Pharmaceutical compositions for enhanced solubility and bioavailability of hydrophobic drugs

Abstract

The present disclosure provides pharmaceutical compositions, e.g., drug-containing nanocomposites, nanosuspensions thereof, and lyophilized powders thereof, that increase the apparent water solubility of hydrophobic active pharmaceutical ingredients and provide improved oral bioavailability and pharmacokinetic properties.

Description

Attorney Docket No.: INLA-OOl / OIWO 353562-2002PHARMACEUTICAL COMPOSITIONS FOR ENHANCED SOLUBILITY ANDBIO A VAILABILITY OF HYDROPHOBIC DRUGSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 691,617, filed September 6, 2024, which is incorporated herein by reference in its entirety.FIELD

[0002] The present disclosure relates to pharmaceutical compositions that enhance the apparent solubility of a hydrophobic drugs and provide improved oral bioavailability. In embodiments, the pharmaceutical compositions may be nanocomposites, nanosuspensions thereof or lyophilized powders thereof.BACKGROUND OF THE INVENTION

[0003] Hydrophobic drug substances tend to exhibit poor or inconsistent bioavailability when administered orally in large part due to their low aqueous solubility, slow in vivo dissolution rates, and / or low permeability across intestinal membranes. The poor bioavailability of orally administered, hydrophobic drugs is particularly problematic considering that approximately 10% of currently marketed drugs exhibit poor water solubility.

[0004] Despite ongoing research into formulation and drug delivery technologies that can improve the oral bioavailability of hydrophobic drugs, success has been limited and numerous challenges remain.

[0005] Accordingly, there remains a need for new strategies to improve the bioavailability and pharmacokinetic properties of hydrophobic drugs.SUMMARY OF THE INVENTION

[0006] The present disclosure provides pharmaceutical compositions for oral administration that improve the bioavailability and pharmacokinetic properties of hydrophobic active pharmaceutical ingredients (API) useful in treating a variety of diseases in conditions. The pharmaceutical composition comprises particles in the nanometer range, such particles comprise the hydrophobic API and certain excipients that significantly increase the water solubility of the hydrophobic API. These drug-containing particles are referred to herein as nanocomposites. Methods of making the disclosed pharmaceutical composition are also provided herein.Attorney Docket No.: INLA-OOl / OIWO 353562-2002

[0007] In some aspects, the present disclosure provides a plurality of drug-containing nanocomposites, each drug-containing nanocomposite comprising: a) a hydrophobic active pharmaceutical ingredient (API); and b) one or more pharmaceutically acceptable surfactants and / or one or more pharmaceutically acceptable water-soluble polymers, wherein the hydrophobic API has: i) a molecular mass of at least about 500 g / mol; and ii) a water solubility of less than about 0.1 mg / mL; and wherein the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm as determined by dynamic light scattering (DLS).

[0008] In other aspects, the present disclosure provides an aqueous nanosuspension comprising a plurality of drug-containing nanocomposites, each drug-containing nanocomposite comprising: a) a hydrophobic active pharmaceutical ingredient (API); and b) one or more pharmaceutically acceptable surfactants and / or one or more pharmaceutically acceptable water-soluble polymers, wherein the hydrophobic API has: i) a molecular mass of at least about 500 g / mol; and ii) a water solubility of less than about 0.1 mg / mL; and wherein the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm as determined by dynamic light scattering (DLS).

[0009] In further aspects, the present disclosure provides a lyophilized powder comprising (1) a plurality of drug-containing nanocomposites, each drug-containing nanocomposite comprising: a) a hydrophobic active pharmaceutical ingredient (API); and b) one or more pharmaceutically acceptable surfactants and / or one or more pharmaceutically acceptable water-soluble polymers, wherein the hydrophobic API has i) a molecular mass of at least about 500 g / mol; and ii) a water solubility of less than about 0.1 mg / mL; and wherein the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm as determined by dynamic light scattering (DLS); and (2) a cryoprotectant.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Fig. 1 shows the concentration of rapamycin detected in deionized water following preparation of F50 (red), 5X F50 (yellow), and 10X F50 nanocomposites in mg / mL (Fig. 1A) and in pg / mL plotted as a log scale (Fig. IB).

[0011] Fig. 2 shows the observed increase in apparent solubility of six hydrophobic drugs when formulated in the drug-containing nanocomposite (NC) of the present disclosure in comparison to the aqueous thermodynamic solubility of the drug reported in the literature.

[0012] Fig. 3A shows the observed increase in apparent solubility (pg / mL) of rapamycin and everolimus provided by drug-containing nanocomposites of the present disclosure obtained from prescreening and scale-up studies in comparison to the aqueous thermodynamic solubilityAttorney Docket No.: INLA-OOl / OIWO 353562-2002 of the drug reported in the literature. The concentration reported aqueous solubility of each drug is shown on the left (pink), then the apparent solubility measured during NC screening (blue), followed by the apparent solubility following scale up and purification via tangential flow filtration (green). Fig. 3B illustrates the same results plotted on a log scale.

[0013] Fig. 4 provides transmission electron microscopy (TEM) images obtained for rapa_F50 lyophilized nanocomposites.

[0014] Fig. 5 provides a graphical representation of the surface functionalization and adsorption process used to isolate rapamycin nanocomposites for additional characterization.

[0015] Fig. 6 shows the powder X-ray powder diffractograms (P-XRD) obtained for the MMT- isolated rapamycin nanocomposites.

[0016] Fig. 7 shows differential scanning calorimetry (DSC) thermograms obtained for the MMT-isolated rapamycin nanocomposites.

[0017] Fig. 8 shows the timeline of nanocomposite precipitation during a one month stability study for 5 mg / mL rapa_F50 lyophilized in the presence of trehalose and reconstituted at day 28 (LYO-Recon); 5 mg / mL of rapamycin F50 stored as a nanosuspension (NS 5 mg / mL); 2.5 mg / mL rapamycin F50 stored as a nanosuspension (NS 2.5 mg / mL); 1 mg / mL rapamycin F50 stored as a nanosuspension (NS 1 mg / mL); and 0.5 mg / mL rapamycin F50 stored as a nanosuspension (NS 0.5 mg / mL).

[0018] Fig. 9 shows the mean plasma concentration versus time curves for rapamycin administered in the nanocomposite formulations compared to a dose-equivalent of rapamycin from the FDA-approved formulation Rapamune® Oral Solution (Rapamune EQ) following a single oral dose of rapamycin at 5 mg / kg (>=5 animals per group, error bar = standard error of the mean).DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0018] As used herein, the term “thermodynamic solubility” means the maximum concentration of the API dissolved in an aqueous media under equilibrium conditions with undissolved material. Thermodynamic solubility refers to the aqueous solubility of the API measured prior to incorporating the API into the drug-containing nanocomposites disclosed herein (also referred to as “free API”).

[0019] As used herein, the term “apparent solubility” means the total concentration of the drug suspended in the deionized water as measured using high-performance liquid chromatography.Attorney Docket No.: INLA-OOl / OIWO 353562-2002

[0020] As used herein, the term "bioavailability" refers to the amount of drug (API) that that is systemically available over time.

[0021] As used herein, an "antisolvent" is any solvent that does not dissolve the hydrophobic API. For a hydrophobic drug, an antisolvent is, for example and without limitation, an aqueous solution such as water. Ethanol is another non-limiting example of a solution that can be used as an antisolvent. Combinations of antisolvents (for example, ethanol and water) are also contemplated by the disclosure.

[0022] As used herein, the word “about” when immediately preceding a stated numerical value covers the acceptable variation of that value in the art. In embodiments, “about” means ± 10% of the numerical value. By way of example, “about 10 mg / mL” means 9 mg / mL to 11 mg / m. Unless expressly stated to the contrary, all ranges cited herein include their upper and lower endpoints and all values therebetween.

[0023] A "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus. In some embodiments, the subject is a human.Nanocomposites of the Invention

[0024] The present disclosure provides a plurality of drug-containing nanocomposites, each drug-containing nanocomposite comprising: a) a hydrophobic active pharmaceutical ingredient (API); and b) one or more pharmaceutically acceptable surfactants and / or one or more pharmaceutically acceptable water-soluble polymers, wherein the hydrophobic API has: i) a molecular mass of at least about 500 g / mol; and ii) a thermodynamic water solubility of less than or equal to 0.1 mg / mL; and wherein the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm as determined by dynamic light scattering (DLS).

[0025] APIs in the nanocomposites of the present disclosure are amorphous or substantially amorphous, e.g., as confirmed by XRPD and / or any other test method known in the art for evaluating the crystallinity of a solid material. An API is “substantially amorphous” when the XRPD does not contain a sufficient number of distinct peaks required to characterize a crystalline form of an API.

[0026] In some embodiments, the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm, e.g., about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 125 nm, about 150 nm, about 175 nm, about 200 nm, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, about 400 nm, about 425 nm, about 450 nm, about 475 nm, about 500 nm, about 525 nm, aboutAttorney Docket No.: INLA-OOl / OIWO 353562-2002550 nm, about 575 nm, about 600 nm, about 625 nm, about 650 nm, about 675 nm, about 700 nm, about 725 nm, about 750 nm, as determined by DLS, including all ranges and values therebetween. In some embodiments, the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm, e.g., about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 125 nm, about 150 nm, about 175 nm, about 200 nm, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, about 400 nm, about 425 nm, about 450 nm, about 475 nm, about 500 nm, about 525 nm, about 550 nm, about 575 nm, about 600 nm, about 625 nm, about 650 nm, about 675 nm, about 700 nm, about 725 nm, or about 750 nm, as determined by DLS, including all ranges and values therebetween. In some embodiments, the nanocomposites have an average particle size ranging from about 75 nm to about 500 nm. In some embodiments, the nanocomposites have an average particle size ranging from about 75 nm to about 350 nm, about 75 nm to about 300 nm, about 75 nm to about 250, or about 75 nm to about 200 nm. In some embodiments, the nanocomposites have an average particle size ranging from about 100 nm to about 500 nm, about 100 nm to about 400, about 100 nm to about 300, about 100 nm to about 250 nm, or about 100 nm to about 200 nm. In some embodiments, the nanocomposites have an average particle size ranging from about 100 nm to about 200 nm. In some embodiments, the nanocomposites have an average particle size ranging from about 100 nm to about 150 nm.

[0027] Without being bound by any theory, the nanocomposites disclosed herein are designed to maximize surface area by reducing particle size, thereby significantly enhancing dissolution rates. It is believed the amorphous structure of the API in the nanocomposites, which due to the absence of crystalline structure, possesses a higher energy state that promotes increased drug solubility. This structural characteristic not only enhances dissolution, but also can improve absorption and overall pharmacokinetic profiles. As a consequence of these advantageous properties, the disclosed nanocomposites provide improved oral bioavailability of hydrophobic active pharmaceutical agents that are otherwise challenging to formulate in a therapeutically effective manner. Additionally, the nanocomposites disclosed herein allow for a lower concentration of drug to be administered while achieving similar or improved bioavailability compared to existing formulations of the same drug approved by regulatory agencies.

[0028] In embodiments, the nanocomposites of the present disclosure comprise a drugcontaining core within a surfactant and / or polymer coating. In some embodiments, the nanocomposites comprise a drug-containing core within a surfactant and / or polymer matrix.Attorney Docket No.: INLA-OOl / OIWO 353562-2002In other embodiments, the nanocomposites of the present disclosure comprise a single phase of homogenous solid that includes a drug and polymer / surf actant.

[0029] Hydrophobic Active Agents

[0030] The hydrophobic active agent of the present disclosure can be any drug that has a molecular mass of at least about 500 g / mol and a thermodynamic water solubility of less than or equal to 0.1 mg / mL.

[0031] In some embodiments, the hydrophobic API has a molecular mass ranging from about 500 g / mol to about 2000 g / mol. In some embodiments, the hydrophobic API has a molecular mass ranging from about 500 g / mol to about 1500 g / mol. In some embodiments, the hydrophobic API has a molecular mass ranging from about 500 g / mol to about 1250 g / mol. In some embodiments, the hydrophobic API has a molecular mass ranging from about 500 g / mol to about 1000 g / mol.

[0032] In some embodiments, the hydrophobic API has a thermodynamic water solubility of less than or equal to 0.1 mg / mL. In some embodiments, the hydrophobic API has a thermodynamic water solubility of from about 0.01 mg / mL to about 0.1 mg / mL, e.g., about 0.015 mg / mL, about 0.02 mg / mL, about 0.025 mg / mL, about 0.03 mg / mL, about 0.035 mg / mL, about 0.04 mg / mL, about 0.045 mg / mL, about 0.05 mg / mL, about 0.055 mg / mL, about 0.06 mg / mL, about 0.065 mg / mL, about 0.07 mg / mL, about 0.075 mg / mL, about 0.08 mg / mL, about 0.085 mg / mL, about 0.09 mg / mL, about 0.095 mg / mL or about 0.1 mg / mL, including all ranges and values therebetween. In some embodiments, the hydrophobic API has a thermodynamic water solubility of from about 0.05 mg / mL to about 0.1 mg / mL.

[0033] In some embodiments, the hydrophobic API is a Biopharmaceutics Classification System (BCS) class II (high permeability, low solubility) or class IV (low permeability, low solubility) drug. In some embodiments, the hydrophobic API is a Biopharmaceutics Classification System (BCS) class II drug. In some embodiments, the BCS class II drug is aceclofenac, altretamine, amiodarone, bicalutamide, carbamazepine, dapsone, danazol, ezetimibe, felodipine, fenofibrate, glibenclamide, gliclazide, griseofulvin, ketoconazole, nifedipine, nitrofurantoin, phenytoin, sulfamethoxazole, telmisartan, trimethoprim, tolbutamide, and valproic acid. In some embodiments, the hydrophobic API is a Biopharmaceutics Classification System (BCS) class IV drug. In some embodiments, the BCS class IV drug is abiraterone, acetazolamide, albendazole, / ?-aminosalicylic acid artemether + lumefantrine, amphotericin B, aprepitant, artesunate, azathioprine sodium, azithromycin, benzthiazide, cefetamet, cefixime, ciclosporin, clofazimine, colestipol, colistin, delafloxacinAttorney Docket No.: INLA-OOl / OIWO 353562-2002 meglumine, dichlorophenamide, dihydrodydrogesterone, diloxanide furoate, dirithromycin, docetaxel, doxacurium chloride, efavirenz, elbasvir, erythromycin stearate, erythromycin ethyl succinate, ethacrynic acid, ethoxzolamide, etoposide, etravirine, furamidine, furosemide, gemfloxacin mesylate, glecaprevir, grazoprevir, haloperidol, indinavir sulfate, ivermectin, letermovir, loperaimide, lopinavir + ritonavir, mebendazole, meclizine, mefloquine hydrochloride, melagatran, metazocin, meticrane, mercaptopurine, mifepristone, moxonidine, nelfinavir mesylate, niclosamide, oxamniquine, paclitaxel, pibrentasvir, pyrantel embonate, pyrimethamine, ribociclib, rimegeprant sulfate, retinol palmitate, ritonavir, saquinavir, selumetinib, sevelamer, spironolactone, sulfadiazine, sulfasalazine, tizoxanide, triclabendazole, vaborbactam, velpatasvir, vibegron, or voxilaprevir. In some embodiments, the hydrophobic API is rapamycin (sirolimus), everolimus, docetaxel, paclitaxel, clozapine, cyclosporin, nystatin, or daptomycin. In some embodiments, the hydrophobic API is rapamycin (sirolimus), everolimus, docetaxel, paclitaxel, clozapine, or cyclosporin.

[0034] In some embodiments, the hydrophobic API has a Log P greater than 1. In some embodiments, the hydrophobic API has a Log P greater than 2. In some embodiments, the hydrophobic API has a Log P greater than 3. In some embodiments, the hydrophobic API has a log P ranging from about 2 to about 7.5. In some embodiments, the hydrophobic API has a log P ranging from about 2.5 to about 7.5. In some embodiments, the hydrophobic API has a log P ranging from about 3 to about 7.5. In some embodiments, the hydrophobic API has a log P ranging from about 2 to about 7. In some embodiments, the hydrophobic API has a log P ranging from about 2.5 to about 7. In some embodiments, the hydrophobic API has a log P ranging from about 3 to about 7. In some embodiments, the hydrophobic API has a log P ranging from about 2.5 to about 6. In some embodiments, the hydrophobic API has a log P ranging from about 2.5 to about 5. In some embodiments, the hydrophobic API has a log P ranging from about 4 to about 6.

[0035] In some embodiments, the hydrophobic API has a concentration in the nanocomposite ranging from about 25% w / w to about 95% w / w, e.g., about 25% w / w, about 30% w / w, about 35% w / w, about 40% w / w, about 45% w / w, about 50% w / w, about 55% w / w, about 60% w / w, about 65% w / w, about 70% w / w, about 75% w / w, about 80% w / w, about 85% w / w, about 90% w / w, or about 95% w / w, including all ranges and values therebetween. In some embodiments, the hydrophobic API has a concentration in the nanocomposite ranging from about 50% w / w to about 95% w / w, about 55% w / w to about 95% w / w, about 60% w / w to about 95% w / w, about 65% w / w to about 95% w / w, about 70% w / w to about 95% w / w, about 75% w / w to aboutAttorney Docket No.: INLA-OOl / OIWO 353562-200295% w / w, or about 80% w / w to about 95% w / w. In some embodiments, the hydrophobic API has a concentration in the nanocomposite ranging from about 70% w / w to about 95% w / w.

[0036] Surfactants

[0037] In some embodiments, the one or more surfactants comprise a water-soluble surfactant. In some embodiments, the one or more surfactants comprise an alkyl sulfate, a polysorbate (Tween®), a sorbitan ester (Span®), an ethoxylated castor oil, a polyoxyethylene fatty ether (Brij®), or any combination thereof. In some embodiments, the one or more surfactants comprise an alkyl sulfate, a polysorbate, or combination thereof. In some embodiments, the one of more surfactants is sodium dodecyl sulfate (SDS), sodium lauryl ether sulfate (SLES), sodium tetradecyl sulfate (STS), sodium octadecyl sulfate (SODS), sodium pareth sulfate, sodium myreth sulfate, polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monolaurate (Span® 20), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), PEG-40 castor oil, or any combination thereof. In some embodiments, the one or more surfactants comprise SDS, STS, polysorbate 60, polysorbate 80, or any combination thereof. In some embodiments, the one or more surfactants comprise SDS or STS. In some embodiments, the one or more surfactants comprise SDS. In some embodiments, the one or more surfactants comprise STS. In some embodiments, the one or more surfactants comprise polysorbate 60 or polysorbate 80. In some embodiments, the one or more surfactants comprise polysorbate 60. In some embodiments, the one or more surfactants comprise polysorbate 80.

[0038] In some embodiments, the one or more surfactants comprise an anionic surfactant, a nonionic surfactant, or any combination thereof. In some embodiments, the one or more surfactants comprise an anionic surfactant. In some embodiments, the one or more surfactants comprise a nonionic surfactant. In some embodiments, the anionic surfactant comprises a hydrocarbon tail comprising from 6 to 24 carbons. In some embodiments, the hydrocarbon tail is saturated. In some embodiments, the hydrocarbon tail is partially unsaturated. In some embodiments, the anionic surfactant comprises a sulfate group. In some embodiments, the anionic sulfate is an alkyl sulfate or an alkyl ether sulfate (AES). In some embodiments, the anionic surfactant is sodium dodecyl sulfate (SDS), sodium lauryl ether sulfate (SLES), sodium tetradecyl sulfate (STS), sodium octadecyl sulfate (SODS), sodium pareth sulfate, sodium myreth sulfate, or any combination thereof. In some embodiments, the one or more anionic surfactants comprises sodium dodecyl sulfate (SDS), sodium lauryl ether sulfate (SLES), sodium pareth sulfate, or sodium myreth sulfate. In some embodiments, the anionic surfactantAttorney Docket No.: INLA-OOl / OIWO 353562-2002 is SDS or STS. In some embodiments, the anionic surfactant is SDS. In some embodiments, the anionic surfactant is STS. In some embodiments, the nonionic surfactant comprises a fatty acid ester and / or ethylene oxide groups. In some embodiments, the nonionic surfactant is a polysorbate (Tween®), a sorbitan ester (Span®), an ethoxylated castor oil, or a polyoxyethylene fatty ether (Brij®). In some embodiments, the nonionic surfactant is polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monolaurate (Span® 20), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), PEG-40 castor oil, or any combination thereof. In some embodiments, the nonionic surfactant is polysorbate 60 or polysorbate 80. In some embodiments, the nonionic surfactant is polysorbate 60. In some embodiments, the nonionic surfactant is polysorbate 80.

[0039] In some embodiments, the one or more surfactants has a concentration in the nanocomposite ranging from about 0.5% w / w to about 10% w / w, e.g., about 0.5% w / w, about 1% w / w, about 1.5% w / w, about 2% w / w, about 2.5% w / w, about 3% w / w, about 3.5% w / w, about 4% w / w, about 4.5% w / w, about 5% w / w, about 5.5% w / w, about 6% w / w, about 6.5% w / w, about 7% w / w, about 7.5% w / w, about 8% w / w, about 8.5% w / w, about 9% w / w, about 9.5% w / w, or about 10% w / w, including all ranges and values therebetween. In some embodiments, the one or more surfactants has a concentration in the nanocomposite ranging from about 0.5% w / w to about 9% w / w, about 0.5% w / w to about 8% w / w, about 0.5% w / w to about 7% w / w, about 0.5% w / w to about 6% w / w, about 0.5% w / w to about 5% w / w w / w, about 1% w / w to about 5% w / w, about 2% w / w to about 5% w / w, or about 3% w / w to about 5% w / w. In some embodiments, the one or more surfactants has a concentration in the nanocomposite ranging from about 0.5% w / w to about 5% w / w.

[0040] Water-Soluble Polymers

[0041] In some embodiments, the one or more water-soluble polymers comprise a poloxamer, a polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), a cellulose polymer, or combination thereof. In some embodiments, the one or more water- soluble polymers comprise PVA, a poloxamer, PVP, or any combination thereof. In some embodiments, the one or more water-soluble polymers comprise PVA, a poloxamer, or any combination thereof. In some embodiments, the one or more water-soluble polymers comprise a poloxamer, PVP, hydroxypropyl methylcellulose (HPMC), or any combination thereof. In some embodiments, the one or more water-soluble polymers comprise PVA, PVP, a poloxamer, PEG, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), or any combination thereof. In some embodiments, the one or more water-soluble polymersAttorney Docket No.: INLA-OOl / OIWO 353562-2002 comprise a poloxamer, PVP, or any combination thereof. In some embodiments, the one or more water-soluble polymers comprise a poloxamer.

[0042] In some embodiments, the poloxamer has a structure according to Formula (I),wherein “a” ranges from about 30 to about 110 and “b” ranges from about 20 to about 60. In some embodiments, “a” ranges from about 30 to about 50 (e.g., 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, including all ranges therein). In some embodiments, “a” ranges from about 35 to about 45. In some embodiments, “a” ranges from about 90 to about 110 (e.g., 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, or 110, including all ranges therein). In some embodiments, “a” ranges from about 95 to about 105. In some embodiments, “b” ranges from about 20 to about 40 (e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, including all ranges therein). In some embodiments, “b” ranges from about 25 to about 35. In some embodiments, “b” ranges from about 45 to about 65 (e.g., 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, or 65). In some embodiments, “b” ranges from about 50 to about 60. In some embodiments, the polymer is pol oxamer 188 (a is about 38 and b is about 29) or pol oxamer 407 (a is about 101 and b is about 56).

[0043] In some embodiments, the water-soluble polymer is PVA. In some embodiments, PVA has a mass average molecular weight (MW) ranging from about 5,000 daltons to about 75,000 daltons (e.g., about 5,000 daltons, about 7,500 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 40,000 daltons, about 50,000 daltons, about 60,000 daltons, about 70,000 daltons, or about 75,000 daltons). In some embodiments, the PVA is PVA (mass average MW about 9,000 to about 10,000) or PVA (mass average MW about 31,000 to about 50,000).

[0044] In some embodiments, the water-soluble polymer has a mass average molecular weight (MW) ranging from about 5,000 daltons to about 200,000 daltons, e.g., about 5,000 daltons, about 7,500 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 40,000 daltons, about 50,000 daltons, about 60,000 daltons, about 70,000 daltons, about 80,000 daltons, about 90,000 daltons, 100,000 daltons about 110,000 daltons, about 120,000 daltons, about 130,000 daltons, about 140,000 daltons, about 150,000 daltons, about 160,000 daltons, about 170,000 daltons, about 180,000 daltons, about 190,000 daltons, or aboutAttorney Docket No.: INLA-OOl / OIWO 353562-2002200,000 daltons, including all ranges and values therebetween. In some embodiments, the water-soluble polymer has a mass average MW ranging from about 10,000 daltons to about 50,000 daltons. In some embodiments, the water-soluble polymer has a mass average MW of about 10,000 daltons. In some embodiments, the water-soluble polymer has a mass average MW of about 40,000 daltons. In some embodiments, the water-soluble polymer has a mass average MW of about 50,000 daltons.

[0045] In some embodiments, the water-soluble polymer is pol oxamer 188 or pol oxamer 407. In some embodiments, the PVA is PVA (mass average MW about 9,000 to about 10,000) or PVA (MW about 31,000 to about 50,000). In some embodiments, the cellulose polymer is hydroxypropyl methylcellulose (HPMC) or carboxymethylcellulose (CMC). In some embodiments, the PVP is PVP (mass average MW 40,000). In some embodiments, the one or more water-soluble polymers is PVP, pol oxamer 188, pol oxamer 407, PEG, HPMC, CMC, or any combination thereof. In some embodiments, the one or more water-soluble polymers is PVA (MW 10,000), PVA (mass average MW 50,000), pol oxamer 188, or pol oxamer 407. In some embodiments, the one or more water-soluble polymers is PVA (mass average MW 10,000) or pol oxamer 407. In some embodiments, the one or more water-soluble polymers is poloxamer 407.

[0046] In some embodiments, the one or more water-soluble polymers has a concentration in the nanocomposite ranging from about 5% w / w to about 25% w / w, e.g., about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, about 10% w / w, about 11% w / w, about 12% w / w, about 13% w / w, about 14% w / w, about 15% w / w, about 16% w / w, about 1% w / w, about 18% w / w, about 19% w / w, about 20% w / w, about 21% w / w, about 22% w / w, about 23% w / w, about 24% w / w or about 25% w / w, including all ranges and values therebetween. In some embodiments, the one or more water-soluble polymers has a concentration in the nanocomposite ranging from about 5% w / w to about 20% w / w, about 5% w / w to about 15% w / w, about 5% w / w to about 10% w / w, about 10% w / w to about 25% w / w, about 10% w / w to about 20% w / w, or about 10% w / w to about 15%. In some embodiments, the one or more water-soluble polymers has a concentration in the nanocomposite ranging from about 5% w / w to about 15% w / w.

[0047] In some embodiments, the ratio of the hydrophobic API to the one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is from about 5: 1 to about 15: 1 by weight, e.g, about 6: 1 by weight, about 7: 1 by weight, about 8: 1 by weight, about 9: 1 by weight, about 10: 1 by weight, about 11 : 1 by weight, about 12: 1 by weight, about 13: 1Attorney Docket No.: INLA-OOl / OIWO 353562-2002 by weight, about 14: 1 by weight, or about 15: 1 by weight, including all ranges and values therebetween. In some embodiments, the ratio of hydrophobic API to the one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is about 7: 1 by weight. In some embodiments, the ratio of hydrophobic API to the one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is about 8: 1 by weight. In some embodiments, the ratio of hydrophobic API to the one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is about 9: 1 by weight. In some embodiments, the ratio of hydrophobic API to the one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is about 10: 1 by weight. In some embodiments, the ratio of hydrophobic API to the one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is about 11 : 1 by weight.Nanosuspensions of the Invention

[0048] The present disclosure also provides an aqueous nanosuspension comprising a plurality of drug-containing nanocomposites, each drug-containing nanocomposite comprising: a) a hydrophobic active pharmaceutical ingredient (API) disclosed herein; and b) one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers disclosed herein, wherein the hydrophobic API has: i) a molecular mass of at least about 500 g / mol; and ii) a water solubility of less than about 0.1 mg / mL; and wherein the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm as determined by dynamic light scattering (DLS).

[0049] In some embodiments, the hydrophobic API disclosed herein is present in the nanosuspension at a concentration of about 0.1 mg / mL to about 10 mg / mL, e.g., about 0.1 mg / mL, about 0.25 mg / mL, about 0.5 mg / mL, about 0.75 mg / mL, about 1 mg / mL, about 1.5 mg / mL, about 2 mg / mL, about 2.5 mg / mL, about 3 mg / mL, about 3.5 mg / mL, about 4 mg / mL, about 4.5 mg / mL, about 5 mg / mL, about 5.5 mg / mL, about 6 mg / mL, about 6.5 mg / mL, about 7 mg / mL, about 7.5 mg / mL, about 8 mg / mL, about 8.5 mg / mL, about 9 mg / mL, or about 9.5 mg / mL, or about 10 mg / mL, including all ranges and values therebetween. In some embodiments, the hydrophobic API in the nanosuspension has a concentration of about 0.5 mg / mL to about 5 mg / mL. In some embodiments, the hydrophobic active agent in the nanosuspension has a concentration of about 1 mg / mL to about 5 mg / mL. In some embodiments, the hydrophobic active agent in the nanosuspension has a concentration of aboutAttorney Docket No.: INLA-OOl / OIWO 353562-20022 mg / mL to about 5 mg / mL. In some embodiments, the hydrophobic active agent in the nanosuspension has a concentration of about 3 mg / mL to about 5 mg / mL.

[0050] In some embodiments, the one or more water-soluble surfactants and / or the one or more water-soluble polymer are present in the nanosuspension at a combined concentration of about 0.05 mg / mL to about 0.75 mg / mL, e.g., about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.55 mg / mL, about 0.6 mg / mL, about 0.65 mg / mL, about 0.7 mg / mL, or about 0.75 mg / mL. In some embodiments, the one or more surfactants and / or the one or more water-soluble polymer are present in the nanosuspension at a combined concentration of about 0.1 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants and / or the one or more water-soluble polymers are present in the nanosuspension at a combined concentration of about 0.2 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants and / or the one or more water-soluble polymers are present in the nanosuspension at a combined concentration of about 0.25 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants and / or the one or more water-soluble polymers are present in the nanosuspension at a combined concentration of about 0.3 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants and / or the one or more water- soluble polymers are present in the nanosuspension at a combined concentration of about 0.5 mg / mL.

[0051] In some embodiments, the one or more surfactants has a total concentration in the nanosuspension of about 0.05 mg / mL to about 0.75 mg / mL, e.g., about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.55 mg / mL, about 0.6 mg / mL, about 0.65 mg / mL, about 0.7 mg / mL, or about 0.75 mg / mL. In some embodiments, the one or more surfactants has a total concentration in the nanosuspension of about 0.05 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants has a total concentration in the nanosuspension of about 0.1 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants has a total concentration in the nanosuspension of about 0.15 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants has a total concentration in the nanosuspension of about 0.2 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants has a total concentration in the nanosuspension of about 0.25 mg / mL to about 0.5 mg / mL. In some embodiments, the one or more surfactants has a total concentration in the nanosuspension of about 0.3 mg / mL to about 0.5 mg / mL. In some embodiments, the one orAttorney Docket No.: INLA-OOl / OIWO 353562-2002 more surfactants and / or the one or more water-soluble polymers are present in the nanosuspension at a combined concentration of about 0.5 mg / mL.

[0052] In some embodiments, the one or more water-soluble polymers has a total concentration in the nanosuspension of about 0.05 mg / mL to about 0.75 mg / mL, e.g., about 0.05 mg / mL, about 0.1 mg / mL, about 0.15 mg / mL, about 0.2 mg / mL, about 0.25 mg / mL, about 0.3 mg / mL, about 0.35 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, about 0.55 mg / mL, about 0.6 mg / mL, about 0.65 mg / mL, about 0.7 mg / mL, or about 0.75 mg / mL. In some embodiments, the one or more water-soluble polymers has a total concentration in the nanosuspension of about 0.1 mg / mL to about 0.45 mg / mL. In some embodiments, the one or more water-soluble polymers has a total concentration in the nanosuspension of about 0.15 mg / mL to about 0.45 mg / mL. In some embodiments, the one or more water-soluble polymers has a total concentration in the nanosuspension of about 0.2 mg / mL to about 0.45 mg / mL. In some embodiments, the one or more water-soluble polymers has a total concentration in the nanosuspension of about 0.25 mg / mL to about 0.45 mg / mL. In some embodiments, the one or more water-soluble polymers has a total concentration in the nanosuspension of about 0.3 mg / mL to about 0.45 mg / mL. In some embodiments, the one or more water-soluble polymers and / or the one or more water- soluble polymers are present in the nanosuspension at a combined concentration of about 0.45 mg / mL.

[0053] In some embodiments, the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm, e.g., about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 125 nm, about 150 nm, about 175 nm, about 200 nm, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, about 400 nm, about 425 nm, about 450 nm, about 475 nm, about 500 nm, about 525 nm, about 550 nm, about 575 nm, about 600 nm, about 625 nm, about 650 nm, about 675 nm, about 700 nm, about 725 nm, about 750 nm, as determined by DLS, including all ranges and values therebetween. In some embodiments, the nanocomposites in the nanosuspension have an average particle size ranging from about 75 nm to about 500 nm, e.g., about 75 nm, about 80 nm, about 85 nm, about 90 nm, about 95 nm, about 100 nm, about 125 nm, about 150 nm, about 175 nm, about 200 nm, about 225 nm, about 250 nm, about 275 nm, about 300 nm, about 325 nm, about 350 nm, about 375 nm, about 400 nm, about 425 nm, about 450 nm, about 475 nm, or about 500 nm, as determined by DLS, including all ranges and values therebetween. In some embodiments, the nanocomposites in the nanosuspension have an average particle size ranging from about 75 nm to about 350 nm, about 75 nm to about 300 nm, about 75 nm toAttorney Docket No.: INLA-OOl / OIWO 353562-2002 about 250, or about 75 nm to about 200 nm. In some embodiments, the nanocomposites in the nanosuspension have an average particle size ranging from about 100 nm to about 500 nm, about 100 nm to about 400, about 100 nm to about 300, about 100 nm to about 250 nm, or about 100 nm to about 200 nm. In some embodiments, the nanocomposites in the nanosuspension have an average particle size ranging from about 100 nm to about 200 nm. In some embodiments, the nanocomposites in the nanosuspension have an average particle size ranging from about 100 nm to about 150 nm.

[0054] The homogeneity of nanocomposite particle size in the nanosuspension can be characterized by determining a poly dispersity index (PDI) using DLS or other method known in the art. In some embodiments, the PDI of the nanocomposites in the nanosuspension, as measured by DLS, is from about 0.05 to about 0.3, e.g., about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, or about 0.5, as determined by DLS, including all ranges and values therebetween. In some embodiments, the PDI of the nanocomposites in the nanosuspension is from about 0.05 to about 0.15. In some embodiments, the PDI of the nanocomposites in the nanosuspension is from about 0.05 to about 0.10.

[0055] The percentage of hydrophobic API entrapped by the nanocomposite is measured by its encapsulation efficiency. In some embodiments, the nanocomposite, isolated or in the nanosuspension, has a drug encapsulation efficiency of about 80% to about 100%, e.g., about 80%, about 85%, about 90%, about 95%, or about 100%, including all ranges and values therebetween. In some embodiments, the nanocomposite has a drug encapsulation efficiency of about 90% to about 100%. In some embodiments, the nanocomposite has a drug encapsulation efficiency of about 90% to about 99%. In some embodiments, the nanocomposite has a drug encapsulation efficiency of about 90% to about 95%. In some embodiments, the nanocomposite has a drug encapsulation efficiency of about 95% to about 100%. In some embodiments, the nanocomposite has a drug encapsulation efficiency of about 95% to about 99%.

[0056] The nanocomposite suspensions of the present disclosure provide an apparent water solubility of hydrophobic API that is higher than the thermodynamic water solubility of the API. In some embodiments, the hydrophobic API in the nanocomposites has an apparent water solubility, as measured by HPLC, that is at least 200 pg / mL, at least 300 pg / mL, at least 400 pg / mL, at least 500 pg / mL, at least 600 pg / mL, at least 700 pg / mL, at least 800 pg / mL, at least 900 pg / mL, or at least 1000 pg / mL higher than the thermodynamic water solubility of the hydrophobic API.Attorney Docket No.: INLA-OOl / OIWO 353562-2002

[0057] In some embodiments, the hydrophobic API in the nanocomposites has an apparent water solubility that is about 0.5-10 mg / mL higher than the thermodynamic water solubility of the free hydrophobic API.

[0058] In some embodiments, the hydrophobic API in the disclosed nanocomposites has an apparent water solubility that is at least 10-fold, at least 20-fold, at least 30-fold, at least 40- fold, at least 50-fold, at least 60-fold, at least 70-fold, at least 80-fold, at least 90-fold, at least 100-fold, at least 150-fold, at least 200-fold, at least 250-fold, at least 300-fold, at last 350- fold, at least 400-fold, at least 450-fold, at least 500-fold, at least 600-fold, at least 700-fold, at least 800-fold, at least 900-fold, at least 1000-fold, at least 1250-fold at least 1500-fold, at least 1750-fold, at least 2000-fold, at least 2500-fold, at least 3000-fold, at least 3500-fold, at least 3750-fold, or at least 4000-fold higher than the thermodynamic water solubility of the free hydrophobic API.

[0059] In some embodiments, the hydrophobic API in the disclosed nanocomposites has an apparent water solubility that is at least 10%, at least 25%, at least 50%, at least 75%, at least 100%, at least 125%, at least 150%, at least 175%, at least 200%, at least 225%, at least 250%, at least 275%, at least 300%, at least 325%, at least 350%, at least 375%, at least 400%, at least 225%, at least 250%, at least 275%, at least 300%, at least 325%, at least 350%, at least 375%, at least 400%, at least 425%, at least 450%, at least 475%, at least 500%, at least 600%, at least 700%, at least 800%, at least 900%, or at least 1000% higher than the thermodynamic water solubility of the free hydrophobic API.

[0060] In some embodiments, the hydrophobic API in the disclosed nanocomposites has an apparent water solubility that is about 50% to about 500% higher than the thermodynamic water solubility of the free hydrophobic API. In some embodiments, the hydrophobic API in the disclosed nanocomposites has an apparent water solubility that is about 100% to about 500%, about 150% to about 500%, about 200% to about 500%, about 100% to about 400%, about 150% to about 400%, or about 200% to about 400%, higher than the thermodynamic water solubility of the free hydrophobic API.

[0061] In some embodiments, the hydrophobic API in the disclosed nanocomposites has an apparent water solubility that is about 10%, about 25%, about 50%, about 75%, about 100%, about 125%, about 150%, about 175%, about 200%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 225%, about 250%, about 275%, about 300%, about 325%, about 350%, about 375%, about 400%, about 425%,Attorney Docket No.: INLA-OOl / OIWO 353562-2002 about 450%, about 475%, or about 500% higher than the thermodynamic water solubility of the free hydrophobic API.Lyophilized Nanocomposites of the Invention

[0062] The present disclosure further provides a lyophilized solid (e.g., powder) comprising (1) a plurality of drug-containing nanocomposites, each drug-containing nanocomposite comprising: a) a hydrophobic active pharmaceutical ingredient (API) disclosed herein; and b) one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers disclosed herein, wherein the hydrophobic API has i) a molecular mass of at least about 500 g / mol; and ii) a thermodynamic water solubility of less than or equal to 0.1 mg / mL; and wherein the nanocomposites have an average particle size ranging from about 75 nm to about 750 nm as determined by dynamic light scattering (DLS); and (2) a cryoprotectant.

[0063] Without being bound by any particular theory, lyophilization of the nanosuspension is believed to prevent nanosized amorphous drug particles from converting into their more thermodynamically stable crystalline forms by inhibiting nucleation and / or growth, thus maintaining the amorphous properties of the API in the nanocomposite that improve the apparent aqueous solubility of the hydrophobic API. The lyophilized nanocomposite can then be reintroduced to water, where they re-disperse to form a nanosuspension of amorphous nanocomposites.

[0064] In some embodiments, the cryoprotectant is an amino acid, sugar, or derivative thereof. In some embodiments, the cryoprotectant is trehalose, sucrose, mannitol, sorbitol, or proline. In some embodiments, the cryoprotectant is trehalose, mannitol, or sorbitol. In some embodiments, the cryoprotectant is trehalose.

[0065] In some embodiments, the cryoprotectant is present in an amount ranging from about 1% w / v to about 30% w / v, e.g., about 1%, w / v, about 2%, w / v, about 3%, w / v, about 4%, w / v, about 5%, w / v, about 6%, w / v, about 7%, w / v, about 8%, w / v, about 9%, w / v, about 10%, w / v, about 12.%, w / v, about 15%, w / v, about 17.5%, w / v, about 20%, w / v, about 22.5%, w / v, about 25%, w / v, about 27.5%, w / v, or about 30%, w / v, including all ranges and values therebetween. In some embodiments, the cryoprotectant is present in an amount ranging from about 10% w / v to about 30% w / v. In some embodiments, the cryoprotectant is present in an amount ranging from about 15% w / v to about 30% w / v. In some embodiments, the cryoprotectant is present in an amount ranging from about 20% w / v to about 30% w / v. In some embodiments, the cryoprotectant is present in an amount ranging from about 20% w / v to about 25% w / v.Attorney Docket No.: INLA-OOl / OIWO 353562-2002Methods of Preparation

[0066] The present invention provides methods for preparing the nanocomposites and aqueous nanosuspensions disclosed herein, the methods comprising: (a) adding a cryoprotectant to the aqueous nanosuspension disclosed herein; (b) freezing the nanosuspension of step (a); and (c) lyophilizing the frozen nanosuspension for a period sufficient to obtain a powder.

[0067] In some embodiments, the cryoprotectant is a sugar, an amino acid, or derivative thereof. In some embodiments, the cryoprotectant is trehalose, mannitol, sorbitol, sucrose, proline, or any combination thereof. In some embodiments, the cryoprotectant is trehalose, mannitol, sorbitol, or any combination thereof.

[0068] In some embodiments, the cryoprotectant is added in an amount ranging from about 10% w / v to about 30% w / v.Methods of Treatment

[0069] The present disclosure also provides methods of treating diseases using the pharmaceutical compositions disclosed herein, e.g., nanocomposites, nanosuspensions thereof, or lyophilized powders thereof.

[0070] In some embodiments, the present disclosure provides methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0071] In some embodiments, the present disclosure provides methods of treating an autoimmune disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0072] In some embodiments, the present disclosure provides methods of treating an inflammatory disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.

[0073] In some embodiments, the present disclosure provides methods of treating a psychological condition or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition disclosed herein.EXAMPLES

[0074] General Methods

[0075] Reagents and solvents were purchased reagent-grade and used without further purification.Attorney Docket No.: INLA-001 / 01WO 353562-2002

[0076] HPLC method for determining apparent water solubility:• Samples were filtered through a 0.22 um filter membrane.• Samples were diluted ~ 10 - 20 times in ethanol (note: the dilution factor can be modified based on the estimated amount of drug contained in each sample).• Each sample was vortexed and subjected to the following HPLC conditions: a. Column: Agilent Eclipse XDB-C 18 b. Mobile phase i. A: DI water (40%) ii. B: acetonitrile (60%) c. Flow rate: 1.0 mL / min d. Run time: 8 min e. Retention time: 6.1 min f. Column Temperature: 45 °C g. UV: 278 nm h. Injection volume: 10 pL

[0077] Example 1. Preparation and Evaluation of Drug-Containing Nanocomposites and Aqueous Nanosuspensions

[0078] A stock solution of hydrophobic API in ethanol (10 - 20 mg / mL) was prepared. Stock solutions of a series of excipient solutions (Table 1) were prepared at a concentration of 5 mg / mL using stirring, heating, and / or sonication to ensure that solute was dissolved (PVA 50 / 186k dissolved at ~ 50 - 60 °C under stirring conditions; polysorbate 60 (Tween® 60) was heated to its melting point ~ 45-50 °C). Working excipient solutions were prepared from the 5 mg / mL stock solutions, such that the total concentration of excipient in the working solutions was 0.5 mg / mL. The working excipient solutions were then stirred at room temperature at a speed of about 1000 rpm and the stock ethanolic solution of hydrophobic API (10-100 pL) was rapidly added below the meniscus, which resulted in antisolvent precipitation and formation of nanoparticles (note: the volume of the excipient solution varied from 1900-1990 pL, such that the total volume of solution after antisolvent precipitation was equal to 2000 pL). Particle size and polydispersity index of the nanocomposites in the suspension were determined by dynamic light scattering and apparent water solubility was measured by HPLC.Attorney Docket No.: INLA-001 / 01WO 353562-2002Table 1. Table of excipients used in screening studies.

[0079] As shown in Table 2 (below), a total over 60 experiments was performed to prepare variety of nanocomposites comprising rapamycin and different excipient combinations. For successful experiments, the size of the resultant particles varied from 750 nm to 95 nm, and the resulting apparent water solubility (concentration of final solution measured by HPLC; see method above) ranged from about 1000 ug / mL to 10 ug / mL. Both the size and solubility enhancements were influenced by the excipients chosen for the experiments. In this study, the largest increases in apparent solubility (i.e., values > 500 ug / mL) were observed in nanocomposites that included sodium dodecyl sulfate either alone, or in combination with at least one water soluble polymer (polyvinylpyrrolidone, PVP; polyvinyl alcohol, PVA; polyethylene glycol, PEG) and / or a second surfactant (e.g., polysorbate 60).ble 2. Properties of Nanocomposites from Screening Study.Attorney Docket No.: INLA-001 / 01WO 353562-2002

[0080] Formulations F30 and F50 were selected for development into concentrated nanosuspensions to examine if further increases in rapamycin solubility could be achieved.

[0081] Preparation of Concentrated Nanosuspensions (NS)

[0082] To prepare a concentrated NS of rapamycin, multiple 2 mL batches were prepared as described above. This was done with either 5 X 2 mL batch (5X) or 10 X 2 mL batch (10X) scale. The 2 mL-solutions were then combined and concentrated via tangential flow (mPES- P / 100 kD filter), and the resulting solution (10 - 20 mL) was concentrated to near the initial starting volume (2 - 4 mL). Following concentration, each sample was again diluted to the original starting volume (10 - 20 mL) by the addition of deionized water, and again concentrated to the lower volume (2 - 4 mL). This step was repeated three times to purify the NCs and to remove any free excipient / drug present following nanoprecipitation. The apparent solubility of the NS was then determined via HPLC (see above method), and the size and poly dispersity index was determined via dynamic light scattering.

[0083] Results: through the preparation and concentration of multiple 2 mL batches of NCs the solubility of rapamycin was further improved (Tables 3A-3C, below). This additional increase in solubility did not impact the particle size or poly dispersity of NCs in the concentrated suspensions. A comparison of the apparent solubility of free rapamycin, F50, F50 (5X), and F50 (10X) in deionized water is provided in Fig. 1A and Fig. IB, which shows the observed increase in apparent solubility of rapamycin afforded by F50 nanocomposite formulation.Attorney Docket No.: INLA-OOl / OIWO 353562-2002Table 3A. Properties of F50 (5X) Nanocomposites Before and After Scale-Up.Table 3B. Properties of F50 (10X) Nanocomposites Before and After Scale-Up.Attorney Docket No.: INLA-001 / 01WO 353562-2002Table 3C. Properties of F30 (10X) Nanocomposites Before and After Scale-Up.

[0084] In summary, these results demonstrate that NC formulations of rapamycin can increase the apparent water solubility >300-fold, compared to the 2.6 pg / mL water solubility of free rapamycin reported in the literature (P. Simamora, et al. “Solubilization of rapamycin” Ini. J. of Pharmaceutics 213(2001), 25-29). The preparation of multiple NC batches and processing into concentrated nanosuspensions of rapamycin (via tangential flow filtration) results in a 379- fold increase in apparent water solubility for F50, a 2379-fold increase in apparent water solubility for F50 (5X), and a 2771-fold increase in apparent water solubility for F50 (10X) (Fig. 1A and Fig. IB).

[0085] The above excipient screening approach was repeated for other hydrophobic APIs including everolimus, docetaxel, paclitaxel, clozapine, and cyclosporin to identify NCs that provide an increase in the apparent aqueous solubility of the drug. Table 4, below, provides representative formulations for each of the six hydrophobic drugs with > 90% drug content and< 300 nm particle size.

[0086] A graphical representation of the apparent increase in aqueous solubility afforded by the technology for each of the drug-containing nanocomposites is provided in Fig. 2. In this study, 1 mg / mL is the maximum possible drug concentration and this level of solubility isAttorney Docket No.: INLA-001 / 01WO 353562-2002 achieved by each of the drug-containing NCs. For comparison, the water solubility of free drug reported in the literature is provided (Knox C, Wilson M, Klinger CM, et al. DrugBank 6.0: the DrugBank Knowledgebase for 2024. Nucleic Acids Res. 2024 Jan 5;52(D1):D1265- D1275. doi: 10.1093 / nar / gkad976).

[0087] In view of the results in Fig. 2, it can be seen that the formulation approach disclosed herein is widely applicable to a variety of different drugs.Table 4. Representative Optimized Nanosuspension Formulations for Six Hydrophobic APIs.Attorney Docket No.: INLA-OOl / OIWO 353562-2002

[0088] Example 2. Concentration and Lyophilization of Rapamycin- and Everolimus- Containing Nanocomposites

[0089] Following the screening of the six drugs and the identification of a series of formulation compositions that stabilized NCs of each at an apparent solubility of 1 mg / mL, additional studies were conducted on selected rapamycin and everolimus NC formulations to demonstrate that the apparent solubility afforded by these formulations can be further enhanced by scale-up and concentration via tangential flow filtration.

[0090] Scale-up and concentration of Nanosuspensions via tangential flow filtration (TTF)

[0091] To prepare concentrated nanosuspensions of drug, multiple 2 mL batches (1 mg / mL drug) were prepared as described above. These 2 mL solutions were then combined and the resulting solution (10-20 mL) was then concentrated to a fraction of this volume (2-4 mL) via tangential flow filtration (mPES-P / 100 kD filter). Following concentration, each sample was then again diluted to the original starting volume (10-20 mL) by the addition of deionized water, and again concentrated to the lower volume (2-4 mL). This step was repeated three times to purify the NC’s and to remove any free excipient / drug present following nanoprecipitation. Following this step, the apparent solubility of the NCs was determined via HPLC, and the size and poly dispersity index was determined via dynamic light scattering.

[0092] For this study, the NC formulations for rapamycin and everolimus were coded as rapa_F50 and ever_F6, respectively. The composition of rapa_F50 and ever_F6 from the NC screening protocol are illustrated in Table 5.Table 5. Compositions of Concentrated Nanosuspensions Comprising Rapamycin- and Everolimus-Containing NCs.Attorney Docket No.: INLA-OOl / OIWO 353562-2002

[0093] It was considered that the actual w / w% of drug within the NCs would be higher than the theoretic values reported in Table 5, as not all of the excipients would be incorporated into the NCs during nanoprecipitation, and the resulting excess excipients would be removed during TTF. To investigate this possibility, the excipient composition of concentrated rapa_F50 was determined via evaporative light scattering (ELS) detection to quantify excipient levels following purification (i.e., repeated washing with DI water and TTF).

[0094] Excipient quantification was conducted using an Agilent 1260 Infinity II HPLC system (Agilent Technologies, Santa Clara, CA, USA) coupled with an evaporative light-scattering detector (ELSD). The assay was calibrated using SDS, PVA, and P407 diluted in water over a broad range of concentrations (1 to 100 ug / mL). The excipients evaluated were Sodium Dodecyl Sulfate (SDS), Poly(vinyl alcohol) with a molecular weight of 50,000 (PVA 50k), and Poloxamer 407 (P407). Chromatographic separation was conducted using an Agilent ELSD 1260 system equipped with an Acclaim Surfactant Plus 5 pm column (4.6 x 150 mm). The mobile phase consisted of two components: A was 10 mM ammonium acetate at pH 5.2 and B was acetonitrile. A gradient elution was applied as follows: initial conditions of 80% A and 20% B were held for 1.1 minutes, changed to 32% A and 68% B at 2.5 minutes, followed by a wash with 100% B from 2.6 to 6.5 minutes. Conditions reverted to initial settings at 6.6 minutes and maintained until 9 minutes. The flow rate was constant at 0.8 mL / min throughout the 9-minute run. Instrument settings included an evaporator temperature of 70°C, nebulizer temperature of 40°C, gas flow rate of 1.60 SLM, and a column temperature of 30°C. The injection volume was set at 20 pL. Sample preparation involved dissolving each excipient at 5 mg / mL in water, followed by serial dilution to a concentration range of 1 pg / mL to 100 pg / mL.Attorney Docket No.: INLA-OOl / OIWO 353562-2002Retention times observed were 3.0 minutes for SDS, 4.7 minutes for PVA 50k, and 7.6 minutes for P407, indicating distinct separation characteristics for each compound under the employed conditions.

[0095] The exact composition of rapa_F50 (following nanoprecipitation, concentration, and tangential flow) is summarized in Table 6. Here it was observed that the actual drug loading level was 87.6 % w / w, which is about 20% higher than the theoretical value for the NCs.Table 6. Summary of the Final Composition of rapa_F50 NCs Determined Via Evaporative Light Scattering (ELS) And High Performance Liquid Chromatography (HPLC).1Data obtained for a 4.3 mg / mL nanosuspension of rapamycin (rapa_F50) that was scaled up and purified via tangential flow filtration (TFF). Excipient concentrations were measured to be 0.07 mg / mL, 0.48 mg / mL, and 0.06 mg / mL for SDS, PVP50k, and P407, respectively.

[0096] The resulting increase in apparent solubility afforded following tangential flow filtration (TFF) for rapa_F50 and ever_F6 is summarized in Fig. 3A and Fig. 3B. These results demonstrate that scale-up and purification of the NC via TTF resulted in a significant increase in apparent solubility compared to values obtained during screening. For example, the apparent solubility of rapamycin (rapa_F50) following TFF was ~4-fold higher than the solubility observed during screening and ~400-fold higher than the reported aqueous solubility of the drug. Similarly, the apparent solubility of everolimus (ever_F6) following TFF was ~5-fold higher than the solubility observed during screening and ~400-fold higher than the reported aqueous solubility of the drug.

[0097] It is understood that the same approach would be equally applicable to other hydrophobic APIs, including the four drugs included in NC screening.

[0098] Lyophilization to isolate NC in the solid stateAttorney Docket No.: INLA-001 / 01WO 353562-2002

[0099] It has been demonstrated that suspensions of NCs can be isolated via lyophilization in the presence of a cryoprotectant. Briefly, a solution of concentrated drug-containing NCs (~ 5 mg / mL) was supplemented with 20% trehalose, frozen in dry ice for 30 min and then lyophilized overnight. This lyophilization process enables the NCs to be frozen and reconstituted in MilliQ water, while preserving the nano properties of the NCs.

[0100] Table 7 illustrates the effects of lyophilization in the presence of various cryoprotectants on particle size and PDI for rapa_F50. As illustrated by the data, >20% trehalose afforded equivalent NC properties.Table 7. Effect of Cryoprotectant (CP)Type and Concentration on Properties of Lyophilized rapa_F50 NCs.1Results for size, PDI and concentration were obtained following lyophilization in the presence of cryoprotectant and reconstitution in the same volume of MilliQ water.

[0101] Example 3. Characterization of Hydrophobic Drug-Containing Nanocomposites

[0102] TEM was conducted on nanocomposite formulations of rapamycin after lyophilization(rapa_F50 and rapa_F50_Lyo).

[0103] Procedure: rapamycin NCs were deposited onto a Quantifoil Multi A holey carbon film on a 300 mesh copper grid, with controlled room temperature and humidity. Excess was removed before flash freezing the samples in liquid ethane at -183 °C. The samples wereAttorney Docket No.: INLA-OOl / OIWO 353562-2002 maintained below -170 °C using liquid nitrogen and imaged using a FEI Tecnai G2 F20 microscope equipped with a Gatan 4k CCD camera at 200 kV in bright field mode.

[0104] The TEM images in Fig. 4 reveal nanoparticles with a spherical morphology and a size that was in agreement with the DLS analysis. Zeta potential analysis of rapa_F50 and rapa_F50_Lyo revealed both NC’s to have a negative surface charge (-28.6 mV for rapa_F50 and -28.3 mV for rapa_F50_Lyo).

[0105] Rapamycin Solid Form Characterization in Nanocomposites

[0106] In order to characterize the solid form of the hydrophobic API within the nanoparticles, it was necessary to remove them from solution prior to lyophilization, as the lyophilization process could induce solid form transformations. Montmorillonite (MMT) was used to adsorb the NCs from a solution. This allowed for the isolation and filtration of MMT with the adsorbed nanoparticles. This method also helps preserve the original physical state of the drug that is encapsulated within the nanoparticles, which is needed for accurate characterization and ensuring that any observed properties are inherent to the NCs themselves, not artifacts created by external manipulation (e.g., heating or cooling processes).

[0107] The formulations (rapa_F50 and rapa_F50_lyo) were isolated from their respective nanosuspensions for solid state characterization of the drug via adsorption onto functionalized montmorillonite (MMT) clay particles. For this process (see Fig. 5), the surface of the MMT particles was functionalized using protamine sulfate salt (PA), a polycationic peptide. PA generates a positively-charged MMT surface that facilitates electrostatic interactions with the negatively-charged nanoparticles for NP adsorption and isolation. Briefly, 45 mg of MMT was suspended in 18 mL deionized water and supplemented with 5 mg PA / g MMT. The resulting suspension was stirred at 800 rpm overnight prior to the dropwise addition of concentrated NCs, both rapa_F50 and rapa_F50_lyo, respectively. The isolation process was adapted from: Kumar et al., Colloids and Surfaces B: Biointerfaces 175 (2019), 554-555. The process described in Fig. 5 enabled the successful isolation of rapamycin NCs at a drug loading level on MMT of 8.8% (w / w). The resulting nanocomposite-loaded MMT particles were then characterized by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) to determine the solid state of the rapamycin within the NCs.

[0108] As shown in Fig. 6, no characteristic diffraction peaks of rapamycin being observed in rapa_F50-MMT or rapa_F50-Lyo-MMT. DSC analysis resulted in no melting peak for rapamycin being detected in any of the rapa_F50-MMT rapa_F50-Lyo-MMT nanocomposite sample thermograms (Fig. 7). Taken together, these results indicate that the rapamycin loadedAttorney Docket No.: INLA-OOl / OIWO 353562-2002 within the NCs is amorphous when adsorbed onto the carrier particles, which suggests that the hydrophobic API nanoparticles resulting from the nanoprecipitation process are also amorphous.

[0109] Physical Stability of Rapamycin Nanocomposites

[0110] To quantify the physical stability of rapa_F50 NCs, batches of various concentrations were prepared and stored at room temperature in the presence of light for one month. In all cases the nanosuspensions were prepared fresh and purified via tangential flow prior to initiating the study. This ensured the removal of excess excipients from the solution. NC size and PDI were then periodically measured via DLS to determine the stability of the NCs (Fig. 8). Here it was observed that 5 mg / mL and 2.5 mg / mL nanosuspension of rapa_F50 precipitated within 2 weeks. Nanosuspensions made to a concentration of 1 mg / mL and 0.5 mg / mL rapa_F50 remained stable throughout the experiment. Advantageously, nanosuspensions of rapa_F50 (LYO-Recon; 5 mg / mL) that were lyophilized and stored in a solid state for the duration of the one month study could be successfully reconstituted at day 28. Thus, lyophilization of rapa_F50 enhances the shelf-life of the nanoparticles.

[0111] Example 4. Pharmacokinetics (PK) of Drug-Containing Nanocomposites

[0112] To evaluate PK, rapa_F50 NCs were administered to healthy (female) Sprague Dawley rats via oral gavage at a dose of 5 mg / kg. The results obtained were compared to rats dosed with a Phosal / Tween® 80 vehicle emulating the composition of Rapamune® Oral Solution.

[0113] The rapa_F50 and rapa_F50_lyoNCs demonstrated an improved plasma concentrationtime profile and PK parameters. The maximum plasma concentrations (Cmax) reached 85.86 ng / mL at 0.75 hours for rapa_F50 and 81.59 ng / mL at 0.50 hours for rapa_F50_lyo, which were significantly higher than 42.73 ng / mL at 1 hour for the Phosal / Tween® 80 vehicle. The area under the concentration-time curve (AUC) from 0-4 hours was -130 h. ng / mL for rapa_F50, -200 h. ng / mL for rapa_F50_lyo, and -80 h. ng / mL for Phosal / Tween® 80, respectively. Extended analysis up to 12 hours showed AUC values of -200 h. ng / mL, -400 h. ng / mL, and -150 h. ng / mL, respectively (Fig. 9).

[0114] Summary: the present disclosure provides a novel method to prepare and concentrate a drug nanocomposite formulation with - 90% drug content and < 200 nm particle size. Based on the data collected from screening six unique hydrophobic drugs, and other methods, a group of water-soluble excipients was identified that are generally applicable to the stabilization of NCs for hydrophobic drugs.Attorney Docket No.: INLA-OOl / OIWO 353562-2002

[0115] The disclosed NC formulations can significantly increase the apparent water solubility of hydrophobic APIs and also significantly improve oral bioavailability. These NCs can be lyophilized (in the presence of a cryoprotectant) and reconstituted in water without affecting their properties. The lyophilized NCs can be stored for prolonged periods of time, upon reconstitution. A selected nanocomposite formulation of rapamycin was administered to animals (female Sprague-Dawley rats) and results in improved pharmacokinetics compared to a liquid formulation of rapamycin, equivalent in composition to Rapamune® Oral Solution.

Claims

Attorney Docket No.: INLA-OOl / OIWO 353562-2002CLAIMSWhat is claimed is:

1. A plurality of drug-containing nanocomposites, each drug-containing nanocomposite comprising: a) a hydrophobic active pharmaceutical ingredient (API); and b) one or more water-soluble surfactants and / or one or more water-soluble polymers, wherein the hydrophobic API has: i) a molecular mass of at least about 500 g / mol; and ii) a thermodynamic water solubility of less than or equal to 0.2 mg / mL prior to incorporation into the drug-containing nanocomposite; and wherein the plurality of drug-containing nanocomposites has an average particle size ranging from about 75 nm to about 750 nm as determined by dynamic light scattering (DLS).

2. The plurality of drug-containing nanocomposites of claim 1, wherein the one or more water-soluble surfactants comprises an anionic surfactant, nonionic surfactant, or any combination thereof.

3. The plurality of drug-containing nanocomposites of claim 1 or 2, wherein the one or more water-soluble surfactants comprises an anionic surfactant.

4. The plurality of drug-containing nanocomposites of claim 2 or 3, wherein the anionic surfactant comprises a hydrocarbon tail comprising from 6 to 24 carbons.

5. The plurality of drug-containing nanocomposites of claim 4, wherein the hydrocarbon tail is saturated.

6. The plurality of drug-containing nanocomposites of any one of claims 2-5, wherein the anionic surfactant comprises a sulfate group.

7. The plurality of drug-containing nanocomposites of any one of claims 2-6, wherein the anionic sulfate is an alkyl sulfate or an alkyl ether sulfate (AES).Attorney Docket No.: INLA-001 / 01WO 353562-20028. The plurality of drug-containing nanocomposites of any one of claims 2-7, wherein the anionic surfactant is sodium dodecyl sulfate (SDS), sodium lauryl ether sulfate (SLES), sodium pareth sulfate, sodium tetradecyl sulfate (STS), or sodium myreth sulfate or any combination thereof.

9. The plurality of drug-containing nanocomposites of any one of claims 2-8, wherein the anionic surfactant is SDS.

10. The plurality of drug-containing nanocomposites of claim 1 or 2, wherein the one or more water-soluble surfactants comprises a nonionic surfactant.

11. The plurality of drug-containing nanocomposites of any one of claims 2 and 4-10, wherein the nonionic surfactant comprises a fatty acid ester and / or ethylene oxide groups.

12. The plurality of drug-containing nanocomposites of any one of claims 2 and 4-11, wherein the nonionic surfactant is a polysorbate (Tween®), a sorbitan ester (Span®), an ethoxylated castor oil, or a polyoxyethylene fatty ether (Brij®) or any combination thereof.

13. The plurality of drug-containing nanocomposites of any one of claims 2 and 4-12, wherein the nonionic surfactant is polysorbate 20, polysorbate 60, polysorbate 80, sorbitan monolaurate (Span® 20), sorbitan monopalmitate (Span® 40), sorbitan monostearate (Span® 60), sorbitan monooleate (Span® 80), PEG-40 castor oil, or any combination thereof.

14. The plurality of drug-containing nanocomposites of claim 1, wherein the one or more water-soluble surfactants is an alkyl sulfate, a polysorbate, or any combination thereof.

15. The plurality of drug-containing nanocomposites of claim 1, wherein the one or more water-soluble surfactants is SDS, STS, polysorbate 60, polysorbate 80, or any combination thereof.

16. The plurality of drug-containing nanocomposites of any one of claims 1-15, wherein the one or more water-soluble polymers comprises a poloxamer, polyethylene glycol (PEG),Attorney Docket No.: INLA-001 / 01WO 353562-2002 polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), a cellulose polymer, or any combination thereof.

17. The plurality of drug-containing nanocomposites of any one of claims 1-16, wherein the one or more water-soluble polymers comprises PVA, PVP, a poloxamer of Formula (I),wherein a ranges from about 30 to about 110 and b ranges from about 20 to about 60 , PEG, hydroxypropyl methylcellulose (HPMC), carboxymethylcellulose (CMC), or any combination thereof.

18. The plurality of drug-containing nanocomposites of any one of claims 1-17, wherein the one or more water-soluble polymers comprises PVA with a molecular weight (MW) ranging from about 7,000 to about 12,500, a poloxamer of Formula (I),wherein a ranges from about 90 to about 110 and b ranges from about 50 to about 60, or any combination thereof.

19. The plurality of drug-containing nanocomposites of any one of claims 1-18, wherein the one or more water-soluble polymers comprises PVA (MW of about 9,000 to about 10,000), pol oxamer 407, or any combination thereof.

20. The plurality of drug-containing nanocomposites of any one of claims 1-17, wherein the one or more water-soluble polymers comprises PVA, PVP, or any combination thereof.

21. The plurality of drug-containing nanocomposites of any one of claims 1-20, wherein the one or more water-soluble polymer has a mass average molecular weight (MW) ranging from about 5,000 daltons to about 200,000 daltons.Attorney Docket No.: INLA-001 / 01WO 353562-200222. The plurality of drug-containing nanocomposites of any one of claims 1-21, wherein the one or more water-soluble polymer has a mass average MW ranging from about 10,000 daltons to about 50,000 daltons.

23. The plurality of drug-containing nanocomposites of any one of claims 1-22, wherein the one or more water-soluble polymer comprise a poloxamer, and the poloxamer is pol oxamer 188 or poloxamer 407.

24. The plurality of drug-containing nanocomposites of any one of claims 1-23, wherein the hydrophobic API has a molecular mass ranging from about 500 g / mol to about 2000 g / mol.

25. The plurality of drug-containing nanocomposites of any one of claims 1-24, wherein the hydrophobic API is present in the drug-containing nanocomposites at a concentration ranging from about 70% to about 95% w / w.

26. The plurality of drug-containing nanocomposites of any one of claims 1-25, wherein the one or more surfactants is present in the drug-containing nanocomposites at a concentration ranging from about 0.5% to about 5% w / w.

27. The plurality of drug-containing nanocomposites of any one of claims 1-26, wherein the one or more water-soluble polymers is present in the drug-containing nanocomposites at a concentration ranging from about 5% to about 15% w / w.

28. The plurality of drug-containing nanocomposites of any one of claims 1-27, wherein the drug-containing nanocomposites have an average particle size ranging from about 75 nm to about 200 nm or from about 100 nm to about 150 nm.

29. The plurality of drug-containing nanocomposites of any one of claims 1-28, wherein the ratio of the hydrophobic API to the one or more water-soluble surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is from about 5: 1 to about 15: 1 by weight.Attorney Docket No.: INLA-001 / 01WO 353562-200230. The plurality of drug-containing nanocomposites of any one of claims 1-29, wherein the ratio of hydrophobic API to the one or more surfactants and / or one or more pharmaceutically acceptable water-soluble polymers is about 9: 1 by weight.

31. The plurality of drug-containing nanocomposites of any one of claims 1-30, wherein the hydrophobic API is a Biopharmaceutics Classification System (BCS) class II or class IV drug.

32. The plurality of drug-containing nanocomposites of any one of claims 1-30, wherein the hydrophobic API is rapamycin, everolimus, docetaxel, paclitaxel, clozapine, or cyclosporin.

33. An aqueous nanosuspension comprising the plurality of drug-containing nanocomposites of any one of claims 1-32.

34. The aqueous nanosuspension of claim 33, wherein the hydrophobic active API is present in the nanosuspension at a concentration of greater than or equal to about 0.5 mg / mL.

35. The aqueous nanosuspension of claim 33 or 34, wherein the hydrophobic active agent is present in the nanosuspension at a concentration of about 0.5 mg / mL to about 10 mg / mL.

36. The aqueous nanosuspension of any one of claims 33-35, wherein the one or more water-soluble surfactants and / or the one or more water-soluble polymers are present in the nanosuspension at a combined concentration of about 0.05 mg / mL to about 0.75 mg / mL.

37. The aqueous nanosuspension of any one of claims 33-36, wherein the one or more water-soluble surfactants and / or the one or more water-soluble polymers are present in the nanosuspension at a combined concentration of about 0.5 mg / mL.

38. The aqueous nanosuspension of any one of claims 33-37, wherein the one or more surfactants has a total concentration in the nanosuspension of about 0.05 mg / mL to about 0.5 mg / mL.Attorney Docket No.: INLA-001 / 01WO 353562-200239. The aqueous nanosuspension of any one of claims 33-38, wherein the one or more water-soluble polymer has a total concentration in the nanosuspension of about 0.1 mg / mL to about 0.45 mg / mL.

40. The aqueous nanosuspension of any one of claims 33-39, wherein the PDI of the nanocomposites is from about 0.05 to about 0.6, as determined by dynamic light scattering (DLS).

41. The aqueous nanosuspension of any one of claims 33-40, wherein the PDI of the nanocomposites is from about 0.05 to about 0.3, as determined by DLS.

42. The aqueous nanosuspension of any one of claims 33-41, wherein the PDI of the nanocomposites is from about 0.05 to about 0.15, as determined by DLS.

43. The aqueous nanosuspension of any one of claims 33-42, wherein the average particle size of the nanocomposites is from about 75 nm to about 200 nm.

44. The aqueous nanosuspension of any one of claims 33-43, wherein the average particle size of the nanocomposites is from about 100 nm to about 150 nm.

45. The aqueous nanosuspension of any one of claims 33-44, wherein the nanocomposites have an encapsulation efficiency of about 80-100%.

46. The drug-containing nanocomposite of any one of claims 1-32, or the aqueous nanosuspension of any one of claims 33-45, wherein the hydrophobic API in the drugcontaining nanocomposites has an apparent water solubility that is 100% to 1000% greater than the thermodynamic water solubility of the free hydrophobic API.

47. The drug-containing nanocomposite of any one of claims 1-32, or the aqueous nanosuspension of any one of claims 33-46, wherein the hydrophobic API in the nanocomposites has an apparent water solubility that is at least 200 pg / mL, at least 300 pg / mL, at least 400 pg / mL, at least 500 pg / mL, or at least 1000 pg / mL higher than theAttorney Docket No.: INLA-001 / 01WO 353562-2002 thermodynamic water solubility of the hydrophobic API prior to incorporation in the drugcontaining nanocomposites.

48. The drug-containing nanocomposite of any one of claims 1-32, or the aqueous nanosuspension of any one of claims 33-46, wherein the hydrophobic API in the drugcontaining nanocomposites has an apparent water solubility that is about 0.5-10 mg / mL higher than the thermodynamic water solubility of the free hydrophobic API.

49. A lyophilized powder comprising:(1) the plurality of the drug-containing nanocomposites of any one of claims 1-32; and(2) a cryoprotectant.

50. The lyophilized powder of claim 49, wherein the cryoprotectant is trehalose, mannitol, sorbitol, sucrose, or proline, or any combination thereof.

51. The lyophilized powder of claim 49 or 50, wherein the cryoprotectant is present in an amount ranging from about 10% w / v to about 30% w / v.

52. The lyophilized powder of any one of claims 49-51, wherein the drug-containing nanocomposites are stable for at least 25 days when stored at room temperature and in the presence of light.

53. The lyophilized powder of any one of claims 49-52, wherein after reconstitution in water, the average particle size of the nanocomposites ranges from about 125 nm to about 175 nm, as determined by DLS.

54. The lyophilized powder of any one of claims 49-53, wherein the average particle size of the nanocomposites after reconstitution in water ranges from about 140 nm to about 160 nm, as determined by DLS.Attorney Docket No.: INLA-001 / 01WO 353562-200255. The lyophilized powder of any one of claims 49-54, wherein the PDI of the nanocomposites after reconstitution in water is from about 0.05 to about 0.1, as determined by DLS.

56. A method of preparing a lyophilized powder comprising drug-containing nanocomposites, comprising:(a) adding a cryoprotectant to the aqueous nanosuspension of any one of claims 33- 48;(b) freezing the nanosuspension of step (a); and(c) lyophilizing the frozen nanosuspension of step (b) for a period sufficient to obtain a powder.

57. The method of claim 56, wherein the cryoprotectant is trehalose, mannitol, or sorbitol.

58. The method of claim 56 or 57, wherein the cryoprotectant is added in an amount ranging from about 10% w / v to about 30% w / v.

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