Peg- and lecithin-free self-assembling microemulsions carrying cannabinoids and methods for use thereof

Abstract

The present invention relates to compositions in the form of PET- and lecithin-free microemulsion preconcentrates that contain at least one cannabinoid, at least one polyglyceryl- containing surfactant, at least one polyol and a preservative. When contacted with either an aqueous medium, gastric or intestinal fluid, the microemulsion preconcentrates self-assemble into microemulsions that are stable in gastric and intestinal fluids. The invention is also related to methods of making and methods of using the microemulsion preconcentrates.

Description

TITLE: PEG- AND LECITHIN-FREE SELF-ASSEMBLING MICROEMULSIONS CARRYING CANNABINOIDS AND METHODS FOR USE THEREOFFIELD

[0001] The present invention relates to microemulsions and more specifically to PEG- and lecithin-free microemulsions carrying a cannabinoid.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. The bioavailability of an active ingredient, denoting the concentration of the active ingredient entering systemic circulation, is a critical parameter in the nutraceutical and pharmaceutical industry. Active ingredients are further defined as providing a biologically active or other direct effect in the diagnosis, mitigation, prevention, treatment or cure of a disease or affecting the structure or any function of the body of humans or animals.

[0003] IDS encompass various formulations, including emulsions, nanoemulsions, and microemulsions. 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) represent water-free microemulsion preconcentrates that exhibit properties akin to microemulsions upon dilution and self-assembly in aqueous environments. The evolution of diverse IDS types has led to their application across various sectors, including pharmaceuticals, nutraceuticals, and cosmetics.

[0004] 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.

[0005] Within the realm of potential IDS characterized by these advantageous attributes, SMEIDS emerge as particularly captivating. The intrinsic nanoscale dimensions of SMEIDS self-assembled in aqueous environments carry a pivotal role in enhancing the uptake and bioavailability of active ingredients. Embedded within SMEIDS self-assembled in aqueous environments, these nanoscale colloidal dispersions exist in a state of thermodynamic equilibrium, demonstrating diameters ranging from 1 to 500 nm. This dimensional spectrum facilitates the unhindered conveyance of active components through constricted pores. The pursuit of nanometer-sized diameters in SMEIDS self-assembled in aqueous environments is underpinned by the aspiration to optimize the surface area- to- volume ratio. SMEIDS offers two discernible advantages relative to conventional emulsions. Firstly, their manufacturing process does not utilize specialized high-shear methods; instead, mild mixing suffices. Secondly, SMEIDS self-assembled in aqueous environments exist as thermodynamically stable microemulsions, mitigating the requisite for supplementary stabilizing agents resulting ineconomically streamlined compositions. The water-free SMEIDS compositions boast a high concentration of oil and surfactants, enabling a robust loading capacity for active ingredients. This characteristic not only facilitates ease of manufacture but also ensures biological stability by effectively inhibiting microbial growth due to low water activity. In essence, the integration of these features within SMEIDS presents a multifaceted and elegant solution for effective IDS.

[0006] 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. Consequently, there is a growing awareness that cosmetic, pharmaceutical, and food products incorporating PEGylated ingredients may induce anti-PEG antibodies, potentially influencing the clearance dynamics of future applied PEGylated formulations.

[0007] In recent years, cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), have undergone legalization in numerous countries. The inherent hydrophobic nature of these compounds, with water solubilities typically below 3 milligrams per liter (mg / L), has spurred the development of innovative water-soluble formulations such as nanoemulsions and microemulsions. These compositions have notably elevated the water solubilities of cannabinoids to an impressive 50,000 mg / L.14A noteworthy variant among microemulsions is the advent of CBD-containing SMEIDS, which have been meticulously compared to the traditional delivery method involving CBD and mixed chain triglyceride (MCT) oil — a prevalent carrier in the cannabis industry. The CBD-containing SMEIDS have exhibited substantial enhancements, revealing a 2.9-fold increase in the area under the curve (AUCo-sh) and a remarkable 4.4-fold surge in the maximum concentration measured in the plasma (Cmax).15In practical terms, this implies that consumers could ingest significantly less CBD — 4.4-fold less — through the CBD-containing SMEIDS to achieve equivalent therapeutic effects as compared to the conventional CBD and MCT oil formulation. Moreover, the CBD-containing SMEIDS have demonstrated a threefold acceleration in the time to achieve maximum concentration in the plasma (Tmax) relative to the conventional CBD and MCT oil formulation. This suggests that consumers can experience the therapeutic effects of CBD threefold faster, particularly evident one-hour post-consumption. It is noteworthy that the ingredients utilized in these highlighted SMEIDS, as well as other formulations revealed in the prior art, heavily feature PEG, commonly known as PEGylated ingredients. While PEGylated ingredients offer convenient manufacturing solutions for converting hydrophobic active ingredients like CBD and THC, they are not without drawbacks. Undesirable downstream effects in consumers have been associated with PEGylated ingredients, potentially compromising their consistent performance.SUMMARY

[0008] Various embodiments disclosed herein are drawn towards water-insoluble active ingredients incorporated in microemulsion pre-concentrates, alternatively named selfmicroemulsifying ingredient delivery systems (SMEIDS), that are devoid of water, PEG, and lecithin.

[0009] In some aspects, the techniques described herein relate to a composition for waterinsoluble active ingredients, including: a microemulsion pre-concentrate devoid of water, PEG and lecithin; wherein the microemulsion pre-concentrate includes: a water insoluble active ingredient; a first polyglyceryl-containing (POGylated) surfactant; a polyol; and a preservative.

[0010] In some aspects, the techniques described herein relate to a method for making a microemulsion pre-concentrate composition devoid of water, PEG and lecithin, the method including combining: a water-insoluble active ingredient; a first POGylated surfactant; a polyol; and a preservative.

[0011] In some aspects, the techniques described herein relate to a method for using a microemulsion pre-concentrate composition, the method including: administering the microemulsion pre-concentrate composition by at least one of: systemic, parenteral, oral, intrathecal, intraarticular, nasal, ophthalmic and topical administration; wherein the microemulsion pre-concentrate composition includes: a water-insoluble active ingredient; a first POGylated surfactant; a polyol; and a preservative.

[0012] 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

[0013] As used herein and in the appended claims, the terms “approximately” and “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.

[0014] 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.

[0015] 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 and the like. "Consisting of’ shall mean excluding more than trace elements of other ingredients and substantial method steps for administering the compositions of this disclosure.

[0016] 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.

[0017] As used herein, the term “active ingredient” is meant to refer to any cannabinoid. Active ingredients can be naturally sourced or synthesized. Examples of active ingredients include butare not limited to: Tetrahydrocannabinolic acid A (THCA-A), Tetrahydrocannabinolic acid B (THCA-B), Tetrahydrocannabinol (THC), Tetrahydrocannabinolic acid C (THCA-C), Tetrahydrocannbinol C (THC-C), Tetrahydrocannabi varinic acid (THCVA), Tetrahydrocannabivarin (THCV), Tetrahydrocannabior colic acid (THCA-C), Tetrahydrocannabiorcol (THC-C), Delta-7-cis-iso-tetrahydrocannabi varin, A- tetrahydrocannabinolic acid (A8-THCA), A-tetrahydrocannabinol (A- THC), Cannabidiolic Acid (CBDA), Cannabidiol (CBD), Cannabidiol monomethyl ether (CBDM), Cannabidiol-C(CBD-C), Cannabidivarinic Acid (CBDVA), Cannabidivarin (CBDV), Cannabidiorcol (CBD-C), Cannabigerolic Acid (CBGA), Cannabigerolic Acid monomethylether (CBGAM), Cannabigerol (CBG), Cannabigerol monomethylether (CBGM), Cannabigerovarinic Acid (CBGVA), Cannabigerovarin (CBGV), Cannabichromenic Acid (CBCA), Cannabichromene (CBC), Cannabichromevarinic Acid (CB CVA), Cannabichromevarin (CBCV), Cannabicyclolic acid (CBLA), Cannabicyclol (CBL), Cannabicyclovarin (CBLV), Cannabielsoic add A (CBEA-A), Cannabielsoic add B (CBEA-B), Cannabielsoin (CBE), Cannabinolic add (CBNA), Cannabinol (CBN), Cannabinol methylether (CBNM), Cannabinol-C(CBN-C), Cannabivarin (CBV), Cannabino-C(CBN-C), Cannabiorcol (CBN-C), Cannabinodiol (CBND), Cannabinodivarin (CBDV), Cannabitriol (CBT), 10-Ethoxy-9-hydroxy-A"-tetrahydrocannabinol, 8.9- Dihydroxy-A& #39; -tetrahydrocannabinol (8.9-Di-OH CBT-C), Cannabitriolvarin (CBTV), Ethoxy-cannabitriol varin (CBTVE), Dehydrocannabifuran (DCBF), Cannbifuran (CBF), Cannabichromanon (CBCN), Cannabicitran (CBT), lO-Oxo-A& #39; -tetrahydrocannabinol (OTHC), A-cis-tetrahydrocannabinol (cis-THC), Cannabiripsol (CBR), 3,4,5,6-tetrahydro-7- hydroxy-alpha-alpha-2-trim, ethyl-9-n-propyl-2,6-methano-2H- 1 -benzoxocin-5-methanol (OH- iso-HHCV), Trihydroxy-delta-9-tetrahydrocannabinol (triCH-THC), Isocanabinoids, Epigallocatechin gallate or combinations thereof.

[0018] As used herein, the term “terpene” is meant to refer to P-Myrcene, D-Limonene, P- Ocimene, y-Terpinene, a-Terpinene, a-Terpineol, a-Pinene, P-Pinene, Linalool, Camphene, Terpinolene, a-Phellandrene, y-Cadinene, A3-Carene, p-Cymene, fenchol, 1, 8-cineole (eucalyptol), P-Caryophyllene, Caryophyllene Oxide, Humulene, (a-Caryophyllene), P-Elemene, Guaiol, Eudesmol Isomers, Nerolidol, Gurjunene, y-Cadinene, P-Farnesene, carvone, taxadiene, squalene, geraniol, geranyl farnesol, lycopene or mixtures thereof; or antioxidants, fat-soluble vitamins, fatty acids, carotenoids, hormones, metabolic factors, phytochemicals, phytonutrients, phytosterols and vitamin derivatives.

[0019] 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.

[0020] 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.Nanomulsions are formulated by encapsulating active ingredients through high-energy processes, specifically high-pressure homogenization, ultrasonication, and others. Nanoemulsions may be prepared without surfactants to produce oil-in-water systems that result in highly unstable formulations due to droplet coalescence The principal constituent within nanoemulsions is waterwith other constituents such as surfactants, carrier oils, sugars, polyols, preservatives, and antioxidants.

[0021] 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. This type of microemulsion is also referred to as droplet microemulsions or swollen micelle systems. 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.

[0022] 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, in the conventionally recognized sense, 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.

[0023] 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 has insignificant 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.

[0024] 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).

[0025] 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).

[0026] 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.

[0027] As used herein, the term “poly(ethylene glycol)-containing” or “PEGylated” is meant to refer to a surfactant, polymer, microemulsion, nanoemulsion, or SMEIDS that contains poly(ethylene) glycol. Other names for polyethylene glycol include polyethylene oxide or polyoxyethylene. Examples of PEGylated surfactants include but are not limited to: octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, triton x-100, polyethoxylated tallow amine, polyethylene glycol nonyl phenyl ether, cocamide diethanoloamine, poloxamers, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, arlacel 165, arlacel 170, ethoxylated 25 alcohols such as Brij, Tergitol NP- 40 and NP-70, polysorbates, polyoxyethanyl- cholesterol-sebacate (PCS), polyoxyethanyl-tocopheryl- sebacate, poly oxy ethanyl- ubiquinol-sebacate poly oxy ethanyl-sitosterol-sebacate, D-a-Tocopherol polyethylene glycol 1000 succinate (TPGS) and related polyethylene gly col-modified tocopheryl derivatives.

[0028] As used herein, the term “poly(ethylene glycol)-free” or “PEG-free” is meant to refer to formulations that do not contain PEGylated ingredients described in the previous paragraph but are not limited to the disclosed PEGylated ingredients.

[0029] 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.

[0030] 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. Examples of cationic surfactants include but are not limited to: ethyl lauroyl arginate, benzalkonium chloride, benzethonium chloride (BZT), cetrimonium bromide (CTAB), cetyl pyridinium chloride (CPC), octenidine dihydrochloride, dimethyldioctadecylammonium chloride, dioctadecyldimethylammonium bromide (DODAB), cetyltrimethylammonium chloride.

[0031] 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. Examples of POGylated surfactants include but are not limited to: Polyglyceryl-3 stearate, Polyglyceryl-3 oleate, Polyglyceryl-3 laurate, Polyglyceryl-3 caprylate, Polyglyceryl-3 palmitate, Polyglyceryl-3 myristate, Polygly ceryl- 10 Hydroxy stearate, Polyglyceryl-4 Caprate, Polyglyceryl-4 Caprylate, Polyglyceryl- 10 Eicosadioate, Polygly ceryl- 10 Behenate, Polyglyceryl-4 Laurate, Polyglyceryl-4 Isostearate, Polyglyceryl- 10 Oleate, Polygly ceryl- 10 Stearate, Polyglyceryl-4 Oleate, Polyglyceryl-5 Laurate, Polyglyceryl-8 Oleate, Polyglyceryl-8 Stearate, Polyglyceryl- 10 Palmitate, Polyglyceryl- 10 Isostearate, Polyglyceryl- 10 Laurate,Polyglyceryl- 10 Myristate, Polygly eery 1-5 Myristate, Polyglyceryl-5 Isostearate, Polyglyceryl- 5 Stearate, Polyglyceryl-6 Isostearate, Polyglyceryl-6 Stearate, Polyglyceryl-5 Oleate, Polygly eery 1-6 Oleate, Polyglyceryl- 10 fatty ester (POLY ALDO® 10-2-P), Polyglyceryl- 10 Caprylate / Caprate and Polyglyceryl- 10, Heptahydroxystearate, Polyglyceryl-5 Triisostearate, Polyglyceryl-5 Dioleate, Polyglyceryl- 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, Polyglyceryl- 10 Pentaoleate, Polyglyceryl- 10 Decaoleate, Polyglyceryl-6 Pentastearate, Polyglyceryl-6 Octastearate, Polyglyceryl- 10 Decaisostearate, Polygly eery 1-10 Di oleate, Polyglyceryl-8 Decaerucate, Polygly eery 1-8 Decaisostearate, Polyglyceryl- 10, Pentaisostearate, Polyglyceryl- 10 Nonaisostearate, Polyglyceryl- 10 Dipalmitate, Polyglyceryl-8 Decaricinoleate, Poly glyceryl- 10 Diisostearate, polyglycerol esters of interesterified castor oil fatty acids, and combinations thereof.

[0032] As used herein, the term “carrier oil” is meant to refer to edible oils that are formulated in SMEIDS that include but are not limited to: medium-chain triglycerides (MCT), short-chain triglycerides, glyceryl monooleate, glyceryl monolinoleate, glyceryl palmitate, glyceryl palmitostearate, glyceryl ricinoleate, glyceryl esters of saturated fatty acids, glyceryl behenate, behenic acid, capry lie / capric glycerides sesame oil or coconut oil and a mineral oil, cannabis oil (hemp oil), coconut oil, cottonseed oil, soybean oil, glyceryl distearate, glyceryl isostearate, glyceryl aurate, glyceryl stearate, Amaranth oil, apricot oil, apple seed oil, argan oil, avocado oil, Acai oil, Almond oil, beech nut oil, babassu oil, Brazil nut oil, bitter gourd oil, bottle gourd oil, ben oil, bomeo tallow nut oil, black seed oil, blackcurrent seed oil, borage seed oil, butternut squash seed oil, cape chestnut oil, carob pod oil, cocoa butter, cocklebur oil, cohune oil, coriander seed oil, cashew oil, canola oil, coconut oil, com oil, cottonseed oil, date seed oil, dika oil, extra virgin olive oil, eugsi seed oil, evening primrose oil, false flax oil, flaxseed oil, grape seed oil, grapefruit seed oil, hazelnut oil, hemp oil, kapok seed oil, kenaf seed oil, lallemantia oil, lemon oil, macadamia oil, mongongo oil, marula oil, meadowfoam seed oil, mustard oil, niger seed oil, nutmeg butter, orange oil, okra seed oil, olive oil, papaya seed oil, persimmon seed oil, pequi oil, pili nut oil, pomegranate seed oil, poppyseed oil, praeaxi oil, prune kernel oil, seed oil perilla seed oil, palm oil, peanut oil, pecan oil, pine nut oil, pistachio oil, pumpkin seed oil, quinoa oil, ramtil oil, rice bran oil, royle oil, rapeseed oil, safflower oil, sacha inchi oil, sapote oil, seje oil, shea butter, sesame oil, soybean oil, Extra Virgin Olive Oil, taramira oil, tea seed oil, thistle oil, tigemut oil, tobacco seed oil, tomato seed oil, virgin olive oil, walnut oil, watermelon seed oil, wheat germ oil, and combinations thereof.

[0033] As used herein, the term “reducing agent” or “antioxidant” is meant to refer to ingredients that act as a reducing agent with antioxidant capabilities that include but are not limited to: vitamin E and its variations, vitamin C, ubiquinol, L-ascorbic acid-8-palmitate, or combinations thereof.

[0034] 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.Examples

[0035] The following non-limiting Examples are illustrative of the present disclosure:Example 1: SMEIDS with THC and / or CBD at Various Compositions with stability in FaSSGF and FaSSIFExample 2. Powderized THC and / or CBD SMEIDSExample 3. SMEIDS mixing and encapsulating in softgels at industrial scaleExample 1: SMEIDS with THC and / or CBD at Various Compositions with stability in FaSSGF and FaSSIF

[0036] Exemplary CBD isolate (CBDi, 99% purity) can be sourced from, but not limited to, from True North Cannabis. Exemplary THC distillate (THCd, 94% purity) can be sourced from, but not limited to, The Green Room. Exemplary polyglyeryl-10 oleate (Polyaldo 10-1-0, 10-1- O) 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). Exemplary propylene glycol (PG, 99.9% purity and USP grade) can be sourced from, but not limited to, Fusion Flavours. Mirenat-N (90% PG and 10% ethyl lauroyl arginate) can be sourced from, but not limited to, Vedeqsa. Beta- Caryophyllene (bCar, 90-100% purity) can be sourced from, but not limited to, Vigon (item # 500796). Mixed-chain triglyceride (MCT) oil can be sourced from, but not limited to, Jedwards (SKU # Cl 000). Exemplary polygly eery 1-3 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 polygly ceryl-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).

[0037] The following SMEIDS formulations were prepared according to the compositions listed in Tables 1, 4, 7, 10, and 13. The surfactants were individually warmed in a water bath with water set at 85-95 °C for at least 15 minutes. THCd oil was prepared by mixing THCd, MCT oil, and bCar at a 1: 1: 1 mass ratio with heating up to 55 °C. CBDi or THCd oil was carefully added into scintillation vials followed by the surfactant listed in tables 1, 4, 7, 10 and 13 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 SMIEDS.[00381 Table 1. SMEIDS codes and compositions with CBD isolate (CBDi) or THC distillate oil (THCd oil comprising THC distillate, MCT oil, and beta-caryophyllene), Polyaldo 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 surfactants (surf.) to oil (CBDi or THCd oil) mass ratios.

[0039] SMEIDS compositions were firstly investigated for the active ingredient loading capacity to understand the limits of CBD or THC loading in the microemulsion preconcentrates. The SMEIDS system derives from the previous developments incorporating curcumin in SMEIDS where stable self-microemulsifying systems included 10-1-CC to 10-1-0 mass ratio of 3.0-4.5 with propylene glycol and ethyl lauroyl arginate compositions above 10 and 1 w / w%, respectively. CBDi or THCd oil was incorporated in the derived SMEIDS system ranging from 2.4-10.2 w / w%. THCd oil was firstly prepared by blending THC distillate with MCT oil and bCar at a 1:1 :1 mass ratio to produce a liquid that is easier to dispense. The addition of a terpene, bCar, was added as a viscosity enhancer as well as the potential benefits surrounding the terpene upon ingestion. After cooling the SMEIDS, no crystallization was observed for a month while maintaining flowable liquids at room temperature (18-25 °C).

[0040] SMEIDS included in Tables 1, 4, 7, 10 and 13 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), and chloride (59 mM) with pH 1.6. Gastric fluids in a fed state introduce complex factors such as the various food types and beverages 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 ± standard error of the mend [SEM]) of resting water and the gastric fluid rose to 242 ± 9 mL upon drinking a cup of water (240 g). The gastric water volumedeclined 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, each of the SMEIDS in Table 1, 4, 7, 10, and 13 were diluted 353-fold in FaSSGF with temperatures maintained at 37±2 °C and the self-assembled microemulsions were monitored for up to six hours. The visual scores for the homogeneity of the microemulsion are as follows: transparent microemulsion with no observed precipitation or phase-separation = score 5, translucent microemulsion with no observed precipitation or phaseseparation = score 4, opaque microemulsions with no observed precipitation or phase-separation = score 3, observed phase separation or sedimentation = score 2, observed precipitation or crystallization = score 1.

[0041] Table 2, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 1 incubated in fasted state simulated gastric fluid (FaSSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0042] SMEIDS presented in Table 1 were appropriately diluted in FaSSGF and the selfassembled microemulsions were monitored for 6 hours as shown in Table 2. Stable and transparent self-assembled microemulsions were unexpectedly formed and maintained in FaSSGF for 6 hours with SMEIDS 1.1, 1.2, 1.5, and 1.6 which incorporated CBDi or THCd oil at compositions ranging from 2.4-4.9 w / w%. As the THCd oil compositions increased to 7.2 and 9.5 w / w%, gel-like sedimentation at the bottom of the tube was observed at 4 and 5 hours for SMEIDS 1.3 and 1.4 respectively. Interestingly, SMEIDS 1.3 initially self-assembled into transparent microemulsions that devolved into translucent microemulsions after 30 minutes in FaSSGF. SMEIDS 1.4 immediately self-assembled into translucent microemulsions indicative of nearing the upper limit on THCd oil loading in the SMEIDS. SMEIDS 1.7 and 1.8 incorporatedCBDi at 7.8 and 10.2 w / w%, respectively, and showed accelerated destabilization where the gellike sediment was observed after 2 hours for both SMEIDS. Interestingly, SMEIDS 1.8 initially self-assembled into translucent microemulsions that devolved into opaque microemulsions within 15 minutes in FaSSGF. Directly comparing the self-assembled stability results of SMEIDS 1.4 to 1.8, it seems that the incorporation of bCar and MCT oil as viscosity enhancers for the THCd oil has extended to provide enhanced stability of self-assembled microemulsions. To clarify, SMEIDS 1.8 incorporated CBDi at 10.2 w / w% while SMEIDS 1.4 incorporated THCd at 3.2 w / w%. An unexpected result is focussed on SMEIDS that can self-assemble into stable microemulsions with total surfactants to oil phase (CBDi, or THCd, MCT oil, and bCar) mass ratios as low as 7.1. For example, a similar SMEIDS system incorporated curcumin at around 10 w / w% that destabilized within 15 minutes in FaSSG at 37 °C. As consumed water empties from the gastric stage in 45 minutes, all the SMEIDS investigated in Table 1 are classified as stable self-assembled microemulsions for the gastric stage. It is preferable to bypass the gastric fluid due to the acidic environment by the use of enteric capsules or softgels that selectively aim to disintegrate in the neutral intestinal fluid.

[0043] SMEIDS included in Table 1 were investigated for self-assembly in simulated intestinal fluid in a fasted state (FaSSIF). 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 the 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. Therefore, the selected SMEIDS were diluted 113-fold in FaSSIF with temperatures maintained at 37±2 °C and the selfassembled microemulsion was monitored for up to six hours. The visual scores for the homogeneity of the microemulsion 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 crystallization = score 1.

[0044] Table 3, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 1 incubated in fasted state simulated intestinal fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0045] SMEIDS presented in Table 1 were appropriately diluted in FaSSIF and the selfassembled microemulsions were monitored for 6 hours at 37 °C as shown in Table 3. Stable and transparent self-assembled microemulsions were unexpectedly formed and maintained in FaSSIF for 6 hours with SMEIDS 1.1, 1.2, 1.5, and 1.6 which incorporated CBDi or THCd oil at compositions ranging from 2.4-4.9 w / w%. Both SMEIDS 1.5 and 1.6 were self-assembled into transparent microemulsions that devolved into translucent microemulsions after 30 minutes in FaSSIF that maintained stability for up to 6 hours. SMEIDS 1.3 and 1.4 self-assembled into microemulsions that were stable for up to 4.5 hours in FaSSIF at 37 °C. Importantly, SMEIDS 1.3 self-assembled into transparent microemulsions that were maintained for up to 5 hours in FaSSIF at 37 °C. For reference, SMEIDS 1.3 self-assembled into transparent microemulsions in FaSSGF that devolved into translucent microemulsions within 30 minutes. The self-assembled microemulsion stability of SMEIDS 1.3 and 1.4 in FaSSIF is slightly longer relative to the stability of the self-assembled microemulsions in FaSSGF. This indicates that the acidic pH of the FaSSGF plays a role in self-assembled microemulsion stability. The same observation is observed with SMEIDS 1.7 and 1.8 which maintained stability in FaSSIF for up to 4 and 3 hours, respectively. For reference, SMEIDS 1.7 and 1.8 formed the gel-like sediment within 2 hours when incubated in FaSSGF at 37 °C. As all of the SMEIDS demonstrated stability in FaSSIF for up to 3 hours, they are deemed stable for self-assembly in intestinal fluid. These SMEIDS are both free of PEG and lecithin. Antioxidants and preservatives can be optionally added in the concentration range of 10-1,000 parts per million to preserve the chemical stability of the active ingredients. The PG may be replaced with other viscosity enhancers such as, but not limited to, glycerol, oligofructose, inulin, and PEG which is less than 2,000 daltons (or grams per mole).The PG and eLA compositions were held constant in all SMEIDS, and we wanted to investigate if PG can be varied along with eLA either absent or varied in compositions.[00461 Table 4, SMEIDS codes and compositions with CBD isolate (CBDi) and Polyaldo 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 to 10-1-0 and total surfactants (surf.) to oil (CBDi or THCd oil) mass ratios.

[0047] SMEIDS compositions incorporating CBDi at around 7.5 w / w% were further investigated with varied PG and eLA compositions in the microemulsion preconcentrates as shown in Table 4. As SMEIDS 1.7 incorporated CBDi at 7.8 w / w% which demonstrated instability in both FaSSGF and FaSSIF, the CBDi composition was also maintained at 7-8 w / w% to investigate the stability enhancements of PG and eLA for the self-assembled microemulsions. PG was incorporated in the range of 8.6-39.3 w / w% either alone or with eLA with compositions ranging from 1-4 w / w%. Single surfactant systems were also investigated using only 10-1-CC or 10-1-0. After cooling the SMEIDS, no crystallization was observed for a month while maintaining flowable liquids at room temperature (18-25 °C).

[0048] Table 5, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 4 incubated in fasted state simulated gastric fluid (FaSSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0049] SMEIDS presented in Table 4 were appropriately diluted in FaSSGF and the selfassembled microemulsions were monitored over a period of 6 hours at 37 °C as shown in Table 5. Stable and translucent self-assembled microemulsions were unexpectedly formed and maintained in FaSSGF for 6 hours with SMEIDS 4.4 and 4.10. SMEIDS 4.4 incorporated PG at 35.9 w / w% and eLA at 4 w / w% while maintaining the 10-1 -CC / 10-1-0 mass ratio at 3.8 whereas SMEIDS 4.10 incorporated 10-1 -CC alone with PG at 18.3 w / w% and eLA at 2.0 w / w%. Interestingly, SMEIDS 4.1 -4.4 demonstrate that the reduced composition of PG and eLA resulted in relatively less stable self-assembled microemulsions as SMEIDS 4.1 destabilized by crystallization within 1 hour in FaSSGF at 37 °C. A similar observation applies to SMEIDS 4.5- 4.8 with eLA absent where longer stability is maintained when PG is incorporated at 39.3 w / w% in SMEIDS 4.8. For reference, SMEIDS 4.5 surprisingly destabilized by gel-like sedimentation within 2 hours while SMEIDS 4.8 destabilized by crystallization within 4 hours in FaSSGF at 37 °C. The single surfactant systems incorporating 10-1-CC unexpectedly self-assembled into translucent microemulsions using SMEIDS 4.9 and 4.10. A gel-like sediment was observed in the eLA-absent SMEIDS 4.9 within 5 hours in FaSSGF at 37 °C while incorporating eLA at 2 w / w% in SMEIDS 4.10 maintained stability for up to 6 hours. Using 10-1-0 as the only surfactant in SMEIDS 4.11 and 4.12 resulted in opaque self-assembled microemulsions that are indicative of microemulsions with relatively larger diameters that show accelerated destabilization relative to one-surfactant systems using 10-1-CC. For reference, the singlesurfactant systems using 10-1-0, SMEIDS 4.11 and 4.12, destabilized within 3 and 4.5 hours in FaSSGF at 37 °C, respectively. As consumed water empties from the gastric stage at 45 minutes,all the SMEIDS investigated in Table 1 are classified as stable self-assembled microemulsions for the gastric stage. However, it is preferable to bypass the gastric fluid due to the acidic environment by the use of enteric capsules or softgels that selectively aim to disintegrate in the neutral intestinal fluid.

[0050] Table 6, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 4 incubated in fasted state simulated intestinal fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0051] SMEIDS presented in Table 4 were appropriately diluted in FaSSIF and the selfassembled microemulsions were monitored over a period of 6 hours at 37 °C as shown in Table 6. Stable transparent and translucent self-assembled microemulsions were unexpectedly formed and maintained in FaSSIF for 6 hours with SMEIDS 4.1-4.3. SMEIDS 4.4 self-assembled into translucent microemulsions that maintained its stability for up to 5.5 hours in FaSSIF. SMEIDS 4.4-4.8 showed signs of instability after 5.5 hours in FaSSIF with crystallization. In these cases with eLA present or not and PG ranging from 8.6-39.3 w / w%, SMEIDS 4.1-4.8 self-assembled into stable microemulsions that maintained stability for up to 5 hours in FaSSIF at 37 °C. The single-surfactant systems incorporated 10-1-CC, SMEIDS 4.9 and 4.10, also maintained stability for up to 5 hours in FaSSIF at 37 °C. The single-surfactant system incorporating 10-1-0, SMEIDS 4.11 and 4.12, self-assembled into opaque microemulsions that demonstrated durable stability in FaSSIF relative to stability in FaSSGF. These SMEIDS are both free of PEG and lecithin. Antioxidants and preservatives can be optionally added in the concentration range of 10-1,000 parts per million to preserve the chemical stability of the active ingredients. The PG may be replaced with other viscosity enhancers such as, but not limited to, glycerol, oligofructose, inulin, and PEG which is less than 2,000 daltons (or grams per mole). As a consumed glass of water has an expected residency time of 1 hour at the intestinal stage, all of the SMEIDS in Table 6 are deemed stable for disintegration and dissolution in intestinal fluid.F00521 Table 7, SMEIDS codes and compositions with THC distillate oil (THC distillate, MCT oil, and beta-caryophyllene), Polyaldo 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 to 10-1-0 and total surfactants (surf.) to oil (THCd oil) mass ratios.

[0053] SMEIDS compositions incorporating THCd oil were further investigated with various PG and eLA compositions in the microemulsion preconcentrates. As SMEIDS 1.4 incorporated THCd oil at 9.5 w / w% which demonstrated instability in both FaSSGF and FaSSIF within 6 hours, the THCd oil composition was also maintained at around 10 w / w% to investigate the stability enhancements of PG and eLA for the self-assembled microemulsions. PG was incorporated in the range of 9.0-39.3 w / w% either alone or with eLA with compositions ranging from 1-4 w / w%. Single surfactant systems were also investigated using only 10-1-CC or 10-1-0 with PG and either eLA present or absent. After cooling the SMEIDS, no crystallization was observed for a month while maintaining flowable liquids at room temperature (18-25 °C).

[0054] Table 8, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 7 incubated in fasted state simulated gastric fluid (FaSSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0055] SMEIDS presented in Table 7 were appropriately diluted in FaSSGF and the selfassembled microemulsions were monitored for 6 hours at 37 °C as shown in Table 8. Stable and translucent self-assembled microemulsions were unexpectedly formed and maintained in FaSSGF for 6 hours with SMEIDS 7.3, 7.4, and 7.9-7.12. A similar observation is made again with stability enhancements when appropriate levels of eLA are incorporated in SMEIDS 7.3 and 7.4. SMEIDS 7.1 incorporated PG at 9.0 w / w% with eLA at 1.0 w / w% which formed a gel-like sediment within 3 hours in FaSSGF at 37 °C. The microemulsions destabilized into a transparent gel-like sediment but this will need to be quantified to determine the ratio of CBD and THC in the sediment compared to CBD and THC that remains solubilized in the FaSSGF. The transparent gel-like sediment can potentially comprise free polyglycerol esters of fatty acids that do not contain CBD or THC due to the hydrogen bonding in the polyglycerol chains. The SMEIDS that were absent of eLA showed an accelerated destabilization relative to SMEIDS incorporating eLA. For example, SMEIDS 7.8 incorporated PG at 39.3 w / w% that destabilized within 2.5 hours in FaSSGF at 37 °C. It was unexpected that the single-surfactant systems with eLA present or absent maintained their stability for the duration of the investigation. As the gastric fluid is acidic, it is preferable to bypass the gastric fluid with the use of enteric capsules of softgels that selectively aim to disintegrate in the neutral intestinal fluid.

[0056] Table 9, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 7 incubated in fasted state simulated intestinal fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0057] SMEIDS presented in Table 7 were appropriately diluted in FaSSIF and the selfassembled microemulsions were monitored over a period of 6 hours at 37 °C as shown in Table 9. All of the SMEIDS in Table 7 self-assembled into either transparent, translucent, or opaque microemulsions and unexpectedly maintained stability in FaSSIF at 37 °C for 6 hours. It seems that the incorporation of MCT oil and bCar at around 3.2 w / w% facilitates enhanced selfassembled microemulsion stability. For clarity, each of the SMEIDS in Table 7 incorporated THCd at around 3.2 w / w%. These SMEIDS are also noted to be free of PEG and lecithin. Antioxidants, such as vitamin E, may be added in the range of 10-1,000 parts per million. The PG may be replaced with other viscosity enhancers such as, but not limited to, glycerol, oligofructose, inulin, and PEG which is less than 2,000 daltons (or grams per mole).[00581 Table 10. SMEIDS codes and compositions with CBD isolate (CBDi), THC distillate oil (THC distillate, MCT oil, and beta-caryophyllene), Polyaldo 10-1-CC (10-1-CC), Polyaldo 10-1- O (10-1-0), propylene glycol (PG), and ethyl lauroyl arginate (eLA) along with the 10-1-CC to 10-1-0 and total surfactants (surf.) to oil (CBDi and THCd oil) mass ratios.

[0059] SMEIDS compositions were further investigated with varied PG and eLA compositions in the microemulsion preconcentrates incorporating both CBDi and THCd oil as shown in Table 10. The total oil composition of each of the SMEIDS in Table 10 cumulates to around 10 w / w% with around 5 w / w% CBDi and 1.6 w / w% of each of THCd, bCar, and MCT oil. PG was incorporated in the range of 8.8-29.5 w / w% either alone or with eLA with compositions ranging from 1-3 w / w%. Single surfactant systems were also investigated using only 10-1-CC or 10-1-0. After cooling of the SMEIDS systems, no crystallization was observed for a month while maintaining flowable liquids at room temperature (18-25 °C).

[0060] Table 11. The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 10 incubated in fasted state simulated gastric fluid (FaSSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0061] SMEIDS presented in Table 10 were appropriately diluted in FaSSGF and the selfassembled microemulsions were monitored for 6 hours at 37 °C as shown in Table 11. Stable and opaque self-assembled microemulsions were unexpectedly formed and maintained in FaSSGF for 6 hours with SMEIDS 10.9 and 10.10 using only 10-1-0. As these microemulsions selfassembled into opaque microemulsions, the diameter of the microemulsions is expected to be larger than 150 nanometers (nm) but these larger microemulsions were stable in FaSSGF at 37 °C for 6 hours. SMEIDS 10.1-10.8 formed either transparent or translucent microemulsions that maintained their stability in FaSSGF at 37 °C for 1.25 hours. The microemulsions destabilized into a transparent gel-like sediment. The transparent gel-like sediment can potentially comprise free polyglycerol esters of fatty acids that do not contain CBD or THC due to the hydrogen bonding in the polyglycerol chains. Stability enhancements were difficult to observe between formulations when comparing similar compositions of PG or eLA. Consumed water empties from the gastric stage at 45 minutes and therefore all the SMEIDS investigated in Table 10 are classified as stable self-assembled microemulsions. It is preferable to bypass the gastric fluid due to the acidic environment with the use of enteric capsules or softgels that selectively aim to disintegrate in the neutral intestinal fluid.

[0062] Table 12, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 10 incubated in fasted state simulated intestinal fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0063] SMEIDS presented in Table 10 were appropriately diluted in FaSSGF and the selfassembled microemulsions were monitored for 6 hours at 37 °C as shown in Table 11. Except for SMEIDS 10.9 and 10.10, transparent and translucent self-assembled microemulsions maintained their stability for up to 1.75 hours in FaSSIF at 37 °C. Significant stability enhancements are observed when eLA is incorporated maintaining the stability of the self-assembled microemulsions by up to 60 minutes. For example, SMEIDS 10.2 did not incorporate eLA and exhibited the transparent gel-like sediment within 2 hours in FaSSIF at 37 °C whereas SMEIDS 10.1 incorporated eLA at 1.0 ww / % and transparent gel-like sediment was formed within 3 hours in FaSSIF at 37 °C. The microemulsions destabilized into a transparent gel-like sediment. The transparent gel-like sediment can potentially comprise free polyglycerol esters of fatty acids that do not contain CBD or THC due to the hydrogen bonding in the polyglycerol chains. It was unexpected that the single surfactant system using 10-1-0 showed stability in FaSSGF but then formed a transparent gel-like sediment in FaSSIF within 1.5 hours. The single-surfactant system using 10-1-CC, SMEIDS 10.7-10.8, maintained the stability of the self-assembled microemulsion for up to 3 hours in FaSSIF, which is an enhanced stability relative to maintaining stability in FaSSGF for up to 2 hours. The expected residency time for selfassembled microemulsions in the intestinal stage is 1.5 hours indicating that SMEIDS 10.1-10.8 are classified as stable SMEIDS intended to dissolve in intestinal fluid. These SMEIDS are both free of PEG and lecithin. Antioxidants and preservatives can be optionally added in the concentration range of 10-1,000 parts per million to preserve the chemical stability of the active ingredients. The PG may be replaced with other viscosity enhancers such as, but not limited to, glycerol, oligofructose, inulin, and PEG which is less than 2,000 daltons (or grams per mole).

[0064] Table 13, SMEIDS codes and compositions with THC distillate oil (THC distillate, MCT oil, and beta-caryophyllene), CBD isolate (CBDi), propylene glycol (PG), ethyl lauroyl arginate (eLA) and either polyaldo 10-1-laurate (10-1-L), Caprol PGE 860 (PGE 860), Caprol MPGO (MPGO) or Caprol (3GO) and polysorbate 80 (PS80) along with the total surfactants (surf.) to oil (CBDi and THCd oil) mass ratios.

[0065] SMEIDS compositions using single-surfactant systems were further investigated by incorporating both CBDi and THCd oil and maintaining PG and eLA constant at around 18 w / w% and 2 w / w%, respectively, as shown in Table 10. The total oil composition of each of the SMEIDS in Table 10 cumulates to around 10 w / w% with around 5 w / w% CBDi and 1.6 w / w% of each of THCd, bCar, and MCT oil. Single surfactant systems were investigated using other POGylated surfactants such as 10-1-L, PGE 860, and MPGO. 3 GO failed to be used in a singlesurfactant system due to difficulty in dissolution that resulted in microemulsions demonstrating diameters in the millimetre range. Therefore, 3 GO was incorporated with a PEGylated ingredient, polysorbate 80 (PS80, trade name: Tween 80) with the anticipated potential to break up the millimeter-sized microemulsions into nanometer-sized microemulsions. SMEIDS that incorporated PS80 varied the 3GO to PS80 mass ratio from 1 : 1 to 46.7: 1 and CBDi and THCd oil combinations were investigated at around two loadings of 5 and 10 w / w%. The PG and eLA were also maintained at 18 w / w% and 2 w / w% in the SMEIDS incorporating 3GO and PS80. After cooling the SMEIDS systems, no crystallization was observed for a month while maintaining flowable liquids at room temperature (18-25 °C).

[0066] Table 14, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 13 incubated in fasted state simulated gastric fluid (FaSSGF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0067] SMEIDS presented in Table 13 were appropriately diluted in FaSSGF and the selfassembled microemulsions were monitored for 6 hours at 37 °C as shown in Table 14. Unlike the other single-surfactant SMEIDS systems investigated, SMEIDS 13.1-13.3 demonstrated instability of the self-assembled microemulsions within 0.75 hours in FaSSGF at 37 °C. For reference, SMEIDS 10.7 and 10.8 incorporated 10-1-CC and maintained stability in FaSSGF for up to 2 hours in FaSSGF at 37 °C. Except for 10-1-L, SMEIDS 13.2 and 13.3 incorporated PGE 860 and MPGO, respectively, which resulted in opaque self-assembled microemulsions. A significant stability enhancement trend is observed with the SMEIDS incorporating 3 GO and PS80 in SMEIDS 13.4-13.11. For example, SMEIDS 13.7 quickly destabilized within 15 minutes in FaSSGF at 37 °C. As the 3GO and PS80 mass ratio narrows down to 1 : 1 in SMEIDS 13.4, the self-assembled microemulsions demonstrate stability enhancements that maintained stability for up to 1.25 hours in FaSSGF at 37 °C. As the cannabinoid loading is decreased from around 10 w / w% to 5 w / w%, SMEIDS 13.8-13.11 self-assembled into microemulsions that unexpectedly maintained longer stability in FaSSGF. For instance, SMEIDS 13.11 incorporated a 3GO:PS80 mass ratio of 29.2:1 with a cannabinoid oil loading of around 5 w / w% that maintained the stability of the self-assembled microemulsions in FaSSGF for up to 1 hour in FaSSGF at 37 °C. Consumed water empties from the gastric stage at 45 minutes and therefore all the SMEIDS investigated in Table 14 are on the limits of the targeted stability of the selfassembled microemulsions. More time is targeted for microemulsion stability as there is additional transit time expected through the intestines and circulation in the blood. It is preferable to bypass the gastric fluid due to the acidic environment with the use of enteric capsules or softgels that selectively aim to disintegrate in the neutral intestinal fluid.

[0068] Table 15, The visual scores of the self-assembled microemulsions from the SMEIDS codes in Table 13 incubated in fasted state simulated intestinal fluid (FaSSIF) for up to six hours at 37 °C. The visual scores are described in paragraph 0040.

[0069] SMEIDS presented in Table 13 were appropriately diluted in FaSSIF and the selfassembled microemulsions were monitored for 6 hours at 37 °C as shown in Table 15. All of the SMEIDS self-assembled into microemulsions in FaSSIF in a similar microemulsion quality relative to self-assembling in FaSSGF. All of the SMEIDS also demonstrated longer stability in FaSSIF relative to the stability observed in FaSSGF. SMEIDS 13.1 incorporated 10-1-L that maintained the stability of the self-assembled microemulsion for up to 1 hour in FaSSIF at 37 °C. SMEIDS 13.2 and 13.3 incorporated PGE 860 and MPGO and maintained the stability of the self-assembled microemulsion for up to 0.75 hours in FaSSIF at 37 °C. A similar stability enhancement trend is observed with increasing compositions ofPS80 in SMEIDS 13.4-13.11. However, the unexpected stability enhancement observed with SMEIDS 13.5 and 13.6 maintained the stability of the self-assembled microemulsions for up to 1.5 hours. Similarly, reducing the cannabinoid oil composition to around 5 w / w% permitted for the stability of the self-assembled microemulsions to be maintained for more than 4.5 hours FaSSIF at 37 °C for SMEIDS 13.9 and 13.10. Comparing SMEIDS 13.7 to 13.11, reducing the cannabinoid oil loading in the SMEIDS allowed for a suitable stability time frame for the self-assembled microemulsions to potentially transit through the intestines and enter the systemic circulation. For reference, SMEIDS 13.11 incorporated a 3GO to PS80 mass ratio of 29.2:1. This SMEIDS template has the potential to utilize 3 GO and PS 80 systems in regulated markets that permit polyglycerol esters of fatty acids with an average chain length of 3 glycerol units. These SMEIDS are both free of PEG and lecithin. Antioxidants and preservatives can be optionally added in the concentration range of 10-1,000 parts per million in order to preserve the chemical stability of the active ingredients. The PG may be replaced with other viscosity enhancers such as, but not limited to, glycerol, oligofructose, inulin, and PEG which is less than 2,000 daltons (or grams per mole). The expected transit time in the intestinal tract is 1.5 hours and nearly all of the SMEIDS in Table 15, except for 13.1-13.3, demonstrate suitable stability. There is also transit time to be anticipated in the systemic circulation.Example 2. Powderized THC and / or CBD SMEIDS

[0070] The invention of SMEIDS and filling liquid into softgels is one manufacturing pathway however another manufacturing pathway includes filling powders into capsules. In thismanufacturing pathway, the liquified SMEIDS may be plated or captured onto powder plating agents to convert the liquids into powders. Table 16 indicates a master stock composition of the possible SMEIDS using POGylated. Tables 17-27 include the compositions of the indicated hydrophobic ingredient, TCH and / or CBD, along with the surfactants listed in those tables. THC and / or CBD is indicated in the following tables, but SMEIDS is not limited to THC and / or CBD and can include other hydrophobic ingredients that exhibit poor or very poor water solubility. Table 28 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.100711 Table 16. Master stock composition breakdown of SMEIDS used to blend with a plating agent to be processed further or filled into capsules.100721 Table 17. Master stock composition breakdown of SMEIDS containing THC and / or CBD and / or terpene(s) and Polyalso 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.[00731 Table 18. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) and Polyaldo 10-1-0 used to blend with a plating agent to be processed further or filled into capsules.100741 Table 19. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) and Polyaldo 10-1-L used to blend with a plating agent to be processed further or filled into capsules.19.6 70[00751 Table 20. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) and Polyaldo 10-1-P used to blend with a plating agent to be processed further or filled into capsules.100761 Table 21. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) and Caprol MPGO used to blend with a plating agent to be processed further or filled into capsules.(00771 Table 22. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) and Caprol PGE860 used to blend with a plating agent to be processed further or filled into capsules.100781 Table 23. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) and Caprol 3 GO used to blend with a plating agent to be processed further or filled into capsules.100791 Table 24. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s), ethyl lauroyl, arginate and Polyaldo 10-1-CC used to blend with a plating agent to be processed further or filled into capsules.100801 Table 25. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) and Polyaldo 10-1-0 used to blend with a plating agent to be processed further or filled into capsules.10081] Table 26. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) 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.[00821 Table 27. Master stock composition breakdown of SMEIDS containing THC and / or CBD and or terpenes(s) 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.100831 Table 28. Master stock composition breakdown of the plated powder blended with the SMEIDS indicated in Tables 17-27 with a plating agent to be processed further or filled into capsules.Example 3. SMEIDS mixing and encapsulating in softgels at industrial scale

[0084] 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, by enteric coating. An example of the homogeneous mixing of SMEIDS and then encapsulating in softgels is described below:

[0085] a) SMEIDS 10.2 is scaled up to 50 kg using identical compositions. The ingredients are appropriately 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.

[0086] 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 stirred until homogenous, per visual inspection.

[0087] 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

[0088] d) The cooled SMEIDS is then utilized in an appropriate semi-automatic or automatic softgel filling machine where SMEIDS is encapsulated in a softgel

[0089] e) Appropriate drying, quality control, and polishing of the softgels proceed afterwards

[0090] It should be apparent to those skilled in the art that many more modifications besides those already described are possible without departing from the inventive concepts herein.

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 polyglyceryl-containing (POGylated) surfactant; a polyol; and a preservative.

2. The composition of claim 1 , wherein the active ingredient comprises at least one of a cannabinoid, a mixture of cannabionoids, a terpene, and a mixture of terpenes.

3. The composition of claim 1, wherein the water insoluble active ingredient comprises 0.02 to 15.00% w / w; the first POGylated surfactant comprises 85.00 to 99.98% w / w; and the preservative comprises 0.01 to 1.00% w / w of the microemulsion pre-concentrate.

4. The composition of claim 1 , further comprising a second POGylated surfactant, wherein a mass ratio of the first POGylated surfactant to the second POGylated surfactant is 3.0 to 4.5.

5. The composition of claim 4, wherein the water insoluble active ingredient comprises 0.02 to 15.00% w / w; the first POGylated surfactant comprises 63.75 to 81.80% w / w; the second POGylated surfactant comprises 15.45 to 25% w / w; and the preservative comprises 0.01 to 1.00% w / w of the microemulsion pre-concentrate.

6. The composition of claim 1 , wherein the first POGylated surfactant comprises a cationic surfactant.

7. The composition of claim 6, wherein: the water insoluble active ingredient comprises 0.10 to 10 %w / w; the polyol comprises 5 to 40% w / w; the cationic surfactant comprises 1 to 4% w / w; and the preservative comprises 0.0001 to 0.100% w / w.

8. The composition of claim 1, wherein the water-insoluble active ingredient comprises at least one water-insoluble active ingredient with a water solubility of less than 0.2 milligram per milliliter (mg / ml).

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

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

11. The composition of claim 1 , wherein the microemulsion pre-concentrate comprises a selfassembled Self-Microemulsifying Ingredient Delivery System (SMEIDS) having an average diameter less than 300 nm.

12. The composition of claim 11, wherein the self-assembled SMEIDS is stable in a fasted state simulated gastric or intestinal fluid for at least 2 hours at 37° C.

13. A method for making a microemulsion pre-concentrate composition devoid of water, PEG and lecithin, the method comprising combining, heating and blending: a water-insoluble active ingredient; a first POGylated surfactant; a polyol; and a preservative.

14. The method of claim 13, wherein the water-insoluble active ingredient comprises at least one of a cannabinoid, a mixture of cannabinoids, a terpene, and a mixture of terpenes.

15. The method of claim 13, further comprising combining a second POGylated surfactant, a mass ratio of the first POGylated surfactant to the second POGylated surfactant being 3.0 to 4.5.

16. The method of claim 13, wherein the first POGylated surfactant comprises a cationic surfactant.

17. The method of claim 13, further comprising containing the microemulsion pre-concentrate composition in a softgel capsule.

18. The method of claim 13, wherein the microemulsion pre-concentrate composition is diluted and self-assembled in at least one of an aqueous medium, a gastric fluid and an intestinal fluid; and further wherein an average diameter of the microemulsion pre-concentrate is less than 300 nm.

19. The method of claim 13, wherein the microemulsion pre-concentrate is stable in simulated gastric or intestinal fluid for at least two hours at 37° C.

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

21. The method of claim 20, wherein the microemulsion pre-concentrate composition further comprises a second POGylated surfactant.

22. The method of claim 21, wherein at least one of the first POGylated surfactant and the second POGylated surfactant comprises a cationic surfactant.

23. The method of claim 20, wherein the administration comprises oral administration and the microemulsion pre-concentrate composition is encapsulated in a capsule of softgel before oral administration.

24. 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: a cellulose; a microfine cellulose; a microcrystalline cellulose; a dicalcium phosphate dihydrate; a zein powder; a magnesium carbonate; a dextrin; a dextrose; a dextrate; a dextran; a starch; a pregelatinized starch; a sucrose; a xylitol; a lactitol; a mannitol; a sorbitol; a sodium chloride; a hyaluronic acid; a silica dioxide; a fiber; a citrus fiber; an oligofructose; a rice bran powder; a dehydol OD5; an alpha-lactose monohydrate; an anhydrous lactose; a spray- dried alpha-lactose monohydrate; and a granulated alpha-lactose monohydrate.

25. The composition of claim 24, wherein: the water insoluble active ingredient comprises 0.4 %w / w; the first POGylated surfactant comprises 17.58% w / w; the preservative comprises 0.020%; and the plating powder agent comprises 80% w / w.

26. The composition of claim 24, wherein: the water insoluble active ingredient comprises 0.1 to 2%w / w; the first POGylated surfactant comprises 5 to10% w / w; the second POGylated surfactant comprises 0 to 10% w / w; the preservative comprises 0.01 to 1 %; and the plating powder agent comprises 60 to 80% w / w.

27. The composition of claim 24, further comprising ethyl lauroyl arginate as a cationic surfactant.

28. The composition of claim 27, wherein: the water insoluble active ingredient comprises 0.4 %w / w; the first POGylated surfactant comprises 8.79% w / w; the second POGylated surfactant comprises 8.79% w / w; ethyl lauroyl arginate comprises 2% w / w; the preservative, comprises 0.020%; and the plating powder agent comprises around 80% w / w.

29. The composition of claim 24, wherein the active ingredient comprises at least one of a cannabinoid, a mixture of cannabinoids, a terpene, and a mixture of terpenes.

30. The composition of claim 24, wherein the first POGylated surfactant comprises polyglyceryl- 10 caprate / captylate (Polyaldo 10-1-CC).

31. The composition of claim 24, wherein the preservative comprises vitamin E.

32. The composition of claim 24, wherein the plating powder agent comprises microcrystalline cellulose.

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