolite of about 10 pg / mL or greater or about 15 pg / mL or greater in about one hour or less. In some embodiments, the methods and uses provide a plasma concentration of naproxen metabolite of about 10 pg / mL or greater, about 15 pg / mL or greater or about 20 pg / mL or greater, for approximately the length of the treatment period. In some embodiments, the plasma concentration of naproxen metabolite of about 10 pg / mL or greater, about 15 pg / mL or greater or about 20 pg / mL or greater is concomitant with relief of acute pain.Treatment Indications

[0110] In some embodiments, the acute pain is selected from, but not limited to, postoperative pain, peri-operative pain, dysmenorrhea, interstitial cystitis, headache including migraine, pain due to a trauma, renal or biliary colic, arthritis, dental pain, musculoskeletal pain, lower back pain, fibromyalgia, pain of infectious origin, pain resulting from cancer and pain induced by gout, or combinations thereof.

[0111] In some embodiments, the post-operative pain is pain following a surgery selected from, but not limited to orthopedic, abdominal, pelvic, dental, plastic, cosmetic, neurological, urological, bariatric, gastric, cardiac, orthoscopic, vascular, endovascular, laparoscopic, oncological, colorectal, podiatric, ocular, otoplastic, rhinoplastic, and throat surgery, or combinations thereof.

[0112] In some embodiments, the orthopedic surgery is selected from, but not limited to, bunionectomy total hip, total knee, bilateral total knee, spine, shoulder, ankle, soft tissue surgeries, spinal fusion, rotator cuff repair, laminectomy, fracture repair, and discectomy. In some embodiments, the orthopedic surgery is bunionectomy or combinations thereof. Therefore, in some embodiments, the acute pain is post-operative pain from a bunionectomy.

[0113] In some embodiments, the abdominal and / or pelvic surgery is selected from, but not limited to, abdominoplasty, inguinal hernia repair such as open inguinal hernectomy, abdominal hysterectomy, abdominal laparotomy, cholecystectomy, vaginal hysterectomy, ventral hernia repair, myomectomy, salpingo-oophorectomy, bariatric, partial colectomy surgeries, and gynecologic or genitourinary surgery, or combinations thereof. In some embodiments, the abdominal and / or pelvic surgery is inguinal hernia repair. In some embodiments, inguinal hernia repair is open inguinal herniotomy. In some embodiments, the abdominal and / or pelvic surgery is abdominoplasty, or combinations thereof.

[0114] In some embodiments, the acute pain is headache pain including migraine, photophobia and phonophobia. In some embodiments, the acute pain is migraine pain.

[0115] In some embodiments, the post-operative pain is pain resulting from dental surgery.

[0116] In some embodiments, the acute pain is dental pain.

[0117] In some embodiments, the acute pain is dysmenorrhea. In some embodiments, the acute pain is primary or secondary dysmenorrhea. In some embodiments, the acute pain is primary dysmenorrhea.

[0118] In some embodiments, the acute pain is recurrent pain (optionally flare up pain). Accordingly, in some embodiments, the method comprises repeating the treatmentperiod to treat recurrent pain. In these embodiments, the treatment period is repeated after a "drug holiday" or a period of no administration of any doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof or, for example, administration of placebo doses. In some embodiments, the treatment period is repeated as needed (for example, when the recurrent pain occurs). In some embodiments, the period of no administration of any doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for 3 days to about 30 days. In some embodiments, the treatment periods are repeated for as long as treatment is needed, for example, for many months or years.

[0119] In some embodiments, the recurrent pain comprises any acute pain treatable by inhibition of COX-1 and / or COX-2 that can re-occur. In some embodiments, the recurrent pain comprises acute pain associated with chronic pain conditions. In some embodiments, the recurrent pain comprises any acute pain associated with, but not limited to osteoarthritis, urinary tract infections, acute exacerbations of chronic obstructive pulmonary disease, headaches (such as migraines) and dysmenorrhea.

[0120] In some embodiments, acute pain is any corresponding version of acute pain that is identified in a pediatric population.

[0121] In some embodiments, the acute pain is post-operative pain and the one and optionally two oral loading doses are administered about 24 hours, about 20 hours, about 16 hours, about 14 hours or about 12 hours before surgery. In some embodiments, the acute pain is post-operative pain, and the one ortwo oral loading doses are administered on the day of the surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administered before the surgery on the day of the surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administered about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 hours or about 1 hour to about 2 hours before surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administered about 8 hours, about 6 hours, about 5 hours, about 4 hours, about 2 hours or about 1 hour before surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administered during the surgery. In some embodiments, the acute pain is post-operative pain and one loading dose is administered after the surgery on the day of the surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administered immediately after surgery. In some embodiments, the acute pain is postoperative pain and one oral loading dose is administered about 30 minutes to about 8 hours after surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administered about 1 hour to about 6 hours after surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administeredabout 2 hours, about 3 hours, or about 4 hours after surgery. In some embodiments, the acute pain is post-operative pain and one oral loading dose is administered during surgery.

[0122] In some embodiments, the acute pain is post-operative pain and the method comprises administering two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, the two oral loading doses are a first and a second oral loading dose. Accordingly, in some embodiments, the method comprises administering a first oral loading dose comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and followed by administering a second oral loading dose comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, the two loading oral doses are administered at times selected from before, during and after the surgery. In some embodiments, the second oral loading dose is administered on the second, third, fourth, fifth, sixth or seventh day, optionally on the second day after administration of the first oral loading dose. In some embodiments, the method comprises administering the second oral loading dose on the third day or fourth day after administration of the first oral loading dose.

[0123] In some embodiments, the acute pain is trauma, and the one and optionally two oral loading doses are administered after the trauma on the day the trauma was induced. In some embodiments, one oral loading dose is administered 15 minutes to about 20 hours, about 15 minutes to about 25 hours, about 30 minutes to about 18 hours, about 30 minutes to about 12 hours, about 30 minutes to about 6 hours, about 30 minutes to about 4 hours, about 1 hour to about 6 hours or about 1 hour to about 4 hours after trauma.

[0124] In some embodiments, the one and optionally two oral loading doses are administered in advance of expected or possible trauma, such as in the cases of entry into situations that are at high risk for trauma. In some embodiments, one oral loading dose is administered about 24 hours, about 20 hours, about 16 hours, about 14 hours or about 12 hours before expected or possible trauma. In some embodiments, one oral loading dose is administered before the expected or possible trauma on the day of the expected or possible trauma. In some embodiments, one oral loading dose is administered about 1 hour to about 8 hours, about 1 hour to about 6 hours, about 1 hour to about 4 hours, about 1 hour to about 3 or about 1 hour to about 2 hours before the expected or possible trauma. In some embodiments, one oral loading doses is administered about 8 hours, about 6 hours, about 5 hours, about 4 hours, about 2 hours or about 1 hour before he expected or possible trauma.

[0125] In some embodiments, the acute pain is trauma and the method comprises administering two oral loading doses independently comprising greater than 600 mg ofamorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, the two oral loading doses are a first and a second loading dose. Accordingly, in some embodiments, the method comprises administering a first oral loading doses comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and followed by administering a second oral loading doses comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, the two oral loading doses are administered at times selected from before, during and after the trauma. In some embodiments, the second oral loading dose is administered on the second, third, fourth, fifth, sixth or seventh day, optionally on the second day after administration of the first oral loading dose. In some embodiments, the method comprises administering the second oral loading dose on the third day or fourth day after administration of the first oral loading dose.

[0126] The methods and uses of the application are for treating all severities of pain.

[0127] It would be appreciated by a person skilled in the art that pain rating scales are well known and used in daily clinical practice to measure pain intensity. For example, commonly used measurement scales include the Visual Analog Scale (VAS), the Graphic Rating Scale (GRS), the Simple Descriptor Scale (SDS), the Numerical Rating Scale (NRS), the Faces Rating Scale (FRS) and Total Pain Relief (TOTPAR) and / or Sum of Pain Intensity Difference (SPID). Particularly in acute pain, Total Pain Relief (TOTPAR) and / or Sum of Pain Intensity Difference (SPID) are the metrics commonly used to assess pain in the art. Numeric Rating Scales (NRS) which are similar to VAS in acute pain trials are also available. In some embodiments, the visual analog scale (VAS) is a 10 cm. vertical or horizontal line with word anchors at the extremes, such as “no pain” on one end and “pain as bad as it could be” at the other. The patient is asked to make a mark along the line to represent pain intensity. In the Visual Analog Scale (VAS), moderate or severe pain is defined as a pain intensity of > about 50 mm on a 0-100 mm visual analog scale (VAS). In some embodiments, moderate pain is characterized as a pain intensity of > about 50 mm and < about 70 mm on a 1-100 mm VAS. And severe pain is characterized as a pain intensity of > about 70 mm on a 1 -100 mm VAS. The graphic rating scale (GRS) is a variation of the visual scale which adds words such as include “no pain”, “mild”, “severe or numbers between the extremes. The descriptor scale (SDS) is a list of adjectives such as “no pain”, “mild”, “moderate” or “severe describing different levels of pain intensity. The numerical pain rating scale (NPRS) refers to a numerical rating of 0 to 10 or 0 to 5 or to a visual scale with both words and numbers. A visual analogue scale (VAS) version of the Western Ontario and McMaster Universities Arthritis Index (WOMAC) is also commonly used.

[0128] In some embodiments, treatment of the subject is assessed using one or more biomarkers known to represent activation of pathways that result in pain reduction, including but not limited to, plasma levels of thromboxane B2(TXB2), prostaglandin E2(PGE2), interleukin 1 Beta (IL-1 p), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-a) and / or C- reactive protein (CRP). Levels of these markers that are indicative of a pain reduction response are known in the art as are methods to detect their levels in a subject.

[0129] Accordingly, in some embodiments, the acute pain is mild to moderate, moderate to moderately severe or moderately severe to severe.Loading Doses

[0130] In some embodiments, each loading dose, for example one oral loading dose, provides a plasma concentration of naproxen, a metabolite of otenaproxesul, of about 10 pg / mL or greater, about 15 pg / mL or greater, or about 20 pg / mL or greater, 30 minutes or less, or about 45 minutes or less, about 60 minutes or less, about 75 minutes or less, about 90 minutes or less after administration. In some embodiments, each loading dose provides a plasma concentration of naproxen of about 10 pg / mL or greater, about 15 pg / mL or greater, or about 20 pg / mL or greater in about 60 minutes or less after administration. In some embodiments, each loading dose provides a plasma concentration of naproxen of about 10 pg / mL or greater or about 15 pg / mL or greater in about 60 minutes or less after administration.

[0131] In some embodiments, each oral loading dose comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof provides a plasma concentration of naproxen that is greater than a plasma concentration of naproxen provided by a loading dose comprising crystalline otenaproxesul or a pharmaceutically acceptable salt thereof under otherwise identical conditions and equivalent doses of otenaproxesul or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, each oral loading dose comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof provides a Ceo of naproxen of about 10 pg / mL or greater, about 15 pg / mL or greater or about 20 pg / mL or greater, after administration.

[0133] In some embodiments, each oral loading dose comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof provides a C60of naproxen that is greater compared to a C60of naproxen provided by a loading dose comprising crystalline otenaproxesul or a pharmaceutically acceptable salt thereof under otherwise identical conditions and equivalent doses of otenaproxesul or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, each oral loading dose comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof provides a C60of naproxen that is greater compared to a C60of naproxen provided by crystalline otenaproxesul after oral administration under otherwise identical conditions and equivalent doses of otenaproxesul.

[0135] In some embodiments, each oral loading dose comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof provide a C60of naproxen that is about 3 to about 12, about 4 to about 10, about 5 to about 10, about 4 to about 8, about 5 to about 9 or about 6 to about 9 times greater compared to a Ceo of naproxen provided by a loading dose comprising crystalline otenaproxesul or a pharmaceutically acceptable salt thereof after oral administration under otherwise identical conditions and equivalent doses of otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, one oral loading dose, optionally each oral loading dose, comprising amorphous otenaproxesul or a pharmaceutically acceptable salt thereof provides a plasma concentration of naproxen metabolite of 15 pg / mL or greater within about 30 minutes to about 1 hour after administration.

[0136] Any method for determination of plasma concentration of naproxen metabolite may be used. In some embodiments, the method used to determine plasma concentration of naproxen metabolite is a LC-MS-MS method. In some embodiments, the method used to determine plasma concentration levels is provided in Nucro-Technics Bioanalytical Report No. 345625 entitled “LC-MS / MS method development and quantification of naproxen, desmethyl naproxen (M20), and desmethyl naproxen sulfate (M26) in human plasma samples (Non- GLP)”, 2018, which discloses for Sample Preparation and Extraction: A 75 pL aliquot of each sample (calibration standards / quality controls / samples) was aliquoted into pre-labelled tubes. To each aliquoted sample, 300 pL of working internal standard (IS) solution (500 ng / mL of IS in acetonitrile / methanol, 75 / 25, v / v) was added (Exception: 300 pL of acetonitrile / methanol (75 / 25, v / v) was added to double blank). All tubes were vortexed adequately, followed by centrifugation at 13000 rpm for 5 minutes. A 150 pL aliquot of the organic supernatant was transferred to clean glass tubes. After evaporation at 40°C, the dry residues were reconstituted in 300 pL of USP Purified Water, followed by adequate vortexing. The prepared samples were injected into an LC-MS / MS system which comprised a 6400 Series MS / MS instrument coupled to an Agilent Model 1200 Series liquid chromatography pump and a CTC PAL autosampler. The sample run time was 9.5 minutes on an ACE 5 C18 column (50 x 2.1 mm; 5 uM) using a gradient mixture. Mobile phase A consisted of 6% methanol, 2% acetonitrile and 5mM ammonium acetate; Mobile phase B consisted of 90% acetonitrile and 5 mM ammonium acetate.

[0137] In some embodiments, the method comprises administering two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or apharmaceutically acceptable salt thereof. In some embodiments, the two oral loading doses are a first and a second oral loading dose. Accordingly, in some embodiments, the method comprises administering a first oral loading doses comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering a second oral loading doses comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the second loading oral dose is administered on the third, fourth, fifth, sixth or seventh day, optionally on the third, fourth, fifth, sixth after administration of the first loading dose. In some embodiments, the method comprises administering the second loading oral dose on the third day or fourth day after administration of the first oral loading dose.

[0139] In some embodiments, the method further comprises administering one or more placebo doses after administration of the first oral loading dose. In some embodiments, the one or more placebo doses are administered at intervals of about 6 hours, about 12 hours, about 18 hours, about 24 hours or about 36 hours or combinations thereof after administration of the first oral loading dose until the end of the treatment period. In some embodiments, the one or more placebo doses are administered at intervals of about 12 hours after or about 24 hours or combinations thereof after administration of the first oral loading dose until the end of the treatment period.

[0140] In some embodiments, the method comprises administering two oral loading doses, and the method further comprises administering one or more placebo doses after administration of the first oral loading dose, and optionally one or more times after administration of the second oral loading dose until the end of the treatment period. In some embodiments, the one or more placebo doses are administered at intervals of about 6 hours, about 12 hours, about 18 hours, about 24 hours or about 36 hours or combinations thereof after administration of the first oral loading dose until administration of the second oral loading dose, and optionally at intervals of about 6 hours, about 12 hours, about 18 hours, about 24 hours or about 36 hours orcombinations thereof after administration of the second oral loading dose until the end of the treatment period. In some embodiments, the one or more placebo doses are administered at intervals of about 12 hours after or about 24 hours or combinations thereof after administration of the first oral loading dose until administration of the second oral loading dose, and optionally at intervals of about 12 hours or about 24 hours or combinations thereof after administration of the second oral loading dose until the end of the treatment period.

[0141] In some embodiments, the one or two oral loading doses independently comprise about 625 mg or greater, about 650 mg or greater, about 675 mg or greater, about 700 mg or greater, about 725 mg or greater, about 750 mg or greater, about 775 mg or greater, about 800 mg or greater, about 825 mg or greater, about 850 mg or greater, about 875 mg or greater, about 900 mg or greater, about 925 mg or greater, about 950 mg or greater, about 1000 mg or greater, about 1025 mg or greater, about 1050 mg or greater, about 1075 mg or greater, about 1 100 mg or greater, about 1125 mg or greater, about 1150 mg or greater, about 1175 mg or greater, about 1200 mg or greater, about 1225 mg or greater, about 1250 mg or greater, about 1275 mg or greater, about 1300 mg or greater, about 1325 mg or greater, about 1350 mg or greater, about 1375 mg or greater, about 1400 mg or greater, about 1425 mg or greater, about 1450 mg or greater about 1475 mg or greater or about 1500 mg or greater of amorphous otenaproxesul. In some embodiments each of the one or two oral loading dose comprises about 625 mg or greater, about 650 mg or greater, about 675 mg or greater, about 700 mg or greater, about 725 mg or greater, about 750 mg or greater, about 775 mg or greater, or about 800 mg or greater of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, the one or two oral loading doses independently comprise about 625 mg to about 2000 mg, about 650 mg to about 2000 mg, about 675 mg to about 2000 mg, about 700 mg to about 2000 mg, about 725 mg to about 2000 mg, about 750 mg to about 2000 mg, about 775 mg to about 2000 mg, about 800 mg to about 2000 mg, about 825 mg to about 2000 mg, about 850 mg to about 2000 mg, about 875 mg to about 2000 mg, about 900 mg to about 2000 mg, about 925 mg to about 2000 mg, about 950 mg to about 2000 mg, about 1000 mg to about 2000 mg, about 1250 mg to about 2000 mg, about 1500 mg to about 2000 mg, about 625 mg to about 1500 mg, about 650 mg to about 1500 mg, about 675 mg to about 1500 mg, about 700 mg to about 1500 mg, about 725 mg to about 1500 mg, about 750 mg to about 1500 mg, about 775 mg to about 1500 mg, about 800 mg to about 1500 mg, about 825 mg to about 1500 mg, about 850 mg to about 1500 mg, about 875 mg to about 1500 mg, about 900 mg to about 1500 mg, about 925 mg to about 1500 mg, about 950 mg to about 1500 mg, about 1000 mg to about 1500 mg, about 625 mg to about 1000 mg, about 650 mg to about 1000 mg, about 675 mg to about 1000 mg, about 700 mg to about 1000 mg, about 725 mg to about 1000 mg, about 750 mg to about 1000 mg, about 775 mg to about 1000 mg, about 800 mg to about 1000 mg, about 825 mg to about 1000 mg, about 850 mg to about 1000 mg, about 875 mg to about 1000 mg, about 900 mg to about 1000 mg, about 925 mg to about 1000 mg or about 950 mg to about 1000 mg of amorphous otenaproxesul. In some embodiments, the one or two oral loading doses independently comprise about 650 mg to about 2000 mg, about 700 mg to about 2000 mg, about 750 mg to about 2000 mg, about800 mg to about 2000 mg, about 825 mg to about 2000 mg, about 850 mg to about 2000 mg, about 700 mg to about 1500 mg, about 750 mg to about 1500 mg, about 800 mg to about 1500 mg, about 850 mg to about 1500 mg, about 900 mg to about 1500 mg, about 950 mg to about 1500 mg or about 1000 mg to about 1500 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0143] In some embodiments, the one or two oral loading doses independently comprise about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1 175 mg about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg3about 1475 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg or about 2000 mg of amorphous otenaproxesul. In some embodiments, the one or two oral loading doses independently comprise about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg about 925 mg, about 950 mg, about 975 mg, or about 1000 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0144] In some embodiments, the second oral loading dose comprises the same amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof as the first oral loading dose. In some embodiments, the second oral loading dose comprises a lower amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof than the first loading dose.Maintenance Doses

[0145] In some embodiments, the method comprises administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the method comprises administering one oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. Therefore, in some embodiments, the method comprises administering one oral loading dose comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof,followed by administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0147] In some embodiments, the method comprises administering two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. Therefore, in some embodiments, the method comprises administering two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0148] In some embodiments, the one or two oral loading doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof comprise a greater amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof than each of the one or more oral maintenances doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0149] In some embodiments, the one or two oral loading doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof comprise an amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof as described above.

[0150] A person skilled in the art will understand that there are many possible combinations of oral loading doses and maintenance doses that will provide the desired cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0151] In some embodiments, the one or more oral maintenance doses are administered one or more times per day. In some embodiments, one oral maintenance dose is administered per day. In some embodiments, two or three oral maintenance doses are administered per day. In some embodiments, two oral maintenance doses are administered per day. In some embodiments, one or more oral maintenance doses are administered on consecutive days and / or on non-consecutive days. When the one or more oral maintenance doses are administered on non-consecutive days, it is an embodiment, that an oral placebo dose is administered on the days that the maintenance dose is not administered. Therefore, in some embodiments, the method further comprises administering one or more oral placebo doses. In some embodiments, the one or more oral placebo doses are administered on days or time intervals where no oral maintenance dose is administered. In some embodiments, oneor more placebo doses are administered in place of the one or more oral maintenance doses in a dosing schedule.

[0152] In some embodiments, the one or more oral maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 42 hours, or about 48 hours or combinations thereof after administration of the one or two oral loading doses. In some embodiments, the one or more oral maintenance doses are administered sequentially at intervals of 6 hours, about 12 hours, about 18 hours, about 24 hours or combinations thereof after administration of the one or two oral loading doses. In some embodiments, the one or more oral maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof after administration of the one or two oral loading doses. In some embodiments, the one or more oral maintenance doses are administered sequentially at intervals of about 12 hours after administration of the one or two oral loading doses. In some embodiments, when two oral loading doses are administered (i.e., first and second oral loading doses) the one or more oral maintenance doses are administered at the above intervals after the second loading dose. In some embodiments, when one oral loading dose is administered the one or more oral maintenance doses are administered at the above intervals after the one oral loading dose.

[0153] In an exemplary embodiment, one oral loading dose is administered in the morning and the one or more oral maintenance doses are administered sequentially at intervals of about 12 hours thereafter (e.g., beginning in the evening on the same day).

[0154] In some embodiments, the one or more oral maintenance doses independently comprise about 25 mg to about 425 mg, about 25 mg to about 400 mg, about 50 mg to about 400 mg, about 75 mg to about 400 mg, about 100 mg to about 400 mg, about 125 mg to about 400 mg, about 150 mg to about 400 mg, about 175 mg to about 400 mg, about 200 mg to about 400 mg, about 225 mg to about 400 mg, about 250 mg to about 400 mg, about 300 mg to to about 400 mg, about 350 mg to about 400 mg, about 25 mg to about 350 mg, about 50 mg to about 400 mg, about 75 mg to about 350 mg, about 100 mg to about 350 mg, about 125 mg to about 350 mg, about 150 mg to about 350 mg, about 175 mg to about 350 mg, about 200 mg to about 350 mg, about 225 mg to about 350 mg, about 250 mg to about 350 mg, about 300 mg to to about 350 mg or about 350 mg of amorphous otenaproxesul, or a pharmaceutically acceptable salt thereof. In some embodiments, each oral maintenance dose independently comprises about 25 mg to about 400 mg or about 25 mg to about 350 mg of amorphous otenaproxesul, or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the one or more oral maintenance doses independently comprise about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 425 mg or about 450 mg of amorphous otenaproxesul, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more oral maintenance doses independently comprises about 25 mg, about 50 mg, 100 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, or about 450 mg of amorphous otenaproxesul, or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more oral maintenance doses independently comprises about 25 mg, about 50 mg, 100 mg, about 200 mg, about 300 mg or about 400 mg of amorphous otenaproxesul, or a pharmaceutically acceptable salt thereof.

[0156] In some embodiments, one to twenty, one to nineteen, one to eighteen, one to seventh, one to sixteen, one to fifteen, one to fourteen, one to thirteen, one to twelve, one to eleven, one to ten, one to nine, one to eight, one to seven, one to six, one to five, one to four or one to three oral maintenance doses are administered. In some embodiments, one to fifteen, one to fourteen, one to thirteen, one to twelve, one to eleven one to ten, one to nine or one to seven oral maintenance doses are administered.

[0157] In some embodiments, the one or more oral maintenance doses are the same, i.e., each maintenance dose comprises the same amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more oral maintenances doses are different, i.e., each maintenance dose comprises a different amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, or a number of the one or more maintenance doses are the same but are different from a remaining number of maintenance doses, and the remaining number of maintenance doses are the same or different.

[0158] Therefore, in some embodiments, the one or more oral maintenance doses are different and administering one or more oral maintenance doses comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof comprises administering one or more first oral maintenance doses, followed by one or more second maintenance doses and optionally followed by one or more third oral maintenance up to one or more eighth (optionally, one or more third, one or more fourth, one or more fifth, one or more sixth, one or more seventh or one or more eighth oral maintenance doses) oral maintenance doses each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0159] Accordingly, in some embodiments, administering one or more oral maintenance doses comprises administering one or more first oral maintenance doses, followed by administering one or more second oral maintenance doses, and followed by administering one or more third oral maintenance doses, each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, administering one or more oral maintenance doses comprises administering one or more first oral maintenance doses, followed by administering one or more second maintenance doses, followed by administering or more third oral maintenance doses, and followed by administering one or more fourth oral maintenance doses each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, administering one or more oral maintenance doses comprises administering one or more first oral maintenance doses, followed by administering one or more second oral maintenance doses, followed by administering or more third oral maintenance doses, followed by administering one or more fourth oral maintenance doses and followed by administering one or more fifth oral maintenance doses, each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, administering one or more oral maintenance doses comprises administering one or more first oral maintenance doses, followed by administering one or more second maintenance doses, followed by administering or more third oral maintenance doses, followed by administering one or more fourth oral maintenance doses, followed by administering one or more fifth maintenance doses, and followed by administering one or more sixth oral maintenance doses, each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, administering one or more oral maintenance doses comprises administering one or more first oral maintenance doses, followed by administering one or more second oral maintenance doses, followed by administering or more third oral maintenance doses, followed by administering one or more fourth oral maintenance doses, followed by administering one or more fifth oral maintenance doses, followed by administering one or more sixth oral maintenance doses and administering one or more seventh oral maintenance doses, followed by each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, administering one or more oral maintenance doses comprises administering one or more first oral maintenance doses, followed by administering one or more second oral maintenance doses, followed by administering or more third oral maintenance doses, followed by administering one or more fourth oral maintenance doses, followed by administering one or more fifth oral maintenancedoses, followed by administering one or more sixth oral maintenance doses, followed by administering one or more seventh oral maintenance doses and followed by administering one or more eighth oral maintenance doses, each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0160] In some embodiments, the one or more oral maintenance doses are decreased stepwise by an amount after a suitable period of time. Accordingly, in some embodiments, each of the one or more first, second, and optionally third up to eighth oral maintenance doses is greater than a following maintenance dose (i.e., the one or more maintenance doses are tapered).

[0161] In some embodiments, the one or more oral maintenance doses (optionally, one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eighth oral maintenance doses) are tapered doses, and are decreased stepwise by about 250 mg, about 225 mg, about 200 mg, about 175 mg, about 50 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg or about 25 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof between each dose over a suitable period of time (i.e. between the first and the second and the second and the third oral maintenance doses, and between the third and optional fourth, the optional fourth and optional fifth, the optional fifth and the optional sixth, the optional sixth and the optional seventh, the optional seventh and the optional eighth, oral maintenance doses, and so on to the end of the treatment period). In some embodiments, the one or more oral maintenance doses (optionally one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eighth oral maintenance doses) are decreased stepwise by about 200 mg, about 150 mg, about 100 mg, about 75 mg, about 50 mg or 25 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof over a suitable period of time. In some embodiments, the one or more oral maintenance doses (optionally one or more first maintenance doses and one or more second oral maintenance doses and optionally one or more third up to one or more eighth oral maintenance doses) are decreased stepwise by about 100mg, about 50mg or about 25 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof over a suitable period of time.

[0162] Accordingly, in some embodiments, administering one or more maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof comprises administering one or more first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof,followed by administering one or more second oral maintenance doses comprising about 100 mg to about 350 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more third up to one or more eighth oral maintenance doses comprising about 25 mg to about 150 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0163] In some embodiments, the one or more maintenance doses (one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eighth oral maintenance doses) are not tapered. In some embodiments, one or more of the one or more second up to the optionally one or more eight maintenance dose is greater than a previous maintenance dose. In some embodiments, the one or more first oral maintenance doses are less that the one or more second maintenance doses. In some embodiments, the one or more first oral maintenance doses are less that the one or more second maintenance doses and the one or more second, third and optionally fourth up to eighth maintenance doses are tapered doses. In some embodiments, the one or more first oral maintenance doses are less that the one or more second maintenance doses, and only one first oral maintenance dose is administered.

[0164] Accordingly, in some embodiments, administering one or more maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof comprises administering one first oral maintenance dose comprising about 25 mg to about 400 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more second oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more third up to one or more eighth oral maintenance doses comprising about 25 mg to about 275 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one first oral maintenance dose is less that the one or more second oral maintenance doses and the one or more second and optionally one or more third up to one or more eighth oral maintenance doses are tapered oral doses.

[0165] In some embodiments, one, two, three, four, five or six of each oral maintenance dose is independently administered (optionally, one, two, three, four, five or six of the one or more first, the one or more second oral maintenance doses and optionally oneor more third up to one or more eighth oral maintenance doses dose are independently administered). In some embodiments, one to six, one to five, one to four, one to three, one or two of each oral maintenance doses are administered.

[0166] In some embodiments, the one or more oral maintenance doses (optionally, the one or more first oral maintenance doses, one or more second maintenance doses, optionally one or more third oral maintenance doses up to one or more eight oral maintenance doses) are sequentially increased or decreased by an amount at intervals of about 6 hours to about 72 hours, about 6 hours to about 60 hours, about 6 hours to about 48 hours, about 6 hours to about 36 hours, about 6 hours to about 24 hours, about 6 hours to about 12 hours, about 12 hours to about 72 hours, about 12 hours to about 60 hours, about 12 hours to about 48 hours, about 12 hours to about 36 hours or about 12 hours to about 24 hours, or combinations thereof. In some embodiments, the one or more oral maintenance doses are sequentially increased or decreased stepwise by an amount at intervals of about 6 hours to about 48 hours, about 6 hours to about 36 hours, about 6 hours to about 24 hours, about 12 hours to about 72 hours, about 12 hours to about 48 hours, about 12 hours to about 36 hours or about 12 hours to about 24 hours, or combinations thereof. In some embodiments, the one or more oral maintenance doses are sequentially increased or decreased by an amount at intervals of about 12 hours to about 36 hours. In some embodiments, the one or more oral maintenance doses are increased or decreased stepwise by an amount every about 6 hours, about 12 hours, about 18 hours, about 24 hours, 30 hours, about 36 hours, about 42 hours, about 48 hours, about 54 hours, about 60 hours, or combinations thereof. In some embodiments, the one or more oral maintenance doses are increased or decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours, about 36 hours, about 42 hours, or combinations thereof. In some embodiments, the one or more oral maintenance doses are sequentially increased or decreased stepwise by an amount at intervals of about 12 hours, about 24 hours, about 36 hours or combinations thereof. In some embodiments, when the one or more maintenance doses are tapered, i.e., the one or more oral maintenance doses are sequentially decreased by an amount at the intervals described above.Treatment Period

[0167] In some embodiments, the treatment period is 14 days or less, 13 days or less, 12 days or less, 1 1 days or less, 10 days or less, 9 days or less, 8 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less or 1 day. In some embodiments, the treatment period is 7 days or less, 6 days or less, 5 days or less 4 days or less. In some embodiments, the treatment period is 5 days or less. In some embodiments, the treatment period is 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days,6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the treatment period is for 7 days, 6 days, 5 days or 4 days. In some embodiments, the treatment period is 5 days.Treatment period intervals

[0168] In some embodiments, the methods and uses are repeated. In some embodiments, the methods and uses are repeated once, twice or three times. In some embodiments, the methods and uses are repeated recurrently, for example, weekly, biweekly or monthly. In some embodiments, the methods and uses are repeated after an interval of time after administration of a last dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. In some embodiments, the interval of time between treatment periods is at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 10 days, at least 12 days, at least 14 days, at least 16 days, at least 21 days, at least 28 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days or at least 63 days. In some embodiments, the interval between treatment period is at least 2 days, at least 5 days, at least 7 days, at least 10 days, at least 12 days or at least 14 days.

[0169] It would be appreciated by the skilled person that during the interval of time between treatment periods, no amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is administered. In some embodiments, placebo doses are administered during the interval of time between treatment periods.

[0170] In some embodiments, the repeated methods and uses are the same or the repeated methods and uses are different.Exemplary Dosage Regimens

[0171] In some embodiments, the one or more maintenance doses are tapered. Accordingly, in an exemplary embodiment, the method comprises administering one oral loading dose comprising about 625 mg to about 1500 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more second oral maintenance doses comprising about 100 mg to about 350 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, andoptionally followed by administering one or more third up to one or more eighth oral maintenance doses comprising about 25 mg to about 150 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eight oral maintenance doses are sequentially administered at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof, after administration of the first oral loading dose, and the one or more first and one or more second oral maintenance doses and optionally the one or more third up to one or more eight oral maintenance doses are sequentially decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours, about 36 hours, about 42 hours, or combinations thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 5 days or less and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0172] In an exemplary embodiment, the method comprises administering one oral loading dose comprising about 650 mg to about 1000 mg, of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more second oral maintenance doses comprising about 100 mg to about 300 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and followed by administering one or more third oral maintenance doses comprising about 25 mg to about 175 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more fourth and one or more fifth oral maintenance doses comprising about 25 mg to about 100 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one or more first, second and third oral maintenance doses and optionally one or more fourth and fifth oral maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof, after administration of the first loading dose, and the one or more first, second and third oral maintenance doses and optionally one or more fourth and fifth oral maintenance doses aresequentially decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours, about 36 hours, about 42 hours, or combinations thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 5 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0173] In an exemplary embodiment, the method comprises administering one oral loading dose comprising about 650 mg to about 1000 mg, of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one to four first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more second oral maintenance doses comprising about 150 mg to about 275 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and followed by administering one to four third oral maintenance doses comprising about 75 mg to about 175 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one to four fourth oral maintenance doses comprising about 25 mg to about 75 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and followed by administering one to four fifth oral maintenance doses comprising about 25 mg to about 50 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one or more first to one or more fifth oral maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof, after administration of the first loading dose, and the one or more first to one or more fifth oral maintenance doses are sequentially decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours or about 36 hours, or combinations thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 5 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0174] In an exemplary embodiment, the method comprisesadministering one oral loading dose comprising about 800 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering two first oral maintenance doses comprising about 300 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one second oral maintenance dose comprising about 200 of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and followed by administering one third oral maintenance dose comprising about 100 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering three fourth oral maintenance doses comprising about 50 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and followed by administering two fifth oral maintenance doses comprising about 25 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein each of the oral maintenance doses are administered sequentially at intervals of about 12 hours after administration of the first oral loading dose, for a treatment period of 5 days, and wherein the method provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0175] In some embodiments, the one or more maintenance doses (one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eighth oral maintenance doses) are not tapered. Accordingly, in an exemplary embodiment, the method comprises administering one oral loading dose comprising about 650 mg to about 1000 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one first oral maintenance dose comprising about 25 mg to about 400 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more second oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more third oral maintenance doses comprising about 150 mg to about 275 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, andoptionally followed by administering one or more fourth up to one or more eighth maintenance doses comprising about 25 mg to about 150 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one first oral maintenance dose is less than the one or more second oral maintenance doses and the one or more second, third and optionally fourth up to eighth oral maintenance doses are tapered oral doses, wherein the one first oral maintenance dose is administered about 6 hours to 12 hours after administration of the oral loading dose, and the one or more second, one or more third and optionally one or more fourth to one or more eighth maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof, after administration of the one first oral maintenance dose, and the one or more second, one or more third to optionally one or more fourth to one or more eighth maintenance doses are sequentially decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours or about 36 hours, or combinations thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 5 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

[0176] In some embodiments, in the methods of the application, the loading dose is administered in the morning followed by administration of the one or more oral maintenance doses at intervals of about 12 hours thereafter (i.e., beginning in the evening on the same day).

[0177] A person skilled in the art would appreciate that each of the one or more first oral maintenance doses, (optionally, each of the one or more second oral maintenance doses, or each of the one or more third oral maintenance doses up to the one or more eighth oral maintenance doses) are the same (i.e., comprise the same amount of the amorphous otenaproxesul, or a pharmaceutically acceptable salt thereof.)

[0178] A person skilled in the art would appreciate that each dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, including all loading and maintenance doses can be administered as a single oral dosage form comprising the entire dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, or in two or more oral dosage forms each oral dosage form comprising a divided dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, the divided doses adding up to the entire dose of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. Divided doses are common when the dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is higher, for example a 800 mg dose of amorphous otenaproxesul ora pharmaceutically acceptable salt thereof can be administered as four oral dosage forms, each comprising 200 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0179] In some embodiments, the method provides pain relief within about 30 minutes to about 2 hours, about 1 hour to about 2 hours, about 30 minutes to about 1.5 hours after administration of the loading dose. In some embodiments, the method provides pain relief within 30 minutes or less, within 60 minutes or less, within 90 minutes or less, or within 120 minutes or less after administration of the first loading dose (optionally, one loading dose).

[0180] In some embodiments, the methods and uses of the application provide a Tmax of naproxen metabolite in a subject within 60 minutes or less, within 90 minutes or less, or within 120 minutes or less after administration of the first oral loading dose (optionally, one loading dose).

[0181] In some embodiments, the therapeutic methods and uses of the application provide a Cmax of naproxen metabolite of about 20 pg / mL to about 100 pg / mL, about 30 pg / mL to about 80 pg / mL, about 40 pg / mL to about 70 pg / mL, or about 50 pg / mL to about 65 pg / mL following oral administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof to a subject.

[0182] In some embodiments, the therapeutic methods and uses of the application provide an AUC of naproxen metabolite of from about 500 pg*hr / mL to about 4000 pg*hr / mL, from 500 pg*hr / mL to about 3500 pg*hr / mL or about 500 pg*hr / mL to about 3000 following oral administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof to a subject.

[0183] In some embodiments, the therapeutic methods and uses of the application provide a lower steady state (e.g, Day 4) AUC of naproxen compared to otherwise identical methods and uses except comprising administering equivalent doses of crystalline otenaproxesul under identical conditions.

[0184] In some embodiments, the methods and uses provide an AUC of naproxen metabolite of about 400-600 pg*hr / mL. In some embodiments, the compositions of the application provide an AUC of naproxen of about 500 pg*hr / mL to about 3500 pg*hr / mL or about 500 pg*hr / mL to about 3000 pg*hr / m, following administration to a subject.

[0185] In some embodiment, the methods and uses of the application are 80% to 125% bioequivalent to otherwise equivalent methods and uses except comprising crystalline otenaproxesul or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the subject is a subject at risk of liver injury. In some embodiments, the subject “in need thereof’ is a subject in need of treatment for acute pain.

[0187] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0188] In some embodiments, the methods of the application provide sustained acute pain relief.

[0189] In some embodiments, the method further comprises the use or administration of other known agents useful for treating or preventing acute pain.

[0190] In some embodiments, the other known agents useful for treating or preventing migraine comprise a triptan, including Sumatriptan.

[0191] In some embodiments, when used with other known agents useful for treating or preventing acute pain, the methods of the application reduce the amount of the other known agents used or administered. In some embodiments, when used with other known agents useful for treating or preventing acute pain, the methods of the application reduces the amount of the other known agents by about 40% to 60% within about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours or about 72 hours post administration the loading dose.

[0192] When used in combination with other agents or therapies, it is an embodiment that amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is administered contemporaneously with those agents or therapies. As used herein, “contemporaneous administration” of two substances or therapies to a subject means providing each of the two substances or therapies so that they are both biologically active in the individual at the same time. The exact details of the administration will depend on the pharmacokinetics of the two substances or therapies in the presence of each other and can include administering the two substances or therapies within a few hours of each other, or even administering one substance or therapy within 24 hours of administration of the other if the pharmacokinetics are suitable. Design of suitable dosing regimens is routine for one skilled in the art. In particular embodiments, the substances or therapies will be administered substantially simultaneously, i.e., within minutes of each other, or in a single composition in the case of administration of two substances. It is a further embodiment of the present application that a combination of agents or therapies is administered to a subject in a non-contemporaneous fashion.

[0193] It is an embodiment that the another known agent useful for treating or preventing acute pain is administered or used according to the treatment protocol for the other known agent.

[0194] In some embodiments, the amorphous otenaproxesul, or pharmaceutically acceptable salt thereof, comprises, consists essentially of or consists of at least about 95 wt% of the amorphous otenaproxesul, or the pharmaceutically acceptable salt thereof, wherein the wt% is based on the total weight of otenaproxesul. In some embodiments, the amorphous otenaproxesul, or pharmaceutically acceptable salt thereof comprises at least about 95 wt%, at least about 96 wt%, at least about 97 wt%, at least about 98 wt%, at least about 99 wt% at least about 99.5 wt%, at least about 99.6 wt%, at least about 99.7 wt%, at least about 99.8 wt% or at least about 99.9 wt% of the amorphous otenaproxesul, or the pharmaceutically acceptable salt thereof in amorphous form, wherein the wt% is based on the total weight of otenaproxesul

[0195] In some embodiments, within the limits of detection, using for example, XRPD, the amorphous otenaproxesul, or a pharmaceutically acceptable salt thereof, is 100% in the amorphous form, or is 0% in a crystalline form. In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof comprises non detectable amounts of crystalline otenaproxesul as measured, for example, by XPRD.Amorphous otenaproxesul in amorphous solid dispersions

[0196] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof for use in the methods and uses of the application is an amorphous solid dispersion. As described in Applicant’s co-pending PCT patent application no. PCT / CA2023 / 051347, the Applicant has developed amorphous solid dispersions of otenaproxesul in a polymer matrix which have been shown to be stable to crystallization over at least one month. The amorphous solid dispersions have also been shown to provide a significantly enhanced bioavailability of otenaproxesul, when compared with crystalline otenaproxesul.

[0197] In some embodiments, the amorphous otenaproxesul, or pharmaceutically acceptable salt thereof is formulated into an amorphous solid dispersion as described herein below and the present application includes methods of treating or preventing acute pain in a subject in need thereof comprising administering oral amorphous solid dispersions of the application comprising amounts of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof (e.g., loading doses or maintenance doses) as described in the regimens above.

[0198] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof is molecularly dispersed in the polymer.

[0199] In some embodiments, the amorphous otenaproxesul is in a neutral form (i.e., not a pharmaceutically acceptable salt thereof).

[0200] The Applicant has developed amorphous solid dispersions of otenaproxesul in a dispersed in a polymer which have been shown to be stable to crystallization. Therefore, in some embodiments, the amorphous solid dispersion is a stable amorphous solid dispersion.

[0201] By “stable” or “stable to crystallization” as used herein in reference to an amorphous solid dispersion means no significant increase in amount of crystalline otenaproxesul over a given length of time. In some embodiments, there is less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1 % increase in amount of crystalline otenaproxesul over a given length of time. In some embodiments, there is less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% increase in amount of crystalline otenaproxesul over a given length of time. In some embodiments, there is no detectable amounts of crystalline otenaproxesul as measured by XRPD over a given length of time.

[0202] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in a form that is about 90 wt% or more, about 92 wt% or more, about 94 wt% or more, about 95 wt% or more, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt% or more amorphous form. In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in a form that is about 95 wt% or more, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt% or more amorphous form.

[0203] In some embodiments, the amorphous solid dispersion is stable to crystallization for at least one month, at least two months, at least three months, at least four months, at least five months, at least six months, at least eight months, at least ten months, at least twelve months, at least fourteen months, at least eighteen months, at least twenty months or at least at least twenty-four months.

[0204] In some embodiments, the polymer provides stability of the amorphous solid dispersion. Therefore, in some embodiments, the polymer is a stabilizing polymer, and the amorphous solid dispersion comprises amorphous otenaproxesul or pharmaceutically acceptable salt thereof and a stabilizing polymer.

[0205] By “stabilizing” as used herein in reference to a polymer means no significant increase in amount of crystalline otenaproxesul in amorphous solid dispersion comprising the polymer over a given length of time. In some embodiments, there is less than about 10%, less than about 8%, less than about 6%, less than about 5%, less than about 4%, less than about 3%, less than about 2%, or less than about 1% increase in amount of crystalline otenaproxesul over a given length of time. In some embodiments, there is less than about 5%,less than about 4%, less than about 3%, less than about 2%, or less than about 1% increase in amount of crystalline otenaproxesul over a given length of time. In some embodiments, there is no detectable amounts of crystalline otenaproxesul within the limits of detection as measured by XRPD over a given length of time.

[0206] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof in the amorphous solid dispersion comprises 10 wt% or less, 8 wt% or less, 6 wt% or less, 5 wt% or less, 4 wt% or less, 3 wt% or less32 wt% or less, or 1 wt% or less crystalline otenaproxesul, wherein the wt% is based on the total weight of otenaproxesul. In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof in the amorphous solid dispersion comprises 2 wt% or less or 1 wt% or less crystalline otenaproxesul, wherein the wt% is based on the total weight of otenaproxesul.

[0207] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof in the amorphous solid dispersion consists of 0.5 wt%, 0.4 wt%, 0.3 wt%, 0.2 wt% or 0.1 wt% or less crystalline otenaproxesul wherein the wt% is based on the total weight of otenaproxesul. In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof in the amorphous solid dispersion consists of 0.1 wt% or less crystalline otenaproxesul, wherein the wt% is based on the total weight of otenaproxesul. In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof consists of non detectable amounts of crystalline otenaproxesul by XPRD.

[0208] In some embodiments, the solid-state form of otenaproxesul or pharmaceutically acceptable salt thereof, such as the otenaproxesul, or pharmaceutically acceptable salt thereof, substance in the amorphous dispersion, is determined by methods known in art, for example, by Polarized Light Microscopy, X-Ray Powder Diffraction (XPRD), Differential Scanning Calorimetry (DSC), or other standard techniques known in the art.

[0209] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in an amount of about 15% to about 60%, about 15% to about 50%, about 15% to about 50%, about 20% to about 50%, about 30% to about 50% or about 35% to about 50% by weight of the amorphous solid dispersion. In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in an amount of about 20% to about 50%, about 30% to about 50%, about 35% to about 50% or about 35% to about 45% by weight of the amorphous solid dispersion. In some embodiments, amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in an amount of about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50% or about 55% by weight of the amorphous solid dispersion. In some embodiments, amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in an amount of about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, or about 50% by weight of the amorphous solid dispersion. In some embodiments, amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in an amount of about 35% by weight of the amorphous solid dispersion.

[0210] In some embodiments, the polymer is present in the amorphous solid dispersion in an amount of about 40% to about 80%, 40% to about 70%, about 40% to about 65%, about 50% to about 80%, about 50% to about 70%, about 50% to about 65%, about 55% to about 65%, about 50% to about 60%, about 60% to about 65% by weight of the amorphous solid dispersion.[0021 1] In some embodiments, the weight ratio of amorphous otenaproxesul, or pharmaceutically acceptable salt thereof, to the polymer in the amorphous solid dispersion is about 1 :1 to about 1 :4, or about 1 .5 to about 1 :4. In some embodiments, the weight ratio of amorphous otenaproxesul, or pharmaceutically acceptable salt thereof, to the polymer in the amorphous solid dispersion is about 1 :1 , about 1 :2, about 1 :3, about 1 :4, about 1 :1.5, about 1 :1.75 or about 1 :1.8.

[0212] In some embodiments, the polymer is selected from one or more pharmaceutically acceptable acidic, neutral or basic polymers. In some embodiments, the one or more pharmaceutically acceptable polymers are selected from acidic polymers. In some embodiments, the one or more pharmaceutically acceptable polymers are selected from neutral polymers. In some embodiments, when a neutral polymer is used, the amorphous solid dispersion further comprises one or more antioxidants.

[0213] The Applicants have investigated the preparation of amorphous solid dispersions of otenaproxesul or pharmaceutically acceptable salt thereof with various polymers, including, for example, hydroxypropylmethylcellulose acetate succinate (HPMC- AS), hydroxypropylmethylcellulose (hypromellose, HPMC), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone vinyl acetate (PVP VA, copovidone), methacrylic acid-methyl methacrylate copolymers, polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer, PEG3350, PEG 8000 and polyacrylic acid and combinations thereof.

[0214] Various amorphous solid dispersions of otenaproxesul were prepared. Amorphous solid dispersions of otenaproxesul or pharmaceutically acceptable salt thereof were prepared using various polymers and combinations of polymers.

[0215] The Applicants further tested the stability of the prepared amorphous solid dispersions to crystallization. Most polymers or combinations thereof tested were stabilizing polymers capable of preventing crystallization of otenaproxesul in the amorphous solid dispersion on their own or in combination. Some polymers, such as for example, polyacrylic acid, polyvinylpyrrolidone K-30, HPMC E5 and a combination of PEG8000 and hydroxypropylmethylcellulose acetate succinate (HPMCAS) may optionally be used in combination with stabilizing agents to improve the stability of the prepared amorphous solid dispersions to crystallization.

[0216] In some embodiments, the polymer is selected from polyvinylpyrrolidone (PVP) based polymers, polyethylene glycol (PEG) based polymers, cellulose based polymers, acrylate based polymers, chitosan, polyvinyl alcohol / polyethylene glycol graft copolymers, polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymers and polyvinyl acetate phthalate, and combinations of one or more of the listed polymers.

[0217] In some embodiments, the polymer is selected from hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), poly(vinylpyrrolidone-co-vinyl acetate (PVP / VA), cellulose acetate phthalate (CAP) and polymeric polymethacrylates (e.g., EUDRAGIT® such as EUDRAGIT® L100), and mixtures thereof. In some embodiments, the polymer is selected from hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), poly(vinylpyrrolidone-co-vinyl acetate (PVPA / A) and cellulose acetate phthalate (CAP), and mixtures thereof.

[0218] In some embodiments, the polymer is selected from polymers of: cellulose optionally functionalized with combinations of alkyl ethers, alkyl esters, and phthalate esters; vinyl alcohol; vinyl acetate; propylene glycol, oxyethylene; oxypropylene; acrylic acid, methacrylic acid; methyl methacrylate; ethylene glycol; ethylene glycol glycerides; ethylene oxide; propylene oxide; 2-ethyl-2-oxazoline; maleic acid; methyl vinyl ether; vinyl caprolactam; polyvinylpyrrolidone and combinations thereof.

[0219] In some embodiments, the polymer is selected from polymers of: cellulose optionally functionalized with combinations of alkyl ethers, alkyl esters, and phthalate esters; vinyl alcohol; vinyl acetate; oxyethylene; oxypropylene; acrylic acid, methacrylic acid; methyl methacrylate; ethylene glycol; ethylene glycol glycerides; ethylene oxide; propylene oxide; 2- ethyl-2-oxazoline; maleic acid; methyl vinyl ether; vinyl caprolactam; polyvinylpyrrolidone,combinations of one or more of the preceding polymers, and propylene glycol in combination with one or more of the preceding polymers.

[0220] In some embodiments, the polymer is selected from polyvinylpyrrolidone (PVP) based polymers, polyethylene glycol (PEG) based polymers, cellulose based polymers, acrylate based polymers, chitosan, polyvinyl alcohol / polyethylene glycol graft copolymers, polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymers and polyvinyl acetate phthalate, and combinations of one or more of the listed polymers.

[0221] In some embodiments, the polymer is selected from polyvinylpyrrolidone (PVP) based polymers, cellulose based polymers, acrylate based polymers, chitosan, polyvinyl alcohol / polyethylene glycol graft copolymers, polyvinyl caprolactam polyvinyl acetatepolyethylene glycol graft copolymers and polyvinyl acetate phthalate, and combinations thereof, combinations of one or more of the listed polymers, and polyethylene glycol (PEG) based polymers in combination with one or more of the listed polymers.

[0222] In some embodiments, the polymer is selected from polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate (PVP VA), crospovidone (PVPP), methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), polyethylene glycol (PEG), methacrylate copolymers, polyacrylic acid, chitosan, polyvinyl alcohol / polyethylene glycol graft copolymers, polyvinyl caprolactam polyvinyl acetate-polyethylene and combinations thereof.

[0223] In some embodiments, the polymer is selected from polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate (PVP VA), crospovidone (PVPP), methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), methacrylate copolymers, polyacrylic acid, chitosan, polyvinyl alcohol / polyethylene glycol graft copolymers, polyvinyl caprolactam polyvinyl acetate-polyethylene, combinations of one or more of the listed polymers, and polyethylene glycol (PEG) based polymers in combination with one or more of the listed polymers, provided HPMC does not comprise E type HPMC comprising a viscosity of about 5cP or greater.

[0224] In some embodiments, the polymer is selected from polyvinylpyrrolidone K-12, polyvinylpyrrolidone vinyl acetate (PVP VA), crospovidone (PVPP), hydroxypropylmethylcellulose E3 (HPMC E3), hydroxypropylmethylcellulose acetate succinate (HPMCAS), methacrylate copolymers, polyvinyl alcohol / polyethylene glycol graftcopolymers and polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymers, and combinations thereof.

[0225] In some embodiments, the polymer comprises one polymer. In some embodiments, the polymer comprises a mixture of two or more polymers. In some embodiments, the polymer is one polymer. In some embodiments, the polymer is a mixture of two or more polymers.

[0226] In some embodiments, the polyvinylpyrrolidone (PVP) based polymers are selected from polyvinylpyrrolidone, polyvinylpyrrolidone / vinylacetate copolymer (PVP VA, copovidone), and crospovidone (PVPP, cross linked polyvinylpyrrolidone) and combinations thereof.

[0227] Amorphous solid dispersions of otenaproxesul prepared with polyacrylic acid, polyvinylpyrrolidone K-30, HPMC E5 and a combination of PEG8000 and hydroxypropylmethylcellulose acetate succinate (HPMCAS) were found to provide amorphous solid dispersion that showed some crystallization of the otenaproxesul in the amorphous solid dispersion and therefore the amorphous solid dispersion optionally comprise further stabilizing agents.

[0228] In some embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone comprising a K value of about 10 to less than about 30, about 10 to less than about 25, about 10 to less than about 17, about 10 to less to than about 15, about 12 to less than about 30, about 12 to less than about 25, about 12 to less than about 17, about 12 to less to than about 15. In some embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone comprising a K value of about 25, about 17, about 15, about 12 or about 10. In some embodiments, the polyvinylpyrrolidone is polyvinylpyrrolidone comprising a K value of 12 (e.g. polyvinylpyrrolidone K-12). In some embodiments, the polyvinylpyrrolidone is a polyvinylpyrrolidone with a K value of about 10 to about 30, about 10 to about 17, about 10 to about 25, about 12 to about 30, about 17 to about 30 or about 25 to about 30. In some embodiments, the polyvinylpyrrolidone (PVP) based polymers do not comprise polyvinylpyrrolidone with a K grade of 30 or greater.

[0229] In some embodiments, the K value of polyvinylpyrrolidone is a value related to the relative viscosity of PVP aqueous solution. In some embodiments, the viscosity is generally related to the molecular weight of the PVP wherein the higher the K value correlates to a higher molecular weight of the PVP.

[0230] In some embodiments, the cellulose based polymers are selected from methylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose (hypromellose, HPMC), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropylmethylcelluloseacetate succinate (HPMCAS) and cellulose acetate phthalate (CAP) and combinations thereof.

[0231] In some embodiments, the polymer is HPMCAS. In some embodiments, HPMCAS is a mixture of acetic acid and monosuccinic acid esters of hydroxypropylmethylcellulose. In some embodiments, HPMCAS is commercially available. For example, HPMCAS is commercially available as AquaSolve™ (Global Specialty Chemicals Inc., Delaware, U.S.).

[0232] In some embodiments, HPMCAS is available in various different grades L, H and G, (e.g., HPMCAS- H, HPMCAS- L and HPMCAS-M) differentiated by the ratio of succinyl and acetyl substituents on the HPMC backbone. In some embodiments, the HPMCAS is HPMCAS-H or HPMCAS-L. In some embodiments, the HPMCAS is HPMCAS-H. HPMCAS is soluble in a wide range of organic solvents, making it compatible with a range of different active pharmaceutical ingredients. In some embodiments, the grades of HPMCAS comprise fine (F) and granular (G). Therefore, in some embodiments, the HPMCAS is HPMCAS-H and the HPMCAS-H is selected from HPMCAS-HG and HPMCAS-HF. In some embodiments, the HPMCAS is HPMCAS-HG.

[0233] In some embodiments, HPMCAS is HPMCAS-HG.

[0234] In some embodiments, HPMC is E, F or K type HPMC. In some embodiments,HPMC is E type (HPMC E). In some embodiments, E type HPMC comprises an average content of methoxyl groups of 29% and an average content of hydroxypropyl groups of 10%. In some embodiments, HPMC is a low viscosity HPMC. In some embodiments, HPMC E is a low viscosity HPMC E. In some embodiments, the HPMC has viscosity of about 4 cP or less or about 5 cP or less. In some embodiments, the HPMC has viscosity of about 3 cP to about 6 cP or about 4 cP or lower to about 5 cP. In some embodiments, the E type HPMC is E3. In some embodiments, the E type HPMC is not E5 or E15. In some embodiments, the cellulose based polymers do not comprise E type hydroxypropylmethylcellulose comprising a viscosity of about 5cP or greater, In some embodiments, the PEG based polymers in combination with one or more of the listed polymers is not propylene glycol 8000 in combination with hydroxypropylmethylcellulose acetate succinate in a weight ratio of about 1.2:1 of the PEG 8000 to hydroxypropylmethylcellulose acetate succinate.

[0235] In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 40% to about 80%, 40% to about 70%, about 40% to about 65%, about 50% to about 80%, about 50% to about 70%, about 50% to about 65%, about 55% to about 65%, about 50% to about 60%, about 60% to about 65% by weight of the amorphous solid dispersion. In some embodiments, HPMCAS is present in the amorphous solid dispersion inan amount of about 50% to about 60%, about 55% to about 65% or about 60% to about 65% by weight of the amorphous solid dispersion. In some embodiments, the HPMCAS is present in the amorphous solid dispersion in an amount of about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, or about 80% by weight of the amorphous solid dispersion. In some embodiments, the HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion. In some embodiments, the weight ratio of otenaproxesul, or pharmaceutically acceptable salt thereof, to the HPMCAS in the amorphous solid dispersion is about 1 :1 to about 1 :4. In some embodiments, the weight ratio of otenaproxesul, or pharmaceutically acceptable salt thereof, to HPMCAS in the amorphous solid dispersion is about 1 :4 or about 1 :1 .8.

[0236] In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 50% to about 60% or about 60% to about 65% by weight of the amorphous solid dispersion and the Tg of the amorphous solid dispersion is about 62°C to about 65°C. In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion and the Tg of the amorphous solid dispersion is about 63°C to about 64°C.

[0237] In some embodiments, the acrylate based polymer is selected from methacrylate copolymers. In some embodiments, the methacrylate copolymers are selected from cationic, anionic and neutral methacrylate copolymers.

[0238] In some embodiments, the cationic methacrylate copolymers are aminoalkylmethacrylate copolymers. In some embodiments, the aminoalkylmethacrylate copolymers are Eudragit® E such as Eudragit® E PO.

[0239] In some embodiments, the anionic methacrylate copolymers are methacrylic acid copolymers. In some embodiments, anionic methacrylic acid copolymers are selected from Eudragit® L (such as Eudragit® L100) or Eudragit® S.

[0240] In some embodiments, the neutral methacrylate copolymer are methacrylic acid copolymers. In some embodiments, neutral methacrylic acid copolymers are selected from Eudragit® RL, Eudragit® RS and Eudragit® NE.

[0241] In some embodiments, the methacrylate copolymers are selected from cationic and anionic methacrylate copolymers.

[0242] In some embodiments, the acrylate based polymer is not polyacrylic acid.

[0243] In some embodiments, the polyethylene glycol (PEG) based polymers have a molecular weight of less than 8000 g / Mol. In some embodiments, polyethylene glycol (PEG)based polymers have a molecular weight of about 3350 to about 8000 g / Mol. In some embodiments, polyethylene glycol (PEG) based polymers are in solid form.

[0244] In some embodiments, the polyvinyl alcohol / polyethylene glycol graft copolymers is Kollicoat®.

[0245] In some embodiments, the polyvinyl caprolactam polyvinyl acetatepolyethylene glycol graft copolymer is Soluplus®.

[0246] In some embodiments, the polymer comprises a mixture of two polymers. In some embodiments, the polymer comprises a mixture of two polymers, wherein one of the two polymer is HPMCAS. In some embodiments, the other of the two polymers is selected from PVP / VA and polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymer.

[0247] In some embodiments, the polymer is PVP / VA. In some embodiments, PVP / VA is a polyvinylpyrrolidone / vinylacetate copolymer. In some embodiments, PVP / VA is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a ratio of 6:4 by mass (PVP / VA64). Therefore, in some embodiments, PVP / VA is PVP / VA64. In some embodiments, PVP / VA64 is commercially available. For example, PVP / VA64 is available as Kollidon® VA 64 supplied from BASF Pharma (Ludwigshafen, Germany).

[0248] In some embodiments, PVP / VA is present in the amorphous solid dispersion in an amount of about 40% to about 70%, about 40% to about 65%, about 50% to about 80%, about 50% to about 70%, about 50% to about 65%, about 50% to about 60%, about 55% to about 65%, about 60% to about 65% by weight of the amorphous solid dispersion. In some embodiments, PVP / VA is present in the amorphous solid dispersion in an amount of about 50% to about 65%, about 50% to about 55% or about 60% to about 65% by weight of the amorphous solid dispersion by weight of the amorphous solid dispersion. In some embodiments, the PVP / VA is present in the solid dispersion in an amount of about 50%, about 55%, to about 60% or about 65% by weight of the amorphous solid dispersion. In some embodiments, the PVP / VA is present in the amorphous solid dispersion in an amount of about 65% by weight of the solid dispersion. In some embodiments, the PVP / VA is present in the amorphous solid dispersion in an amount of about 50% by weight of the amorphous solid dispersion. In some embodiments, the weight ratio of otenaproxesul, or pharmaceutically acceptable salt thereof, to the PVP / VA in the amorphous solid dispersion is about 1 :1 to about 1 :2.

[0249] In some embodiments, the amorphous solid dispersion consists essentially of amorphous otenaproxesul, or pharmaceutically acceptable salt thereof, and a polymer. In some embodiments, the amorphous solid dispersion further comprises one or more additivesknown in the art. In some embodiments, the one or more additives are selected from antioxidants, solubilizers and surfactants.

[0250] In some embodiments, the one or more additives are antioxidants. Therefore, in some embodiments, the amorphous solid dispersion further comprises one or more antioxidants.

[0251] In some embodiments, the antioxidant is any antioxidant suitable for use with an amorphous solid dispersion comprising otenaproxesul or pharmaceutically acceptable salt thereof and a polymer. Therefore, in some embodiments, the amorphous solid dispersion comprises amorphous otenaproxesul or pharmaceutically acceptable salt thereof, a polymer and optionally one or more antioxidants. In some embodiment, the amorphous solid dispersion consists essentially of amorphous otenaproxesul or pharmaceutically acceptable salt thereof, a polymer and optionally one or more antioxidants.

[0252] In some embodiments, the one or more additives are antioxidants and the antioxidants are selected from ascorbic acid, tartaric acid, fumaric acid, citric acid, DL-a- tocopherol, tocopheryl polyethylene glycol succinate (TPGS, Vitamin E TPGS), vitamin A, vitamin C, vitamin D, vitamin E, carotenoids, flavanoids, isoflavanoids, beta-carotene, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), glutathione, lycopene, gallic acid and esters thereof (e.g. propyl gallate), salicylic acid and esters thereof, sulfites, alcohols, amines, amides, sulfoxides, surfactants, and mixtures thereof. In some embodiments, the one or more antioxidants are selected from ascorbic acid, tartaric acid, fumaric acid, citric acid, DL-a-tocopherol, vitamin E TPGS, vitamin A, vitamin C, vitamin D, vitamin E, BHT, BHA, propyl gallate, and mixtures thereof. In some embodiments, the one or more antioxidants are selected from vitamin E TPGS and BHT. In some embodiments, the antioxidant is BHT.

[0253] In some embodiments, the one or more antioxidants are present in the amorphous solid dispersion in an amount of about 0.1 % to about 1 %, about 0.1 % to about 0.75%, about 0.1 % to about 0.5%, about 0.1 % to about 0.4%, about 0.2% to about 0.5%, about 0.2% to about 0.4%, about 0.3% to about 0.5%, or about 0.4% to about 0.5% by weight of the amorphous solid dispersion. In some embodiments, the one or more antioxidants are present in the amorphous solid dispersion in an amount of about 0.2% to about 0.5% about 0.3% to about 0.5%, or about 0.4% to about 0.5% by weight of the amorphous solid dispersion.

[0254] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof in the amorphous solid dispersion comprises a total impurity of less than about 2 wt%, less than about 1 .5 wt%, less than about 1 wt%, less than about 0.9 wt%, less than about 0.8 wt%, less than about 0.7 wt%, less than about 0.6 wt%, less than about 0.5 wt%, less than about 0.4 wt%, less than about 0.3 wt%, less than about 0.2 wt% or lessthan about 0.1 wt%. In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof in the amorphous solid dispersion comprises a total impurity of less than about 0.8 wt%, less than about 0.7 wt%, less than about 0.6 wt%, less than about 0.5 wt%, less than about 0.4 wt%, less than about 0.3 wt%, less than about 0.2 wt% or less than about 0.1 wt%.

[0255] In some embodiments, the amorphous otenaproxesul or pharmaceutically acceptable salt thereof in the amorphous solid dispersion comprises a total impurity of less than about 1 wt%, less than about 0.9 wt%, less than about 0.8 wt%, less than about 0.7 wt%, less than about 0.6 wt%, less than about 0.5 wt% after one month at temperature of about 30°C to about 50°C.

[0256] In some embodiments the impurities comprise any metabolite or degradation product of otenaproxesul or pharmaceutically acceptable salt thereof.

[0257] In some embodiments, the amorphous solid dispersion comprises less 0.02 wt% (e.g., non-detectable levels) of naproxen when stored at a temperature of about 30°C or about 50°C for one month. In some embodiments, the amorphous solid dispersion comprises less than about 0.2 wt%, less than about 0.1 wt% or less than about 0.05 wt% impurity observed at relative retention time (RRT) 0.24 (4-hydroxybenzonitrile) when stored at a temperature of about 30°C or about 50°C for one month. In some embodiments, the amorphous solid dispersion comprises less than about 0.2 wt%, less than about 0.1 wt% or less than about 0.05 wt% impurity observed at RRT 0.85 when stored at a temperature of about 30°C or about 50°C for one month. In some embodiments, the amorphous solid dispersion comprises less than 0.02 wt% (e.g., non-detectable levels) of impurity observed at RRT 0.85 when stored at a temperature of about 30°C or about 50°C for one month. In some embodiments, the amorphous solid dispersion comprises less than about 0.2 wt% or less than about 0.1 wt% impurity observed at RRT 0.85 (otenaproxesul-amide) when stored at a temperature of about 30°C or about 50°C for one month. In some embodiments, the amorphous solid dispersion comprises less than about 0.2 wt% or less than about 0.1 wt% impurity observed at RRT 1 .1 1 when stored at a temperature of about 30°C or about 50°C for one month.

[0258] It would be appreciated by a person skilled in the art that various methods of analyzing (characterization and quantification) the impurities are well established in the art. For example, various spectroscopic techniques, such as NMR, MS, IR etc. and chromatographic techniques, such as HPLC, HPLC-TLC, HPLC-CE and hyphenated methods, such as LC-MS-MS, HPLC-DAD-MS, HPLC-NMR, GC-MS & LC-MS known in the art can be used for analyzing impurities.

[0259] In some embodiments, the impurities are analyzed using HPLC. In some embodiments, the impurities are analyzed using HPLC following the protocols described in Example 13. Therefore, in some embodiments HPLC analyses are performed using a C18 150 mm x 4.6 mm, 5 pm or equivalent column, with a flow rate of 1.0 mL / min, an injection volume of 10 pL, a column temperature of 25 °C, a sample temperature of 5 °C and a wavelength for detection of 254 nm. In some embodiments, the eluents used are (1) A: 1 .8 g K2HPO4.3H2O dissolved in 1000 mL of water and pH adjusted to 5.5 using orthophosphoric acid and B: acetonitrile; or (2) A: 1.4 g K2HPO4.3H2O dissolved in 1000 mL of water and pH adjusted to 7.0 with 85% phosphoric acid and B: acetonitrile.

[0260] In some embodiments, the amorphous solid dispersions are prepared by spray drying (or lyophilization), melt extrusion, freeze drying, rotary evaporation, solvent-controlled precipitation, pH-controlled precipitation, drum drying, supercritical fluid technology or other solvent removal process. In some embodiments, the amorphous solid dispersion is prepared by spray-draying. Therefore, in some embodiments, the amorphous dispersion is an amorphous spray-dried dispersion (SDD).

[0261] In some embodiments, the amorphous solid dispersion comprises particles having a D50 below about 50 pM, below about 45 pM, below about 40 pM, below about 35 pM or below about 30 pM. In some embodiment, the amorphous solid dispersion comprises particles having D50 below about 40 pM, below about 35 pM or below about 32 pM. In some embodiments, the amorphous solid dispersion comprises particles having a D90 below about 80 pM, below about 75 pM or below about 70 pM.

[0262] In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 50% to about 60% or about 60% to about 65% by weight of the amorphous solid dispersion and the amorphous solid dispersion comprises particles having a D50 below about 40 pM, below about 35 pM or below about 32 pM. In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion and the amorphous solid dispersion comprises particles having a D90 below about 75 pM or below about 70 pM. In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion and the amorphous solid dispersion comprises particles having a D90 below about 70 pM. In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion and the amorphous solid dispersion comprises particles having a D90 of 60 pM to about 70 pM

[0263] In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 60% to about 65% by weight of the amorphous solid dispersion and theamorphous solid dispersion comprises particles having a Sauter mean diameter (e.g., surface area mean) [D 3,2] of less than 10 pM. In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion and the amorphous solid dispersion comprises particles having a Sauter mean diameter [D 3,2] of about 8 pM to 10 pM.

[0264] In some embodiments, HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion and the Tg of the amorphous solid dispersion is about 63°C to about 64°C.

[0265] In some embodiments, the amorphous solid dispersion further comprises one or more sustaining agents.

[0266] In some embodiments, the one or more sustaining agents are combined with the otenaproxesul or pharmaceutically acceptable salt thereof and the polymer in the amorphous solid dispersion to form the amorphous solid dispersion comprising otenaproxesul or pharmaceutically acceptable salt thereof, the polymer and the sustaining agent. Therefore, in some embodiments, the sustaining agent is present with the polymer in the amorphous solid dispersion.

[0267] In some embodiments, the amorphous solid dispersions are the amorphous solid dispersions provided in Examples 7A and 7B.

[0268] Accordingly, in some embodiments, the amorphous solid dispersion comprises amorphous otenaproxesul or pharmaceutically acceptable salt thereof, a polymer, optionally one or more additives and optionally one or more sustaining polymers. In some embodiments, the one or more additives is one or more antioxidants. In some embodiments, the amorphous solid dispersion comprises amorphous otenaproxesul or pharmaceutically acceptable salt thereof, a polymer, optionally one or more antioxidants and optionally one or more sustaining polymers. In some embodiments, the amorphous solid dispersion consists essentially of amorphous otenaproxesul or pharmaceutically acceptable salt thereof, a polymer, optionally one or more antioxidants and optionally one or more sustaining polymers.Amorphous otenaproxesul in compositions comprising amorphous solid dispersions of amorphous otenaproxesul

[0269] In some embodiments, the amorphous solid dispersions in the methods and uses of the application are formulated with one or more conventional excipients known in the art used in the preparation of pharmaceutical compositions for administration to subjects in a biologically compatible form suitable for administration in vivo.

[0270] Therefore, in some embodiments, the amorphous solid dispersion is formulated into an oral pharmaceutical composition comprising the amorphous solid dispersion and one or more pharmaceutically acceptable excipients.

[0271] Accordingly, in some embodiments, the amorphous solid dispersion is formulated into an oral pharmaceutical composition comprising the amorphous solid dispersion and one or more pharmaceutically acceptable excipients and the present application includes methods of treating or preventing acute pain in a subject in need thereof comprising administering oral pharmaceutical compositions of the application comprising the amorphous solid dispersions of the application described herein and comprising amounts of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof (e.g., loading and maintenance doses) as described in the regimens above.

[0272] In some embodiments, the amorphous solid dispersion is granulated together with one or more pharmaceutically acceptable excipients to form granules. In some embodiments, the one or more pharmaceutically acceptable excipients comprise one or more intragranular pharmaceutically acceptable excipients and one or more extragranular pharmaceutically acceptable excipients.

[0273] Accordingly, in some embodiments, the oral pharmaceutical composition comprises the amorphous solid dispersion, and one or more intragranular pharmaceutically acceptable excipients and / or one or more extragranular pharmaceutically acceptable excipients. In some embodiments, the amorphous solid dispersion is granulated together with the one or more intragranular pharmaceutically acceptable excipients to form granules. Accordingly, in some embodiments, the oral pharmaceutical composition comprises a granule comprising the amorphous solid dispersion, and one or more intragranular pharmaceutically acceptable excipients; and one or more extragranular pharmaceutically acceptable excipients.

[0274] In some embodiments, the oral pharmaceutical composition comprises about 25% to about 65% of the amorphous solid dispersion of the application, by weight of the composition. In some embodiments, the pharmaceutical composition comprises about 35% to about 65% of the amorphous solid dispersion of the application by weight of the composition. In some embodiments, the oral pharmaceutical composition comprises about 40% of the amorphous solid dispersion by weight of the composition. In some embodiments, the oral pharmaceutical composition comprises about 65% of the amorphous solid dispersion of the application by weight of the composition. In some embodiments, the oral pharmaceutical composition comprises about 30% to about 35% of the amorphous solid dispersion of the application by weight of the composition.

[0275] In some embodiments, the oral pharmaceutical composition optionally further comprises one or more sustaining agents external to the amorphous solid dispersion. In some embodiments, the sustaining agent is combined with the amorphous solid dispersion after the amorphous solid dispersion has been formed. In some embodiments, the amorphous solid dispersion is granulated together with the one or more intragranular pharmaceutically acceptable excipients and the one or more optional sustaining agents to form granules. Accordingly, in some embodiments, the oral pharmaceutical composition comprises: a granule comprising the amorphous solid dispersion and one or more intragranular pharmaceutically acceptable excipients; one or more extragranular pharmaceutically acceptable excipients; and optionally one or more sustaining agents, wherein the one or more sustaining agents are present in the granule external to the amorphous solid dispersion and / or are present in the amorphous solid dispersion.

[0276] In some embodiments, the weight ratio of the one or more sustaining agents to amorphous solid dispersion is about 1 :1 to about 2:5. In some embodiments, the weight ratio of the one or more sustaining agents to amorphous solid dispersion is about 1 :1 to about 2:3.

[0277] In some embodiments, the one or more sustaining agents are in an amount of about 35% to about 60%, about 35% to about 50%, about 35% to about 40% or about 40% by weight of the granule. In some embodiments, the one or more sustaining agents is in an amount about 35% to about 40% or about 40% by weight of the granule.

[0278] In some embodiments, the one or more sustaining agents are one or more sustaining agents as described above. In some embodiments, the one or more sustaining agents is a polymer. In some embodiments, the one or more sustaining agents are selected from HPMCAS and PVP.

[0279] In some embodiments, the one or more sustaining agent external to the solid dispersion is HPMCAS. In some embodiments, the amorphous solid dispersion is granulated together with the one or more intragranular pharmaceutically acceptable excipients and HPMCAS to form granules.

[0280] In some embodiments, the amorphous solid dispersion comprises PVP / VA in an amount of from 55% to about 65% by weight of the amorphous solid dispersion, and HPMCAS is present external to the amorphous solid dispersion in a weight ratio of sustaining agent to amorphous solid dispersion of about 1 :1 .5. In some embodiments, the amorphous solid dispersion comprises PVP / VA in an amount of from 55% to about 65% by weight of the amorphous solid dispersion and HPMCAS is present external to the amorphous soliddispersion in a weight percent ratio of sustaining agent to amorphous solid dispersion of about 1 :1.5.

[0281] In some embodiments, the HPMCAS is present external to the amorphous solid dispersion in the granule in an amount of about 35% to about 60%, about 35% to about 50%, about 35% to about 40% or about 40% by weight of the granule. In some embodiments, the HPMCAS is present external to the amorphous solid dispersion in the granule in an amount about 35% to about 40% or about 40% by weight of the granule.

[0282] In some embodiments, the oral pharmaceutical composition comprises about 30% to about 60% of the one or more intragranular pharmaceutically acceptable excipients wherein the percentage amount is by total weight of the pharmaceutical composition. In some embodiments, the oral pharmaceutical composition comprises about 30% to about 35% of the one or more intragranular pharmaceutically acceptable excipients wherein the percentage amount is by weight of the pharmaceutical composition. In some embodiments, the amorphous solid dispersion of the application and the one or more intragranular pharmaceutically acceptable excipients are granulated together to form granules.

[0283] In some embodiments, the one or more intragranular pharmaceutically acceptable excipients are selected from one or more intragranular pharmaceutically acceptable additives, fillers, disintegrants, lubricants, and glidants. In some embodiments, the one or more intragranular pharmaceutically acceptable excipients are selected from one or more intragranular pharmaceutically acceptable fillers, disintegrants, lubricants and glidants.

[0284] In some embodiments, the oral pharmaceutical composition comprises about 0.5% to about 3% of the one or more intragranular pharmaceutically acceptable additives wherein the percentage amount is by weight of the pharmaceutical composition. In some embodiments, the oral pharmaceutical composition comprises about 0.5% to about 2% of the one or more intragranular pharmaceutically acceptable additives wherein the percentage amount is by weight of the pharmaceutical composition.

[0285] In some embodiments, the oral pharmaceutical composition comprises about 30% to about 50% of the one or more intragranular pharmaceutically acceptable fillers wherein the percentage amount is by weight of the pharmaceutical composition. In some embodiments, the oral pharmaceutical composition comprises about 25% to about 50% or about 25% to about 45%, about 30% to about 40% or about 30% to about 35% of the one or more intragranular pharmaceutically acceptable fillers wherein the percentage amount is by weight of the pharmaceutical composition.

[0286] In some embodiments, the oral pharmaceutical composition further comprises about 2% to about 8% of one or more intragranular pharmaceutically acceptable disintegrantswherein the percentage amount is by weight of the pharmaceutical composition. In some embodiments, the oral pharmaceutical composition further comprises about 2% to about 5% of one or more intragranular pharmaceutically acceptable disintegrants wherein the percentage amount is by weight of the pharmaceutical composition.

[0287] In some embodiments, the oral pharmaceutical composition further comprises about 0.1 % to about 3%, about 0.1 % to about 2%, about 0.1 % to about 1 % of one or more intragranular pharmaceutically acceptable glidants and lubricants wherein the percentage amount is by weight of the pharmaceutical composition.

[0288] In some embodiments, the oral pharmaceutical composition comprises about 45% to about 65% of an amorphous solid dispersion of the application; about 25% to about 50% of one or more intragranular pharmaceutically acceptable fillers; about 2% to about 8% of one or more intragranular pharmaceutically acceptable disintegrants, about 0.1 % to about 2% of one or more intragranular pharmaceutically acceptable glidants and lubricants; optionally about 0.5% to about 2% of the one or more intragranular pharmaceutically acceptable additives; wherein the percentage amount is by weight of the pharmaceutical composition.

[0289] In some embodiments, the oral pharmaceutical composition comprises: about 55% to about 65% of an amorphous solid dispersion of the application; about 25% to about 35% of one or more intragranular pharmaceutically acceptable fillers; about 2% to about 6% of one or more intragranular pharmaceutically acceptable disintegrants, about 0.1 % to about 1 % of one or more intragranular pharmaceutically acceptable glidants and lubricants, and optionally about 1 % to about 2% of the one or more intragranular pharmaceutically acceptable additives; wherein the percentage amount is by weight of the pharmaceutical composition.

[0290] In some embodiments, the oral pharmaceutical composition comprises about 40% to about 60% of an amorphous solid dispersion of the application; about 25% to about 50% of one or more intragranular pharmaceutically acceptable fillers, about 2% to about 8% of one or more intragranular pharmaceutically acceptable disintegrants, about 0.1 % to about 1 % of one or more intragranular pharmaceutically acceptable glidants and lubricants, wherein the percentage amount is by weight of the pharmaceutical composition.

[0291] In some embodiments, the oral pharmaceutical composition comprises about 25% to about 40% of an amorphous solid dispersion of the application, about 15% to about 25% of one or more sustaining agents; about 1 % to about 2% of the one or more intragranular pharmaceutically acceptable additives; about 10% to about 30% of one or more intragranular pharmaceutically acceptable fillers, about 2% to about 8% of one or more intragranular pharmaceutically acceptable disintegrants, about 0.1 % to about 1 % of one or more intragranular pharmaceutically acceptable glidants and lubricants, wherein the percentage amount is by weight of the composition.

[0292] In some embodiments, the oral pharmaceutical composition comprises about 25% to about 40% of an amorphous solid dispersion of the application, about 15% to about 25% of one or more sustaining agents; about 10% to about 30% of one or more intragranular pharmaceutically acceptable fillers, about 2% to about 8% of one or more intragranular pharmaceutically acceptable disintegrants, about 0.1 % to about 1 % of one or more intragranular pharmaceutically acceptable glidants and lubricants, wherein the percentage amount is by weight of the composition.

[0293] In some embodiments, the one or more extragranular pharmaceutically acceptable excipients are selected from one or more extragranular pharmaceutically acceptable fillers (including diluents), disintegrants, lubricants and glidants. In some embodiments, the one or more extragranular pharmaceutically acceptable excipients are selected from one or more extragranular pharmaceutically acceptable disintegrants, lubricants and glidants. In some embodiments, the oral pharmaceutical composition comprises about 2% to about 8% of the one or more extragranular pharmaceutically acceptable disintegrants and about 0.1 % to about 1 % of the one or more extragranular pharmaceutically acceptable glidants and lubricants extragranularly wherein the percentage amount is by weight of the composition.

[0294] In some embodiments, the one or more additives are selected from antioxidants, solubilizing agents and surfactants. In some embodiments, the one or more additives are selected from antioxidants and solubilizing agents.

[0295] In some embodiments, the one or more antioxidants are any antioxidants known in the art. In some embodiments, the one or more antioxidants are one or more antioxidants as described above. In some embodiments, the one or more antioxidants are selected from ascorbic acid, tartaric acid, fumaric acid, citric acid, DL-a-tocopherol, TPGS, vitamin A, vitamin C, vitamin D, vitamin E, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, and combinations thereof. In some embodiments, the one or more antioxidants are selected from ascorbic acid and citric acid.

[0296] In some embodiments, the one or more solubilizing agents are any agents that are known to increase the solubility of an active agent. In some embodiments, the one or more solubilizing agents are selected from trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium hyaluronate, sodium alginate, chitosan and its derivatives, polyethylene glycol (PEG) and mono-, di- and triglycerides and mono- and diesters of PEG, glycerin, propylene glycol, Triacetin, N,N-dimethylacetamide, poly(vinyl pyrrolidone), Labrasol®, pyrrolidone, dimethyl sulfoxide, N-(-beta-Hydroxyethyl)- lactamide, 1-methyl-2-pyrrolidinone, triglycerides, monothioglycerol, sorbitol, lecithin, methylparaben, propylparaben, sodium taurocholate, poloxamer, copovidone, diethylene glycol monoethyl ethe (Transcutol®), propylene glycol, polyoxyethylene sorbitan (e.g. polysorbates, Tween), sodium lauryl sulfate, polyoxyl-ethylated castor oils (e.g. Cremophor®), poloxamer (e.g. Pluronic® and Lutrol®) and meglumine. In some embodiments, the one or more solubilizing agent is selected from sodium lauryl sulfate, poloxamer and meglumine.

[0297] In some embodiments, the one or more surfactants are any agent that is known in the art to lower the surface tension between a liquid and a solid that could improve the wetting of the active agent or improve the solubility of an active agent. In some embodiments, the one or more surfactants are selected from sodium lauryl sulfate, sodium laureth sulfate, fatty acid esters of polyoxyethylene sorbitan (e.g. polysorbates, Tween), polyoxyl-ethylated castor oils (e.g. Cremophor®), poloxamer (e.g. Pluronic® and Lutrol®), polyoxyethylene esters of 12-hydroxystearic acid (e.g. Solutol®), polyethylene glycol, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropyl cellulose ethers, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose ethers, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethylcellulose acetate stearate, noncrystalline cellulose, polyvinyl alcohol (PVA), polyvinylpyrrolidone / vinyl acetate copolymer, and poloxamines. In some embodiments, the one or more surfactants is selected from sodium lauryl sulfate and poloxamer.

[0298] In some embodiments, the one or more intragranular and extragranular pharmaceutically fillers (or diluents) are independently selected from lactose, mannitol, sorbitol, isomalt, xylitol, microcrystalline cellulose, silicified microcrystalline cellulose, calcium diphosphate, and starch and mixtures thereof. In some embodiments, the one or more intragranular and extragranular pharmaceutically fillers are independently selected from lactose, mannitol, and microcrystalline cellulose and mixtures thereof. In some embodiments, the one or more intragranular and extragranular pharmaceutically fillers are independently selected from mannitol, and microcrystalline cellulose and mixtures thereof.

[0299] In some embodiments, the one or more intragranular or extragranular pharmaceutically disintegrants are any agent known in the art which facilitates the break-upof a solid preparation or disintegration after administration or use. In some embodiments, the one or more intragranular or extragranular pharmaceutically disintegrants are independently selected from sodium starch gycolate, sodium alginate, carboxymethyl cellulose sodium, methyl cellulose, croscarmellose sodium, croscarmellose calcium, guar gum, low substituted hydroxypropyl cellulose and crospovidone and mixtures thereof. In some embodiments, the one or more intragranular or extragranular pharmaceutically disintegrants are independently selected from carboxymethyl cellulose sodium and crospovidone and mixtures thereof.

[0300] In some embodiments, the one or more intragranular and extragranular pharmaceutically lubricants are any agent known in the art that is added to a powder blend to prevent the compacted powder mass from sticking to the equipment during the tableting or encapsulation process. In some embodiments, the one or more intragranular and extragranular pharmaceutically lubricants are independently selected from magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, sodium stearyl fumarate, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, stearic acid, sucrose fatty acid esters and sodium benzoate and mixtures thereof. In some embodiments, intragranular and extragranular pharmaceutically the lubricant is magnesium stearate.

[0301] In some embodiments, the one or more intragranular and extragranular pharmaceutically glidants are any agent known in the art that are used in tablet and capsule formulations to improve flow-properties during tablet or capsule compression. In some embodiments, the one or more intragranular and extragranular pharmaceutically glidants are independently selected from calcium phosphate tribasic, powdered cellulose, silicon dioxide, magnesium silicate, magnesium trisilicate and talc and mixtures thereof. In some embodiments, the intragranular and extragranular pharmaceutically glidant is silicon dioxide.

[0302] A person skilled in the art will appreciate that there is overlap between the above described additives and excipients used in the pharmaceutical compositions herein, since a given additive or excipients is often classified differently by different person of skilled in the art or is commonly used for any of several different functions. The above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives.

[0303] In an exemplary embodiment, the oral pharmaceutical composition comprises: about 55% to about 65% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and HPMCAS wherein the HPMCAS is present in the amorphous solid dispersion in an amount of about 50% to about 60%, about 55% to about 65%, about 60% to about 65% or about 60% by weight of the amorphous solid dispersion;about 30% to about 35% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers; about 2% to about 4% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants; about 0.1 % to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants, and optionally about 0.5% to about 2% by weight of the composition of one or more intragranular pharmaceutically acceptable additives.

[0304] In some embodiments, in a further exemplary embodiment, the oral pharmaceutical composition comprises: about 55% to about 65% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and HPMCAS wherein the HPMCAS is present in the amorphous solid dispersion in an amount of about 60% to about 65% by weight of the amorphous solid dispersion; about 1% to about 2% by weight of the composition of one or more intragranular pharmaceutically acceptable additives; about 30% to about 35% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from mannitol and microcrystalline cellulose and mixtures thereof; about 2% to about 4% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants selected from carboxymethyl cellulose sodium and crospovidone and mixtures thereof; and about 0.1 % to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants.

[0305] In some embodiments, the oral pharmaceutical composition comprises: about 60% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and HPMCAS wherein the HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion; about 30% to about 35% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from an equal mixture of mannitol and microcrystalline cellulose;about 3% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants wherein the disintegrant is carboxymethyl cellulose sodium; about 0.1% to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants, and optionally about 0.5% to about 2% by weight of the composition of one or more intragranular pharmaceutically acceptable additives selected from antioxidants and solubilizers.

[0306] In some embodiments, the oral pharmaceutical composition comprises: about 60% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and HPMCAS wherein the HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion; about 32% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from an equal mixture of mannitol and microcrystalline cellulose; about 3% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants wherein the disintegrant is carboxymethyl cellulose sodium; and about 0.1% to about 1% by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants and optionally about 1 % to about 2% by weight of the composition of one or more intragranular pharmaceutically acceptable additives selected from antioxidants, solubilizers and surfactants.

[0307] In an exemplary embodiment, the oral pharmaceutical composition comprises: about 55% to about 65% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and HPMCAS wherein the HPMCAS is present in the amorphous solid dispersion in an amount of about 50% to about 60%, about 55% to about 65% or about 60% to about 65% by weight of the amorphous solid dispersion; about 30% to about 35% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers; about 2% to about 4% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants; and about 0.1% to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants.

[0308] In some embodiments, the oral pharmaceutical composition comprises:about 55% to about 65% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and HPMCAS wherein the HPMCAS is present in the amorphous solid dispersion in an amount of about 60% to about 65% by weight of the amorphous solid dispersion; about 30% to about 35% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from mannitol and microcrystalline cellulose and mixtures thereof; about 2% to about 4% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants selected from carboxymethyl cellulose sodium and crospovidone and mixtures thereof; and about 0.1% to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants.

[0309] In some embodiments, the oral pharmaceutical composition comprises: about 60% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and HPMCAS wherein the HPMCAS is present in the amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion; about 32% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from an equal mixture of mannitol and microcrystalline cellulose; about 3% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants wherein the disintegrant is carboxymethyl cellulose sodium; and about 0.1% to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants.

[0310] In some embodiments, the HPMCAS is HPMCAS-H. In some embodiments, the HPMCAS is HPMCAS-HG.

[0311] In an exemplary embodiment, the pharmaceutical composition comprises: about 35% to about 45% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and PVP / VA wherein the PVP / VA is present in the amorphous solid dispersion in an amount of about 50% to about 60%, about 55% to about 65% or about 60% to about 65% by weight of the amorphous solid dispersion; about 45% to about 55% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers;about 4% to about 8% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants; about 0.1 % to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants; and optionally about 1 % to about 2% by weight of the composition of one or more intragranular pharmaceutically acceptable additives.

[0312] In an exemplary embodiment, the oral pharmaceutical composition comprises: about 35% to about 45% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and PVP / VA wherein the PVP / VA is present in the amorphous solid dispersion in an amount of about 50% to about 60%, about 55% to about 65% or about 60% to about 65% by weight of the amorphous solid dispersion; about 45% to about 55% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers; about 4% to about 8% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants; and about 0.1% to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants.

[0313] In some embodiments, the oral pharmaceutical composition comprises: about 35% to about 45% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and PVP / VA wherein the PVP / VA is amorphous solid dispersion in an amount of about 60% to about 65% by weight of the amorphous solid dispersion; about 45% to about 55% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from mannitol and microcrystalline cellulose and mixtures thereof; about 4% to about 8% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants selected from carboxymethyl cellulose sodium and crospovidone and mixtures thereof; and about 0.1% to about 1% by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants. In some embodiments, the amorphous solid dispersion further comprises about 0.2% to about 0.5% of one or more antioxidants by weight of the amorphous solid dispersion.

[0314] In some embodiments, the oral pharmaceutical composition comprises: about 40% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and PVP / VA wherein the PVP / VA is amorphous solid dispersion in an amount of about 65% by weight of the amorphous solid dispersion; about 50% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from an equal mixture of mannitol and microcrystalline cellulose; about 6% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants wherein the disintegrant is crospovidone; and about 0.1% to about 1% by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants. In some embodiments, the amorphous solid dispersion further comprises about 0.2% to about 0.5% of one or more antioxidants by weight of the amorphous solid dispersion.

[0315] In some embodiments, the oral pharmaceutical composition comprises: about 25% to about 35% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and PVP / VA wherein the PVP / VA is present in the amorphous solid dispersion in an amount of about 40% to about 65% or about 45% to about 55% by weight of the amorphous solid dispersion; about 15% to about 25% by weight of the composition of HPMCAS; about 30% to about 40% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers; about 4% to about 8% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants; about 0.1 % to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants; and optionally about 1 % to about 2% by weight of the composition of one or more intragranular pharmaceutically acceptable additives.

[0316] In some embodiments, the oral pharmaceutical composition comprises: about 25% to about 35% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and PVP / VA wherein the PVP / VA is present in the amorphous solid dispersion in an amount of about 40% to about 65% or about 45% to about 55% by weight of the amorphous solid dispersion;about 15% to about 25% by weight of the composition of HPMCAS; about 30% to about 40% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers; about 4% to about 8% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants; and about 0.1 % to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants.

[0317] In some embodiments, the pharmaceutical composition comprises: about 25% to about 35% by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and a PVP / VA wherein the PVP / VA is present in the amorphous solid dispersion in an amount of about 45% to about 55% by weight of the amorphous solid dispersion; about 15% to about 25% by weight of the composition of HPMCAS; about 30% to about 40% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from mannitol and microcrystalline cellulose and mixtures thereof about 4% to about 8% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants selected from carboxymethyl cellulose sodium and crospovidone and mixtures thereof; and about 0.1 % to about 1 % by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants. In some embodiments, the amorphous solid dispersion further comprises about 0.2% to about 0.5% of one or more antioxidants by weight of the amorphous solid dispersion.

[0318] In some embodiments, the oral pharmaceutical composition comprises: about 31 % by weight of the composition of an amorphous solid dispersion comprising amorphous otenaproxesul or pharmaceutically acceptable salt thereof and a PVP / VA wherein the PVP / VA is present in the amorphous solid dispersion in an amount of about 50% by weight of the amorphous solid dispersion: about 21 % by weight of the composition of HPMCAS; about 36% by weight of the composition of one or more intragranular pharmaceutically acceptable fillers selected from an equal mixture of mannitol and microcrystalline cellulose;about 6% by weight of the composition of one or more intragranular pharmaceutically acceptable disintegrants wherein the disintegrant is crospovidone; and about 0.1% to about 1% by weight of the composition of one or more intragranular pharmaceutically acceptable glidants and lubricants. In some embodiments, the amorphous solid dispersion further comprises about 0.2% to about 0.5% of one or more antioxidants by weight of the amorphous solid dispersion.

[0319] In some embodiments, the oral pharmaceutical composition further comprises about 2% to about 8% of one or more extragranular pharmaceutically acceptable disintegrants selected from carboxymethyl cellulose sodium and crospovidone and mixtures thereof, and about 0.1% to about 1 % of one or more extragranular pharmaceutically acceptable glidants and lubricants extragranularly by weight of the composition.

[0320] In some embodiments, the oral pharmaceutical composition further comprises a film coat. In some embodiments, the film coat comprises one or more film-forming substances selected from hydroxypropyl methyl cellulose, polyethylene glycol, propyl cellulose, methyl cellulose, polyvinyl alcohol, polymethacrylates and carrageen and mixtures thereof. In some embodiments, the film coat is an Opadry® film coating system.

[0321] In some embodiments, the oral pharmaceutical compositions are formulated as solid or semi-solid oral formulations. In some embodiments, the oral pharmaceutical compositions are formulated as solid oral compositions or formulations.

[0322] In some embodiments, the oral pharmaceutical compositions are formulated in the form of a tablet such as ingestible tablets or buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions or suspensions, and the like.

[0323] In some embodiments, the pharmaceutical compositions are formulated for administration, or use, as a tablet.

[0324] In some embodiments, the present application includes methods of treating or preventing acute pain in a subject in need thereof comprising administering tablets comprising amorphous solid dispersions of the application comprising amounts of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof (e.g., loading doses and maintenance doses) as described in the regimens above. In some embodiments, the tablets comprise amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, dispersed in a polymer matrix formed from a pharmaceutically acceptable polymer; one or more pharmaceutical acceptable ingredients selected from the group consisting of one or more diluents, one or more disintegrants, one or more lubricants, one or more glidants; andoptionally one or more film coating agents as described herein. In some embodiments, the tablet is formulated to comprise a loading dose or a maintenance dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof as described herein.

[0325] In some embodiments, the loading dose or maintenance doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof are respectively provided in a single oral pharmaceutical composition of the application (i.e. dosage form). In some embodiments, the loading dose or maintenance dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof are provided as two or more pharmaceutical compositions of the application each comprising a divided dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, the divided doses adding up to the entire dose of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, each divided dose is the same or different. In some embodiments, each divided dose is the same.

[0327] In some embodiments, the loading dose or each maintenance dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof are independently divided into 2 to 6, 2 to 5, 2 to 4, or 2 to 3 divided doses which can be suitably formulated into 2 to 6, 2 to 5, 2 to 4, or 2 to 3 pharmaceutical compositions respectively comprising one divided dose, the divided doses adding up to the entire dose of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof

[0328] In an exemplary embodiment, the loading dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is divided into two to four divided doses which can be suitably formulated into two to four pharmaceutical compositions comprising one divided dose, the divided doses adding up to the entire dose of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the loading dose is 600 mg or 800 mg and the loading dose thereof and the loading dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is divided into three and four divided doses which can be suitably formulated into three and four pharmaceutical compositions comprising one divided dose of 200 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, respectively.Packages and Kits of the application

[0329] In some embodiments, the present application includes a pharmaceutical package or kit comprising: one oral loading dose comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, andinstructions for administration of the one oral loading dose of the amorphous otenaproxesul or the pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0330] In some embodiments, the package or kit further comprises a second oral loading dose comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0331] In some embodiments, the present application also includes a pharmaceutical package or kit comprising: one or two oral loading doses comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and one or more oral maintenance doses comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0332] In an exemplary embodiment, the package or kit comprises one or two oral loading doses of the amorphous otenaproxesul or the pharmaceutically acceptable salt thereof, two to eleven, five to eleven, seven to eleven, five to nine or seven to nine oral maintenance doses of the amorphous otenaproxesul or the pharmaceutically acceptable salt thereof.

[0333] In some embodiments, the pharmaceutical packages or kits of the application further comprises one or more oral placebo doses. In some embodiments, the one or more oral placebo doses are formulated as one or more oral pharmaceutical compositions.

[0334] In some embodiments, the pharmaceutical package or kit further comprises instructions for administration of the oral loading dose(s) or one or more oral maintenance doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof to a subject in need thereof and optionally the placebo doses. In some embodiments, the instructions direct administration of the oral loading doses or maintenance doses to the subject according to a method of treating or preventing acute pain as described herein.

[0335] In some embodiments, the present application further includes a package or kit comprising: two or more oral maintenance doses comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and instructions for administration of the two or more oral maintenance doses, to a subject in need thereof.

[0336] In an exemplary embodiments, the package or kit comprises two to eleven, five to eleven, seven to eleven, five to nine or seven to nine oral maintenance doses comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0337] In some embodiments, each oral loading dose or each oral maintenance dose (optionally, first maintenance dose, second maintenance dose and / or optionally third maintenance doses up to eighth maintenance dose) in the pharmaceutical packages or kits of the application comprise amounts of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof as described above.

[0338] In some embodiments, the one or more oral maintenance doses in the pharmaceutical packages or kits of the application are the same or are different. In some embodiments, the one or more oral maintenance doses are different and comprise first maintenance doses, second maintenance doses and / or optionally third maintenance doses up to eighth maintenance doses as described herein. In some embodiments, the one or more oral maintenance doses are different. In some embodiments, the one or more oral maintenance doses are tapered or are not tapered as described above.

[0339] In some embodiments, each oral loading dose or each oral maintenance dose is independently formulated into an oral amorphous solid dispersion of the application as described above. In some embodiments, each oral loading dose or each oral maintenance dose is independently formulated into an oral pharmaceutical composition of the application as described above.

[0340] In some embodiments, each oral loading dose or each oral maintenance dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof are respectively formulated into a single oral pharmaceutical composition of the application in the pharmaceutical package or kit. In some embodiments, each oral loading dose or each oral maintenance dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is formulated into two or more oral pharmaceutical compositions of the application each comprising a divided dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, the divided doses adding up to the dose of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

[0341] In some embodiments, the pharmaceutical packages or kits of the application further comprises one or more oral placebo doses. In some embodiments, the one or more oral placebo doses are formulated as one or more oral pharmaceutical compositions.

[0342] In some embodiments, the oral pharmaceutical compositions of the application are tablets, caplets or capsules. In some embodiments, the oral pharmaceutical compositions of the application are tablets.

[0343] In some embodiments, the pharmaceutical packages or kits are adapted and arranged to carry out any method of the present application.In some embodiments the package or kit will identify the oral loading dose(s) and / or the subsequent one or more oral maintenance doses for the course of treatment period. Therefore, in some embodiments, the package or kit further comprise identifiers to identify the oral pharmaceutical compositions and / or to designate a daily course of treatment for specific doses consistent with the methods and uses described herein. In some embodiments, the identifiers identify the pharmaceutical compositions by number or day, for example, by the day of the treatment period the pharmaceutical composition is to be administered. For example, in some embodiments, the pharmaceutical composition comprising the loading dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is identified as “1” or “Day 1”. In some embodiments, the treatment period is 14 days or less, 13 days or less, 12 days or less, 11 days or less, 10 days or less, 9 days or less, 8 days or less, 7 days or less, 6 days or less, 5 days or less, 4 days or less, 3 days or less, 2 days or less or 1 day. In some embodiments, the treatment period is 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the treatment period is for 7 days, 6 days, 5 days or 4 days. In some embodiments, the treatment period is 5 days.

[0344] In some embodiments, the package or kit is a blister pack, a pill dispenser, a clam shell dispenser or tray. In some embodiments, each oral pharmaceutical composition of the application comprising a dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof; or two or more oral pharmaceutical compositions of the application each comprising a divided dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, the divided doses adding up to the entire dose of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, is contained within one blister in the blister pack or one compartment in the pill or clam shell dispenser or tray.

[0345] In some embodiments, the blister pack, pill dispenser, clam shell dispenser or tray comprises one or two oral loading doses and / or one or more oral maintenance doses sufficient for a treatment period of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day. In some embodiments, the blister pack comprises one or two oral loading doses and / or one or more oral maintenancedoses sufficient for a treatment period of 13 days, 8 days, 7 days, 5 days, 3 days, 2 days or 1 day. In some embodiments, the package or kit is a blister pack.III. Methods of Preparation

[0346] In some embodiments, the amorphous solid dispersions of the application are prepared by any suitable microprecipitation process known in the art. In some embodiments, the amorphous solid dispersions are prepared by spray drying (or lyophilization), melt extrusion, freeze drying, rotary evaporation, solvent-controlled precipitation, pH-controlled precipitation, drum drying, supercritical fluid technology or other solvent removal process. In some embodiments, the amorphous solid dispersions are prepared by spray drying. Therefore, the amorphous solid dispersions of the application are spray-dried solid dispersions (SDDs).

[0347] Spray drying is a process well known to those skilled in the art for preparing amorphous solid dispersions. In some embodiments, the amorphous solid dispersions are prepared by spray-dried solid dispersion, fluidized bed spray-dried solid dispersion, or spray granulation solid dispersion techniques known in the art.

[0348] In some embodiments, the spray drying comprises dispersing or dissolving otenaproxesul or a pharmaceutically acceptable salt thereof and the polymer(s) and optionally sustaining agent in a suitable solvent to form a feed solution, pumping the feed solution through an atomizer into a drying chamber, and removing the solvent to form the amorphous solid dispersion in the drying chamber. In some embodiments, the drying chamber uses hot gases, such as forced air, nitrogen, nitrogen-enriched air, or argon to dry particles. In some embodiments, the feed solution is atomized by conventional means known in the art, such as a two-fluid sonicating nozzle and a two-fluid non-sonicating nozzle. In some embodiments, the spray drying comprises dissolving otenaproxesul or a pharmaceutically acceptable salt thereof and the polymer(s).

[0349] In some embodiments, spray drying is carried out using standard equipment used for spray drying. In some embodiments, spray-drying processes and spray-drying equipment are described generally in Perry’s Chemical Engineers’ Handbook, Sixth Edition (R. H. Perry, D. W. Green, J. O. Maloney, eds.) McGraw-Hill Book Co. 1984, page 20-54 to 20-57.

[0350] In some embodiments, the suitable solvent is any solvent or mixture of solvents in which both the drug substance and the polymer have adequate solubility, e.g. solubility that is greater than about 1 mg / ml. In some embodiments, the suitable solvent is selected from dichloromethane, chloroform, ethanol, methanol, 2-propanol, ethyl acetate, acetone, water or mixtures thereof. In some embodiments, the suitable solvent is acetone.

[0351] In some embodiments, the amorphous solid dispersion is dried following preparation to remove any residual solvent, for example to remove solvent to International Council for Harmonisation (ICH) limits. In some embodiments, the amorphous solid dispersion is dried at a temperature of about 30°C to about 50°C, or about 40°C, for about 20 hours to about 30 hours, or about 24 hours, under reduced pressure in an inert gas atmosphere.

[0352] In some embodiments, the amorphous solid dispersion is formulated as a granule e.g., by a granulation process, and may include one or more intragranular excipients such as fillers, disintegrants, lubricants and glidants. In some embodiments, the granulation process is any suitable granulation process known in art. In some embodiments, the granulation process is by wet granulation or dry granulation (such as via roller compaction).

[0353] In some embodiments, the granules and extragranular disintegrants, lubricants and glidants are combined and compressed into a solid oral dosage form such as tablet by conventional processes known herein and as described in the Examples section below.

[0354] Otenaproxesul can be prepared by various synthetic processes. The selection of a particular process is within the purview of the person of skill in the art. For example, otenaproxesul can be prepared by methods known in the art, for example, by the methods disclosed in US 8,541 ,398.

[0355] Salts of otenaproxesul may be formed by methods known to those of ordinary skill in the art, for example, by reacting otenaproxesul with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in aqueous medium followed by lyophilization.

[0356] Throughout the processes described herein it is to be understood that, where appropriate, suitable protecting groups will be added to and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in “Protective Groups in Organic Synthesis”, T.W. Green, P.G.M. Wuts, Wiley-lnterscience, New York, (1999). It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final product, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to one skilled in the art. Examples of transformations are given herein and it is to be understood that the described transformations are not limitedonly to the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, “Advanced Organic Chemistry”, March, 4thed. McGraw Hill (1992) or, “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquidliquid or solid-liquid extraction, which will be readily understood by one skilled in the art.EXAMPLES

[0357] The following non-limiting examples are illustrative of the present application:Example 1: Phase 1 single ascending dose (SAD) clinical trial (State of the art)

[0358] Otenaproxesul (crystalline form) was orally administered at a range of doses to healthy volunteers, both as a single dose, and as a daily (or twice-daily) dose for 14 days. Each cohort consisted of 8 subjects, with 6 receiving otenaproxesul and 2 receiving placebo. A total of 8 cohorts were studied in the single-dose study (25 mg, 75 mg, 150 mg, 300 mg, 500 mg, 1000 mg, 1500 mg and 2000 mg), and 3 cohorts in the multiple-dose study (250 and 750 once daily, and 750 mg bid (e.g., 1500 mg / day) for 14 days). All adverse events were recorded, and blood samples were drawn prior to and for at least 72 h after drug administration for measurement of otenaproxesul-derived naproxen levels. Routine cardiovascular, renal, hepatic and hematological biomarkers were monitored, along with clinical signs. Multiple ascending dose studies examined otenaproxesul at doses of 250 and 750 mg once daily, and 750 mg twice daily.

[0359] Otenaproxesul single dose treatment did not produce any serious adverse events across the dose-ranges studied, nor were there any significant gastrointestinal, cardiovascular renal, or hematological findings associated with administration of this drug. As initially observed in animal pharmacokinetics, otenaproxesul administration to humans resulted in a marked prolongation of therapeutically relevant levels of naproxen in the blood, supporting the possibility of once daily dosing for both acute and chronic conditions (Figure 1).

[0360] Otenaproxesul was very well tolerated and shown to be safe at all single, once daily administered dose levels. These studies suggest a high level of safety of this drug.Example 2: A double-blind, placebo-controlled, 4-arm, phase 2b study to assess the efficacy and safety of a 14-day dosing regimen of 3 closes of otenaproxesul versus placebo, orallyadministered once daily to male and female patients diagnosed with osteoarthritis of the knee (State of the art)

[0361] This study evaluated the efficacy of a 14-day dosing regimen of crystalline otenaproxesul at doses of 150 mg, 200 mg and 250 mg compared to placebo in reducing osteoarthritis knee pain (a chronic pain condition) as measured by changes in the posttreatment Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscale pain score relative to each patient’s pretreatment baseline WOMAC assessment. In patients with bilateral knee osteoarthritis, the most painful knee (index knee) or if in both knees of equal pain, then 1 index knee was noted and has been used for the WOMAC assessments throughout the study. The three doses were selected based on state-of-the-art knowledge of efficacy and safety for otenaproxesul at the time of the trial.Methodology:

[0362] This study was a double-blind, placebo-controlled Phase 2B study that explored 3 different doses (150 mg, 200 mg, and 250 mg) of orally administered crystalline otenaproxesul in male and female patients diagnosed with osteoarthritis of the knee. Patients were randomly assigned in a 2:2:1 :1 allocation ratio to otenaproxesul 250 mg, 200 mg, 150 mg, or placebo.

[0363] 384 patients were enrolled and treated during the study including 61 , 125, and132 patients in the otenaproxesul 150 mg, 200 mg, and 250 mg treatment groups, respectively and 66 patients in the placebo group.

[0364] Otenaproxesul was supplied as 150 mg, 200 mg, and 250 mg white, film-coated tablets in which the otenaproxesul was in crystalline form. Patients were instructed to take 1 tablet of otenaproxesul or placebo in the morning after an overnight fast. Food intake was restricted until at least 30 minutes after the morning dose.

[0365] Single time point plasma samples were taken on Days 1 , 4 and 14 of treatment for the measurement of the principal otenaproxesul metabolite, naproxen.

[0366] Whole blood samples were collected pre-treatment for the measurement of genetic variants (polymorphic forms) of the naproxen metabolizing enzyme CYP2C9.

[0367] Whole blood samples were taken pre-treatment and on Days 1 , 4 and 14 for the measurement of thromboxane B2 as an index of cyclo-oxygenase enzyme inhibition. Thromboxane B2levels were measured using the Thromboxane B2Elisa Kit from Cayman Chemical, Ann Arbor Michigan. Instructions provided with the Kit were followed.Efficacy Analysis

[0368] All patients who received 1 dose of study drug (otenaproxesul or placebo) and had at least 1 post-baseline WOMAC pain subscale score observation were included in the primary population for the analysis of efficacy (modified-intent-to-treat population [mITT]). Patients who met the criteria for the primary efficacy analyses and had no major protocol violations that could have impacted the assessment of efficacy (per protocol population [PP]) were evaluated as a supportive analysis. The primary and secondary endpoints were analyzed using a maximum likelihood mixed model repeated measure (MM RM). The model included treatment, visit, baseline WOMAC pain score, and treatment-by-visit interaction as fixed effects, and patient as a random effect. Dose-response analysis was conducted by using a contrast statement to the least squares (LS) means on Day 14 between the dose levels of otenaproxesul and placebo. For patients who received rescue medication within 12 hours before an efficacy assessment, the assessments at that visit were disregarded and considered missing. Analysis of the WOMAC pain subscale score, including the MMRM analysis and descriptive summary, were also presented by sex (male, female) in a subgroup analysis.Pharmacokinetics and Pharmacodynamics Analyses

[0369] The average plasma concentrations for all patients in each treatment group as well as a comparison of the plasma naproxen concentrations for male and female patients within each of the three otenaproxesul treatment arms was assessed.

[0370] The genetic distribution of all genetic variants (polymorphic forms) of the naproxen metabolizing enzyme CYP2C9 are listed for patients with samples available in each treatment group as well as variant distribution for male and female patients within each of the 4 treatment arms.

[0371] Thromboxane B2levels for all patients in each treatment group were presented in a listing.Efficacy Results

[0372] Treatment with crystalline otenaproxesul demonstrated clinically and statistically significant improvement in WOMAC pain, stiffness, and Difficulties Performing Daily Activities (DPDA) subscale scores from Baseline to Day 14 in patients with osteoarthritis of the knee. The study met its primary endpoint for the otenaproxesul 250 mg and 200 mg treatment group comparisons that were powered for formal hypothesis testing. Note, the p- values for the analysis of the secondary efficacy endpoints are to be considered nominal, as no additional alpha adjustments were made.Plasma Naproxen Measurement Results

[0373] Plasma samples were taken at a single time point approximately four hours after dosing on Days 1 , 4, and 14 and analyzed for otenaproxesul metabolite naproxenconcentrations. Comparison of plasma naproxen was made for all patients across the three otenaproxesul treatment groups and by gender within each otenaproxesul treatment group.

[0374] It was noted that female patients had consistently higher levels of plasma naproxen than male patients on Days 1 , 4 and 14 of drug administration regardless of treatment dose.Pharmacodynamic Results

[0375] Blood samples taken pre-drug administration showed no significant differences among the 4 groups with respect to plasma TXB2 concentrations. On Day 1 , significant suppression of TXB2 levels was seen across the 3 otenaproxesul treatment groups. Similar, profound inhibition of TXB2synthesis was also evident on Days 4 (p<0.001) and 14 (p<0.001) in the groups treated with otenaproxesul.Safety Results

[0376] A similar percentage of patients, including 40.9% of patients in the otenaproxesul treatment groups and 36.4% of patients in the placebo dose group experienced at least 1 Treatment Emergent Adverse Event (TEAE) during the study. In the otenaproxesul group, the incidence of TEAEs between the otenaproxesul treatment groups was comparable, ranging from 37.7% patients in the 150 mg treatment group to 43.9% patients in the 250 mg treatment group. The most common TEAEs included hepatic enzyme increased (8.2%) and headache (5.0%). In the placebo group, the most commonly reported TEAE was diarrhea (7.6%).

[0377] The majority of otenaproxesul liver associated TEAEs were alanine aminotransferase (ALT) and / or aspartate aminotransferase (AST) liver transaminase elevations. None of these TEAEs were observed during the 14-day treatment period but were captured at the Day 24 / Early Termination (ET) follow up assessment. Across the otenaproxesul treatment groups, treatment-related increases in ALT and / or AST transaminase levels, the majority of which were rated as mild, were noted in 9.8% (6 / 61) of patients in the 150 mg arm, 7.2% (9 / 125) of patients in the 200 mg arm and 12.9% (17 / 132) patients in the 250 mg arm.

[0378] The higher treatment-related transaminase increases were found to occur more frequently among female patients across the three otenaproxesul treatment groups.

[0379] There were no abnormal data trends seen in the hematology, chemistry (excluding liver enzymes), or urinalysis laboratory test results during the study. No patients died during the study. No patients were discontinued or withdrawn from the study due to liver associated TEAEs and no patient in any treatment arm met the criteria for a Hy’s law case.Gastrointestinal (Gl) Safety Results

[0380] Otenaproxesul was well tolerated at all three administered doses over the 14- day treatment period. Gastrointestinal disorder TEAEs were comparable among patients receiving placebo (18.2%) and patients receiving otenaproxesul (14.5%) and of the 15 patients across the three otenaproxesul treatment arms who were prematurely discontinued from the study, none were discontinued due to TEAEs related to gastrointestinal adverse effects. This Gl safety result is a significant advantage of otenaproxesul over naproxen. It is known in the art that an efficacious dose of naproxen causes noticeable Gl injury in approximately 30% of patients.Renal Safety Results

[0381] No clinically meaningful renal adverse events were reported for any patient. Six patients experienced a urinary tract infection. Pollakiuria and hematuria were noted in one patient each. With one exception, all on-study measures of renal function including serum creatinine, uric acid and electrolytes remained within the normal range or exhibited transient, non-clinically significant changes during the study drug administration period. One 70-year- old female patient treated with otenaproxesul 200 mg for 14 days exhibited a 1 ,5x ULN value for serum creatinine at the Day 24 assessment.Cardiovascular Safety Results

[0382] Mean changes from Baseline to Day 24 / End of Treatment in systolic and diastolic blood pressure and heart rate were small, similar across treatment groups, and not clinically relevant. Single nonserious events of hypertension or blood pressure increased were reported in 2 (1 .6%) patients and 2 (1 .5%) patients in the otenaproxesul 200 mg and 250 mg treatment groups, respectively. All events of hypertension or blood pressure increased were reported as resolved during the study. A single event of hypotension was noted in 1 (0.8%) patient in the otenaproxesul 200 mg treatment group and was also reported as resolved during the study. No patients in the otenaproxesul 150 mg treatment group or in placebo group experienced an event of hypertension or hypotension.Summary and Conclusions

[0383] The primary objective of this study was to evaluate the efficacy of a 14-day dosing regimen of otenaproxesul (ATB-346), where the otenaproxesul in the composition was in crystalline form, at doses of 150 mg, 200 mg and 250 mg compared to placebo, selected based on state-of-the-art knowledge of the efficacy and safety profiles for otenaproxesul known at the time of the trial. This Phase 2B study enrolled a total of 387 patients diagnosed with osteoarthritis of the knee, randomized in a 2:2:1 :1 allocation ratio to receive otenaproxesul250 mg, 200 mg, 150 mg, or placebo. In the otenaproxesul group, 61 patients, 125 patients, and 132 patients received otenaproxesul 150 mg, 200 mg, or 250 mg, respectively. Sixty-six patients received placebo. Most patients (96.1 %) completed the study.

[0384] Treatment with otenaproxesul, where the otenaproxesul in the composition was in crystalline form, demonstrated clinically and statistically significant improvement in WOMAC pain, stiffness, and DPDA subscale scores from Baseline to Day 14.

[0385] Safety was evaluated throughout the study by monitoring Aes, clinical laboratory assessments, physical examination data, vital signs, and concomitant medications.

[0386] A single time point measurement of naproxen, the principal otenaproxesul metabolite in plasma was conducted on patients in all otenaproxesul treatment groups on Day 1 , Day 4 and Day 14 of treatment. To assess the effect of otenaproxesul on the inhibition of cyclo-oxygenase enzymes, circulating plasma levels of the inflammatory biomarker, thromboxane B2 were measured pre-treatment and at Days 1 , 4 and 14 of treatment. Finally, to assess the potential effect of cytochrome P450 polymorphism on the metabolism of otenaproxesul-derived naproxen, blood samples were taken from all patients to characterize the polymorphic variation of CYP2C9.

[0387] Regardless of treatment dose, female patients were found to have consistently higher levels of plasma naproxen than male patients on Days 1 , 4 and 14 of drug administration.

[0388] Blood samples taken pre-drug administration showed no significant differences among the 4 groups with respect to plasma thromboxane B2 concentrations. On Day 1 , significant suppression of thromboxane B2 levels was seen across the 3 otenaproxesul treatment groups (p<0.001). Similar, profound inhibition of thromboxane B2 synthesis was also evident on Days 4 and 14 (p<0.001) in the groups treated with otenaproxesul.

[0389] In summary, treatment with otenaproxesul, where the otenaproxesul in the composition was in crystalline form, at 200 mg and 250 mg once daily demonstrated statistically significant efficacy in reducing WOMAC pain, stiffness, and DPDA subscale scores in patients with osteoarthritis of the knee. Daily treatment with the otenaproxesul at 150 mg demonstrated a positive reduction in pain, stiffness and DPDA (reaching statistical significance on Day 4 for stiffness), as well as marked reduction in plasma thromboxane B2levels on par with reductions observed in patients treated with 200 mg and 250 mg.Example 3: Plasma Naproxen Metabolite Measurements After Otenaproxesul Administration (State of the art)

[0390] Plasma samples were taken at a single time point approximately four hours after dosing on Days 1 , 4, and 14 with 150 mg, 200 mg and 250 mg of otenaproxesul (where the otenaproxesul in the composition was in crystalline form) and analyzed for otenaproxesul metabolite naproxen concentrations.

[0391] Sample Preparation and Extraction: A 75 pL aliquot of each sample (calibration standards / quality controls / samples) was aliquoted into pre-labelled tubes. To each aliquoted sample, 300 pL of working internal standard solution (500 ng / mL of IS in acetonitrile / methanol, 75 / 25, v / v) was added (Exception: 300 pL of acetonitrile / methanol (75 / 25, v / v) was added to double blank). All tubes were vortexed adequately, followed by centrifugation at 13000 rpm for 5 minutes. A 150 pL aliquot of the organic supernatant was transferred to clean glass tubes. After evaporation at 40°C, the dry residues were reconstituted in 300 pL of USP Purified Water, followed by adequate vortexing. The prepared samples were injected into an LC-MS / MS system which comprised a 6400 Series MS / MS instrument coupled to an Agilent Model 1200 Series liquid chromatography pump and a CTC PAL autosampler.

[0392] Comparison of plasma naproxen metabolite was made for all patients across the three otenaproxesul treatment groups and by gender within each otenaproxesul treatment group.

[0393] Female patients were found to have consistently higher levels of plasma naproxen than male patients on Days 1 , 4 and 14 of drug administration. Blood samples for metabolite analyses were collected in coded pre-cooled 4 mL sodium heparin Vacutainers by direct venipuncture. Samples were measured by LC-MS using a validated assay for the measurement of naproxen in human plasma samples.

[0394] This study also looked at levels of TXB2and found no significant differences in TXB2levels between males and females at each dose and time point.Example 4: Investigation of sex-based dosage for otenaproxesul via Pharmacokinetics (PK) / Pharmacodynamics and Absorption, Metabolism, Excretion (AME) Clinical Study (State of the Art)

[0395] The trial described in this example was designed to test the efficacy (via thromboxane inhibition as a proxy biomarker) and safety of <150 mg / day (for example 75 mg / day, 100 mg / day or 125 mg / day) of otenaproxesul, where the otenaproxesul in the composition was in crystalline form, in otherwise healthy older adults, ages 40-75, and also to identify ideal sex-based dosages for otenaproxesul. The study was designed in part on the observation that across the otenaproxesul treatment groups, treatment-related >3 x ULN (“upper limit of normal”) ALT and / or AST transaminase levels were noted (almost exclusively after the 14-day dosing interval) in 9.8% (6 / 61) of patients in the 150 mg arm, 7.2% (9 / 125) ofpatients in the 200 mg arm and 12.9% (17 / 132) patients in the 250 mg arm, with this issue being substantially biased towards females),

[0396] In this clinical trial, 28-day human safety / PK data was generated to complement the 14-day DRF data from Example 2. Biomarker data / dose (e.g., thromboxane B2) were also generated using standard ELISA assay kits.Research Population

[0397] Healthy older volunteers (for example, age 40-70) were enrolled. Patients with well-managed, depression, hypertension, type-2 diabetes are allowed. None demonstrated acute pain conditions. All serum chemistry must be WNL at study start. At least 50% of all females across both Study A and Study B were post-menopausal.

[0398] Healthy older volunteers (age 40-70) were enrolled and treated during the study, including 60 female volunteers (Study Group A) and 60 male volunteers (Study Group A).

[0399] Otenaproxesul was supplied as 75 mg, 100 mg and 125 mg, brown, film-coated tablets and was in crystalline form. Patients were instructed to take 1 tablet of otenaproxesul in the morning after an overnight fast. Food intake was restricted until at least 30 minutes after the morning dose.Study groups and Doses

[0400] The study enrolled a total of 42 subjects on either a 75 mg or 100 mg dose per day of otenaproxesul, of whom 35 had completed the 28-day drug administration period, with seven subjects having been administered the drug for 21 days before the study was paused. Whole blood was taken pre-treatment and on set days after treatment for the measurement of biomarkers, for example, thromboxane B2, alanine aminotransferase, aspartate aminotransferase, bilirubin, alkaline phosphatase, and indicators such as otenaproxesul metabolites.

[0401] Three subjects in the 100 mg cohort, who had completed the full drug administration period, exhibited liver transaminase elevations exceeding five times the upper limit of normal, triggering the required pause. Other indicators of liver function for these subjects were normal. The study incorporated an in-clinic post-administration observation period of 14 days.Example 5: Liver transaminase elevations (LTE) for crystalline otenaproxesul at various dosing schedules

[0402] As noted above, the plasma naproxen metabolite levels from the clinical trials were examined and it was determined that a plasma naproxen metabolite (M25) of >10 to 15 pg / mL is associated with a therapeutic effect. Ideally, these plasma levels of M25 should be reached within one hour after administration of otenaproxesul. Detailed analysis of the plasma naproxen concentrations from the clinical trial indicated that single doses of, for example, about 75 mg to about 250 mg of otenaproxesul, where the otenaproxesul in the composition was in crystalline form, in a treatment naive subject would likely not have the desired pharmacokinetic properties to enable rapid attainment of a therapeutic M25 concentration of >10 to 15 pg / mL.

[0403] Analysis of the clinical data showed that there were no observed adverse liver effects, specifically transient elevations of liver transaminases at any single dose of the otenaproxesul between 25 mg to 2000 mg or at multiple dose administrations of the otenaproxesul at doses of 150 mg, 200 mg or 250 mg for seven days. When liver safety findings are observed, cumulative naproxen metabolite plasma drug exposure over the prescribed treatment period exceeded 4000 pg*hr / mL.

[0404] Table 1 summarizes the plasma naproxen metabolite exposure data for both liver-safe and liver-adverse otenaproxesul treatment protocols.Table 11- Total = [(283 pg*hr / mL x 6 days) + 396 pg*hr / mL terminal phase] = 1698 + 396 = 2094 pg*hr / mL2-ltalicized numbers are imputed or extrapolated from existing pharmacokinetic data.

[0405] Based on the surprising results in Table 1 , it was proposed that dosing schemes for otenaproxesul would need to generate M25 plasma AUC0-«. level below 4000 pg*hr / mL to enhance liver safety. Additionally, desired dosing schemes should achieve a plasma naproxen metabolite (M25) of >15 to 20 pg / mL within 60 minutes of dosing, or about >10 to 20 pg / mL within about 30 min to about 60 min of dosing.

[0406] Liver safety related to treatment regimens not exceeding the proposed 4000 pg*hr / mL total AUC plasma M25 exposure were confirmed in a clinical study in which three cohorts consisting of 16 healthy subjects (8 males / 8 females) per group were administered one of three crystalline otenaproxesul treatment regimens. Data were collected over a 312- hour period at protocol-specified intervals. Sampling was most frequent during the first 2 hours post drug administration. Treatment regimens were (i) otenaproxesul single dose 1500 mg (Total 1500 mg); (ii) crystalline otenaproxesul Day 1 single dose 1500 mg plus 100 mg on Days 2-5 (Total 1900 mg) or (iii) crystalline otenaproxesul single dose 2000 mg (Total 2000 mg). No subjects in any ofthe three treatment arms exhibited any liver adverse effects. Plasma exposure calculations are shown in Table 2 below.Table 2Example 6: Analysis of 2000 mg doses - regimens for safety and efficacy

[0407] It is noted from the pharmacokinetic curves in Figure 1 showing naproxen metabolite (M25) plasma levels following single dose crystalline otenaproxesul administrations in healthy subjects from the Phase 1 single ascending dose (SAD) study in Example 1 , the time to attain maximal plasma concentration of M25 varies widely between 6 and 48 hours across the dosage spectrum. However, while the Cmax of the 2000 mg dose is 24 hours, it is noted that it also exhibited a “pseudo-Cmax” at 2 hours of greater than >10 pg / mL to 15 pg / mL that would provide sufficient M25 concentrations within the first two hours and potentially alleviate pain (these values for the optimal plasma naproxen metabolite levels were determined from an analysis of the Phase I and Phase II clinical trials). Further, it is noted that the naproxen metabolite plasma levels greater than >10 to 15 pg / mL were maintained for the entire 72 hours test period. Therefore, while not being bound by theory, a single 2000 mg treatment is predicted to provide pain relief for 3 days and possibly to 5 days based upon measured and projected M25 plasma concentrations. If a supplemental dose were required after day 3, any single dosage strength 1500 mg could be administered without exceeding the cumulative naproxen (M25) metabolite plasma drug exposure of 4000 pg*hr / mL.

[0408] Table 3 summarizes the plasma concentration levels of naproxen metabolite over time following administration of 2000 mg of crystalline otenaproxesul.Table 3

[0409] The above 2000 mg dose was provided to subjects as 8x 250 mg tablets. A further study was conducted where the 2000 mg dose of crystalline otenaproxesul was provided to 16 subjects as smaller 10x 200 mg tablets. Table 4 summarizes the plasma concentration levels of naproxen metabolite over time following administration of the smaller tablets 200 mg tablets. It can be seen that administration of 2000 mg of crystalline otenaproxesul in smaller tablets resulted in a faster dissolution, with a Cmax at approximately 4 hours.Table 4

[0410] These results confirm the proposal that a faster dissolution rate can be achieved by lowering the concentration of otenaproxesul in each individual tablet. However,the administration of 10 tablets to a subject as to obtain the desired dosage amount would likely not be clinically viable.Example 7 Amorphous otenaproxesul[0041 1] Amorphous otenaproxesul was obtained using slow evaporation crystallization wherein saturated solutions obtained after removing solids from slurry experiments were allowed to slowly evaporate as described below.

[0412] Slurry: Based on the initial solubility screen, a volume (either 0.5 or 2 mL) of solvent was added to as received crystalline otenaproxesul and stirred for 3 or 10 days at 25 °C. If solids were present after the 3 or 10 day slurry was complete, the solids were isolated by centrifuge filtration. The isolated solids were analyzed by XRPD and then dried at 40 °C and analyzed again by XRPD. If any new forms were observed in the XRPD diffractogram, then additional characterization was done by TGA, DSC and PLM.

[0413] Slow Evaporation: Saturated solutions obtained from 10 day slurry of crystalline otenaproxesul in different solvents were allowed to slowly evaporate uncapped at ambient temperature in a solvent hood until solvent evaporated (ca. 3 — 7 days). Solids were analyzed by XRPD before and after drying at 40 °C.

[0414] Amorphous otenaproxesul was obtained using slow evaporation crystallization process with isopropanol as solvent.

[0415] The glass transition temperature of amorphous otenaproxesul was determined to be 37°C.

[0416] Amorphous otenaproxesul was also found to have a tendency to crystallize, for example, on standing and during routine work up procedures.Example 8A: Exemplary amorphous solid dispersions comprising otenaproxesul and compositions thereof

[0417] Exemplary amorphous solid dispersions 1 -8 were prepared by spray-drying. The weight ratio of otenaproxesul (or ATB-346) to polymer (and optionally to antioxidant) in the exemplary amorphous solid dispersions (ASD) as well as parameters used to manufacture the exemplary amorphous solid dispersions (ASD) are provided in Table 5.Table 5Example 8B: Additional exemplary amorphous solid dispersions comprising otenaproxesulAmorphous solid dispersions

[0418] Additional polymers were evaluated for their use to form amorphous solid dispersions of otenaproxesul as shown in tables 5A to 50

[0419] Amorphous solid dispersions were obtained by spray-drying using a Yamato Pulvis Basic Unit, model GB-210 Lab Spray Dryer with two-fluid nozzle model GF-300, internal nozzle diameter 711 pm at batch size of 10, 50 and 100 g / lot.

[0420] Spray drying solution: The polymer was dispersed into the solvent and mixed by magnetic stirring. Otenaproxesul (ATB-364) was then added and mixed until completely dissolved. For the amorphous solid dispersion in which the polymer was insoluble in acetone, two solutions were separately prepared: 1) otenaproxesul in acetone and 2) polymer in DCM, MeOH or mixtures of DCM / MeOH then both solutions were mixed, and no recrystallization occurred.

[0421] Spray drying process: The liquid flow rate was 15±2 g / min; inlet temperature 70±5oC except for PEG containing dispersions which was done at lower temperature, outlet temperature was NMT 50°C; atomization air pressure 0.20±0.05 MPa and drying gas flow rate 0.3-0.4 m3 / min. After all liquid was sprayed the heating was stopped and the spray dried material was allowed to cool down to 35°C before stopping the blower. The spray-dried material was transferred from the spray-dryer to a vacuum oven at 45±5°C and -25±2 in Hgfor secondary drying. For PEG8000 only amorphous solid dispersion secondary drying was done at RT / vacuum -25 in Hg.Table 5 A: ASD No 1Table 5 B: ASD No 9Table 5 C: ASD No. 10Table 5 D: ASD No. 11Table 5 E: ASD No 12Table 5 G: ASD No. 8* HPMC E3 insoluble in Acetone, ATB-364 partially soluble in MeOH and in DCM, both are soluble in 70:15:15 w / w solvent mixtureTable 5 H: ASD No 14Table 5 I: ASD No 15

[0422] *PVP K-30 insoluble in Acetone, ATB-364 partially soluble in DCM, both are soluble in 70:30 w / w solvent mixtureTable 5 J: ASD No 16*PAA insoluble in Acetone, ATB-364 partially soluble in MeOH, both are soluble in 70:30 w / w solvent mixtureTable 5 K: ASD No 17Hypromellose insoluble in Acetone, ATB-364 partially soluble in MeOH and in DCM, both are soluble in 70:15:15 w / w solvent mixture.Table 5 L: ASD No 18Table 5 M: Formulation No. 1*PEG800 insoluble in Acetone, ATB-364 partially soluble in DCM, both are soluble in 70:30 w / w solvent mixtureTable 5 N: Formulation No. 2* HPMC E15 insoluble in Acetone, agglomeration of polymer by contact with API -acetone solutionTable 5 O: Formulation No. 3*PEG 3350 insoluble in Acetone, ATB-364 partially soluble in DCM, both are soluble in 70:30 w / w solvent mixture

[0423] Completely dissolved otenaproxesul and polymer spray-drying solutions were obtained using PEG3350 (Table 50) and PEG8000 65% (Table 5M) however no spray dried material was obtained. A sticking film on the cyclone was obtained from both polymers at all inlet temperatures tested (PEG8000, 70°C; PEG3350, 65°C; and PEG8000, 52°C). Formulations with HPMCE15 (Table 5 N), precipitation of the polymer HPMCE15 was observed when the polymeric DCM / MeOH solution was mixed with the API-acetone solution. The spray-drying was not done. Formulation with 35% PEG8000, Table 5 L) spray-dried material was sticky after spray-drying but became non-sticky powder after secondary drying (22 hours at RT / -25 in Hg).Physical Characterization Of Amorphous solid dispersions i) Residual solvent:

[0424] Thermal Gravimetric Analysis (TGA) was used to determine the level of residual solvent and moisture (volatile content) after spray drying and secondary drying. The analysis was performed using a TA Instrument Q50 thermogravimetric analyzer at scanning speed of 10°C / min over a temperature range of 25 to 120°C. The samples were heated in a platinum open crucible in nitrogen atmosphere 60 mL / min.

[0425] Volatile content: Residual solvent and moisture on spray-dried material was determined by TGA. It was found that after 60 minutes at 45±5°C and vacuum -25 in Hg the volatile content of the ASD with HPMCAS as polymer is 0.3-0.4 % w / w. For solid with hygroscopic polymers the final water content depends on the initial moisture content of the polymer. For ASDs using Poly acrylic acid (PAA) (Table 5 J), the solvent system was Acetone 70 % / Methanol 30%. ASD was dried at 45°C and -25in Hg after 90 and 180 min. TGA results were 3.850% and 3.508%, respectively, higherthan observed forthe PAA (0.877%) compared to all other samples. The secondary drying temperature was increased to 60°C and after 60 minutes the volatile content by TGA was still higher (3.307%) than expected (< 0.877%). Formulation with Eudragit E PO (Table 5 H) showed TGA 0.3% independently of the batch size 10 / 50 gram and with or without secondary drying applied.Table 6: Volatile Content of A by TGA and Yieldii) X-Ray Powder Diffraction

[0426] The crystal state was verified by X-Ray Powder Diffraction (XRPD) using a Bruker X-ray diffractometer model D2 Phaser (Karlsruhe, Germany), with Cu Ka radiation (A=1 .5406 A) at an increment of 0.01 °20 with a 0.2 s step time (scan rate of 3.0 ° 20 / min) over a range of 3-56° 20, an 0.6 mm opening slit, a 1 .0 mm scatter plate and a 2.5 mm detector window. The samples were analyzed using a low volume sample holder and were kept under a constant rotation of 15 rpm during the analysis.Results:

[0427] After manufacturing the ASDs were examined by XRPD. The X-ray pattern of ASD No. 1 and ASD No. 9 to 18 are typical of amorphous materials.

[0428] In the formulation with PVP K-30, the acetone in the solvent mixture was increased to 70% and the solution was passed through a 60-mesh screen. The resulting ASD showed amorphous X-ray diffraction patterns. All other spray drying solutions in multi-solvent systems were similarly prepared using 70% acetone and passing the solution through a 60- mesh screen before spraying and no crystalline peaks were observed.

[0429] PEG8000 is a semicrystalline polymer with two intense characteristic peaks at19.3 and 23.4 ° 20. The powder from ASD No. 18 showed the two peaks characteristic of PEG 8000. iii) Thermal Analysis:

[0430] Thermal analysis was done by TGA and Differential Scanning Calorimetry (DSC). TGA was performed using a TA Instrument Q50 at scanning speed of 20°C / min over a temperature range of RT to 800°C. The samples were heated in a platinum open crucible in nitrogen atmosphere 60 mL / min. DSC analysis was completed with a TA Instrument Q20. The samples were heated in a Tzero Aluminum pan with lid from TA Instruments at 5 °C / min under a nitrogen purge of 50 mL / min.Example 9: Exemplary compositions comprising amorphous solid dispersions comprising otenaproxesul granulated with sustaining agents external to the amorphous solid dispersions

[0431] Exemplary compositions comprising amorphous solid dispersions granulated with sustaining agents external to the amorphous solid dispersion to form granules comprising the solid dispersion and an external sustaining agent were further prepared. For example, the following compositions comprising a granule comprising an exemplary amorphous solid dispersion and one or more external sustaining agents were prepared.

[0432] Exemplary composition no. 1 : Exemplary ASD No 3 (31 .25 wt%) and external HPMCAS-HF (20.83 wt %) by weight of total pharmaceutical formulation (i.e., tablet). Therefore, exemplary ASD No. 3 and external HPMCAS-HF were present in a weight ratio of 1 .5:1 of ASD to external HPMCAS-HF

[0433] Exemplary composition no 2: Exemplary ASD No. 8 and external HPMCAS- HF (1.5:1 ratio of ASD:external HPMCAS-HF)Example 10A: Polymorphic stability studies of exemplary amorphous solid dispersion comprising otenaproxesul

[0434] Exemplary amorphous solid dispersions comprising otenaproxesul were maintained under various temperature and relative humidity (RH) to assess the stability of the amorphous solid dispersion (e.g., resistance to crystallization).

[0435] In one study, exemplary amorphous solid dispersions nos. 1 , 4, 5, and 6 (see Example 8A) were maintained at 30°C and 65% RH and 50°C and 11 % RH under open conditions and all found be fully amorphous after one month by XRPD.

[0436] In a further study, the formulations were maintained at 40°C and 75% relative humidity (RH) under closed conditions for one month. After one month, all formulations were found to be fully amorphous except exemplary ASD no. 7 comprising Eudragit and exemplary ASD no. 8 comprising HPMC-2910 (HPMC E3). While not being bound by theory, water was used as a co-solvent in the process of preparing ASD no. 7 and ASD no. 8. The presence of water may have contributed to the crystallization of these exemplary ASD’s. The high percentage of otenaproxesul in ASD no. 7 comprising Eudragit could have further contributed to crystallization.

[0437] Exemplary XRPDs of ASD nos.1 , 2 and 3 after being maintained at 40°C and 75% relative humidity (RH) under closed condition for one month is shown in Figure 2.

[0438] In a subsequent study, exemplary ASD no.1 was analyzed by scanning electron microscopy (SEM) to assess particle morphology and visual assessment of crystallinity. Examplary ASD no.1 showed typical particle morphology with spherical and collapsed sphere particles. Some surface roughness and possible onset of particle fusing were observed. No sign of crystals present. No change in particle morphology was observed in the 1 -month samples.Example 10B: Polymorphic stability studies of exemplary amorphous solid dispersions

[0439] Additional polymorphic stability studies were conducted with the exemplary amorphous solid dispersions described in Example 8B.

[0440] Amorphous ASD samples were stored in open and closed cap high density polyethylene (HDPE) bottles at 40°C / 75% RH conditions to evaluate the amorphous state stability in 35% drug load ASDs.

[0441] ASD powders were placed into opened and closed plastic (HDPE) bottles at 40°C / 75%RH. The samples were analyzed for Appearance and by XRPD. Samples from closed bottle were analyzed only if open bottle sample failed (recrystallization of ATB-346 or deliquescence).

[0442] The results for 1 , 2 and 4 weeks of storage are summarized in Table 7. Table 1 indicates the observed appearance of the ASD and morphology by XRPD. XRPD patterns of the ASDs after 4 weeks of storage in open bottles were taken. 7 of 1 1 ASD that were placed at 40°C / 75%RH remained amorphous after 4 weeks in open container, while recrystallisation of otenaproxesul was observed from formulations comprising poly acrylic acid (PAA, ASD No16), Polyvinylpyrrolidone K30 (PVP K30, ASD No 15) and HPMC E5 (ASD No 175) after 1 and 4 weeks, respectively.

[0443] For PVP K12 containing ASD (ASD No. 12) deliquescence was observed when directly exposed to high humidity (open cap) but amorphous state was verified for samples in closed cap bottle.

[0444] After 1 week at 40°C / 75%RH otenaproxesul was found to recrystallize from ASD comprising HPMCAS-HG + PEG 8000 (35%) (ASD No. 18Table 7: Further results of stability testing of ASDs at 40°C / 75%RHExample 11: Dissolution studies of exemplary amorphous solid dispersions of Example 8A

[0445] An in vitro gastric to intestinal transfer test was performed for biorelevant dissolution of exemplary ASD no 6 except with varying amounts of external HPMCAS-HF and using 0.1 N HCI gastric media with an addition of intestinal media after 30 minutes for a final composition of 0.5% simulated intestinal fluid (SIF) in phosphate buffer saline (PBS) at pH 6.5. Otenaproxesul concentration was monitored by absorbance using Pion UV-vis probes and standard curve. The crystalline otenaproxesul and exemplary ASD no. 6 were run as controls.

[0446] Exemplary ASD no. 6 showed comparable dissolution performance to samples with external HPMCAS-HF until 80 minutes (50 minutes in IB). After 80 minutes, the exemplary ASD no. 6 started to precipitate and drop in concentration, while the exemplary composition no. 1 with external HPMCAS-HF sustained Cmax for the rest of the test. A higher ratio of HPMCAS-HF to polymer appeared to slightly increase Cmax but showed comparable sustainment to the lower ratios of external polymer.

[0447] Exemplary ASD no. 3 (50 / 49.5 / 0.5 ATB-346 / PVPVA64 / BHT) and 8 (35 / 65 ATB-346 / HPMC-2910 (E3)) were also evaluated alone and with a 1 .5:1 ratio of ASD:external HPMCAS-HF polymer.

[0448] Exemplary ASD no. 1 , ASD no 2 and ASD No 3 were further evaluated. Dissolution profiles of various exemplary ASD of the application (e.g, exemplary ASD no. 1 , ASD no 2 and ASD No 3) on day 1 (initial) and after 1 -month 40°C at 75% relative humidity under dosed conditions using the in vitro gastric to intestinal transfer test using 0.1 N HCI are provided in Figure 3. As can be seen from Figure 3, exemplary ASD No. 1 showed no change in dissolution performance after 1 month of closed storage conditions (curves 1 and 4). For PVP exemplary ASD No. 3 the 1 -month stability formulation showed slightly faster dissolution kinetics than the originally prepared PVP formulation (curves 3 and 6) but comparable sustainment of drug concentration with other PVP formulations, (ASD No. 3, curves 2 and 5) over the 90-minute test period. No substantive differences in dissolution characteristics were noted among the ASD formulations containing 35% or 50% PVP.Example 12: Glass transitions temperatures of exemplary amorphous solid dispersions

[0449] The glass transition temperatures (Tg) of the exemplary amorphous solid dispersions were evaluated over a temperature range of -20 °C to 160 °C using modulated differential scanning calorimetry (DSC) at a heating rate of 2.5 °C / min and are provided in Table 8. The Tg for exemplary amorphous solid dispersions obtained using modulated DSC at 2.5 °C / min are provided in Table 9. The Tg for exemplary amorphous solid dispersions after one month at 40°C / 75% RH under closed conditions obtained using modulated DSC at 2.5 °C / min are provided in Table 10. Samples were placed in Tzero Aluminum hermetic / non- hermitic pans and typically contained between 1 to 6 mg of amorphous solid dispersion. The Tg value was determined by measuring the mid-point by half-height of the DSC response.Table 8Table 9Table 10

[0450] The Tg of exemplary amorphous solid dispersion no. 1 (35 / 65 ATB-346Z HPMCAS-H) was found to be 62.8 ± 0.2 °C (batch 1 , Example 8A) and 64.0 ± 0.9 °C (batch 2, Example 8A) using modulated DSC.Example 13: Solubility data of crystalline otenaproxesul compared to exemplary an amorphous solid dispersions

[0451] Table 11 shows the solubility enhancement of exemplary amorphous solid dispersion no. 1 compared to crystalline otenaproxesul in simulated intestinal fluid (SIF).Table 11Example 14: Particle-size distribution characterization of exemplary amorphous solid dispersions

[0452] The particle-size distribution from an approximate 600 g batch of exemplary ASD no. 1 was evaluated and results provided in Table 12.Table 12

[0453] Particle size data from a 3 kilogram demonstration batch of exemplary ASD No. 1 measured at different spray drying pressures ranging from 0.5 bar to 4 bar are shown in the Table 13.Table 13Example 15: Purity Studies of exemplary solid dispersions

[0454] The stability of the exemplary amorphous solid dispersions were evaluated using HPLC and are shown in Tables 14 A and B.Table 14 A*ND=not detected, <LOQ=below limit of quantitation, 0.05% of WS, <LOD=below limit of detection set at 0.02% calculated from LOQ, RRT=Relative Retention TimeTable 14B| Formulation | RRT - 0.85 | RRT - 0.87 | ATB-346 | RRT - 1.11 |HPLC methods for purity / impurity determinations

[0455] HPLC analyses were performed on a Waters 2695 or Agilent 1200, or equivalent, instrument. The column was an ACE-5 C18 150 mm x 4.6 mm, 5 pm or equivalent column. The flow rate was 1 .0 mL / min, the injection volume was 10 pL, the column temperature was 25 °C, the sample temperature was 5 °C and the wavelength for detection was 254 nm. Two eluents were used which were either (1) A: 1 .8 g K2HPO4.3H2) dissolved in 1000 mL of water and pH adjusted to 5.5 using orthophosphoric acid and B: acetonitrile; or (2) A: 1 .4 g K2HPO4.3H2O dissolved in 1000 mL of water and pH adjusted to 7.0 with 85% phosphoric acid and B: acetonitrile.

[0456] The gradient used for (1) is presented in Table 15.Table 15

[0457] The gradient used for (2) is presented in Table 16.Table 16

[0458] Under conditions (1) the retention times and RRT’s that were obtained are provided in Table 17.Table 17

[0459] Under conditions (2) the retention times and RRT’s that were obtained are shown in Table 18.Table 18Example 16: Exemplary oral pharmaceutical compositions of the applicationA. Exemplary pharmaceutical compositions comprising exemplary ASDs of the application.

[0460] Exemplary oral dosage form pharmaceutical compositions of the application (for example, exemplary composition of the application no. 3 (comprising exemplary ASD no. 1), exemplary composition of the application no. 4 (comprising exemplary ASD no. 2) and exemplary composition of the application no. 5 (comprising exemplary ASD no.3) were prepared. Table 19 shows the ingredient lists of exemplary oral dosage form pharmaceutical compositions 3, 4 and 5.Table 19Manufacturing process of exemplary oral dosage form pharmaceutical compositions

[0461] Blending: The exemplary ASD, filler(s), intragranulardisintegrant, intragranular glidant and optionally sustaining agent were blended in a Turbula bench top Blender for 2 min @ 32 rpm

[0462] The blend was then passed through No. 20 Sieve for delumping followed by further blending for 10 min @ 32 rpm. Lubricant was then added and the mixture blended for 4 min @ 32 rpm.

[0463] Granulation: Slugging was performed via single station, manual press. Slugs were milled via mortar and pestle and passed through a No. 20 sieve.

[0464] Extragranular disintegrant and extragranular glidant were the added and blended for 10 min @ 32 rpm, after which extragranular lubricant (Sieved) was added and further blended for 4 min @ 32 rpm.

[0465] Compression: The blend was compressed using a single station, manual tablet press with a target tensile strength of 2.5 Mpa. The tablet was then tested for rate of disintegration in 0.01 N HCI (pH 2.0) media and dissolution.Formulation dissolution and stability

[0466] The rate of dissolution of exemplary oral dosage form pharmaceutical compositions 3, 4 and 5 were tested. Results are provided in Table 20 A.Table 20 A

[0467] Exemplary final oral pharmaceutical compositions 3 and 5 disintegrated quickly at 1 :16 [rnimsec] and 1 :46 [min:sec] respectively. Exemplary oral pharmaceutical composition 4 gelled, and the disintegration test was stopped at 30 minutes when appreciable disintegration progress has stopped. Tablets comprising HPMCAS had good disintegration time.

[0468] A single tablet of exemplary final oral pharmaceutical compositions 3 and 5 were dosed into a USP II dissolution vessel (800 mL and 500 mL final volume for 200 mg and 125 mg tablets respectively) for a 0.25 mg / mL dose, consistent with SDD dosing. Exemplary composition 3 was found to perform better than exemplary composition 5. Exemplary composition 5 showed comparable Cmax and sustainment to exemplary composition 3 but slightly slower dissolution rate. Exemplary composition 3 showed comparable dissolution rate and sustainment to its ASD (exemplary ASD no. 1).B: Additional exemplary oral pharmaceutical compositions - comprising additives

[0469] The addition of additives such as antioxidants, buffering agents, alkalinizing agents, solubilizers, surfactants was investigated.

[0470] Exemplary composition of the application no. 3 (Exemplary composition of the application no. 3-a comprising exemplary ASD no. 1) was modified to include one or more further additives to provide the following pharmaceutical composition of the application.

[0471] The final blends were prepared by dry granulation. To obtain granules to mimic the dry granulation was done by slugging. The intragranular ingredients except the magnesium stearate were mixed for 2 minutes at 28 rpm using a Globe Pharma MiniBlend ™ V-Blender with 0.5-quart stainless steel shell. The mixture was screened using a No 20 (850 pm openings) sieve, poured back into the blender, and mixed for 2 minutes at 28 rpm. The magnesium stearate was passed through a No 40 (425 pm) sieve premixed with a volume equivalent of blend from the blender and mixed for 2 minutes at 28 rpm minutes. The blend was compressed to slug using Korsch XP1 single station tablet press equipped with 11 mm round flat tooling. The slugs were comilled at speed 1750 rpm using a Quadro Comil model U5 fitted with a 9525 pm square screen then the pieces of slugs were comilled using a 1016 pm grated round screen. Extragranular excipients except the magnesium stearate were passed through a No 40 sieve then mixed with the granules using the V-blender for 2 min at 28 rpm. The magnesium stearate was screened using a No 40 sieve and premixed with an equivalent volume quantity of blend. The magnesium stearate premix was loaded into the V- blender and mixed for 2 min at 28 rpm. 200 mg tablets were compressed using the single station tablet press Korsch XP1 equipped with 9.91x18.97 mm oval shaped chrome tipped tooling.Table 20 B: Exemplary composition 3-a (control)Table 20 C: Exemplary Composition 6Table 20 D: Exemplary Composition 7Table 20 E: Exemplary Composition 8Table 20 F: Exemplary Composition 9Table 20 G: Exemplary Composition 10C. Additional exemplary oral pharmaceutical compositions comprising exemplary ASDs

[0472] The formulations were prepared as described in Part B above.Table 20 H: Exemplary composition 11Table 20 I: Exemplary composition 12Table 20 J: Exemplary composition 13Table 20 K: Exemplary composition 14Table 20 L: Exemplary composition 15Table 20 M: Exemplary composition 16Table 20 N: Exemplary composition 17In vitro dissolution rate

[0473] Dissolution profiles of the exemplary compositions showed that some exemplary formulations dissolved faster than 200 mg tablets exemplary composition 3. Complete and faster release (70% dissolved within 10 minutes) was observed for exemplary composition 15 from ASD No. 13 containing Soluplus 35%. Approx 50% dissolution were reached with formulations exemplary composition 10 using Poloxamer as surfactant and Eudragit as polymer. Very poor dissolution profiles were observed for formulations exemplary composition 13, exemplary composition 14 and exemplary composition 16 using Kollidon VA64, PVPK12 and HPMC E3 as lower molecular weights polymers in ASDs.Example 17: Stability and H2S studiesFormulation stability in simulated intestinal fluid (SIF)

[0474] Assay design: 1 mg of exemplary ASD no. 1 and crystalline otenaproxesul were weighed in separate glass vials. SIF was added to prepare a 1 mg / ml solution which was incubated at 37 °C with 5% CO2. 120 pl was removed at 0.5, 1 , 2, 3, 4 and 8 hrs and quenched in DPD (N,N-dimethyl-p-phenylenediamine sulfate) and FeCI3solutions. A calibration curve was prepared to quantify amount of H2S released. A blank and 10 mM stock was also analyzed. The methylene blue was analyzed using HPLC.Observations:

[0475] Both the formulations displayed low solubility.

[0476] Exemplary ASD no. 1 showed a rapid and significant amount of H2S release. 3.3 pM in 30 minutes with increasing amounts over time with 12.5 pM at the 8h timepoint.

[0477] Crystalline otenaproxesul did not release significant H2S initially but did so over time reaching 8.5 pM at the 8h timepoint (Table 21).Table 21Formulation stability in simulated gastric fluid (SGF)

[0478] Assay design: 1 mg of exemplary ASD no. 1 and crystalline otenaproxesul were weighed in separate glass vials. SGF was added to prepare a 1 mg / ml solution which was incubated at 37 °C with 5% CO2. 120 pl was removed at 0, 0.5, 1 , 2, 3, 4 and 8 hrs and quenched in DPD and FeCI3solutions. A blank and 10 mM stock was also analyzed. The methylene blue was analyzed using HPLC.Observations:

[0479] As H2S is volatile in the acidic form the calibration curve was not plotted, however H2S release was compared to To.

[0480] Both the formulations displayed low solubility.

[0481] Exemplary ASD no. 1 showed faster and larger amount of H2S release compared to crystalline otenaproxesul (Table 22).Table 22Example 18: Comparative Assessment of the Pharmacokinetics (PK) andPharmacodynamics (PD) of Selected Treatment Regimens of an Amorphous solid Dispersion Formulation of Otenaproxesul in healthy human subjects

[0482] Design: This was an open-label, randomized, three-arm PK study. Arm(s) of this study was conducted in groups. The same protocol requirements and procedures were followed for each group.

[0483] The recruitment start corresponded with the study’s Informed Consent Form (ICF) approval date, at which time study specific recruitment began. The anticipated end of study was the last scheduled procedure. Unscheduled visits and adverse event (AE) followup occurred after the end of study procedures. The expected duration of subject participation in this study (from voluntary signing of the ICF to the last scheduled study procedure) will be approximately 41 days for Arm 1. The expected duration of subject participation in this study (from voluntary signing of the ICF to the last scheduled study procedure) will be approximately 43 days for Arms 2 and 3.

[0484] Treatments: Subjects received one of the following treatments as outlined in Table 23:

[0485] Test Product 1 : otenaproxesul 25 mg Amorphous Dispersion (AD) tablets (e.g., compositions comprising ASD No. 1 , for example, exemplary composition 3, with 25 mg otenaproxesul)

[0486] Test Product 2: otenaproxesul 100 mg Amorphous Dispersion (AD) tablets (e.g., compositions comprising ASD No. 1 , for example, exemplary composition 3, with 100 mg otenaproxesul)Table 23 Dosing in all Arms

[0487] Randomization: Subjects were randomly assigned to one treatment arm according to a predetermined computer-generated randomization scheme (procedure PLAN in SAS® [version 9.4 or later]). Subjects were assigned consecutive subject numbers in an ascending order. Each number identified a subject and determined the sequence of drug product administration according to the randomization scheme.

[0488] Sample Size: Thirty-six (36) subjects were enrolled into this PK study. Each arm included 4 male subjects and 8 female subjects, with a minimum of 50% Caucasian subjects. Only volunteers who were treated were considered enrolled.

[0489] Study Population: The study population consisted of healthy, non-smoking, male and female volunteers from 18 to 59 years of age. Subjects who participated in one arm of the study were not permitted to participate in a subsequent arm. Subjects enrolled in the study satisfied the subject selection criteria no more than 30 days prior to the first drug administration.Results and Discussion

[0490] This study was designed to assess the safety of treatment regimensusing compositions comprising amorphous solid dispersions of otenaproxesul, and to measure the pharmacokinetic concentration-time profiles of each treatment regimen using otenaproxesul loading doses of 200 mg, 400 mg, and 600 mg within 60-90 minutes of drug administration. The dosage regimens were designed based on in vivo dog and rat pharmacokinetic studies as descibed in Applicant’s co-pending PCT patent application no. PCT / CA2023 / 051347.

[0491] Concentration-time profiles for all three treatment arms are shown in Figure 4. The 5-day treatment regimens (arms 2 and 3) were tracked over 124 hours while the single dose administration of 600 mg (arm 1) was assessed over a 72-hour period.

[0492] The principal naproxen (M25) pharmacokinetic parameters obtained from the three treatment regimens are summarized in Table 24.Table 24

[0493] The resultant M25 plasma concentrations and the AUC plasma exposures are linear, dose-proportional and exhibited the expected characteristics of the compositions comprising the amorphous dispersion formulation. Some findings from the study are summarized below.

[0494] Treatment 1 (600 mg arm): 889.3 ± 1 11 .9 pg*hr / mL

[0495] Treatment 2 (200 mg loading dose; 700 mg total drug: 1078.1 ± 271 pg*hr / mL

[0496] Treatment 3 (400 mg loading dose; 1400 mg total drug: 1821 ± 483.5 pg*hr / mL

[0497] Unexpectedly, AUC exposures were lower than predicted from the animal amorphous pharmacokinetics studies and, without wishing to be bound by theory, this appears to be driven by a faster elimination of M25 from plasma as evidenced in the 600 mg treatment (arm 1) which did not include any follow on maintenance doses.

[0498] The faster elimination decreases overall AUC exposure and therefore, increases the safety factor of the tested regimens allowing for a broader / higher range of loading doses (in particular) and tapering doses.

[0499] With reference to the 600 mg loading dose, the mean M25 plasma concentration over the first two hours increased from 4.1 pg / mL at thirty minutes to 19.6 pg / mL at the 2-hour mark.

[0500] In the 5-day treatment regimens (Figure 4), the maximal M25 plasma concentration attained at 6 hours on Day 1 by a loading dose of 200 mg or 400 mg began to decline over the next 6 hours before being “revived”, i.e., the M25 plasma concentrations are increased by the 12-hour 100 mg or 200 mg maintenance dose administration, respectively, and maintained throughout the 48 hour critical pain assessment phase.

[0501] Follow on tapered maintenance doses beyond 48 hours in both treatment regimens mediated a gradual decline in M25 concentrations.

[0502] The M25 plasma concentrations within the first 4 hours of drug administration of each treatment regimen are shown in Figure 5. The M25 concentration increased roughly 7-fold over this time interval consistent with the faster absorption kinetics of the amorphous dispersion formulation.

[0503] Hydrogen Sulfide Kinetics Following Amorphous Dispersion Treatment Administrations

[0504] Hydrogen sulfide plasma concentrations were measured at specified times over the complete course of each treatment regimen (arms 1 to 3).

[0505] Hydrogen sulfide concentrations were found to peak between 90-120 minutes post-administration following 200 mg, 400 mg and 600 mg loading doses. The 600 mg loading dose (arm 1) yielded significant H2S increases over baseline of 1 .4- and 1 .9-fold at 30 minutes and 60 minutes, respectively. After attaining peak concentration, tapered doses in 200 mg and 400 mg regimens (arms 2-3) slow the rate of H2S return to baseline versus 600 mg treatment without tapered doses, as expected. Across the three treatment regimens baseline H2S levels were essentially restored within 72-hours of initial drug administration (loading dose).

[0506] Hydrogen sulfide concentrations exhibited dose-proportional behaviour across the three loading dose administrations (e.g., 200 mg, 400 mg and 600 mg otenaproxesul) over the first 12-hours (Figure 6) and for the two 5-day treatment regimens (arms 2 and 3) over 120 hours (Figure 7).

[0507] Hydrogen sulfide released from all three loading dose administrations (e.g, 200 mg, 400 mg and 600 mg otenaproxesul) attained maximal plasma concentration 2-hours post drug administration (Figure 8, top graph) which was fully 2-hours before maximal M25 levels were attained (Figure 8, bottom graph).

[0508] Without being bound by theory, based on the 600 mg loading dose plot (Figure 8 top graph), it can be seen that the H2S levels at 1 .5 hours and 2 hours are nearly identical, therefore, there may be a trend towards earlier H2S maximal plasma concentrations with higher loading doses, e.g., 700 or 800 mg loading dose.

[0509] The fold increase of exogenous plasma H2S over baseline value is shown in Figure 9. The 600 mg loading dose increased H2S by 2.6-fold within 2 hours of drug administration. All treatment regimens displayed a controlled tapering of plasma H2S with return to baseline measures at approximately 72-hours, i.e., before the end of a 5-day treatment.

[0510] Correlation of plasma H2S and M25 plasma concentrations are shown in Figure 10. Larger black circles indicate estimated values for curve-fitting purposes. Hydrogen sulfide concentrations were maximal in the first 90-120 minutes, and remained significantly above baseline for 12-hours before returning to pre-treatment value at the 72-hour assessment.Conclusions

[0511] The M25 pharmacokinetic data generated from administration of compositions comprising amorphous dispersion of otenaproxesul exhibited linear, dose-proportional responses consistent with the observed pharmacokinetics behaviour of the AD formulations tested in animal studies. There was a markedly improved absorption of M25 from the compositions comprising amorphous dispersions of otenaproxesul relative to previous administrations using the compositions comprising crystalline otenaproxesul.

[0512] However, relative to the animal pharmacokinetics measures, M25 underwent faster plasma elimination in human subjects resulting in lower overall AUC exposures lower than predicted and thereby supportive of a broader safety exposure window relative to the postulated safety exposure limit of 4000 pg*hr / mL.

[0513] Pharmacokinetic measures of H2S detailed a rapid release from the compositions comprising amorphous dispersions of otenaproxesul with maximal plasma concentration attained within 2 hours of drug administration. Dose-proportional fold increase of baseline H2S ranged from approximately 1.6 to 2.6 across the three treatment administrations (arms 1 to 3) at peak H2S concentrations.

[0514] Baseline plasma concentrations of H2S were normalized within 72 hours for both the 600 mg single treatment (arm 1) and for the 200 mg and 400 mg 5-day treatments (arms 2 and 3). Importantly, it was found that use of a tapered dose protocol for the 5-day treatment regimens did not negatively affect liver H2S biosynthetic pathways since the plasma H2S were found to normalize on treatment and at the 1-week post-treatment (288 hour) assessment.

[0515] No abnormal liver safety biomarkers were reported in this study.Example 19: Analysis of proposed human clinical treatment regimens based using simulated models

[0516] Based on the pharmacokinetic studies of otenaproxesul, simulated human models of naproxen exposure and pharmacokinetics, new 5 day treatment regimens having increased loading doses of otenaproxesul were developed as shown in Table 25. The new treatment regimens were analyzed for liver safety using the simulated models.Table 25

[0517] Simulations included 15 days of no drug treatment after administration of last maintenance dose.

[0518] The results of the simulation analyses using the amounts of otenaproxesul as described in Table 25 indicated that all proposed dosing regimens are predicted to be safe with respect to ALT elevations with no concerning clinically relevant ALT rebound levels during or post treatment. The results further indicated that continuous tapered doses appear to improve safety. For example, proposed dosage regimen 3 (e.g Treatment 3) using a 800 mg loading dose and consistent dose tapering from day 1 to day 5 indicated the lowest ALT rebound. The results also indicated that proposed dosage regimens 1 to 5 (e.g treatments 1-5 using a 800 mg loading dose) had more individuals with naproxen plasma concentration above 15 pg / mL at 1 hour compared to treatment protocols using a 600 mg loading dose.Example 20: Abdominoplasty trial design using loading doses with increased amounts of otenaproxesul

[0519] Exemplary compositions of the application comprising ASD No.1 (e.g. exemplary composition 3) will be prepared comprising dose strengths of 25 mg to 200 mg of otenaproxesul, e.g., 25 mg, 50 mg, 100 mg and 200 mg.

[0520] This study is designed as multi-center, randomized, double-blind, placebo- controlled study to evaluate efficacy and safety of otenaproxesul for acute pain following abdominoplasty. An objection of this study is, for example, to evaluate the analgesic efficacy of treatment regimens with otenaproxesul having loading doses with increased amounts of otenaproxesul on acute post-operative pain following abdominoplasty compared with placebo, and / orto determine the safety and tolerability of treatment regimens with otenaproxesul having loading doses with increased amounts of otenaproxesul in participants following abdominoplasty.Methodology

[0521] Study Design: This is a 3-arm, 5-day, multi-center, randomized, double-blind, placebo-controlled, trial.

[0522] A total of approximately 360 participants undergoing abdominoplasty without collateral procedures will be randomized 1 :1 :1 to 1 of 3 treatment arms (high dose: low dose: placebo). Participants will receive study drug as oral treatment every 12 hours starting within 4 hours after abdominoplasty as described below. Treatment and Observation

[0523] After surgery, participants will be transferred to the recovery room. Participants’ postsurgical pain will be assessed periodically via the NPRS and the CPRS until A) the participant qualifies for randomization, or B) 4 hours have passed after completion of surgery. Participant must report a verbal score of >5 on the NPRS and ‘moderate’ or ‘severe’ on the CPRS to be eligible for randomization. If the participant reports qualifying pain scores to the study coordinator, the participant subsequently will be randomized 1 :1 :1 to 1 of 3 treatment arms and receive the first assigned treatment dose. Participants will receive 10 doses of the assigned treatment, one dose every 12 hours, according to their treatment arm.

[0524] The participant will be confined to the study site for at least 120 hours post-surgery for study assessments.

[0525] Participants will be assessed for pain intensity at rest using the (Numerical Pain Rating Scale) NPRS at 0.5, 1 , 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 20, 24, 28, 32, 36, 44, 48 hoursfollowing the first dose of study drug. Participants will also be assessed for the onset of confirmed perceptible and meaningful pain relief using the 2-stopwatch technique Participants will also be asked to rate their pain intensity with activity (sitting up at a 45-degree angle and coughing) using the NPRS (NPRS-A) at various points.

[0526] Number of Participants (planned): 360 participants (n=120 for each treatment arm).Study Drug, Dosage, and Mode of Administration:

[0527] Otenaproxesul, a novel NSAID that releases hydrogen sulfide, will be administered as 25 mg, 50 mg, 100 mg, or 200 mg tablets. To maintain proper blinding requirements, matching placebo tablets will be provided as appropriate to ensure all participants receive the same number and size of tablets. Participants will receive the assigned treatment dose every 12 hours beginning at Hour 0, for 108 hours (a total of 10 doses).

[0528] Study drug will be administered according to the table 26 below.Table 26

[0529] Otenaproxesul and placebo will be taken orally with 240 mL of water. Participants will receive all doses in the clinic.

[0530] Duration of Participation: Including the Screening Period, the total study duration for each participant will be approximately 42 days.

[0531] Reference Therapy: The Placebo arm will receive only placebo tablets and will receive the same number and size tablets as the high dose and low dose arms.

[0532] While the present application has been described with reference to examples, it is to be understood that the scope of the claims should not be limited by the embodiments set forth in the examples but should be given the broadest interpretation consistent with the description as a whole.

[0533] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

Claims

CLAIMS:1 . A method of treating or preventing acute pain in a subject in need thereof comprising: administering one or two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 14 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

2. The method of claim 1 , wherein the method provides a plasma concentration of naproxen metabolite of about 10 pg / mL or greater or about 15 pg / mL or greater in about one hour or less.

3. The method of claim 1 or claim 2, wherein the acute pain is selected from, but not limited to, post-operative pain, peri-operative pain, dysmenorrhea, interstitial cystitis, headache including migraine, pain due to a trauma, renal or biliary colic, arthritis, dental pain, musculoskeletal pain, lower back pain, fibromyalgia, pain of infectious origin, pain resulting from cancer and pain induced by gout, or combinations thereof.

4. The method of claim 3, wherein the acute pain is post-operative pain and the postoperative pain is pain following a surgery selected from, but not limited to orthopedic, abdominal, pelvic, dental, plastic, cosmetic, neurological, urological, bariatric, gastric, cardiac, orthoscopic, vascular, endovascular, laparoscopic, oncological, colorectal, podiatric, ocular, otoplastic, rhinoplastic, and throat surgery, or combinations thereof.

5. The method of claim 1 or claim 2, wherein the acute pain is recurrent pain.

6. The method of claim 5, wherein acute pain is dysmenorrhea.

7. The method of any one of claims 1 to 6, wherein the method comprises administering two oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and the two oral loading doses are a first and a second oral loading dose.

8. The method of claim 7, wherein the second oral loading dose comprises the same amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof as the first oral loading dose, or the second oral loading dose comprises a lower amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof than the first loading dose.

9. The method of any one of claims 1 to 8, wherein the one or two oral loading doses independently comprise about 650 mg to about 2000 mg, about 700 mg to about 2000 mg, about 750 mg to about 2000 mg, about 800 mg to about 2000 mg, about 825 mg to about 2000 mg, about 850 mg to about 2000 mg, about 700 mg to about 1500 mg, about 750 mg to about 1500 mg, about 800 mg to about 1500 mg, about 850 mg to about 1500 mg, about 900 mg to about 1500 mg, about 950 mg to about 1500 mg or about 1000 mg to about 1500 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

10. The method of any one of claims 1 to 6, wherein the method comprises administering one or more oral maintenance doses independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein method comprises administering one oral loading doses independently comprising greater than 600 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

12. The method of claim 10 or claim 11 , wherein the one or more oral maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 42 hours, or about 48 hours or combinations thereof after administration of the one or two oral loading doses.

13. The method of any one of claims 10 to 12, wherein the one or more oral maintenance doses each comprise the same amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

14. The method of any one of claims 10 to 12, wherein the one or more oral maintenance doses independently comprise a different amount of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and administering one or more oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof comprises administering one or more first oral maintenance doses, followed by one or more second maintenance doses and optionally followed by one or more third oral maintenance up to one or more eighth oral maintenance doses, each oral maintenance dose independently comprising about 25 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

15. The method of any one of claims 10 to 14, wherein the one or more oral maintenance doses independently comprise about 25 mg to about 400 mg, about 50 mg to about 400 mg, about 75 mg to about 400 mg, about 100 mg to about 400 mg, about 125 mg to about 400 mg, about 150 mg to about 400 mg, about 175 mg to about 400 mg, about 200 mg to about 400 mg, about 225 mg to about 400 mg, about 250 mg to about 400 mg, about 300 mg to to about 400 mg, about 350 mg to about 400 mg, about 25 mg to about 350 mg, about 50 mg to about 400 mg, about 75 mg to about 350 mg, about 100 mg to about 350 mg, about 125 mg to about 350 mg, about 150 mg to about 350 mg, about 175 mg to about 350 mg, about 200 mg to about 350 mg, about 225 mg to about 350 mg, about 250 mg to about 350 mg, about 300 mg to to about 350 mg or about 350 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 10 to 14, wherein the one or two oral loading doses independently comprise about 650 mg to about 2000 mg, about 700 mg to about 2000 mg, about 750 mg to about 2000 mg, about 800 mg to about 2000 mg, about 825 mg to about 2000 mg, about 850 mg to about 2000 mg, about 700 mg to about 1500 mg, about 750 mg to about 1500 mg, about 800 mg to about 1500 mg, about 850 mg to about 1500 mg, about 900 mg to about 1500 mg, about 950 mg to about 1500 mg or about 1000 mg to about 1500 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

17. The method of any one of claims 14 to 16, wherein the one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eighth oral maintenance doses are tapered doses, and are decreased stepwise by about 250 mg, about 225 mg, about 200 mg, about 175 mg, about 50 mg, about 125 mg, about 100 mg, about 75 mg, about 50 mg or about 25 mg, of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof between each dose over a suitable period of time18. The method of any one of claims 14 to 17, wherein the method comprises administering one or more first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, followed by administering one or more second oral maintenance doses comprising about 100 mg to about 350 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally followed by administering one or more third up to one or more eighth oral maintenance doses comprising about 25 mg to about 150 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

19. The method of any one of claims 14 to 16, wherein the one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eighth oral maintenance doses are not tapered.

20. The method of claim 19, wherein the method comprises: administering one first oral maintenance dose comprising about 25 mg to about 400 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one or more second oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally administering one or more third up to one or more eighth oral maintenance doses comprising about 25 mg to about 275 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one first oral maintenance dose is less that the one or more second oral maintenance doses and the one or more second and optionally one or more third up to one or more eighth oral maintenance doses are tapered oral doses.21 . The method of any one of claims 14 to 20, wherein one, two, three, four, five or six of each oral maintenance dose is independently administered.

22. The method of any one of claims 14 to 21 , wherein the one or more oral maintenance doses are sequentially increased or decreased stepwise by an amount at intervals of about 6 hours to about 48 hours, about 6 hours to about 36 hours, about 6 hours to about 24 hours, about 12 hours to about 72 hours, about 12 hours to about 48 hours, about 12 hours to about 36 hours or about 12 hours to about 24 hours, or combinations thereof.

23. The method of any one of claims 1 to 22, wherein the treatment period is 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day.

24. The method of claim 14, wherein the method comprises administering one oral loading dose comprising about 625 mg to about 1500 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one or more first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof,administering one or more second oral maintenance doses comprising about 100 mg to about 350 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally administering one or more third up to one or more eighth oral maintenance doses comprising about 25 mg to about 150 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one or more first and one or more second oral maintenance doses and optionally one or more third up to one or more eight oral maintenance doses are sequentially administered at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof, after administration of the first oral loading dose, and the one or more first and one or more second oral maintenance doses and optionally the one or more third up to one or more eight oral maintenance doses are sequentially decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours, about 36 hours, about 42 hours, or combinations thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 5 days or less and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

25. The method of claim 24, wherein the method comprises administering one oral loading dose comprising about 650 mg to about 1000 mg, of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one to four first oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one or more second oral maintenance doses comprising about 150 mg to about 275 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and administering one to four third oral maintenance doses comprising about 75 mg to about 175 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one to four fourth oral maintenance doses comprising about 25 mg to about 75 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, andadministering one to four fifth oral maintenance doses comprising about 25 mg to about 50 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one or more first to one or more fifth oral maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof, after administration of the first loading dose, and the one or more first to one or more fifth oral maintenance doses are sequentially decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours or about 36 hours, or combinations thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 5 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

26. The method of claim 25, wherein the method comprises administering one oral loading dose comprising about 800 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering two first oral maintenance doses comprising about 300 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one second oral maintenance dose comprising about 200 of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and administering one third oral maintenance dose comprising about 100 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering three fourth oral maintenance doses comprising about 50 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and administering two fifth oral maintenance doses comprising about 25 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof. wherein each of the oral maintenance doses are administered sequentially at intervals of about 12 hours after administration of the first oral loading dose, for a treatment period of 5 days, and wherein the method provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

27. The method of claim 15, wherein the method comprises administering one oral loading dose comprising about 650 mg to about 1000 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof,administering one first oral maintenance dose comprising about 25 mg to about 400 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one or more second oral maintenance doses comprising about 150 mg to about 450 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, administering one or more third oral maintenance doses comprising about 150 mg to about 275 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and optionally administering one or more fourth up to one or more eighth maintenance doses comprising about 25 mg to about 150 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, wherein the one first oral maintenance dose is less than the one or more second oral maintenance doses and the one or more second, third and optionally fourth up to eighth oral maintenance doses are tapered oral doses, wherein the one first oral maintenance dose is administered about 6 hours to 12 hours after administration of the oral loading dose, and the one or more second, one or more third and optionally one or more fourth to one or more eighth maintenance doses are administered sequentially at intervals of about 6 hours, about 12 hours or about 18 hours or combinations thereof, after administration of the one first oral maintenance dose, and the one or more second, one or more third to optionally one or more fourth to one or more eighth maintenance doses are sequentially decreased stepwise by an amount at intervals of about 12 hours, about 18 hours, about 24 hours, 30 hours or about 36 hours, or combinations thereof, wherein administration of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof is for a treatment period of 5 days or less, and provides a cumulative plasma naproxen metabolite (M25) exposure of less than about 4000 pg*hr / mL.

28. The method of any one of claim 14 to 27, wherein loading dose is administered in the morning and the one or more oral maintenance doses are administered sequentially at intervals of about 12 hours thereafter.

29. The method of any one of claim 14 to 27, wherein the method provides a Tmax of naproxen metabolite in a subject within 60 minutes or less, within 90 minutes or less, or within 120 minutes or less after administration of the first oral loading dose.

30. The method of any one of claim 1 to 29, wherein the amorphous otenaproxesul, or pharmaceutically acceptable salt thereof is formulated into an amorphous solid dispersion.

31. The method of claim 30, wherein the amorphous solid dispersion comprises amorphous otenaproxesul or pharmaceutically acceptable salt thereof and a polymer.

32. The method of claim 30 or claim 31 , wherein the polymer is a stabilizing polymer.

33. The method of any one of claims 30 to 32, wherein the amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in a form that is about 90 wt% or more, about 92 wt% or more, about 94 wt% or more, about 95 wt% or more, about 96 wt%, about 97 wt%, about 98 wt%, or about 99 wt% or more amorphous form.

34. The method of any one of claims 30 to 33, wherein the amorphous otenaproxesul or pharmaceutically acceptable salt thereof is present in the amorphous solid dispersion in an amount of about 15% to about 60%, about 15% to about 50%, about 15% to about 50%, about 20% to about 50%, about 30% to about 50% or about 35% to about 50% by weight of the amorphous solid dispersion.

35. The method of any one of claims 30 to 34, wherein the polymer is present in the amorphous solid dispersion in an amount of about 40% to about 80%, 40% to about 70%, about 40% to about 65%, about 50% to about 80%, about 50% to about 70%, about 50% to about 65%, about 55% to about 65%, about 50% to about 60%, or about 60% to about 65% by weight of the amorphous solid dispersion.

36. The method of any one of claims 30 to 35, wherein the weight ratio of amorphous otenaproxesul, or pharmaceutically acceptable salt thereof, to the polymer in the amorphous solid dispersion is about 1 :1 to about 1 :4, about 1 :1 .5, about 1 :1 .75 or about 1 :1 .8.

37. The method of any one of claims 30 to 36, wherein the polymer is selected from polyvinylpyrrolidone (PVP) based polymers, polyethylene glycol (PEG) based polymers, cellulose based polymers, acrylate based polymers, chitosan, polyvinyl alcohol / polyethylene glycol graft copolymers, polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymers and polyvinyl acetate phthalate, and combinations of one or more of the listed polymers.

38. The method of any one of claims 30 to 36, wherein the polymer is selected from polyvinylpyrrolidone, polyvinylpyrrolidone vinyl acetate (PVP VA), crospovidone (PVPP), methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), methacrylate copolymers, polyacrylic acid, chitosan, polyvinyl alcohol / polyethylene glycol graft copolymers, polyvinyl caprolactam polyvinyl acetatepolyethylene, combinations of one or more of the listed polymers, and polyethylene glycol (PEG) based polymers in combination with one or more of the listed polymers, provided HPMC does not comprise E type HPMC comprising a viscosity of about 5cP or greater.

39. The method of any one of claims 30 to 36, wherein the polymer is selected from polyvinylpyrrolidone K-12, polyvinylpyrrolidone vinyl acetate (PVP VA), crospovidone (PVPP), hydroxypropylmethylcellulose E3 (HPMC E3), hydroxypropylmethylcellulose acetate succinate (HPMCAS), methacrylate copolymers, polyvinyl alcohol / polyethylene glycol graft copolymers and polyvinyl caprolactam polyvinyl acetate-polyethylene glycol graft copolymers, and combinations thereof.

40. The method of claim 39, wherein the polymer is HPMCAS.41 . The method of claim of any one of claims 30 to 40, wherein the amorphous solid dispersion further comprises one or more additives and the one or more additives are one or more antioxidants and the one or more antioxidants are present in the amorphous solid dispersion in an amount of about 0.1 % to about 1 %, about 0.1 % to about 0.75%, about 0.1 % to about 0.5%, about 0.1 % to about 0.4%, about 0.2% to about 0.5%, about 0.2% to about 0.4%, about 0.3% to about 0.5%, or about 0.4% to about 0.5% by weight of the amorphous solid dispersion.

42. The method of claim of any one of claims 30 to 41 , wherein the amorphous solid dispersion further comprises one or more sustaining agents.

43. The method of claim 42, wherein the one or more sustaining agents are combined with the otenaproxesul or pharmaceutically acceptable salt thereof and the polymer in the solid dispersion to form the amorphous solid dispersion comprising otenaproxesul or pharmaceutically acceptable salt thereof, the polymer and the sustaining agent.

44. The method of any one of claims 30 to 43, wherein the amorphous solid dispersion is formulated into an oral pharmaceutical composition comprising an amorphous solid dispersion of any one of claims 30 to 43 and one or more pharmaceutically acceptable excipients.

45. The method of claim 44, wherein the one or more pharmaceutically acceptable excipients comprise one or more intragranular pharmaceutically acceptable excipients and one or more extragranular pharmaceutically acceptable excipients.

46. The method of claim 44, wherein the amorphous solid dispersion is granulated together with the one or more intragranular pharmaceutically acceptable excipients to form granules.

47. The method of claim 45 or claim 46, wherein the one or more intragranular pharmaceutically acceptable excipients are selected from one or more intragranular pharmaceutically acceptable additives, fillers, disintegrants, lubricants, and glidants, and the one or more extragranular pharmaceutically acceptable excipients are selected from one or more extragranular pharmaceutically acceptable fillers, disintegrants, lubricants and glidants.

48. The method of any one of claims 44 to 47, wherein the pharmaceutical composition comprises about 25% to about 65% of the amorphous solid dispersion, by weight of the composition.

49. The method of any one of claims 44 to 48, wherein the pharmaceutical composition comprises: about 45% to about 65% of the amorphous solid dispersion of any one of claims 31 to 47; about 25% to about 50% of the one or more intragranular pharmaceutically acceptable fillers; about 2% to about 8% of the one or more intragranular pharmaceutically acceptable disintegrants, about 0.1 % to about 2% of the one or more intragranular pharmaceutically acceptable glidants and lubricants; and optionally about 0.5% to about 2% of one or more intragranular pharmaceutically acceptable additives; wherein the percentage amount is by weight of the pharmaceutical composition.

50. The method of any one of claims 44 to 49, wherein the pharmaceutical composition further comprises one or more sustaining agents external to the amorphous solid dispersion.51 . The method of claim 50, wherein the weight ratio of the one or more sustaining agents to amorphous solid dispersion is about 1 :1 to about 2:5.

52. The method of claim 50 or 51 , wherein the one or more sustaining agents is a polymer.

53. The method of claim 50 or 51 , wherein the pharmaceutical compositions is formulated for administration as a tablet.

54. A pharmaceutical package or kit comprising: one oral loading dose comprising greater than 600 mg, about 650 mg to about 2000 mg, about 700 mg to about 2000 mg, about 750 mg to about 2000 mg, about 800 mg to about 2000 mg, about 825 mg to about 2000 mg, about 850 mg to about 2000 mg, about 700 mg to about 1500 mg, about 750 mg to about 1500 mg, about 800 mg to about 1500 mg, about 850 mg to about 1500 mg, about 900 mg to about 1500 mg, about 950 mg to about 1500 mg or about 1000 mg to about 1500 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and instructions for administration of the one oral loading dose of the amorphous otenaproxesul or the pharmaceutically acceptable salt thereof, to a subject in need thereof.

55. The pharmaceutical package or kit of claim 54, wherein the pharmaceutical package or kit further comprises a second oral loading dose comprising greater than 600 mg, about 650 mg to about 2000 mg, about 700 mg to about 2000 mg, about 750 mg to about 2000 mg, about 800 mg to about 2000 mg, about 825 mg to about 2000 mg, about 850 mg to about 2000 mg, about 700 mg to about 1500 mg, about 750 mg to about 1500 mg, about 800 mg to about 1500 mg, about 850 mg to about 1500 mg, about 900 mg to about 1500 mg, about 950 mg to about 1500 mg or about 1000 mg to about 1500 mg.

56. A pharmaceutical package or kit comprising: one or two oral loading doses each independently comprising greater than 600 mg, about 650 mg to about 2000 mg, about 700 mg to about 2000 mg, about 750 mg to about 2000 mg, about 800 mg to about 2000 mg, about 825 mg to about 2000 mg, about 850 mg to about 2000 mg, about 700 mg to about 1500 mg, about 750 mg to about 1500 mg, about 800 mg to about 1500 mg, about 850 mg to about 1500 mg, about 900 mg to about 1500 mg, about 950 mg to about 1500 mg or about 1000 mg to about 1500 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, and one or more oral maintenance doses each independently comprising about 25 mg to about 400 mg, about 50 mg to about 400 mg, about 75 mg to about 400 mg, about 100 mg to about 400 mg, about 125 mg to about 400 mg, about 150 mg to about 400 mg, about 175 mg to about 400 mg, about 200 mg to about 400 mg, about 225 mg to about 400 mg, about 250 mg to about 400 mg, about 300 mg to to about 400 mg, about 350 mg to about 400 mg, about 25 mg to about 350 mg, about 50 mg to about 400 mg, about 75 mg to about 350 mg, about 100 mg to about 350 mg, about 125 mg to about 350 mg, about 150 mg to about 350 mg, about 175 mg to about 350 mg, about 200 mg to about 350 mg, about 225 mg to about 350 mg, about 250 mg to about 350 mg, about 300 mg to to about 350 mg or about 350 mg of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

57. The pharmaceutical package or kit of claim 56, wherein the pharmaceutical package or kit further comprises instructions for administration of the oral loading dose(s) or one or more oral maintenance doses of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof to a subject in need thereof according to a method of any one of claims 1 to 29.

58. The pharmaceutical package or kit of any one of claims 54 to 57, wherein each oral loading dose or each oral maintenance dose is independently formulated into an oral pharmaceutical composition as defined in any one of claims 44 to 53.

59. The pharmaceutical package or kit of claim 58, wherein each oral loading dose or each oral maintenance dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof are respectively formulated into a single oral pharmaceutical composition, or each oralmaintenance dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof are respectively formulated into wo or more oral pharmaceutical compositions each comprising a divided dose of amorphous otenaproxesul or a pharmaceutically acceptable salt thereof, the divided doses adding up to the entire dose of the amorphous otenaproxesul or a pharmaceutically acceptable salt thereof.

60. The pharmaceutical package or kit of any one of claims 54 to 59, wherein the pharmaceutical packages or kits further comprise one or more oral placebo doses, and the one or more placebo doses are formulated as one or more oral pharmaceutical compositions61. The pharmaceutical package or kit of any one of claims 58 to 60, wherein the pharmaceutical package or kit is a blister pack, a pill dispenser, a clam shell dispenser or tray.

63. The pharmaceutical package or kit of claim 62, wherein the blister pack, pill dispenser, clam shell dispenser or tray comprises one or two pharmaceutical compositions comprising a loading dose or one and / or more pharmaceutical compositions comprising a maintenance dose sufficient for a treatment period of 14 days, 13 days, 12 days, 11 days, 10 days, 9 days, 8 days, 7 days, 6 days, 5 days, 4 days, 3 days, 2 days or 1 day.

64. The method of any one of claims 1 to 53 or the pharmaceutical package or kit of any one of claims 54 to 63, wherein the amorphous otenaproxesul is in a neutral form.