Intranasal formulations of celastrol

Abstract

The present disclosure provides pharmaceutical compositions of celastrol, pharmaceutically acceptable salts thereof and polymorphs thereof. The provided pharmaceutical compositions are useful for intranasal administration of celastrol, pharmaceutically acceptable salts thereof and polymorphs thereof.

Description

INTRANASAL FORMULATIONS OF CELASTROLRELATED APPLICATIONS

[0001] This application claims priority to, and the benefit of, US Provisional Application No. 63 / 599,918, filed on November 16, 2023, the content of which is incorporated herein by reference in its entirety.FIELD

[0002] This application relates to intranasal formulations of celastrol.BACKGROUND OF THE DISCLOSURE

[0003] Celastrol, a naturally occurring quinone methide triterpene derived from the Thunder of God Vine, has been identified as a pleiotropic compound showing anti-tumor, antiinflammatory, anti-hypertensive, and anti-diabetic activity in numerous cellular and in vivo models. Moreover, in a recent Harvard study, the herbal extracts of the Thunder of God Vine has been shown to function as an appetite suppressant in rodents and may potentially become the key ingredient in obesity drugs.

[0004] As such, there exists a need to produce pharmaceutical formulations suitable for administration to humans or other animals. The present disclosure addresses these needs and provides related advantages as well.SUMMARY OF THE INVENTION

[0005] In some aspects, provided herein are pharmaceutical compositions (e.g., for intranasal delivery) comprising celastrol.

[0006] In some aspects, provided herein is a pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) an emulsifier or surfactant; and(iii) a mucoadhesive or viscosifier; wherein the pharmaceutical composition is in the form of a liquid suspension.

[0007] In some aspects, provided herein is a pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) a polysorbate; and(iii) a cellulose; wherein the pharmaceutical composition is in the form of a liquid suspension.

[0008] In some aspects, provided herein is a pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof in an amount of from about 1 wt.% to about 5 wt.%;(ii) hydroxypropyl-beta-cyclodextrin (HPBCD) or trehalose in an amount of from about 60 wt.% to about 70 wt.%; and(iii) hydroxypropyl methyl cellulose (HPMC) in an amount of from about 10 wt.% to about 40 wt.%; wherein the pharmaceutical composition is in the form of a powder.

[0009] In some aspects, provided herein is a method of treating a disease or condition by intranasally administering a pharmaceutical composition of the disclosure.

[0010] In some aspects, provided herein is a method of intranasally administering celastrol.DRAWINGS

[0011] FIG. 1 is a graph summarizing the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of a dry powder intranasal formulation (Dry A as described in Example 3) at a dose concentration of 2 mg / kg. The numbers identify the tested rats (rats number 13, 14, 15, and 16).

[0012] FIG. 2 is a graph summarizing the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of a dry powder intranasal formulation (Dry A as described in Example 3) at a dose concentration of 2 mg / kg. The numbers identify the tested rats (rats number 17, 18, 19, and 20).

[0013] FIG. 3 is a graph summarizing the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of a liquid intranasal formulation (Liquid A asdescribed in Example 3) at a dose concentration of 2 mg / kg. The numbers identify the tested rats (rats number 5, 6, 7, and 8).

[0014] FIG. 4 is a graph summarizing the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of a liquid intranasal formulation (Liquid B as described in Example 3) at a dose concentration of 2 mg / kg. The numbers identify the tested rats (rats number 9, 10, 11, and 12).

[0015] FIG. 5 is a graph summarizing the concentration of celastrol in plasma of male Sprague Dawley rats following oral dosing of celastrol at a dose concentration of 2 mg / kg. The numbers identify the tested rats (rats number 1, 2, 3, and 4).

[0016] FIG. 6 is a graph comparing the mean concentrations of celastrol in plasma of male Sprague Dawley rats (average of tested rats) following intranasal administration of formulations Dry A, Dry B, Liquid A, and Liquid B, and oral dosing of celastrol at a dose concentration of 2 mg / kg. The numbers identify the tested rats (rats number 1, 2, 3, and 4).

[0017] FIG. 7 is an XRPD spectrum of crystalline Form III of celastrol.DETAILED DESCRIPTIONDefinitions

[0001] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology such as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.

[0018] The term “about” refers to being within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. “About” can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value.Unless otherwise clear from the context, all numerical values provided herein are modified by the term “about.”

[0019] The terms “crystalline form”, “single crystalline form” and “polymorph” are synonymous and refer to a solid form having a highly regular chemical structure. A crystalline form can have distinguishing, characteristic properties (e.g., XRPD data or thermal data such as DSC and TGA profiles). The term “polymorph” also includes pseudo-polymorphs, which aretypically different solvates of a material, and thus their properties differ from one another. Thus, each distinct polymorph and pseudo-polymorph described herein is considered to be a distinct single crystalline form herein.

[0020] As used herein, the term “salt” refers to ionic compounds that result from the neutralization reaction of an acid and a base. They are composed of related numbers of cations (positively charged ions) and anions (negative ions) so that the product is electrically neutral (without a net charge). These component ions can be inorganic, such as chloride (Cl—), or organic, such as acetate (C2H3O2-); and can be monatomic, such as fluoride (F-), or polyatomic, such as sulfate (SO42— ).

[0021] The terms “administration”, “administer” and the like, as they apply to, for example, a patient, cell, tissue, organ, or biological fluid, refer to contact of, for example, a pharmaceutical agent or a pharmaceutical composition comprising same, to the patient, cell, tissue, organ, or biological fluid. In the context of a cell, administration includes contact (e.g., in vitro or ex vivo) of a reagent to the cell, as well as contact of a reagent to a fluid, where the fluid is in contact with the cell.Pharmaceutical compositions

[0022] The present disclosure provides pharmaceutical compositions comprising celastrol (3- hydroxy-9p,13a-dimethyl-2-oxo-24,25,26-trinoroleana-l(10),3,5,7-tetraen-29-oic acid), or a pharmaceutically acceptable salt or polymorph thereof. Celastrol has the chemical formula:(celastrol).

[0023] In some embodiments, a pharmaceutical composition of the disclosure comprises:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof(ii) an emulsifier or surfactant;(iii) a mucoadhesive or viscosifier; and(iv) a preservative.

[0024] In some embodiments, a pharmaceutical composition of the disclosure comprises:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) a polysorbate;(iii) a cellulose; and(iv) a preservative.

[0025] In some embodiments, the pharmaceutical composition of the disclosure comprises the emulsifier or surfactant at a concentration of from about 5 mg / mL to about 50 mg / mL (e.g., from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 30 mg / mL, or from about 20 mg / mL to about 30 mg / mL). In some embodiments, the pharmaceutical composition of the disclosure comprises the emulsifier or surfactant at a concentration of about 25 mg / mL.

[0026] In some embodiments, the pharmaceutical composition of the disclosure comprises the emulsifier or surfactant at a molar concentration of from about 5 mM to about 40 mM, e.g., from about 10 mM to about 30 mM. In some embodiments, the pharmaceutical composition of the disclosure comprises the emulsifier or surfactant at a molar concentration of about 20 mM.

[0027] In some embodiments, the pharmaceutical composition of the disclosure comprises the mucoadhesive or viscosifier at a concentration of from about 0.1 mg / mL to about 5 mg / mL, e.g., from about 0.1 mg / mL to about 4 mg / mL, from about 0.1 mg / mL to about 3 mg / mL, from about 0.1 mg / mL to about 2 mg / mL, or from about 0.5 mg / mL to about 1.5 mg / mL). In some embodiments, the pharmaceutical composition of the disclosure comprises the mucoadhesive or viscosifier at a concentration of about 1 mg / mL.

[0028] In some embodiments, the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of from about 5 mg / mL to about 50 mg / mL (e.g., from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 10 mg / mL to about 20 mg / mL, or from about 15 mg / mL to about 20 mg / mL). In some embodiments, the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of about 18 mg / mL.

[0029] In some embodiments of the pharmaceutical composition of the disclosure, the surfactant is a nonionic surfactant. In some embodiments of the pharmaceutical composition of thedisclosure, the emulsifier or surfactant is a polysorbate. For example, in some embodiments of the pharmaceutical composition of the disclosure, the emulsifier or surfactant is selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80). In some embodiments of the pharmaceutical composition of the disclosure, the emulsifier or surfactant is polyoxyethylene (20) sorbitan monolaurate (tween 20, polysorbate 20).

[0030] In some embodiments of the pharmaceutical composition of the disclosure, the mucoadhesive or viscosifier is selected from methylcellulose (MC), carboxymethylcellulose (CMC) sodium carboxymethylcellulose (Na-CMC), hydroxypropylmethylcellulose (HPMC), hydroxethylcellulose (HEC), microcrystalline cellulose (MCC), xanthan gum, acacia, tragacanth, alginates, guar gum, colloidal silicon dioxide, and combinations thereof. In some embodiments of the pharmaceutical composition of the disclosure, the mucoadhesive or viscosifier is selected from methylcellulose (MC), carboxymethylcellulose (CMC) sodium carboxymethylcellulose (Na- CMC), hydroxypropylmethylcellulose (HPMC), hydroxethylcellulose (HEC), microcrystalline cellulose (MCC), and combinations thereof. In some embodiments of the pharmaceutical composition of the disclosure, the mucoadhesive or viscosifier is selected from microcrystalline cellulose (MCC), sodium carboxymethyl cellulose (Na-CMC) and a combination thereof (MCC- NaCMC). In some embodiments of the pharmaceutical composition of the disclosure, the mucoadhesive or viscosifier is hydroxypropylmethylcellulose (HPMC). In some embodiments of the pharmaceutical composition of the disclosure, the mucoadhesive or viscosifier is a combination of microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (Na-CMC) (MCC- NaCMC).

[0031] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the preservative at a concentration of up to about 1 mg / mL (e.g., up to about 0.1 mg / mL, up to about 0.2 mg / mL, up to about 0.3 mg / mL, up to about 0.4 mg / mL, up to about 0.5 mg / mL, up to about 0.6 mg / mL, up to about 0.7 mg / mL, up to about 0.8 mg / mL, or up to about 0.9 mg / mL).

[0032] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the preservative at a concentration of from about 0.01 mg / mL to 1.00 mg / mL (e.g., from about 0.01 mg / mL to about 0.8 mg / mL, from about 0.01 mg / mLto about 0.6 mg / mL, from about 0.01 mg / mL to about 0.4 mg / mL, from about 0.01 mg / mL to about 0.2 mg / mL, from about 0.05 mg / mL to about 0.2 mg / mL, or from about 0.05 mg / mL to about 0.15 mg / mL). In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the preservative at a concentration of about 0.1 mg / mL.

[0033] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the preservative at a molar concentration of from about 0.1 mM to about 0.5 mM (e.g., from about 0.2 mM to about 0.4 mM). In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the preservative at a molar concentration of about 0.3 mM.

[0034] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the polysorbate at a molar concentration of from about 5 mg / mL to about 50 mg / mL.

[0035] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the polysorbate at a molar concentration of from about 5 mM to about 40 mM (e.g., from about 10 mM to about 30 mM). In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the polysorbate at a molar concentration of about 20 mM.

[0036] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the cellulose at a concentration of from about 0.1 mg / mL to about 5 mg / mL (e.g., from about 5 mg / mL to about 50 mg / mL). In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises cellulose at a concentration of about 18 mg / mL.

[0037] In some embodiments, the pharmaceutical composition of the disclosure comprises the pharmaceutical agent at a concentration of from about 5 mg / mL to about 50 mg / mL (e.g., from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 30 mg / mL, or from about 15 mg / mL to about 25 mg / mL). In some embodiments, the pharmaceutical composition of the disclosure comprises the pharmaceutical agent at a concentration of about 20 mg / mL.

[0038] In some embodiments, the pharmaceutical composition of the disclosure comprises the pharmaceutical agent at a molar concentration of from about 10 mM to about 70 mM (e.g., from about 20 mM to about 60 mM, or from about 40 mM to about 50 mM). In some embodiments,the pharmaceutical composition of the disclosure comprises the pharmaceutical agent at a molar concentration of about 44 mM.

[0039] In some embodiments of the pharmaceutical composition of the disclosure, the preservative is selected from potassium sorbate, chlorobutanol, methyl paraben, propyl paraben, butyl paraben, benzethonium chloride, sodium benzoate, and sorbic acid, and benzalkonium chloride. In some embodiments of the pharmaceutical composition of the disclosure, the preservative is benzalkonium chloride.

[0040] In some embodiments of the pharmaceutical composition of the disclosure, the cellulose is hydroxypropylmethylcellulose (HPMC) or a combination of microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (Na-CMC) (MCC-NaCMC).

[0041] In some embodiments of the pharmaceutical composition of the disclosure, the polysorbate is selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80). In some embodiments of the pharmaceutical composition of the disclosure, the polysorbate is polyoxyethylene (20) sorbitan monolaurate (tween 20, polysorbate 20).

[0042] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the pharmaceutical agent in an amount of about 2 wt.%.

[0043] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the HPBCD or trehalose in an amount in an amount of about 68 wt.%.

[0044] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition comprises the HPMC in an amount in an amount of about 30 wt.%.

[0045] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and an emulsifier or surfactant in a wt / wt ratio of from about 1:0.6 to about 1:2 (e.g., about 1:0.6, about 1:0.7, about 1:0.8, about 1:0.9, about 1:1.0, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, about 1:1.5, about 1:1.6, about 1:1.7, about 1:1.8, about 1:1.9, or about 1:2.0). In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and an emulsifier or surfactant in a wt / wt ratio of about 1:1.3.

[0046] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and a preservative in a wt / wt ratio of from about 1:0.001 to about 1:0.01 (e.g., about1:1:0.001, about 1:0.002, about 1:0.003, about 1:0.004, about 1:0.005, about 1:0.006, about 1:0.007, about 1:0.008, about 1:0.009, or about 1:0.01). In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and a preservative in a wt / wt ratio of about 1:0.005.

[0047] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent, the emulsifier or surfactant and the preservative in a wt / wt ratio of about 1:1.3:0.005.

[0048] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the mucoadhesive or viscosifier in a wt / wt ratio of from about 1:0.01 to about 1:0.1 (e.g., about 1:0.01, about 1:0.02, about 1:0.03, about 1:0.04, about 1:0.05, about 1:0.06, about 1:0.07, about 1:0.08, about 1:0.09, about 1:0.1). In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the mucoadhesive or viscosifier in a wt / wt ratio of about 1:0.05. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the mucoadhesive or viscosifier in a wt / wt ratio of from about 1:0.3 to about 1:1.5 (e.g., about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, or about 1:1.5). In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the mucoadhesive or viscosifier in a wt / wt ratio of about 1:0.9. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent, the emulsifier or surfactant and the mucoadhesive or viscosifier in a wt / wt ratio of about 1:1.3:0.05. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent, the emulsifier or surfactant and the mucoadhesive or viscosifier in a wt / wt ratio of about 1:1.3:0.9.

[0049] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the polysorbate in a wt / wt ratio of from about 1:0.6 to about 1:2. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the polysorbate in a wt / wt ratio of about 1:1.3.

[0050] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and a preservative in a wt / wt ratio of from about 1:0.001 to about 1:0.01. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and a preservative in a wt / wt ratio of about 1:0.005. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent, the polysorbate and the preservative in a wt / wt ratio of about 1:1.3:0.005.

[0051] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the cellulose in a wt / wt ratio of from about 1:0.01 to about 1:0.1. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the cellulose in a wt / wt ratio of about 1:0.05.

[0052] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the cellulose in a wt / wt ratio of from about 1:0.3 to about 1:1.5 (e.g., about 1:0.3, about 1:0.4, about 1:0.5, about 1:0.6, about 1:7, about 1:0.8, about 1:0.9, about 1:1, about 1:1.1, about 1:1.2, about 1:1.3, about 1:1.4, or about 1:1.5). In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent and the cellulose in a wt / wt ratio of about 1:0.9.

[0053] In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent, the polysorbate and the cellulose in a wt / wt ratio of about 1:1.3:0.05. In some embodiments, the pharmaceutical composition comprises the pharmaceutical agent, the polysorbate and the cellulose in a wt / wt ratio of about 1:1.3:0.9.

[0054] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical agent is celastrol.

[0055] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical agent is a polymorph of celastrol.

[0056] In some embodiments, the polymorph of celastrol is a crystalline Form III of celastrol, wherein the crystalline Form III of celastrol is characterized by an X-ray powder diffraction pattern further comprising one or more peaks at 20 angles (±0.2) selected from the group consisting of 13.60°, 14.65°, 18.74°, and 19.10°.

[0057] In some embodiments, the crystalline Form III of celastrol is characterized by an X- ray powder diffraction pattern that is substantially the same as Figure 7.

[0058] In some embodiments, the crystalline Form III of celastrol is characterized by a differential scanning calorimetry (DSC) profile with no endothermic peak and an exothermic peak at about 215 °C (onset).

[0059] In some embodiments, the crystalline Form III of celastrol is characterized by thermal gravimetric analysis (TGA) profile with about 0.5% weight loss at about the exothermic peak at about 215 °C (onset).

[0060] In some embodiments, the crystalline Form III of celastrol is anhydrous. In some embodiments, the crystalline Form III of celastrol comprises about 5000 ppm or less of n-heptane (e.g., about 70 ppm or less of n-heptane). In some embodiments, the crystalline form comprises about 5000 ppm or less of 2-methyltetrahydrofuran (e.g., about 500 ppm or less of 2- methyltetrahydrofuran). In some embodiments, the crystalline form comprises about 5000 ppm or less of ethyl acetate (e.g., about 10 ppm or less of ethyl acetate). In some embodiments, the crystalline Form III of celastrol comprises about 3,000 ppm or less of methanol (e.g., 1,500 ppm or less of methanol). In some embodiments, the crystalline Form III of celastrol comprises about 5000 ppm or less of ethanol (e.g., about 600 ppm or less of ethanol). In some embodiments, the crystalline Form III of celastrol is free of methanol, ethanol, and / or dichloromethane. In some embodiments, the crystalline Form III of celastrol has at least 99.8% purity. In some embodiments, the crystalline Form III of celastrol is a crystalline Form III described in US Provisional patent application No. 63 / 384,153 and in International Application No. PCT / US23 / 80122, each of which is hereby incorporated by reference in its entirety.

[0061] In some embodiments, a pharmaceutical composition of the disclosure is in the form of a suspension (e.g., a liquid suspension). In some embodiments, a pharmaceutical composition of the disclosure is a liquid pharmaceutical composition.

[0062] In some embodiments of the pharmaceutical composition of the disclosure, the liquid pharmaceutical composition is a fast-acting pharmaceutical composition.

[0063] In some embodiments of the pharmaceutical composition of the disclosure, the pharmaceutical composition is in the form of a nasal spray or nose drops.

[0064] In some embodiments, a pharmaceutical composition of the disclosure is a spray dried powder.

[0065] In some embodiments, as demonstrated e.g., in Example 3, the intranasal administration of the pharmaceutical compositions described herein to a subject yields a peak concentration (Cmax) of celastrol in the blood plasma of up to 20 ng / mL.

[0066] In some embodiments, as demonstrated e.g., in Example 3, the intranasal administration of the pharmaceutical compositions described herein to a subject yields an area under concentration curve (AUCo-iast) of celastrol in the blood plasma of up to 90 ng*hr / mL.

[0067] In some embodiments, as demonstrated e.g., in Example 3, the intranasal administration of the pharmaceutical compositions described herein to a subject yields a time to maximal plasma concentration (Tmax) of celastrol in blood plasma of said subject of from about 10 min to about 1 hour.

[0068] In some embodiments, the pharmaceutical composition described herein is a nasal dosage form (i.e., a dosage form for intranasal administration).

[0069] Nasal dosage forms include solutions, suspensions, emulsions, powders, and gel compositions for nasal delivery. Such dosage forms are administered, for example, using any nebulization and / or atomization device. Non-limiting examples of delivery devices include nasal sprays (e.g., aqueous nasal sprays, hydroalcoholic nasal sprays, or nonaqueous-based nasal sprays), dropper bottles, sophisticated spray pumps (e.g. metered dose spray pumps), dry powder nasal sprays, dry-powder inhalers, and aspirators.

[0070] In some embodiments, intranasal administration of the pharmaceutical compositions described herein to a subject leads to faster absorption of the pharmaceutical agent into the bloodstream compared to administration by other routes, e.g., oral administration.EXAMPLESExample 1 - Preparation of Spray Dried Formulations

[0071] Two feed solutions were prepared on a 3g total solids scale, incorporating a celastrol drug substance (comprising a crystalline Form III of celastrol) at 2% w / w, alongside 30% w / w hydroxypropyl methyl cellulose (HPMC) and either hydroxypropyl-beta-cyclodextrin (HPBCD) or trehalose or sorbitol. The celastrol drug substance was initially dissolved in methanol to form a clear bright orange colored solution. HPMC was then slowly added to the celastrol drug substance-methanol solution and stirred until fully dispersed. Separately, trehalose or HP-beta- cyclodextrin were dissolved in the deionised water. The aqueous solution was then added dropwise to the celastrol drug substance-HPMC-methanol solution with stirring to form the final feed. The feed was spray dried immediately after the combination of the organic and aqueous phases.

[0072] The composition of the two feed solutions is summarized in Table 1.Table 1: Feed solutions for spray drying

[0073] Both feed solutions were spray dried on a spray drier (ProCepT 4M8) fitted with an ultrasonic nozzle, an inlet temperature of 105 °C to achieve an outlet of ~85 °C, and a feed rate of 2 g / min. For both batches, the majority of powder deposited directly into the collection pot. The resultant powders were orange, free flowing powders. Comparable processing yields were seen for the two batches.Table 2: Spray Dried BatchesParticle Size Distribution

[0074] Spray dried powders were analyzed for particle size using a laser diffraction particle sizer (Sympatec) equipped with a dispersion unit (RODOS / ASPIROS) and an R3 lens at a dispersion pressure of 1 bar (n=3). Narrow particle size distributions were produced for both powders, with <2% of particles below 10 pm. The particle size distributions for both powders are summarized in Table 3.Table 3: Particle size distribution of spray dried powdersLoss on Drying

[0075] The residual moisture / solvent content of the spray dried powders was determined (n=l) by loss of mass on drying at 60°C using thermogravimetric analysis (TGA). Residual moisture content (RMC) values are summarized below alongside T=0 data.Table 4: Residual moisture content of spray dried formulationsAssay and Related Substances

[0076] The celastrol assay of the spray dried powders were determined (n=2) by HPLC. Assay data indicates that the celastrol drug substance was fully retained in both spray dried powders.Table 5: Assay of spray dried formulationsExample 2- Preparation of liquid formulation for intranasal administration

[0077] Stock solutions of polysorbate 20, benzalkonium chloride, a combination of microcrystalline cellulose and sodium carboxymethyl cellulose (MCC-NaCMC; Vivapur MCG 61 IP), and hydroxypropyl methylcellulose (HPMC; HPMC 60SH-4000), were prepared and combined in a 20 mL volumetric flask in the quantities summarized in Table 6, and diluted with ultrapure water and thoroughly mixed. Both suspensions produced were brightly orange colored suspensions.Table 6: Preparation of liquid formulationsTable 7: Composition of liquid FormulationspH & Viscosity of liquid formulations

[0078] The pH and viscosity of both suspensions were determined and is summarized inTable 8.Table 8: pH and viscosity of liquid formulationsAssay and Related Substances

[0079] The celastrol drug substance assay of the liquid formulations was determined (n=2) by HPLC. Assay data indicates that celastrol drug substance was fully retained in both suspensions.Table 9: Assay of liquid formulationsExample 3 - Intranasal administration of formulations of the disclosure

[0080] Sprague Dawley rats aged 5-6 weeks and weighing approximately 150-250g (N=8) were intranasally administered formulations Dry A, Dry B, Liquid A, and Liquid B, described in Examples 1 and 2, at a dosing volume of 0.1 mL / kg (corresponding to a dose concentration of 2 mg / kg). Additional rats (N=4) were administered the celastrol drug substance (comprising a crystalline Form III of celastrol) formulated in 0.01% w / v polysorbate 80, delivered via oral gavage at a dosing volume of 10 mL / kg.

[0081] Whole blood samples (-100 pl) were obtained at 5 min, 15 min, 30 min, Ih, and 4h or at 5 min, 15 min, 30 min, Ih, 2h, 4h, 8h, and 24h after administration and immediately placed back on wet ice. After centrifugation at 6000 rpm for 5 minutes at 4°C, plasma was collected and stored at -80°C until analysis. The concentration of celastrol in the blood samples wasdetermined by LC-MS. Table 10 summarizes the results of the study.Table 10: Pharmacokinetic parameters of Celastrol

[0082] FIG. 1 shows the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of a dry powder intranasal formulation (Dry A) at a dose concentration of 2 mg / kg.

[0083] FIG. 2 shows the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of a dry powder intranasal formulation (Dry A a) at a dose concentration of 2 mg / kg.

[0084] FIG. 3 shows the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of the liquid intranasal formulation Liquid A at a dose concentration of 2 mg / kg.

[0085] FIG. 4 shows the concentration of celastrol in plasma of male Sprague Dawley rats following intranasal dosing of the liquid intranasal formulation Liquid B at a dose concentration of 2 mg / kg.

[0086] FIG. 5 shows the concentration of celastrol in plasma of male Sprague Dawley rats following oral dosing of celastrol at a dose concentration of 2 mg / kg.

[0087] FIG. 6 compares the mean concentrations of celastrol in plasma of male Sprague Dawley rats (average of tested rats) following intranasal administration of formulations Dry A, Dry B, Liquid A, and Liquid B, and oral dosing of celastrol at a dose concentration of 2 mg / kg.

[0088] As demonstrated above, intranasal administration using the tested liquid formulations resulted in plasma concentrations of celastrol that were comparable to or higher than plasma concentrations of celastrol administered orally. However, maximum plasma concentrations (Cmax) were achieved faster following the intranasal administration than following oral administration (at about Ih following the intranasal administration compared to 4h following oral administration).Enumerated EmbodimentsEmbodiment 1. A pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) an emulsifier or surfactant; and(iii) a mucoadhesive or viscosifier; wherein the pharmaceutical composition is in the form of a liquid suspension.Embodiment 2. The pharmaceutical composition of claim 1, comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof(ii) an emulsifier or surfactant;(iii) a mucoadhesive or viscosifier; and(iv) a preservative.Embodiment 3. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a concentration of from about 5 mg / mL to about 50 mg / mL.Embodiment 4. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a concentration of from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 30 mg / mL, or from about 20 mg / mL to about 30 mg / mL.Embodiment 5. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a concentration of about 25 mg / mL.Embodiment 6. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a molar concentration of from about 5 mM to about 40 mM.Embodiment 7. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a molar concentration of from about 10 mM to about 30 mM.Embodiment 8. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a molar concentration of about 20 mM.Embodiment 9. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of from about 0.1 mg / mL to about 5 mg / mL.Embodiment 10. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of from about 0.1 mg / mL to about 4 mg / mL, from about 0.1 mg / mL to about 3 mg / mL, from about 0.1 mg / mL to about 2 mg / mL, or from about 0.5 mg / mL to about 1.5 mg / mL.Embodiment 11. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of about 1 mg / mL.Embodiment 12. The pharmaceutical composition of any one of embodiments 1-8, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of from about 5 mg / mL to about 50 mg / mL.Embodiment 13. The pharmaceutical composition of any one of embodiments 1-8, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 20 mg / mL, from about 10 mg / mL to about 20 mg / mL, or from about 15 mg / mL to about 20 mg / mL.Embodiment 14. The pharmaceutical composition of any one of embodiments 1-8, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of about 18 mg / mL.Embodiment 15. The pharmaceutical composition of any one of the preceding embodiments, wherein the surfactant is a nonionic surfactant.Embodiment 16. The pharmaceutical composition of any one of the preceding embodiments, wherein the emulsifier or surfactant is a polysorbate.Embodiment 17. The pharmaceutical composition of any one of the preceding embodiments, wherein the emulsifier or surfactant is selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80).Embodiment 18. The pharmaceutical composition of any one of the preceding embodiments, wherein the emulsifier or surfactant is polyoxyethylene (20) sorbitan monolaurate (tween 20, polysorbate 20).Embodiment 19. The pharmaceutical composition of any one of the preceding embodiments, wherein the mucoadhesive or viscosifier is selected from methylcellulose (MC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na-CMC), hydroxypropylmethylcellulose (HPMC), hydroxethylcellulose (HEC), microcrystalline cellulose (MCC), and combinations thereof.Embodiment 20. The pharmaceutical composition of any one of the preceding embodiments, wherein the mucoadhesive or viscosifier is selected from methylcellulose (MC), microcrystalline cellulose (MCC), sodium carboxymethylcellulose (Na-CMC), hydroxypropylmethylcellulose (HPMC), and combinations thereof.Embodiment 21. The pharmaceutical composition of any one of the preceding embodiments, wherein the mucoadhesive or viscosifier is selected from microcrystalline cellulose (MCC), sodium carboxymethyl cellulose (Na-CMC) and a combination thereof (MCC- NaCMC).Embodiment 22. The pharmaceutical composition of any one of embodiments 1-20, wherein the mucoadhesive or viscosifier is hydroxypropylmethylcellulose (HPMC).Embodiment 23. The pharmaceutical composition of any one of embodiments 1-20, wherein the mucoadhesive or viscosifier is a combination of microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (Na-CMC) (MCC-NaCMC).Embodiment 24. A pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) a polysorbate; and(iii) a cellulose; wherein the pharmaceutical composition is in the form of a liquid suspension.Embodiment 25. The pharmaceutical composition of embodiment 24, wherein the pharmaceutical composition comprises:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) a polysorbate;(iii) a cellulose; and(iv) a preservative.Embodiment 26. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the preservative at a concentration of up to about 1 mg / mL.Embodiment 27. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the preservative at a concentration of up to about 0.1 mg / mL, up to about 0.2 mg / mL, up to about 0.3 mg / mL, up to about 0.4 mg / mL, up to about 0.5 mg / mL, up to about 0.6 mg / mL, up to about 0.7 mg / mL, up to about 0.8 mg / mL, or up to about 0.9 mg / mL.Embodiment 28. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the pharmaceutical composition comprises the preservative at a concentration of from about 0.01 mg / mL to 1.00 mg / mL.Embodiment 29. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the pharmaceutical composition comprises the preservative an amount of from about 0.01 mg / mL to about 0.8 mg / mL, from about 0.01 mg / mL to about 0.6 mg / mL, from about 0.01 mg / mL to about 0.4 mg / mL, from about 0.01 mg / mL to about 0.2 mg / mL, from about 0.05 mg / mL to about 0.2 mg / mL, or from about 0.05 mg / mL to about 0.15 mg / mL.Embodiment 30. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the preservative at a concentration of about 0.1 mg / mL.Embodiment 31. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the preservative at a molar concentration of from about 0.1 mM to about 0.5 mM.Embodiment 32. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the preservative at a molar concentration of from about 0.2 mM to about 0.4 mM.Embodiment 33. The pharmaceutical composition of any one of embodiments 2-23 and 25, wherein the pharmaceutical composition comprises the preservative at a molar concentration of about 0.3 mM.Embodiment 34. The pharmaceutical composition of any one of embodiments 24-33, wherein the pharmaceutical composition comprises the polysorbate at a molar concentration of from about 5 mg / mL to about 50 mg / mL.Embodiment 35. The pharmaceutical composition of any one of embodiments 24-33, wherein the pharmaceutical composition comprises the polysorbate at a molar concentration of from about 5 mM to about 40 mM.Embodiment 36. The pharmaceutical composition of any one of embodiments 24-33, wherein the pharmaceutical composition comprises the polysorbate at a molar concentration of from about 10 mM to about 30 mM.Embodiment 37. The pharmaceutical composition of any one of embodiments 24-33, wherein the pharmaceutical composition comprises the polysorbate at a molar concentration of about 20 mM.Embodiment 38. The pharmaceutical composition of any one of embodiments 24-37, wherein the pharmaceutical composition comprises the cellulose at a concentration of from about 0.1 mg / mL to about 5 mg / mL.Embodiment 39. The pharmaceutical composition of any one of embodiments 24-37, wherein the pharmaceutical composition comprises the cellulose at a concentration of from about 5 mg / mL to about 50 mg / mL.Embodiment 40. The pharmaceutical composition of any one of embodiments 24-37, wherein the pharmaceutical composition comprises cellulose at a concentration of about 18 mg / mL.Embodiment 41. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the pharmaceutical agent at a concentration of from about 5 mg / mL to about 50 mg / mL.Embodiment 42. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the pharmaceutical agent at a concentration of from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 30 mg / mL, or from about 15 mg / mL to about 25 mg / mL.Embodiment 43. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the pharmaceutical agent at a concentration of about 20 mg / mL.Embodiment 44. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the pharmaceutical agent at a molar concentration of from about 10 mM to about 70 mM.Embodiment 45. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the pharmaceutical agent at a molar concentration of from about 20 mM to about 60 mM.Embodiment 46. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the pharmaceutical agent at a molar concentration of from about 40 mM to about 50 mM.Embodiment 47. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical composition comprises the pharmaceutical agent at a molar concentration of about 44 mM.Embodiment 48. The pharmaceutical composition of any one of embodiments 2-23 and 25- 47, wherein the preservative is selected from potassium sorbate, chlorobutanol, methyl paraben, propyl paraben, butyl paraben, benzethonium chloride, sodium benzoate, and sorbic acid, and benzalkonium chloride.Embodiment 49. The pharmaceutical composition of any one of embodiments 2-23 and 25- 47, wherein the preservative is benzalkonium chloride.Embodiment 50. The pharmaceutical composition of any one of embodiments 24-49, wherein the cellulose is hydroxypropylmethylcellulose (HPMC) or a combination of microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (Na-CMC) (MCC- NaCMC).Embodiment 51. The pharmaceutical composition of any one of embodiments 24-50, wherein the polysorbate is selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80).Embodiment 52. The pharmaceutical composition of any one of embodiments 24-50, wherein the polysorbate is polyoxyethylene (20) sorbitan monolaurate (tween 20, polysorbate 20).Embodiment 53. A pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof in an amount of from about 1 wt.% to about 5 wt.%;(ii) hydroxypropyl-beta-cyclodextrin (HPBCD) or trehalose in an amount of from about 60 wt.% to about 70 wt.%; and(iii) hydroxypropyl methyl cellulose (HPMC) in an amount of from about 10 wt.% to about 40 wt.%; wherein the pharmaceutical composition is in the form of a powder.Embodiment 54. The pharmaceutical composition of embodiment 53, wherein the pharmaceutical composition comprises the pharmaceutical agent in an amount of about 2 wt.%.Embodiment 55. The pharmaceutical composition of embodiment 53 or 54, wherein the pharmaceutical composition comprises the HPBCD or trehalose in an amount in an amount of about 68 wt.%.Embodiment 56. The pharmaceutical composition of any one of embodiments 53-55, wherein the pharmaceutical composition comprises the HPMC in an amount in an amount of about 30 wt.%.Embodiment 57. The pharmaceutical composition of any one of the preceding embodiments, wherein the pharmaceutical agent is celastrol.Embodiment 58. The pharmaceutical composition of any one of embodiments 1-56, wherein the pharmaceutical agent is a polymorph of celastrol.Embodiment 59. The pharmaceutical composition of embodiment 58, wherein the polymorph of celastrol is a crystalline Form III of celastrol, wherein the crystalline Form III of celastrol is characterized by an X-ray powder diffraction pattern comprising peaks at 20 angles (±0.2) selected from the group consisting of 9.51°, 14.81°, and 16.84°.Embodiment 60. The pharmaceutical composition of embodiment 59, wherein the polymorph of celastrol is a crystalline Form III of celastrol, wherein the crystalline Form III of celastrol is characterized by an X-ray powder diffraction pattern further comprising one or more peaks at 20 angles (±0.2) selected from the group consisting of 13.60°, 14.65°, 18.74°, and 19.10°.Embodiment 61. The pharmaceutical composition of embodiment 59 or 60, wherein the crystalline Form III of celastrol is characterized by an X-ray powder diffraction pattern that is substantially the same as Figure 7.Embodiment 62. The pharmaceutical composition of any one of embodiments 59-61, wherein the crystalline Form III of celastrol is characterized by a differential scanning calorimetry (DSC) profile with no endothermic peak and an exothermic peak at about 215 °C (onset).Embodiment 63. The pharmaceutical composition of any one of embodiments 59-62, wherein the crystalline Form III of celastrol is characterized by thermal gravimetric analysis (TGA) profile with about 0.5% weight loss at about the exothermic peak at about 215 °C (onset).Embodiment 64. The pharmaceutical composition of any one of embodiments 59-63, wherein the crystalline Form III of celastrol is anhydrous.Embodiment 65. The pharmaceutical composition of any one of embodiments 59-64, wherein the crystalline Form III of celastrol comprises about 5000 ppm or less of n-heptane.Embodiment 66. The pharmaceutical composition of any one of embodiments 59-64, wherein the crystalline Form III of celastrol comprises about 70 ppm or less of n-heptane.Embodiment 67. The pharmaceutical composition of any one of embodiments 59-66, wherein the crystalline form comprises about 5000 ppm or less of 2-methyltetrahydrofuran.Embodiment 68. The pharmaceutical composition of any one of embodiments 59-66, wherein the crystalline form comprises about 500 ppm or less of 2-methyltetrahydrofuran.Embodiment 69. The pharmaceutical composition of any one of embodiments 59-68, wherein the crystalline form comprises about 5000 ppm or less of ethyl acetate.Embodiment 70. The pharmaceutical composition of any one of embodiments 59-68, wherein the crystalline form comprises about 10 ppm or less of ethyl acetate.Embodiment 71. The pharmaceutical composition of any one of embodiments 59-70, wherein the crystalline Form III of celastrol comprises about 3,000 ppm or less of methanol.Embodiment 72. The pharmaceutical composition of any one of embodiments 59-70, wherein the crystalline Form III of celastrol comprises about 1,500 ppm or less of methanol.Embodiment 73. The pharmaceutical composition of any one of embodiments 59-72, wherein the crystalline Form III of celastrol comprises about 5000 ppm or less of ethanol.Embodiment 74. The pharmaceutical composition of any one of embodiments 59-72, wherein the crystalline Form III of celastrol comprises about 600 ppm or less of ethanol.Embodiment 75. The pharmaceutical composition of any one of embodiments 59-74, wherein the crystalline Form III of celastrol is free of methanol, ethanol, and / or dichloromethane.Embodiment 76. The pharmaceutical composition of any one of embodiments 59-75, wherein the crystalline Form III of celastrol has at least 99.8% purity.Embodiment 77. The pharmaceutical composition of any one of the preceding embodiments, wherein the liquid pharmaceutical composition is a fast-acting pharmaceutical composition.Embodiment 78. The pharmaceutical composition of any one of embodiments 1-52 and 57- 77, wherein the liquid pharmaceutical composition is in the form of a nasal spray or nose drops.Embodiment 79. A pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) an emulsifier or surfactant; and(iii) a mucoadhesive or viscosifier.Embodiment 80. A method of treating a disease or condition comprising intranasally administering a pharmaceutical composition of any one of the preceding embodiments.Embodiment 81. A method of treating a disease or condition comprising intranasally administering celastrol.Embodiment 82. The method of embodiment 81, wherein the celastrol is administered using a nasal spray, nose drops, or a powder inhaler.Embodiment 83. The method of embodiment 81 or 82, wherein the disease or condition is obesity or an obesity -related disease or disorder.Embodiment 84. The method of embodiment 83, wherein the obesity-related disease or disorder is selected from the group consisting of obesity, pre-obesity, morbid obesity, Prader-Willi Syndrome, Hypothalamic Injury Associated Obesity, Non-alcoholic steatohepatitis, hyperlipidemia, hypertension, diabetes, lipodystrophy, fatty liver, Bardet-Biedl Syndrome, Cohen Syndrome, cardiovascular disease, arthritis, stroke, metabolic syndrome and MOMO Syndrome.Embodiment 85. The method of embodiment 81 or 82, wherein the disease or condition is selected from the group consisting of gastric cancer, multiple myeloma, melanoma, leukemia, lymphoma, renal cell carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, head and neck cancer, non- small cell lung carcinoma, brain cancer, and glioblastoma multiform (GBM).Embodiment 82. A method of intranasally administering celastrol comprising administering a pharmaceutical composition of any one of Embodiments 1-79.EQUIVALENTS

[0089] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS1. A pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) an emulsifier or surfactant; and(iii) a mucoadhesive or viscosifier.

2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a concentration of from about 5 mg / mL to about 50 mg / mL.

3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the emulsifier or surfactant at a molar concentration of from about 5 mM to about 40 mM.

4. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of from about 0.1 mg / mL to about5 mg / mL.

5. The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutical composition comprises the mucoadhesive or viscosifier at a concentration of from about 5 mg / mL to about 50 mg / mL.

6. The pharmaceutical composition of any one of the preceding claims, wherein the emulsifier or surfactant is a polysorbate.

7. The pharmaceutical composition of any one of the preceding claims, wherein the mucoadhesive or viscosifier is selected from methylcellulose (MC), carboxymethylcellulose (CMC), sodium carboxymethylcellulose (Na-CMC), hydroxypropylmethylcellulose (HPMC), hydroxethylcellulose (HEC), microcrystalline cellulose (MCC), and combinations thereof.

8. A pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof;(ii) a polysorbate; and(iii) a cellulose.

9. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition is in the form of a liquid suspension.

10. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition further comprises (iv) a preservative.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition comprises the preservative at a concentration of up to about 1 mg / mL.

12. The pharmaceutical composition of any one of claims 8-11, wherein the pharmaceutical composition comprises the polysorbate at a molar concentration of from about 5 mg / mL to about 50 mg / mL.

13. The pharmaceutical composition of any one of claims 8-11, wherein the pharmaceutical composition comprises the polysorbate at a molar concentration of from about 5 mM to about 40 mM.

14. The pharmaceutical composition of any one of claims 8-13, wherein the pharmaceutical composition comprises the cellulose at a concentration of from about 0.1 mg / mL to about 5 mg / mL.

15. The pharmaceutical composition of any one of claims 8-13, wherein the pharmaceutical composition comprises the cellulose at a concentration of from about 5 mg / mL to about 50 mg / mL.

16. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical composition comprises the pharmaceutical agent at a concentration of from about 5 mg / mL to about 50 mg / mL.

17. The pharmaceutical composition of any one of claims 1-16, wherein the pharmaceutical composition comprises the pharmaceutical agent at a molar concentration of from about 10 mM to about 70 mM.

18. The pharmaceutical composition of any one of claims 10-17, wherein the preservative is selected from potassium sorbate, chlorobutanol, methyl paraben, propyl paraben, butyl paraben, benzethonium chloride, sodium benzoate, and sorbic acid, and benzalkonium chloride.

19. The pharmaceutical composition of any one of claims 8-18, wherein the cellulose is hydroxypropylmethylcellulose (HPMC) or a combination of microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (Na-CMC) (MCC-NaCMC).

20. The pharmaceutical composition of any one of claims 8-19, wherein the polysorbate is selected from polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monopalmitate (polysorbate 40), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80).

21. A pharmaceutical composition comprising:(i) a pharmaceutical agent selected from celastrol, a pharmaceutically acceptable salt thereof, and a polymorph thereof in an amount of from about 1 wt.% to about 5 wt.%;(ii) hydroxypropyl-beta-cyclodextrin (HPBCD) or trehalose in an amount of from about 60 wt.% to about 70 wt.%; and(iii) hydroxypropyl methyl cellulose (HPMC) in an amount of from about 10 wt.% to about 40 wt.%; wherein the pharmaceutical composition is in the form of a powder.

22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises the pharmaceutical agent in an amount of about 2 wt.%, the HPBCD or trehalose in an amount in an amount of about 68 wt.%, and the HPMC in an amount in an amount of about 30 wt.%.

23. The pharmaceutical composition of any one of the preceding claims, wherein the pharmaceutical agent is celastrol.

24. The pharmaceutical composition of any one of claims 1-22, wherein the pharmaceutical agent is a polymorph of celastrol.

25. The pharmaceutical composition of claim 24, wherein the polymorph of celastrol is a crystalline Form III of celastrol, wherein the crystalline Form III of celastrol is characterized by an X-ray powder diffraction pattern comprising peaks at 20 angles (±0.2) selected from the group consisting of 9.51°, 14.81°, and 16.84°.

26. The pharmaceutical composition of claim 24, wherein the polymorph of celastrol is a crystalline Form III of celastrol, wherein the crystalline Form III of celastrol is characterized by an X-ray powder diffraction pattern further comprising one or more peaks at 20 angles (±0.2) selected from the group consisting of 13.60°, 14.65°, 18.74°, and 19.10°.

27. The pharmaceutical composition of any one of claims 24-26 wherein the crystalline Form III of celastrol comprises about 5000 ppm or less of n-heptane, 2-methyltetrahydrofuran, ethyl acetate, and / or ethanol, and / or about 3,000 ppm or less of methanol.

28. The pharmaceutical composition of any one of claims 24-27, wherein the crystalline Form III of celastrol has at least 99.8% purity.

29. The pharmaceutical composition of any one of the preceding claims, wherein the liquid pharmaceutical composition is a fast-acting pharmaceutical composition.

30. The pharmaceutical composition of any one of claims 1-20 and 23-29, wherein the liquid pharmaceutical composition is in the form of a nasal spray or nose drops.

31. A method of treating a disease or condition comprising intranasally administering a pharmaceutical composition of any one of the preceding claims.

32. A method of intranasally administering celastrol comprising administering a pharmaceutical composition of any one of claims 1-31.

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