WO2022170398A1 - Formulations for improved bioavailability of fenretinide - Google Patents

Abstract

The technology relates to self-emulsifying compositions comprising fenretinide or a fenretinide analogue, a mixed medium- or long-chain glyceride, at least one surfactant and optionally an alcohol. The compositions provide improved in vitro solubility and in vivo plasma exposure of fenretinide and fenretinide analogues.

Description

FORMULATIONS FOR IMPROVED BIOAVAILABILITY OF FENRETINIDE

Technical Field

[001] The technology relates to self-emulsifying pharmaceutical compositions of fenretinide or analogues thereof that provide improved bioavailability of the fenretinide or analogue thereof.

Cross reference to related application

[002] This application claims the benefit of Australian Provisional Application No. 2021900342 filed 11 February 2021, the entire contents of which are incorporated by reference herein.

Background

[003] N-(4-hydroxyphenyl) retinamide (4-HPR) displays promising anti-flaviviral properties in vitro and in vivo and has an established safety record in adult and paediatric cancer patients. Fenretinide was initially developed as a less toxic and better tolerated derivative of retinoic acid and has been extensively studied because of its chemo- protective and anti tumor activities described when used on a variety of malignant cells, including non-small cell lung cancer, neuroblastoma, Kaposi's sarcoma, breast cancer and glioma.

[004] However, despite fenretinide's promising anticancer and anti-flaviviral activities its limited oral bioavailability, notably due to its poor water solubility, represents a significant challenge to clinical use.

[005] Fenretinide has been formulated in corn oil-containing soft-gelatin capsules, but such formulations have been shown to result in variable and low systemic exposures (i.e. poor bioavailability). Also, because of the poor solubility of fenretinide in corn oil compositions this requires the use of large dose volumes and consequently patient compliance is a concern, especially in pediatric subjects. Fenretinide has also been formulated in a lipid matrix, Lym-X-Sorb (LXS), administered as an oral powder delivered in non-milk fat-containing foods, as a slurry in non-milk fat-containing, or soy-based nutritional supplements. However, these formulations are associated with significant gastrointestinal side-effects, especially at higher doses as well as significant patient withdrawal due to the taste and texture of the formulations.

[006] The most commonly used clinical formulation of fenretinide is a lipid suspension composed of corn oil and polysorbate 80 surfactant. In patients, plasma levels of up to 12.9 mM were achieved at a dose of 4000 mg/m²/day, but patient compliance issues were reported due to the large dose volumes required. [007] Accordingly, there is a need for an optimized formulation of fenretinide with enhanced solubility and in vivo pharmacokinetic properties. The present inventors have developed a self-emulsifying lipid-based fenretinide formulation with improved in vitro solubility and in vivo plasma exposure.

Summary

[008] In a first aspect, there is provided a self-emulsifying composition comprising fenretinide or a fenretinide analogue, a mixed medium- or long-chain glyceride, and at least one surfactant. The composition may comprise an alcohol such as ethanol or diethylene glycol monoethyl ether (Transcutol®).

[009] The fenretinide analogue may be selected from the group comprising 4-oxo-N-(4- hydroxyphenyl)retinamide, N-(4-methoxyphenyl)retinamide (4-MPR), 4- hydroxybenzylretinone, 4-(retinamido)phenyl-C-glucuronide, 4-(retinamido)phenyl-C- glucoside, 4-(retinamido)benzyl-C-xyloside, 1-^-D-glucopyranosyl) retinamide, 1-(D- glucopyranosyluronosyl) retinamide, bexarotene, or a compound of Formula I:

wherein:

R is OH, COOH, CH₂OH, CH₂CH₂OH, or CH₂COOH; carbons a-d and f-i are optionally substituted with one or more groups selected from CH3, OH, COOH, (CH3)2 and CH2OH, or any combination thereof; and carbon e is optionally substituted with a C1-C3 alkyl group that is optionally substituted with CH3 and/or OH.

[010] In one embodiment, the composition comprises at least 45mg/g of the fenretinide or fenretinide analogue.

[011] In one embodiment, the medium or long-chain glyceride may comprise C6-C14 fatty acids and esters thereof, for example the medium or long-chain glyceride may be glyceryl caprylate/caprate, such as Capmul® MCM NF (National Formulary) or Capmul® MCM EP (European Pharmacopoeia).

[012] In an embodiment, the medium or long-chain glyceride comprises 32-52% monoglycerides, 40-55% diglycerides, 5-20% triglycerides, e.g. Maisine® CC. [013] In some embodiments, the composition comprises 35%-75% surfactant. The surfactant may be selected from Capryol 90, Lauroglycol 90, Kolliphor RH 40, Cremophor EL, Labrasol, Gelucire 44/14, Tween 85, Polysorbate 80 or any combination thereof.

[014] In one embodiment, the surfactant is Lauroglycol 90, Tween 85, or both.

[015] In one embodiment, the composition comprises: i. 15-60% medium- or long-chain glycerides; ii. 35-75% surfactant; iii. optionally 0.1%-30% alcohol; and iv. at least 45mg/g fenretinide or fenretinide analogue.

[016] For example, the composition may comprise 25% Maisine CC (32-52% monoglycerides, 40-55% diglycerides, 5-20% triglycerides), 25% Lauroglycol 90, 10% Ethanol, and 40% Tween 85, and at least 45mg/g fenretinide or fenretinide analogue.

[017] Alternatively, the composition may comprise 50% Maisine CC (32-52% monoglycerides, 40-55% diglycerides, 5-20% triglycerides), 10% Ethanol, 40% Tween 85, and at least 45mg/g fenretinide or fenretinide analogue.

[018] In some embodiments, the composition comprises a cytochrome P450 inhibitor. The cytochrome P450 inhibitor may be selected from 1-aminobenzotriazole (ABT), propyl gallate, fluvoxamine, clopidogrel, gemfibrzil, fluoxetine, paroxetine, clarithromycin, itraconazole, ciprofloxacin, enoxacin, ticlopidine, fluconazole, bupropion, quinidine, terbinafine, boceprevir, cobicistat, danoprevir, ritonavir, elvitegravir, grapefruit juice, indinavir, ketoconazole, lopinavir, paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir, telaprevir, tipranavir, telithromycin, troleandomycin, voriconazole, idelalisib, nefazodone, nelfinavir, quinidine, or any combination thereof.

[019] In one embodiment the composition provided increased bioavailability of the fenretinide or the fenretinide analogue compared to the bioavailability of the fenretinide or the fenretinide analogue in the absence of the mixed medium- or long-chain glyceride, or the at least one surfactant.

[020] In a second aspect, there is provided a dosage form comprising the composition of the first aspect. The dosage form may be formulated for oral administration, e.g. as a capsule, cachet, or liquid.

[021] In one embodiment, the dosage form is formulated for twice daily administration of the fenretinide or fenretinide analogue. [022] In a third aspect there is provided a method of increasing the bioavailability of fenretinide or a fenretinide analogue in a subject, the method comprising administering the composition of the first aspect or the dosage from of the second aspect to the subject.

[023] In one embodiment the administration of the composition or dosage form under a non-fasted condition provides an increase of the maximum plasma concentration (Cmax) and/or the extent of absorption (AUC) of the fenretinide or fenretinide analogue compared to the administration of fenretinide or fenretinide analogue in a corn oil formulation or an aqueous suspension.

[024] In one embodiment the bioavailability of the fenretinide or the fenretinide analogue is about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% 19%, or at least 20%, for example about 13%.

Definitions

[025] Throughout this specification, unless the context clearly requires otherwise, the word 'comprise', or variations such as 'comprises' or 'comprising', will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[026] Throughout this specification, the term 'consisting of means consisting only of.

[027] Throughout this specification, the term 'consisting essentially of means the inclusion of the stated element(s), integer(s) or step(s), but other element(s), integer(s) or step(s) that do not materially alter or contribute to the working of the invention may also be included.

[028] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present technology. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present technology as it existed before the priority date of each claim of this specification.

[029] Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the technology recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements.

[030] In the context of the present specification, the terms 'a' and 'an' are used to refer to one or more than one (i.e. at least one) of the grammatical object of the article. By way of example, reference to 'an element' means one element, or more than one element. [031] In the context of the present specification, the term 'about' means that reference to a figure or value is not to be taken as an absolute figure or value, but includes margins of variation above or below the figure or value in line with what a skilled person would understand according to the art, including within typical margins of error or instrument limitations. In other words, use of the term 'about' is understood to refer to a range or approximation that a person skilled in the art would consider to be equivalent to a recited value in the context of achieving the same function or result.

[032] The terms 'therapeutically effective amount' or 'pharmacologically effective amount' or 'effective amount' refer to an amount of an agent sufficient to produce a desired therapeutic or pharmacological effect in the subject being treated. The terms are synonymous and are intended to qualify the amount of each agent that will achieve the goal of improvement in disease severity and/or the frequency of incidence over treatment of each agent by itself, while preferably avoiding or minimising adverse side effects, including side effects typically associated with other therapies. Those skilled in the art can determine an effective dose using information and routine methods known in the art.

[033] Those skilled in the art will appreciate that the technology described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the technology includes all such variations and modifications. For the avoidance of doubt, the technology also includes all of the steps, features, and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps, features and compounds.

[034] In order that the present technology may be more clearly understood, preferred embodiments will be described with reference to the following drawings and examples.

Brief Description of the Drawings

[035] Figure 1. Drug distribution profiles after in vitro digestion of formulation candidates #23, #25, #31 and loaded at 13.4 ± 4.3 mg/g (target 11 mg/g), 5.2 ± 3.4 mg/g (target 11 mg/g), 152.7 ± 58.2 mg/g (target 116 mg/g) and 2.3 ± 0.3 mg/g (target 2 mg/g) respectively. ISM.

[036] Figure 2. In vivo exposure in mice to 4-HPR formulations. Mice were orally dosed with 20 mg/kg 4-HPR. Data represent mean plasma concentration vs time profiles (mean ± SEM, N=3).

[037] Figure 3. Plasma concentrations of 4-HPR following IV administration to male C57BI/6 mice with or without 50 mg/kg ABT b.i.d. via the oral route. [038] Figure 4. The role of CYP450 metabolism in the systemic clearance and oral bioavailability of 4-HPR in mice. A) Mice were orally dosed with 20 mg/kg 4-HPR, with and without 50mg/kg ABT. B) Mice were dosed IV at 2 mL/kg, with and without 50mg/kg ABT.

[039] Figure 5. Simulated exposure profiles in mice for twice-daily dosage of 4-HPR in the listed formulations.

Description of Embodiments

[040] As described herein, the present inventors have developed a self-emulsifying lipid- based fenretinide formulation with improved in vitro solubility and in vivo plasma exposure. Equilibrium solubility experiments were performed with various excipients, and based upon these results, optimised compositions were prepared and their solubility properties determined. An in vitro lipid digestion model was used to test the dispersion and digestion of candidate formulations before in vivo pharmacokinetic properties were measured in an animal model. Self-emulsifying lipid-based formulation approaches increased in vivo bioavailability by approximately 3-fold compared to a known corn oil clinical formulation, but surprisingly other exposure parameters remained similar across a number of formulations. This stimulated an evaluation of limits to bioavailability that revealed a significant enterocyte-based first pass liability, with extremely high plasma protein binding revealed as a contributing factor to lower than expected first pass hepatic clearance.

[041] The optimised compositions disclosed herein comprise fenretinide or a fenretinide analog, at least one surfactant, a mixed medium- or long-chain glyceride, and optionally an alcohol.

[042] The compositions described herein provides a number of advantages that include any one or more of the following:

• Increased fenretinide or fenretinide analogue solubility up to at least about 80mg/g compared to about 2mg/g for a conventional corn oil solution. This allows for reduced dose volumes and/or increasing maximum tolerated dose.

• Increased in vivo plasma exposure of fenretinide or a fenretinide analogue at the same dose as the existing corn oil/polysorbate formulation as described in US 4,665,098.

• Comparable in vivo plasma exposure to fenretinide or fenretinide analogue as compared to an 'efficacy formulation' which was shown to be effective in preventing Dengue Virus lethality in a mouse model. • Modelled pharmacokinetic properties indicate that that twice-daily dosage of the compositions disclosed herein achieve a three-fold greater plasma concentration of fenretinide at the same dose as the conventional corn oil formulation.

Fenretinide and fenretinide analogues

[043] In some embodiments, the compositions comprise fenretinide (all-trans-N-(4- hydroxyphenyl) retinamide is also known as 4-HPR, retinoic acid p-hydroxyanilide), has CAS registry number 65646-68-6 and has the following formula:

[044] In other embodiments, fenretinide analogs (including fenretinide metabolites) may also be used in the compositions of the present invention. As used herein, a 'fenretinide analogue' is a compound that shares chemical structural features with fenretinide and comprises one or more modifications thereto, and which exhibits similar biological activity as fenretinide (but may exhibit such activity to a different extent).

[045] Examples of fenretinide analogues that may be used in the compositions and dosage forms disclosed herein include, but are not limited to, 4-oxo-N-(4-hydroxyphenyl) retinamide (4-oxo-4-HPR), N-(4-methoxyphenyl)retinamide (4-MPR), 4- Hydroxybenzylretinone, C-glycoside and arylamide analogues of N-(4-hydroxyphenyl) retinamide-O-glucuronide, including but not limited to 4-(retinamido)phenyl-C-glucuronide, 4-(retinamido)phenyl-C-glucoside, 4-(retinamido)benzyl-C-xyloside; and retinoyl 3- glucuronide analogues such as, for example, 1-^-D-glucopyranosyl) retinamide, 1-(D- glucopyranosyluronosyl) retinamide and bexarotene.

[046] In one embodiment, the fenretinide analogue is a compound according to Formula I:

wherein:

R is OH, COOH, CH2OH, CH2CH2OH, or CH₂COOH; carbons a-d and f-i are optionally substituted with one or more groups selected from CH₃, OH, COOH, (CH₃)₂ and CH₂OH, or any combination thereof, and carbon e is optionally substituted with a C₁-C₃ alkyl group that is optionally substituted with CH₃ and/or OH. [047] In some embodiments, a salt, hydrate, solvate, tautomer or stereoisomer of fenretinide or the fenretinide analogue is used. For example, a potassium salt of fenretinide.

[048] In some embodiments, the composition comprises at least 4% by mass of the formulation (i.e. 40 mg/g) of fenretinide or fenretinide analogue. For example, the concentration of the fenretinide or fenretinide analogue can be 4%, 5%, 6%, 7%, 8%, or at least 9% by mass of the composition. That is, the fenretinide or fenretinide analogue can be present in the composition at a concentration of at least 40 mg/g, 50 mg/g, 60 mg/g,

70 mg/g, 80 mg/g, or higher.

Mixed medium or long-chain glyceride

[049] The compositions comprise a mixed medium or long-chain glyceride which include, but are not limited to fatty acids and esters thereof (e.g., C6-C18 fatty acids, C7-C12 fatty acids, Cs-Cio fatty acids, or Cs fatty acids, C10 fatty acids, Cn fatty acids, C12 fatty acids C13 fatty acids, C_M fatty acids, Cisfatty acids, Cie fatty acids, C17 fatty acids, or C18 fatty acids). Exemplary fatty acids include, but are not limited to, caprylic acid, capric acid, octanoic acid, decanoic acid, undecanoic acid, lauric acid, myristic acid, stearic acid, oleic acid, linoleic acid, and linolenic acid. In some embodiments, the fatty acids are saturated. In other embodiments, the fatty acids contain at least one double bond, and in certain embodiments contain 2, 3, or 4 double bonds. In one embodiment the linoleic acid is Masine.

[050] Suitable mixed medium or long-chain glycerides include partial triglycerides. Partial triglycerides are fatty acid mono-esters of glycerol, fatty acid di-esters of glycerol, and, in some embodiments, combinations of these mono- and diglycerides. Diglycerides can be esterified with the same or different fatty acids. Partial triglycerides are well known in the art and are widely commercially available. Commercially available examples of such a mixture of partial triglycerides are Capmul® MCM NF and Capmul® MCM EP.

[051] Other mixtures of medium- or long-chain glycerides are known in the art and include Imwitor® 988 (glyceryl mono-/di-caprylate), Imwitor® 742 (glyceryl mono-di- caprylate/caprate), Imwitor® 308 (glyceryl mono-caprylate), Imwitor® 191 (glyceryl mono stearate), Softigen® 701 (glyceryl mono-/di-ricinoleate), Capmul® MCM (glyceryl caprylate/caprate), Capmul® MCM(L) (liquid form of Capmul MCM), Capmul® GMO (glyceryl mono-oleate), Capmul® GDL (glyceryl dilaurate), Maisine® (glyceryl mono- linoleate), Peceol® (glyceryl mono-oleate), Myverol® 18-92 (distilled monoglycerides from sunflower oil) and Myverol® 18-06 (distilled monoglycerides from hydrogenated soyabean oil), Precirol® ATO 5 (glyceryl palmitostearate) and Gelucire® 39/01 (semi-synthetic glycerides, i.e., C12-18 mono-, di- and tri-glycerides). [052] Preferred mixtures are Maisine® CC or Capmul® MCM-EP.

[053] Maisine® CC comprises 32-52% monoglycerides, 40-55% diglycerides, 5-20% triglycerides. Maisine® CC is a limpid liquid at ambient temperature. Capmul® MCM-EP is glyceryl caprylate/caprate.

[054] In some embodiments, the composition comprises about 15% to about 60% by mass of the mixed medium or long-chain glyceride, for example about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% mixed medium or long-chain glyceride by mass of the composition.

Surfactant

[055] The compositions also include at least one surfactant.

[056] In one embodiment, the surfactant has a low hydrophilic-lipophilic balance (HLB) value, that is a HLB value that is less than 10. For example, the low HLB surfactant may be Capryol 90, or Lauroglycol 90.

[057] In another embodiment, the surfactant has a high hydrophilic-lipophilic balance (HLB) value, that is a HLB value that is greater than 10, typically, the high HLB value will not exceed 40. Surfactants having a high HLB value are hydrophilic and have a high solubility in water, Suitable high HLB surfactants may be selected from Kolliphor RH 40, Cremophor EL, Labrasol, Gelucire 44/14, Tween 85, and Polysorbate 80.

[058] In some embodiments, the compositions comprise a mixture of a low HLB and a high HLB surfactant. For example, either or both of Capryol 90 and Lauroglycol 90 may be combined with any one or more of Kolliphor RH 40, Cremophor EL, Labrasol, Gelucire 44/14, Tween 85, and Polysorbate 80, for example a combination of Lauroglycol 90 and Tween 85.

[059] In one embodiment, the combination of surfactants has a combined HLB value of about 12 to about 20, preferably about 14.

[060] The surfactant, or combination of surfactants, should be present at a concentration of at least 35% by weight of the composition. Useful surfactant concentrations range from about 35% to about 75% by weight, for example about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of the composition. Preferred total concentrations of the surfactants range from about 40% to about 65% and any value between 40% and 50%.

[061] In one embodiment, the composition comprises about 50% Tween 85, or about 25% Lauroglycol 90 and about 40% Tween 85. Alcohol

[062] The compositions optionally comprise an alcohol as a co-solvent. Suitable alcohols include methanol, ethanol, n-propanol, isopropanol, butanol, or a polyhydric alcohol. The polyhydric alcohol may be selected from the group consisting of erythritol, xylitol, adonitol, arabitol, mannitol, sorbitol, and dulcitol. In one embodiment, the alcohol is Transcutol® (diethylene glycol monoethyl ether (DEGEE)). The alcohol may be a mixture of ethanol and a polyhydric alcohol, preferably the alcohol is ethanol.

[063] The alcohol content of the composition may vary from about 5% to about 30% (vol/vol). For example, the alcohol content of the composition may be about 0.1%, 1%,

2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5%, 20%, 22.5%, 25%, 27.5% or about 30% (vol/vol).

[064] In one embodiment, the composition is a self-emulsifying composition comprising i. 15-60% medium- or long-chain glycerides, for example 25% or 50% Maisine CC; ii. 35-75% surfactant, for example 40% Tween 85, or a combination of Lauroglycol 90 and Tween 85 such as 25% Lauroglycol 90 and 40% Tween 85; and iii. optionally 0.1%-30% alcohol, for example 10% ethanol.

[065] In one embodiment, the composition is a self-emulsifying composition comprising 25% Maisine CC, 25% Lauroglycol 90, 10% Ethanol, and 40% Tween 85 (composition 25 in Table 2).

[066] In an alternative embodiment, the composition is a self-emulsifying composition comprising 50% Maisine CC, 10% Ethanol, 40% Tween 85 (composition 23 in Table 2).

[067] The fenretinide or an analogue thereof can be dissolved at up to at least 8% by mass of the formulation (i.e. at least 80 mg/g).

Solubility and stability

[068] As demonstrated herein, (see Examples 1 and 2) the compositions and dosage forms disclosed herein provide improved solubility of fenretinide and fenretinide analogues compared to that which would be predicted by additive solubility in the individual excipients which make up the composition.

[069] For example, as set out in Tables 1 and 2, the solubility of some exemplary compositions (compositions 11, 13, 19, 23, 25, 26) showed greater fenretinide solubility than predicted from the solubility in each component of the composition.

[070] In aqueous environments in vivo, lipids tend to be digested by enzymatic action and the solubility of compounds present in lipid formulations is reduced and compounds can precipitate when lipid formulations are dispersed in aqueous solutions. However, compositions 23 and 25 (Table 2) yielded significant quantities of soluble fenretinide after dispersion, and markedly lower precipitation was observed compared to the corn oil-based clinical formulation. Accordingly, in some embodiments the compositions are stable after aqueous dispersion.

[071] In some embodiments, the compositions retain at least 60% of the total fenretinide or fenretinide analogue in the oil and aqueous phase after dispersion in an aqueous solution. For example, the compositions retain at least 60%, 65%, 70%, 75%, or at least about 80% of the total fenretinide or fenretinide analogue in the oil and aqueous phase after dispersion in an aqueous solution.

Improved bioavailability

[072] Bioavailability refers to the fraction (%) of the fenretinide or fenretinide analogue that reaches the systemic circulation when a medication is administered via routes other than intravenously.

[073] As demonstrated herein, (see Example 4) the compositions and dosage forms disclosed herein provide improved bioavailability.

[074] In some embodiments, the increase in bioavailability attributable to the compositions can be determined by measuring total systemic fenretinide or fenretinide analogue concentrations after administration of the composition or dosage form. For example, oral administration of fenretinide in the corn oil formulation of Example 4 results in bioavailability of around 4% for fenretinide. In contrast, oral administration of a composition of the invention provides a bioavailability of around 13% for fenretinide.

[075] In some embodiments, the compositions disclosed herein, when administered orally, provide bioavailability of around 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% 19%, or at least 20% for fenretinide or a fenretinide analogue.

[076] In some embodiments, the increase in bioavailability is defined as an increase in the Area Under the Curve (AUC) compared to the corn oil formulation used in Example 4. AUC is the integrated measure of systemic drug concentrations over time in units of mass time/volume. The AUC from time zero (the time of dosing) to time infinity (when no drug remains in the body) following the administration of the composition or dosage form is a measure of the exposure of the subject to the fenretinide or fenretinide analogue. For instance, oral administration of 10 mg of fenretinide in the corn oil formulation may result in total plasma AUC of around 9 h*pM. In contrast, oral administration of a composition of the invention provides a plasma AUC of around 36 h*pM. That is, in some embodiments the compositions of the invention provide a 4-fold improvement in bioavailability of fenretinide or a fenretinide analogue. In other embodiments, the compositions of the invention provide a 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold or at least 10-fold increase in bioavailability of fenretinide or a fenretinide analogue compared to the corn oil formulation used in Example 4.

[077] In some embodiments, the bioavailability may be further improved by including in the composition an effective amount of a Cytochrome p450 inhibitor such as 1- aminobenzotriazole (ABT), propyl gallate, fluvoxamine, clopidogrel, gemfibrzil, fluoxetine, paroxetine, clarithromycin, itraconazole, ciprofloxacin, enoxacin, ticlopidine, fluconazole, bupropion, quinidine, terbinafine, boceprevir, cobicistat, danoprevir, ritonavir, elvitegravir, grapefruit juice, indinavir, ketoconazole, lopinavir, paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir, telaprevir, tipranavir, telithromycin, troleandomycin, voriconazole, idelalisib, nefazodone, nelfinavir, quinidine, or any combination thereof.

[078] In some embodiments, the increase in bioavailability attributable to the compositions does not involve changes or substantial changes in the average dose, dose volume or Tmax (time to maximum plasma concentration).

Dosage Forms

[079] The compositions described herein may be used to prepare a medicament, such as by formulation into dosage forms using techniques generally known in the art. A summary of such pharmaceutical compositions may be found, for example, in Remington's Pharmaceutical Sciences (the latest edition) Mack Publishing Co., Easton, Pa. The compositions of the invention can be used singly or as components of mixtures. Preferred forms of the compounds are those for systemic administration as well as those for topical or transdermal administration. Formulations designed for timed release are also within the scope of the invention. Formulation in unit dosage form is also envisaged.

[080] In unit dosage form, the composition is divided into unit doses containing appropriate quantities of the composition. The unit dosage may be in the form of a package containing discrete quantities of the composition. Non-limiting examples are packeted tablets or capsules, and powders in vials or ampoules.

[081] Methods for the preparation of the compositions of the invention include formulating the compositions with one or more inert, pharmaceutically acceptable carriers into a dosage from encapsulating the composition. Suitable dosage forms include, but are not limited to capsules, cachets, and suppositories. [082] For oral administration, the composition can be in the form of, for example, a tablet, capsule, a soft gelatin (softgel) capsule, a hard gelatin capsule, or liquid. The composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets, hardgel capsules or softgel capsules.

[083] In some embodiments, hard or soft capsules contain the compositions of the invention, optionally in conjunction with non-aqueous, and/or water miscible solvents such as polyethylene glycol and the like. Hydrophilic solvents compatible with softgel capsules can include PEG400, PEG800, ethanol, glycerin, PPG, polysorbates, povidone (PVP), and the like containing up to about 5-8% water. The softgel capsules can optionally contain a buffer, a co-solvent, a lipophilic surfactant, a hydrophilic surfactant, a plasticizer, a bioavailability enhancer, or a fatty acid.

[084] In one aspect, the dosage forms are formulated as enteric coated delayed release oral dosage forms, i.e. , as an oral dosage form of a composition as described herein which utilizes an enteric coating to affect release in the small intestine or large intestine. Any coatings can be applied to the capsule to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above.

[085] The coating may be a sugar coating, a film coating (e.g., based on hydroxypropyl methylcellulose, methylcellulose, methyl hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone), or an enteric coating (e.g., based on methacrylic acid copolymer, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, shellac, and/or ethylcellulose).

[086] In other embodiments, a polymer for delayed release of the fenretinide or fenretinide analogue may used to coat the dosage form. Examples of a rate controlling coating include, but are not limited to, hydroxypropyl cellulose, hypromellose, ethyl cellulose, and prop-2- enoic acid. One suitable example of a prop-2-enoic acid is Carbopol® (Noveon or Dow Chemical Co.). Examples of delay release polymers include a neutral methacrylic polymer such as Eudragit® FS30D, Eudragit® S100, Eudragit® L100-55 and/or any mixture or combination thereof (Rohm). Specific chemical structures of the Eudragit polymers are disclosed in Dos Santos J et al. , Pharmaceutics, 2021 Sep 8;13(9):1424 and incorporated by reference herein. Eudragit® L100-55 is an enteric polymer which can be used in coated dosage forms to target the drug release in the upper small intestine where the pH is above 5.5. Eudragit® S100 can be used to achieve targeted drug release in the lower small intestine to the colon, where the pH is above 7. The modified release components of the formulations of this invention can be formulated with any, and/or a mixture, of the above polymers, to achieve the desired plasma concentration profiles. The choice of the polymers that can be used in the invention includes, but is not limited to, Eudragit®, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate LF, and hydroxypropyl methylcellulose acetate succinate HF.

[087] It is envisaged that conventional coating techniques such as spray or pan coating can be employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of delivery in the intestinal tract is reached.

Uses of the Composition and the Dosage Form

[088] The compositions and the dosage forms disclosed herein can be used for preventing, treating, or ameliorating (e.g., alleviating) one or more symptoms and/or severity of any disease or condition that is subject to prevention or treatment by administering fenretinide or a fenretinide analog.

[089] Alternatively, the compositions may be used to prepare a medicament for preventing, treating, or ameliorating (e.g., alleviating) one or more symptoms and/or severity of any disease or condition that is subject to prevention or treatment by administering fenretinide or a fenretinide analogue.

[090] For example, conditions that may be prevented or treated by the compositions or dosage forms disclosed herein include hyperproliferative disorders, malignancies and neoplasms including, but are not limited to, malignant disorders such as breast cancers; osteosarcomas; angiosarcomas; fibrosarcomas and other sarcomas (e.g., Ewing's sarcoma, Kaposi's sarcoma); leukemias; lymphomas (e.g., non-Hodgkin's lymphoma); sinus tumors; ovarian, urethral, bladder, prostate and other genitourinary cancers; colon esophageal and stomach cancers and other gastrointestinal cancers; lung cancers (non-small cell lung cancers); myelomas; pancreatic cancers; liver cancers; kidney cancers; endocrine cancers; skin cancers (e.g., melanoma, basal cell carcinoma); head and neck carcinoma and brain or central and peripheral nervous (CNS) system tumors, malignant or benign, including gliomas and neuroblastomas.

[091] Other examples of diseases or conditions that can be treated or prevented by administering the compositions or dosage forms disclosed herein include premalignant and non-neoplastic or non-malignant hyperproliferative disorders such as myelodysplastic disorders; cervical carcinoma; familial intestinal polyposes such as Gardner syndrome; oral leukoplakias; histiocytoses; keloids; hemangiomas; hyperproliferative arterial stenosis, inflammatory arthritis; hyperkeratoses and papulosquamous eruptions including arthritis. Also included are viral-induced hyperproliferative diseases such as warts and Epstein-Barr virus (EBV)-induced disease (i.e. , infectious mononucleosis), scar formation, and the like.

[092] Other diseases or conditions may be prevented or treated by the compositions or dosage forms disclosed herein include conditions associated with inflammation of the respiratory tract such as cystic fibrosis, allergic asthma, a disease or condition associated with a lipid or fatty acid imbalance (DHA/AA imbalance), including infections (e.g., opportunistic infections) of the respiratory tract (e.g., Haemophilus influenzae,

Pseudomonas aeruginosa, Streptococcus pneumoniae, Streptococcus pyogenes, Mycobacterium tuberculosis, Candida albicans or Aspergillus fumigatus) and bone diseases (osteopenia or osteoporosis), as well as neural diseases or conditions associated with neuroinflammation and/or microglial activation, such as neural injury (e.g., spinal cord injury) and neurodegenerative diseases (e.g., Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, and Huntington's disease). Other diseases or conditions may be prevented or treated by administering the compositions or dosage forms disclosed herein include HIV/AIDS, allergic encephalomyelitis, ichthyosis, and metabolic conditions such as diabetes and obesity, as well as ophthalmic conditions such as various macular degenerations and dystrophies, including but not limited to dry-form age-related macular degeneration (dry AMD) and Stargardt Disease.

[093] In some embodiments, the compositions and the dosage forms disclosed herein can be used for preventing, treating, or ameliorating (e.g., alleviating) one or more symptoms and/or severity of a flavivirus infection, preferably dengue virus (DENV) infection. In some embodiments, the flavivirus infection is an infection by the yellow fever virus (YFV), West Nile virus (WNV), or Japanese encephalitis virus (JEV).

[094] It is also envisaged that subjects having Chikungunya virus (CHIKV) will benefit from administration of an effective amount of a composition or dosage form disclosed herein.

[095] The compositions disclosed herein may be prepared as a medicament for the treatment of flavivirus infection, to reduce symptom severity in a subject having or suspected of having a flavivirus, for the prevention of infection by a flavivirus, or for the prevention of antibody dependent enhanced (ADE) DENV infection.

[096] In an alternative embodiment, the compositions of the invention may also be prepared as a medicament for the treatment of CHIKV infection, to reduce symptom severity in a subject having or suspected of having CHIKV infection, or for the prevention of infection by CHIKV.

[097] There is also provided the compositions or dosage forms described herein when used to treat flavivirus infection, reduce symptom severity in a subject having or suspected of having a flavivirus infection, prevent infection by a flavivirus or CHIKV, or prevent ADE DENV infection.

[098] The invention further provides for the compositions or dosage forms described herein for treating flavivirus or CHIKV infection, reducing symptom severity in a subject having or suspected of having a flavivirus or CHIKV infection, preventing infection by a flavivirus or CHIKV, or preventing ADE DENV infection.

[099] The compositions or dosage forms of the present invention may be administered in combination with other agents, for example, other anticancer or antiviral agents.

[0100] The terms 'combination therapy' or 'adjunct therapy' in defining the use of a composition or dosage form of the present invention and one or more other pharmaceutical agents, are intended to embrace administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is intended as well to embrace co-administration of these agents in a substantially simultaneous manner, such as in a single formulation having a fixed ratio of these active agents, or in multiple, separate formulations of each agent. In addition, these terms are also intended to embrace the presence of one or more other pharmaceutical agents in the composition or dosage form.

[0101] In accordance with various embodiments of the present invention, fenretinide or a fenretinide analogue may be formulated for administration in combination with one or more other therapeutic agents. Thus, in accordance with various embodiments of the present invention, compositions or dosage forms described herein may be included in combination treatment regimens with other known treatments or therapeutic agents, and/or adjuvant or prophylactic agents.

[0102] The therapeutically effective amount of fenretinide or fenretinide analogue that is administered and the dosage regimen for treating a disease or condition with the compositions or dosage forms of the present invention depends on a variety of factors, including the age, weight, sex, and medical condition of the subject, the severity of the disease or condition, the route and frequency of administration, the particular compound (fenretinide or fenretinide analogue) employed, as well as the pharmacokinetic properties (e.g., adsorption, distribution, metabolism, excretion) of the drug in the individual treated, and thus may vary widely. Such treatments may be administered as often as necessary and for the period of time judged necessary by the treating physician. One of skill in the art will appreciate that the dosage regime or therapeutically effective amount of the fenretinide or fenretinide analogue to be administered may need to be optimized for each individual. The compositions may contain fenretinide or fenretinide analogue in the range of about 0.1 mg to 2000 mg, typically in the range of about 0.5 mg to 500 mg and more typically between about 1 mg and 200 mg. A daily dose of about 1000 mg/m²/day to about 6000 mg/m²/day, for example 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500 or about 6000mg/m²/day. Alternatively, the does may be about 0.01 mg/kg to 100 mg/kg body weight, typically between about 0.1 mg/kg and about 50 mg/kg body weight, depending on the route and frequency of administration. The daily dose will typically be administered in one or multiple, e.g., two, three or four, doses per day.

[0103] Combination regimens may involve the active agents being administered together, sequentially, or spaced apart as appropriate in each case. Combinations of active agents including fenretinide or fenretinide analogues may be synergistic.

[0104] The co-administration of fenretinide or a fenretinide analogue in a composition or dosage forms disclosed herein may be effected by the fenretinide or analogue being in the same unit dose as another active agent, or the fenretinide or analogue and one or more other active agent(s) may be present in individual and discrete unit doses administered at the same, or at a similar time, or at different times according to a dosing regimen or schedule. Sequential administration may be in any order as required, and may require an ongoing physiological effect of the first or initial compound to be current when the second or later compound is administered, especially where a cumulative or synergistic effect is desired.

[0105] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

Examples

Example 1: In vitro evaluation - 4-HPR is relatively soluble in mixed medium-chain lipids

[0106] Equilibrium solubility of 4-HPR in individual excipients was measured in a range of commonly-used lipid-based formulation components (Table 1), including medium- and long- chain lipids, low- and high-HLB (hydrophobic lipophilic balance) surfactants and cosolvents. 4-HPR was relatively highly soluble in mixed medium-chain lipids (e.g. Capmul MCM EP, 34 ± 4.3 mg/g), cosolvent ethanol (113 ± 1.3 mg/g), low-HLB surfactants (Lauroglycol 90, 39 ± 1.4 mg/g) and high-HLB surfactants (Tween 85, 71 ± 9.1 mg/g).

Table 1. Equilibrium solubility (concentration in mg/g) of 4-HPR in individual excipients. Values are mean ± SD (n=3).

Example 2: 4-HPR is relatively soluble in self-emulsifying lipid formulations based on mixed medium-chain lipids

[0107] The equilibrium solubility results were used to guide the development of lipid-based formulations of primarily type III of the lipid formulation classification system (Table 2) (Pouton (2006) European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences, 29 (3-4), pp. 278-287). Measured equilibrium solubility values were compared to predicted equilibrium solubility values (based on additive solubility in individual excipients), with the majority of formulations underperforming the predicted values. Some formulations were better able to solubilise 4- HPR than predicted (ID no's 11, 13, 19, 23, 25, 26), with formulation candidates 23 and 25 selected for further study based on their stability after dispersion 1:5 in water. For comparison, the corn oil-based clinical formulation (no 31) (Gibbs and Kotwal, 1987) and mouse model efficacy formulation (Fraser et al. , (2014) The Journal of infectious diseases, 210 (11), pp. 1780-1791.) were also included.

Table 2. Equilibrium solubility of 4-HPR in self-emulsifying lipid-based formulations. Values are mean + SD (n=3). Expected solubilities calculated additively based on individual excipient solubility results in Table 1 .

Example 3: 4-HPR formulations retain greater solubilisation than existing formulations after in vitro digestion

[0108] An in vitro lipid digestion model was used to investigate the properties of the formulations after dispersion and digestion, with lipid digestion understood to generally reduce the solubilising properties of lipid-based formulations, leading to drug precipitation. The distribution of 4-HPR in the oil, aqueous and pellet phases of formulations 23 and 25, the corn oil-based clinical formulation and the efficacy study suspension was measured over time (Figure 1). The corn oil-based clinical formulation and the efficacy formulation were marked by significant drug precipitation upon dispersion and digestion respectively. In contrast, lipid-based formulations 23 and 25 yielded significant 4-HPR solubilisation after dispersion, and markedly lower precipitation was observed.

Example 4: In vivo evaluation - 4-HPR increases in vivo exposure

[0109] To test the in vivo pharmacokinetic properties of the candidate formulations, systemic exposure of 4-HPR was studied in non-fasted male C57BI/6 mice. 4-HPR was rapidly absorbed when given orally in an aqueous suspension vehicle (HPMC-SV) (Figure 2), however the apparent oral bioavailability was only 4% (Table 3). Absorption was also rapid when given as the efficacy formulation, however compared to the aqueous suspension, exposure was notably higher and the apparent bioavailability increased to approximately 13%, suggesting a possible solubilising effect of serum in the efficacy formulation. Oral administration of the lipid-based formulation (formulation #25) resulted in 4-HPR exposure that was comparable to the efficacy formulation, both in terms of plasma Cmax and AUC. Based on these results, there is no substantial increase in exposure of 4- HPR with the lipid-based formulation relative to the efficacy formulation, with both formulations achieving an apparent absolute bioavailability of 13%.

Table 3. Summary of pharmacokinetic parameters for 4-HPR in male C57BI/6 mice following singledose oral administration

Example 5: 4-HPR exposure in vivo is limited by both solubility and extensive first- pass intestinal elimination

[0110] To define the contribution of first-pass hepatic metabolism, 4-HPR was administered IV in a non-aqueous formulation (10% DMSO v/v in PEG400) and the concentration-time profile and associated pharmacokinetic parameters were determined (Table 4, Without ABT). Very low in vivo systemic clearance (4.4 mL/min/kg) was observed, raising the possibility of significant intestinal first-pass metabolism.

[0111] 4-HPR is understood to be metabolised by cytochrome P450 isoforms. To evaluate the possibility that oral bioavailability of 4-HPR may be limited by intestinal and hepatic first- pass metabolism, the systemic clearance and oral bioavailability of 4-HPR in C57BI/6 mice in the absence and presence of the pan-CYP inhibitor, 1-aminobenzotriazole (ABT) was studied (Table 4). The changes in IV half-life and clearance for 4-HPR in ABT-treated mice, relative to mice that were not pre-treated with ABT, are consistent with reduced CYP- mediated metabolism (Table 4, Figure 3). However, the decrease in clearance was relatively minor (<0.2-fold) suggesting that CYP-mediated metabolism is not the predominant systemic clearance pathway for 4-HPR. This is not overly surprising given that metabolism of 4-HPR by multiple enzyme systems has been reported previously. Of particular note was the suggestion that the methoxyphenyl ether metabolite, 4-MPR (whose formation is most likely mediated by methyltransferase(s) rather than CYPs), was reported to be the major metabolite of 4-HPR in BDF mice.

Table 4. Summary of pharmacokinetic parameters for 4-HPR in male C57BI/6 mice following singledose administration in the presence or absence of CYP inhibitor 1-aminobenzotriazole (ABT).

[0112] In contrast to the IV data, oral exposure of 4-HPR in ABT-treated animals was almost 5- fold higher than that observed previously in mice that had not been pre-treated with ABT (Table 4, Figure 4B). Elimination of 4-HPR from the systemic circulation occurs predominantly within the liver and so the evidence of a relatively minor contribution of CYP to the systemic clearance (i.e. after IV dosing) indicates that CYP enzymes within the enterocyte limit the oral bioavailability of 4-HPR. Susceptibility to significant enterocyte- based CYP metabolism with minimal hepatic CYP metabolism suggested a significant contribution of plasma protein binding of 4-HPR.

[0113] Comparing the PK profiles of oral administration of lipid formulation 2 to the corn oil clinical formulation, the lipid-based formulation (Formulation #25) resulted in approximately 5-fold greater exposure and 4-fold greater bioavailability (Figure 4, Table 5). Similar to the lipid formulation (formulation #25), the oral exposure of 4-HPR in the corn oil formulation was increased almost 4-fold in mice treated with ABT. Taken together, these results suggest that exposure of 4-HPR is limited both by solubility (which can be improved using an optimised lipid-based formulation) and by extensive first pass elimination (which can be improved by inhibition of CYP450 with a CYP inhibitor).

Table 5. Summary of pharmacokinetic parameters for 4-HPR in male C57BI/6 mice following singledose oral administration of the corn oil clinical formulation in the presence or absence of CYP inhibitor 1-aminobenzotriazole (ABT).

Example 6: Significant plasma protein binding may explain the differing hepatic and intestinal clearance rates of 4-HPR

[0114] To investigate the mechanism behind the low contribution of hepatic clearance and the more important role of intestinal clearance of 4-HPR, the extent of plasma protein binding of 4-HPR was determined by rapid equilibrium dialysis (RED) using both human and mouse plasma. This revealed that 4-HPR is >99.95% bound in both human and mouse plasma (Table 6). Thus, differing contributions of hepatic and intestinal clearance of 4-HPR can be attributed to the differences in unbound concentrations within the enterocyte and the hepatocyte, given the very high plasma protein binding of 4-HPR.

Table 6. Protein binding data for 4-HPR in human and mouse plasma. Values are presented as the mean ± SD of n=3-4 independent dialysis units.

Example 7: Simulated exposure profiles suggest that BID dosage regime is likely to maintain 4-HPR above the minimum effective plasma concentration

[0115] Simulated exposure profiles for twice-daily oral dosage of 4-HPR at 20 mg/kg in mice were generated, showing that the minimum plasma concentration under this dosage regime was approximately 1.2 mM for Lipid formulation 2 (formulation #25), and 1.0 pM the efficacy formulation. Given that this same BID dosage regime showed efficacy in a mouse model of dengue virus infection, this suggests that the minimum effective plasma concentration of 4-HPR is around 1.0 pM. Unlike the lipid formulation (formulation #25), the corn oil clinical formulation was predicted to result in a minimum plasma concentration of approximately 0.3 pM, well-below the minimum effective concentration.

[0116] As such, this orally-administered self-emulsifying lipid formulation of 4-HPR dramatically increases exposure at equivalent dosages to the accepted corn oil clinical formulation, implying a role for this formulation in increasing the practicality of 4-HPR treatment in clinical settings.

Claims

Claims:

1. A self-emulsifying composition comprising fenretinide or a fenretinide analogue, a mixed medium- or long-chain glyceride, and at least one surfactant.

2. The self-emulsifying composition of claim 1 further comprising an alcohol.

3. The self-emulsifying composition of claim 2, wherein the alcohol is ethanol or diethylene glycol monoethyl ether.

4. The composition of any one of claims 1 to 3 wherein the fenretinide analogue is selected from the group consisting of 4-oxo-N-(4-hydroxyphenyl)retinamide, N-(4- methoxyphenyl)retinamide (4-MPR), 4-hydroxybenzylretinone, 4-(retinamido)phenyl-C- glucuronide, 4-(retinamido)phenyl-C-glucoside, 4-(retinamido)benzyl-C-xyloside, 1-(b-0- glucopyranosyl) retinamide, l-(D-glucopyranosyluronosyl) retinamide, bexarotene, or a compound of Formula I:

wherein:

R is OH, COOH, CH₂OH, CH₂CH₂OH, or CH₂COOH; carbons a-d and f-i are optionally substituted with one or more groups selected from CH3, OH, COOH, (CH3)2 and CH2OH, or any combination thereof; and carbon e is optionally substituted with a C1-C₃ alkyl group that is optionally substituted with CH₃ and/or OH.

5. The composition of any one of claims 1 to 4 comprising at least 45mg/g of the fenretinide or fenretinide analogue.

6. The composition of any one of claims 1 to 5, wherein the medium or long-chain glyceride comprises C6-C18 fatty acids and esters thereof.

7. The composition of claim 6, wherein the medium or long-chain glyceride is glyceryl caprylate/caprate

8. The composition of claim 7, wherein the glyceryl caprylate/caprate is Capmul® MCM NF (glyceryl caprylate/caprate) or Capmul® MCM EP (glyceryl caprylate/caprate).

9. The composition of claim 6, wherein the medium or long-chain glyceride comprises 32-52% monoglycerides, 40-55% diglycerides, 5-20% triglycerides.

10. The composition of claim 9, wherein the medium or long-chain glyceride is Maisine® CC.

11. The composition of any one of claims 1 to 10, comprising 35%-75% of the surfactant.

12. The composition of any one of claims 1 to 11 , wherein the surfactant is selected from Capryol 90, Lauroglycol 90, Kolliphor RH 40, Cremophor EL, Labrasol, Gelucire 44/14, Tween 85, Polysorbate 80 or any combination thereof.

13. The composition of claim 12, wherein the surfactant is Lauroglycol 90, Tween 85, or both.

14. The composition of any one of claims 1 to 13, comprising i. 15-60% medium- or long-chain glycerides; ii. 35-75% surfactant; iii. 0%-30% alcohol; and iv. at least 45mg/g fenretinide or fenretinide analogue.

15. The composition of claim 14, comprising 25% Maisine® CC (32-52% monoglycerides, 40-55% diglycerides, 5-20% triglycerides), 25% Lauroglycol 90, 10% Ethanol, and 40% Tween 85.

16. The composition of claim 14, comprising 50% Maisine® CC (32-52% monoglycerides, 40-55% diglycerides, 5-20% triglycerides), 10% Ethanol, and 40% Tween 85.

17. The composition of any one of claims 1 to 16, further comprising a cytochrome P450 inhibitor.

18. The composition of claim 17, wherein the cytochrome P450 inhibitor is selected from 1-aminobenzotriazole (ABT), propyl gallate, fluvoxamine, clopidogrel, gemfibrzil, fluoxetine, paroxetine, clarithromycin, itraconazole, ciprofloxacin, enoxacin, ticlopidine, fluconazole, bupropion, quinidine, terbinafine, boceprevir, cobicistat, danoprevir, ritonavir, elvitegravir, grapefruit juice, indinavir, ketoconazole, lopinavir, paritaprevir, ombitasvir, dasabuvir, posaconazole, saquinavir, telaprevir, tipranavir, telithromycin, troleandomycin, voriconazole, idelalisib, nefazodone, nelfinavir, quinidine, or any combination thereof.

19. The composition of any one of claims 1 to 18 wherein the fenretinide or the fenretinide analogue has increased bioavailability compared to the bioavailability of the fenretinide or the fenretinide analogue in the absence of the mixed medium- or long-chain glyceride, or the at least one surfactant.

20. A dosage form comprising the composition of any one of claims 1 to 19.

21. The dosage form of claim 20, formulated for oral administration.

22. The dosage form of claim 21, wherein the dosage form is a capsule, cachet, or liquid.

23. The dosage form of any one of claims 20 to 22, formulated for twice daily administration.

24. A method of increasing the bioavailability of fenretinide or a fenretinide analogue in a subject, the method comprising administering the composition of any one of claims 1 to 19 or the dosage from of any one of claims 20 to 23 to the subject.

25. The method of claims 24, wherein the administration of the composition or dosage from under a non-fasted condition provides an increase of the maximum plasma concentration (Cmax) and/or the extent of absorption (AUC) of the fenretinide or fenretinide analogue compared to the administration of fenretinide or fenretinide analogue in a corn oil formulation or an aqueous suspension.

26. The method of claim 24 or 25, wherein the bioavailability of the fenretinide or the fenretinide analogue is about 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% 19%, or at least 20%.

27. The method of claim 26, wherein the bioavailability of the fenretinide or the fenretinide analogue is about 13%.