Microemulsion formulations

Abstract

The present disclosure relates to compositions of microemulsion formulations for the delivery of lipophilic pharmacologically active agents or combinations of lipophilic pharmacologically active agents. The microemulsion formulations may be supplied as soft gel capsules for oral delivery or as solutions suitable for intravenous administration. The compositions find use in reducing inflammation and / or pain.

Description

. PATENT COOPERATION TREATY (PCT) APPLICATION MICROEMULSION FORMULATIONS Inventor(s): Brijesh GILL Citizen of USA, Residing at 715 Glen Echo Lane Houston, TX 77024 Assignee: The Board of Regents of The University of Texas System 210 West 7th Street Austin, Texas 78701 Entity: SmallMICROEMULSION FORMULATIONS CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 63 / 575,051, filed April 5, 2024, U.S. Provisional Patent Application Serial No. 63 / 575,063, filed April 5, 2024, U.S. Provisional Patent Application Serial No.63 / 575,124, filed April 5, 2024, and U.S. Provisional Patent Application Serial No.63 / 759,963, filed February 18, 2025, the contents of which are incorporated by reference herein in their entirety. TECHNICAL FIELD

[0002] The present disclosure relates to compositions of microemulsion formulations for the delivery of lipophilic pharmacologically active agents or combinations of lipophilic pharmacologically active agents. The microemulsion formulations may be supplied as soft gel capsules for oral delivery or as solutions suitable for intravenous administration. The compositions can find use in reducing inflammation and / or pain. BACKGROUND

[0003] Oral medication is the most common form of drug delivery because of the convenience of administration, patient preference, cost-effectiveness, and ease of large-scale manufacturing. Patient compliance with oral formulations is generally higher than with other forms of delivery such as parenteral routes (intravenous, subcutaneous and intramuscular injections) and inhalation for respiratory drugs. Despite these advantages, the development of oral formulations can present challenges, such as those due to the physicochemical properties of the active substance. For example, certain products with desirable anti-inflammatory efforts, such as cannabinoids and curcumin, are not water-soluble and they are poorly absorbed when taken orally. In addition, some products, such as cannabinoids, resveratrol and luteolin, are heavily oxidized in the intestine. Others, such as erinacine A, quercetin, luteolin, curcumin and cannabinoids, undergo extensive first-pass metabolism in the liver. Intestinal oxidation and first-pass metabolism both undesirably reduce the amount of active agent available in the bloodstream. Provided herein are solutions to these and other needs. BRIEF SUMMARY

[0004] In some aspects, provided herein is a microemulsion formulation comprised of 30- 60% by volume polysorbate surfactant, 10-20% by volume fatty acid and 20-50% by volume co-surfactant. In some embodiments, the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20, the fatty acid is one or more of oleic acid and linoleic acid, the co- surfactant is one or more of propylene glycol and ethanol. In some embodiments, thepolysorbate surfactant is, or comprises polysorbate 80, the fatty acid is, or comprises oleic acid, and the co-surfactant is, or comprises propylene glycol. In some embodiments, the polysorbate surfactant is, or comprises polysorbate 20, the fatty acid is, or comprises oleic acid, and the co-surfactant is, or comprises ethanol. In some embodiments, the polysorbate surfactant is, or comprises polysorbate 80, the fatty acid is, or comprises a combination of oleic acid and linoleic acid, and the co-surfactant is, or comprises propylene glycol. In some embodiments, the microemulsion formulation is comprised of 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid and 42.85% by volume co-surfactant. In some embodiments, the polysorbate surfactant, the fatty acid and the co-surfactant are present in a ratio of 3:1:3 by volume. The microemulsion formulation can comprise particles, and in some embodiments, >80% of the particles in the microemulsion have an average diameter between 10 and 100 nanometers. In some embodiments, the microemulsion formulation comprises less than 20, 10, 5, 4, 3, 2, or 1% water. In some embodiments, the microemulsion formulation comprises no water. In some embodiments, the microemulsion formulation further comprises a pharmacologically active agent. In another embodiment, the microemulsion formulation comprises a first pharmacologically active agent and a second pharmacologically active agent. Further provided are methods of delivering the pharmacologically active agent or the first pharmacologically active agent and the second pharmacologically active agent.

[0005] In some aspects, the microemulsion formulation is comprised of 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid, and 20-50% by volume co-surfactant, and a pharmacologically active agent. In some embodiments, the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20, the fatty acid is one or more of oleic acid and linoleic acid, the co-surfactant is one or more of propylene glycol and ethanol. In some embodiments, the microemulsion formulation further comprises a second pharmacologically active agent. In some embodiments, the pharmacologically active agent is lipophilic. In some embodiments, the polysorbate surfactant is, or comprises polysorbate 80, the fatty acid is, or comprises oleic acid and the co-surfactant is, or comprises propylene glycol. In some embodiments, the polysorbate surfactant is polysorbate 80, the fatty acid is a combination of oleic acid and linoleic acid, and the co-surfactant is propylene glycol. In some embodiments, the polysorbate surfactant is polysorbate 20, the fatty acid is oleic acid, and the co-surfactant is ethanol. In some embodiments, the formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid and 42.85% by volume co-surfactant. In some embodiments, the polysorbate surfactant, the fatty acid and the co-surfactant are present in a ratio of 3:1:3 by volume. The microemulsion formulation can comprises a particle size wherein >80% of said particle size has an average diameter between 10 and 100 nanometers. In some embodiments, the active agent includes or excludes a cannabinoid, a curcuminoid, apolyphenol, a carotenoid, an organosulfur compound, a glucobrassicin, an isothiocyanate, a lignan, a phytosterol, a carnitine, or an anti-oxidant. In some embodiments, the active agent is a broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC). In some embodiments, the broad-spectrum hemp extract contains at least 80% by weight cannabidiol (CBD). In some embodiments, the broad-spectrum hemp extract contains 84% to 87% by weight cannabidiol (CBD). In some embodiments, the broad-spectrum hemp extract has a concentration of up to 50 mg / ml. In some embodiments, the active agent is cannabidiol (CBD). In some embodiments, the cannabidiol has a concentration of up to 100 mg / ml. In some embodiments, the cannabidiol has a concentration of 3 mg / ml to 50 mg / ml. In some embodiments, the active agent is curcumin. In some embodiments, the curcumin is a turmeric extract comprising 95% curcuminoids, or comprising at least 95% curcuminoids. In some embodiments, the curcumin has a concentration of up to 50 mg / ml. In some embodiments, the active agent is resveratrol. In some embodiments, the resveratrol has a concentration of up to 75 mg / ml. In some embodiments, the active agent is lion’s mane extract. In some embodiments, the lion’s mane extract has a concentration of up to 1500 mg / ml. The microemulsion formulation can be administered orally. The microemulsion formulation can be administered intravenously.

[0006] In some aspects, provided herein is a soft gel capsule filled with and / or comprising a microemulsion formulation comprising an active agent. For example, the soft gel capsule can comprise any of the microemulsion formulations provided herein comprising a pharmacologically active agent. In some embodiments, each capsule contains up to 50 mg broad-spectrum hemp extract. In some embodiments, each capsule contains up to 100 mg CBD. In some embodiments, each capsule contains up to 30 mg curcumin. In some embodiments, each capsule contains up to 100 mg resveratrol. In some embodiments, each capsule contains up to 1500 mg lion’s mane extract.

[0007] In a further aspect, the microemulsion formulation is comprised of 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid, and 20-50% by volume co-surfactant, a first pharmacologically active agent, and a second pharmacologically active agent. In some embodiments, the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20, the fatty acid is one or more of oleic acid and linoleic acid, and the co-surfactant is one or more of propylene glycol and ethanol. In some embodiments, the first pharmacologically active agent and the second pharmacologically active agent is a cannabinoid, a curcuminoid, a polyphenol, a carotenoid, an organosulfur compound, a glucobrassicin, an isothiocyanate, a lignan, a phytosterol, a carnitine, or an antioxidant (or any combination thereof) and the first pharmacologically active agent is different from the second pharmacologically active agent. In some embodiments, the polysorbate surfactant is, or comprises polysorbate 80, the fatty acidis, or comprises oleic acid and the co-surfactant is, or comprises propylene glycol. In some embodiments, the formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid and 42.85% by volume co-surfactant. In some embodiments, the polysorbate surfactant, the fatty acid and the co-surfactant are present in a ratio of 3:1:3 by volume. The microemulsion formulation can comprises a particle size wherein >80% of said particle size has an average diameter between 10 and 100 nanometers. In some embodiments, the microemulsion formulation can be administered orally. In some embodiments, the microemulsion formulation can be administered intravenously. In some embodiments, the first pharmacologically active agent is a cannabinoid substantially free of tetrahydrocannabinol (THC) and the second pharmacologically active agent is curcumin. In some embodiments, the polysorbate surfactant is 30-60% by volume polysorbate 80, the fatty acid is 10-20% by volume oleic acid, the co-surfactant is 20-50% by volume propylene glycol, the first pharmacologically active agent is a cannabinoid with a concentration up to 50 mg / ml, and the second pharmacologically active agent is curcumin with a concentration of up to 40 mg / ml. In some embodiments, the cannabinoid is a broad-spectrum hemp extract with a concentration of 2 mg / ml to 15 mg / ml. In some embodiments, the broad-spectrum hemp extract contains at least 80% by weight cannabidiol (CBD). In some embodiments, the broad-spectrum hemp extract contains 87% by weight cannabidiol (CBD). In some embodiments, the cannabinoid is cannabidiol (CBD) with a concentration is of 2 mg / ml to 20 mg / ml. In some embodiments, the curcumin is a turmeric extract comprising about 95% curcuminoids with a concentration is 2 mg / ml to 30 mg / ml. In some embodiments, the microemulsion formulation comprises 42.85% by volume propylene glycol, 14.3% oleic acid by volume and 42.85% by volume polysorbate 80. In some embodiments, the polysorbate surfactant is 42.85% by volume polysorbate 80, the fatty acid is 14.3% by volume oleic acid, the co-surfactant is 42.85% by volume propylene glycol, the cannabinoid is broad-spectrum hemp extract with a concentration of 4 mg / ml to 5 mg / ml, and the curcumin is a turmeric extract with a concentration of 8 mg / ml to 10 mg / ml.

[0008] In some aspects, the disclosure provides a soft gel capsule filled with a microemulsion formulation of a first pharmacologically active agent with a concentration up to 200 mg / ml and a second pharmacologically active agent with a concentration up to 200 mg / ml, and the microemulsion emulsion comprises 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid and 20-50% co-surfactant. In some embodiments, the soft gel capsule is filled with a microemulsion formulation where the first pharmacologically active agent is a cannabinoid substantially free of tetrahydrocannabinol (THC) with a concentration of up to 50 mg / ml, the second pharmacologically active agent is curcumin with a concentration of up to 40 mg / ml, the polysorbate surfactant is polysorbate 80, the fatty acid is oleic acid, and the co- surfactant is propylene glycol. In some embodiments, the cannabinoid is CBD, and eachcapsule contains CBD in a concentration of 1 mg / ml to 30 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml. In some embodiments, the cannabinoid is CBD, and each capsule contains 2.5 mg to 5 mg of CBD and 5 mg to 10 mg of curcumin. In some embodiments, the cannabinoid is broad-spectrum hemp extract, and each capsule contains broad-spectrum hemp extract in a concentration of 5 mg / ml to 10 mg / ml and curcumin is in a concentration of 10 mg / ml to 20 mg / ml. In some embodiments, the cannabinoid is broad- spectrum hemp extract, and each capsule contains 2.5 mg to 5 mg of broad-spectrum hemp extract and 4 mg to 10 mg of curcumin. In some embodiments, each capsule contains 5 mg of broad-spectrum hemp extract and 10 mg of curcumin. In some embodiments, the curcumin is a turmeric extract comprising about 95% curcuminoids. In some embodiments, each soft gel capsule contains a microemulsion formulation comprising 42.85% by volume propylene glycol, 14.3% oleic acid by volume and 42.85% by volume polysorbate 80. In some embodiments, each soft gel capsule contains a microemulsion formulation where the polysorbate 80, the oleic acid and the propylene glycol are present in a ratio of 3:1:3 by volume. In some embodiments, the first pharmacologically active agent is broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC) with a concentration of 5 mg / ml to 10 mg / ml, the second pharmacologically active agent is turmeric extract with a concentration of 10 mg / ml to 20 mg / ml, the polysorbate surfactant is 42.85% by volume polysorbate 80, the fatty acid is 14.3% by volume oleic acid, the co-surfactant is 42.85% by volume propylene glycol. In some embodiments, the first pharmacologically active agent is 2.5 mg to 5 mg broad-spectrum hemp extract standardized to 87% cannabidiol, the second pharmacologically active agent is 4 mg to 10 mg turmeric extract standardized to 95% curcuminoids, the polysorbate surfactant is 42.85% by volume polysorbate 80, the fatty acid is 14.3% by volume oleic acid, and the co-surfactant is 42.85% by volume propylene glycol.

[0009] In some aspects, the disclosure provides a method of reducing inflammation or pain comprising administering to a patient a pharmacologically effective amount of the microemulsion formulation of the disclosure comprising one of a pharmacologically active agent or a first pharmacologically active agent and a second pharmacologically active agent. In some embodiments, the inflammation or pain is due to arthritis. In some embodiments, the inflammation or pain is musculoskeletal. In some embodiments, the pharmacologically effective amount of the microemulsion formulation is or is not delivered orally or intravenously. In some embodiments, the pharmacologically effective amount of the soft gel capsule is delivered orally.

[0010] Some embodiments, relate to a method of providing analgesic (pain relief), anti- inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, and / orhepatoprotective effects comprising administering to a patient a pharmacologically effective amount of any of the microemulsion formulations or of the soft gel capsule disclosed herein.

[0011] The microemulsion formulation or soft gel capsule can include or exclude analgesic (pain relief), anti-inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, hepatoprotective effects, and / or the like.

[0012] In some embodiments, the first and second active agents act synergistically in the microemulsion formulation or soft gel capsule.

[0013] In some embodiments, the microemulsion is formed without external input of energy. In some embodiments, the external input of energy is heat or high-shear mixing or the like.

[0014] Some embodiments of the disclosure relate to a microemulsion formulation comprising, 42.85% by volume polysorbate 80; 14.3% by volume oleic acid; 42.85% by volume propylene glycol; a cannabinoid that is broad-spectrum hemp extract with a concentration of 5 mg / ml to 10 mg / ml; and a turmeric extract in a concentration of 10 mg / ml to 20 mg / ml. The formulation can also exclude 1 or 2 of these components.

[0015] A soft gel capsule comprising, a broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC) with a concentration of 5 mg / ml to 10 mg / ml; a turmeric extract with a concentration of 10 mg / ml to 20 mg / ml; 42.85% by volume polysorbate 80; 14.3% by volume oleic acid; and 42.85% by volume propylene glycol. The soft gel capsule can also exclude 1 or 2 of these components.

[0016] Some embodiments of the disclosure relate to a soft gel capsule comprising, a broad- spectrum hemp extract substantially free of tetrahydrocannabinol (THC) with a concentration of 5 mg / ml to 10 mg / ml; a turmeric extract with a concentration of 10 mg / ml to 20 mg / ml; 42.85% by volume polysorbate 80; 14.3% by volume oleic acid; and 42.85% by volume propylene glycol. The soft gel capsule can also exclude 1 or 2 of these components.

[0017] Some embodiments of the disclosure relate to a soft gel capsule comprising, 2.5 mg to 5 mg broad-spectrum hemp extract standardized to 87% cannabidiol; 4 mg to 10 mg turmeric extract standardized to 95% curcuminoids; 42.85% by volume polysorbate 80; 14.3% by volume oleic acid; and 42.85% by volume propylene glycol. The soft gel capsule can also exclude 1 or 2 of these components.

[0018] Other objects of the disclosure may be apparent to one skilled in the art upon reading the following specification and claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Certain novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrativeembodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

[0020] FIGS. 1A-1C show photographs of the transmission electron microscopy (TEM) analysis of microemulsion Formulation N. FIG 1A (magnification 50kx; scale bar 50 nm) shows the generally homogeneous composition of the particles within the microemulsion comprising >90% of the sample volume; FIG. 1B (magnification 25kx; scale bar 0.1 um) shows the occasional occurrence of larger particles; FIG 1C is a high magnification image (100kx; scale bar 20 nm) showing the clear micellar structure of the formulation at the nanoscale level.

[0021] FIG. 2 shows the particle size distribution of microemulsion Formulation A as determined by Dynamic Light Scattering (DLS).

[0022] FIG. 3 shows the particle size distribution of microemulsion Formulation L as determined by Dynamic Light Scattering (DLS).

[0023] FIG. 4 shows the particle size distribution of microemulsion Formulation N as determined by Dynamic Light Scattering (DLS).

[0024] FIG. 5 shows the particle size distribution of microemulsion Formulation O as determined by Dynamic Light Scattering (DLS).

[0025] FIG. 6 shows the particle size distribution of microemulsion Formulation P as determined by Dynamic Light Scattering (DLS). DETAILED DESCRIPTION

[0026] This application is not limited to particular methodologies and the specific compositions described as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, because the scope of the present application will be limited only by the appended claims and their equivalents.

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure relates. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, certain preferred methods and materials are described herein.

[0028] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise.

[0029] Throughout this application, the term “about” is used according to its plain and ordinary meaning to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value.

[0030] It should be understood that all of the individual values and sub-ranges of values contained within an explicitly disclosed range are also specifically contemplated and should be considered disclosed unless the context specifically indicates otherwise. The foregoing applies regardless of whether in particular cases some or all of these aspects are explicitly disclosed.

[0031] The term "and / or" as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that "at least one of” or "one or more" of the listed items is present or used.

[0032] The terms “comprise” (and any form of comprise, such as “comprises” and “comprising”), “have” (and any form of have, such as “has” and “having”), “include” (and any form of include, such as “includes” and “including”) and “contain” (and any form of contain, such as “contains” and “containing”) are open-ended linking verbs. As a result, any composition or method of the present disclosure that “comprises,” “has,” “includes” or “contains” one or more elements possesses those one or more elements, but is not limited to possessing only those one or more elements. Likewise, an element of a composition or method of the present disclosure that “comprises,” “has,” “includes” or “contains” one or more features possesses those one or more features, but is not limited to possessing only those one or more features, and moreover, any one or more of these features may be excluded.

[0033] The term “cannabinoid” or “cannabinoids” refers to a single compound such as cannabidiol or to a mixture of hemp-derived compounds that do not contain a substantial amount of tetrahydrocannabinol.

[0034] The abbreviation “CBD” refers to cannabidiol.

[0035] “Patient” refers to a mammal, which is preferably human.

[0036] The terms “reduce”, “reducing” and “reduction”, when applied to a condition or symptom (e.g. inflammation and / or pain), all refer to a lessening of said condition or symptom (e.g. inflammation and / or pain). These terms are meant to include the concepts of improvement, alleviation, amelioration, control, or management of symptoms. Inflammation may be due to a variety of causes, including, but not limited to, inflammation due to arthritis, or musculoskeletal inflammation. Reducing inflammatory pain refers to reducing the symptoms of pain (including eliminating them entirely), avoiding the occurrence of pain and / or reducing the severity of symptoms of pain.

[0037] The term “substantially free of tetrahydrocannabinol” refers to a composition with a minimally detectable amount of tetrahydrocannabinol (THC) and closely related psychoactive substances. Specifically, the term indicates that THC is present in less than a minimum observable quantity (MOQ) of 0.1% or less by weight. Alternatively, an aspect may have undetectable levels of tetrahydrocannabinol, which may or may not be detectable by any means disclosed herein.

[0038] The abbreviation “THC” refers to tetrahydrocannabinol, chemically known as delta-9- tetrahydrocannabinol.

[0039] The term “pharmacologically effective amount” refers to the amount of a composition that, when administered to a patient for reducing or improving inflammation and / or pain, is sufficient to effect such reduction or improvement. A pharmacologically effective amount may reduce pain associated with inflammation. Further, a pharmacologically effective amount of a composition may increase mobility of one or more joints in a patient suffering from arthritis. The pharmacologically effective amount will vary depending on the severity of the condition causing the inflammation or pain, and the age, weight, and other physiological factors, of the patient to be treated. Overview

[0040] The present disclosure relates to novel microemulsion formulations, methods of formulating a microemulsion formulation, and methods of treatment using microemulsion formulations, and the like. The formulations can be suitable as a vehicle for the oral or intravenous delivery of pharmacologically active agents. Such agents, such as lipophilic agents, can have poor or no solubility in water and are thus difficult to formulate using conventional methods. The microemulsion formulations of the present disclosure can be particularly useful in the delivery of certain products with pharmacological activity or combinations thereof. These active agents formulated as microemulsions can find use as pharmaceuticals and nutritional or dietary supplements. The microemulsion formulations may be supplied as soft gel capsules for oral delivery or as solutions suitable for oral or intravenous administration. Certain formulations of the disclosure find use as therapies for subjects with inflammation or pain.

[0041] Despite the advantages of orally delivered medications, the development of oral formulations can present challenges, such as those due to the physicochemical properties of the active substance, including as poor water solubility and intestinal membrane permeability. Further, orally administered substances in conventional formulations are subject to first pass metabolism in the liver which can substantially reduce the bioavailability of an administered dose. In certain situations, rapid delivery of poorly water soluble substances is desirable.These situations include, for example, amelioration of acute pain. In such cases, intravenous administration of a liquid formulation may be used. As with oral formulations, homogeneous liquid formulations are preferable to suspensions because they facilitate absorption of the active substance into target tissues. Additionally, delivery of such substances may be desirable where oral administration is not possible. For example, critically ill or injured patients may not have enteral access, particularly when intubated for mechanical ventilation, or when a patient is vomiting. Further, intravenous administration has the additional advantage of avoiding first-pass metabolism in the liver as well as providing immediate, rapid distribution of the formulation throughout the body. The microemulsions described herein address these oral and intravenous formulation and bioavailability challenges. Microemulsion Formulations

[0042] Microemulsion formulations offer several benefits over conventional liquid formulations including increased absorption, improved clinical potency, and decreased drug toxicity (Azad, Sk., et al., World J. Current Med. Pharm. Res., 2(2):201-205). Microemulsions are typically composed of an oil, a surfactant, a co-surfactant, and water. A microemulsion may readily be distinguished from a macroemulsion by its optical properties. A true microemulsion is optically transparent because the particle size (~100 nanometers or less) is smaller than the wavelength of visible light while regular emulsions are cloudy. The particle size of a microemulsion may be determined by dynamic light scattering (DLS) and by transmission electron microscopy (TEM).

[0043] Microemulsions exist in a thermodynamically favorable state that remains stable for years. Due their thermodynamic properties, microemulsions disclosed herein can form without the external input of energy in the form of heat or high-shear mixing. For example, the disclosed microemulsion formulations may be produced by simply stirring the components together at minimal speed at room temperature.

[0044] In contrast, macroemulsion formulations contain large (>1 micron) particles produced by high-shear mixing of the pharmacologically active compounds with one or more oils, a surfactant (most commonly lecithin) and water. These emulsions are not shelf-stable, as they will separate back into their constituent fluid layers after days of sitting still (hence the instruction to "shake well before using" that can be seen on product labels). The large globules can be easily seen under ordinary light microscopy. Numerous products on the commercial market claim to be "liposomal" formulations of, for example, curcumin or cannabinoids are, in fact, macroemulsions.

[0045] Microemulsions can find use as formulations for the delivery of pharmaceuticals and other pharmacologically active agents that are not otherwise soluble in water.Pharmacologically active compounds must be in solution in order to interact with cell surface or intracellular receptors and targets. Use of microemulsion formulations can improve the pharmacokinetics of these compounds (Prasad, C., et al., Nature, Scientific Reports, 2020, 10:8587). Microemulsions of lipid-encased particles (i.e., liposomes) of sub-micron size are readily absorbed after oral administration and are able to pass through the enterocyte intact. Larger particles are processed in the smooth endoplasmic reticulum and repackaged into chylomicrons. Microemulsions are widely understood to undergo less first-pass metabolism by the liver versus standard emulsions, dramatically improving the overall oral bioavailability of the compounds contained therein (Prasad, 2020).

[0046] In some aspects, the disclosed microemulsion formulation provides a particle size such that >80% of the microemulsion particles have an average diameter ranging between 10 and 100 nanometers. Thus, the microemulsion may also be referred to as a nanoemulsion. Particles of this size are typical of the LDL and VLDL lipoproteins, which are easily absorbed into the enterocyte and endoplasmic reticulum after oral administration. Without wishing to be bound by theory, the particles can be then physiologically transported into the intestinal lymph rather than the portal venous circulation. Transport into the intestinal lymphatic system can substantially increase the bioavailability of the formulated active agent by avoiding first pass metabolism in the liver via the portal circulation. Intestinal lymph is transported via the thoracic duct into the systemic circulation at the confluence of the left subclavian and internal jugular veins. This route can provide wide systemic distribution of lymph-transported compounds and increased activity before they are filtered much more slowly by the liver, in comparison to immediate delivery of compounds to the liver via portal circulation.

[0047] Avoidance of first pass liver metabolism may also reduce the hepatic toxicity of an active agent such as CBD. Some clinical trials, particularly the early trials of CBD for pediatric epilepsy, showed some level of hepatic toxicity, with the primary trial of Epidiolex® (cannabidiol) showing that 13% of patients had an increase of certain liver enzyme levels 3x or greater above baseline. The FDA has expressed concern about possible hepatic toxicity of CBD preparations for this reason. Without wishing to be bound by theory, by dramatically reducing the concentration of CBD delivered to the liver (via the hepatic artery in constitutive fashion rather than a pulse-dose via the portal vein), the disclosed microemulsion formulation is expected to reduce any putative CBD liver toxicity. The same may hold true for other active agents with liver toxicity.

[0048] First pass metabolism by the cells of the intestine and liver may also be avoided by direct intravenous injection. This route of administration may be preferred in certain clinical situations; for example, a critically ill or injured patient who is, orotracheally intubated formechanical ventilation may not have access to the gastrointestinal tract. Also, patients who are vomiting cannot utilize orally delivered formulations. Further, intravenous delivery of active agents in the disclosed microemulsion formulation may prevent a too-rapid clearance of the agents from the circulation and increase bioavailability.

[0049] The microemulsion-forming components of the present disclosure can be comprised of an oil, a surfactant, and a co-surfactant. Typical microemulsions also contain water. In some embodiments of the disclosure, no water is necessary in the microemulsion formulations. Instead, the active agent(s) utilized are soluble in the either co-surfactant (e.g., propylene glycol or ethanol) or in the oil. In some embodiments, a microemulsion forms spontaneously when the components of the formulation are mixed even though no water is added to the oil, surfactant and co-surfactant. Although water is usually added to a liquid pharmaceutical formulation to deliver a pharmacologically active agent, it is not necessary in the present formulations, and in some aspects avoids additional undesirable volume. Thus, the fact that the microemulsion formulations do not require addition of water provides certain advantages. The microemulsion is formulated without the active addition of water, making it substantially free of water. However, some water is naturally present due to moisture from the atmosphere or nominal amounts of water originally present in the component oil, surfactant and co- surfactant.

[0050] Optionally, in some embodiments, water may be added to the microemulsion formulation of the present disclosure in order to deliver a supplemental water-soluble agent, such as a pharmaceutical excipient. Excipients include, but are not limited to, vitamins, flavoring, taste-masking agents, sweeteners, preservatives, anti-oxidants, and / or the like. In one embodiment, water-soluble vitamins, such as thiamine, niacin, vitamin B6, vitamin B12, and / or the like, may be added. Any of these additional water-soluble agents may be added singly or in combination. The amount of water and excipient or excipients added is such that the overall formulation including the pharmacologically active agent or agents remains a microemulsion. The ratio of the oil, surfactant, co-surfactant and water may be adjusted in order to maintain the desired concentration of the pharmacologically active agent or agents in the microemulsion formulation. In some embodiments, the amount of water added is, is at most, or is less than 20%, 19%, 18%, 17%, 16%,15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% by volume (or any range derivable therein).

[0051] In some aspects, the oil component of the microemulsion formulation comprises a fatty acid. Any suitable fatty acid, or combination of fatty acids, may be used. As used herein, the term “fatty acid” includes one or more fatty acids. In some aspects, the oil component of the microemulsion formulation is a medium to long-chain fatty acid. The fatty acid may be liquidat room temperature. The fatty acid may be straight-chained or branched. The fatty acid may be a saturated or unsaturated aliphatic carboxylic acid, and may contain at least 8 and not more than about 20 carbons. The fatty acid may contain at, at most, or at least 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbons (or any range derivable therein). Suitable fatty acids include, but are not limited to, oleic, linoleic, linolelaidic, denticetic, caprylic, capric, lauric, lauroleic, myristic, myristioleic, palmitic, palmitoleic, physeteric, rumenic, stearic acids, and / or the like, though any of these may be excluded in an embodiment. The oil component may also comprise a combination of one or more suitable fatty acids, such as any of the aforementioned fatty acids. Suitable combinations of fatty acids may vary according to the overall composition of the microemulsion formulation. The amount of individual fatty acids may be adjusted to maintain an overall microemulsion formulation while the amounts of the pharmacologically active agent or agents are varied.

[0052] In some embodiments, the fatty acid is oleic acid. Oleic acid [cis-9-octadecenoic acid or (Z)-octadec-9-enoic acid] is a mono-unsaturated omega-nine fatty acid. It is an odorless, colorless or pale yellow oil having the chemical formula C18H34O2[CH3(CH2)7CH=CH(CH2)7COOH] with a molecular mass of 282.46 g / mol. Oleic acid is the most widely distributed of all the natural fatty acids and present in practically all naturally occurring lipids including edible oils such as olive, cod, corn and palm oils. Oleic acid is a GRAS food additive under the Federal Food, Drug and Cosmetics Act and is widely used as a pharmaceutical excipient and emulsifying agent. Oleic acid is available from a variety of commercial sources.

[0053] In another embodiment, the fatty acid is linoleic acid. Linoleic acid (cis, cis-9,12- octadecadienoic acid) is a polyunsaturated omega-6 fatty acid having the chemical formula HOOC(CH2)7CH=CHCH2CH=CH(CH2)4CH3and a molecular mass of 280.45 g / mol. It is a colorless liquid that is virtually insoluble in water, but soluble in many organic solvents. An essential fatty acid for humans, linoleic acid typical occurs in natural sources as a triglyceride rather than as a free fatty acid. In one embodiment, the linoleic acid is conjugated linoleic acid (CLA), a mixture of octadecadienoic acid isomers found in meat and dairy products where the two double –C=C- bonds are separated by a single bond. An example of a CLA is rumenic acid (9Z,11E-octadeca-9,11-dienoic acid). Linoleic acid and CLA are available from a variety of commercial sources.

[0054] In a further embodiment, the fatty acid is a combination of oleic acid and linoleic acid. Suitable combinations of linoleic acid and oleic acid may vary according to the overall composition of the microemulsion formulation. The amount of linoleic acid may be adjusted to maintain an overall microemulsion formulation while the amounts of the pharmacologicallyactive agent or agents are varied. In some embodiments, the fatty acid is 10% by volume linoleic acid and 90% by volume oleic acid. In other embodiments, the fatty acid is up to 50% by volume linoleic acid and 50% by volume oleic acid. In some embodiments, the fatty acid comprises 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% by volume linoleic acid (or any range derivable therein). In some embodiments, the fatty acid comprises 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% by volume oleic acid (or any range derivable therein). In some embodiments, the fatty acid is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% by volume linoleic acid (or any range derivable therein) and 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, or 50% by volume oleic acid (or any range derivable therein) respectively.

[0055] Surfactants are substances that tend to reduce the surface tension of a liquid in which they are dissolved thereby increasing the spreading and wetting properties of the liquid. In aqueous solutions, surfactants behave like organic compounds that are amphiphilic, meaning they contain both hydrophobic groups (tails) and hydrophilic groups (heads). In emulsions, the hydrophilic heads align at the water or polar solvent interface and the hydrophobic tails align toward the oil. Therefore, a surfactant contains both a water-insoluble (or oil-soluble) segment and a water-soluble segment. This property allows surfactants to act as detergents, wetting agents, emulsifiers, foaming agents, and dispersants. Surfactants are classified as anionic, nonionic, cationic and amphoteric. Surfactants suitable for use in the microemulsion formulation of the disclosure are non-ionic.

[0056] Synthetic non-ionic surfactants suitable for use as components of the microemulsion formulation include polysorbates and polyoxyethylene / polyoxypropylene block copolymers. Examples include, but are not limited to, polysorbate 20 (e.g., Tween® 20), polysorbate 60 (e.g., Tween® 60), polysorbate 80 (e.g., Tween® 80), stearyl alcohol, polyethylene glycol derivatives of hydrogenated castor oil (e.g., Cremophor® RH 40 or Cremophor® RH 60), sorbitan monolaurate (e.g., Span® 20), sorbitan monopalmitate (e.g., Span® 40), sorbitanmonostearate (e.g., Span® 60), polyoxyethylene (20) oleyl ether (e.g., Brij® 020), polyoxyethylene (20) cetyl ether (e.g., Brij® 58), polyoxyethylene (10) cetyl ether (e.g., Brij® 010), polyoxyethylene (10) oleyl ether (e.g., Brij® 010), polyoxyethylene (100) stearyl ether (e.g., Brij® S100), polyoxyethylene (10) stearyl ether (e.g., Brij® S10), polyoxyethylene (20) stearyl ether (e.g., Brij® S20), polyoxyethylene (4) lauryl ether (e.g., Brij® L4), polyoxyethylene (20) cetyl ether (e.g., Brij® 93), polyoxyethylene (2) cetyl ether (e.g., Brij® S2), caprylocaproyl polyoxyl-8 glyceride (e.g., Labrasol®), polyethylene glycol (20) stearate (e.g., Myrj™ 49), polyethylene glycol (40) stearate (e.g., Myrj™ S40), polyethylene glycol (100) stearate (e.g., Myrj™ S100), polyethylene glycol (8) stearate (e.g., Myrj™ S8), and polyoxyl 40 stearate (e.g., Myrj™ 52), and / or the like, and / or mixtures thereof. It is contemplated that any of these may also be excluded in an embodiment.

[0057] In one embodiment, the surfactant is a polysorbate. Polysorbates are nonionic surfactants and emulsifiers derived from polyethoxylated sorbitan and fatty acids that are commonly used in oral and topical pharmaceutical dosage forms, foods and cosmetics. The polysorbates are viscous, water-soluble, pale yellow liquids produced by reacting sorbitol with ethylene oxide. The polyoxyethylenated sorbitan is then reacted with fatty acids obtained from vegetable fats and oils such as stearic acid, lauric acid, and oleic acid to form an ester. Common trade names for polysorbates include Tween®, Kolliphor®, Scattics, Alkest®, and Canarcel®.

[0058] In one embodiment, the surfactant is polysorbate 80 [polyoxyethylene (80) sorbitan monooleate], a mixture of polyoxyethylene ethers of mixed partial oleic acid esters of sorbitol anhydrides. Polysorbate 80 is a lemon-to-amber colored oily liquid at room temperature with a faint, characteristic odor. Polysorbate 80 is used as a pharmaceutical excipient to stabilize aqueous formulations of medications for parenteral or oral administration or vaccinations. It is also used as a lubricant in eye drops. Polysorbate 80 is a GRAS food additive useful as an emulsifier in a variety of food products. It is available from a variety of commercial sources under trade names including Tween® 80, Kolliphor® PS 80, and Alkest® TW 80.

[0059] In another embodiment, the surfactant is polysorbate 20 [polyoxyethylene (20) sorbitan monolaurate], a mixture of polyoxyethylene ethers of mixed partial lauric acid esters of sorbitol anhydrides. Polysorbate 20 is a yellow to yellow-green viscous liquid at room temperature with an approximate density of 1.1 g / ml. Polysorbate 20 is used as a pharmaceutical excipient to stabilize emulsions and suspensions of aqueous formulations of medications for parenteral or oral administration. It also has a number of industrial uses. Polysorbate 20 is a GRAS food additive. It is available from a variety of commercial sources under trade names including Tween® 20, Kolliphor® PS 20, and Alkest® TW 20, Montanox 20, and Kotilen-20.

[0060] The co-surfactant component of the microemulsion formulation can serve to create a microemulsion when added to the other components. An embodiment of the microemulsion formulation utilizes propylene glycol as the co-surfactant. Propylene glycol, also known as 1,2- dihydroxypropane or propane-1,2-diol, is a viscous, colorless liquid with a slightly sweet taste having the chemical formula CH3CH(OH)CH2OH and molecular mass 76.095 g / mol. It is miscible with broad range of solvents, including water, acetone and chloroform. Propylene glycol is a GRAS food additive and is approved in the U.S. and Europe for use as a vehicle for topical, oral and certain intravenous pharmaceutical preparations where the active ingredient is not water soluble.

[0061] Propylene glycol is rapidly absorbed in the intestine with essentially complete bioavailability after absorption (“Propylene glycol used as an excipient”, European Medicines Agency Report, 2017, p.6, 14; EMA / CHMP / 334655 / 2013). Thus, without wishing to be bound by theory, in some embodiments, if the nanoemulsion of the disclosure breaks down into its components (oil, surfactant and co-surfactant) in the stomach, it is expected that the active agent will remain in solution in the propylene glycol, allowing the agent to still be easily absorbed in the intestine.

[0062] In some embodiments, the co-surfactant component of the microemulsion formulation is ethanol (ethyl alcohol; CH3CH2OH). Ethanol may be used as the co-surfactant if the pharmacologically active agent or agents have better solubility in ethanol than in other co- surfactants such as propylene glycol. Ethanol may also be used as the co-surfactant if the overall characteristics of the microemulsion formulation are more desirable than those obtained with other co-surfactants for particular active agent or agents. Ethanol suitable for use is 95% or greater food or pharmaceutical grade produced in accordance with US Pharmacopeia (USP) standards. In some embodiments, the co-surfactant is at least, at most, at or about 95%, 96%, 97%, 98%, 99%, 99.5% or 100% ethanol, or any range derivable therein. Food or pharmaceutical grade ethanol is available from numerous manufacturers.

[0063] The microemulsion formulation of the disclosure may contain 20-50% by volume co- surfactant, or 25-50% by volume co-surfactant, or 30-50% by volume co-surfactant, or 35-50% by volume co-surfactant, or 40-45% by volume co-surfactant, and 10-20% by volume fatty acid, or 10-15% by volume fatty acid, and 30-60% by volume polysorbate surfactant, or 35- 55% by volume polysorbate surfactant, or 35-50% by volume polysorbate surfactant, or 40- 45% by volume polysorbate surfactant, or 40-50% by volume polysorbate surfactant.

[0064] The microemulsion formulation may contain 20-50% by volume co-surfactant, such as any suitable co-surfactant. The microemulsion formulation may contain at least, at most, orat or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, or 50% by volume co-surfactant, or any range derivable therein.

[0065] The co-surfactant may comprise propylene glycol. The microemulsion formulation may contain 20-50% by volume propylene glycol, 25-50% by volume propylene glycol, 30-50% by volume propylene glycol, or 35-50% by volume propylene glycol, or 40-45% by volume propylene glycol. The microemulsion formulation may contain at least, at most, or at or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, or 50% by volume propylene glycol, or any range derivable therein.

[0066] The co-surfactant may comprise ethanol. The microemulsion formulation may contain 20-50% by volume ethanol, 30-50% by volume ethanol, or 35-50% by volume ethanol, or 40- 45% by volume ethanol. The microemulsion formulation may contain at least, at most, or at or about 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, or 50% by volume ethanol, or any range derivable therein.

[0067] The microemulsion formulation may contain 10-20% by volume fatty acid or 10-15% fatty acid, such as any suitable fatty acid or combination of fatty acids. The microemulsion formulation may contain at least, at most, or at or about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% by volume fatty acid, or any range derivable therein.

[0068] The fatty acid may comprise oleic acid. The microemulsion formulation may contain 10-20% by volume oleic acid, or 10-15% by volume oleic acid. The microemulsion formulation may contain at least, at most, or at or about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% by volume oleic acid, or any range derivable therein.

[0069] The fatty acid may comprise a combination of oleic acid and linoleic acid, which together add up to the total amount of fatty acid in the microemulsion formulation described above. The microemulsion formulation may contain 10-20% by volume oleic acid and linoleic acid, or 10-15% by volume oleic acid and linoleic acid. The microemulsion formulation may contain at least, at most, or at or about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20% by volume oleic acid and linoleic acid, or any range derivable therein. In a one embodiment, the combination fatty acid is 5-15% by volume linoleic acid and 85-95% by volume oleic acid. In another embodiment, the combination fatty acid is 10% by volume linoleic acid and 90% oleic acid. In some embodiments, the fatty acid comprises 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50% by volume linoleic acid (or any range derivable therein). In some embodiments, the fatty acid comprises 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%,38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 90% by volume oleic acid (or any range derivable therein). In some embodiments, the fatty acid is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or 50%, by volume linoleic acid (or any range derivable therein) and 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80%, 79%, 78%, 77%, 76%, 75%, 74%, 73%, 72%, 71%, 70%, 69%, 68%, 67%, 66%, 65%, 64%, 63%, 62%, 61%, 60%, 59%, 58%, 57%, 56%, 55%, 54%, 53%, 52%, 51%, or 50% by volume of oleic acid (or any range derivable therein).

[0070] The microemulsion formulation may contain 30-60% by volume polysorbate surfactant, such as any suitable polysorbate surfactant. The microemulsion formulation may contain at least, at most, or at or about 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% by volume polysorbate surfactant, or any range derivable therein.

[0071] In another aspect, the polysorbate surfactant may be polysorbate 80. The microemulsion may contain 30-60% by volume polysorbate 80, or 35-55% by volume polysorbate 80, or 35-50% by volume polysorbate 80, or 40-45% by volume polysorbate 80, or 40-50% polysorbate 80. The microemulsion formulation may contain at least, at most, or at or about 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% by volume polysorbate 80, or any range derivable therein.

[0072] In another aspect, the polysorbate surfactant may be polysorbate 20. The microemulsion may contain 30-60% by volume polysorbate 20, or 35-55% by volume polysorbate 20, or 35-50% by volume polysorbate 20, or 40-45% by volume polysorbate 20, or 40-50% polysorbate 20. The microemulsion formulation may contain at least, at most, or at or about 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 49, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60% by volume polysorbate 20, or any range derivable therein.

[0073] In one embodiment, the formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid, and 42.85% by volume co-surfactant.

[0074] In one embodiment, the microemulsion formulation may contain 42.85% by volume propylene glycol, 14.3% oleic acid by volume and 42.85% by volume polysorbate 80.

[0075] In another embodiment, the microemulsion formulation may contain 42.85% by volume.Isoflavones Biochanin A Soybeans Carotenoids Alpha-carotene Carrots Beta-carotene Carrots Lutein Carrots Lycopene Carrots Zeaxanthin Carrots Organosulfur compounds L-cysteine sulfoxides Garlic Alliin Garlic Glutathione Garlic Ajoene Garlic Glucobrassicin Indole-3-carbinol Broccoli Isothiocyanates Sinigrin Brussels sprouts Allyl isothiocyanate Horse radish Gluconasturtin Watercress Lignans Enterodiol Tea Enterlactone Fiber-rich cereals Pinoresinol Sesame seeds Phytosterols Campesterol Bananas Stigmasterol Soybeans Beta-sitosterol Hazelnut Carnitine L-carnitine Meat, dairy products Acetyl-L-carnitine Meat, dairy productsCompound Class Examples Source Propionyl-L-carnitine Meat, dairy products L-carnitine-L-tartrate Meat, dairy products Anti-oxidants Alpha-lipoic acid Meat, carrots, beets Coenzyme Q10 Meat, seafood

[0084] In some embodiments, the pharmacologically active agent is a cannabinoid. As known in the art, “cannabinoids” are a class of chemical compounds that act on cannabinoid receptors. Cannabinoids are are biologically active, chemical constituents of hemp or cannabis thought to have anti-inflammatory and other desirable properties. They are lipophilic substances that are poorly soluble in water. Hemp is obtained from plants of the genus Cannabis, more specifically, Cannabis sativa or Cannabis sativa L. Other sources include Cannabis indica and Cannabis ruderalis.

[0085] The principle physiologically active components of hemp are the cannabinoids tetrahydrocannabinol (THC) and cannabidiol (CBD). Although THC and CBD are chemically similar, their chemical properties differ as does their interaction with endocannabinoid receptors. In addition, hemp contains a complex herbal mixture of several classes of compounds, including other cannabinoids, terpenoids, flavonoids and steroids (Jin, D., et al., Nature Scientific Reports, 2020, 10:3309). These additional components may contribute to the therapeutic effects of traditional Cannabis preparations. Minor cannabinoids, such cannabinol (CBN), cannabigerol (CBG), and cannabichromene (CBC), may also have therapeutic potential.

[0086] The presence of THC (delta-9-tetrahydocannabinol or Δ9-tetrahydrocannabinol) and other psychoactive components of hemp are undesirable when cannabinoids are the active agents in microemulsion formulations of the present disclosure. THC is widely understood to be the compound responsible for the effects of acute marijuana intoxication and does not possess any substantial anti-inflammatory properties. Additionally, legally produced hemp extracts in the United States are currently required to contain no more than 0.3% THC. The cannabinoid component of the microemulsion of the disclosure is substantially free of THC, meaning that it has a minimum observable quantity (MOQ) of less than 0.1% by weight of THC.

[0087] In some embodiments, the cannabinoid component of the microemulsion formulation is a broad-spectrum hemp extract, also herein known as “hemp extract”. The broad-spectrumhemp extract (THC-depleted) suitable for use can be obtained from a variety of commercial sources. A typical commercially available broad-spectrum extract contains about 82% by weight CBD, 3-4% by weight minor cannabinoids (natural phenols and secondary phytochemicals) and 14-15% by weight terpenes and flavonoids (plant extracts). The extract, also known as distillate, is typically a yellow-to-amber, translucent, viscous to semi-solid liquid with a CBD content of at least 80% by weight CBD. In some embodiments, the CBD content is about 80% to about 90% by weight. For example, the CBD content of the broad-spectrum hemp extract can be at least, at most, or at or about 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, or 90% by weight (or any range derivable therein). In some embodiments, the CBD content is 84% to 87% by weight. In one embodiment, the CBD content is standardized to 87% by weight. In some embodiments, the amount of CBD present in commercial broad-spectrum hemp extract is supplemented by the addition of purified CBD, which is incorporated in the microemulsion formulation disclosed herein.

[0088] In other embodiments, the cannabinoid component of the microemulsion formulation is purified CBD. CBD has the chemical formula C21H30O2 and a molecular weight of 314.5 g / mol. The current IUPAC preferred name is 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2- en-1-yl]-5-pentylbenzene-1,3-diol. While it is possible to chemically synthesize CBD, it may be more conveniently obtained by purifying hemp extracts. CBD is available from a variety of commercial sources. In another embodiment, the microemulsion may contain or not contain other cannabinoids with anti-inflammatory properties, either alone or in combination with CBD or each other, such as cannabigerol (CBG), cannabinol (CBN), cannabichromene (CBC), cannabidiolic acid (CBDA), or cannabigerivarin (CBGV).

[0089] In some embodiments, the pharmacologically active agent component is curcumin. Turmeric, also known as Indian saffron, is a bright yellow, aromatic powder obtained from rhizomes of Curcuma longa L. from the ginger family Zingiberaceae. Curcumin, an orange- yellow crystalline powder, is the most active component found in turmeric, comprising 2-5% of the rhizome content (Pituch-Zdanowska, A., et al., Nutrients, 2022, 14:5249) and it thought to have anti-inflammatory and other desirable properties. The chemical compound with the trivial name of curcumin is known as diferuloyl methane or by its IUPAC name, (1E,6E)-1,7-bis(4- hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, with the molecular formula C21H20O6and molecular weight of 368.38 g / mol. It is insoluble in water, but is soluble in ethanol, propylene glycol, and acetic acid. While it is possible to use the chemically pure compound as the active agent in the microemulsion, the microemulsion formulation preferably comprises plant-based curcumin isolated from turmeric rhizome as an extract. This extract is typically a mixture of the closely related curcuminoids, diferuloyl methane (77%), demethoxycurcumin (18%) and bisdemethoxycurcumin (5%) (Aggerwal, B.B., et al., eds., The molecular targetsand therapeutic uses of curcumin in health and disease, 2007, Springer Science & Business Media, Vol.595, page 2), collectively herein known as “curcumin”. In some embodiments, the turmeric extract comprises 50% curcuminoids. In other embodiments, the turmeric extract comprises 60%, 70%, 80%, 85%, 90%, or 95% curcuminoids. In one embodiment, the turmeric extract is standardized to 95% curcuminoids. The turmeric extract can comprise any suitable percentage of curcuminoids, such as at least, at most, or at or about 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% curcuminoids (or any range derivable therein). Turmeric extract or curcumin suitable for use in the microemulsion formulation is available from a variety of commercial sources.

[0090] In some embodiments, the pharmacologically active agent is resveratrol. Resveratrol is a stilbenoid, a type of natural phenol, and a phytoalexin produced by several plants in response to injury or when the plant is under attack by pathogens such as bacteria or fungi or in response to exposure to radiation or physical injury. Sources of resveratrol in food include the skin of grapes, blueberries, raspberries, mulberries and peanuts. Resveratrol is thought to have anti-oxidant properties and has been reported to have cardiovascular effects (e.g., expanding blood vessels and reducing blood clotting) and to decrease pain and swelling. Chemically, resveratrol is known as 3,5,4′-trihydroxy-trans-stilbene or by the I.U.P.A.C. name 5-[(E)-2-(4-hydroxyphenyl)ethen-1-yl]benzene-1,3-diol, with a molecular formula C14H12O3and a molecular weight of 228.247 g / mol. The compound also exists as a cis isomer. The white powder is sparingly soluble in water and soluble in DMSO and ethanol. Resveratrol suitable for use in the microemulsion formulation is available from a variety of commercial sources.

[0091] In another embodiment, the pharmacologically active agent is lion’s mane also known herein as lion’s mane extract. Lion’s mane extract derives from the mushroom species Hericium erinaceus and has historically been used to treat digestive, neurological, and inflammatory disorders. Other names for this tooth fungus mushroom are yamabushitake, hou tou gu, bearded tooth fungus and bearded hedgehog. The mushrooms are saprophytic and usually grow on dead hardwood trees in the wild. H. erinaceus may also be cultivated. Other members of genus Hericium, including H. coralloides (Coral tooth fungus), H. americanum (Bear’s head tooth fungus), H. flagellum, and H. rajendrae, also provide possible health- promoting phytochemicals (Kostanda, E., et al., Int. J. Mol. Sci., 2024, 25:5949). The extract made from lion’s mane fruit bodies and / or mycelia or extracts made from lion’s mane fruit bodies and / or mycelia contain a variety of pharmacologically active components, including polysaccharides such as beta-glucan, corallocins (benzofuranone- and isoindolinone-type meroterpenoids), erinacerins (isoindoline-1-ones), hericioic acids, hericenes (geranyl-resorcinols), hericenones (monoterpenoids), hericerins, erinacines (cyathane-type diterpenoids) and erinacins (Kostanda, 2024). Lion’s mane mushrooms, lion’s mane extract, and its constituents, are available from a variety of commercial services.

[0092] In some embodiments, lion’s mane mushroom fruiting bodies and / or mycelia may be dried, ground up, and dissolved in one or more components of the microemulsion formulation. In other embodiments, lion’s mane mushroom fruiting bodies and / or mycelia may be extracted with water or ethanol, or another suitable solvent, and the extract dissolved in one or more components of the microemulsion formulation. The lion’s mane extract useful may be enriched in one or more of its constituent phytochemicals. In one embodiment, the lion’s mane extract comprises a defined amount of erinacines. In another embodiment, the lion’s mane extract comprises a defined amount of erinacine A. In a further embodiment, the lion’s mane extract comprises a defined amount of hericenones. In a further embodiment, the lion’s mane extract comprises a defined amount of hericenone C and / or E. In another embodiment, the lion’s mane extract comprises a defined amount of erinacines and a defined amount of hericenones. In another embodiment, the lion’s mane extract comprises a defined amount of erinacine A and a defined amount of hericenone C and / or E.

[0093] In some embodiments, the concentration of the first pharmacologically active agent in the microemulsion is from about 0.5 mg / ml to about 200 mg / ml, about 0.5 to about 150 mg / ml, 0.5 mg / ml to about 100 mg / ml, about 1 mg / ml to about 50 mg / ml, from about 2 mg / ml to about 30 mg / ml, about 3 mg / ml to about 20 mg / ml, or about 3 mg / ml to about 30 mg / ml, all values inclusive. In a further embodiment, the concentration is from 0.5 mg / ml to 200 mg / ml, 0.5 to 150 mg / ml, 0.5 mg / ml to 100 mg / ml, from 1 mg / ml to 50 mg / ml, from 2 mg / ml to 30 mg / ml or from 3 mg / ml to 20 mg / ml, or any range derivable therein, all values inclusive. In some embodiments, the concentration of active agent can at least, at most, or at or about 200 mg / ml, 195 mg / ml, 190 mg / ml, 185 mg / ml, 180 mg / ml, 175 mg / ml, 170 mg / ml, 165 mg / ml, 160 mg / ml, 155 mg / ml, 150 mg / ml, 145 mg / ml, 140 mg / ml, 135 mg / ml, 130 mg / ml, 125 mg / ml, 120 mg / ml, 115 mg / ml, 110 mg / ml, 105 mg / ml, 100 mg / ml, 95 mg / ml, 90 mg / ml, 85 mg / ml, 80 mg / ml, 75 mg / ml, 70 mg / ml, 65 mg / ml, 60 mg / ml, 55 mg / ml, 50 mg / ml, 45 mg / ml, 40 mg / ml, 35 mg / ml, 30 mg / ml, 25 mg / ml, 20 mg / ml, 15 mg / ml, 10 mg / ml, 5 mg / ml, 1 mg / ml, or 0.5 mg / ml, or any range derivable therein. In other embodiments, the concentration of active agent can be up to about 200 mg / ml, about 150 mg / ml, about 100 mg / ml, about 95 mg / ml, about 90 mg / ml, about 85 mg / ml, about 80 mg / ml, about 75 mg / ml, about 70 mg / ml, about 65 mg / ml, about 60 mg / ml, about 55 mg / ml, about 50 mg / ml, about 45 mg / ml, about 40 mg / ml, about 35 mg / ml, about 30 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, 1 mg / ml, or about 0.5 mg / ml, or any range derivable therein. For some embodiments, the concentration of active agent can be about 0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, about 100 mg / ml, about 150 mg / ml, or about 200 mg / ml, or any range derivable therein. In other embodiments, the concentration can be 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 85 mg / ml, 90 mg / ml, 95 mg / ml, 100 mg / ml, 150 mg / ml, or 200 mg / ml, or any range derivable therein. The concentration of the active agent can be at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 150, 175, or 200 mg / ml, or any range derivable therein. In some embodiments, the concentration of the active agent can be at least, at most, or at or about, 0.1, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, 180, 200, 250 mg / ml, or any range derivable therein. In some embodiments, the concentration of the active agent can be greater if the solubility of the active agent in the microemulsion formulation so permits.

[0094] According to another aspect, the active agent is broad-spectrum hemp extract. In one embodiment, the concentration of hemp extract in the microemulsion is from about 0.5 mg / ml to about 50 mg / ml, from about 1 mg / ml to about 40 mg / ml, from about 2 mg / ml to about 30 mg / ml or from about 3 mg / ml to about 20 mg / ml, or any range derivable therein, all values inclusive. In a further embodiment, the concentration is from 0.5 mg / ml to 50 mg / ml, from 1 mg / ml to 40 mg / ml, from 2 mg / ml to 30 mg / ml or from 3 mg / ml to 20 mg / ml, or any range derivable therein, all values inclusive. In other embodiments, the concentration of broad- spectrum hemp extract can be up to 50 mg / ml, 45 mg / ml, 40 mg / ml, 35 mg / ml, 30 mg / ml, 25 mg / ml, 20 mg / ml, 15 mg / ml, 10 mg / ml, 5 mg / ml, 1 mg / ml, or 0.5 mg / ml, or any range derivable therein. In other embodiments, the concentration of broad-spectrum hemp extract can be up to about 50 mg / ml, about 45 mg / ml, about 40 mg / ml, about 35 mg / ml, about 30 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, 1 mg / ml, or about 0.5 mg / ml. For some embodiments, the concentration of broad-spectrum hemp extract can be about 0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml,about 45 mg / ml, or about 50 mg / ml. In other embodiments, the concentration can be 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, or 50 mg / ml. In one embodiment, the concentration of broad-spectrum hemp extract can be up to 50 mg / ml. In another preferred embodiment, the concentration of hemp extract can be 3 mg / ml to 20 mg / ml. In some embodiments, the concentration of the broad-spectrum hemp extract can be at least, at most, or at or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein.

[0095] According to a further aspect, the active agent is cannabidiol (CBD). In one embodiment, the concentration of CBD in the microemulsion is from about 0.5 mg / ml to about 100 mg / ml, about 1 mg / ml to about 50 mg / ml, from about 2 mg / ml to about 30 mg / ml, about 3 mg / ml to about 20 mg / ml, or about 3 mg / ml to about 30 mg / ml, or any range derivable therein, all values inclusive. In a further embodiment, the concentration is from 0.5 mg / ml to 100 mg / ml, from 1 mg / ml to 50 mg / ml, from 2 mg / ml to 30 mg / ml or from 3 mg / ml to 20 mg / ml, all values inclusive. In other embodiments, the concentration of CBD can be up to 100 mg / ml, 95 mg / ml, 90 mg / ml, 85 mg / ml, 80 mg / ml.75 mg / ml, 70 mg / ml, 65 mg / ml, 60 mg / ml, 55 mg / ml, 50 mg / ml, 45 mg / ml, 40 mg / ml, 35 mg / ml, 30 mg / ml, 25 mg / ml, 20 mg / ml, 15 mg / ml, 10 mg / ml, 5 mg / ml, 1 mg / ml, or 0.5 mg / ml, or any range derivable therein. In other embodiments, the concentration of CBD can be up to about 100 mg / ml, about 95 mg / ml, about 90 mg / ml, about 85 mg / ml, about 80 mg / ml, about 75 mg / ml, about 70 mg / ml, about 65 mg / ml, about 60 mg / ml, about 55 mg / ml, about 50 mg / ml, about 45 mg / ml, about 40 mg / ml, about 35 mg / ml, about 30 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, 1 mg / ml, or about 0.5 mg / ml, or any range derivable therein. For some embodiments, the concentration of CBD can be about 0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, or about 100 mg / ml, or any range derivable therein. In other embodiments, the concentration can be 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml,85 mg / ml, 90 mg / ml, 95 mg / ml, or 100 mg / ml. In one embodiment, the concentration of CBD can be up to 100 mg / ml. In another embodiment, the concentration of CBD can be 3 mg / ml to 50 mg / ml. In some embodiments, the concentration of the CBD can be at least, at most, or at or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein.

[0096] According to another aspect, the active agent is curcumin. In one embodiment, the concentration of curcumin in the microemulsion is from about 0.5 mg / ml to about 50 mg / ml, from about 0.5 mg / ml to about 40 mg / ml, from about 0.5 mg / ml to about 30 mg / ml, from about 1 mg / ml to about 25 mg / ml, from about 2 mg / ml to about 25 mg / ml or from about 3 mg / ml to about 20 mg / ml, or any range derivable therein, all values inclusive. In a further embodiment, the concentration is from 0.5 mg / ml to 50 mg / ml, 0.5 mg / ml to 40 mg / ml, 0.5 mg / ml to 30 mg / ml, from 1 mg / ml to 25 mg / ml, from 2 mg / ml to 25 mg / ml or from 3 mg / ml to 20 mg / ml, all values inclusive. In other embodiments, the concentration of curcumin can be up to 50 mg / ml, 40 mg / ml, 30 mg / ml, 25 mg / ml, 20 mg / ml, 15 mg / ml, 10 mg / ml, 5 mg / ml, 1 mg / ml, or 0.5 mg / ml, or any range derivable therein. In other embodiments, the concentration of curcumin can be up to about 50 mg / ml, about 40 mg / ml, about 30 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, 1 mg / ml, or about 0.5 mg / ml, or any range derivable therein. For some embodiments, the concentration of curcumin can be about 0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, or about 30 mg / ml. In other embodiments, the concentration can be 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml.40 mg / ml, 45 mg / ml, or 50 mg / ml, or any range derivable therein. In one embodiment, the concentration of curcumin can be up to 20 mg / ml. In another embodiment, the concentration of curcumin can be 3 mg / ml to 20 mg / ml. In some embodiments, the concentration of the curcumin can be at least, at most, or at or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein.

[0097] According to another aspect, the active agent is resveratrol. In one embodiment, the concentration of resveratrol in the microemulsion is from about 0.5 mg / ml to about 75 mg / ml,about 1 mg / ml to about 50 mg / ml, from about 2 mg / ml to about 30 mg / ml, about 3 mg / ml to about 20 mg / ml, or about 3 mg / ml to about 25 mg / ml, or any range derivable therein, all values inclusive. In a further embodiment, the concentration is from 0.5 mg / ml to 75 mg / ml, from 1 mg / ml to 50 mg / ml, from 2 mg / ml to 30 mg / ml or from 3 mg / ml to 20 mg / ml, all values inclusive. In other embodiments, the concentration of resveratrol can be up to 75 mg / ml, 70 mg / ml, 65 mg / ml, 60 mg / ml, 55 mg / ml, 50 mg / ml, 45 mg / ml, 40 mg / ml, 35 mg / ml, 30 mg / ml, 25 mg / ml, 20 mg / ml, 15 mg / ml, 10 mg / ml, 5 mg / ml, 1 mg / ml, or 0.5 mg / ml, or any range derivable therein. In other embodiments, the concentration of resveratrol can be up to about 75 mg / ml, about 70 mg / ml, about 65 mg / ml, about 60 mg / ml, about 55 mg / ml, about 50 mg / ml, about 45 mg / ml, about 40 mg / ml, about 35 mg / ml, about 30 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, about 5 mg / ml, 1 mg / ml, or about 0.5 mg / ml, or any range derivable therein. For some embodiments, the concentration of resveratrol can be about 0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, or about 75 mg / ml, or any range derivable therein. In other embodiments, the concentration can be 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, or 75 mg / ml, or any range derivable therein. In one embodiment, the concentration of resveratrol can be up to 75 mg / ml. In another embodiment, the concentration of resveratrol can be 3 mg / ml to 25 mg / ml. In some embodiments, the concentration of the resveratrol can be at least, at most, or at or about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein.

[0098] According to another aspect, the active agent is lion’s mane extract. In some embodiments, the concentration of the lion’s mane in the microemulsion is from about 5 mg / ml to about 1500 mg / ml, about 10 mg / ml to about 1000 mg / ml, from about 20 mg / ml to about 750 mg / ml, about 50 mg / ml to about 500 mg / ml, or about 100 mg / ml to about 250 mg / ml, or any range derivable therein, all values inclusive. In a further embodiment, the concentration is from 5 mg / ml to 1500 mg / ml, from 10 mg / ml to 1000 mg / ml, from 20 mg / ml to 750 mg / ml, from 50 mg / ml to 500 mg / ml, or from 100 mg / ml to 250 mg / ml, or any range derivable therein, all values inclusive. In some embodiments, the concentration of lion’s mane can be up to 1500 mg / ml,1000 mg / ml, 750 mg / ml, 500 mg / ml, 250 mg / ml, 150 mg / ml, 125 mg / ml, 100 mg / ml, 95 mg / ml, 90 mg / ml, 85 mg / ml, 80 mg / ml, 75 mg / ml, 70 mg / ml, 65 mg / ml, 60 mg / ml, 55 mg / ml, 50 mg / ml, 45 mg / ml, 40 mg / ml, 35 mg / ml, 30 mg / ml, 25 mg / ml, 20 mg / ml, 15 mg / ml, 10 mg / ml, 5 mg / ml, 1 mg / ml, or 0.5 mg / ml, or any range derivable therein. In other embodiments, the concentration of lion’s mane can be up to about 1500 mg / ml, about 1000 mg / ml, about 750 mg / ml, about 500 mg / ml, about 250 mg / ml, about 150 mg / ml, about 125 mg / ml, about 100 mg / ml, about 95 mg / ml, about 90 mg / ml, about 85 mg / ml, about 80 mg / ml, about 75 mg / ml, about 70 mg / ml, about 65 mg / ml, about 60 mg / ml, about 55 mg / ml, about 50 mg / ml, about 45 mg / ml, about 40 mg / ml, about 35 mg / ml, about 30 mg / ml, about 25 mg / ml, about 20 mg / ml, about 15 mg / ml, about 10 mg / ml, or about 5 mg / ml, or any range derivable therein. For some embodiments, the concentration of lion’s mane can be about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 50 mg / ml, about 55 mg / ml, about 60 mg / ml, about 65 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 85 mg / ml, about 90 mg / ml, about 95 mg / ml, about 100 mg / ml, about 125 mg / ml, about 150 mg / ml, about 250 mg / ml, about 500 mg / ml, about 750 mg / ml, about 1000 mg / ml, or about 1500 mg / ml, or any range derivable therein. In other embodiments, the concentration can be 5 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 85 mg / ml, 90 mg / ml, 95 mg / ml, 100 mg / ml, 125 mg / ml, 150 mg / ml, 250 mg / ml, 500 mg / ml, 750 mg / ml, 1000 mg / ml, or 1500 mg / ml, or any range derivable therein. In some embodiments, the concentration of the lion’s mane can be at least, at most, or at or about, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 250, 500, 750, 1000, or 1500 mg / ml, or any range derivable therein.

[0099] In some aspects, the microemulsion formulation contains a combination of two different pharmacologically active agents selected from Table 1. The concentration of the each of the first pharmacologically active agent and of the second pharmacologically active agent may vary independently according to the amounts described above for the first pharmacologically active agent. When two pharmacologically active agents are present, the concentration of each agent is adjusted such that the overall formulation remains a microemulsion. Such adjustments may depend upon the solubility profile of the particular pharmacologically active agent. Although the pharmacologically active agents in Table 1 are lipophilic, some may be partially hydrophilic which may affect the total concentration of the active agent in the microemulsion formulation.

[0100] In some aspects, the microemulsion formulation contains a combination of the pharmacologically active agents cannabinoid and curcumin, herein known as a “cannabinoid / curcumin formulation”. The concentration of cannabinoid and of curcumin eachmay vary independently in the cannabinoid / curcumin formulation. According to one aspect, the final concentration of cannabinoid in the cannabinoid / curcumin formulation is from about 0.5 mg / ml to about 50 mg / ml both values inclusive. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is at least, at most, or at or about 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg / ml, or any range derivable therein. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation can be up to 45 mg / ml, 40 mg / ml, 35 mg / ml, 30 mg / ml, 25 mg / ml, 20 mg / ml, 15 mg / ml, 10 mg / ml, 5 mg / ml, or 1 mg / ml, or any range derivable therein. For some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation can be about 0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml, or about 50 mg / ml, or any range derivable therein. In some aspects, the cannabinoid / curcumin formulation comprises about 20 mg / ml to about 30 mg / ml of cannabinoid.

[0101] In another embodiment, the cannabinoid is cannabidiol (CBD) and has a concentration of at least, at most, or at or about 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, or 15 mg / ml, or any range derivable therein in the cannabinoid / curcumin formulation. In another embodiment, the CBD has a concentration of 4 mg / ml to 12 mg / ml. In another embodiment, the CBD has a concentration of 4 mg / ml to 9 mg / ml. In another embodiment, the CBD has a concentration of 3 mg / ml to 10 mg / ml. In another embodiment, the CBD has a concentration of 4.25 mg / ml. In another embodiment, the CBD has a concentration of 8.7 mg / ml.

[0102] In another embodiment, the cannabinoid is broad-spectrum hemp extract and has a concentration of of at least, at most, or at or about 2mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, or 15 mg / ml, or any range derivable therein in the cannabinoid / curcumin formulation. In another embodiment, the broad-spectrum hemp extract has a concentration of 3 mg / ml to 14 mg / ml. In another embodiment, the broad-spectrum hemp extract has a concentration of 4 mg / ml to 12 mg / ml. In another embodiment, the hemp extract has a concentration of 5 mg / ml to 10 mg / ml. In a further embodiment, the broad-spectrum hemp extract has a concentration of 5 mg / ml. In another embodiment, the broad-spectrum hemp extract has a concentration of 10 mg / ml.

[0103] In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is at least, at most, or at or about any of: 0.5 mg / ml, 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 15 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml, and 50 mg / ml, or any derivable range therein. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is at or about 4.25 mg / ml. In some embodiments, the concentration of cannabinoid in in the cannabinoid / curcumin formulation is 4.25 mg / ml. In some embodiments, the concentration of cannabinoid in in the cannabinoid / curcumin formulation is at or about 8.7 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is 8.7 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is at or about 10 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is 10 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is at or about 5 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is 5 mg / ml.

[0104] In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is between about 0.5 mg / ml and about 50 mg / ml, both values inclusive. In some embodiments, the concentration of cannabinoid in the microemulsion is between 0.5 mg / ml and 50 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is between about 20 mg / ml and about 30 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is between 20 mg / ml and 30 mg / ml. In some embodiments, the concentration of cannabinoid in the microemulsion is between about 3 mg / ml and about 15 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is between 2 mg / ml and 15 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is between about 4 mg / ml and about 12 mg / ml. In some embodiments, the concentration of cannabinoid in the microemulsion is between 4 mg / ml and 12 mg / ml. In some embodiments, the concentration of cannabinoid in the microemulsion is between about 4 mg / ml and about 9 mg / ml. In some embodiments, the concentration of cannabinoid in the microemulsion is between 4 mg / ml and 9 mg / ml. In some embodiments, the concentration of cannabinoid in the microemulsion is between about 5 mg / ml and about 10 mg / ml. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is between 5 mg / ml and 10 mg / ml.

[0105] According to one aspect, the maximum final concentration of cannabinoid in the cannabinoid / curcumin formulation is from about 0.5 mg / ml to about 50 mg / ml both values inclusive. In some embodiments, the concentration of cannabinoid can be greater than any of:0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 11 mg / ml, about 12 mg / ml, about 13 mg / ml, about 14 mg / ml, about 15 mg / ml, about 16 mg / ml, about 17 mg / ml, about 18 mg / ml, about 19 mg / ml, about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 26 mg / ml, about 27 mg / ml, about 28 mg / ml, about 29 mg / ml, about 30 mg / ml, about 31 mg / ml, about 32 mg / ml, about 33 mg / ml, about 34 mg / ml, about 35 mg / ml, about 36 mg / ml, about 37 mg / ml, about 38 mg / ml, about 39 mg / ml, about 40 mg / ml, about 41 mg / ml, about 42 mg / ml, about 43 mg / ml, about 44 mg / ml, about 45 mg / ml, about 46 mg / ml, about 47 mg / ml, about 48 mg / ml, about 49 mg / ml, and about 50 mg / ml, or any range derivable therein. In some embodiments, the concentration of cannabinoid can be less than any of: about 0.5 mg / ml, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 11 mg / ml, about 12 mg / ml, about 13 mg / ml, about 14 mg / ml, about 15 mg / ml, about 16 mg / ml, about 17 mg / ml, about 18 mg / ml, about 19 mg / ml, about 20 mg / ml, about 21 mg / ml, about 22 mg / ml, about 23 mg / ml, about 24 mg / ml, about 25 mg / ml, about 26 mg / ml, about 27 mg / ml, about 28 mg / ml, about 29 mg / ml, about 30 mg / ml, about 31 mg / ml, about 32 mg / ml, about 33 mg / ml, about 34 mg / ml, about 35 mg / ml, about 36 mg / ml, about 37 mg / ml, about 38 mg / ml, about 39 mg / ml, about 40 mg / ml, about 41 mg / ml, about 42 mg / ml, about 43 mg / ml, about 44 mg / ml, about 45 mg / ml, about 46 mg / ml, about 47 mg / ml, about 48 mg / ml, about 49 mg / ml, and about 50 mg / ml or any range derivable therein. In some embodiments, the concentration of cannabinoid in the cannabinoid / curcumin formulation is at least, at most, or at or about, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein.

[0106] In some embodiments, the cannabinoid in the cannabinoid / curcumin formulation is cannabidiol (CBD). In some embodiments, the concentration of CBD is up to 50 mg / ml. In some embodiments, the concentration of CBD in the cannabinoid / curcumin formulation is between 2 mg / ml and 15 mg / ml. In some embodiments, the concentration of CBD in the cannabinoid / curcumin formulation is between 3 mg / ml and 15 mg / ml. In some embodiments, the concentration of CBD is between about 4 mg / ml and about 12 mg / ml. In some embodiments, the concentration of CBD is between 4 mg / ml and 12 mg / ml. In some embodiments, the concentration of CBD is between about 4 mg / ml and about 9 mg / ml. In some embodiments, the concentration of CBD is between 4 mg / ml and 9 mg / ml. In someembodiments, the concentration of CBD in the cannabinoid / curcumin formulation is at or about 4.25 mg / ml. In some embodiments, the concentration of CBD in the cannabinoid / curcumin formulation is 4.25 mg / ml. In some embodiments, the concentration of CBD in the cannabinoid / curcumin formulation is at or about 8.7 mg / ml. In some embodiments, the concentration of CBD in the cannabinoid / curcumin formulation is 8.7 mg / ml. In some embodiments, the concentration of CBD in the cannabinoid / curcumin formulation is at or about 4.25 mg / ml and the concentration of curcumin in the cannabinoid / curcumin formulation is at or about 8.6 mg / ml. In some embodiments, the concentration of CBD in the microemulsion is at least, at most, or at or about, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein .

[0107] In some embodiments, the cannabinoid in the cannabinoid / curcumin formulation is broad-spectrum hemp extract. In some embodiments, the concentration of broad-spectrum hemp extract is up to 50 mg / ml. In other embodiments, the concentration of the broad- spectrum hemp extract is 35 mg / ml. In some embodiments, the concentration of broad- spectrum hemp extract in the cannabinoid / curcumin formulation is between about 2 mg / ml and about 15 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is between 2 mg / ml and 15 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is between about 4 mg / ml and about 12 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is between 4 mg / ml and 12 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is between about 5 mg / ml and about 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract is between 5 mg / ml and 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the microemulsion is at or about 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is at or about 5 mg / ml. In some embodiments, the concentration of hemp extract in the cannabinoid / curcumin formulation is 5 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is at or about 2.1 mg / ml and the concentration of curcumin in the cannabinoid / curcumin formulation is at or about 8.6 mg / ml. In some embodiments, theconcentration of broad-spectrum hemp extract in the microemulsion is at least, at most, or at or about, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein.

[0108] In some aspects, the final concentration of curcumin in the cannabinoid / curcumin formulation is from about 1 mg / ml to about 40 mg / ml both values inclusive. In some embodiments, the concentration of curcumin is up to 40 mg / ml. For some embodiments, the concentration of curcumin can be at least, at most, or at or about 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, 10 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 21 mg / ml, 22 mg / ml, 23 mg / ml, 24 mg / ml, 25 mg / ml, 26 mg / ml, 27 mg / ml, 28 mg / ml, 29 mg / ml, 30 mg / ml, 31 mg / ml, 32 mg / ml, 33 mg / ml, 34 mg / ml, 35 mg / ml, 36 mg / ml, 37 mg / ml, 38 mg / ml, 39 mg / ml, 40 mg / ml, or any range derivable therein. In one embodiment, the cannabinoid / curcumin formulation comprises 10 mg / ml to 20 mg / ml of curcumin. In another embodiment, the concentration of curcumin is 20 mg / ml. In a further embodiment, the concentration of curcumin is 10 mg / ml. In some embodiments, the concentration of curcumin in the cannabinoid / curcumin formulation is at least, at most, or at or about, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein.

[0109] In other aspects, the microemulsion formulation comprises a combination of resveratrol and curcumin, as described herein and in the Examples. In some embodiments, the concentration of resveratrol is up to 200 mg / ml in the microemulsion formulation, and the concentration of curcumin is up to 50 mg / ml. In other embodiments, the resveratrol is in a concentration of 1 mg / ml to 200 mg / ml and curcumin is in a concentration of 1 mg / ml to 50 mg / ml or each in any derivable concentration therein. In some embodiments, the resveratrol is in a concentration of 1 mg / ml to 50 mg / ml and the curcumin is in a concentration of 3 mg / ml to 25 mg / ml or each in any derivable concentration therein. In some embodiments, the resveratrol has a concentration of 10 mg / ml to 40 mg / ml and curcumin has a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments, the resveratrol has a concentration of 10 mg / ml to 30 mg / ml and curcumin has a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments,the resveratrol has a concentration of about 20 mg / ml and curcumin has a concentration of about 10 mg / ml or each in any derivable concentration therein. In some embodiments, the resveratrol has a concentration of 20 mg / ml and curcumin has a concentration of 10 mg / ml or each in any derivable concentration therein. In some embodiments, in the microemulsion formulation, the concentration of resveratrol at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein, and the concentration of curcumin is at least, at most, or at or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg / ml or any range derivable therein.

[0110] In some embodiments, the microemulsion formulation comprises a combination of lion’s mane extract and curcumin, for example, as described herein and in the Examples. In some embodiments, the concentration of lion’s mane extract is up to 100 mg / ml in the microemulsion formulation, and the concentration of curcumin is up to 50 mg / ml. In some embodiments, the microemulsion formulation comprises lion’s mane extract in a concentration of 1 mg / ml to 50 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml or each in any derivable concentration therein. In some embodiments, the lion’s mane extract has a concentration of 10 mg / ml to 40 mg / ml and curcumin has a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments, the lion’s mane extract has a concentration of 10 mg / ml to 30 mg / ml and curcumin has a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments, the lion’s mane extract has a concentration of about 20 mg / ml and the curcumin has a concentration of about 10 mg / ml or each in any derivable concentration therein. In some embodiments, the lion’s mane extract has a concentration of 20 mg / ml and curcumin has a concentration of 10 mg / ml or each in any derivable concentration therein. In some embodiments, in the microemulsion formulation, the concentration of lion’s mane extract is at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any range derivable therein, and the concentration of curcumin is at least, at most, or at or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg / ml or any range derivable therein. Methods of microemulsion formulation preparation

[0111] In some aspects, provided herein are methods of preparation of the microemulsion formulation as described by any of the composition embodiments described herein. In some embodiments, the microemulsion components (polysorbate surfactant, fatty acid, and co- surfactant) are stirred together at room temperature until a microemulsion forms. For example, the stirring step can be for at least, at most, or at or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,minutes, or any range derivable therein. In another embodiment, the components (polysorbate 80, oleic acid, and propylene glycol) are stirred together at room temperature until a microemulsion forms. In another embodiment, the components (polysorbate 20, oleic acid, and propylene glycol) are stirred together at room temperature until a microemulsion forms. In another embodiment, the components (polysorbate 20, oleic acid, and ethanol) are stirred together at room temperature until a microemulsion forms. In a further embodiment, the components (polysorbate 20, oleic acid, linoleic acid, and ethanol) are stirred together at room temperature until a microemulsion forms. In another embodiment, the components (polysorbate 20, oleic acid, linoleic acid, and propylene glycol) are stirred together at room temperature until a microemulsion forms.

[0112] A method for preparing the microemulsion formulation containing a pharmacologically active agent or a combination of pharmacologically active agents can comprise any suitable steps and in any suitable order apparent to one having skill in the art. Exemplary non-limiting sequences of steps for preparing such microemulsions are provided below. In some embodiments, one or two of the steps can be excluded. In some embodiments, water is not added in any of the steps of the method. In some embodiments, less than 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%. by volume water is added.

[0113] In one embodiment, the process comprises the following steps: 1) dissolving an active agent in co-surfactant by stirring at room temperature, 2) adding a fatty acid and stirring at room temperature, and 3) adding a polysorbate surfactant and stirring at room temperature until a microemulsion forms.

[0114] In some embodiments, the pharmacologically active agent is chosen from Table 1. In some embodiments a first pharmacologically active agent is chosen from Table 1 and a different second pharmacologically active is chosen from Table 1. In some embodiments the fatty acid is oleic acid or linoleic acid or a combination thereof. In some embodiments, thesurfactant is polysorbate 20 or polysorbate 80. In some embodiments, the co-surfactant is propylene glycol or ethanol.

[0115] In one embodiment, the process comprises the following steps: 1) dissolving curcumin in propylene glycol by stirring at room temperature, 2) adding oleic acid and stirring at room temperature, and 3) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0116] In another embodiment, the process comprises the following steps: 1) dissolving curcumin in propylene glycol by stirring at room temperature, 2) adding oleic acid and stirring at room temperature, and 3) adding polysorbate 20 and stirring at room temperature until a microemulsion forms.

[0117] In a further embodiment, the process comprises the following steps: 1) dissolving curcumin in ethanol by stirring at room temperature, 2) adding oleic acid and stirring at room temperature, and 3) adding polysorbate 20 and stirring at room temperature until a microemulsion forms.

[0118] In another embodiment, the process comprises the following steps: 1) dissolving cannabidiol in propylene glycol by stirring at room temperature, 2) adding oleic acid and stirring at room temperature, and 3) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0119] In a further embodiment, the process comprises the following steps: 1) dissolving broad-spectrum hemp extract in oleic acid by stirring at room temperature, 2) adding propylene glycol and stirring at room temperature, and 3) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0120] In another embodiment, the process comprises the following steps: 1) melting broad-spectrum hemp extract at 85 °C, 2) adding the melted extract to oleic acid and stirring, 3) adding propylene glycol and stirring at room temperature, and 4) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0121] In a further embodiment, the process comprises the following steps:1) dissolving resveratrol in propylene glycol by stirring at room temperature, 2) adding oleic acid and stirring at room temperature, and 3) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0122] In another embodiment, the process comprises the following steps: 1) dissolving lion’s mane extract in propylene glycol by stirring at room temperature, 2) adding oleic acid and stirring at room temperature, and 3) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0123] In a further embodiment, the composition is prepared by a process comprising the following steps: 1) dissolving cannabidiol in propylene glycol by stirring at room temperature, 2) adding curcumin and stirring at room temperature, 3) adding oleic acid and stirring at room temperature, and 4) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0124] In another embodiment, the process comprises the following steps: 1) dissolving hemp extract in oleic acid by stirring at room temperature, 2) dissolving CBD in propylene glycol by stirring at room temperature, 3) adding curcumin to the propylene glycol / CBD solution and stirring at room temperature, 4) adding the oleic acid / broad-spectrum hemp extract solution into the propylene glycol / CBD / curcumin solution and stirring at room temperature, and 5) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0125] In another embodiment, the composition is prepared by a process comprising the following steps: 1) dissolving lion’s mane extract in propylene glycol by stirring at room temperature, 2) adding curcumin and stirring at room temperature, 3) adding oleic acid and stirring at room temperature, and 4) adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0126] In a further embodiment, the composition is prepared by a process comprising the following steps: 1) dissolving resveratrol in propylene glycol by stirring at room temperature,2) adding curcumin and stirring at room temperature, 3) adding oleic acid and stirring at room temperature, and 4) adding polysorbate 80 and stirring at room temperature until a microemulsion forms. An aqueous-soluble agent may optionally be included in any of the above methods. When desired, the additional agent (or agents) can be separately dissolved in water. In one embodiment, the aqueous solution is added to the microemulsion as the final step after all other components have been incorporated and the mixture stirred until a complete microemulsion forms. In another embodiment, the aqueous solution is added after the co- surfactant and the mixture is stirred until a complete microemulsion forms.

[0127] Some embodiments of the disclosure relate to a method for preparing the microemulsion formulation containing a pharmacologically active agent or a combination of pharmacologically active agents can comprise any suitable steps and in any suitable order apparent to one having skill in the art. Exemplary non-limiting sequences of steps for preparing such microemulsions are provided. In some embodiments, water is not added in any of the steps of the method. In some embodiments, less than 20%, 15%, 10%, or 5%, 4%, 3%, 2%, or 1% by volume water is added. The method can include or exclude 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 43, 44, or 45 of the following steps: dissolving an active agent in co-surfactant by stirring at room temperature; adding a fatty acid and stirring at room temperature; adding a polysorbate surfactant and stirring at room temperature until a microemulsion forms; selecting a pharmacological agent from Table 1; selecting a first pharmacologically active agent chosen from Table 1 and a different second pharmacologically active chosen from Table 1; dissolving curcumin in propylene glycol by stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving curcumin in propylene glycol by stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 20 and stirring at room temperature until a microemulsion forms; dissolving curcumin in ethanol by stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 20 and stirring at room temperature until a microemulsion forms; dissolving cannabidiol in propylene glycol by stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving broad-spectrum hemp extract in oleic acid by stirring at room temperature; adding propylene glycol and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; melting broad- spectrum hemp extract at 85 °C; adding the melted extract to oleic acid and stirring; addingpropylene glycol and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving resveratrol in propylene glycol by stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving lion’s mane extract in propylene glycol by stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving cannabidiol in propylene glycol by stirring at room temperature; adding curcumin and stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving hemp extract in oleic acid by stirring at room temperature; dissolving CBD in propylene glycol by stirring at room temperature; adding curcumin to the propylene glycol / CBD solution and stirring at room temperature; adding the oleic acid / broad-spectrum hemp extract solution into the propylene glycol / CBD / curcumin solution and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving lion’s mane extract in propylene glycol by stirring at room temperature; adding curcumin and stirring at room temperature; adding oleic acid and stirring at room temperature; adding polysorbate 80 and stirring at room temperature until a microemulsion forms; dissolving resveratrol in propylene glycol by stirring at room temperature; adding curcumin and stirring at room temperature; adding oleic acid and stirring at room temperature; and adding polysorbate 80 and stirring at room temperature until a microemulsion forms.

[0128] An aqueous-soluble agent may optionally be included in any of the above methods. When desired, the additional agent (or agents) can be separately dissolved in water. In one embodiment, the aqueous solution is added to the microemulsion as the final step after all other components have been incorporated and the mixture stirred until a complete microemulsion forms. In another embodiment, the aqueous solution is added after the co- surfactant and the mixture is stirred until a complete microemulsion forms. Soft Gel Capsule Compositions

[0129] The microemulsion can be formulated and / or administered in liquid form, or as a capsule, such as a soft gel capsule or a hard gel capsule. In some embodiments, the microemulsion formulation is formulated as a soft gel capsule. A soft gel capsule is an oral dosage form made essentially of gelatin and a plasticizer used to deliver liquid or oil-based solutions, suspensions, or semisolid formulations. Compared with hard capsules, soft gel capsules are typically thicker and include ingredients such as glycerin to obtain their soft textures. A wide variety of pharmaceuticals and nutritional supplements, such as omega-3 fish oils, are formulated as soft gels. Many consumers prefer soft gelatin capsules as they are easier to swallow than tablets. In addition, soft gels conveniently deliver consistent quantitiesof liquid formulations. For a general review of soft gel dosage forms, see G. Deepak, et al., “Soft Gelatin Capsules: Development, Applications and Recent Patents” (Int. Res. J. Inventions Pharm Sci., 2014, 2:3, pp.163-173).

[0130] Encapsulation methods of manufacture of soft gel capsules are well known in the art. The original rotary die encapsulation process and machinery was invented in the 1930s by Robert Pauli Scherer (U.S. Patent No.2,288,327). The modern encapsulation process can be described as a form / fill / seal process. Typically, two flat ribbons of shell material are manufactured and brought together on a twin set of rotating dies. The dies contain recesses in the desired size and shape, which cut out the ribbons into a two-dimensional shape, and form a seal around the outside. At the same time, a pump delivers a precise dose of the microemulsion through a nozzle incorporated into a heated filling wedge whose tip sits between the two ribbons in between two die pockets at the point of cut out. The wedge injection causes the two flat ribbons to expand into the die pockets, thus creating the three-dimensional finished product. A die then cuts the ribbon into the finished soft gel. After encapsulation, the soft gels are dried if necessary.

[0131] In some embodiments, the shell-material ribbon can be made of a gelatin mixture heated and pressed into a thin, flat shape. This mixture must be strong enough to hold the formulation within the capsule once it is dried and sealed but still be easily digestible within the stomach. While the mixture is still warm and in liquid form, it is spread across rotating cylinders and stretched into shape. Next, cool air is applied to solidify the gelatin ribbon into a thin, stable layer. Although two ribbons are brought together with no space between them on the rotating dies, they remain distinct layers. The drying process is adapted such that the final soft gel product has the desired finish and durability. In some embodiments, the soft gels are dried for a period of time ranging from about 24 to about 120 hours at an environmental relative humidity of about 1% to about 40% at a temperature range of about 20°C to about 25°C.

[0132] The gelatin mixture utilized can be comprised of pharmaceutical grade gelatin, plasticizer and water. In one embodiment, the gelatin is a protein made from collagen taken from animal-based sources, typically bovine, porcine or piscine. Plasticizer makes the soft gel elastic and pliable. The gelatin to plasticizer to water ratio, as well as the precise components of the shell material, are varied such that the final soft gel product has the desired appearance, mechanical stability, texture, finish, durability, shelf life and resistance to leakage of the encapsulated microemulsion. The components of the shell material are optimized to minimize interactions between it and the filled microemulsion.Consideration is also given to optimizing the manufacturing process. Common plasticizers suitable for use can include sorbitol, maltitol, mannitol, xylitol and glycerin. It is contemplated that any of these may also be excluded in an embodiment. Mixtures of plasticizers may be used. Optionally, the gelatin mixture may contain coloring agents, opacifiers, preservatives, flavoring and the like. It is contemplated that any of these may also be excluded in an embodiment. An example of an opacifying agent is titanium dioxide which produces an opaque capsule useful in preventing possible photo degradation of the capsule’s contents.

[0133] In another embodiment, soft gels may be made of non-animal-based materials including pullanan and hypromellose instead of gelatin. Pullanan is a water-soluble polysaccharide comprised of repeating maltotriose residues produced from starch by the yeast-like fungus Aureobasidium pullulans. Hypromellose (hydroxypropyl methylcellulose) is a semi-synthetic, viscoelastic polymer, produced from plant-based cellulose.

[0134] The soft gel capsules may be manufactured in a variety of sizes and shapes. In one embodiment, oblong-shaped #8 soft gel capsules with a nominal volume of 0.5 ml are used. In another embodiment, oblong-shaped #10 soft gel capsules with a nominal fill of 0.5 ml are used. In another embodiment, oblong-shaped #10 soft gel capsules with a nominal fill of 0.6 ml are used. In some embodiments, oblong or oval #4 soft gel capsules with a nominal volume of 0.25 ml are used. In other embodiments, oblong or oval #12 soft gel capsules with a nominal volume of 0.8 ml are used. In further embodiments, oblong or oval #20 soft gel capsules with a nominal volume of 1.0 ml are used. In some embodiments, oblong #26 or oval #30 soft gel capsules with a nominal volume of 1.5 ml are used. In another embodiment, the soft gel capsule is filled with any nominal volume of a microemulsion formulation that it accommodates while maintaining a suitable desired appearance, mechanical stability, texture, finish, durability, shelf life and resistance to leakage of the encapsulated microemulsion.

[0135] In one aspect, each soft gel capsule may contain a microemulsion formulation having a concentration of pharmaceutically active agent according to any of the concentrations of active agents of Table 1 provided herein. In some embodiments, the soft gel capsule contains at or about any of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg or any derivable range therein, of active agent. In some embodiments, the soft gel capsule contains at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 125, 150, 175, or 200 mg, or any derivable range therein, of the active agent. In some embodiments, the soft capsule may contain larger amounts of the active agent.

[0136] In further embodiments, the soft gel capsule contains a cannabinoid. In some embodiments, the soft gel capsule contains at or about any of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or any derivable range therein, of the cannabinoid broad-spectrum hemp extract. In other embodiments, the soft gel capsule contains at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of broad-spectrum hemp extract. In other embodiments, the soft gel capsule contains at or about any of 1 mg, 4 mg, 4.25 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, or any derivable range therein, of cannabinoid CBD. In some embodiments, the soft gel capsule contains at least, at most, or at or about, 1, 2, 3, 4, 4.25, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of CBD.

[0137] In further embodiments, the soft gel capsule contains at or about any of 1 mg, 5 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, or any derivable range therein, of pharmacologically active agent curcumin. In some embodiments, the soft gel capsule contains at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of curcumin.

[0138] In other embodiments, the soft gel capsule contains at or about any of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, or 100 mg or any derivable range therein, of pharmacologically active agent resveratrol. In some embodiments, the soft gel capsule contains at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of resveratrol.

[0139] In other embodiments, the soft gel capsule contains at or about any of 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 125 mg or 150 mg, or any derivable range therein, of the pharmacologically active agent lion’s mane extract. In some embodiments, the soft gel capsule contains at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 110, 120, 125, 130, 140, or 150 mg, or any derivable range therein of lion’s mane.

[0140] In other embodiments, each soft gel capsule may contain a microemulsion formulation of two pharmaceutically active agents according to any of the concentrations of active agents in Table 1 provided herein. In the case where two active agents are present, the concentration of each agent is adjusted such that the overall formulation remains a microemulsion.

[0141] In some embodiments, the soft gel capsule contains a microemulsion comprising broad-spectrum hemp extract and curcumin, for example, as described herein and in the Examples. In some embodiments, each capsule contains broad-spectrum hemp extract in a concentration of 1 mg / ml to 30 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml. In some embodiments, each capsule contains broad-spectrum hemp extract in a concentration of 3 mg / ml to 20 mg / ml and curcumin in a concentration of 5 mg / ml to 20 mg / ml. In some embodiments, each capsule contains broad-spectrum hemp extract in a concentration of 5 mg / ml to 10 mg / ml and curcumin in a concentration of 10 mg / ml to 20 mg / ml. In some embodiments, each soft gel capsule contains broad-spectrum hemp extract in a concentration of 5 mg / ml and curcumin in a concentration of 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the soft gel capsule is up to 50 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the soft gel capsule is between about 2 mg / ml and about 15 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is between 2 mg / ml and 15 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the cannabinoid / curcumin formulation is between about 4 mg / ml and about 12 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the soft gel capsule is between 4 mg / ml and 12 mg / ml. In some embodiments, the concentrationof broad-spectrum hemp extract in the soft gel capsule is between about 5 mg / ml and about 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract is between 5 mg / ml and 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the microemulsion in the soft gel capsule is at or about 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the soft gel capsule is 10 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the soft gel capsule is at or about 5 mg / ml. In some embodiments, the concentration of hemp extract in the soft gel capsule is 5 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the soft gel capsule is at or about 2.1 mg / ml and the concentration of curcumin in the soft gel capsule is at or about 8.6 mg / ml. In some embodiments, the concentration of broad-spectrum hemp extract in the soft gel capsule is at least, at most, or at or about, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any derivable range therein. In some aspects, the final concentration of curcumin in the soft gel capsule is from about 1 mg / ml to about 40 mg / ml both values inclusive. In some embodiments, the concentration of curcumin in the soft gel capsule is up to 40 mg / ml. For some embodiments, the concentration of curcumin in the soft gel capsule can be greater than about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 5 mg / ml, about 6 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, or about 30 mg / ml, about 35 mg / ml, or about 40 mg / ml, or any derivable range therein. In one embodiment, the cannabinoid / curcumin formulation in the soft gel capsule comprises 10 mg / ml to 20 mg / ml of curcumin. In another embodiment, the concentration of curcumin is 20 mg / ml. In a further embodiment, the concentration of curcumin is 10 mg / ml. In some embodiments, the concentration of curcumin in the cannabinoid / curcumin formulation in the soft gel capsule is at least, at most, or at or about, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg / ml, or any derivable range therein.

[0142] In some embodiments, each soft gel capsule contains 2.5 mg to 5 mg of broad- spectrum hemp extract and 4 mg to 10 mg of curcumin. In some embodiments, each soft gel capsule contains 5 mg of broad-spectrum hemp extract and 10 mg of curcumin. In someembodiments, the soft gel capsule containing a cannabidiol / curcumin formulation contains between about 5 mg and about 15 mg curcumin. In some embodiments, the soft gel capsule contains at or about any of 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg or 30 mg curcumin, or any derivable range therein. In some embodiments, the soft gel capsule contains at or about 10 mg turmeric extract standardized to contain 95% curcuminoids. In some embodiments, the soft gel capsule contains 10 mg turmeric extract standardized to 95% curcuminoids. In some embodiments, the soft gel capsule contains at or about 9.5 mg curcumin in 10 mg turmeric extract standardized to 95% curcuminoids. In some embodiments, the soft gel capsule contains 9.5 mg curcumin in 10 mg turmeric extract standardized to contain about 95% curcuminoids. In some embodiments, the soft gel capsule contains at or about 10 mg curcumin. In some embodiments, the soft gel capsule contains 10 mg curcumin. In some embodiments, the soft gel capsule contains between about 1 and about 10 mg broad-spectrum hemp extract. In some embodiments, the soft gel capsule contains at or about any of 1 mg, 2 mg, 3 mg, 4 mg, 4.25 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, or 60 mg broad-spectrum hemp extract, or any derivable range therein. In some embodiments, the soft gel capsule contains at or about 5 mg broad-spectrum hemp extract standardized to 87% CBD. In some embodiments, the soft gel capsule contains 5 mg broad-spectrum hemp extract standardized to 87% CBD. In some embodiments, the soft gel capsule contains at or about 4.25 mg CBD in 5 mg broad-spectrum hemp extract standardized to 87% CBD. In some embodiments, the soft gel capsule contains 4.25 mg CDB in 5 mg broad-spectrum hemp extract standardized to 87% CBD.

[0143] In some embodiments, the soft gel capsule contains a cannabinoid / curcumin formulation contains at least, at most, or at or about, 1, 2, 3, 4, 4.25, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of cannabinoid. In some embodiments, the soft gel capsule containing a cannabidiol / curcumin formulation contains at least, at most, or at or about, 1, 2, 3, 4, 4.25, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of CBD. In some embodiments, the soft gel capsule containing a broad-spectrum hemp / curcumin formulation contains at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of broad- spectrum hemp extract. In some embodiments, the soft gel capsule containing a cannabidiol / curcumin or a broad-spectrum hemp / curcumin formulation contains at least, at most, or at or about, 1, 2, 3, 4, 5, 6, 7, 8, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg, or any derivable range therein of curcumin.

[0144] In some embodiments, each soft gel capsule may contain a microemulsion having a concentration of CBD and of curcumin as specified above. In some embodiments, each capsule contains CBD in a concentration of 3 mg / ml to 20 mg / ml and curcumin in a concentration of 4 mg / ml to 15 mg / ml. In some embodiments, each capsule contains CBD in a concentration of 1 mg / ml to 30 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml. In some embodiments, each capsule contains CBD in a concentration of 5 mg / ml and curcumin in a concentration of 10 mg / ml. In some embodiments, the soft gel capsule contains between about 5 mg and about 15 mg curcumin. In some embodiments, the soft gel capsule contains at or about any of 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, or 30 mg curcumin, or any derivable range therein. In some embodiments, the soft gel capsule contains at or about 10 mg curcumin. In some embodiments, the soft gel capsule contains 10 mg curcumin. In some embodiments, the soft gel capsule contains between about 1 and about 10 mg CBD. In some embodiments, the soft gel capsule contains at or about any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, or 75 mg CBD, or any derivable range therein.

[0145] In some embodiments, the soft gel capsule contains a microemulsion comprising resveratrol and curcumin, for example, as described herein and in the Examples. In some embodiments, each capsule contains resveratrol in a concentration of 1 mg / ml to 50 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml or each in any derivable concentration therein. In some embodiments, each capsule contains resveratrol in a concentration of 10 mg / ml to 40 mg / ml and curcumin in a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments, each capsule contains resveratrol in a concentration of 10 mg / ml to 30 mg / ml and curcumin in a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments, each soft gelcapsule contains resveratrol in a concentration of about 20 mg / ml and curcumin in a concentration of about 10 mg / ml or each in any derivable concentration therein. In some embodiments, each soft gel capsule contains resveratrol in a concentration of 20 mg / ml and curcumin in a concentration of 10 mg / ml or each in any derivable concentration therein.

[0146] In some embodiments, each soft gel capsule contains 10 mg to 30 mg of resveratrol and 5 mg to 10 mg of curcumin. In some embodiments, each soft gel capsule contains 20 mg of resveratrol and 10 mg of curcumin. In some embodiments, the soft gel capsule containing a resveratrol / curcumin formulation contains between about 5 mg and about 15 mg curcumin. In some embodiments, the soft gel capsule contains at or about any of 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg or 30 mg curcumin, or any derivable range therein. In some embodiments, the soft gel capsule contains at or about 10 mg curcumin. In some embodiments, the soft gel capsule contains 10 mg curcumin. In some embodiments, the soft gel capsule contains between about 1 and about 30 mg resveratrol. In some embodiments, the soft gel capsule contains at or about any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg resveratrol, or any derivable range therein. In some embodiments, the soft gel capsule contains at or about 20 mg resveratrol. In some embodiments, the soft gel capsule contains 20 mg resveratrol.

[0147] In some embodiments, the soft gel capsule contains a microemulsion comprising lion’s mane extract and curcumin, for example, as described herein and in the Examples. In some embodiments, each capsule contains lion’s mane extract in a concentration of 1 mg / ml to 50 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml or each in any derivable concentration therein. In some embodiments, each capsule contains lion’s mane extract in a concentration of 10 mg / ml to 40 mg / ml and curcumin in a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments, each capsule contains lion’s mane extract in a concentration of 10 mg / ml to 30 mg / ml and curcumin in a concentration of 5 mg / ml to 20 mg / ml or each in any derivable concentration therein. In some embodiments, each soft gel capsule contains lion’s mane extract in a concentration of about 20 mg / ml and curcumin in a concentration of about 10 mg / ml or each in any derivable concentration therein. In some embodiments, each soft gel capsule contains lion’s mane extract in a concentration of 20 mg / ml and curcumin in a concentration of 10 mg / ml or each in any derivable concentration therein.

[0148] In some embodiments, each soft gel capsule contains 10 mg to 35 mg of lion’s mane extract and 5 mg to 10 mg of curcumin. In some embodiments, each soft gel capsule contains 25 mg of lion’s mane extract and 10 mg of curcumin. In some embodiments, the soft gelcapsule containing a lion’s mane extract / curcumin formulation contains between about 5 mg and about 15 mg curcumin. In some embodiments, the soft gel capsule contains at or about any of 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg or 30 mg curcumin, or any derivable range therein. In some embodiments, the soft gel capsule contains at or about 10 mg curcumin. In some embodiments, the soft gel capsule contains 10 mg curcumin. In some embodiments, the soft gel capsule contains between about 1 and about 35 mg lion’s mane extract. In some embodiments, the soft gel capsule contains at or about any of 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 9.5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, or 35 mg lion’s mane extract, or any derivable range therein. In some embodiments, the soft gel capsule contains at or about 25 mg. In some embodiments, the soft gel capsule contains 25 mg lion’s mane extract.

[0149] As will be apparent to one of skill in the art, in some embodiments, a dose of any of the foregoing amounts of active agent in the microemulsion formulation can be comprised in a single soft gel capsule, or can be comprised in multiple soft gel capsules. For example, a single dose of 10 mg active agent can be comprised in a single soft gel capsule containing 10 mg active agent, or in two soft gel capsules containing 5 mg active agent each. Inflammation

[0150] Inflammation is the body’s natural response to many primary etiologies. Numerous natural products have historically been used to treat inflammation. In some embodiments, the present disclosure describes microemulsion formulations of such pharmacologically active agents useful in the treatment of inflammation. Further, microemulsion formulations of combinations of products may be used in the treatment of inflammation and its associated pain, as well as in other conditions. In some aspects, a synergistic combination of active agents, for example, cannabinoids and curcumin formulated as a microemulsion, is used. The formulation, for example, the cannabinoid / curcumin formulation, can find use in treatment such as treatments for inflammation and / or its associated pain. Examples of inflammatory diseases and conditions include, but are not limited to, arthritis, musculoskeletal disorders, inflammatory bowel disease and autoimmune skin conditions.

[0151] Arthritis is a very common condition, especially in people older than 50, as well as in other mammals as they age. Arthritis causes joint pain, stiffness and inflammation, most commonly in hands and wrists, knees, hips, feet and ankles, shoulders and the lower back. Typically, arthritis breaks down the natural tissue of joints (degeneration) or causes inflammation. Pain from inflammation can be severe and accompanied by swelling, stiffness or reduced range of joint motion. Types of arthritis include osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, psoriatic arthritis and juvenile arthritis.

[0152] Musculoskeletal pain can result from inflammation caused by exercise overexertion, overuse, or specific athletic training. For example, patients with tendon disorders, common in the general population and more frequently in athletes, often give rise to inflammation (Azzini, G.O., et al., Exp. Biol. Medicine, 2023, 248:445-455). Even in the absence of arthritis, or any specific musculoskeletal or connective tissue disorder, muscular or tendinous pain after exertion is a nearly universal human experience.

[0153] The term inflammatory bowel disease (IBD) mainly refers to two conditions (ulcerative colitis and Crohn’s disease) that are characterized by chronic inflammation of the gastrointestinal (GI) tract. Active disease usually causes rectal bleeding and diarrhea and will often also result in pain, fatigue and weight loss. Patients with chronic intestinal inflammation also have an increased risk of developing bowel cancer. Ulcerative colitis (UC) is a chronic, relapsing, and remitting IBD that affects the large intestine (colon) and rectum. Crohn’s disease usually affects the small intestine, although it can affect any portion of the intestinal tract.

[0154] Autoimmune diseases occur when the body’s immune system attacks healthy skin or tissue. Autoimmune skin diseases manifest with a variety of symptoms including rashes, blisters, lesions and scaly patches. Types of dermatological autoimmune disorders include alopecia arreata, Bechet’s disease, dermatitis herpetiformis, dermatomyositis, eczema (atopic dermatitis), lichen planus, lupus of the skin, scleroderma, pemphigoid, pemphigus, and psoriasis. Alopecia areata is a common, non-scarring alopecia, mainly manifested as sudden localized patchy alopecia (hair loss) which can be treated with injected corticosteroids. Psoriasis is a chronic disease in which the immune system becomes overactive, causing skin cells to multiply too quickly. Patches of skin become scaly and inflamed, most often on the scalp, elbows and knees. Having psoriasis increases the risk of developing psoriatic arthritis, a chronic form of arthritis that causes pain, stiffness and swelling of the joints and entheses. Current treatments aim to stop the rapid proliferation of skin cells and to remove scales.

[0155] In one embodiment, a microemulsion described herein, for example, curcumin and CBD, provide synergistic anti-inflammatory actions that find use in the treatment of the above- named conditions and others. The pathways of cellular inflammation are highly complex and interwoven. Due to this network effect, blocking a single pathway usually provides only a partial or blunted effect on inflammation, because alternative pathways can and do eventually activate the same downstream cellular targets as the blocked pathway. While not wishing to be bound by any particular theory, the strength of the novel microemulsion formulation in improving inflammation and its resultant pain likely lies in the ability of the two active compounds to block different cellular signaling pathways simultaneously. This activity isprovided across the broad range of cell types involved in inflammation. Activity modulating the inflammatory response occurs at both the cell surface and in the cell interior. Modulating this diversity of cellular targets provides a much broader improvement in inflammation than either compound alone, because so many of the targets differ between the two compounds.

[0156] Curcumin is known to act by binding to cell surface receptors and activating or inhibiting certain cellular pathways. In particular, curcumin is known to activate GPR97, one of the same cell surface receptors activated by anti-inflammatory steroids (Harada, N., et al., Biochem. Biophys. Res. Commun., 2022, 595:41-46). Curcumin inhibits the production of AA (arachidonic acid, a primary signaling molecule in inflammation and pain) at the membrane level by blocking phosphorylation of phospholipase A2, thus blocking the hydrolysis of membrane phospholipids into AA (Hong, J., et al., Carcinogenesis, 2004, 25:1671). Further downstream, curcumin has been shown to be an inhibitor of the activity of cyclooxygenase, which is a major node in the production of AA metabolites (Huang, M. T., et al., Cancer Res., 1991, 51:813–819). In addition to cell surface effects, curcumin has known downstream effects on at least 30 intracellular targets involved in inflammation.

[0157] Cannabidiol, by contrast, works chiefly by acting on specific cell surface receptors (CB1 and CB2). The CB1 receptor is found primarily in the central nervous system (Herkenham, M., et al., J. Neurosci., 1991, 11:563–583), which represents the likely locus for pain relief from CBD. Of particular interest to the modulation of inflammation, the CB2 receptor is found primarily on immune cells, with CB2 receptors having been demonstrated on every cell type that has been investigated to date, including B cells, T cells, basophils, eosinophils, dendritic cells, mast cells, monocytes, macrophages, microglia, NK cells, neutrophils, and platelets (Turcotte, C., et al., Cell Mol. Life Sci., 2016, 73(23):4449-4470). CBD metabolites also activate CB1 and CB2 and these activities may actually predominate over direct activation by CBD at the CB2 receptor.

[0158] CBD is also a known direct activator of other cell surface receptors, with the most evidence supporting activity at TRPV and serotonin (5-HT1A) (Bih, I. C., et al., Neurotherapeutics, 2015, 12:699-730). Other known targets for CBD include the G-protein receptors GPR55, GPR18, GPR 119, as well as the glycine receptor (Atalay S., et al., Antioxidants (Basel), 2019, 9(1):21). In addition to all of these receptor effects, CBD has more than 60 known molecular targets in the cell interior (Britch S.C, et al., Psychopharmacology (Berlin), 2021, 238(1):9-28). Finally, curcumin is known to cross-activate the CB2 receptor (Pawar, H.D., et al., Life (Basel), 2022, 12(5):624), providing another synergy with CBD.

[0159] In another embodiment, the active agent(s), for example curcumin and lion’s mane extract, may provide synergistic neuroprotective effects. Lion’s mane extract has been shownto stimulate production of nerve growth factor (NGF) in rat cell models (Kostanda, 2024). Curcumin may enhance the primary neuroprotective actions of the various NGF-stimulating components of lion’s mane. Curcumin’s anti-inflammatory activity has been demonstrated in neural cell lines (Cole, G. M., et al., Adv. Exp. Med. Biol., 2007, 595:197-212). Additionally, curcumin has demonstrated the ability to reduce amyloid plaque burden in murine models of Alzheimer’s Disease and reduce inflammation related to large amyloid burdens (Cole, 2007). Thus, curcumin may serve to limit neural cell damage, allowing the neurotropic lion’s mane to have a greater beneficial effect than it would alone.

[0160] In some embodiments, the formulations can provide benefits such as analgesic (pain relief), anti-inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, hepatoprotective effects and / or the like. When two active agents are used, the active agents can act synergistically. Dosing and Indications

[0161] In one embodiment, the microemulsion formulation, for example the cannabinoid / curcumin microemulsion, finds use as a treatment for inflammation and / or its associated pain. The amount of microemulsion formulation that will be effective in reducing inflammation in a patient will depend on the specific nature of the condition causing the inflammation and can be determined by standard clinical techniques known in the art. In addition, in vitro or in vivo assays may optionally be employed to help identify optimal dosage ranges. The specific dose level for any particular individual will depend upon a variety of factors including the age, body weight, general physical and mental health, genetic factors, environmental influences, sex, diet, time of administration, route of administration, rate of excretion, and the severity of the particular problem being treated. Dosing may be provided alone or in combination with other drugs and may continue as long as required for effective reduction of inflammation and / or pain.

[0162] Suitable dosage ranges for oral administration of the microemulsion formulation are generally about 0.001 mg to about 100 mg of active ingredient per kilogram body weight, preferably from about 0.025 mg to about 50 mg of active ingredient per kilogram body weight, and more preferably about 0.05 to about 25 mg / kg-body weight per day. Dosage ranges may be readily determined by methods known to the skilled artisan. Daily doses may be given once per day or divided into two or more doses. A dosing frequency can be two to three times a day. A single dose may be administered as one or more soft gel capsules. In some embodiments, a suitable dose for oral administration of the microemulsion formulation can comprise any amount of curcumin and / or cannabinoid described herein, such as an amount encapsulated in a soft gel capsule or combination thereof.

[0163] Suitable dosage ranges for intravenous administration of the microemulsion formulation are generally about 0.001 mg to about 200 mg of active ingredient per kilogram body weight, preferably from about 0.025 mg to about 100 mg of active ingredient per kilogram body weight, and more preferably about 0.05 to about 50 mg / kg-body weight per day. Dosage ranges may be readily determined by methods known to the skilled artisan. Daily doses may be given once per day or divided into two or more doses.

[0164] The standard dose of soft gel capsules can be two capsules twice a day when the capsules contain the cannabinoid / curcumin microemulsion formulation and each capsule contains 2.5 mg to 5 mg of broad-spectrum hemp extract and 4 mg to 10 mg of curcumin. In one embodiment, the capsules are taken on an empty stomach, optimally thirty minutes before eating. In another embodiment, for the treatment of established long-term or age-related pain and / or inflammation, two capsules are taken three times a day. In a further embodiment, two capsules are taken three times a day then reduced to twice a day after significant pain relief is achieved. In another embodiment, for the treatment of exercise-induced pain and / or inflammation, two capsules are taken twice a daily. In another embodiment, two capsules are taken before or after intense physical activity.

[0165] The formulation, for example the cannabinoid / curcumin microemulsion formulation, finds use in reducing, improving, alleviating, ameliorating, and / or inflammation in patients suffering from certain conditions. The microemulsion formulation can be used by those experiencing discomfort due to activities such as exercise, minor injuries, or repetitive motions, including, but not limited to, muscle soreness from workouts or discomfort from tasks such as lifting. The microemulsion formulation can also be used by individuals experiencing on-going discomfort or pain, associated with joint issues that develop over time. In one embodiment, the inflammation is due to arthritis and / or improving mobility in patients with arthritis. Types of arthritis include osteoarthritis, rheumatoid arthritis, gout, ankylosing spondylitis, psoriatic arthritis and juvenile arthritis.

[0166] In another embodiment, the formulation, for example the cannabinoid / curcumin formulation, finds use in reducing musculoskeletal inflammation, and in particular, reducing pain resulting from over-exertion.

[0167] In another embodiment, the formulation, for example the cannabinoid / curcumin microemulsion formulation, is useful in reducing inflammation due to inflammatory bowel disease (IBD). Types of IBD include ulcerative colitis and Crohn’s disease.

[0168] In a further embodiment, the formulation, for example the cannabinoid / curcumin formulation finds use in reducing inflammation due to certain autoimmune skin diseases such as psoriasis, lichen planus and alopecia arreata.

[0169] In a further embodiment, the formulation, for example the cannabinoid / curcumin formulation, finds use as an anti-oxidant, an anti-microbial, an anti-anxiety agent, a neuroprotective, a cardioprotective, and / or a hepatoprotective. In another embodiment, the formulation, for example cannabinoid / curcumin microemulsion formulation finds use in supporting wound healing, managing arthritis and overall joint health, improving metabolic management, promoting overall wellness, and / or assisting in kicking additions. RECITATION OF ASPECTS

[0170] Exemplary aspects of the present disclosure are provided in the following numbered embodiments.

[0171] Aspect 1 is a microemulsion formulation comprising 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid, and 20-50% by volume co-surfactant.

[0172] Aspect 2 is the microemulsion formulation of aspect 1, wherein the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20.

[0173] Aspect 3 is the microemulsion formulation of aspect 1 or 2, wherein the fatty acid is one or more of oleic acid and linoleic acid.

[0174] Aspect 4 is the microemulsion formulation of any one of aspects 1 to 3, wherein the co-surfactant is one of more of propylene glycol and ethanol.

[0175] Aspect 5 is the microemulsion formulation of any one of aspects 1 to 4, wherein the polysorbate surfactant is polysorbate 80, the fatty acid is oleic acid, and the co-surfactant is propylene glycol.

[0176] Aspect 6 is the microemulsion formulation of any one of aspects 1 to 4, wherein the polysorbate surfactant is polysorbate 20, the fatty acid is oleic acid, and the co-surfactant is propylene glycol.

[0177] Aspect 7 is the microemulsion formulation of any one of aspects 1 to 4, wherein the polysorbate surfactant is polysorbate 20, the fatty acid is oleic acid, and the co-surfactant is ethanol.

[0178] Aspect 8 is the microemulsion formulation of any one of aspects 1 to 4, wherein the polysorbate surfactant is polysorbate 80, the fatty acid is a combination of oleic acid and linoleic acid, and the co-surfactant is propylene glycol.

[0179] Aspect 9 is the microemulsion formulation of any one of aspects 1 to 8, wherein the formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid, and 42.85% by volume co-surfactant.

[0180] Aspect 10 is the microemulsion formulation of any one of aspects 1 to 8, wherein the polysorbate surfactant, the fatty acid, and the co-surfactant are present in a ratio of 3:1:3 by volume.

[0181] Aspect 11 is the microemulsion formulation of any one of aspects 1 to 10, wherein the microemulsion formulation comprises particles, and wherein >80% of the particles in the microemulsion formulation have an average diameter between 10 and 100 nanometers.

[0182] Aspect 12 is the microemulsion of any one of aspects 1 to 11, wherein the microemulsion formulation comprises less than 20, 10, 5, 4, 3, 2, or 1% water.

[0183] Aspect 13 is the microemulsion of any one of aspects 1 to 12, wherein the microemulsion formulation comprises no added water.

[0184] Aspect 14 is the microemulsion formulation of any one of aspects 1 to 13, further comprising a pharmacologically active agent.

[0185] Aspect 15 is the microemulsion formulation of any one of aspects 1 to 13, further comprising a first pharmacologically active agent and a second pharmacologically active agent.

[0186] Aspect 16 is a method of delivering a pharmacologically active agent to a subject, comprising delivering an active agent in the microemulsion formulation of any one of aspects 1 to 14 or the active agent in the microemulsion formulation of aspect 14 or 15.

[0187] Aspect 17 is a microemulsion formulation comprising 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid, 20-50% by volume co-surfactant, and a pharmacologically active agent.

[0188] Aspect 18 is the microemulsion formulation of aspect 17, wherein the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20.

[0189] Aspect 19 is the microemulsion formulation of aspect 17 or 18, wherein the fatty acid is one or more of oleic acid and linoleic acid.

[0190] Aspect 20 is the microemulsion formulation of any one of aspects 17 to 19, wherein the co-surfactant is one of more of propylene glycol and ethanol.

[0191] Aspect 21 is the microemulsion formulation of any one of aspects 17 to 20, comprising a second pharmacologically active agent.

[0192] Aspect 22 is the microemulsion formulation of any one of aspects 17 to 21, wherein the pharmacologically active agent is lipophilic.

[0193] Aspect 23 is the microemulsion formulation of any one of aspects 17 to 22, wherein the polysorbate surfactant is polysorbate 80, the fatty acid is oleic acid, and the co-surfactant is propylene glycol.

[0194] Aspect 24 is the microemulsion formulation of any one of aspects 17 to 22, wherein the polysorbate surfactant is polysorbate 80, the fatty acid is a combination of oleic acid and linoleic acid, and the co-surfactant is propylene glycol.

[0195] Aspect 25 is the microemulsion formulation of any one of aspects 17 to 22, wherein the polysorbate surfactant is polysorbate 20, the fatty acid is oleic acid, and the co-surfactant is ethanol.

[0196] Aspect 26 is the microemulsion formulation of any one of aspects 17 to 25, wherein the formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid, and 42.85% by volume co-surfactant.

[0197] Aspect 27 is the microemulsion formulation of any one of aspects 17 to 26, wherein the polysorbate surfactant, the fatty acid and the co-surfactant are present in a ratio of 3:1:3 by volume.

[0198] Aspect 28 is the microemulsion formulation of any one of aspects 17 to 27, wherein the microemulsion formulation comprises particles, and wherein >80% of the particles in the microemulsion formulation have an average diameter between 10 and 100 nanometers.

[0199] Aspect 29 is the microemulsion formulation of any one of aspects 17 to 28, wherein the pharmacologically active agent is a cannabinoid, a curcuminoid, a mushroom phytochemical, a polyphenol, a carotenoid, an organosulfur compound, a glucobrassicin, an isothiocyanate, a lignan, a phytosterol, a carnitine or an anti-oxidant.

[0200] Aspect 30 is the microemulsion formulation of any one of aspects 17 to 28, wherein the pharmacologically active agent is a broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC).

[0201] Aspect 31 is the microemulsion formulation of aspect 30, wherein the broad-spectrum hemp extract contains at least 80% by weight cannabidiol (CBD).

[0202] Aspect 32 is the microemulsion formulation of aspect 30 or 31, wherein the broad- spectrum hemp extract contains 84% to 87% by weight cannabidiol (CBD).

[0203] Aspect 33 is the microemulsion formulation of any one of aspects 30 to 32, wherein the broad-spectrum hemp extract has a concentration of up to 50 mg / ml.

[0204] Aspect 34 is the microemulsion formulation of any one of aspects 17 to 28, wherein the active agent is cannabidiol (CBD).

[0205] Aspect 35 is the microemulsion formulation of aspect 34, wherein the cannabidiol has a concentration of up to 100 mg / ml.

[0206] Aspect 36 is the microemulsion formulation of any one of aspects 17 to 28, wherein the active agent is curcumin.

[0207] Aspect 37 is the microemulsion formulation of aspect 36, wherein the curcumin is a turmeric extract comprising 95% curcuminoids.

[0208] Aspect 38 is the microemulsion formulation of aspect 36 or 37, wherein the curcumin has a concentration of up to 50 mg / ml.

[0209] Aspect 39 is the microemulsion formulation of any one of aspects 17 to 28, wherein the active agent is resveratrol.

[0210] Aspect 40 is the microemulsion formulation of aspect 39, wherein the resveratrol has a concentration of up to 75 mg / ml.

[0211] Aspect 41 is the microemulsion formulation of any one of aspects 17 to 28, wherein the active agent is lion’s mane extract.

[0212] Aspect 42 is the microemulsion formulation of aspect 41, wherein the lion’s mane extract has a concentration of up to 1500 mg / ml.

[0213] Aspect 43 is the microemulsion formulation of any one of aspects 17 to 42, wherein the microemulsion formulation is administered orally.

[0214] Aspect 44 is the microemulsion formulation of any one of aspects 17 to 42, wherein the microemulsion formulation is administered intravenously.

[0215] Aspect 45 is a soft gel capsule filled with the microemulsion formulation of any one of aspects 17 to 42.

[0216] Aspect 46 is the soft gel capsule of aspect 45, wherein the capsule comprises up to 50 mg broad-spectrum hemp extract.

[0217] Aspect 47 is the soft gel capsule of aspect 45, wherein the capsule comprises up to 100 mg CBD.

[0218] Aspect 48 is the soft gel capsule of aspect 45, wherein the capsule comprises up to 30 mg curcumin.

[0219] Aspect 49 is the soft gel capsule of aspect 45, wherein the capsule comprises up to 100 mg resveratrol.

[0220] Aspect 50 is the soft gel capsule of aspect 45, wherein the capsule comprises up to 1500 mg lion’s mane extract.

[0221] Aspect 51 is a microemulsion formulation comprising 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid, 20-50% by volume co-surfactant, a first pharmacologically active agent, and a second pharmacologically active agent.

[0222] Aspect 52 is the microemulsion formulation of aspect 51, wherein the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20.

[0223] Aspect 53 is the microemulsion formulation of aspect 51 or 52, wherein the fatty acid is one or more of oleic acid and linoleic acid.

[0224] Aspect 54 is the microemulsion formulation of any one of aspects 51 to 53, wherein the co-surfactant is one or more of propylene glycol and ethanol.

[0225] Aspect 55 is the microemulsion formulation of any one of aspects 21 to 44 or aspects 51 to 54, wherein the first pharmacologically active agent and the second pharmacologically active agent are selected from a cannabinoid, a curcuminoid, a mushroom phytochemical, a polyphenol, a carotenoid, an organosulfur compound, a glucobrassicin, an isothiocyanate, a lignan, a phytosterol, a carnitine or an anti-oxidant, and wherein the first pharmacologically active agent is different from the second pharmacologically active agent.

[0226] Aspect 56 is the microemulsion formulation of any one of aspects 51 to 55, wherein the polysorbate surfactant is polysorbate 80, the fatty acid is oleic acid, and the co-surfactant is propylene glycol.

[0227] Aspect 57 is the microemulsion formulation of any one of aspects 51 to 56, wherein the microemulsion formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid and 42.85% by volume co-surfactant.

[0228] Aspect 58 is the microemulsion formulation of any one of aspects 51 to 56, wherein the polysorbate surfactant, the fatty acid and the co-surfactant are present in a ratio of 3:1:3 by volume.

[0229] Aspect 59 is the microemulsion formulation of any one of aspects 51 to 58, wherein the microemulsion formulation comprises particles, and wherein >80% of the particles in the microemulsion formulation have an average diameter between 10 and 100 nanometers.

[0230] Aspect 60 is the microemulsion formulation of any one of aspects 51 to 59, wherein the microemulsion formulation is administered orally.

[0231] Aspect 61 is the microemulsion formulation of any one of aspects 51 to 59, wherein the microemulsion formulation is administered by intravenous injection.

[0232] Aspect 62 is the microemulsion formulation of any one of aspects 21 to 44 or aspects 51 to 61, wherein the first pharmacologically active agent is a cannabinoid substantially free of tetrahydrocannabinol (THC) and the second pharmacologically active agent is curcumin.

[0233] Aspect 63 is the microemulsion formulation of aspect 51, wherein the polysorbate surfactant is 30-60% by volume polysorbate 80, the fatty acid is 10-20% by volume oleic acid, the co-surfactant is 20-50% by volume propylene glycol, the first pharmacologically active agent is a cannabinoid with a concentration up to 50 mg / ml, and the second pharmacologically active agent is curcumin with a concentration of up to 40 mg / ml.

[0234] Aspect 64 is the microemulsion formulation of aspect 63, wherein the cannabinoid is a broad-spectrum hemp extract.

[0235] Aspect 65 is the microemulsion formulation of aspect 64, wherein the broad-spectrum hemp extract has a concentration of 2 mg / ml to 15 mg / ml.

[0236] Aspect 66 is the microemulsion formulation of aspect 64 or 65, wherein the broad- spectrum hemp extract contains at least 80% by weight cannabidiol (CBD).

[0237] Aspect 67 is the microemulsion formulation of any one of aspects 64 to 66, wherein the broad-spectrum hemp extract contains 87% by weight cannabidiol (CBD).

[0238] Aspect 68 is the microemulsion formulation of aspect 63, wherein the cannabinoid is cannabidiol (CBD).

[0239] Aspect 69 is the microemulsion formulation of aspect 68, wherein the cannabidiol (CBD) concentration is 2 mg / ml to 20 mg / ml.

[0240] Aspect 70 is the microemulsion formulation of any one of aspects 63 to 69, wherein the curcumin is a turmeric extract comprising about 95% curcuminoids.

[0241] Aspect 71 is the microemulsion formulation of any one of aspects 63 to 70, wherein the curcumin concentration is 2 mg / ml to 30 mg / ml.

[0242] Aspect 72 is the microemulsion formulation of any one of aspects 63 to 71, wherein the microemulsion formulation comprises 42.85% by volume propylene glycol, 14.3% oleic acid by volume and 42.85% by volume polysorbate 80.

[0243] Aspect 73 is the microemulsion formulation of aspect 63, wherein the polysorbate surfactant is 42.85% by volume polysorbate 80, the fatty acid is 14.3% by volume oleic acid, the co-surfactant is 42.85% by volume propylene glycol, the cannabinoid is broad-spectrum hemp extract with a concentration of 4 mg / ml to 5 mg / ml, and the curcumin is a turmeric extract with a concentration of 8 mg / ml to 10 mg / ml.

[0244] Aspect 74 is a soft gel capsule filled with a microemulsion formulation of a first pharmacologically active agent with a concentration up to 200 mg / ml and a second pharmacologically active agent with a concentration up to 200 mg / ml, wherein the formulation comprises 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid and 20- 50% co-surfactant.

[0245] Aspect 75 is the soft gel capsule of aspect 74, wherein the first pharmacologically active agent is a cannabinoid substantially free of tetrahydrocannabinol (THC) with a concentration of up to 50 mg / ml, the second pharmacologically active agent is curcumin with a concentration of up to 40 mg / ml, the polysorbate surfactant is polysorbate 80, the fatty acid is oleic acid, and the co-surfactant is propylene glycol.

[0246] Aspect 76 is the soft gel capsule of aspect 75, wherein the cannabinoid is CBD and each capsule contains CBD in a concentration of 1 mg / ml to 30 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml.

[0247] Aspect 77 is the soft gel capsule of aspect 75 or 76, wherein the cannabinoid is CBD and each capsule contains 2.5 mg to 5 mg of CBD and 5 mg to 10 mg of curcumin.

[0248] Aspect 78 is the soft gel capsule of aspect 75, wherein the cannabinoid is broad- spectrum hemp extract and each capsule contains broad-spectrum hemp extract in a concentration of 5 mg / ml to 10 mg / ml and curcumin in a concentration of 10 mg / ml to 20 mg / ml.

[0249] Aspect 79 is the soft gel capsule of aspect 75 or 78, wherein the cannabinoid is broad- spectrum hemp extract and each capsule contains 2.5 mg to 5 mg of broad-spectrum hemp extract and 4 mg to 10 mg of curcumin.

[0250] Aspect 80 is the soft gel capsule of any one of aspects 75, 78 or 79, wherein each capsule contains 5 mg of broad-spectrum hemp extract and 10 mg of curcumin.

[0251] Aspect 81 is the soft gel capsule of any one of aspects 75 to 80, wherein the curcumin is a turmeric extract comprising about 95% curcuminoids.

[0252] Aspect 82 is the soft gel capsule of any one of aspects 75 to 81, wherein the microemulsion formulation comprises 42.85% by volume propylene glycol, 14.3% oleic acid by volume and 42.85% by volume polysorbate 80.

[0253] Aspect 83 is the soft gel capsule of any one of aspects 75 to 81, wherein the polysorbate 80, the oleic acid and the propylene glycol are present in a ratio of 3:1:3 by volume.

[0254] Aspect 84 is the soft gel capsule of aspect 74, wherein the first pharmacologically active agent is broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC) with a concentration of 5 mg / ml to 10 mg / ml, the second pharmacologically active agent is turmeric extract with a concentration of 10 mg / ml to 20 mg / ml, the polysorbate surfactant is 42.85% by volume polysorbate 80, the fatty acid is 14.3% by volume oleic acid, and the co- surfactant is 42.85% by volume propylene glycol.

[0255] Aspect 85 is the soft gel capsule of aspect 74, wherein the first pharmacologically active agent is 2.5 mg to 5 mg broad-spectrum hemp extract standardized to 87% cannabidiol, the second pharmacologically active agent is 4 mg to 10 mg turmeric extract standardized to 95% curcuminoids, the polysorbate surfactant is 42.85% by volume polysorbate 80, the fatty acid is 14.3% by volume oleic acid, and the co-surfactant is 42.85% by volume propylene glycol.

[0256] Aspect 86 is a method of reducing inflammation or pain comprising administering to a patient a pharmacologically effective amount of the microemulsion formulation of any one of aspects 14 to 44 or aspects 51 to 73 or of the soft gel capsule of any one of aspects 45 to 50 or aspects 74 to 85.

[0257] Aspect 87 is the method of aspect 86, wherein the inflammation or pain is due to arthritis.

[0258] Aspect 88 is the method of aspect 86, wherein the inflammation or pain is musculoskeletal.

[0259] Aspect 89 is the method of any one of aspects 86 to 88, wherein the pharmacologically effective amount of the microemulsion formulation is delivered orally or intravenously.

[0260] Aspect 90 is the method of any one of aspects 86 to 88, wherein the pharmacologically effective amount of the soft gel capsule is delivered orally.

[0261] Aspect 91 is a method of providing analgesic (pain relief), anti-inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, and / or hepatoprotective effects comprising administering to a patient a pharmacologically effective amount of the microemulsion formulation of any one of aspects 14 to 44 or aspects 51 to 73 or of the soft gel capsule of any one of aspects 45 to 50 or aspects 74 to 85.

[0262] Aspect 92 is the microemulsion formulation or soft gel capsule of any one of the preceding aspects comprising analgesic (pain relief), anti-inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, and / or hepatoprotective effects.

[0263] Aspect 93 is the microemulsion formulation or soft gel capsule of any one of the preceding aspects wherein the first and second active agents act synergistically.

[0264] Aspect 94 is the microemulsion formulation of any of one of the preceding aspects wherein the microemulsion is formed without external input of energy.

[0265] Aspect 95 is the microemulsion formulation of aspect 94, wherein the external input of energy is heat or high-shear mixing.

[0266] Aspect 96 is a microemulsion formulation comprising 42.85% by volume polysorbate 80, 14.3% by volume oleic acid, 42.85% by volume propylene glycol, a cannabinoid that is broad-spectrum hemp extract with a concentration of 5 mg / ml to 10 mg / ml, and a turmeric extract in a concentration of 10 mg / ml to 20 mg / ml.

[0267] Aspect 97 is a soft gel capsule comprising a broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC) with a concentration of 5 mg / ml to 10 mg / ml, a turmeric extract with a concentration of 10 mg / ml to 20 mg / ml, 42.85% by volume polysorbate 80, 14.3% by volume oleic acid, and 42.85% by volume propylene glycol.

[0268] Aspect 98 is a soft gel capsule comprising 2.5 mg to 5 mg broad-spectrum hemp extract standardized to 87% cannabidiol, 4 mg to 10 mg turmeric extract standardized to 95% curcuminoids, 42.85% by volume polysorbate 80, 14.3% by volume oleic acid, and 42.85% by volume propylene glycol. EXAMPLES

[0269] The following examples are offered by way of illustration and not by way of limitation. Example 1 Preparation of Microemulsion Formulation A

[0270] Thirty milliliters propylene glycol (Bluewater Chem Group, Fort Wayne, IN), 10 ml oleic acid (Sierra Chemical Co., West Sacramento, CA) and 30 ml polysorbate 80 (TWEEN 80; Velona Inc., Mount Prospect, IL) were stirred together at room temperature. A pale yellow, transparent microemulsion formed within seconds. The presence of a microemulsion was confirmed by using blue light (λ = 480 nm).Example 2 Preparation of Microemulsion Formulation B

[0271] Ten milliliters oleic acid (Sierra Chemical Co., West Sacramento, CA) were added to 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN), followed by 30 ml polysorbate 20 (TWEEN 20; Velona Inc., Mount Prospect, IL). The mixture was stirred for 15 minutes at room temperature. A pale yellow, transparent microemulsion formed rapidly. The presence of a microemulsion was confirmed by using blue light (λ = 480 nm). Example 3 Preparation of Microemulsion Formulation C

[0272] Ten milliliters oleic acid (Sierra Chemical Co., West Sacramento, CA) were added to 30 ml ethanol (100% ethyl alcohol; 200 proof Industrial Grade denatured with n-heptane; DIY Chemicals, Liberty, TX), followed by 30 ml polysorbate 20 (TWEEN 20; Velona Inc., Mount Prospect, IL). The mixture was stirred for 15 minutes at room temperature. A pale yellow, transparent microemulsion formed rapidly. The presence of a microemulsion was confirmed by using blue light (λ = 480 nm). Example 4 Preparation of Microemulsion Formulation D

[0273] Nine milliliters oleic acid (Sierra Chemical Co., West Sacramento, CA) and 1 ml conjugated linoleic acid (Nutricost, Vineyard, UT) were added to 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN), followed by 30 ml polysorbate 80 (TWEEN 80; Velona Inc., Mount Prospect, IL). The mixture was stirred for 30 minutes at room temperature. A pale yellow, transparent microemulsion formed rapidly. The presence of a microemulsion was confirmed by using blue light (λ = 480 nm). Example 5 Preparation of Curcumin Formulation E

[0274] Curcumin (500 mg; Stratum Nutrition, Carthage, MO) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by slowly stirring at room temperature for one hour. Oleic acid (9 ml; Sierra Chemical Co., West Sacramento, CA), conjugated linoleic acid (1 ml; Nutricost, UT) and 30 ml polysorbate 80 (TWEEN 80; Velona Inc., Mount Prospect, IL)were incorporated by slowly stirring for 90 minutes at room temperature. The microemulsion formation was complete when the opaque mixture became a transparent deep yellow-orange liquid, confirmed by transmission of blue light (λ = 480 nm). Example 6 Preparation of Curcumin Formulation F

[0275] Curcumin (1200 mg; Stratum Nutrition, Carthage, MO) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by slowly stirring at room temperature for two hours. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) and 30 ml polysorbate 80 (TWEEN 80; Velona Inc., Mount Prospect, IL) were incorporated by slowly stirring for two hours at room temperature. The microemulsion formation was complete when the opaque mixture became a transparent deep yellow-orange liquid, confirmed by transmission of blue light (λ = 480 nm). Example 7 Preparation of Curcumin Formulation G

[0276] Curcumin (600 mg; Stratum Nutrition, Carthage, MO) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by slowly stirring at room temperature for one hour. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) and 30 ml polysorbate 20 (TWEEN 20; Velona Inc., Mount Prospect, IL) were incorporated by slowly stirring for ten hours at room temperature. The microemulsion formation was complete when the opaque mixture became a transparent deep yellow-orange liquid, confirmed by transmission of blue light (λ = 480 nm). Example 8 Preparation of Curcumin Formulation H

[0277] Curcumin (500 mg; Stratum Nutrition, Carthage, MO) was dissolved in 30 ml ethanol (200 proof Industrial Grade denatured with n-heptane; DIY Chemicals, Liberty, TX) by slowly stirring at room temperature for one hour. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) and 30 ml polysorbate 20 (TWEEN 20; Velona Inc., Mount Prospect, IL) were incorporated at room temperature. The microemulsion formation started to form immediately. Stirring was continued for six hours. The microemulsion was complete when the opaque mixture became a transparent deep yellow-orange liquid, confirmed by transmission of blue light (λ = 480 nm).Example 9 Preparation of CBD Formulation I

[0278] Cannabidiol (1800 mg; Mile High Labs, Boulder, CO) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by slowly stirring at room temperature for one hour. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) and 30 ml polysorbate 80 (TWEEN 80; Verlona Inc., Mount Prospect, IL) were then incorporated by slowly stirring into the propylene glycol / cannabidiol solution. A microemulsion began to form within seconds. Stirring was continued at room temperature for 1 hour to allow complete incorporation of the components forming a transparent yellow microemulsion as confirmed by transmission of blue light (λ = 480 nm). Example 10 Preparation of Broad-spectrum Hemp Extract Formulation J

[0279] Method 1. Broad-spectrum hemp extract containing 86% CBD (1800 mg; Mile High Labs, Boulder, CO) was dissolved in 10 ml oleic acid (Sierra Chemical Co., West Sacramento, CA) by slowly stirring at room temperature for 10 hours. Propylene glycol (30 ml; Bluewater Chem Group, Fort Wayne, IN) and polysorbate 80 (30 ml; TWEEN 80; Velona Inc., Mount Prospect, IL) were added and the mixture slowly stirred at room temperature for six hours to complete formation of a microemulsion. Formation of the microemulsion was complete when the opaque mixture became a transparent brownish yellow liquid, confirmed by transmission of blue light (λ = 480 nm).

[0280] Method 2. Broad-spectrum hemp extract containing 86% CBD (1800 mg; Mile High Labs, Boulder, CO) was melted in a water bath at 85 °C for 5 minutes, added to 10 ml oleic acid (Sierra Chemical Co., West Sacramento, CA) and stirred for 15 minutes. Propylene glycol (30 ml; Bluewater Chem Group, Fort Wayne, IN) and polysorbate 80 (30 ml; TWEEN 80; Velona Inc., Mount Prospect, IL) were added and the mixture slowly stirred at room temperature for six hours to complete formation of a microemulsion. Formation of the microemulsion was complete when the opaque mixture became a transparent brownish yellow liquid, confirmed by transmission of blue light (λ = 480 nm).Example 11 Preparation of Resveratrol Formulation K

[0281] Resveratrol (1800 mg; BulkSupplements.com, Henderson, NV) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by slowly stirring at room temperature for three hours. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) and 30 ml polysorbate 80 (TWEEN 80; Verlona Inc., Mount Prospect, IL) were then incorporated by slowly stirring into the propylene glycol / resveratrol solution. A microemulsion began to form within seconds. Stirring was continued at room temperature overnight to allow complete incorporation of the components forming a transparent yellow microemulsion as confirmed by transmission of blue light (λ = 480 nm). Example 12 Preparation of Lion’s Mane Formulation L

[0282] Full spectrum lion’s mane extract (720 mg lion’s mane in 5 ml water; Uprooted Extracts, Evergreen, CO) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by stirring at room temperature for fifteen minutes. Oleic acid (12 ml; Sierra Chemical Co., West Sacramento, CA) and 36 ml polysorbate 80 (TWEEN 80; Verlona Inc., Mount Prospect, IL) were then incorporated by stirring into the propylene glycol / lion’s mane solution. A transparent dark brown microemulsion formed rapidly over twenty minutes. Stirring was continued for two hours total. The presence of a microemulsion was confirmed by dynamic light scattering (Example 19). Example 13 Preparation of CBD / Curcumin Formulation M

[0283] Cannabidiol (300 mg; Mile High Labs, Boulder, CO) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by slowly stirring at room temperature for two hours. Curcumin (600 mg; Stratum Nutrition, Carthage, MO) was added and the mixture slowly stirred for 1 hour. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) was incorporated by slowly stirring followed by 30 ml polysorbate 80 (TWEEN® 80; Velona, Inc., Mount Prospect, IL). A microemulsion began to form immediately. The mixture was slowly stirred for 6 hours to allow complete incorporation of the components into a microemulsion. Formation of the microemulsion was complete when the opaque starting mixture becomes a transparent orange-yellow liquid, confirmed by transmission of blue light (λ = 480 nm).Example 14 Preparation of Hemp / Curcumin Formulation N

[0284] Broad-spectrum hemp extract containing 86% CBD (150 mg; Mile High Labs, Boulder, CO) was dissolved in 10 ml oleic acid (Sierra Chemical Co., West Sacramento, CA) by slowly stirring at room temperature for 12 hours. Cannabidiol (180 mg; Mile High Labs Boulder, CO) was dissolved in 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) by slowly stirring at room temperature for two hours. Curcumin (600 mg; Stratum Nutrition, Carthage, MO) was added to the propylene glycol / cannabidiol solution and the mixture slowly stirred for one hour. The oleic acid / hemp extract solution was then incorporated by slowly stirring into the propylene glycol / cannabidiol / curcumin solution followed by 30 ml polysorbate 80 (TWEEN 80; Velona Inc., Mount Prospect, IL). A microemulsion began to form within ten minutes. The mixture was stirred slowly at room temperature for 6 hours to allow complete incorporation of the components into a microemulsion. Formation of the microemulsion was complete when the opaque mixture became a transparent orange-yellow liquid, confirmed by transmission of blue light (λ = 480 nm). Example 15 Preparation of Lion’s Mane / Curcumin Formulation O

[0285] Full spectrum lion’s mane extract (288 mg lion’s mane in 2 ml water; Uprooted Extracts, Evergreen, CO) was added to 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) with stirring at room temperature. Curcumin (350 mg; Stratum Nutrition, Carthage, MO) was added and the mixture stirred for 4 hours at room temperature. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) was added with stirring followed by 31 ml polysorbate 80 (TWEEN 80; Velona Inc., Mount Prospect, IL). A microemulsion formed slowly over 90 minutes. The mixture was stirred slowly at room temperature for 8 hours to allow complete incorporation of the components into a microemulsion. The presence of a microemulsion was confirmed by dynamic light scattering (Example 21). Example 16 Preparation of Resveratrol / Curcumin Formulation P

[0286] Resveratrol (400 mg; BulkSupplements.com, Henderson, NV) was added to 30 ml propylene glycol (Bluewater Chem Group, Fort Wayne, IN) and stirred at room temperature for 30 minutes. Curcumin (400 mg; Stratum Nutrition, Carthage, MO) was added and themixture stirred for 1 hour at room temperature. Oleic acid (10 ml; Sierra Chemical Co., West Sacramento, CA) was added with stirring followed by 30 ml polysorbate 80 (TWEEN 80; Velona Inc., Mount Prospect, IL). A bright orange microemulsion formed over sixty minutes. Stirring at room temperature was continued for 4 hours. The presence of a microemulsion was confirmed by using blue light (λ = 480 nm). Example 17 Particle Size Measurement by Transmission Electron Microscopy

[0287] The size and morphology of particles in the microemulsion were analyzed by transmission electron microscopy (TEM) using a JEM-1200EX (Jeol; Tokyo, Japan). Samples of Formulation N were diluted 1:1000 in distilled water. A small drop was placed on the surface of a 200 mesh formvar / carbon grid, and then wicked off using filter paper after 15 minutes at room temperature. The grid was rinsed with distilled water and stained with 1% uranyl acetate for 15 seconds, then air-dried and imaged. Figure 1 shows the results. Figure 1A (magnification 50kx; scale bar 50 nm) shows the generally homogeneous composition of the particles within the microemulsion comprising >90% of the sample volume as determined by DLS in Example 20 (around 27 nm, range 20-45 nm). Figure 1B (magnification 25kx; scale bar 0.1 um) shows the occasional occurrence of larger particles. Figure 1C is a high magnification image (100kx; scale bar 20 nm) showing the clear micellar structure of the formulation at the nanoscale level. Example 18 Dynamic Light Scattering Measurement of Particle Size of Formulation A

[0288] The Dynamic Light Scattering (DLS) method measures the size of particles suspended in liquid by measuring temporal fluctuations in the intensity of scattered light that reflects the diffusion of the particles. For a general discussion of DLS theory and experimental techniques, see M. Kaszuba, et al., “Measuring sub nanometer sizes using dynamic light scattering” (J. Nanopart. Res., 2008, 10:823-829 DOI 10.1007 / s11051-007-9317-4).

[0289] A sample of Formulation A was diluted with isopropanol (refractive index = 1.45; viscosity = 0.0019128 Pa.s). The sample had a refractive index of 1.4500 and a material absorption index of 0.0010. Particle size was determined using a Litesizer™ DLS 700 instrument (Anton Paar; Graz, Austria) with a side scatter detection angle at a target temperature of 80.60 °F. Twenty repeat measurements were taken. The results were analyzed using the software supplied by the instrument manufacturer. Figure 2 shows the particle size(nm) plotted against the percent present in the sample. The results showed that the weighted particle size distribution for 95.59% of the particles was 16.72 nm (standard deviation 2.80 nm), demonstrating that the formulation is a microemulsion. Example 19 Dynamic Light Scattering Measurement of Particle Size of Formulation L

[0290] A formulation sample containing lion’s mane extract Formulation L was diluted with isopropanol (refractive index = 1.45; viscosity = 0.0019128 Pa.s). Particle size was determined using a ZetaView® Nanoparticle Tracking Analysis instrument (Particle Metrix Gmbh, Inning am Ammersee, Germany) at a temperature of 22.88 °C at a conductivity of 42.00 μS / cm. The results were analyzed using ZetaView software version 8.06.01. Figure 3 shows the particle size (nm) plotted against the percent present in the sample. The results showed that the particle size distribution for 87.3% of the particles was 110.0 nm (standard deviation 82.3) demonstrating that the formulation is a microemulsion. Example 20 Dynamic Light Scattering Measurement of Particle Size of Formulation N

[0291] A formulation sample containing broad-spectrum hemp extract / curcumin Formulation N was diluted with isopropanol (refractive index = 1.45; viscosity = 0.0019128 Pa.s). The sample had a refractive index of 1.4500 and a material absorption index of 0010. Particle size was determined using a Litesizer™ DLS 700 instrument (Anton Paar; Graz, Austria) with a side scatter detection angle at a target temperature of 80.60 °F. Seven repeat measurements were taken. The results were analyzed using the software supplied by the instrument manufacturer. Figure 4 shows the particle size (nm) plotted against the percent present in the sample. The results showed that the weighted particle size distribution for 91.51% of the particles was 27 nm (standard deviation 3.91 nm), demonstrating that the formulation is a microemulsion. Example 21 Dynamic Light Scattering Measurement of Particle Size of Formulation O

[0292] A formulation sample containing lion’s mane extract / curcumin Formulation O was diluted with isopropanol (refractive index = 1.45; viscosity = 0.0019128 Pa.s). Particle size was determined using a ZetaView® Nanoparticle Tracking Analysis instrument (Particle Metrix Gmbh, Inning am Ammersee, Germany) at a temperature of 22.88 °C at a conductivity of42.00 μS / cm. The results were analyzed using ZetaView software version 8.06.01. Figure 5 shows the particle size (nm) plotted against the percent present in the sample. The results showed that the weighted particle size distribution for 91.51% of the particles was 73.1 nm (standard deviation 38.9 nm), demonstrating that the formulation is a microemulsion. Example 22 Dynamic Light Scattering Measurement of Particle Size of Formulation P

[0293] A formulation sample containing resveratrol / curcumin Formulation P was diluted with isopropanol (refractive index = 1.45; viscosity = 0.0019128 Pa.s). Particle size was determined using a ZetaView® Nanoparticle Tracking Analysis instrument (Particle Metrix Gmbh, Inning am Ammersee, Germany) at a temperature of 22.88 °C at a conductivity of 42.00 μS / cm. The results were analyzed using ZetaView software version 8.06.01. Figure 6 shows the particle size (nm) plotted against the percent present in the sample. The results showed that the weighted particle size distribution for 100% of the particles was 76.4 nm (standard deviation 37.2 nm), demonstrating that the formulation is a microemulsion. Example 23 Preparation of Soft Gels of Formulation N

[0294] Using techniques well known in the art, oval-shaped #12 soft gel capsules with a nominal volume of 0.5 ml of Formulation N were prepared by Elevated Softgels (Grand Junction, CO). Formulation N was encapsulated by a gelatin mixture using an Aprila SG200 soft gel encapsulation system (SaintyCo, Zhejiang, Peoples Republic of China). The capsules were transferred to drying racks and dried under air at 25% relative humidity at 60-80 °F for 96 hours. Example 24 Preparation of Soft Gels of Formulations F through L

[0295] Using techniques well known in the art, oval-shaped #12 soft gel capsules with a nominal volume of 0.5 ml of Formulation F, G, H, I, J, K or L are prepared by Elevated Softgels (Grand Junction, CO). The microemulsion formulation is encapsulated by gelatin mixture using an Aprila SG200 soft gel encapsulation system (SaintyCo, Zhejiang, Peoples Republic of China). The capsules are transferred to drying racks and dried under air at 25% relative humidity at 60-80 °F for 96 hours.Example 25 Clinical Study in Arthritic Patients

[0296] Study Population: Twenty-three volunteers (age range: 28-83 years) with joint pain and / or muscle stiffness were enrolled in the study.

[0297] Study Design: A prospective, randomized crossover study to compare the relative efficacy of two different formulations of curcumin / cannabidiol was conducted. Volunteers were randomized to receive a two-week course of either Formulation X or Formulation Y, followed by a three-week washout period, and then a two-week course of the other formulation. Each formulation was taken three times per day on an empty stomach.

[0298] Preparation of study formulations: Both formulations were prepared as microemulsions in polysorbate 80:propylene glycol:oleic acid in the ratio of 3:3:1 by volume using the methods described in Examples 1 and 2. Briefly, Formulation X contained (per dose) 10 mg of 95% curcumin extract and 4.29 mg of cannabidiol. Formulation Y contained 10 mg of 95% curcumin extract and 5 mg of broad-spectrum hemp extract containing 86% cannabidiol, for a final composition of 4.3 mg cannabidiol. The formulations were provided as hard gel capsules.

[0299] Evaluation metric: Volunteers completed the evaluation metric form prior to and on completion of each phase of the crossover trial. The trial utilized a modified short version of the Western Ontario and McMaster Universities Arthritis Index (WOMAC), a globally utilized and widely clinically validated tool for the evaluation of joint pain and stiffness as it impacts physical function across a variety of disease states (Baron, G., et al., Arthritis & Rheumatism, 2007, 57:4, pp.633-638). The modified WOMAC index contained six items: 1) pain while walking on a flat surface, 2) pain while walking up or down stairs, 3) pain that disturbs sleep, 4) pain while sitting or lying down, 5) pain that affects standing upright, and 6) pain or stiffness when first waking up in the morning. Pain was scored on the standard five-point scale (0=none, 1=mild, 2=moderate, 3=severe, 4=extreme). Each item was individually scored on a five-point scale, and those scores were then added to obtain a total score, with the highest possible score being 24. The total scores were multiplied by 4.17 in order to normalize them to the standard WOMAC scale, which has a highest possible score of 100.

[0300] Results: Clinical improvement (defined as a decrease of at least two points on the modified WOMAC index) was seen in 21 of 23 volunteers, for an overall efficacy of 91%. Of the 21 patients who saw clinical improvement, all saw an improvement of at least eight pointswith both formulations. The two volunteers who did not see improvement both had symptoms of spinal nerve radiculopathy including sciatica, suggesting that neither formulation had much effect on volunteers with anatomic nerve impingement. The mean improvement in the modified WOMAC score was calculated considering only the more effective formulation for each subject. Among all study participants including the two non-responders, the mean improvement was 21 points on the modified WOMAC index. Considering only the responders, the mean improvement was 25 points (range, 8-42).

[0301] With respect to the comparison between the two formulations, the study population showed a clear trend towards increased efficacy of the broad-spectrum hemp extract formulation (Formulation Y) versus that containing CBD (Formulation X) alone. The two non- responders saw no improvement with either formulation and were not considered in the comparison. Volunteers receiving the broad-spectrum hemp extract improved by a mean of 25 points, while showing a mean improvement of 12 points when crossed over to the CBD- only formulation (t-test for comparison between groups, p=0.0538). Example 26 Product Preparation

[0302] A soft gel product was prepared with a serving size of 2 soft gel capsules. Each serving size delivers 10 mg Turmeric Extract (as Curcuma longa [Rhizome]) standardized to 95% Curcuminoids (9.5 mg) and 5 mg Hemp Extract (Broad-spectrum) standardized to 97% cannabidiol (4.35 mg). Other ingredients include a soft gel capsule (gelatin, purified water, vegetable glycerin), polysorbate 80, propylene glycol, oleic acid, and distilled water. The product offers over 125 times more bioavailability compared to standard turmeric supplements. Combined benefits include: analgesic (pain relief), anti-inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, and / or hepatoprotective effects.

[0303] All publications and patent applications mentioned in this specification, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.

[0304] From the foregoing it will be appreciated that, although specific embodiments of the disclosure have been described herein for purposes of illustration, various modifications may

Claims

CLAIMS What is claimed is:

1. A microemulsion formulation comprising: 30-60% by volume polysorbate surfactant; 10-20% by volume fatty acid; and 20-50% by volume co-surfactant.

2. The microemulsion formulation of claim 1, wherein the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20.

3. The microemulsion formulation of claim 1 or 2, wherein the fatty acid is one or more of oleic acid and linoleic acid.

4. The microemulsion formulation of any one of claims 1-3, wherein the co-surfactant is one of more of propylene glycol and ethanol.

5. The microemulsion formulation of any one of claims 1-4, wherein the polysorbate surfactant is polysorbate 80; wherein the fatty acid is oleic acid; and wherein the co-surfactant is propylene glycol.

6. The microemulsion formulation of any one of claims 1-4, wherein the polysorbate surfactant is polysorbate 20; wherein the fatty acid is oleic acid; and wherein the co-surfactant is propylene glycol.

7. The microemulsion formulation of any one of claims 1-4, wherein the polysorbate surfactant is polysorbate 20; wherein the fatty acid is oleic acid; and -76-wherein the co-surfactant is ethanol.

8. The microemulsion formulation of any one of claims 1-4, wherein the polysorbate surfactant is polysorbate 80; wherein the fatty acid is a combination of oleic acid and linoleic acid; and wherein the co-surfactant is propylene glycol.

9. The microemulsion formulation of any one of claims 1-8, wherein the formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid, and 42.85% by volume co-surfactant.

10. The microemulsion formulation of any one of claims 1-8, wherein the polysorbate surfactant, the fatty acid, and the co-surfactant are present in a ratio of 3:1:3 by volume.

11. The microemulsion formulation of any one of claims 1-10, wherein the microemulsion formulation comprises particles, and wherein >80% of the particles in the microemulsion formulation have an average diameter between 10 and 100 nanometers.

12. The microemulsion of any one of claims 1-11, wherein the microemulsion formulation comprises less than 20, 10, 5, 4, 3, 2, or 1% water.

13. The microemulsion of any one of claims 1-12, wherein the microemulsion formulation comprises no added water.

14. The microemulsion formulation of any one of claims 1-13, further comprising a pharmacologically active agent.

15. The microemulsion formulation of any one of claims 1-13, further comprising a first pharmacologically active agent and a second pharmacologically active agent.

16. A method of delivering a pharmacologically active agent to a subject, comprising delivering an active agent in the microemulsion formulation of any one of claims 1-13 or the active agent in the microemulsion formulation of claims 14 or 15.

17. A microemulsion formulation comprising: 30-60% by volume polysorbate surfactant; 10-20% by volume fatty acid; -77-20-50% by volume co-surfactant; and a pharmacologically active agent.

18. The microemulsion formulation of claim 17, wherein the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20.

19. The microemulsion formulation of claim 17 or 18, wherein the fatty acid is one or more of oleic acid and linoleic acid.

20. The microemulsion formulation of any one of claims 17-19, wherein the co-surfactant is one of more of propylene glycol and ethanol.

21. The microemulsion formulation of any one of claims 17-20, comprising a second pharmacologically active agent.

22. The microemulsion formulation of any one of claims 17-21, wherein the pharmacologically active agent is lipophilic.

23. The microemulsion formulation of any one of claims 17-22, wherein the polysorbate surfactant is polysorbate 80; wherein the fatty acid is oleic acid; and wherein the co-surfactant is propylene glycol.

24. The microemulsion formulation of any one of claims 17-22, wherein the polysorbate surfactant is polysorbate 80; wherein the fatty acid is a combination of oleic acid and linoleic acid; and wherein the co-surfactant is propylene glycol.

25. The microemulsion formulation of any one of claims 17-22, wherein the polysorbate surfactant is polysorbate 20; wherein the fatty acid is oleic acid; and wherein the co-surfactant is ethanol. -78-26. The microemulsion formulation of any one of claims 17-25, wherein the formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid, and 42.85% by volume co-surfactant.

27. The microemulsion formulation of any one of claims 17-26, wherein the polysorbate surfactant, the fatty acid and the co-surfactant are present in a ratio of 3:1:3 by volume 28. The microemulsion formulation of any one of claims 17-27, wherein the microemulsion formulation comprises particles, and wherein >80% of the particles in the microemulsion formulation have an average diameter between 10 and 100 nanometers.

29. The microemulsion formulation of any one of claims 17-28, wherein the pharmacologically active agent comprises a cannabinoid, a curcuminoid, a mushroom phytochemical, a polyphenol, a carotenoid, an organosulfur compound, a glucobrassicin, an isothiocyanate, a lignan, a phytosterol, a carnitine or an anti-oxidant, or any combination thereof.

30. The microemulsion formulation of any one of claims 17-28, wherein the pharmacologically active agent is a broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC).

31. The microemulsion formulation of claim 30, wherein the broad-spectrum hemp extract contains at least 80% by weight cannabidiol (CBD).

32. The microemulsion formulation of claim 30 or 31, wherein the broad-spectrum hemp extract contains 84% to 87% by weight cannabidiol (CBD).

33. The microemulsion formulation of any one of claims 30-32, wherein the broad-spectrum hemp extract has a concentration of up to 50 mg / ml.

34. The microemulsion formulation of any one of claims 17-28, wherein the active agent is cannabidiol (CBD).

35. The microemulsion formulation of claim 34, wherein the cannabidiol has a concentration of up to 100 mg / ml.

36. The microemulsion formulation of any one of claims 17-28, wherein the active agent is curcumin. -79-37. The microemulsion formulation of claim 36, wherein the curcumin is a turmeric extract comprising 95% curcuminoids.

38. The microemulsion formulation of claim 36 or 37, wherein the curcumin has a concentration of up to 50 mg / ml.

39. The microemulsion formulation of any one of claims 17-28, wherein the active agent is resveratrol.

40. The microemulsion formulation of claim 39, wherein the resveratrol has a concentration of up to 75 mg / ml.

41. The microemulsion formulation of any one of claims 17-28, wherein the active agent is lion’s mane extract.

42. The microemulsion formulation of claim 41, wherein the lion’s mane extract has a concentration of up to 1500 mg / ml.

43. The microemulsion formulation of any one of claims 17-42, wherein the microemulsion formulation is administered orally.

44. The microemulsion formulation of any one of claims 17-42, wherein the microemulsion formulation is administered intravenously.

45. A soft gel capsule filled with the microemulsion formulation of any one of claims 17-42.

46. The soft gel capsule of claim 45, wherein the capsule comprises up to 50 mg broad- spectrum hemp extract.

47. The soft gel capsule of claim 45, wherein the capsule comprises up to 100 mg CBD.

48. The soft gel capsule of claim 45, wherein the capsule comprises up to 30 mg curcumin.

49. The soft gel capsule of claim 45, wherein the capsule comprises up to 100 mg resveratrol.

50. The soft gel capsule of claim 45, wherein the capsule comprises up to 1500 mg lion’s mane extract.

51. A microemulsion formulation comprising: 30-60% by volume polysorbate surfactant; -80-10-20% by volume fatty acid; 20-50% by volume co-surfactant; a first pharmacologically active agent; and a second pharmacologically active agent.

52. The microemulsion formulation of claim 51, wherein the polysorbate surfactant is one or more of polysorbate 80 and polysorbate 20.

53. The microemulsion formulation of claim 51 or 52, wherein the fatty acid is one or more of oleic acid and linoleic acid.

54. The microemulsion formulation of any one of claims 51-53, wherein the co-surfactant is one or more of propylene glycol and ethanol.

55. The microemulsion formulation of any one of claims 21-44 or claims 51-54, wherein the first pharmacologically active agent and the second pharmacologically active agent are selected from a cannabinoid, a curcuminoid, a mushroom phytochemical, a polyphenol, a carotenoid, an organosulfur compound, a glucobrassicin, an isothiocyanate, a lignan, a phytosterol, a carnitine or an anti-oxidant, and wherein the first pharmacologically active agent is different from the second pharmacologically active agent.

56. The microemulsion formulation of any one of claims 51-55, wherein the polysorbate surfactant is polysorbate 80; wherein the fatty acid is oleic acid; and wherein the co-surfactant is propylene glycol.

57. The microemulsion formulation of any one of claims 51-56, wherein the microemulsion formulation comprises 42.85% by volume polysorbate surfactant, 14.3% by volume fatty acid and 42.85% by volume co-surfactant.

58. The microemulsion formulation of any one of claims 51-56, wherein the polysorbate surfactant, the fatty acid and the co-surfactant are present in a ratio of 3:1:3 by volume. -81-59. The microemulsion formulation of any one of claims 51-58, wherein the microemulsion formulation comprises particles, and wherein >80% of the particles in the microemulsion formulation have an average diameter between 10 and 100 nanometers.

60. The microemulsion formulation of any one of claims 51-59, wherein the microemulsion formulation is administered orally.

61. The microemulsion formulation of any one of claims 51-59, wherein the microemulsion formulation is administered by intravenous injection.

62. The microemulsion formulation of any one of claims 21-44 or claims 51-61, wherein the first pharmacologically active agent is a cannabinoid substantially free of tetrahydrocannabinol (THC) and the second pharmacologically active agent is curcumin.

63. The microemulsion formulation of claim 51, wherein the polysorbate surfactant is 30-60% by volume polysorbate 80; wherein the fatty acid is 10-20% by volume oleic acid; wherein the co-surfactant is 20-50% by volume propylene glycol; wherein the first pharmacologically active agent is a cannabinoid with a concentration up to 50 mg / ml; and wherein the second pharmacologically active agent is curcumin with a concentration of up to 40 mg / ml.

64. The microemulsion formulation of claim 63, wherein the cannabinoid is a broad-spectrum hemp extract.

65. The microemulsion formulation of claim 64, wherein the broad-spectrum hemp extract has a concentration of 2 mg / ml to 15 mg / ml.

66. The microemulsion formulation of claim 64 or 65, wherein the broad-spectrum hemp extract contains at least 80% by weight cannabidiol (CBD).

67. The microemulsion formulation of any one of claims 64-66, wherein the broad-spectrum hemp extract contains 87% by weight cannabidiol (CBD). -82-68. The microemulsion formulation of claim 63, wherein the cannabinoid is cannabidiol (CBD).

69. The microemulsion formulation of claim 68, wherein the cannabidiol (CBD) concentration is 2 mg / ml to 20 mg / ml.

70. The microemulsion formulation of any one of claims 63-69, wherein the curcumin is a turmeric extract comprising about 95% curcuminoids.

71. The microemulsion formulation of any one of claims 63-70, wherein the curcumin concentration is 2 mg / ml to 30 mg / ml.

72. The microemulsion formulation of any one of claims 63-71, wherein the microemulsion formulation comprises 42.85% by volume propylene glycol, 14.3% oleic acid by volume and 42.85% by volume polysorbate 80.

73. The microemulsion formulation of claim 63, wherein the polysorbate surfactant is 42.85% by volume polysorbate 80; wherein the fatty acid is 14.3% by volume oleic acid; wherein the co-surfactant is 42.85% by volume propylene glycol; wherein the cannabinoid is broad-spectrum hemp extract with a concentration of 4 mg / ml to 5 mg / ml; and wherein the curcumin is a turmeric extract with a concentration of 8 mg / ml to 10 mg / ml.

74. A soft gel capsule filled with a microemulsion formulation of a first pharmacologically active agent with a concentration up to 200 mg / ml and a second pharmacologically active agent with a concentration up to 200 mg / ml, wherein said formulation comprises 30-60% by volume polysorbate surfactant, 10-20% by volume fatty acid and 20-50% co-surfactant.

75. The soft gel capsule of claim 74, wherein the first pharmacologically active agent is a cannabinoid substantially free of tetrahydrocannabinol (THC) with a concentration of up to 50 mg / ml; -83-wherein the second pharmacologically active agent is curcumin with a concentration of up to 40 mg / ml; wherein the polysorbate surfactant is polysorbate 80; wherein the fatty acid is oleic acid; and wherein the co-surfactant is propylene glycol.

76. The soft gel capsule of claim 75, wherein the cannabinoid is CBD and wherein each capsule contains CBD in a concentration of 1 mg / ml to 30 mg / ml and curcumin in a concentration of 3 mg / ml to 25 mg / ml.

77. The soft gel capsule of claim 75 or 76, wherein the cannabinoid is CBD and wherein each capsule contains 2.5 mg to 5 mg of CBD and 5 mg to 10 mg of curcumin.

78. The soft gel capsule of claim 75, wherein the cannabinoid is broad-spectrum hemp extract and wherein each capsule contains broad-spectrum hemp extract in a concentration of 5 mg / ml to 10 mg / ml and curcumin in a concentration of 10 mg / ml to 20 mg / ml.

79. The soft gel capsule of claim 75 or 78, wherein the cannabinoid is broad-spectrum hemp extract and wherein each capsule contains 2.5 mg to 5 mg of broad-spectrum hemp extract and 4 mg to 10 mg of curcumin.

80. The soft gel capsule of any one of claims 75, 78 or 79, wherein each capsule contains 5 mg of broad-spectrum hemp extract and 10 mg of curcumin.

81. The soft gel capsule of any one of claims 75-80, wherein the curcumin is a turmeric extract comprising about 95% curcuminoids.

82. The soft gel capsule of any one of claims 75-81, wherein the microemulsion formulation comprises 42.85% by volume propylene glycol, 14.3% oleic acid by volume and 42.85% by volume polysorbate 80.

83. The soft gel capsule of any one of claims 75-81, wherein the polysorbate 80, the oleic acid and the propylene glycol are present in a ratio of 3:1:3 by volume.

84. The soft gel capsule of claim 74, -84-wherein the first pharmacologically active agent is broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC) with a concentration of 5 mg / ml to 10 mg / ml; wherein the second pharmacologically active agent is turmeric extract with a concentration of 10 mg / ml to 20 mg / ml; wherein the polysorbate surfactant is 42.85% by volume polysorbate 80; wherein the fatty acid is 14.3% by volume oleic acid; and wherein the co-surfactant is 42.85% by volume propylene glycol.

85. The soft gel capsule of claim 74, wherein the first pharmacologically active agent is 2.5 mg to 5 mg broad-spectrum hemp extract standardized to 87% cannabidiol; wherein the second pharmacologically active agent is 4 mg to 10 mg turmeric extract standardized to 95% curcuminoids; wherein the polysorbate surfactant is 42.85% by volume polysorbate 80; wherein the fatty acid is 14.3% by volume oleic acid; and wherein the co-surfactant is 42.85% by volume propylene glycol.

86. A method of reducing inflammation or pain comprising administering to a patient a pharmacologically effective amount of the microemulsion formulation of any one of claims 14-44 or claims 51-73 or of the soft gel capsule of any one of claims 45-50 or claims 74-85.

87. The method of claim 86, wherein the inflammation or pain is due to arthritis.

88. The method of claim 86, wherein the inflammation or pain is musculoskeletal.

89. The method of any one of claims 86-88, wherein the pharmacologically effective amount of the microemulsion formulation is delivered orally or intravenously.

90. The method of any one of claims 86-88, wherein the pharmacologically effective amount of the soft gel capsule is delivered orally. -85-91. A method of providing analgesic (pain relief), anti-inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, and / or hepatoprotective effects comprising administering to a patient a pharmacologically effective amount of the microemulsion formulation of any one of claims 14-44 or claims 51-73 or of the soft gel capsule of any one of claims 45-50 or claims 74-85.

92. The microemulsion formulation or soft gel capsule of any one of the preceding claims comprising analgesic (pain relief), anti-inflammatory, antioxidant, antimicrobial, anti-anxiety, neuroprotective, cardioprotective, and / or hepatoprotective effects.

93. The microemulsion formulation or soft gel capsule of any one of the preceding claims wherein the first and second active agents act synergistically.

94. The microemulsion formulation of any of one of the preceding claims wherein the microemulsion is formed without external input of energy.

95. The microemulsion formulation of claim 94, wherein the external input of energy is heat or high-shear mixing.

96. A microemulsion formulation comprising, 42.85% by volume polysorbate 80; 14.3% by volume oleic acid; 42.85% by volume propylene glycol; a cannabinoid that is broad-spectrum hemp extract with a concentration of 5 mg / ml to 10 mg / ml; and a turmeric extract in a concentration of 10 mg / ml to 20 mg / ml.

97. A soft gel capsule comprising, a broad-spectrum hemp extract substantially free of tetrahydrocannabinol (THC) with a concentration of 5 mg / ml to 10 mg / ml; a turmeric extract with a concentration of 10 mg / ml to 20 mg / ml; 42.85% by volume polysorbate 80; 14.3% by volume oleic acid; and -86-42.85% by volume propylene glycol.

98. A soft gel capsule comprising, 2.5 mg to 5 mg broad-spectrum hemp extract standardized to 87% cannabidiol; 4 mg to10 mg turmeric extract standardized to 95% curcuminoids; 42.85% by volume polysorbate 80; 14.3% by volume oleic acid; and 42.85% by volume propylene glycol. -87-

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