WO2025085641A1

WO2025085641A1 - The synthesis and characterization of end-group modified poloxamers

Info

Publication number: WO2025085641A1
Application number: PCT/US2024/051788
Authority: WO
Inventors: Michael J. Yost; Yuri Peterson; Sarah G. DENNIS-LITTLE; Timothy W. HANKS; Dylan SINGHI; Robert Harris; Hayden FREDERICKS; Madeline TURNIPSEED; Steven Kahn
Original assignee: MUSC Foundation for Research and Development
Current assignee: MUSC Foundation for Research and Development
Priority date: 2023-10-17
Filing date: 2024-10-17
Publication date: 2025-04-24
Anticipated expiration: 2026-04-17

Abstract

The present disclosure is directed to poloxamers linked to small molecules, as well as compositions thereof and uses therefor. The small molecules linked to the poloxamers may be one or more antioxidant compounds that modify the presence of redox molecules such as reactive oxygen species. These poloxamers linked to small molecules may, for example, be used to treat neurodegenerative diseases, muscular dystrophy, burns, and/or radiation oncology patients.

Description

DESCRIPTION THE SYNTHESIS AND CHARACTERIZATION OF END-GROUP MODIFIED POLOXAMERS This application claims the benefit of United States Provisional Application No. 63/590,923 filed October 17, 2023, the entire contents of which are hereby incorporated by reference. BACKGROUND I. Field The present disclosure relates generally to the fields of chemistry and biology. More particularly, it concerns poloxamer compounds and compositions thereof. II. Description of Related Art The need for novel cell membrane healing therapeutics is of great significance to the medical community, as the plasma membrane is the key feature in maintaining conventional cellular responsibilities. Poloxamers (polyalkylene oxides) have been shown to provide enhanced structural stability to the cell membrane and possess membrane resealing properties (Moloughney and Weisleder, 2012; Kwiatkowski et al., 2019). In particular, Poloxamer 188 (P188) has been shown to protect skeletal muscle cells against oxidative stress (Wong et al., 2017). Moreover, the addition of a small molecule therapeutic agent as a cofactor could potentially increase the effectiveness of the polymer. Hence, there is a need for the attachment of these small molecules as head groups to poloxamers to improve the cell membrane healing properties of poloxamers, further attenuating cellular injury and death. 1 4858-4046-6416, v.2 SUMMARY In some aspects, described herein is a poloxamer (polyalkylene oxide) having attached thereto a small molecule agent, wherein the small molecule agent is an antioxidant having the formula: , wherein

the bond between atoms 1 and 2 is a single bond or a double bond; p is 0 or 1; X is absent, CH₂ or S; R is substituted cycloalkyl(C≤8), substituted aryl(C≤8), heteroaryl(C≤8), substituted heteroaryl(C≤8), substituted alkoxy(C≤8), substituted cycloalkoxy(C≤8), substituted aryloxy_(C≤₈₎, heteroaryloxy_(C≤₈₎, substituted heteroaryloxy_(C≤₈₎, substituted arylamino_(C≤₈₎, substituted – alkanediyl(C≤8)–cycloalkyl(C≤8), –alkanediyl(C≤8)–heteroaryl(C≤8), substituted –alkanediyl(C≤8)–heteroaryl(C≤8), substituted – alkanediyl_(C≤8)–aryl_(C≤₈₎, substituted –alkanediyl_(C≤8)– heterocycloalkyl_(C≤₈₎, glutathione; or .

In some embodiments, the bond between atoms 1 and 2 is a single bond. In some embodiments, p is 0. In other embodiments, p is 1. In some embodiments, X is absent. In other 2 4858-4046-6416, v.2 embodiments, X is CH₂. In still other embodiments, X is S. In some embodiments, wherein R is substituted aryl_(C≤₈₎. In other embodiments, R is substituted –alkanediyl_(C≤8)– heterocycloalkyl_(C≤₈₎. In some embodiments, R is glutathione. In some embodiments, the poloxamer is further defined as a compound of the formula: , wherein

n is 78, 79, 80, 81, 82, 98, 99, 100, 101 or 102; m is 25, 26, 27, 28, 29, 30, 63, 64, 65, 66 or 67. In some embodiments, n is 79. In other embodiments, n is 80. In still other embodiments, n is 100. In some embodiments, m is 65. In other embodiments, m is 27. In some embodiments, the poloxamer is further defined as: . In some

.

In some a oxide) having attached thereto a small molecule agent, wherein the poloxamer is selected from a group consisting of: 3 4858-4046-6416, v.2

, 485 - - , . , r In some aspects, described here is a composition comprising: (a) a poloxamer described herein; and (b) an excipient. In some embodiments, the composition comprises from about 0.001% to about 25% poloxamer. In certain embodiments, the composition comprises from about 0.01% to about 10% poloxamer. In some embodiments, the composition comprises from about 0.1% to about 5% poloxamer. 5 4858-4046-6416, v.2 In some embodiments, the composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion. In particular embodiments, the composition is formulated for administration topically. In certain embodiments, the composition is formulated for topical administration to the skin. In some embodiments, the composition is formulated for administration via injection. In some embodiments, the composition is formulated for intraarterial administration, intramuscular administration, intraperitoneal administration, or intravenous administration. In some embodiments, the composition is formulated as a sealant. In some embodiments, the composition is formulated for use in cell membrane healing. In some embodiments, the composition is formulated for use in the treatment of burn wounds. In some embodiments, the composition comprises a buffer. In some embodiments, the buffer comprises water. In some embodiments, the buffer comprises citric acid. In some embodiments, the buffer comprises phosphate buffered saline. In some embodiments, the buffer comprises artificial interstitial fluid. In some embodiments, the composition comprises a gelation temperature modifying agent. In some embodiments, the composition comprises Pluronic^® F127. In some embodiments, the composition comprises from about 0% to about 50% Pluronic^® F127. In particular embodiments, the composition comprises from about 0% to about 40% Pluronic^® F127. In certain embodiments, the composition comprises from about 0% to about 30% Pluronic^® F127. In some embodiments, the composition comprises Triton X-Ethoxylated Octylphenol. In some embodiments, the composition comprises from about 0% to about 5% Triton X- Ethoxylated Octylphenol. In particular embodiments, the composition comprises from about 0% to about 2.5% Triton X-Ethoxylated Octylphenol. In certain embodiments, the composition comprises from about 0% to about 1% Triton X-Ethoxylated Octylphenol. In some aspects, described herein is a method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a poloxamer or composition described herein. 6 4858-4046-6416, v.2 In some embodiments, the disease or disorder is associated with cell membrane damage. In some embodiments, the disease or disorder is associated with oxidative stress. In some embodiments, the disease or disorder is associated with free radical injury. In some embodiments, the disease or disorder is associated with electrical injury. In some embodiments, the disease or disorder is a neurodegenerative disorder. In some embodiments, the neurodegenerative disorder is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, or Huntington’s disease. In some embodiments, the disease or disorder is a muscular dystrophy. In some embodiments, the patient is receiving radiation treatment. In some embodiments, the patient has been diagnosed with a disease or disorder associated with oxidative stress. In some embodiments, the patient is a mammal. In some embodiments, the patient is a human. In some embodiments, the method comprises administering the compound once. In some embodiments, the method comprises administering the compound two or more times. Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. 7 4858-4046-6416, v.2 BRIEF DESCRIPTION OF THE DRAWINGS The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein. FIG.1 shows the LPA modified P188 synthesis results. FIG.2 shows the polymer treated vs. normal H₂O₂ average cell size. FIG.3 shows the polymer treated vs. normal average cell size. FIG.4 shows the polymer treated vs. normal H₂O₂ average cell size. FIG.5 shows the average cell size vs. normal and average of tile count. FIG. 6 shows all of the functionalized variants produced to date with their disposition in the testing matrix. FIG.7 shows Poloxamer 188 (P188) with two lipoic acid end groups on either side. 8 4858-4046-6416, v.2 DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS Here, the inventors report the synthesis and characterization of these poloxamers (polyalkylene oxides) combined with a small molecule therapeutic agent as a cofactor. The attachment of these small molecules will improve the cell membrane healing properties of poloxamers, further attenuating cellular injury and death. See, for example, FIG. 7, which shows Poloxamer 188 (P188) with two lipoic acid end groups on either side. These and other aspects of the disclosure are described in detail below. III. Compounds of the Present Disclosure The compounds of the present disclosure are shown, for example, above, in the summary of the disclosure section, and in the claims and Table 1 below. Table 1. Compounds of the Present Disclosure Compound I_D ^Structure

9 4858-4046-6416, v.2 Compound I_D ^Structure

10 4858-4046-6416, v.2 Compound I_D ^Structure

They may be made using the synthetic methods shown in the Examples section. These methods can be further modified and optimized using the principles and techniques of organic chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, (2013), which is incorporated by reference herein. In addition, the synthetic methods may be further modified and optimized for preparative, pilot- or large-scale production, either batch or continuous, using the principles and techniques of process chemistry as applied by a person skilled in the art. Such principles and techniques are taught, for example, in Anderson, Practical Process Research & Development – A Guide for Organic Chemists (2012), which is incorporated by reference herein. All the compounds of the present disclosure may in some embodiments be used for the prevention and treatment of one or more diseases or disorders discussed herein or otherwise. In some embodiments, one or more of the compounds characterized or exemplified herein as an intermediate, a metabolite, and/or prodrug, may nevertheless also be useful for the prevention and treatment of one or more diseases or disorders. As such, unless explicitly stated to the contrary, all the compounds of the present disclosure are deemed “active compounds” and “therapeutic compounds” that are contemplated for use as active pharmaceutical ingredients (APIs). Actual suitability for human or veterinary use is typically determined using a combination of clinical trial protocols and regulatory procedures, such as those administered by the Food and Drug Administration (FDA). In the United States, the FDA is responsible for protecting the public health by assuring the safety, effectiveness, quality, and security of human and veterinary drugs, vaccines and other biological products, and medical devices. In some embodiments, the compounds of the present disclosure have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, more metabolically stable than, more lipophilic than, more hydrophilic than, and/or have a better pharmacokinetic profile 11 4858-4046-6416, v.2 (e.g., higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the indications stated herein or otherwise. Compounds of the present disclosure may contain one or more asymmetrically- substituted carbon or nitrogen atom and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a chemical formula are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some embodiments, a single diastereomer is obtained. The chiral centers of the compounds of the present disclosure can have the S or the R configuration. In some embodiments, the present compounds may contain two or more atoms which have a defined stereochemical orientation. Chemical formulas used to represent compounds of the present disclosure will typically only show one of possibly several different tautomers. For example, many types of ketone groups are known to exist in equilibrium with corresponding enol groups. Similarly, many types of imine groups exist in equilibrium with enamine groups. Regardless of which tautomer is depicted for a given compound, and regardless of which one is most prevalent, all tautomers of a given chemical formula are intended. In addition, atoms making up the compounds of the present disclosure are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C. In some embodiments, compounds of the present disclosure function as prodrugs or can be derivatized to function as prodrugs. Since prodrugs are known to enhance numerous desirable properties of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the disclosure may, if desired, be delivered in prodrug form. Thus, the disclosure contemplates prodrugs of compounds of the present disclosure as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the disclosure may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly, prodrugs include, for example, compounds described herein 12 4858-4046-6416, v.2 in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a hydroxy, amino, or carboxylic acid, respectively. In some embodiments, compounds of the present disclosure exist in salt or non-salt form. With regard to the salt form(s), in some embodiments the particular anion or cation forming a part of any salt form of a compound provided herein is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (2002), which is incorporated herein by reference. It will be appreciated that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates.” Where the solvent is water, the complex is known as a “hydrate.” It will also be appreciated that many organic compounds can exist in more than one solid form, including crystalline and amorphous forms. All solid forms of the compounds provided herein, including any solvates thereof are within the scope of the present disclosure. IV. Compositions and Formulations Provided herein are compositions and formulations that include at least one active agent and a pharmaceutically acceptable diluent(s), excipient(s), or carrier(s). In some embodiments, the compositions and/or formulations provided herein may comprise Poloxamer 108, Poloxamer 127, Poloxamer 188, Poloxamer 237, Poloxamer 238, Poloxamer 288, Poloxamer 335, Poloxamer 338, Poloxamer 407 or combinations thereof. In certain embodiments, the surfactant may be Poloxamer 188. In certain other embodiments, the poloxamer may be Poloxamer 127. Thermosensitive Gels: Polymers composed of polyoxypropylene and polyoxyethylene form thermosensitive gels when incorporated into aqueous solutions. These polymers have the ability to change from the liquid state to the gel state at temperatures close to body temperature, therefore allowing useful formulations that are applied to the targeted structure. (s). The liquid state-to-gel state phase transition (gelation temperature) is dependent on the polymer concentration, buffer concentration and the ingredients in the solution. In some embodiments, a thermosensitive gel suitable for compositions described herein is an aqueous gel comprising of a polymer of polyoxypropylene and polyoxyethylene. Poloxamer 188 (P188) is a theroreversible polymer composed of polyoxyethylene- polyoxypropylene copolymers. 13 4858-4046-6416, v.2 Other poloxamers include 124, PF-127, 237 (F-87 grade), and 338 (F-108 grade). Aqueous solutions of poloxamers are stable in the presence of acids, alkalis, and metal ions. P188 is a commercially available polyoxyethylene-polyoxypropylene triblock copolymer. In preferred embodiments, a gel formulation described herein comprises P188. In some embodiments, a formulation described herein comprises Pluronic^® F127. In some embodiments, a formulation described herein comprises Triton X. In certain embodiments, a formulation described herein comprises Triton X-Ethoxylated Octylphenol. In some embodiments, functionalized P188 may be mixed with Pluronic^® F127 and Triton X-Ethoxylated Octylphenol. When placed in contact with the body, such a gel preparation will form a semi-solid structure. Furthermore, poloxamers (e.g., P188) have good solubilizing capacity, low toxicity, and are biocompatible. In some embodiments, a gel formulation described herein may comprise from about 0.001% to about 25% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0.005% to about 20% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0.01% to about 15% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0.05% to about 10% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0.06% to about 9% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0.07% to about 8% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0.08% to about 7% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0.09% to about 6% of the poloxamer. In preferred embodiments, a gel formulation described herein may comprise from about 0.1% to about 5% of the poloxamer. In some embodiments, a gel formulation described herein may comprise from about 0% to about 90% of Pluronic^® F127. In some embodiments, a gel formulation described herein may comprise from about 0% to about 80% of Pluronic^® F127. In some embodiments, a gel formulation described herein may comprise from about 0% to about 70% of Pluronic^® F127. In some embodiments, a gel formulation described herein may comprise from about 0% to about 60% of Pluronic^® F127. In some embodiments, a gel formulation described herein may comprise from about 0% to about 50% of Pluronic^® F127. In some embodiments, a gel formulation described herein may comprise from about 0% to about 45% of Pluronic^® F127. 14 4858-4046-6416, v.2 In some embodiments, a gel formulation described herein may comprise from about 0% to about 40% of Pluronic^® F127. In some embodiments, a gel formulation described herein may comprise from about 0% to about 35% of Pluronic^® F127. In preferred embodiments, a gel formulation described herein may comprise from about 0% to about 30% of Pluronic^® F127. In some embodiments, a gel formulation described herein may comprise from about 0% to about 10% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 9% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 8% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 7% of Triton X- Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 6% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 5% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 4% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 3% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 2% of Triton X-Ethoxylated Octylphenol. In some embodiments, a gel formulation described herein may comprise from about 0% to about 1.5% of Triton X-Ethoxylated Octylphenol. In preferred embodiments, a gel formulation described herein may comprise from about 0% to about 1% of Triton X-Ethoxylated Octylphenol. In some embodiments, other commercially-available glycerin-based gels, glycerin- derived compounds, conjugated, or crosslinked gels, matrices, hydrogels, and polymers, as well as gelatins and their derivatives, alginates, and alginate-based gels, and even various native and synthetic hydrogel and hydrogel-derived compounds may be useful in the formulations described herein. In some embodiments, bioacceptable gels include, but are not limited to, alginate hydrogels SAF-GEL™ (ConvaTec, Princeton, N.J.), DUODERM® Hydroactive Gel (Con- vaTec), NU-GEL® (Johnson & Johnson Medical, Arlington, Tex.); CARRASYN® (V) ACEMANNAN HYDROGEL™ (Carrington Laboratories, Inc., Irving, Tex.); glycerin gels ELTA® Hydrogel (Swiss-American Products, Inc., Dallas, Tex.), K-Y® Sterile (Johnson & Johnson), gelatin hydro- gels, chitosan, silicon-base gels (e.g., MEDGEL®) or the like. Other thermosensitive and/or bioacceptable gels suitable for compositions described herein include acrylic acid-based polymers (e.g., CARBOPOL®), cellulose based polymers 15 4858-4046-6416, v.2 (e.g., hydroxypropylmethyl cellulose, carboxymethyl cellulose, or the like), alkyl aryl polyether alcohol-based polymer (e.g., TYLOXAPOL®), or the like. Purification: The purification of poloxamers is based on the removal of low molecular weight components (e.g., oligomers, unreacted material and/or other unwanted impurities that are produced during manufacturing or storage) and/or large molecular weight components (components from unwanted polymer-polymer reactions). The resulting purified product has a narrower PDI with approximately the same molecular weight as the original material. In some embodiments, a purified poloxamer has better gelling characteristics (e.g., a lower Tgel for the same % poloxamer concentration while providing a higher viscosity in the gel state). As used herein, a purified thermosensitive polymer has low polydispersity (i.e., a narrow distribution of molecular weights amongst the individual polymer chains therein). For example, commercially available poloxamers contain certain impurities such as poly(oxyethylene) homopolymer and poly(oxyethylene)/poly(oxypropylene) diblock polymers due to the nature of the manner in which they are produced. The relative amounts of these byproducts increase as the molecular weights of the component blocks increase. In some instances, in commercially available poloxamer 188, byproducts may constitute from about 15 to about 50% by weight of the polymer depending upon the manufacturer, thereby resulting in high polydispersity. In some embodiments, super critical fluid extraction technique is used to fractionate polyoxyalkylene block copolymers. See, U.S. Pat. No. 5,567,859, the disclosure for fractionation of polymers described therein is incorporated herein by reference. In this technique, lower molecular weight fractions in commercially purchased polymer are removed in a stream of CO2 maintained at a pressure of 2200 pounds per square inch (psi) and a temperature of 40 °C, thereby providing purified polymer having low polydispersity. In some embodiments, gel permeation chromatography allows for isolation of fractions of polymers. In some embodiments, one or more of the blocks is purified prior to manufacture of the copolymer. By way of example, purifying either the polyoxypropylene center block during synthesis of the copolymer, or the copolymer product itself (See, U.S. Pat. Nos.5,523,492, and 5,696,298, incorporated herein by reference for such disclosure) allows for manufacture of purified poloxamers. In some embodiments, fractionation of polyoxyalkylene block copolymers is achieved by batchwise removal of low molecular weight species using a salt extraction and liquid phase separation technique (See, U.S. Pat. No.5,800,711, which process of purification of polymers described therein is incorporated herein by reference). Such 16 4858-4046-6416, v.2 fractionation produces polyoxyalkylene block copolymers (e.g., poloxamaer 188 or the like) having improved physical characteristics including increased gel strength, decreased polydispersity, higher average molecular weight, decreased gelling concentration and/or extended gel dissolution profiles compared to commercially available poloxamers. Other processes for purification and/or fractionation of polymers are described in, for example, US 6,977,045 and US 6,761,824 which processes are incorporated herein by reference. In some instances, low molecular weight contaminants of polymers (e.g., poloxamers) cause deleterious side effects in vivo; the use of purified poloxamers in pharmaceutical formulations described herein reduces such in vivo side effects. Accordingly, also contemplated within the scope of embodiments presented herein are formulations comprising purified poly(oxyethylene)/poly(oxypropylene) triblock polymers that are substantially free of the poly(oxyethylene) homopolymers and/or poly(oxypropylene)/poly(oxyethylene) diblock byproducts, thereby narrowing the molecular weight distribution of block copolymers, (i.e., providing low polydispersity). In some embodiments, such purified poly(oxyethylene)/poly(oxypropylene) triblock polymers (e.g., fractionated poloxamers) allow for formulation of active compositions that comprise lower concentrations of the poly(oxyethylene)/poly(oxypropylene) triblock polymers compared to active compositions that comprise non-fractionated poly(oxyethylene)/poly(oxypropylene) triblock polymers. Advantageously, such compositions comprising lower concentrations of fractionated poly(oxyethylene)/poly(oxypropylene) triblock polymers (e.g., poloxamers) retain gelation properties (e.g., gelation between about 15 °C and about 42 °C) and sustained release characteristics (e.g., sustained release of dexamethasone over at least 3 days, 5 days or 7 days) despite having a lower concentration of the poly(oxyethylene)/poly(oxypropylene) triblock polymer. Gelation temperature modifying agents: In some embodiments, pharmaceutical formulations described herein comprise gelation temperature modifying agents. A "gelation temperature modifying agent" or a "gel temperature modifying agent" is an additive added to any formulation described herein, and changes the gelation temperature of the formulation such that the gel temperature of the formulation is maintained between about 14 °C and about 42 °C. A gel temperature modifying agent increases or decreases the gelation temperature of any formulation described herein such that the formulation maintains a gelation temperature of between about 14 °C and about 42 °C. 17 4858-4046-6416, v.2 In some embodiments, a gel temperature modifying agent is a gel temperature increasing agent. For example, where a formulation comprising a thermosensitive polymer has a gelation temperature below 14 °C, addition of a gel temperature increasing agent (e.g., P388, cyclodextrin, carboxymethyl cellulose, hyaluronic acid, Carbopol®, Tween 20, Tween 40, Tween 60, Tween 80, Tween 81, Tween 85, n methyl pyrrolidone, short chain fatty acid salts (e.g., sodium oleate, sodium caprate, sodium caprylate or the like) increases the gelation temperature of the formulation to above 14 °C, to between about 14 °C and about 42 °C. In some embodiments, a gel temperature modifying agent is a gel temperature decreasing agent. For example, where a formulation comprising a thermosensitive polymer has a gelation temperature above 42 °C, addition of a gel temperature decreasing agent (e.g., P388, cyclodextrin, carboxymethyl cellulose, hyaluronic acid, Carbopol®, Tween 20, Tween 40, Tween 60, Tween 80, Tween 81, Tween 85, n methyl pyrrolidone, fatty acid salts (e.g., sodium oleate, sodium caprate, sodium caprylate or the like) decreases the gelation temperature of the formulation to below 42 °C, to between about 14 °C and about 42 °C. In some embodiments, a gel temperature modifying agent is a pH sensitive polymer (e.g., chitosan). In some embodiments, a gel temperature modifying agent is a thermosensitive polymer. In some embodiments, a gel temperature modifying agent is an ion-sensitive polymer (e.g., alginates gel in the presence of calcium ions). In some embodiments, a gel temperature modifying agent is an acrylic acid-based polymer (e.g., Carbopol®). In some embodiments, a gel temperature modifying agent is a cellulose based polymer (e.g., hydroxypropylmethyl cellulose, carboxymethyl cellulose, or the like). In some embodiments, a gel temperature modifying agent is an alkyl aryl polyether alcohol-based polymer (e.g., Tyloxapol®). In some embodiments, a gel temperature modifying agent is a poloxamer. Gelation temperature: In one embodiment, a pharmaceutical formulation described herein is a liquid at about room temperature. In certain embodiments, the pharmaceutical formulation is characterized by a phase transition between about room temperature and about body temperature (including an individual with a serious fever, e.g., up to about 42 °C). In some embodiments, the phase transition occurs between at least about 1 °C below body temperature and body temperature, between at least about 2 °C below body temperature and body temperature, between at least about 3 °C below body temperature and body temperature, between at least about 4 °C below body temperature and body temperature, between at least about 6 °C below body temperature and body temperature, between at least about 8 °C below 18 4858-4046-6416, v.2 body temperature and body temperature, between at least about 10 °C below body temperature and body temperature, between at least about 15 °C below body temperature and body temperature, or between at least about 20 °C below body temperature and body temperature. In some embodiments, a formulation described herein has a gelation temperature of between about 5 °C, 10 °C, 14 °C, 15 °C, 16 °C, 17 °C, 18 °C, 19 °C, or 20 °C, and about 25 °C, 28 °C, 30 °C, 33 °C, 35 °C, 37 °C , 40 °C or 42 °C. In some embodiments, a formulation described herein has a gelation temperature of between about 5 °C and about 42 °C. In some embodiments, a formulation described herein has a gelation temperature of between about 10 °C and about 42 °C. In some embodiments, a formulation described herein has a gelation temperature of between about 14 °C and about 42 °C. Viscosity: In some embodiments, a formulation described herein comprises between about 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55% and about 0.5%, 1%, 5%, 10%, 15%, 20% 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% 80% or 89% of a viscosity enhancing polymer. In some embodiments, a formulation described herein comprises between about 0.1% and about 50% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 0.5% and about 30% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 0.1% and about 20% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 0.1% and about 10% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 0.1% and about 1% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 0.1% and about 0.5% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 1% and about 30% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 1% and about 10% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 10% and about 80% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 10% and about 50% of a viscosity enhancing polymer by weight of the composition. 19 4858-4046-6416, v.2 In some embodiments, a formulation described herein comprises between about 10% and about 30% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 20% and about 75% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 20% and about 65% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 20% and about 50% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 25% and about 75% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 15% and about 75% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 30% and about 75% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 35% and about 75% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 40% and about 75% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 45% and about 75% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 45% and about 65% of a viscosity enhancing polymer by weight of the composition. In some embodiments, a formulation described herein comprises between about 40% and about 60% of a viscosity enhancing polymer by weight of the composition. In some of such embodiments, a viscosity enhancing polymer is a hydrogel, a thermoreversible polymer, an acrylic acid based polymer, a pH sensitive polymer, a polymer sensitive to concentration of ions (e.g., alginate gels in the presence of Calcium ions) and the like. In some embodiments, a formulation described herein comprises about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, or 55% and about 25%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75% or 89% of a poloxamer. In some of such embodiments, a formulation comprising between about 35% and about 80% of poloxamer by weight of the composition, an alcohol (e.g. ethanol) and water exhibits high viscosity (e.g., 5000-8000 cP) at about room temperature (e.g., about 25 °C) or about body temperature (e.g., about 37 °C- 42 °C, including individuals with a fever). 20 4858-4046-6416, v.2 In some embodiments, a formulation described herein comprises between about 10% and about 80% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 10% and about 75% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 15% and about 75% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 20% and about 75% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 25% and about 75% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 30% and about 75% of a thermoreversible polymer of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 35% and about 75% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 40% and about 75% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 45% and about 75% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 45% and about 65% of P188 by weight of the composition. In some embodiments, a formulation described herein comprises between about 40% and about 60% of P188 by weight of the composition. Buffers: In some embodiments, formulations described herein comprise buffers. In one embodiment is a buffer such as acetate or citrate buffer at slightly acidic pH. In some embodiments, the buffer may comprise water. In some embodiments, the buffer may comprise citric acid. In some embodiments, the buffer may comprise phosphate buffered saline. In some embodiments, the buffer may comprise an artificial interstitial fluid. In some embodiments, the buffer may comprise a combination of salts that mimic the artificial interstitial fluid. Other suitable buffers to adjust pH can, in some embodiments, include sodium citrate, potassium citrate, citric acid, sodium dihydrogen phosphate, disodium monophosphate, boric acid, sodium borate, tartrate, phthalate, succinate, acetate, propionate, maleate salts, tris(hydroxymethyl)aminomethane, amino alcohol buffers, and good buffers (such as ACES, PIPES, and MOPOSO), and mixtures thereof. One or more buffers can be added to compositions of the present disclosure. In some embodiments a solution comprising the compositions described herein may have a pH from about 0.5 to about 14.0. In some embodiments a solution comprising the 21 4858-4046-6416, v.2 compositions described herein may have a pH from about 2.0 to about 12.0. In some embodiments a solution comprising the compositions described herein may have a pH from about 4.0 to about 10.0. In some embodiments a solution comprising the compositions described herein may have a pH from about 5.0 to about 8.0. In some embodiments a solution comprising the compositions described herein may have a pH from about 5.5 to about 7.5. In some embodiments a solution comprising the compositions described herein may have a pH from about 5.0 to about 7.0. In some embodiments a solution comprising the compositions described herein may have a pH from about 6.0 to about 8.0. In some embodiments a solution comprising the compositions described herein may have a pH from about 6.5 to about 8.5. In some embodiments a solution comprising the compositions described herein may have a pH from about 4.5 to about 6.5. Solvents: In some embodiments, the release profile of a thickened formulation is modified by selection of an appropriate solvent or combination of solvents. In some embodiments in a formulation described herein, the solvent is water. In some embodiments, a formulation described herein comprises a mixture of solvents (e.g., a mixture of water and an additional solvent such as an alcohol, or the like). In some embodiments, a formulation described herein comprises additional solvents including and not limited to ethanol, propylene glycol, PEG 400, DMSO, N-methyl pyrrolidone or any other auris-suitable solvent. In some embodiments, the additional solvent is a water-miscible solvent. In some embodiments, following administration of a formulation comprising a mixture of solvents, the additional solvent diffuses out into the aqueous and/or biological fluids thereby thickening the composition. In some embodiments, an additional solvent comprises between about 5% to about 50%, between about 10% to about 40%, between about 10% to about 30%, or between about 10% to about 20% of the solvent present in a formulation described herein. In some embodiments, a formulation described herein further comprises additional biocompatible excipients. Example of additional excipients include agents for imaging and/or visualization, penetration enhancers, including and not limited to alkyl saccharides (e.g., dodecyl maltoside, or the like), hyaluronic acid, (including and not limited to Hyalastine®, Hyalectin®, Hyaloftil®), and/or partial esters and/or salts thereof (e.g., barium salt of hyaluronic acid, or any other salt of hyaluronic acid described in WO/1998/017285, salts described therein are incorporated herein by reference), hyaluronidase (e.g., PH-20 (Halzoyme)) or any other excipient that modulates release profile and/or stability and/or permeability and/or drug uptake and/or bioavailability and/or toxicity and/or immunogenicity and/or gelation 22 4858-4046-6416, v.2 characteristics of any formulation described herein. Additional excipients are described in U.S. Appl. Nos. 12/427,663, 12/466,310, 12/472,034, 12/486,697, 12/493,611, 12/494,156, 12/500,486, 12/504,553, 12/506,091, 12/506,127, 12/506,573, 12/506,616, and 12/506,664, the disclosure of excipients described therein is incorporated herein by reference. In preferred embodiments, a formulation described herein comprises Pluronic^® F127. In other preferred embodiments, a formulation described herein comprises Triton X. Any of the compositions described herein can be aqueous compositions. As used herein, ''aqueous'' compositions refer to a spectrum of water-based compositions including, but not limited to, homogeneous solutions in water with solubilized components, emulsified compositions in water stabilized by surfactants or hydrophilic polymers, and viscous or gelled homogeneous or emulsified compositions in water. If maintenance of the osmolarity is required, examples of suitable tonicity adjusting agents that can be included in the poloxamer gel compositions include, but are not limited to: sodium chloride and potassium chloride, glycerin, propylene glycol, mannitol and sorbitol. These agents are typically used individually in amounts ranging from about 0.01 to 2.5% (w/v) and preferably, from about 0.05 to about 1.5% (w/v). Preferably, the tonicity agent will be employed in an amount to provide a final osmotic value of from 10 to 320 mOsm/kg and more preferably between about 200 to about 300 mOsm/kg, and most preferably between about 260 to about 290 mOsm/Kg. Sodium chloride is most preferred to adjust the composition tonicity. Emollients/moisturizers and humectants can be added to the poloxamer gel compositions to provide a soothing composition. Emollients/moisturizers function by forming an oily layer on the top of the skin that traps water in the skin. Petrolatum, lanolin, mineral oil, dimethicone, and siloxy compounds are common emollients. Other emollients include isopropyl palmitate, isopropyl myristate, isopropyl isostearate, isostearyl isostearate, diisopropyl sebacate, propylene dipelargonate, 2-ethylhexyl isononoate, 2-ethylhexyl stearate, cetyl lactate, lauryl lactate, isopropyl lanolate, 2-ethylhexyl salicylate, cetyl myristate, oleyl myristate, oleyl stearate, oleyl oleate, hexyl laurate, and isohexyl laurate, lanolin, olive oil, cocoa butter, shea butter, octyldodecanol, hexyldecanolc dicaprylylether and decyl oleate. Humectants include lecithin, and polyethylene glycol. Humectants function by drawing water into the outer layer of skin. It may be desirable to include water-soluble viscosity builders in the poloxamer gel compositions of the present disclosure. Because of their demulcent effect and possible 23 4858-4046-6416, v.2 hydrophobic interactions with biological tissue, aiding the retention of the compositions on a surface, particularly of biological origin, water-soluble polymers can enhance the compositions interaction with a surface. Because of this behavior, such water-soluble polymers can increase the residence time of the composition on a surface. Water-soluble polymers useful herein include, but are not limited to, aloe vera, methy1cellulose, hydroxyethy1cellulose, hydroxypropy1cellulose, hydroxypropylmethy1cellulose, carboxymethylcellulose, polyquaternium-1, polyquaternium- 6, polyquaternium-10, guar, hydroxypropylguar, hydroxypropylmethylguar, cationic guar, carboxymethylguar, hydroxymethylchitosan, hydroxypropylchitosan, carboxymethylchitosan, N-[(2-hydroxy-3- trimethylammonium)propyl]chitosan chloride, water-soluble chitosan, hyaluronic acid and its salts, chondroitin sulfate, heparin, dermatan sulfate, amylase, amylopectin, pectin, locust bean gum, alginate, dextran, carrageenan, xanthan gum, gellan gum, scleroglucan, schizophyllan, gum arabic, gum ghatti, gum karaya, gum tragacanth, pectins, starch and its modifications, tamarind gum, poly(vinyl alcohol), poly(ethylene oxide), poly(ethylene glycol), poly(methyl vinyl ether), polyacrylamide, poly(N,N- dimethylacrylamide), poly(N-vinylacetamide), poly(N- vinylformamide), poly(2- hydroxyethyl methacrylate), poly(glyceryl methacrylate), poly(N- vinylpyrrolidone), poly(N,N-dimethylaminoethyl methacrylate), poly(N,N-dimethylaminopropyl acrylamide), polyvinylamine, poly(N-isopropylacrylamide) and poly(N-vinylcaprolactam), the latter two hydrated below their Lower Critical Solution Temperatures, and the like, and combinations thereof. Such water-soluble polymers may be employed in amounts ranging from about 0.01 to about 10.0 weight percent. If chelating agents are required to sequester metal ions, such as found in matrix metalloproteases (MMPs), enzymes that can impede tissue formation and healing by breaking down collagen, or in removal of such metal ion deposits on structures, the chelating agent is selected from any compound that is able to sequester monovalent or polyvalent metal ions, such as preferentially including, calcium, magnesium, barium, cerium, cobalt, copper, iron, manganese, nickel, strontium or zinc, and is pharmaceutically or veterinary acceptable if used on biological tissue. Suitable chelating agents comprise, but are not limited to, citric acid, citrate salts, aminocarboxylic acids, ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid, nitrilotripropionic acid, diethylenetriaminepentaacetic acid, 2- 24 4858-4046-6416, v.2 hydroxyethylethylenediaminetriacetic acid, 1,6-diaminohexamethylenetetraacetic acid, 1,2- diaminocyclohexanetetraacetic acid, 0, O'-bis(2-aminoethypethyleneglycoltetraacetic acid, 1,3- diaminopropanetetraacetic acid, N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'- diacetic acid, ethylenediamine-N,N'-diacetic acid, ethylenediamine-N,N'-dipropionic acid, triethylenetetraaminehexaacetic acid, ethylenediamine-N,N'-bis(methylenephosphonic acid), iminodiacetic acid, N,N-bis(2-hydroxyethyl)glycine, 1,3-diamino-2- hydroxypropanetetraacetic acid, 1,2-diaminopropanetetraacetic acid, ethylenediaminetetrakis(methylenephosphonic acid), N-(2-hydroxyethyl)iminodiacetic acid and biphosphonates such as etidronate, and salts thereof. Suitable chelating agents include for example but are not limited to hydroxyalkylphosphonates as disclosed in U.S. Pat. No.5,858,937, specifically the tetrasodium salt of l-hydroxyethylidene-1,l-diphosphonic acid, also referred to as tetrasodium etidronate, commercially available from Monsanto Company as DeQuest 2016 diphosphonic acid sodium salt or phosphonate. V. Routes of Administration Pharmaceutical formulations may be administered by a variety of methods, e.g., orally or by injection (e.g. subcutaneous, intravenous, and intraperitoneal). The compounds disclosed herein may also be administered parenterally, intraperitoneally, intraspinally, or intracerebrally. Dispersions can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms. In topical applications, the poloxamer gel compositions may be delivered in different forms. Exemplary forms include, but not limited to, liquids, creams, foams, lotions, gels and aerosols. These compositions can also be imbibed by swabs, cloth, sponges, foams, dressing materials and non-woven and paper products, such as paper towels and wipes. Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the 25 4858-4046-6416, v.2 use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, sodium chloride, or polyalcohols such as mannitol and sorbitol, in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate or gelatin. The compounds or compositions disclosed herein may also be administered topically to the skin, ear, or mucosal membranes. Administration of the therapeutic compound topically may include formulations of the compounds as a topical solution, lotion, cream, ointment, gel, foam, transdermal patch, or tincture. When the therapeutic compound is formulated for topical administration, the compound may be combined with one or more agents that increase the permeability of the compound through the tissue to which it is administered. Ophthalmic topical administration can be formulated as a solution, suspension, ointment, gel, or emulsion. Finally, topical administration may also include administration to the mucosa membranes such as the inside of the mouth. Such administration can be directly to a particular location within the mucosal membrane such as a tooth, a sore, or an ulcer. In some embodiments, it may be advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the patients to be treated; each unit containing a predetermined quantity of therapeutic compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. In some embodiments, the specification for the dosage unit forms of the disclosure are dictated by and directly dependent on (a) the unique characteristics of the therapeutic compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such a therapeutic compound for the treatment of a selected condition in a patient. In some embodiments, active compounds are administered at a therapeutically effective dosage sufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that may be predictive of efficacy in treating the disease in a human or another animal. In some embodiments, the effective dose range for the therapeutic compound can be extrapolated from effective doses determined in animal studies for a variety of different 26 4858-4046-6416, v.2 animals. In some embodiments, the human equivalent dose (HED) in mg/kg can be calculated in accordance with the following formula (see, e.g., Reagan-Shaw et al., FASEB J., 22(3):659- 661, 2008, which is incorporated herein by reference): HED (mg/kg) = Animal dose (mg/kg) × (Animal Km/Human Km) Use of the Km factors in conversion results in HED values based on body surface area (BSA) rather than only on body mass. K_m values for humans and various animals are well known. For example, the Km for an average 60 kg human (with a BSA of 1.6 m²) is 37, whereas a 20 kg child (BSA 0.8 m²) would have a K_m of 25. K_m for some relevant animal models are also well known, including: mice Km of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster K_m of 5 (given a weight of 0.08 kg and BSA of 0.02); rat K_m of 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey Km of 12 (given a weight of 3 kg and BSA of 0.24). Precise amounts of the therapeutic composition depend on the judgment of the practitioner and are specific to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment and the potency, stability and toxicity of the particular therapeutic formulation. The actual dosage amount of a compound or composition of the present disclosure or composition comprising a compound of the present disclosure administered to a patient may be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. These factors may be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual patient. The dosage may be adjusted by the individual physician in the event of any complication. In some embodiments, the therapeutically effective amount typically will vary from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 100 mg/kg to about 500 mg/kg, from about 1 mg/kg to about 250 mg/kg, from about 10 mg/kg to about 150 mg/kg in one or more dose administrations daily, for one or several days (depending of course of the mode of administration and the factors discussed above). Other suitable dose ranges include 1 mg to 10,000 mg per day, 100 mg to 10,000 mg per day, 500 mg 27 4858-4046-6416, v.2 to 10,000 mg per day, and 500 mg to 1,000 mg per day. In some embodiments, the amount is less than 10,000 mg per day with a range of 750 mg to 9,000 mg per day. Single or multiple doses of the agents are contemplated. Desired time intervals for delivery of multiple doses can be determined by one of ordinary skill in the art employing no more than routine experimentation. As an example, patients may be administered two doses daily at approximately 12-hour intervals. In some embodiments, the agent is administered once a day. The agent(s) may be administered on a routine schedule. As used herein a routine schedule refers to a predetermined designated period of time. The routine schedule may encompass periods of time which are identical, or which differ in length, as long as the schedule is predetermined. For instance, the routine schedule may involve administration twice a day, every day, every two days, every three days, every four days, every five days, every six days, a weekly basis, a monthly basis or any set number of days or weeks there-between. Alternatively, the predetermined routine schedule may involve administration on a twice daily basis for the first week, followed by a daily basis for several months, etc. In some embodiments, a composition disclosed herein is administered to an individual in need thereof once. In some embodiments, a composition disclosed herein is administered to an individual in need thereof more than once. The number of times a composition is administered to an individual in need thereof depends on the discretion of a medical professional, the disorder, the severity of the disorder, and the individual's response to the formulation. In some embodiments, a formulation described herein is administered as prophylactically, therapeutically or as a chronic treatment over an extended period of time. In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the active agent compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time. The length of the time varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365 days. The dose reduction may be from 10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. 28 4858-4046-6416, v.2 Once improvement of the patient's active conditions has occurred, a maintenance active agent dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, is optionally reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, patients require intermittent treatment on a long-term basis upon any recurrence of symptoms. In some embodiments, pharmaceutical formulations described herein are manufactured as ready to use single component solutions that are administered to an individual in need thereof. In other embodiments, pharmaceutical formulations described herein are manufactured as multi-component kits comprising dry-heat sterilized multiparticulate (e.g., micronized, nanoparticles, non-sized particles) active agent powder, a medium for reconstitution of the dry powder (e.g., sterile water or buffer or saline) and/or a solution comprising the poloxamer and a buffer. The dry powder is reconstituted with the sterile medium and/or the solution comprising the poloxamer and buffer just prior to administration of the pharmaceutical formulation to an individual in need thereof. VI. Indications A. Cell Membrane Resealing In some embodiments, the compounds and compositions of the present disclosure can provide use of cells to enhance tissue maintenance and repair for any condition in need thereof. As described above, poloxamers have been shown to provide enhanced structural stability to the cell membrane and possess membrane resealing properties. In some embodiments, the compounds or compositions of the present disclosure may be used to treat chronic skin ulcers, acute wounds or burn wounds, or radiation oncology patients. In some embodiments, the compounds and compositions disclosed herein can be used to treat a neurodegenerative disease or disorder, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, or Huntington’s disease. In some embodiments, the compounds and compositions of the present disclosure can be employed, in particular, in the treatment of wounds, in particular to the skin, the mucous membrane, in the dental area, in the case of mucous membrane/jaw injuries in the oral cavity, or in the case of bums or scalds of the skin or skin diseases accompanied by chronic wounds. Wounds to the skin may be caused, for example, by cuts, punctures, crushing, bites or shot injuries, or may arise as an unavoidable consequence of operations or tooth extractions. 29 4858-4046-6416, v.2 Furthermore, diverse diseases may cause wounds to the skin or flesh or form open ulcers. Relatively large wounds also arise in the case of organ transplants or amputations and have to be provided with therapeutic care topically and locally. In the dental area, relatively small wounds may also arise in the case of carious inflammation and periodontitis and can successfully be treated with the formulations / gels according to the disclosure. If the enamel surface of the tooth is damaged, bacteria penetrate further into the underlying dentine. Pulp processes are present in the radial dentine tubules, meaning that partial or total infection and thus inflammation of the pulp then occurs. If no treatment is given, the consequence is death of the pulp tissue (necrosis) and bacterial decay (gangrene). If the gangrenous masses are not removed, inflammation outside the root tip is the consequence. Granulomas, cysts, fistula formation or abscesses may develop. In some embodiments, the compounds and compositions of the present disclosure can successfully be employed at each of these stages, advantageously after corresponding antibacterial treatment. In some embodiments, the compounds and compositions disclosed herein for the treatment of comparatively deep wounds and can be employed as wound fillers. Thus, for example, deep dermal ulcers, which very frequently weep heavily, can be treated with the gels according to the disclosure. The relatively high viscosity of the gel prevents liquid from trickling out of the wound, or at least reduces this. In addition, however, dry wounds, such as, for example, dry ulcus cruris, can also be treated with the compounds and compositions disclosed herein. Other types of wounds for which the compounds and compositions disclosed herein can be used include, but are not limited to, stage I, II, III decubitus ulcers (pressure sores), ulcus cruris (leg ulcer, leg sore), diabetic foot syndrome, skin ulcers, blood ulcers, first and second-degree bums, grazes and chronic wounds. In some embodiments, the compounds and compositions disclosed herein can be applied to a wound dressing which is known in principle and is commercially available, or, for example, like the plaster described above, can be changed every 12, 24, 48 or 72 hours, preferably every 48 hours, which may principally be necessary due to other factors and circumstances, such as, for example, the formation of wound secretions, bleeding or infections arising, which have to be treated. Various skin conditions may be treated or prevented by the introduction of the cells obtained using the methods disclosed herein. The conditions include skin diseases or disorders. In addition, the composition may be used to treat chronic skin ulcers, infected acute wounds or 30 4858-4046-6416, v.2 burn wounds, infected skin eczema, impetigo, atopic dermatitis, acne, external otitis, vaginal infections, seborrhoic dermatitis, oral infections, paradontitis, conjunctivitis or pneumonia. In certain embodiments, methods are provided for treating or preventing a condition characterized by skin degeneration, comprising administering to a subject in need thereof an effective amount of a composition comprising cells. These methods can include selecting a subject with one or more of these conditions and administering a therapeutically effective amount of the cells sufficient to treat the condition and/or ameliorate symptoms of the condition. The cells may be transplanted in various formats. For example, the cells may be introduced into the target site in the form of cell suspension, or adhered onto a matrix, extracellular matrix or substrate such as a biodegradable polymer, as a monolayer, or a combination. The cells may also be transplanted together (co-transplantation) with other cells. In some embodiment, the cells can be used for autologous grafts to those subjects suitable for receiving regenerative medicine. To determine suitability of cell compositions for therapeutics administration, the cells can first be tested in a suitable animal model. In one aspect, the cells are evaluated for their ability to survive and maintain their phenotype in vivo. Cell compositions are administered to animals (e.g., nude mice). Tissues are harvested after a period of growth and assessed as to whether the cells are still present. A number of animals are available for testing of the suitability of the cell compositions. For example, the Royal College of Surgeon’s (RCS) rat is a well known model of retinal dystrophy (Lund et al., 2006). In addition, cell suitability and survival can be determined by transplantation (e.g. subcutaneous or subretinal) in matrigel in immunodeficient animals such as NOG mice (Kanemura et al., 2014). Human cells or a pharmaceutical composition including these cells, can be used for the manufacture of a medicament to treat a condition in a patient in need thereof. The cells can be previously cryopreserved. In some embodiments, somatic cells obtained from patients can be genetically engineered to correct the disease-causing mutation and engineered to form a tissue. This tissue can be used to replace the endogenous degenerated tissue of the same patient. B. Oxidative Stress Over the past few decades, free and bound reactive radicals, highly reactive and thereby destructive molecules, have come to be appreciated increasingly for their importance to human health and disease. Many common and life-threatening human diseases, including atherosclerosis, cancer, and aging, have radical-based pathological reactions as an underlying mechanism of injury. A radical, or a free radical, is generally understood as a molecule with 31 4858-4046-6416, v.2 one or more unpaired electrons in its outer orbital shell. Many molecular species with bound radicals are monoxides or other oxygen containing compounds, generally referred to as reactive oxygen species (ROS). These highly unstable molecules tend to react rapidly with adjacent molecules, donating, abstracting, or even sharing their outer orbital electron(s). This reaction not only changes the adjacent, target molecule, sometimes in profound and beneficial ways, but it can also damage it, or alternatively the unpaired electron can be passed along to the target, i.e., as in a free radical, generating a second unwanted ROS, which can then go on to react positively or detrimentally with a new target. In fact, much of the high reactivity of ROS is due to their generation of such molecular chain reactions, effectively amplifying their effects. Antioxidants afford protection because they can scavenge ROS and free radicals before they cause damage to the various biological molecules, or prevent oxidative damage from spreading, e.g., by interrupting the radical chain reaction of lipid peroxidation. The reactivity of radicals in the body, and the burden on the body that results in eventual pathological conditions, is known as oxidative stress. For example, oxidative stress in the circulatory system is seen as atherosclerosis and by plaque deposition on the vessel walls. Plaques cause inflammatory responses, which increase radical formation by recruited immune cells, which worsens the cycle. It has been observed that the prime targets of both free radicals and ROS are the polyunsaturated fats in the membrane lipids of cells. The oxidative deterioration of polyunsaturated fats is known as lipid peroxidation. Lipid peroxidation severely impairs membrane function, which is believed to lead to the disorganization of cell structure and function. Products of lipid peroxidation such as malondialdehyde, a known mutagen reactive with proteins and amino acids, are a good measure of the amount of oxidative stress on the body. Lipofuscin, another byproduct of lipid peroxidation, accumulates in the body with age and it is believed that cytosolic buildup of this byproduct compromises brain function. What begins as localized pathological radical reactions thus result in oxidative stress that can and will eventually impact distal organ systems. Vitamins such as vitamin C and vitamin E, both of which are found in foods and available as supplements, help the body reduce effects of oxidative stress. A more powerful combatant against the free radicals and ROS, however, is the body's own self defense system of naturally produced chemicals called antioxidants. These antioxidants act to terminate the propagation of free and bound radicals on ROS either by giving an electron to the free radical or ROS or by hindering their formation. 32 4858-4046-6416, v.2 In some embodiments, the present disclosure provides a method of preventing, alleviating or treating oxidative stress in a subject. Oxidative stress results from abnormally high or prolonged levels of reactive oxygen species, such as superoxide, hydrogen peroxide, nitric oxide, and peroxynitrite (formed by the reaction of nitric oxide and superoxide). The oxidative stress may be accompanied by either acute or chronic inflammation. The oxidative stress may be caused by mitochondrial dysfunction, by activation of immune cells, such as macrophages and neutrophils, by acute exposure to an external agent, such as ionizing radiation or a cytotoxic chemotherapeutic agent (e.g., doxorubicin), by trauma or other acute tissue injury, by ischemia/reperfusion, by poor circulation or anemia, by localized or systemic hypoxia or hyperoxia, by elevated levels of inflammatory cytokines and other inflammation- related proteins, and/or by other abnormal physiological states, such as hyperglycemia or hypoglycemia. In some embodiments, the active agents of the present disclosure are formulated into a composition that retains the prophylactic and therapeutic antioxidant inducing properties of the individual active agents, providing an additive or even synergistic antioxidant inducing effect relative to the effect of each active alone, while also decreasing the toxic side effect(s) to a subject, of the individual active agents of the compositions. The compositions of the present disclosure may be useful to eradicate free and bound radical reactions presently taking place or it may be used as prophylaxis against pathological free or bound radical reactions, which may occur as a result of a possible oxidant promoting incident (e.g., ischemic injury). Accordingly, in pathologies involving oxidative stress alone or oxidative stress exacerbated by inflammation, treatment may comprise administering to a subject or patient a therapeutically effective amount of a compound, such as those described above or throughout this specification. Treatment may be administered preventively in advance of a predictable state of oxidative stress (e.g., organ transplantation or the administration of therapy to a cancer patient), or it may be administered therapeutically in settings involving established oxidative stress and inflammation. Non-limiting embodiments of diseases or disorders associated with oxidative stress include cancer, atherosclerosis, and diabetes, which were not traditionally viewed as inflammatory conditions. In the case of cancer, the inflammatory processes are associated with processes that include tumor formation, progression, metastasis, and resistance to therapy. In some embodiments, the compounds and compositions of this disclosure may be used in the 33 4858-4046-6416, v.2 treatment or prevention of cancers including a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma, or cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid. Many other disorders involve oxidative stress and inflammation in affected tissues, including inflammatory bowel disease; inflammatory skin diseases; mucositis and dermatitis related to radiation therapy and chemotherapy; eye diseases, such as uveitis, glaucoma, macular degeneration, and various forms of retinopathy; transplant failure and rejection; ischemia-reperfusion injury; chronic pain; degenerative conditions of the bones and joints, including osteoarthritis and osteoporosis; asthma and cystic fibrosis; seizure disorders; and neuropsychiatric conditions, including schizophrenia, depression, bipolar disorder, post- traumatic stress disorder, attention deficit disorders, autism-spectrum disorders, and eating disorders, such as anorexia nervosa. Dysregulation of inflammatory signaling pathways is believed to be a major factor in the pathology of muscle wasting diseases, including muscular dystrophy and various forms of cachexia. In some embodiments, the compounds and compositions of the present disclosure may be used to treat muscular dystrophies, such as Duchenne and Becker muscular dystrophies. In another aspect, the compounds and compositions of this disclosure may be used in preventing or treating tissue damage or organ failure, acute and chronic, resulting from oxidative stress exacerbated by inflammation. Examples of diseases that fall in this category include heart failure, liver failure, transplant failure and rejection, renal failure, pancreatitis, fibrotic lung diseases (cystic fibrosis, COPD, and idiopathic pulmonary fibrosis, among others), diabetes (including complications), atherosclerosis, ischemia-reperfusion injury, glaucoma, stroke, autoimmune disease, autism, macular degeneration, and muscular dystrophy. For example, in the case of autism, studies suggest that increased oxidative stress in the central nervous system may contribute to the development of the disease (Chauhan and Chauhan, 2006). Evidence also links oxidative stress and inflammation to the development and pathology of many other disorders of the central nervous system, including psychiatric disorders, such as psychosis, major depression, and bipolar disorder; seizure disorders, such as 34 4858-4046-6416, v.2 epilepsy; pain and sensory syndromes, such as migraine, neuropathic pain, or tinnitus; and behavioral syndromes, such as the attention deficit disorders. See, e.g., Dickerson et al., 2007; Hanson et al., 2005; Kendall-Tackett, 2007; Lencz et al., 2007; Dudhgaonkar et al., 2006; Lee et al., 2007; Morris et al., 2002; Ruster et al., 2005; McIver et al., 2005; Sarchielli et al., 2006; Kawakami et al., 2006; Ross et al., 2003, which are all incorporated by reference herein. For example, elevated levels of inflammatory cytokines, including TNF-α, interferon-α, and IL-6, are associated with major mental illness (Dickerson et al., 2007). Microglial activation has also been linked to major mental illness. Therefore, downregulating inflammatory cytokines and inhibiting excessive activation of microglia could be beneficial in patients with schizophrenia, major depression, bipolar disorder, autism-spectrum disorders, and other neuropsychiatric disorders. Accordingly, in pathologies involving oxidative stress alone or oxidative stress exacerbated by inflammation, treatment may comprise administering to a subject a therapeutically effective amount of a synthetic triterpenoid compound of this disclosure, such as those described above or throughout this specification. Treatment may be administered preventively, in advance of a predictable state of oxidative stress (e.g., organ transplantation or the administration of radiation therapy to a cancer patient), or it may be administered therapeutically in settings involving established oxidative stress and inflammation. In some embodiments, when a synthetic triterpenoid compound of this disclosure is used for treating a patient receiving radiation therapy and/or chemotherapy, the compound of the invention may be administered before, at the same time, and/or after the radiation or chemotherapy, or the compound may be administered in combination with the other therapies. In some embodiments, the compounds and compositions of this disclosure may prevent and/or reduce the severity of side effects associated with the radiation therapy or chemotherapy (using a different agent) without reducing the anticancer effects of the radiation therapy or chemotherapy. Because such side effects may be dose-limiting for the radiation therapy and/or chemotherapy, in some embodiments, the compounds and compositions of this disclosure may be used to allow for higher and/or more frequent dosing of the radiation therapy and/or chemotherapy, for example, resulting in greater treatment efficacy. In some embodiments, the compounds and compositions of this disclosure when administered in combination with the radiation therapy and/or chemotherapy may enhance the efficacy of a given dose of radiation and/or chemotherapy. In some embodiments, the compounds and compositions of this disclosure when administered in combination with the radiation therapy and/or chemotherapy 35 4858-4046-6416, v.2 may enhance the efficacy of a given dose of radiation and/or chemotherapy and reduce (or, at a minimum, not add to) the side effects of the radiation and/or chemotherapy. In some embodiments, and without being bound by theory, this combinatorial efficacy may result from inhibition of the activity of the pro-inflammatory transcription factor NF- ^B by the compound of the invention. NF-κB is often chronically activated in cancer cells, and such activation is associated with resistance to therapy and promotion of tumor progression (e.g., Karin, 2006; Aghajan et al., 2012). Other transcription factors that promote inflammation and cancer, such as STAT3 (e.g., He and Karin 2011; Grivennikov and Karin, 2010), may also be inhibited by the compounds and compositions of this disclosure in some embodiments. The compounds and compositions of this disclosure may also be used to treat or prevent diseases, such as cancer, inflammation, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, autism, amyotrophic lateral sclerosis, Huntington’s disease, autoimmune diseases, such as rheumatoid arthritis, lupus, Crohn’s disease, and psoriasis, inflammatory bowel disease, all other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide or prostaglandins, and pathologies involving oxidative stress alone or oxidative stress exacerbated by inflammation. The compounds and compositions of this disclosure may be used in the treatment or prevention of cancers include a carcinoma, sarcoma, lymphoma, leukemia, melanoma, mesothelioma, multiple myeloma, or seminoma, or cancer of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gall bladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid. VII. Combination Therapy In addition to being used as a monotherapy, the compounds, compositions and methods of the present disclosure described in the present disclosure may also find use in combination therapies. Effective combination therapy may be achieved with a single composition or pharmacological formulation that includes both agents, or with two distinct compositions or formulations, administered at the same time, wherein one composition includes a compound of the present disclosure, and the other includes the second agent(s). The other therapeutic modality may be administered before, concurrently with, or following administration of the compounds of the present disclosure. The therapy using the compounds of the present disclosure may precede or follow administration of the other agent(s) by intervals ranging from minutes to weeks. In embodiments where the other agent and the compounds of the present 36 4858-4046-6416, v.2 disclosure are administered separately, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that each agent would still be able to exert an advantageously combined effect. In such instances, it is contemplated that one would typically administer the compounds of the present disclosure and the other therapeutic agent within about 12-24 hours of each other and, more preferably, within about 6-12 hours of each other, with a delay time of only about 12 hours being most preferred. In some situations, it may be desirable to extend the time period for treatment significantly, however, where several days (2, 3, 4, 5, 6 or 7) to several weeks (1, 2, 3, 4, 5, 6, 7 or 8) lapse between the respective administrations. It also is conceivable that more than one administration of a compound of the present disclosure, or the other agent will be desired. In this regard, various combinations may be employed. By way of illustration, where the compound of the present disclosure is "A" and the other agent is "B", the following permutations based on 3 and 4 total administrations are exemplary: A/B/A B/A/B B/B/A A/A/B B/A/A A/B/B B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A/A B/A/B/A B/A/A/B B/B/B/A A/A/A/B B/A/A/A A/B/A/A A/A/B/A A/B/B/B B/A/B/B B/B/A/B Other combinations are likewise contemplated. Non-limiting examples of pharmacological agents that may be used in the present disclosure include any pharmacological agent known to be of benefit in the treatment of a cancer or hyperproliferative disorder or disease. VIII. Definitions As used herein, the term ''poloxamer'' refers to non-toxic, non-ionic triblock copolymers composed of a central hydrophobic chain of polyoxypropylene (polypropylene oxide) coupled by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)) in the alpha, omega positions. Because the lengths of the polymer blocks can be customized, many different poloxamers exist that have slightly different properties. For the generic term poloxamer, these copolymers are commonly named with the letter P (for poloxamer) followed by three digits: the first two digits multiplied by 100 give the approximate molecular mass of the polyoxypropylene core, and the last digit multiplied by 10 gives the percentage 37 4858-4046-6416, v.2 polyoxyethylene content. For the Pluronic and Synperonic tradenames, coding of these copolymers starts with a letter to define its physical form at room temperature (L = liquid, P = paste, F = flake (solid)) followed by two or three digits, The first digit (two digits in a three- digit number) in the numerical designation, multiplied by 300, indicates the approximate molecular weight of the hydrophobe; and the last digit x 10 gives the percentage polyoxyethylene content. When used in the context of a chemical group: “hydrogen” means −H; “hydroxy” means −OH; “oxo” means =O; “carbonyl” means −C(=O)−; “carboxy” means −C(=O)OH (also written as −COOH or −CO₂H); “halo” means independently −F, −Cl, −Br or −I; “amino” means −NH2; “hydroxyamino” means −NHOH; “nitro” means −NO2; imino means =NH; “cyano” means −CN; “isocyanyl” means −N=C=O; “azido” means −N₃; in a monovalent context “phosphate” means −OP(O)(OH)2 or a deprotonated form thereof; in a divalent context “phosphate” means −OP(O)(OH)O− or a deprotonated form thereof; “mercapto” means −SH; and “thio” means =S; “thiocarbonyl” means −C(=S)−; “sulfonyl” means −S(O)2−; and “sulfinyl” means −S(O)−. In the context of chemical formulas, the symbol “−” means a single bond, “=” means a double bond, and “≡” means triple bond. The symbol “ ” represents an optional bond, which if present is either single or double. The symbol “ ” represents a single bond or a double bond. Thus, the covers, for . And it is understood

such ring atom

Furthermore, it is noted that the covalent bond symbol “−”, when connecting one or two stereogenic atoms, does not indicate any preferred

Instead, it covers all stereoisomers as well as mixtures thereof. The symbol “ ”, when drawn perpendicularly across a bond for methyl) indicates a point of attachment of the group. It is noted

is typically only identified in this manner for larger groups in order to assist the reader in unambiguously identifying a point of attachment. The symbol “ ” means a single bond where the group attached to the thick end of the wedge is

the page.” The symbol “ ” means a single bond where the group attached to the thick end of the wedge is “into the page”. The symbol “ ” means a single bond where the geometry around a double bond (e.g., either E or Z) is undefined. Both options, as well as combinations thereof are therefore intended. Any undefined valency on an atom of a structure shown in this 38 4858-4046-6416, v.2 application implicitly represents a hydrogen atom bonded to that atom. A bold dot on a carbon atom indicates that the hydrogen attached to that carbon is oriented out of the plane of the paper. For the chemical groups and compound classes, the number of carbon atoms in the group or class is as indicated as follows: “Cn” or “C=n” defines the exact number (n) of carbon atoms in the group/class. “C≤n” defines the maximum number (n) of carbon atoms that can be in the group/class, with the minimum number as small as possible for the group/class in question. For example, it is understood that the minimum number of carbon atoms in the groups “alkyl_(C≤₈₎”, “alkanediyl_(C≤₈₎”, “heteroaryl_(C≤₈₎”, and “acyl_(C≤₈₎” is one, the minimum number of carbon atoms in the groups “alkenyl_(C≤₈₎”, “alkynyl_(C≤₈₎”, and “heterocycloalkyl_(C≤₈₎” is two, the minimum number of carbon atoms in the group “cycloalkyl(C≤8)” is three, and the minimum number of carbon atoms in the groups “aryl(C≤8)” and “arenediyl(C≤8)” is six. “Cn-n′” defines both the minimum (n) and maximum number (n′) of carbon atoms in the group. Thus, “alkyl(C2-10)” designates those alkyl groups having from 2 to 10 carbon atoms. These carbon number indicators may precede or follow the chemical groups or class it modifies and it may or may not be enclosed in parenthesis, without signifying any change in meaning. Thus, the terms “C₁-C₄-alkyl”, “C_1-4-alkyl”, “C1-4-alkyl”, “alkyl_(C1-4)”, and “alkyl_(C≤4)” are all synonymous. Except as noted below, every carbon atom is counted to determine whether the group or compound falls with the specified number of carbon atoms. For example, the group dihexylamino is an example of a dialkylamino(C12) group; however, it is not an example of a dialkylamino_(C6) group. Likewise, phenylethyl is an example of an aralkyl_(C=8) group. When any of the chemical groups or compound classes defined herein is modified by the term “substituted”, any carbon atom in the moiety replacing the hydrogen atom is not counted. Thus methoxyhexyl, which has a total of seven carbon atoms, is an example of a substituted alkyl_(C1- 6). Unless specified otherwise, any chemical group or compound class listed in a claim set without a carbon atom limit has a carbon atom limit of less than or equal to twelve. The term “saturated” when used to modify a compound or chemical group means the compound or chemical group has no carbon-carbon double and no carbon-carbon triple bonds, except as noted below. When the term is used to modify an atom, it means that the atom is not part of any double or triple bond. In the case of substituted versions of saturated groups, one or more carbon oxygen double bond or a carbon nitrogen double bond may be present. And when such a bond is present, then carbon-carbon double bonds that may occur as part of keto- 39 4858-4046-6416, v.2 enol tautomerism or imine/enamine tautomerism are not precluded. When the term “saturated” is used to modify a solution of a substance, it means that no more of that substance can dissolve in that solution. The term “aliphatic” signifies that the compound or chemical group so modified is an acyclic or cyclic, but non-aromatic compound or group. In aliphatic compounds/groups, the carbon atoms can be joined together in straight chains, branched chains, or non-aromatic rings (alicyclic). Aliphatic compounds/groups can be saturated, that is joined by single carbon- carbon bonds (alkanes/alkyl), or unsaturated, with one or more carbon-carbon double bonds (alkenes/alkenyl) or with one or more carbon-carbon triple bonds (alkynes/alkynyl). The term “aromatic” signifies that the compound or chemical group so modified has a planar unsaturated ring of atoms with 4n +2 electrons in a fully conjugated cyclic π system. An aromatic compound or chemical group may be depicted as a single resonance structure; however, depiction of one resonance structure is taken to also refer to any other resonance structure. For example: . Aromatic

the delocalized nature of the electrons in the fully conjugated cyclic π system, two non-limiting examples of which are shown below: . The term “alkyl” refers to a

group with a carbon atom as the point of attachment, a linear or branched acyclic structure, and no atoms other than carbon and hydrogen. The groups −CH3 (Me), −CH2CH3 (Et), −CH2CH2CH3 (n-Pr or propyl), −CH(CH3)2 (i-Pr, ⁱPr or isopropyl), −CH2CH2CH2CH3 (n-Bu), −CH(CH3)CH2CH3 (sec-butyl), −CH2CH(CH3)2 (isobutyl), −C(CH3)3 (tert-butyl, t-butyl, t-Bu or ^tBu), and −CH2C(CH3)3 (neo- pentyl) are non-limiting examples of alkyl groups. The term “alkanediyl” refers to a divalent saturated aliphatic group, with one or two saturated carbon atom(s) as the point(s) of attachment, a linear or branched acyclic structure, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The groups −CH₂− (methylene), −CH₂CH₂−, 40 4858-4046-6416, v.2 −CH₂C(CH₃)₂CH₂−, and −CH₂CH₂CH₂− are non-limiting examples of alkanediyl groups. The term “alkylidene” refers to the divalent group =CRR′ in which R and R′ are independently hydrogen or alkyl. Non-limiting examples of alkylidene groups include: =CH2, =CH(CH₂CH₃), and =C(CH₃)₂. An “alkane” refers to the class of compounds having the formula H−R, wherein R is alkyl as this term is defined above. The term “cycloalkyl” refers to a monovalent saturated aliphatic group with a carbon atom as the point of attachment, said carbon atom forming part of one or more non-aromatic ring structures, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. Non-limiting examples include: −CH(CH2)2 (cyclopropyl), cyclobutyl, cyclopentyl, or cyclohexyl (Cy). As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to a carbon atom of the non-aromatic ring structure. The term “cycloalkanediyl” refers to a divalent saturated aliphatic group with two carbon atoms as points of attachment, no carbon-carbon double or triple bonds, and no atoms other than carbon and hydrogen. The is a non-limiting example of cycloalkanediyl group. A “cycloalkane” refers

compounds having the formula H−R, wherein R is cycloalkyl as this term is defined above. The term “alkenyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched, acyclic structure, at least one nonaromatic carbon-carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. Non-limiting examples include: −CH=CH₂ (vinyl), −CH=CHCH₃, −CH=CHCH2CH3, −CH2CH=CH2 (allyl), −CH2CH=CHCH3, and −CH=CHCH=CH2. The term “alkenediyl” refers to a divalent unsaturated aliphatic group, with two carbon atoms as points of attachment, a linear or branched acyclic structure, at least one nonaromatic carbon- carbon double bond, no carbon-carbon triple bonds, and no atoms other than carbon and hydrogen. The groups −CH=CH−, −CH=C(CH₃)CH₂−, −CH=CHCH₂−, and −CH2CH=CHCH2− are non-limiting examples of alkenediyl groups. It is noted that while the alkenediyl group is aliphatic, once connected at both ends, this group is not precluded from forming part of an aromatic structure. The terms “alkene” and “olefin” are synonymous and refer to the class of compounds having the formula H−R, wherein R is alkenyl as this term is defined above. Similarly, the terms “terminal alkene” and “α-olefin” are synonymous and refer 41 4858-4046-6416, v.2 to an alkene having just one carbon-carbon double bond, wherein that bond is part of a vinyl group at an end of the molecule. The term “alkynyl” refers to a monovalent unsaturated aliphatic group with a carbon atom as the point of attachment, a linear or branched acyclic structure, at least one carbon- carbon triple bond, and no atoms other than carbon and hydrogen. As used herein, the term alkynyl does not preclude the presence of one or more non-aromatic carbon-carbon double bonds. The groups −C≡CH, −C≡CCH₃, and −CH₂C≡CCH₃ are non-limiting examples of alkynyl groups. An “alkyne” refers to the class of compounds having the formula H−R, wherein R is alkynyl. The term “aryl” refers to a monovalent unsaturated aromatic group with an aromatic carbon atom as the point of attachment, said carbon atom forming part of a one or more aromatic ring structures, each with six ring atoms that are all carbon, and wherein the group consists of no atoms other than carbon and hydrogen. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. As used herein, the term aryl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. Non-limiting examples of aryl groups include phenyl (Ph), methylphenyl, (dimethyl)phenyl, −C6H4CH2CH3 (ethylphenyl), naphthyl, and a monovalent group derived from biphenyl (e.g., 4-phenylphenyl). The term “arenediyl” refers to a divalent aromatic group with two aromatic carbon atoms as points of attachment, said carbon atoms forming part of one or more six- membered aromatic ring structures, each with six ring atoms that are all carbon, and wherein the divalent group consists of no atoms other than carbon and hydrogen. As used herein, the term arenediyl does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to the first aromatic ring or any additional aromatic ring present. If more than one ring is present, the rings may be fused or unfused. Unfused rings are connected with a covalent bond. Non-limiting examples of arenediyl groups include: 4858-4046-

An “arene” refers to the class of compounds having the formula H−R, wherein R is aryl as that term is defined above. Benzene and toluene are non-limiting examples of arenes. The term “aralkyl” refers to the monovalent group −alkanediyl−aryl, in which the terms alkanediyl and aryl are each used in a manner consistent with the definitions provided above. Non-limiting examples are: phenylmethyl (benzyl, Bn) and 2-phenyl-ethyl. The term “heteroaryl” refers to a monovalent aromatic group with an aromatic carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heteroaryl group consists of no atoms other than carbon, hydrogen, aromatic nitrogen, aromatic oxygen and aromatic sulfur. If more than one ring is present, the rings are fused; however, the term heteroaryl does not preclude the presence of one or more alkyl or aryl groups (carbon number limitation permitting) attached to one or more ring atoms. Non-limiting examples of heteroaryl groups include benzoxazolyl, benzimidazolyl, furanyl, imidazolyl (Im), indolyl, indazolyl, isoxazolyl, methylpyridinyl, oxazolyl, oxadiazolyl, phenylpyridinyl, pyridinyl (pyridyl), pyrrolyl, pyrimidinyl, pyrazinyl, quinolyl, quinazolyl, quinoxalinyl, triazinyl, tetrazolyl, thiazolyl, thienyl, and triazolyl. The term “N-heteroaryl” refers to a heteroaryl group with a nitrogen atom as the point of attachment. A “heteroarene” refers to the class of compounds having the formula H−R, wherein R is heteroaryl. Pyridine and quinoline are non-limiting examples of heteroarenes. The term “heterocycloalkyl” refers to a monovalent non-aromatic group with a carbon atom or nitrogen atom as the point of attachment, said carbon atom or nitrogen atom forming part of one or more non-aromatic ring structures, each with three to eight ring atoms, wherein at least one of the ring atoms of the non-aromatic ring structure(s) is nitrogen, oxygen or sulfur, and wherein the heterocycloalkyl group consists of no atoms other than carbon, hydrogen, nitrogen, oxygen and sulfur. If more than one ring is present, the rings may be fused, bridged, or spirocyclic. As used herein, the term does not preclude the presence of one or more alkyl groups (carbon number limitation permitting) attached to one or more ring atoms. Also, the term does not preclude the presence of one or more double bonds in the ring or ring system, provided that the resulting group remains non-aromatic. Non-limiting examples of heterocycloalkyl groups include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, 43 4858-4046-6416, v.2 tetrahydropyridinyl, pyranyl, oxiranyl, and oxetanyl. The term “N-heterocycloalkyl” refers to a heterocycloalkyl group with a nitrogen atom as the point of attachment. N-pyrrolidinyl is an example of such a group. The term “acyl” refers to the group −C(O)R, in which R is a hydrogen, alkyl, cycloalkyl, or aryl as those terms are defined above. The groups, −CHO, −C(O)CH₃ (acetyl, Ac), −C(O)CH2CH3, −C(O)CH(CH3)2, −C(O)CH(CH2)2, −C(O)C6H5, and −C(O)C6H4CH3 are non- limiting examples of acyl groups. A “thioacyl” is defined in an analogous manner, except that the oxygen atom of the group −C(O)R has been replaced with a sulfur atom, −C(S)R. The term “aldehyde” corresponds to an alkyl group, as defined above, attached to a −CHO group. The term “alkoxy” refers to the group −OR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −OCH3 (methoxy), −OCH2CH3 (ethoxy), −OCH₂CH₂CH₃, −OCH(CH₃)₂ (isopropoxy), or −OC(CH₃)₃ (tert-butoxy). The terms “cycloalkoxy”, “alkenyloxy”, “alkynyloxy”, “aryloxy”, “aralkoxy”, “heteroaryloxy”, “heterocycloalkoxy”, “heteroaralkoxy”, “alkylsilyloxy” and “acyloxy”, when used without the “substituted” modifier, refers to groups, defined as −OR, in which R is cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heterocycloalkyl, heteroaralkyl, alkylsilyl and acyl, respectively. The terms “alkylthio” and “acylthio” refers to the group −SR, in which R is an alkyl group and acyl, respectively. The term “alkylsulfonyl” refers to the group −SO2R, in which R is an alkyl group. The term “alcohol” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with a hydroxy group. The term “ether” corresponds to an alkane, as defined above, wherein at least one of the hydrogen atoms has been replaced with an alkoxy group. The term “alkylamino” refers to the group −NHR, in which R is an alkyl, as that term is defined above. Non-limiting examples include: −NHCH₃ and −NHCH₂CH₃. The term “dialkylamino” refers to the group −NRR′, in which R and R′ can be the same or different alkyl groups. Non-limiting examples of dialkylamino groups include: −N(CH3)2 and −N(CH3)(CH2CH3). The term “amido” (acylamino), when used without the “substituted” modifier, refers to the group −NHR, in which R is acyl, as that term is defined above. A non- limiting example of an amido group is −NHC(O)CH3. The term “heteroaralkyl” refers to the monovalent group −alkanediyl−heteroaryl, in which the terms alkanediyl and heteroaryl are each used in a manner consistent with the 44 4858-4046-6416, v.2 definitions provided above. Non-limiting examples are: pyridinylmethyl and 2-quinolinyl- ethyl. When a chemical group is used with the “substituted” modifier, one or more hydrogen atom has been replaced, independently at each instance, by −OH, −F, −Cl, −Br, −I, −NH2, −NO₂, −CO₂H, −CO₂CH₃, −CO₂CH₂CH₃, −CN, −SH, −OCH₃, −OCH₂CH₃, −C(O)CH₃, −NHCH3, −NHCH2CH3, −N(CH3)2, −C(O)NH2, −C(O)NHCH3, −C(O)N(CH3)2, −OC(O)CH3, −NHC(O)CH₃, −S(O)₂OH, or −S(O)₂NH₂. For example, the following groups are non-limiting examples of substituted alkyl groups: −CH2OH, −CH2Cl, −CF3, −CH2CN, −CH2C(O)OH, −CH₂C(O)OCH₃, −CH₂C(O)NH₂, −CH₂C(O)CH₃, −CH₂OCH₃, −CH₂OC(O)CH₃, −CH₂NH₂, −CH2N(CH3)2, and −CH2CH2Cl. The term “haloalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to halo (i.e. −F, −Cl, −Br, or −I) such that no other atoms aside from carbon, hydrogen and halogen are present. The group, −CH2Cl is a non- limiting example of a haloalkyl. The term “fluoroalkyl” is a subset of substituted alkyl, in which the hydrogen atom replacement is limited to fluoro such that no other atoms aside from carbon, hydrogen and fluorine are present. The groups −CH2F, −CF3, and −CH2CF3 are non- limiting examples of fluoroalkyl groups. Non-limiting examples of substituted aralkyls are: (3-chlorophenyl)-methyl, and 2-chloro-2-phenyl-eth-1-yl. The groups, −C(O)CH2CF3, −CO2H (carboxyl), −CO₂CH₃ (methylcarboxyl), −CO₂CH₂CH₃, −C(O)NH₂ (carbamoyl), and −CON(CH3)2, are non-limiting examples of substituted acyl groups. The groups −NHC(O)OCH₃ and −NHC(O)NHCH₃ are non-limiting examples of substituted amido groups. An “isomer” of a first compound is a separate compound in which each molecule contains the same constituent atoms as the first compound, but where the configuration of those atoms in three dimensions differs. A “salt” as used herein is not particularly limited. A salt of a compound of the present disclosure means a salt routinely used in the organic chemical field. A salt of a compound comprising a carboxyl group may, as a non-limiting example, be a base-addition salt of the carboxyl group. A salt of a compound comprising a amino group or basic heterocyclic group may, as a non-limiting example, be a acid-addition salt of the amino or basic heterocyclic group. Examples of the base-addition salt include: alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammo-nium salts; and organic amine salts such as trimethylamine salt, triethylamine salt, dicyclohexylamine salt, etha-nolamine salt, diethanolamine salt, triethanolamine salt, procaine 45 4858-4046-6416, v.2 salt, and N,N'-dibenzylethylenediamine salt. Examples of the acid-addition salt include: inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, and perchlorate; organic acid salts such as acetate, formate, maleate, fumarate, tartrate, citrate, ascorbate, and trifluoro-acetate; and sulfonates such as methanesulfonate, isethionate, benzenesulfonate, and p-toluenesulfonate. According to the present definitions, a “salt” as used herein may be a pharmaceutically acceptable salt. “Pharmaceutically acceptable salts” means salts of compounds disclosed herein which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as 1,2 ethanedisulfonic acid, 2 hydroxyethanesulfonic acid, 2 naphthalenesulfonic acid, 3 phenylpropionic acid, 4,4′ methylenebis(3 hydroxy 2 ene-1 carboxylic acid), 4 methylbicyclo[2.2.2]oct 2 ene-1 carboxylic acid, acetic acid, aliphatic mono- and dicarboxylic acids, aliphatic sulfuric acids, aromatic sulfuric acids, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, heptanoic acid, hexanoic acid, hydroxynaphthoic acid, lactic acid, laurylsulfuric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, o (4 hydroxybenzoyl)benzoic acid, oxalic acid, p-chlorobenzenesulfonic acid, phenyl-substituted alkanoic acids, propionic acid, p-toluenesulfonic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiarybutylacetic acid, trimethylacetic acid, and the like. Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N methylglucamine and the like. It should be recognized that the particular anion or cation forming a part of any salt of this disclosure is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, and Use (P. H. Stahl & C. G. Wermuth eds., Verlag Helvetica Chimica Acta, 2002). In some embodiments, the salts of the compounds of the present disclosure have an advantage in that they may have useful pharmacological, physical, or chemical properties over compounds known in the prior art, whether for use in the indications stated herein or otherwise. In some embodiments, the compounds and formulas provided herein exist in salt or non-salt form. With regard to the salt form(s), in some 46 4858-4046-6416, v.2 embodiments the particular anion or cation forming a part of any salt form of a compound or formula provided herein is not critical. A “stereoisomer” or “optical isomer” is an isomer of a given compound in which the same atoms are bonded to the same other atoms, but where the configuration of those atoms in three dimensions differs. “Enantiomers” are stereoisomers of a given compound that are mirror images of each other, like left and right hands. “Diastereomers” are stereoisomers of a given compound that are not enantiomers. Chiral molecules contain a chiral center, also referred to as a stereocenter or stereogenic center, which is any point, though not necessarily an atom, in a molecule bearing groups such that an interchanging of any two groups leads to a stereoisomer. In organic compounds, the chiral center is typically a carbon, phosphorus or sulfur atom, though it is also possible for other atoms to be stereocenters in organic and inorganic compounds. A molecule can have multiple stereocenters, giving it many stereoisomers. In compounds whose stereoisomerism is due to tetrahedral stereogenic centers (e.g., tetrahedral carbon), the total number of hypothetically possible stereoisomers will not exceed 2ⁿ, where n is the number of tetrahedral stereocenters. Molecules with symmetry frequently have fewer than the maximum possible number of stereoisomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Alternatively, a mixture of enantiomers can be enantiomerically enriched so that one enantiomer is present in an amount greater than 50%. Typically, enantiomers and/or diastereomers can be resolved or separated using techniques known in the art. It is contemplated that that for any stereocenter or axis of chirality for which stereochemistry has not been defined, that stereocenter or axis of chirality can be present in its R form, S form, or as a mixture of the R and S forms, including racemic and non-racemic mixtures. As used herein, the phrase “substantially free from other stereoisomers” means that the composition contains ≤ 15%, more preferably ≤ 10%, even more preferably ≤ 5%, or most preferably ≤ 1% of another stereoisomer(s). As used herein, “essentially free,” in terms of a specified component, is used to mean that none of the specified component has been purposefully formulated into a composition and/or is present only as a contaminant or in trace amounts. The total amount of the specified component resulting from any unintended contamination of a composition is therefore well below 0.05%, preferably below 0.01%. Most preferred is a composition in which no amount of the specified component can be detected with standard analytical methods. 47 4858-4046-6416, v.2 As used herein the specification, “a” or “an” may mean one or more. The use of the word “a” or “an,” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” As used herein “another” may mean at least a second or more. The terms “comprise,” “have” and “include” are open-ended linking verbs. Any forms or tenses of one or more of these verbs, such as “comprises,” “comprising,” “has,” “having,” “includes” and “including,” are also open-ended. For example, any method that “comprises,” “has” or “includes” one or more steps is not limited to possessing only those one or more steps and also covers other unlisted steps. As used herein, the term "water-immiscible solvent" refers to any non-aqueous or hydrophobic solvent which separates from solution into two distinct phases when mixed with water. The water-immiscible liquid is generally non-polar, with the non-limiting examples of the water immiscible liquid including terpenes, 2-methyltetrahydrofuran, sesquiterpenes, butanone, butyl acetate, heptane, hexane, toluene, dichloromethane, cyclohexane, petroleum ether (60-80), petroleum ether (80-100), petroleum ether (100-120), dibutyl ether, dipentyl ether, hexadecane, tetrachloroethylene, 1,1,1-trichloroethane, or other water-immiscible liquids well known in the art. Other abbreviations used herein are as follows: DMSO, dimethyl sulfoxide; DMF, dimethylformamide; MeOH, methanol; EtOH, ethanol; EtOAc, ethyl acetate; THF, tetrahydrofuran; NaOMe, sodium methoxide; Me2SO4, dimethyl sulfate; K2CO3, potassium carbonate; TBABr, tetrabutylammonium bromide; 2-MeTHF, 2-methyltetrahydrofuran; mCPBA, m-chloroperbenzoic acid; DCM, dichloromethane; MsOH, methanesulfonic acid; PhMe, toluene; T3P, propylphosphonic acid anhydride; DIPEA, diisopropylethylamine; LiBr, lithium bromide; NaCl, sodium chloride; DMAc, N,N-dimethylacetamide; DPPA, diphenylphosphoryl azide; NaOH, sodium hydroxide; H3PO4, phosphoric acid; IPA, isopropanol; IBX, 2-iodoxybenzoic acid; NaHCO₃, sodium bicarbonate; KF, critical in-process control; ID, identification method; IR, infrared spectroscopy; HPLC, high performance liquid chromatography; TEA or Et₃N, triethylamine; LCMS, liquid chromatography mass spectrometry; 48 4858-4046-6416, v.2 ppm, parts per million; ICP-MS, inductively coupled plasma mass spectrometry; GCMS, gas chromatography mass spectrometry; GC, gas chromatography; MW, molecular weight; PyHBr₃ or PyH*Br3, pyridinium tribromide; IM1-9, impurity compounds 1-9; LC, liquid chromatography; RRT, relative retention time; DMS, dimethyl sulfate. TEA, triethylamine; NO, nitric oxide; iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; IFNγ or IFN-γ, interferon-γ; FA, Friedrich’s ataxia; Nrf2, nuclear factor erythroid-derived 2-related factor 2. Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the inherent variation in the method being employed to determine the value, the variation that exists among the study subjects, or a value that is within 10% of a stated value. The above definitions supersede any conflicting definition in any reference that is incorporated by reference herein. The fact that certain terms are defined, however, should not be considered as indicative that any term that is undefined is indefinite. Rather, all terms used are believed to describe the disclosure in terms such that one of ordinary skill can appreciate the scope and practice the present disclosure. I. Examples The following examples are included to demonstrate preferred embodiments. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent techniques discovered by the inventor to function well in the practice of embodiments, and thus can be considered to constitute preferred modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure. Example 1 Compounds AGL-1-019, AGL-1-021, AGL-1-31, AGL-1-45, AGL-1-49, NF-1-039 (described in Table 2) were synthesized using methods similar to the protocol shown in Scheme 1 below. Tables 3.1 and 3.2 show the results of cell swelling tests using different formulations of a functionalized polymer at different time points. 49 4858-4046-6416, v.2 Scheme 1.

How MW f MW f mn l y) )

50 4858-4046-6416, v.2 butyl-4- (2.368g hydroxyph total) l i

Table 3.1. Results of cell swelling tests using different formulations of a functionalized polymer at different time points. Size Readtime = 1 hrs Base- 24 s

51 4858-4046-6416, v.2 21.91 20.97 19.75 18.95 18.14 17.60 16.95

52 4858-4046-6416, v.2 B6 R1C1 23.4 20.7 17.7 16 15.1 14.7 14.6 B6

53 4858-4046-6416, v.2 D5 R2C1 23.7 22.4 21.5 20.9 20.5 20.1 19.9 D5

54 4858-4046-6416, v.2 C1 R1C5 23.9 23 22.7 22.8 22.4 22.3 22.1 C1

55 4858-4046-6416, v.2 Table 3.2. Summary of results of cell swelling tests using different formulations of a functionalized polymer at different time points (average values). 1 2 3 4 5 6 7 N rm l 2191333 2097333 1974667 1894667 1814 176 1694667 67 33 33 67 55 71 67

FIGS. 1-6 describe the LPA modified P188 synthesis results, the polymer treated vs. normal H2O2 average cell size, the polymer treated vs. normal average cell size, the average cell size vs. normal and average of tile count and all of the functionalized variants produced to date with their disposition in the testing matrix. * * * * * * * * * * * * * * * * * All of the compositions and methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims. 56 4858-4046-6416, v.2 REFERENCES The following references to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. Anderson, Practical Process Research & Development – A Guide for Organic Chemists, 2nd ed., Academic Press, New York, 2012. Almeida et al., PLoS ONE., 8(1): e53628, 2013. American Cancer Society. Cancer Facts and Figures 2019. Atlanta: American Cancer Society; 2019. Ardeshir et al., J. Phys. Chem B., 120(33):8631-41, 2016. Cho et al., Korean J. Physiol. Pharmacol., 17(4):267–274, 2013. Denekamp et al., Radiother. Oncol., 39(2):191, 1996. Emanuele and Balasubramaniam, Drugs R&D., 14:73-83, 2014. Ethyol^® (Amifostine) [Label] MedImmune Oncology, Inc., 2003. Franken et al., Nature Protocols., 1(5):2315-2319, 2006. Grindel et al., J. Pharm. Sci., 90(9):1936-1947, 2002. Gu et al., PLOS One., 9(5):e95968, 2014. Halperin et al., Perez & Brady’s Principles and Practice of Radiation Oncology. Philadelphia: Lippincott; 2019. Handbook of Pharmaceutical Salts: Properties, and Use, Stahl and Wermuth Eds., Verlag Helvetica Chimica Acta, 2002. Jairam et al., JAMA Oncol., 5(7):1028–1035, 2019. Kang et al., Laboratory Animal Research., 35:17, 2019. Kim et al., Langmuir., 36(13):3393-3403, 2020. Kwiatkowski et al., Cell Phys.318(2):C253-C262, 2019. LENT SOMA tables. Radiother. Oncol., 35(1):17-60, 1995. Machtay et al., J. Clin. Oncol., 26; 3582-9, 2008. Maduro et al., Cancer Treat Rev., 29:471-88, 2003. Mariotto et al., J. Natl. Cancer Inst., 103(2):117-128, 2011. Merchant et al., J. Surg. Res., 74:131-140, 1998. Moloughney and Weisleder, Recent Pat. Biotechnol., (3):200-211, 2012. 57 ^{4858-4046-6416, v. 2} Orringer et al., JAMA., 286(17):2099-2106, 2001. Prasanna et al., Transl. Cancer Res., 1(1):35-48, 2012. Quantitative Analyses of Normal Tissue Effects in the Clinic. Int. J. Radiat. Oncol. Biol. Phys. S1-S160, 2010. Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008. Small and Woloschak, Radiation Toxicity: A Practical Guide. Switzerland: Springer; 2008. Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Ed., Wiley, 2013. Sun et al., J. Radiat. Res., 55(4):683-689, 2014. Todd and Thomas, Oncologic Emergency Medicine: Principles and Practice. Switzerland: Springer; 2016. Warren et al., Int. J. Cancer., 131(11):2519-27, 2012. Westbury and Yarnold, Clin. Oncol. (R. Coll. Radiol.), 24(10):657-672, 2012. Wong et al., Annals of Biomed. Eng., 45(4):1083-1092, 2017. 58 ^{4858-4046-6416, v. 2}

Claims

WHAT IS CLAIMED IS: 1. A poloxamer (polyalkylene oxide) having attached thereto a small molecule agent, wherein the small molecule agent is an antioxidant having the formula: , wherein

the bond between atoms 1 and 2 is a single bond or a double bond; p is 0 or 1; X is absent, CH₂ or S; R is substituted cycloalkyl(C≤8), substituted aryl(C≤8), heteroaryl(C≤8), substituted heteroaryl(C≤8), substituted alkoxy(C≤8), substituted cycloalkoxy(C≤8), substituted aryloxy(C≤8), heteroaryloxy(C≤8), substituted heteroaryloxy_(C≤₈₎, substituted arylamino_(C≤₈₎, substituted – alkanediyl(C≤8)–cycloalkyl(C≤8), –alkanediyl(C≤8)–heteroaryl(C≤8), substituted –alkanediyl(C≤8)–heteroaryl(C≤8), substituted – alkanediyl(C≤8)–aryl(C≤8), substituted –alkanediyl(C≤8)– heterocycloalkyl_(C≤₈₎, glutathione; or .

2. The poloxamer of claim 1, wherein the bond between atoms 1 and 2 is a single bond.

3. The poloxamer of either claim 1 or claim 2, wherein p is 0. 59 ^{4858-4046-6416, v. 2}

4. The poloxamer of either claim 1 or claim 2, wherein p is 1.

5. The poloxamer according to any one of claims 1-4, wherein X is absent.

6. The poloxamer according to any one of claims 1-4, wherein X is CH2.

7. The poloxamer according to any one of claims 1-4, wherein X is S.

8. The poloxamer according to any one of claims 1-7, wherein R is substituted aryl(C≤8).

9. The poloxamer according to any one of claims 1-7, wherein R is substituted – alkanediyl(C≤8)–heterocycloalkyl(C≤8).

10. The poloxamer according to any one of claims 1-7, wherein R is glutathione.

11. The poloxamer of claim 1, wherein the poloxamer is further defined as a compound of the formula: , wherein

n is 78, 79, 80, 81, 82, 98, 99, 100, 101 or 102; m is 25, 26, 27, 28, 29, 30, 63, 64, 65, 66 or 67.

12. The poloxamer according to any one of claims 1-11, wherein n is 79.

13. The poloxamer according to any one of claims 1-11, wherein n is 80.

14. The poloxamer according to any one of claims 1-11, wherein n is 100.

15. The poloxamer according to any one of claims 1-14, wherein m is 65.

16. The poloxamer according to any one of claims 1-14, wherein m is 27.

17. The poloxamer of claim 10, wherein the poloxamer is further defined as: .

18. The poloxamer of claim 10, wherein the poloxamer is further defined as: 60 ^{4858-4046-6416, v. 2}

.

19.` A poloxamer a small molecule agent, wherein the poloxamer is selected from a group consisting of: ,

, r

20. A composition comprising: (a) a poloxamer according to any one of claims 1-19; and (b) an excipient. 62 ^{4858-4046-6416, v. 2}

21. The composition of claim 20, wherein the composition comprises from about 0.001% to about 25% poloxamer.

22. The composition of claim 39, wherein the composition comprises from about 0.01% to about 10% poloxamer.

23. The composition of claim 39, wherein the composition comprises from about 0.1% to about 5% poloxamer.

24. The composition according to any one of claims 20-23, wherein the composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

25. The composition of claim 24, wherein the composition is formulated for administration topically.

26. The composition of claim 25, wherein the composition is formulated for topical administration to the skin.

27. The composition of claim 24, wherein the composition is formulated for administration via injection.

28. The composition of claim 24, wherein the composition is formulated for intraarterial administration, intramuscular administration, intraperitoneal administration, or intravenous administration.

29. The composition of claim 20, wherein the composition is formulated as a sealant.

30. The composition of claim 29, wherein the composition is formulated for use in cell membrane healing.

31. The composition of claim 29, wherein the composition is formulated for use in the treatment of burn wounds. 63 ^{4858-4046-6416, v. 2}

32. The composition according to any one of claims 20-29, wherein the composition comprises a buffer.

33. The composition of claim 32, wherein the buffer comprises water.

34. The composition of claim 32, wherein the buffer comprises citric acid.

35. The composition of claim 32, wherein the buffer comprises phosphate buffered saline.

36. The composition of claim 32, wherein the buffer comprises artificial interstitial fluid.

37. The composition according to any one of claims 20-32, wherein the composition comprises a gelation temperature modifying agent.

38. The composition according to any one of claims 20-37, wherein the composition comprises Pluronic^® F127.

39. The composition of claim 38, wherein the composition comprises from about 0% to about 50% Pluronic^® F127.

40. The composition of claim 39, wherein the composition comprises from about 0% to about 40% Pluronic^® F127.

41. The composition of claim 39, wherein the composition comprises from about 0% to about 30% Pluronic^® F127.

42. The composition according to any one of claims 20-38, wherein the composition comprises Triton X-Ethoxylated Octylphenol.

43. The composition of claim 38, wherein the composition comprises from about 0% to about 5% Triton X-Ethoxylated Octylphenol.

44. The composition of claim 39, wherein the composition comprises from about 0% to about 2.5% Triton X-Ethoxylated Octylphenol.

45. The composition of claim 39, wherein the composition comprises from about 0% to about 1% Triton X-Ethoxylated Octylphenol.

46. A method of treating or preventing a disease or disorder in a patient in need thereof comprising administering to the patient a pharmaceutically effective amount of a poloxamer or composition according to any one of claims 1-42.

47. The method of claim 46, wherein the disease or disorder is associated with cell membrane damage. 64 ^{4858-4046-6416, v. 2}

48. The method of claim 46, wherein the disease or disorder is associated with oxidative stress.

49. The method of claim 48, wherein the disease or disorder is associated with free radical injury.

50. The method of claim 46, wherein the disease or disorder is associated with electrical injury.

51. The method of claim 46, wherein the disease or disorder is a neurodegenerative disorder.

52. The method of claim 50, wherein the neurodegenerative disorder is Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, or Huntington’s disease.

53. The method of claim 46, wherein the disease or disorder is a muscular dystrophy.

54. The method of claim 46, wherein the patient is receiving radiation treatment.

55. The method of claim 46, wherein the patient has been diagnosed with a disease or disorder associated with oxidative stress.

56. The method of claim 46, wherein the patient is a mammal.

57. The method of claim 56, wherein the patient is a human.

58. The method according to any one of claims 46-57, wherein the method comprises administering the compound once.

59. The method according to any one of claims 46-57, wherein the method comprises administering the compound two or more times. 65 ^{4858-4046-6416, v. 2}