Self-assembling microemulsions carrying nutraceuticals and methods for use thereof

Abstract

The present invention relates to compositions in the form of cationic microemulsion preconcentrates that contain at least one lipophilic and water-insoluble active agent, at least one polyglyceryl-containing emulsifier, at least one cationic emulsifier, carrier oils, solubilizers, antioxidants, and preservatives. When contacted with either an aqueous medium, gastric or intestinal fluid, the cationic microemulsion preconcentrates self-assemble into cationic microemulsions that are stable in gastric and intestinal fluids. The invention is also related to methods of making and methods of using the cationic microemulsion preconcentrates.

Description

TITLE: SELF-ASSEMBLING MICROEMULSIONS CARRYING NUTRACEUTICALS AND METHODS FOR USE THEREOFFIELD

[0001] The present invention relates to microemulsions and more specifically to cationic microemulsions carrying nutraceuticals.BACKGROUND

[0002] Ingredient Delivery Systems (IDS) are designed to augment the water solubility of active ingredients characterized by poor water solubility, thereby enhancing the bioavailability of the active ingredient. Emulsions, nanoemulsions and microemulsions typically consist of surfactants, stabilizers, antioxidants, preservatives, and solvents, with water being the predominant ingredient. Self-Microemulsifying Ingredient Delivery Systems (SMEIDS) are water-free microemulsion preconcentrates that exhibit properties akin to microemulsions upon dilution and self-assemble in aqueous environments.

[0003] The evolution of diverse IDS types has led to their application across various sectors, including pharmaceuticals, nutraceuticals, and cosmetics. Despite the development of diverse IDS, obstacles in market penetration persist, including constrained loading capacity, production complexities, use of relatively expensive ingredients, and the incorporation of non-food-grade substances with uncertain safety profiles. Hence, there is a pressing need to investigate IDS, utilizing safe and food-grade components, to forge a more viable avenue for commercialization.

[0004] PEG is widely utilized in the production of water-soluble products. Despite its convenience, the incorporation of PEG-containing (PEGylated) ingredients has been linked to the emergence of anti -PEG antibodies. While administering lower doses of PEGylated ingredients may mitigate downstream effects, it can compromise the delivery system and reduce therapeutic efficacy.SUMMARY

[0005] Various embodiments disclosed herein are drawn towards water-insoluble active ingredients incorporated in microemulsion preconcentrates, alternatively named selfmicroemulsifying ingredient delivery systems (SMEIDS)

[0006] Thus, by one aspect of the present disclosure a SMEIDS composition is provided including a water-insoluble active ingredient, a polyglyceryl containing (POGylated) surfactant, a polyol, a preservative and and antioxidant, the SMEIDS being devoid of water, PEG and lecithin.

[0007] In another aspect, a method of preparing a SMEIDS composition is provided that includes a water-insoluble active ingredient, a POGylated surfactant, a polyol, a preservative and an antioxidant.

[0008] In another aspect, a method of using a SMEIDS composition is provided, including administering the composition by targeting systemic, parenteral, oral, intrathecal, intraarticular, nasal, ophthalmic and / or topical means.

[0009] Various objects, features, aspects and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying tables.DETAILED DESCRIPTION

[0010] As used herein and in the appended claims, the terms “approximately” “about” mean to be nearly the same as a referenced number or value. As used herein, the terms “approximately” and “about” should be generally understood to encompass ±20%, or alternatively ±15%, or alternatively ±10%, or alternatively ±5%, or alternatively ±2% of a specified amount, frequency, value, or other numerical designation.[Oil] The preferred methods, devices, and materials are now described with all technical and scientific terms used herein having the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs unless defined otherwise. Nothing herein is to be construed as an admission that the disclosure is not entitled to antedate such disclosure by virtue of prior disclosure.

[0012] As used herein, the term "Consisting essentially of’ when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the intended use. Thus, a composition consisting essentially of the elements as defined herein would not exclude trace contaminants from the isolation and purification method and pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives andthe like. "Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure.

[0013] As used herein, the term “ingredient delivery system” or “IDS” is meant to refer to delivery systems that were developed to deliver the ingredient in question. IDS has various applications in multiple industries that are packaged in softgels, capsules, dissolvable strips, edibles, beverages, cosmetics, and others.

[0014] As used herein, the term “active ingredient” is meant to refer to any ingredient that provides a biologically active or other direct effect in the diagnosis, mitigation, prevention, treatment or cure of a disease or affects the structure or any function of the body of humans or animals.

[0015] As used herein, the term “emulsions” is meant to refer to mixtures of two or more immiscible liquids with droplet sizes or emulsion diameters exceeding 1,000 nm.

[0016] As used herein, the term “nanoemulsions” is meant to refer to mixtures of two or more immiscible liquids characterized by thermodynamic instability and kinetic stability.

[0017] As used herein, the term “microemulsions” is meant to refer to mixtures of two or more immiscible liquids characterized by thermodynamic stable isotropic liquids. Typical microemulsions used in the food and pharmaceutical industry focus on oil-in-water microemulsions that consist of nanometer-sized spheroid particles comprised of oil and surfactants dispersed in water. Microemulsions are formulated with active ingredients through low-energy processes that include, but are not limited to, mixing, dilution, or heating and cooling techniques in aqueous environments. The principal constituent within microemulsions is water with other constituents such as surfactants, carrier oils, sugars, polyols, preservatives, and antioxidants.

[0018] As used herein, the term “self-microemulsifying ingredient delivery systems (SMEIDS)” is meant to refer to water-free microemulsion preconcentrates that self-assemble into microemulsions upon contact with aqueous environments. The self-assembled microemulsion is expected to be non-opaque or practically non-opaque colloidal dispersions. The principal constituent is a surfactant or a combination of surfactants with other constituents such as active ingredients, carrier oils, sugars, polyols, preservatives, and antioxidants.

[0019] As used herein, the term “stable SMEIDS” is meant to refer to SMEIDS formulations that are self-assembled in aqueous environments and maintain a single-phase microemulsion that hasinsignificant or is devoid of crystalization, precipitation, or liquid phase separation. Aqueous environments include, but are not limited to water, gastric, intestinal or colonic fluid in fasted or fed states or a simulated form of any of the previously stated fluids.

[0020] As used herein, the term “fasted-state simulated gastric fluid (FaSSGF)” is meant to refer to a dissolution medium that aids the investigation of a formulation dissolving in the stomach after drinking a glass of water. Compositions of FaSSGF include a pH of 1.6, taurocholate (0.08 millimole [mM]), phospholipids (0.02 mM), sodium (34 mM), and chloride (59 mM).

[0021] As used herein, the term “fasted-state simulated intestinal fluid (FaSSIF)” is meant to refer to a dissolution medium that aids the investigation of a formulation dissolving in the upper intestine after drinking a glass of water. Compositions of FaSSIF include a pH of 6.5, taurocholate (3 mM), phospholipids (0.75 mM), sodium (148 mM), chloride (106 mM), and phosphate (29 mM).

[0022] As used herein, the term “cationic” is meant to refer to a positive electrostatic charged microemulsion relative to a conventional microemulsion. For example, if a conventional microemulsion exhibits a surface charge of -20 millivolts (mV), then a cationic microemulsion would exhibit a surface charge that is more positive than -20 mV, such as -19, -18, -17-, -16, -15, -14, -13, -12, -11, -10, -9, -8, -7, -6, -5, -4, -3, -2, -1, 0, positive values, and fractions within the range, for example, but not limited to, 10.25, 16.72, 18.5, and 19.95 using millivolt (mV) units.

[0023] As used herein, the term “polyethylene gly col-containing” or “PEGylated” is meant to refer to a surfactant, polymer, microemulsion, nanoemulsion, or SMEIDS that contains poly(ethylene) glycol.

[0024] As used herein, the term “polyethylene glycol-free” or “PEG-free” is meant to refer to formulations that do not contain PEGylated ingredients.

[0025] As used herein, the term “lecithin-free” is meant to refer to formulations that are essentially free of lecithin, lysolecithin, mono- and di-alkyl phosphatidylcholines, phosphatidylethanolamines, phosphatidylinositols and phosphatidylglycerols that can be obtained through chemical synthesis or animal or vegetable sources.

[0026] As used herein, the term “cationic surfactant” is meant to refer to surfactants that exhibit a net positive charge. The positive charge is commonly offered through the incorporated nitrogen in different variations that include, but are not limited to, primary, secondary, and tertiary amines.

[0027] As used herein, the term “polyglceryl-containing” or “POGylated” is meant to refer to a surfactant, polymer, microemulsion, nanoemulsion, or SMEIDS that contain glyceryl polymers with a degree of polymerization of n that is greater than 2. The polyglyceryl polymer is commonly chemically attached to a fatty acid, multiple fatty acids, or other hydrophobic molecules or polymers through an ester or ether bond. POGylated surfactants also exist as a monoester that has one fatty acid attached or multiesters where multiple fatty acids are attached to the polyglyceryl. The fatty acid chain consists essentially of carbon chains that range from 6 to 18 carbons.

[0028] As used herein, the term “carrier oil” is meant to refer to edible oils that are formulated in SMEIDS.

[0029] As used herein, the term “reducing agent” or “antioxidant” is meant to refer to ingredients that act as a reducing agent with antioxidant.

[0030] As used herein, the term “polyols” is meant to refer to small-chain carbohydrates that contain multiple hydroxyl groups that include but are not limited to glycerol or triol and propylene glycol or diol. ii. Examples

[0031] The following non-limiting Examples are illustrative of the present disclosure: Example 1 : Curcumin SMEIDS with one surfactantExample 2: Curcumin SMEIDS with two or more surfactants and carrier oil or co-solvent Example 3. SMEIDS Dispersion in Fasted-State Simulated Gastric Fluid Example 4. SMEIDS Dispersion in Fasted-State Simulated Intestinal FluidExample 5. Disintegration and Solubility of Curcumin in Simulated Gastric Fluid (SGF) of Commercially Available Supplements versus our Optimized SMEIDSExample 6. SMEIDS Incorporating either Resveratrol or Coenzyme Q10 and Dispersion Analysis in Boiling water, Fasted State Simulated Gastric Fluid, or Fasted State Simulated Intestinal Fluid.Example 7. Powderized Curcumin SMEIDSExample 8. SMEIDS mixing and encapsulating in softgels at industrial scaleExample 1: Curcumin SMEIDS with one surfactant

[0032] Exemplary turmeric extract with 95% curcuminoids (curcumin) can be sourced, but not limited to, BulkSupplements.com (Sku: curc25). Exemplary polyglyceryl-3 monooleate (Caprol 3GO, 3GO) can be sourced, but not limited to, Abitech (Lot no. 230925-9). Exemplary polyglyeryl-10 mono- and dioleate (Caprol PGE 860) can be sourced, but not limited to, Abitech (Lot no. 231004-9). Exemplary polyglyceryl-3 monooleate blended with polyglyeryl-10 mono- and di-oleate (Caprol MPGO) can be sourced, but not limited to, Abitech (Lot no. 230215-9). Exemplary polyglyeryl-10 laurate (Polyaldo 10-1-L, 10-1-L) can be sourced from, but not limited to, Lonza or Arxada (Product code 192646). Exemplary polyglyeryl-10 oleate (Polyaldo 10-1-0, 10-1-0) can be sourced from, but not limited to, Lonza or Arxada (Product code 1007182). Exemplary polyglyeryl-10 caprate / caprylate (Polyaldo 10-1-CC, 10-1-CC) can be sourced from, but not limited to, Lonza or Arxada (Product code 177445).

[0033] The following SMEIDS formulations were prepared according to the compositions listed in Tables 1-6. The surfactants (3 GO, PGE 860, MPGO, 10-1-L, 10-1-0, 10-1-CC) were individually warmed in a water bath with water set at 85-95 °C for at least 15 minutes. Curcumin was carefully added into scintillation vials followed by the surfactant listed in tables 1 -6 using an appropriate analytical scale with readability down to 1 mg. The scintillation vials were placed on a hotplate to increase the temperature of the SMEIDS liquid ranging from 60-130 °C for 30 minutes with intermittent shaking of the scintillation vials. The SMEIDS were verified for homogeneous mixing by testing if light can transmit through the SMLEDS.

[0034] Once homogeneity was confirmed, less than 0.1 g of the warmed SMLEDS were added into another scintillation vial. Boiling water was then added at a 25-fold mass of the added SMEIDS and the scintillation vial was vigorously shaken for 60 seconds. Achieving realistic dilution scenarios in human contexts involves diluting substances within aqueous environments found in the oral ingestion pathway, such as simulated gastric or intestinal fluids, considering fasted states. The 25-fold dilution in boiling water investigates the self-microemulsifying or selfassembly capacity of the formulated SMEIDS using water near its boiling temperature of 100 °C. This will provide insight on which formulations to develop further.

[0035] Observations are made on the formulated SMEIDS as well as the 25-fold dilution in boiling water the day of as well as 7 and 14 days after self-assembly. The visual scores on the formulated water-free SMEIDS are as follows: crystalization where the SMEIDS is opaque and not flowable at room temperature, score = 0, SMEIDS that is opaque, devoid of crystalization butalso not flowable at room temperature, score = 1, SMEIDS that is translucent or transparent, devoid of crystalization, and not flowable at room temperature, score = 2, and SMEIDS that is translucent or transparent, devoid of crystalization, and flowable at room temperature, score = 3. The visual scores for the self-assembled SMEIDS are as follows: crystalization, phase separation, or coalescence, score = 0, opaque microemulsion, score = 1, translucent microemulsion, score = 2, transparent microemulsion, score = 3.

[0036] Table 1. SMEIDS compositions with curcumin (cure.) and Caprol 3GO (3GO) along with the surfactant (3GO) to curcumin mass ratio along with their respective SMEIDS codes.

[0037] Table 2. SMEIDS compositions with curcumin (cure.) and Caprol PGE 860 (PGE 860) along with the surfactant (860) to curcumin mass ratio along with their respective SMEIDS codes.

[0038] Table 3. SMEIDS compositions with curcumin (cure.) and Caprol MPGO (MPGO) along with the surfactant (MPGO) to curcumin mass ratio along with their respective SMEIDS codes.

[0039] Table 4. SMEIDS compositions with curcumin (cure.) and Polyaldo 10-1-L (10-1-L) along with the surfactant (10-1-L) to curcumin mass ratio along with their respective SMEIDS codes.

[0040] Table 5. SMEIDS compositions with curcumin (cure.) and Polyaldo 10-1-0 (10-1-0) along with the surfactant (10-1-0) to curcumin mass ratio along with their respective SMEIDS codes.

[0041] Table 6. SMEIDS compositions with curcumin (cure.) and Polyaldo 10-1-CC (10-1-CC) along with the surfactant (10-1-CC) to curcumin mass ratio along with their respective SMEIDS codes.

[0042] Table 7. Observations of the formulated SMEIDS and SMEIDS self-assembled in boiling water after 6 hours, 7 days, and 14 days. The visual scores are defined in paragraph 0049 and the SMEIDS codes are referenced from the previous tables.

[0043] SMEIDS, otherwise known as microemulsion preconcentrates, have been formulated with curcumin and either polyglyceryl-3 monooleate (Caprol 3GO [ 3GO], SMEIDS 1.1 -1.6), polyglyceryl- 10 mono- and dioleate (Caprol PGE 860 [PGE 860], SMEIDS 2.1-2.4), polyglyceryl-3 monooleate blended with polyglyeryl-10 mono- and di-oleate (Caprol MPGO, [MPGO], SMEIDS 3.1-3.4), polyglyceryl- 10 monolaurate (Polyaldo 10-1-L [10-1-L], SMEIDS 4.1-4.4), polygly eery 1-10 monooleate (Polyaldo 10-1-0 [10-1-0], SMEIDS 5.1-5.6), and polyglyceryl- 10 caprate / caprylate (Polyaldo 10-1-CC [10-1-CC], SMEIDS 6.1-6.6). The respective self-assembled microemulsions were also monitored for up to 14 days at room temperature using boiling water in the dilution process as shown in Table 7.

[0044] One emulsifier was used in each SMEIDS and the curcumin composition was varied from 1.9 - 25.6 w / w%. Except for SMEIDS containing MPGO (SMEIDS 3.1), mixing the emulsifiers with curcumin at 14.7-25.6% induced either curcumin crystalization or the cooled formulation was opaque and not flowable (SMEIDS 1.1-1.3, 2.1, 3.1, 4.1, 5.1-5.3, 6.1-6.3). The flowability of SMEIDS is important for two factors: the manufacturability of the formulations at large scale, and dispersion within gastric or intestinal fluid. Indeed the difficulty to disperse in boiling water and remain stable in cooled-down environments was observed in all cases where self-assembled microemulsions destabilized the day of self-assembly. Boiling water was used at temperatures above 85 °C to facilitate rapid dispersibility, but the temperature of gastric orintestinal fluid is 37 ± 2 °C which may not emulate the self-assembled microemulsions using boiling water. The opaque microemulsions then phase-separated or crystalized within 7 days after self-assembly. This concludes that using one emulsifier with a curcumin composition above 15% produces SMEIDS that are unstable, difficult manufacturability in softgels at scale, with unfavourable and unstable dispersion in boiling water.

[0045] Similar observations were observed with all emulsifiers when curcumin was incorporated at 5-10 w / w%. Using either 3GO, PGE 860, MPGO, and 10-1-CC with a curcumin composition around 5 w / w% (SMEIDS 1.5, 2.3, 3.3 6.5), and 3GO, MPGO, and 10-1-CC with curcumin around 10 w / w% (SMEIDS 1.4, 3.2, and 6.4), the cooled SMEIDS were flowable at room temperature and did not crystalize within the cooled down SMEIDS. These SMEIDS selfassembled to either opaque microemulsions or microemulsions that did not fully dissolve the SMEIDS and crystals or gel were observed after the addition of boiling water. Ultimately, all of the formulations with curcumin at 5-10 w / w% phase-separated or crystalized within 14 days after self-assembly.

[0046] SMEIDS and the self-assembled microemulsions prepared with curcumin at compositions less than 2.5 w / w% yielded more favourable results for the prepared SMEIDS and the microemulsions self-assembled in boiling water. SMEIDS containing 3GO, PGE 860, MPGO, and 10-1-CC prepared translucent or transparent SMEIDS that were flowable at room temperature (SMEIDS 1.6, 2.4, 3.4, 6.6). SMEIDS containing 10-1-L and 10-1-0 were not flowable at room temperature (SMEIDS 4.4, 5.6). Opaque microemulsions self-assembled from SMEIDS using PGE 860, 10-1-L, and 10-1-0 were stable up to 7 days after self-assembly (SMEIDS 2.4, 4.4, 5.6). Lastly, SMEIDS containing 10-1-CC with the curcumin composition at 2.5 w / w% self-assembled into an unexpected transparent microemulsion on the day of selfassembly (SMEIDS 6.6). These transparent microemulsions crystalized the next day and indicate that one emulsifier is not sufficient for microemulsion stability in water. These results guide the next set of formulations where additional emulsifiers will be added and viscosity enhancers will be used to produce flowable SMEIDS. Therefore, curcumin should be incorporated in SMEIDS at compositions less than 5 w / w / % and using one emulsifier does not self-assemble into stable microemulsions for up to 14 days when diluted in boiling water.Example 2: Curcumin SMEIDS with two or more surfactants and carrier oil or co-solvent

[0047] Exemplary turmeric extract with 95% curcuminoids (curcumin) can be sourced, but not limited to, BulkSupplements.com (Sku: curc25). Exemplary polyglyceryl-3 monooleate (Caprol 3GO, 3GO) can be sourced, but not limited to, Abitech (Lot no. 230925-9). Exemplary polyglyeryl-10 mono and di-oleate (Caprol PGE 860) can be sourced, but not limited to, Abitech (Lot no. 231004-9). Exemplary polyglyceryl-3 monooleate blended with polyglyeryl-10 mono- and dioleate (Caprol MPGO) can be sourced, but not limited to, Abitech (Lot no. 230215-9). Exemplary polyglyeryl-10 laurate (Polyaldo 10-1-L, 10-1-L) can be sourced, but not limited to, Lonza (Product code 192646). Exemplary polyglyeryl-10 oleate (Polyaldo 10-1-0, 10-1-0) can be sourced, but not limited to, Lonza (Product code 1007182). Exemplary polyglyeryl-10 caprate / caprylate (Polyaldo 10-1-CC, 10-1-CC) can be sourced, but not limited to, Lonza (Product code 177445).

[0048] The following SMEIDS were prepared according to the compositions listed in Tables 8, 10, 12, and 14. The surfactants (3GO, PGE 860, MPGO, 10-1-L, 10-1-0, 10-1-CC) were individually warmed in a water bath with water set at 85-95 °C for at least 15 minutes. Curcumin was carefully added into scintillation vials followed by the surfactant listed in tables 8, 10, 12, and 14 using an analytical scale with readability down to 1 mg. The scintillation vials were placed on a hotplate to increase the temperature of the SMEIDS liquid ranging from 80-125 °C for 10 minutes with intermittent shaking of the scintillation vials. The SMEIDS formulations were verified for homogeneous mixing by testing if light can transmit through the SMLEDS formulations.

[0049] Once homogeneity was confirmed, less than 0.1 g of the warmed SMLEDS formulations were added into another scintillation vial. Boiling water was then added at a 25-fold mass of the added SMEIDS formulations and the scintillation vial was vigorously shaken for 60 seconds. Achieving realistic dilution scenarios in human contexts involves diluting substances within aqueous environments found in the oral ingestion pathway, such as simulated gastric or intestinal fluids, considering both fed and fasted states. The realistic dilution scenarios will be tested later. The 25-fold dilution in boiling water investigates the self-microemulsifying capacity of the formulated SMEIDS using water near its boiling temperature of 100 °C. This will provide guidance on which formulations to develop further.

[0050] Observations are made on the formulated SMEIDS as well as the 25-fold dilution in boiling water the day of as well as 7 and 14 days after self-assembly. The visual scores on theformulated water-free SMEIDS are as follows: observed crystalization where the SMEIDS is opaque and not flowable at room temperature, , score = 0, SMEIDS that is opaque, devoid of crystalization but also not flowable at room temperature, score = 1, SMEIDS that is translucent or transparent, devoid of crystalization, and not flowable at room temperature, score = 2, and SMEIDS that is translucent or transparent, devoid of crystalization, and flowable at room temperature, score = 3. The visual scores for the SMEIDS self-assembled into microemulsions are as follows: crystalization, phase separation, or coalescence is observed, score = 0, opaque microemulsion, score = 1, translucent microemulsion, score = 2, transparent microemulsion, score = 3.

[0051] Table 8. SMEIDS compositions with curcumin (cure.), Polyaldo 10-1-0 (10-1-0), Caprol 3 GO (3 GO), sunflower oil (SO), glycerol (Gly), propylene glycol (PG), and ethyl lauroyl arginate (eLA) along with their respective formulation (form.) codes. The mass ratios of 10-1-0 to 3GO, as well as the mass ratio of total surfactants (combination of 10-1-0, 3GO, and eLA) to oil phase (curcumin and SO) [tS / O] are calculated.

[0052] Table 9. Observations of the formulated SMEIDS and self-assembled SMEIDS in boiling water after 6 hours, 7 days, and 14 days. Visual scores are defined in paragraph 0065 and the SMEIDS codes are referenced from the previous tables.

[0053] SMEIDS and self-assembled microemulsions were investigated using polyglyceryl-3 monooleate (Caprol 3GO, [3GO]) and polyglyceryl- 10 monooleate (Polyaldo 10-1-0, [10-1-0]) either alone or with sunflower oil (SO), glycerol (gly), propylene glycol (PG), and ethyl lauroyl arginate (eLA) as shown in Table 8. Observations of self-assembled microemulsions from each SMEIDS in boiling water and stability when stored at room temperature for up to 14 days are shown in Table 9. Only SMEIDS 8.1 formulated with SO and SMEIDS formulated with Gly or PG (SMEIDS 8.5-8.10) produced flowable SMEIDS when cooled to room temperature. In all cases, the self-assembled microemulsions were opaque and destabilized, mainly by phase separation, within 7 days after self-assembly. This concludes that the mixture of 3GO with 10-1- O alone or with the addition of gly, PG, eLA or SO does not produce stable translucent or transparent microemulsions.

[0054] Table 10. SMEIDS compositions with curcumin (cure.), Polyaldo 10-1-CC (10-1-CC), Caprol MPGO (MPGO), Caprol PGE 860 (860), propylene glycol (PG), and sunflower oil (SO) along with their respective formulation (form.) codes. The mass ratios of 10-1-0 to MPGO or 860, as well as the mass ratio of total surfactants (combination of 10-1-CC, MPGO, and 860) to oil phase (curcumin and SO) [tS / O] are calculated.

[0055] Table 11. Observations of the formulated SMEIDS and self-assembled SMEIDS in boiling water after 6 hours, 7 days, and 14 days. Visual scores are defined in paragraph 0065 and the formulation (form.) codes are referenced from the previous tables.

[0056] SMEIDS and self-assembled microemulsions were investigated using combinations of polyglyceryl- 10 caprate / caprylate (Polyaldo 10-1-CC, 10-1-CC), polyglyceryl-3 monooleate and polyglyceryl- 10 monooleate (Caprol MPGO, MPGO), polyglyceryl- 10 mono- and dioleate (Caprol PGE 860), sunflower oil (SO) and propylene glycol (PG) with curcumin ranging from 2.0-4.9 w / w% as shown in Table 10. Observations of the prepared SMEIDS and the stability of their respective self-assembled microemulsions in boiling water and stored at room temperature for up to 14 days are shown in Table 11. Except for using 10-1-CC and MPGO alone (SMEIDS 10.5), nearly all of the SMEIDS contained PG around 10 w / w% which resulted in flowable SMEIDS when cooled to room temperature. Moreover, the 10-1-CC to either MPGO or PGE 860 mass ratio was fixed at around 4.0: 1.0 as determined by results that will be discussed later. All of the formulations prepared translucent or transparent microemulsions when self-assembled in boiling water with three microemulsions that showed unexpected results of microemulsion stability for up to 7 days after self-assembly (SMEIDS 10.2-10.4). It is interesting that theincorporation of SO ranging from 1.6-6.0 w / w% provided enhanced stability as the total surfactants to oil mass ratio decreased down to 10: 1 for the microemulsions up to 7 days after self-assembly (SMEIDS 10.2-10.4). All of the formulations were destabilized 14 days after selfassembly. Although relatively stable microemulsions are self-assembled using 10-1-CC and MPGO or PGE 860 blends, MPGO contains mixtures of polyglyceryl-3 monooleate and polyglyceryl- 10 mono- and dioleate and PGE 860 contains polyglyceryl- 10 mono- and dioleate that can have variable compositions between manufactured batches. It is preferable to remove the batch-to-batch variability and utilize ingredients that contain one emulsifier. Therefore, 10-1-CC and MPGO or PGE 860 blends produce stable and flowable SMEIDS that self-assemble into translucent or transparent microemulsions that are not stable for up to 14 days after selfassembly.

[0057] Table 12. SMEIDS compositions with curcumin (cure.), Polyaldo 10-1-CC (10-1-CC), Caprol MPGO (MPGO), Caprol PGE 860 (860), propylene glycol (PG), and sunflower oil (SO) along with their respective formulation (form.) codes. The mass ratios of 10-1-CC : 10-1-L : 10- 1-0 (C:L:O), as well as the mass ratio of total surfactants (combination of 10-1-CC, 10-1-L, 10- l-O, and eLA) to oil phase (curcumin) [tS / O], are calculated.

[0058] Table 13. Observations of the formulated SMEIDS and self-assembled microemulsions in boiling water after 6 hours, 7 days, and 14 days. Visual scores are defined in paragraph 0065 and the SMEIDS codes are referenced from the previous tables.

[0059] SMEIDS and the self-assembled microemulsions were investigated using Polyglyceryl- 10 caprate / caprylate (Polyaldo 10-1-CC, [10-1-CC]), polyglyceryl- 10 monolaurate (Polyaldo [10-1-L], 10-1-L) and polygly eery 1-10 monooleate (Polyaldo 10-1-0, [10-1-0]) either alone or with propylene glycol (PG) and ethyl lauroyl arginate (eLA) as shown in Table 12. Observations of the prepared SMEIDS and the stability of self-assembled SMEIDS in boiling water and stored at room temperature for up to 14 days are shown in Table 13. SMEIDS 12.1-12.4 were not flowable when cooled to room temperature but SMEIDS 12.5 was flowable due to the presence of PG at 17.2 w / w%. Nearly all of the SMEIDS self-assembled into translucent or transparent microemulsions when in boiling water but SMEIDS 12.1-12.4 crystalized the next day. Only SMEIDS 12.5 unexpectedly self-assembled into stable and translucent microemulsions for up to 14 days after self-assembly when stored at room temperature. This provides insight into the stable compositions of eLA with 10-1-CC, 10-1-L, and 10-1-0 that self-assemble into stable microemulsions in boiling water. The hydrophobic component of eLA, lauric ester, may anchor into the self-assembled microemulsion oil core while the positive charge from the guanidine group aids in the stability of the microemulsion. Therefore, 10-1-CC, 10-1-L, 10-1-0, eLA, and blends produce stable and flowable SMEIDS that produce translucent microemulsions that are stable 14 days after self-assembly. SMEIDS 12.5 warrants further investigation in simulated gastric and intestinal fluids.

[0060] Table 14. SMEIDS compositions with curcumin (cure.), Polyaldo 10-1-CC (10-1-CC), Polyaldo 10-1-0 (10-1-0), Caprol (3GO), propylene glycol (PG), sunflower oil (SO), and ethyl lauroyl arginate (eLA) along with their respective formulation (form.) codes. The mass ratios of 10-1-CC to co- surfactants (combination of 10-1-0, 3GO, eLA), as well as the mass ratio of total surfactants (combination of 10-1-CC, 10-1-0, 3GO, eLA) to the oil phase (curcumin and SO) [tS / O] are calculated.

[0061] Table 15. Observations of the formulated SMEIDS and self-assembled SMEIDS in boiling water after 6 hours, 7 days, and 14 days. Visual scores are defined in paragraph 0065 and the SMEIDS codes are referenced from the previous tables.

[0062] SMEIDS and their self-assembled microemulsions were investigated using Polyglyceryl- 10 caprate / caprylate (Polyaldo 10-1-CC, 10-1-CC), polygly ceryl- 10 monooleate (Polyaldo 10-1- O, 10-1-0), and polygly eery 1-3 monooleate (Caprol 3GO, 3GO) either alone or with propylene glycol (PG), sunflower oil (SO) and ethyl lauroyl arginate (eLA) as shown in Table 14. The SMEIDS were categorized into four series groups of series A-D to discuss the results. Observations of the self-assembled microemulsions in boiling water from each respective SMEIDS stored at room temperature for up to 14 days are shown in Table 15.

[0063] Series A found in Table 14 and the self-assembled microemulsions include SMEIDS 14.1-14.12 that focus on the mixture of 10- 1 -CC with 3 GO at various mass ratios along with the addition of PG. Most of these SMEIDS were flowable when cooled down to room temperature with a select few that were transparent (SMEIDS 14.1, 14.2, 14.6, 14.7, 14.9-14.12). These flowable liquids are mainly due to the incorporation of 3 GO which is a flowable liquid at room temperature while incorporating 3GO at composition ranges from 1.2-33.8 w / w%. Two of the Series A SMEIDS self-assembled into opaque microemulsions in boiling water that evolved into phase separation or crystalization (14.8, 14.10). These SMEIDS incorporated curcumin at 13.2 and 5.0 w / w%, respectively, indicating that the total surfactants to oil (tS / O) mass ratio of 6.6 and 16.9 is not sufficient to maintain stable microemulsions. Most of the self-assembled SMEIDS of series A self-assembled into translucent or transparent microemulsions in boiling water. Importantly, four SMEIDS maintained the stability of the formed microemulsions up to 14 days after self-assembly (SMEIDS 14.1-14.4). Curcumin compositions were lower than 2.0 w / w% and the tS / O mass ratio was above 43.4 indicating that these parameters are predictors of self-assembled microemulsion stability. Four of the Series A formulations were stable for up to 14 days and will be investigated further in simulated gastric and intestinal fluids.

[0064] Series B found in Table 14 and the self-assembled microemulsions include SMEIDS 14.13-14.18 that focus on the mixture of 10-1-CC with 10-1-0 at various 10-1 -CC / 10-1-0 mass ratios ranging from 2.0-3.7 and curcumin compositions ranging from 2.1-9.6 w / w%. All of the prepared SMEIDS were not flowable liquids when cooled to room temperature, but were able toself-assemble into translucent or transparent microemulsions in boiling water, excluding SMEIDS 14.13. The opaque microemulsion self-assembled by SMEIDS 14.13 is due to the higher composition of curcumin at 9.6 w / w%. Stable microemulsions were either translucent or transparent up to 7 days after self-assembly (SMEIDS 14.14-14.17). Notably, transparent microemulsions are self-assembled when the 10-1-CC / 10-1-0 mass ratio is above 3.6 (SMEIDS 14.16, 14.17) indicating that the mass ratio should be targeted at or above this mass ratio. All of the formulations were destabilized 14 days after self-assembly. This provides insight that nonfl owable SMEIDS can be self-assembled into transparent microemulsions using the preferred 10- 1-CC to 10-1-0 mass ratio at or above 3.6 while a mass ratio ranging from 2.0-3.4 selfassembles into translucent microemulsions.

[0065] Series C found in Table 14 and the self-assembled microemulsions include SMEIDS 14.19-14.29 that focus on the mixture of 10-1-CC with 10-1-0 at various 10-1 -CC / 10-1-0 mass ratios ranging from 2.2-4.2 and incorporation of PG as a viscosity enhancer. All of the series C SMEIDS prepared flowable liquids except SMEIDS 14.19 which incorporated curcumin at 14.2 w / w%. When curcumin was incorporated at 14.2 w / w% in SMEIDS 14.19, the opaque microemulsion self-assembled and destabilized 7 days after self-assembly. When curcumin was incorporated at 3.4-7.0 w / w% in SMEIDS 14.20-14.29, translucent and transparent microemulsions self-assembled which destabilized by 14 days after self-assembly. Some of the self-assembled microemulsions destabilized by 7 days after self-assembly that incorporated curcumin at 4.9-7.0 w / w% with PG ranging from 10.0-29.4% w / w% and tS / O lower than 15.4 (SMEIDS 14.21-14.23). With the curcumin composition lower than 2.0 w / w%, translucent or transparent microemulsions self-assembled and maintained stability up to 7 days after selfassembly (SMEIDS 14.26-14.29). The 10-1-CC / 10-1-0 mass ratio ranged from 2.2-4.0 with the tS / O mass ratio above 35.4. However, these microemulsions destabilized by 14 days after selfassembly. Therefore, incorporating curcumin at less than 2 w / w% with the addition of PG to blends that contain 10-1-CC to 10-1-0 mass ratios of 2.2-4.0 provides flowable SMEIDS that self-assembled into translucent or transparent microemulsions while maintaining stability up to 7 days after self-assembly.

[0066] Series D found in Table 14 and the self-assembled microemulsions include SMEIDS codes 14.30-14.46 that focus on the mixture of 10- 1 -CC with 10-1-0 at various 10-1-CC / 10-1-0 mass ratios ranging from 2.6-4.5, or each surfactant alone, and incorporation of PG, SO, andeLA at various compositions. The incorporation of PG ranging from 8.6-35.5 w / w% permitted the SMEIDS to remain flowable with curcumin compositions ranging from 4.7-10.5 w / w% (14.30-14.38). Some of the self-assembled microemulsions were opaque and destabilized before 7 days after self-assembly (SMEIDS 14.30-14.32). The SMEIDS that incorporated curcumin ranging from 4.7-6.6 w / w% self-assembled into translucent or transparent microemulsions except using either 10-1-CC or 10-1-0 alone with eLA (SMEIDS 14.39, 14.40). This shows that the combination of either 10-1-CC and 10-1-0 with eLA unexpectedly decreases the microemulsion size relative to using each surfactant alone. The mixture of caprylate, caprate, and oleate may also pack better in the oil core of the microemulsion when curcumin is present. Six SMEIDS with a curcumin composition lower than 2.7 w / w% unexpectedly resulted in both flowable and transparent SMEIDS when cooled to room temperature that self-assembled into translucent or transparent (SMEIDS 14.41-14.46). These formulations unexpectedly maintained their translucency or transparency for up to 14 days after self-assembly where the 10-1-CC to 10- 1-0 mass ratio was above 2.9 in all formulations. Incorporating SO up to 5.0 w / w% did not interfere with the microemulsion self-assembly and stability while decreasing the tS / O mass ratio to 10.8 (SMEIDS 14.45, 14.46). SO easily interacts and dissolves with the caprate, caprylate, and oleate components of the surfactants located in the oil core of the microemulsions. The stable self-assembled microemulsions tolerated the incorporation of eLA up to 4.0% (SMEIDS 14.41). Incorporating eLA in the SMEIDS containing both 10-1-CC and 10-1-0 provided an unexpected result of stable self-assembled microemulsions for up to 14 days when incorporating curcumin compositions lower than 2.7 w / w%. In addition, self-assembling translucent or transparent microemulsions is possible when incorporating eLA and curcumin in the range of 4.7-5.5 w / w% to maintain stability up to 7 days after self-assembly. It is noted that transparent microemulsions are indications that the diameters of the microemulsions are less than 150 nm, whereas translucent microemulsions would indicate that the microemulsion diameter is larger than 150 nm. A select number of unstable SMEIDS along with the stable SMEIDS will proceed to the investigation of self-assembly in simulated gastric and intestinal fluids.Example 3. SMEIDS Dispersion in Fasted-state Simulated Gastric Fluid

[0067] Select SMEIDS tabulated in the previous tables were investigated for self-assembly in simulated gastric fluid in a fasted state. Exemplary fasted state simulated gastric fluid (FaSSGF,Biorelevent.com Ltd.) includes, but is not limited to, dissolution medium containing taurocholate (0.08 millimole [mM]), phospholipids (0.02 mM), sodium (34 mM), chloride (59 mM), and pH 1.6. It is noted that an academic publication investigated resting volumes of gastric components in fasted and fed states.1Gastric fluids in a fed state introduce complex factors such as the variable food that may be consumed coupled with variable gastric volumes. If the selected SMEIDS were provided to a consumer, they would be preferably instructed to ingest the SMEIDS on an empty stomach, or in a fasted state. The fasted stomach, otherwise known as fasted gastric fluid, contained 35 ± 7 mL (mean ± SEM) of resting water and the gastric fluid rose to 242 ± 9 mL upon drinking a cup of water (240 g). The gastric water volume declined rapidly after that with a half-emptying time of 13 ± 1 min. The mean gastric volume returned to baseline 45 min after the drink. A consumer would preferably ingest a softgel containing 0.68 g of the SMEIDS formulations, with a standardized cup of water that has a volume of 240 g. Once the softgel expectedly disintegrates in the stomach, the SMEIDS would be diluted 353-fold. Therefore, the selected SMEIDS were diluted 353-fold in FaSSGF with temperatures maintained at 37±2 °C and the self-assembled microemulsion was monitored for up to six hours. The visual scores for the homogeneity of the emulsion are as follows: transparent microemulsion with no observed precipitation or phase-separation = score 5, translucent microemulsion with no observed precipitation or phase-separation = score 4, opaque microemulsions with no observed precipitation or phase-separation = score 3, observed phase separation or sedimentation = score 2, observed precipitation or crystalization = score 1.

[0068] Table 16. SMEIDS compositions with curcumin (cure.), Polyaldo 10-1-CC (10-1-CC), Polyaldo 10-1-0 (10-1-0), Caprol (3GO), ethyl lauroyl arginate (eLA), sunflower oil (SO), and propylene glycol (PG) along with their respective SMEIDS codes. The mass ratios of total surfactants (10-1-CC, 10-1-0, 3GO, eLA) to the oil phase (Cur, SO) [tS / O] are shown.

[0069] Table 17. The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 16 incubated in Fasted State Simulated Gastric Fluid (FaSSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0083.

[0070] Series A of the SMEIDS found in Table 16 incorporated curcumin in the range of 7.0- 10.5 w / w% with PG present along with eLA present or absent. The three SMEIDS were tested in FaSSGF at 37 °C at appropriate dilutions that self-assembled into opaque or translucent microemulsions which resulted in all microemulsions destabilizing within 45 minutes as shown in Table 17 (SMEIDS 14.32, 14.33, 4.3). The microemulsions did not precipitate but sedimented at the bottom of the tube indicating that the microemulsions increased in size and were no longer soluble in the FaSSGF. The addition of PG and eLA did not aid the stability of the selfassembled microemulsions. The total surfactant to oil (tS / O) mass ratios for the three SMEIDS were lower than 11.9 indicating that there is an insufficient amount of surfactant to stabilize selfassembled microemulsions encapsulating curcumin. The incubation at 37 °C and acidic conditions, pH 1.6, along with the sodium present in FaSSGF interact with the polyglycerol units in the microemulsions further destabilizing the self-assembled microemulsions. These results clearly show that SMEIDS incorporating curcumin at compositions higher than 7.0 w / w% are unstable when diluted in FaSSGF at 37 °C.

[0071] Series B of the SMEIDS found in Table 16 incorporated curcumin in the range of 4.7-5.4 w / w% with PG present along with eLA present or absent. This series shows a direct comparison of SMEIDS incorporating only one surfactant with eLA (SMEIDS 14.39, 14.40), two surfactant systems with PG (SMEIDS 14.22-14.24), and two surfactant systems with PG and eLA (SMEIDS 14.35-14.38). Self-assembly of the one surfactant system with eLA in FaSSGF at 37 °C resulted in translucent microemulsions that destabilized after 1.5 hours (SMEIDS 14.39, 14.40). Self-assembly of the two surfactant systems with PG in FaSSGF at 37 °C resulted in translucent microemulsions that were destabilized by sedimentation in the range of 0.75-3.50 hours (SMEIDS 14.22-14.24). Specifically, SMEIDS 14.22 incorporated curcumin at 5.0 w / w% with PG at 29.4 w / w% and the self-assembled microemulsions destabilized within 0.75 hours in FaSSGF at 37 °C. SMEIDS 14.23 and 14.24 incorporated PG at 19.4 and 9.5 w / w% and destabilized within 3.0 and 3.5 hours, respectively. The tS / O mass ratios of the previously mentioned SMEIDS ranged from 13.1 to 18.3, but destabilization occurred within 3.5 hours. Directly comparing similar PG compositions and incorporating eLA in two surfactant systems, an unexpected stability enhancement was observed as seen in the stability results of SMEIDS14.36-14.38 in FaSSGF at 37 °C. While the tS / O mass ratios are similar between SMEIDS 14.22-14.24 and 14.36-14.38, the addition of the third surfactant, eLA, in SMEIDS 14.36-14.38 enhances the stability of self-assembled microemulsions which are translucent for up to 6 hours in FaSSGF at 37 °C. Specifically comparing SMEIDS 14.22 and 14.36, which included PG at around 28 w / w%, SMEIDS 14.36 demonstrated stability for up to 6 hours mainly due to the eLA present at 3.0 w / w%. Identical interpretations are made with the SMEIDS containing around 20% PG (SMEIDS 14.23, 14.37) and 10% PG (SMEIDS 14.24, 14.38). The self-assembled microemulsion using SMEIDS 14.35 destabilized after 3 hours as the tS / O mass ratio was reduced to below 12.4 with 35.6 w / w% PG and 4.0 w / w% eLA. These stability results strongly indicate that the two surfactant systems with eLA can be stable in FaSSGF if the tS / O remains higher than 13.3 as captured in SMEIDS 14.36. It is also noted that 3 hours of stability in FaSSGF was 3 times passed the expected residency time in gastric fluid in a fasted state, and these microemulsions are deemed stable for gastric release. However, it would be conservative to select SMEIDS 14.36-14.38 as the self-assembled microemulsions show durable stability in FaSSGF. Series B of Table 16 highlights the unexpected benefit of incorporating eLA in SMEIDS that contain curcumin at around 5 w / w%.

[0072] Series C of the SMEIDS found in Table 16 incorporated curcumin in the range of 1.7-3.4 w / w% with eLA, SO, 3GO, and PG present or absent. All of the microemulsions self-assembled from series C SMEIDS remained stable transparent, translucent, or opaque microemulsions for up to 6 hours at 37 °C, except for SMEIDS 14.4. SMEIDS 14.4 included a 10-1-CC to the combination of 10-1-0 and 3GO mass ratio of 2.8 which may explain the instability results in FaSSGF. Excluding SMEIDS 14.45 and 14.46, the tS / O mass ratios of the Series C SMEIDS were above 25.4 which explains the stability of the self-assembled microemulsions in FaSSGF for up to 6 hours. A benefit to microemulsion stability was not observed when incorporating the SO up to 4.9% (SMEIDS 14.45, 14.46) as the SMEIDS that incorporated curcumin at lower than 3.4 w / w% self-assembled into microemulsions with durable stability. It is noted that transparent microemulsions are indications that the diameters of the microemulsions are less than 150 nm, whereas translucent microemulsions would indicate that the microemulsion diameter is larger than 150 nm. As most of these formulations were stable in FaSSGF for up to 6 hours, it was also not possible to capture the benefits of eLA with SMEIDS incorporating curcumin at compositions lower than 3.4 w / w%.Example 4. SMEIDS Dispersion in Fasted-state Simulated Intestinal Fluid

[0073] Select SMEIDS tabulated in Table 16 were investigated for self-assembly in simulated intestinal fluid in a fasted state. Exemplary fasted state simulated intestinal fluid (FaSSIF) can be sourced from, but is not limited to, Biorelevent.com Ltd. that prepares dissolution medium containing taurocholate (3 mM), phospholipids (0.75 mM), sodium (148 mM), chloride (106 mM), phosphate (29 mM), and pH 6.5. It is noted that an academic publication investigated resting volumes of intestinal components in fasted and fed states.1The intestinal fluid in a fed state is variable and dependent on the food that may be consumed which also varies the intestinal fluid volume. If the selected SMEIDS were provided to a consumer, they would be preferably instructed to ingest the SMEIDS on an empty stomach, or in a fasted state. After 45 minutes of a consumer drinking a cup of water, the 240 mL of water emptied the stomach and the intestinal water volume was measured at 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL. Some commercially available capsules and softgels target the disintegration of the capsule or softgel in the intestines, called enteric capsules or softgels, bypassing the acidic environment found within the stomach. Enteric capsules or softgel shells comprise polymers that do not disintegrate in the acidic gastric fluid and delay the disintegration by targeting intestinal fluid conditions such as a neutral pH of 6.5. Once the enteric capsule or softgel that carries 0.68 g of SMEIDS expectedly disintegrates in the intestine, the SMEIDS would be diluted 113-fold in intestinal fluid.

[0074] Therefore, the selected SMEIDS were diluted 113-fold in FaSSIF with temperatures maintained at 37±2 °C and the self-assembled microemulsion was monitored for up to six hours. The visual scores for the homogeneity of the emulsion are as follows: transparent microemulsion with no observed precipitation or phase-separation = score 5, translucent microemulsion with no observed precipitation or phase-separation = score 4, opaque microemulsions with no observed precipitation or phase-separation = score 3, observed phase separation or sedimentation = score 2, observed precipitation or crystalization = score 1.

[0075] Table 18. The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 16 incubated in fasted state simulated intestinal fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0089.

[0076] Series A of the SMEIDS found in Table 16 ncorporated curcumin in the range of 7.0-10.5 w / w% with PG present along with eLA present or absent. Overall, series A of the SMEIDS found in Table 16 showed relatively durable stability in FaSSIF as shown in Table 18 when compared to FaSSGF. All of the Series A formulations were stable for up to 1.75 hours which is passed the expected residency time in intestinal fluid. In contrast, SMEIDS 14.32 and 14.33 both destabilized within 15 minutes in FaSSGF. The durable stability in FaSSIF is likely due to the near-neutral pH, pH = 6.5. The SMEIDS incorporating curcumin at higher than 7.0 w / w% arelikely candidate formulations to be used with enteric capsules or softgels where the gastric environment is preferably bypassed.

[0077] Series B of the SMEIDS found in Table 16 incorporated curcumin in the range of 4.7-5.5 w / w% with PG present along with eLA present or absent. The self-assembled microemulsion from each SMEIDS This series shows a direct comparison of SMEIDS incorporating only one surfactant with eLA (SMEIDS 14.39, 14.40), two surfactant systems with PG (SMEIDS 14.22- 14.24), and two surfactant systems with PG and eLA (SMEIDS 14.35-14.38). Interestingly, the one surfactant SMEIDS with eLA self-assembled into translucent microemulsions in FaSSIF that destabilized within 4.5 hours at 37 °C (SMEIDS 14.39-14.40). Similar but delayed destabilization is observed for the SMEIDS incorporating two surfactants with PG where SMEIDS 14.22-14.24 self-assembled into microemulsions that were stable in FaSSIF for up to3.5 hours at 37 °C. For reference, SMEIDS 14.22 self-assembled into opaque microemulsions that destabilized within 45 minutes in FaSSGF at 37 °C. Similar self-assembled microemulsion stability enhancements are captured in FaSSIF for two surfactant SMEIDS with PG up to 27.0 w / w% and eLA up to 3.0 w / w% (SMEIDS 14.36-14.38). Interestingly, the two surfactants SMEIDS 14.35 incorporating PG at 35.6 w / w% and eLA at 4.0 w / w% self-assembled into transparent microemulsions that devolved into opaque microemulsions and destabilized after 5 hours in FaSSIF at 37 °C. For reference, SMEIDS 14.35 self-assembled into microemulsions that destabilized within 3.5 hours in FaSSGF at 37 °C. An unexpected stability enhancement is observed again when directly comparing the microemulsions with eLA absent, SMEIDS 14.22- 14.24, to eLA present, SMEIDS 14.36-14.38. Therefore, SMEIDS 14.36-14.38 may be filled in conventional capsules or softgels that disintegrate in gastric fluid or enteric capsules or softgels that disintegrate in intestinal fluid showing similar self-assembled microemulsion stability. From the perspective of the stability of the active ingredient, curcumin, it would be a conservative decision to bypass the gastric conditions and self-assemble the microemulsion in intestinal fluids. The unexpected stability enhancement of incorporating eLA with curcumin at around 5.0 w / w% in the self-assembled microemulsions was captured again when incubated in FaSSIF conditions similar to the self-assembled microemulsion stability enhancements when incubated in FaSSGF.

[0078] Series C of the SMEIDS found in Table 16 incorporated curcumin in the range of 1.7-3.4 w / w% with PG present along with 3 GO, SO, and eLA present or absent. All of the Series C SMEIDS self-assembled into microemulsions that demonstrated stability in FaSSIF for up to 6hours at 37 °C, excluding SMEIDS 14.4. SMEIDS 14.4 self-assembled into unstable microemulsions in FaSSGF similar to FaSSIF conditions which may be due to the 10-1-CC to the combination of 10-1-0, 3GO mass ratio of 2.8. It is noted that transparent microemulsions are indications that the diameters of the microemulsions are less than 150 nm, whereas translucent microemulsions would indicate that the microemulsion diameter is larger than 150 nm. As most of these formulations were stable in FaSSIF for up to 6 hours, it was not possible to capture the stability benefits of eLA with SMEIDS incorporating curcumin at compositions lower than 3.4 w / w%. These SMEIDS are both free of PEG and lecithin. Antioxidants and preservatives will be required to be added in the concentration range of 10-1,000 parts per million in order to preserve the chemical stability of the active ingredient.Example 5. Disintegration and Solubility of Curcumin in Simulated Gastric Fluid (SGF) of Commercially Available Supplements versus the Optimized SMEIDS

[0079] The curcumin solubility in SGF using six commercially available supplements containing curcumin that sold on Amazon.com and carried at least 6,000 customer reviews at the time of purchase was directly compared. As a reference, turmeric powder purchased from a grocery store was inserted into a capsule. The ingredients of the six commercially available curcumin supplements are listed in Table 19 along with our two optimized SMEIDS that incorporated eLA or not. One capsule or softgel was placed in a beaker that contained 250 mL of SGF containing 0.2 weight / volume% sodium chloride and 0.7 volume / volume% hydrogen chloride with a pH of 1.2. Each of these beakers was placed in an incubator shaker that was set to 37 °C. The solutions in each beaker were stirred for 30 seconds every 20 minutes. After 3 hours of incubation, 2.0 mL from each beaker was collected and then centrifuged at 3,000 rotations per minute (RPM) for 2 minutes. 1.0 mL of the supernatant was then filtered through a 0.45 nylon syringe filter and quantified for curcumin through High-Performance Liquid Chromatography (HPLC). The quantified HPLC results are shown in Table 20.

[0080] Table 19. List of ingredients in the commercially available curcumin supplements, turmeric purchased from a grocery store, and the optimized formulations discussed in this patent

[0081] Table 20. Quantitative HPLC Results of the Solubilized Curcumin in Simulated GastricFluid after 3 hours of incubation at 37 °C.supplements in SGF came back with expected results. In general, the six commercially available curcumin supplements demonstrated that more than 99.9% of curcumin that was packaged in the capsules or softgels did not dissolve and remain suspended in SGF after 3 hours of incubation at37 °C. As some of the commercially available curcumin supplements included turmeric root (Curcuma longa) as the dominant ingredient, it was assumed that this ingredient included at most 2% curcumin. Some of the commercially available curcumin supplements also included turmeric extract standardized to 95% curcuminoids, of which 77% of the curcuminoids are curcumin as reported in academic literature. The curcumin mass solubilized per 250 mL is quantified by HPLC analysis and then extrapolated to the 250 mL volume of SGF used in the incubation period. As seen in Table 20, the commercially available curcumin supplements demonstrated insignificant enhancement of the solubility of curcumin when compared to turmeric powder purchased from a grocery store. Piper nigrum, which is included in C1-C3 competitors, coconut oil, included in the C4 competitor, and ginseng extract and ginger root, included in the C5 competitor, did not enhance the solubility of curcumin in SGF. The gamma-cyclodextrin, included in the C6 competitor, was anticipated to increase the solubility of curcumin in SGF but HPLC analysis confirms that an insignificant mass of curcumin was solubilized and stable during incubation in SGF. The turmeric powder solubility also came back as expected as curcumin is known to exhibit very poor water-solubility. If you averaged the solubilized curcumin per 250 mL from the 6 commercially available curcumin supplements and turmeric powder bought from the grocery store, then the average curcumin solubilized in 250 mL of SGF is 0.016 mg or 64 nanograms / mL (ng / mL). This is in line with the reported curcumin solubility of 11 ng / mL in water.2The increase in curcumin solubility in SGF is most likely due to lower pH and salt. In conclusion, ingesting turmeric powder purchased from a grocery store is as efficient as ingesting the mentioned curcumin supplements in terms of solubilizing curcumin in SGF.

[0083] The optimized SMEIDS, with eLA absent or present, discussed in this patent performed as expected in a third-party laboratory. The SMEIDS OS1 and OS2 included around 6.4 mg of curcumin per capsule. Once these capsules disintegrated in the SGF, the self-assembled microemulsions were sufficiently stable for the 3 -hour incubation period. After filtering through a 0.45 nylon syringe filter and extrapolating to the SGF volume of 250 mL, 5.438 mg and 5.490 mg of curcumin were unexpectedly quantified to be solubilized in SGF for SMEIDS OS1 and OS2, respectively. Interestingly. SMEIDS OS2 contained eLA that unexpectedly resulted in 0,053 mg more curcumin solubilized in SGF relative to SMEIDS OS1. This is an extension of the microemulsion stability enhancement that was visually observed in FaSSGF in Table 17 (SMEIDS 14.23 and 14.37). The missing 0.0530 mg in using SMEIDS OS1 formulation mayhave precipitated and captured in the centrifuge pellet or the microemulsions grew in size to be filtered out when using the 0.45 nylon syringe filter. Using the averaged curcumin solubilized at 0.016 mg per 250 mL from the six commercially available curcumin supplements and turmeric purchased from a grocery store, there is a 339- and 343 -fold solubility enhancement using SMEIDS OS1 and OS2. It is anticipated that the enhanced curcumin solubility confirmed in this study using SMEIDS OS1 and OS2 will significantly increase the bioavailability of curcumin when administered to animals or patients.Example 6. SMEIDS Incorporating either Resveratrol or Coenzyme Q10 and Dispersion Analysis in Boiling water, Fasted State Simulated Gastric Fluid, or Fasted State Simulated Intestinal Fluid.

[0084] We wanted to explore if the optimized SMEIDS is also capable of incorporating and encapsulating other natural health ingredients that share similar hydrophobic properties as curcumin. For this expansion, resveratrol and coenzyme Q10 were chosen as two hydrophobic active ingredients that both exhibit very poor water solubility. An optimal mass ratio of 10-1 -CC to 10-1-0 has been concluded from the previous paragraphs as 3.0-4.5. Therefore, targetting the 10-1-CC: 10-1-0 mass ratio at 4.0 while maintaining PG at around 18 w / w% and eLA at around 2 w / w% will be used as a SMEIDS template to incorporate either resveratrol or coenzyme Q10 alone ranging from around 2.5-10.0 w / w%. The four SMEIDS containing either resveratrol or coenzyme Q10 are found in Table 21.

[0085] Table 21. SMEIDS compositions with either resveratrol (Resv.) or Coenzyme Q10 (COQ10), and Polylado 10-1-CC (10-1-CC), Polyaldo 10-1-0 (10-1-0), propylene glycol (PG), and ethyl lauroyl arginate (eLA) along with the 10-1-CC / 10-1-0 and total surfactant (10-1-CC, 10-1-0, eLA) to oil phase (Resv. or COQIO) [tS / O] mass ratios.boiling water the day of as well as 7 and 14 days after self-assembly. The visual scores on the formulated water-free SMEIDS are as follows: crystalization where the SMEIDS is opaque and not flowable at room temperature, score = 0, SMEIDS that is opaque, devoid of crystalization but also not flowable at room temperature, score = 1, SMEIDS that is translucent or transparent, devoid of crystalization, and not flowable at room temperature, score = 2, and SMEIDS that is translucent or transparent, devoid of crystalization, and flowable at room temperature, score = 3. The visual scores for the self-assembled SMEIDS are as follows: crystalization, phase separation, or coalescence, score = 0, opaque microemulsion, score = 1, translucent microemulsion, score = 2, transparent microemulsion, score = 3.

[0087] Table 22. Observations of the formulated SMEIDS and diluted SMEIDS in boiling water after 6 hours, 7 days, and 14 days. Visual scores are defined in paragraph 00103 and the SMEIDS codes are referenced from Table 21.flowable oils at room temperature mainly due to the PG compositions of around 18 w / w% (SMEIDS 21.1-21.4). Six hours after self-assembly in boiling water, each of the SMEIDS self-assembled into opaque microemulsions that destabilized within 7 days. These results would indicate a concern however the expected residency time of the microemulsions in gastric fluid is less than 45 minutes and in intestinal fluid is less than an hour. The microemulsion stability test in FaSSGF and FaSSIF would be more appropriate to gauge the suitability of the SMEIDS systems.

[0089] The SMEIDS containing coenzyme Q10 ranging from 2.7-9.4 w / w% is easily homogenized into either flowable or non- flowable oils at room temperature (SMEIDS 21.5- 21.8). Only SMEIDS 21.5 that contained coenzyme Q10 at 2.7 w / w% remained flowable whereas coenzyme Q10 at 5.1 w / w% or higher solidified when cooled to room temperature. An interesting observation is that all of the SMEIDS containing coenzyme Q10 solidified the next day potentially due to coenzyme Q10 packing with the fatty acids of the surfactants employed. All of the solidified oils containing coenzyme Q10 were investigated by melting and liquefying at the physiologically relevant temperature of 37 °C. To clarify, SMEIDS containing coenzyme Q10 would be heated for homogenization and then inserted into either capsules or softgels that would then solidify overnight. The solidified product would be consumed by the individual where the solidified product would melt, liquify, and disperse in either gastric or intestinal fluids. When self-assembled in boiling water, SMEIDS 21.5 and 21.6 self-assembled into transparent microemulsions while SMEIDS 21.7 and 21.8 self-assembled into opaque microemulsions.Therefore, maintaining the composition of coenzyme Q10 lower than 5.1 w / w% in SMEIDS aids in the self-assembly of transparent microemulsions that are expected to be less than 150 nanometers in diameter. Similar to the SMEIDs containing resveratrol, all of the SMEIDs containing coenzyme Q10 destabilized within 7 days after self-assembly. The microemulsion stability test in FaSSGF and FaSSIF would be more appropriate to gauge the suitability of the SMEIDS systems.

[0090] Table 23. The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 21 incubated in Fasted State Simulated Gastric Fluid (FASSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0089.

[0091] Table 24. The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 21 incubated in Fasted State Simulated Intestinal Fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0089.

[0092] With a similar stable self-assembled system with curcumin, SMEIDS incorporating resveratrol was found to be stable in both FaSSGF and FaSSIF. Specifically, SMEIDS incorporating resveratrol at 2.6 or 4.9 w / w% demonstrated unexpected stability in both FaSSIF and FaSSGF for up to 6 hours at 37 °C (SMEIDS 21.1, 21.2). The tS / O mass ratio in SMEIDS 21.2 was 15.6 indicating that this is the minimum tS / O mass ratio to ensure stability of the selfassembled microemulsions encapsulating resveratrol in both FaSSGF and FaSSIF for up to 6 hours at 37 °C. SMEIDS 21.3 incorporated resveratrol at 7.5 w / w% and the self-assembled microemulsion destabilized within 0.75 hours in FaSSGF and 1.50 hours in FaSSIF. SMEIDS 21.4 incorporated resveratrol at 9.8 w / w% and the self-assembled microemulsion destabilized within 0.25 hours in FaSSGF and 1.25 hours in FaSSIF. In both destabilized cases, the selfassembled microemulsions grew in size and were sedimented at the bottom of the tube where nocrystalization or precipitation was observed. Antioxidants and preservatives can be added to minimize the degradation and oxidation of the active ingredient, resveratrol if required. These SMEIDS are both free of PEG and lecithin. The stable SMEIDS 21.1 and 21.2 are suitable candidates that can either self-assemble in gastric or intestinal conditions. However, from the perspective of the active ingredient stability, it is preferred to release the self-assembled microemulsion containing resveratrol in the intestinal fluid to bypass the harsh gastric conditions.

[0093] Different stability patterns are observed for SMEIDS containing coenzyme Q10 where only one of the four formulations was stable in both FaSSGF and FaSSIF. SMEIDS 21.5 incorporated coenzyme QI 0 at 2.7 w / w% and self-assembled into transparent microemulsions in both FaSSGF and FaSSIF which maintained stability in both FaSSGF and FaSSIF for up to 6 hours at 37 °C. Therefore, the tS / O mass ratio should range around 30 in order to ensure the stability of the self-assembled microemulsions in FaSSGF and FaSSIF. SMEIDS 21.6 incorporated coenzyme Q10 at 5.1 w / w% and self-assembled into transparent microemulsions that crystalized in FaSSGF within 3.0 hours and in FaSSIF within 2.5 hours at 37 °C. Both of these time points are passed the expected residency time of the microemulsions in gastric and intestinal conditions and this result is determined to be stable. SMEIDS 21.7 and 21.8 incorporated coenzyme Q10 at 7.3 and 9.4 w / w% and self-assembled into transparent or translucent microemulsions that quickly and similarly crystallized at 0.75 and 1.25 hours in FaSSGF and FaSSIF, respectively. If required, antioxidants and preservatives can be added to minimize the degradation and oxidation of the active ingredient, resveratrol. These SMEIDS are both free of PEG and lecithin. SMEIDS 21.5 is a suitable formulation for coenzyme QI 0 that can be dispersed in either gastric or intestinal conditions. However, from the perspective of the stability of the active ingredient, coenzyme Q10, it is preferred to release the SMEIDS in the intestinal fluid to bypass the harsh gastric conditions.

[0094] The optimized SMEIDS template is capable of incorporating and encapsulating other active ingredients that share similar hydrophobic properties as curcumin. For this expansion, active ingredients that exhibit poor or very poor water solubility are preferable candidates that were described in paragraph 0018. An optimal mass ratio of 10-1 -CC to 10-1-0 has been concluded from the previous paragraphs as 3.0-4.5. The composition of PG can range from 10- 40 w / w% while the composition of eLA can range from 1-4 w / w% in the total SMEIDScomposition. These SMEIDS are both free of PEG and lecithin. Antioxidants and preservatives can be added to minimize the degradation and oxidation of the active ingredient if required.Example 7. Powderized Curcumin SMEIDS

[0095] The invention of SMEIDS and filling liquid into softgels is one manufacturing pathway however another manufacturing pathway includes filling powders into capsules. In this manufacturing pathway, the liquified SMEIDS may be plated or captured onto powder plating agents to convert the liquids into powders. Table 25 indicates a master stock composition of the possible SMEIDS using POGylated. Tables 26-36 include the compositions of the indicated hydrophobic ingredient, curcumin, along with the surfactants listed in those tables. Curcumin is indicated in the following tables, but SMEIDS is not limited to curcumin and can include other hydrophobic ingredients that exhibit poor or very poor water solubility. Table 42 indicates the compositions of the liquified SMEIDS that are converted to plated powders using the compositions stated in the table. The main result of the plated powder is it produces free-flowing powders that can be easily incorporated into food products, gel products, and pellets. The solids produced by the encapsulation process yielded flowable powders with resting angles near 30°, and particles ranging from 2 to 10 microns that make the powders amenable to integration into solid products to be incorporated into capsules. The plating agent includes, but is not limited to, cellulose, microfine cellulose, microcrystalline cellulose, dicalciumphosphate dihydrate, zein powder, magnesium carbonate, dextrin, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, hyalonic acid, silica dioxide, fiber, citrus fiber, oligofrustose, rice bran powder, Dehydol OD5, alpha-lactose monohydrate, anhydrous lactose, spray dried alpha-lactose monohydrate, granulated alpha-lactose monohydrate, and combinations thereof. The plated SMEIDS can be processed further to blend with other powders conventionally used to fill powders into capsules to fine-tune the compressibility, flowability, tensile strength.

[0096] Table 25. Master stock composition breakdown of SMEIDS used to blend with a plating agent to be processed further or filled into capsules.

[0097] Table 26. Master stock composition breakdown of SMEIDS containing curcumin and Polyalso 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.

[0098] Table 27. Master stock composition breakdown of SMEIDS containing curcumin andPolyaldo 10-1-0 used to blend with a plating agent to be processed further or filled into capsules.

[0099] Table 28. Master stock composition breakdown of SMEIDS containing curcumin andPolyaldo 10-1-L used to blend with a plating agent to be processed further or filled into capsules.

[0100] Table 29. Master stock composition breakdown of SMEIDS containing curcumin andPolyaldo 10-1-P used to blend with a plating agent to be processed further or filled into capsules.

[0101] Table 30. Master stock composition breakdown of SMEIDS containing curcumin and Caprol MPGO used to blend with a plating agent to be processed further or filled into capsules.

[0102] Table 31. Master stock composition breakdown of SMEIDS containing curcumin andCaprol PGE860 used to blend with a plating agent to be processed further or filled into capsules.

[0103] Table 32. Master stock composition breakdown of SMEIDS containing curcumin and Caprol 3 GO used to blend with a plating agent to be processed further or filled into capsules.

[0104] Table 33. Master stock composition breakdown of SMEIDS containing curcumin, ethyl lauroyl, arginate and Polyaldo 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.

[0105] Table 34. Master stock composition breakdown of SMEIDS containing curcumin andPolyaldo 10-1-0 used to blend with a plating agent to be processed further or filled into capsules.

[0106] Table 35. Master stock composition breakdown of SMEIDS containing curcumin and Polyaldo 10-1-0 and Polyaldo 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.

[0107] Table 36. Master stock composition breakdown of SMEIDS containing curcumin and Polyalso 10-1-L, Polyaldo 10-1-0 and Polyaldo 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.

[0108] Table 37. Master stock composition breakdown of the plated powder blended with the SMEIDS indicated in Tables 26-36 with a plating agent to be processed further or filled into capsules.Example 8. SMEIDS mixing and encapsulating in softgels at industrial scale

[0109] The viscosity of the formulation should normally be in the range of 50-1000 ePoise (=0.05-1 Pas) at the temperature chosen for the filling process. For the filling of the formulation into softgel capsules, the process temperature is not allowed to exceed 30-40 °C (the temperature depends on the manufacturer). The formulation must be liquid and have a viscosity that allows it to be pumpable at the filling temperature. SMEIDS can also fill into soft or hard gelatin capsules. Soft gelatin capsules are manufactured and filled in one operation and may be filled at temperatures of up to 40 °C. Hard gelatin capsule may be filled with temperatures up to 70 °C. Hard gelatin capsules filled with compositions that remain liquid at storage temperature require sealing to prevent leakage, for example, gelatin banding. The process of liquid filling of hard gelatin capsules and product requirements are described, in W. J. Bowtie, Pharmaceutical Technology Europe, October 1998: V.M. Young, Pharmaceutical Manufacturing and Packaging Sourcer, March 1999: and E.T. Coole. Pharmaceutical Technology International.September / October 1989. Additionally, capsules may be processed further, for example, byenteric coating. An example of the homogeneous mixing of SMEIDS and then encapsulating in softgels is described below:

[0110] a) SMEIDS 14.37 is scaled up to 50 kg using identical compositions. The ingredients are weighed and placed into an appropriate stainless-steel vessel. Antioxidants, such as vitamin E, may be added in the range of 10-1,000 parts per million.

[0111] b) The mixture is then heated to the temperature range of 60-130 °C and stirred, using appropriate equipment, for 120 minutes. The SMEIDS is mixed until homogenous, per visual inspection.

[0112] c) The SMEIDS is allowed to cool to a temperature range of 20-40 °C where SMEIDS has sufficient viscosity to be filled and encapsulated in softgels

[0113] d) The cooled SMEIDS is then utilized in an appropriate semi-automatic or automatic softgel filling machine where SMEIDS is encapsulated in a softgel

[0114] e) Appropriate drying, quality control, and polishing of the softgels proceed afterwards.

[0115] It will be clear to one having skill in the art that further variations to the specific details disclosed herein can be made, resulting in other embodiments that are within the scope of the invention disclosed. All parameters, quantities, proportions, and configurations described herein are examples only and may be changed depending on the specific embodiment. Accordingly, the scope of the invention is to be construed in accordance with the substance defined by the following claims.

Claims

CLAIMSWhat is claimed is:

1. A composition for water-insoluble active ingredients, comprising: a microemulsion pre-concentrate devoid of water, PEG and lecithin; wherein the microemulsion pre-concentrate comprises: a water insoluble active ingredient; a first polygly ceryl- containing (POGylated) surfactant; a polyol; and a preservative.

2. The composition of claim 1, further comprising a second POGylated surfactant.

3. The composition of claim 2, wherein the mass ratio of the first POGylated surfactant to the second POGylated surfactant is 3.0 to 4.5 and the total POGylated surfactant comprises 50 to 98% weight / weight (w / w%) of the microemulsion pre-concentrate.

4. The composition of claim 1 or claim 2, wherein at least one of the first surfactant and the second surfactant comprises a cationic surfactant.

5. The composition of claim 1 or claim 2, wherein: the water insoluble active ingredient comprises 0.1-10.0 %w / w; the polyol comprises 5 to 40% w / w; the first surfactant comprises 50 to 98% w / w; the second surfactant comprises 0 to 50% w / w; and the preservative comprises 0.001 to 0.100%.

6. The composition of claim 1 or claim 2, wherein the water-insoluble active ingredient comprises at least one water-insoluble active ingredient with water solubility of less than 0.2 mg / ml.

7. The composition of claim 1 or claim 2, wherein the first POGylated surfactant comprises polyglyceryl- 10 caprate / caprylate (Polyaldo 10-1-CC).

8. The composition of claim 2, wherein the second POGylated surfactant comprises at least one of:Polygly ceryl-3 stearate; Polygly eery 1-3 oleate (Caprol 3 GO); Polyglyceryl-3 laurate; Polyglyceryl-3 caprylate; Polyglyceryl-3 palmitate; Polyglyceryl-3myristate; Polyglyceryl- 10 Hydroxystearate; Polyglyceryl-4 Caprate; Polyglyceryl- 4 Caprylate; Polygly ceryl- 10 Eicosadioate; Polyglyceryl- 10 Behenate;Polyglyceryl-4 Laurate; Polyglyceryl-4 Isostearate; Polyglyceryl- 10 Oleate (POLY ALDO® 10-1-0); Polyglyceryl- 10 Stearate; Polyglyceryl-4 Oleate; Polygly eery 1-5 Laurate; Polygly ceryl-8 Oleate; Polyglyceryl-8 Stearate; Polygly ceryl- 10 Palmitate; Polygly ceryl- 10 Isostearate; Polyglyceryl- 10 Laurate; Polyglyceryl- 10 Myristate; Polygly ceryl-5 Myristate; Polygly ceryl-5 Isostearate; Polyglyceryl- 5 Stearate; Polygly ceryl-6 Isostearate; Polygly eery 1-6 Stearate; Polygly ceryl-5 Oleate;Polygly ceryl-6 Oleate; Polyglyceryl- 10 fatty ester (POLY ALDO® 10-2-P);Polygly ceryl- 10 Caprylate / Caprate (POLY ALDO® 10-1-CC) and Polyglyceryl- 10 Heptahydroxystearate; Polyglyceryl-5 Triisostearate; Polygly eery 1-5 Dioleate; Polygly ceryl- 10 Pentastearate; Polyglyceryl- 10 Pentahydroxy stearate;Polyglyceryl-5 Trioleate; Polyglyceryl-6 Tricaprylate; Polyglyceryl- 10 Distearate;Polygly ceryl- 10 Tristearate; Polyglyceryl-6 Dioleate; Polyglyceryl-6 Distearate;Polygly ceryl- 10 Pentaoleate; Polygly ceryl- 10 Decaoleate; Polyglyceryl-6 Pentastearate; Polyglyceryl-6 Octastearate; Polygly ceryl- 10 Decaisostearate; Polygly ceryl- 10 Di oleate; Polyglyceryl-8 Decaerucate; Polyglyceryl-8 Decaisostearate; Polyglyceryl- 10 Pentaisostearate; Polyglyceryl- 10 Nonaisostearate; Polygly ceryl- 10 Dipalmitate; Polyglyceryl-8 Decaricinoleate;Poly glyceryl- 10 Diisostearate; and polyglycerol esters of inter-esterified castor oil fatty acids.

9. The composition of claim 1 or claim 2, wherein the polyol comprises at least one of propylene glycol and glycerol.

10. The composition of claim 1 or claim 2, wherein the microemulsion pre-concentrate is converted into a powder using a plating powder comprising at least one of:Cellulose; microfine cellulose; microcrystalline cellulose; dicalciumphosphate dihydrate; zein powder; magnesium carbonate; dextrin; dextrose; dextrates; dextran; starches; pregelatinized starch; sucrose, xylitol, lactitol; mannitol; sorbitol; sodium chloride; hyalonic acid; silica dioxide, fiber, citrus fiber; oligofrustose; rice bran powder; Dehydol OD5; alpha-lactose monohydrate; anhydrous lactose; spray dried alpha-lactose monohydrate; and granulated alpha-lactose monohydrate.

11. A method for making a SMEIDS composition, the method comprising combining: a water-insoluble active ingredient; a first POGylated surfactant; a polyol; and a preservative.

12. The method of claim 11, further comprising combining a second POGylated surfactant.

13. The method of claim 11 or claim 12, wherein at least one of the first and second POGylated surfactant comprises a cationic surfactant.

14. The method of claim 11 or claim 12, further comprising containing the SMEIDS composition in a softgel capsule.

15. The method of claim 11 or claim 12, wherein the SMEIDS composition is diluted and self-assembled in at least one of an aqueous medium, a gastric fluid and an intestinal fluid; and further wherein the average diameter of the self-assembled SMEIDS is less than 300 nm.

16. The method of claim 11 or claim 12, wherein the self-assembled SMEIDS is stable in simulated gastric or intestinal fluid for at least two hours at 37° C.

17. A method for using a SMEIDS composition, the method comprising: administering the composition by at least one of: systemic, parenteral, oral, intrathecal, intraarticular, nasal, opthalmic and topical administration; wherein the SMEIDS composition comprises: a water-insoluble active ingredient; a first POGylated surfactant; a polyol; and a preservative.

18. The method of claim 17, wherein the SMEIDS composition further comprises a second POGylated surfactant.

19. The method of claim 17 or claim 18, wherein at least one of the first and second POGylated surfactants comprises a cationic surfactant.

20. The method of claim 17, wherein the administration is by oral administration and the SMEIDS composition is encapsulated in a capsule of softgel before oral administration.

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