Dilutable formulations of cannabinoids and methods for preparing same

Abstract

The present disclosure provides cannabinoid-added formulations, as well as methods for preparing same. [Selection diagram] None

Description

Technical Field

[0001] The present disclosure provides cannabinoid-added preparations and methods for preparing them.

Background Art

[0002] References considered relevant as background to the subject matter disclosed herein are listed below. [1]WO2008 / 058366 [2]A. Spernath, A. Aserin, Advances in Colloid and Interface Science 2006, 128 [3]A. Spernath, A. Aserin, N. Garti, Journal of Colloid and Interface Science 2006, 299, 900 to 909 [4]A. Spernath, A. Aserin, N. Garti, Journal of Thermal Analysis and Calorimetry 2006, 83 [5]N. Garti, A. Spernath, A. Aserin, R. Lutz, Soft Matter, 2005, 1 [6]A. Spernath, A. Aserin, L. Ziserman, D. Danino, N. Garti, Journal of Controlled Release, 2007, 119 [7]WO03 / 105607

[0003] The above references cited in this specification should not be construed as meaning that they are in any way relevant to the patentability of the presently disclosed subject matter.

[0004] Cannabinoids have been used for years, inter alia, to relieve pain and inflammation-related syndromes, spasms, asthma, sleep disorders, depression, loss of appetite and other medical conditions. Cannabinoids are a group of active compounds mainly found in the resin-producing female inflorescences of the cannabis plant. Although various cannabinoid compounds have been identified in the literature to date, two compounds in particular, namely tetrahydrocannabinol (THC) and cannabidiol (CBD), have been the main focus in medical applications.

[0005] THC is a psychoactive compound that has harmful long-term effects on users, while CBD is not considered a psychoactive drug and is thought to be safely ingestible via various routes of administration. Both compounds are typically found in plant sources as mixtures in various concentration ranges. To formulate into pharmaceutical compositions, cannabinoids are often extracted from plant sources by various methods or synthesized.

[0006] One commonly used method is extraction with a carrier oil, where the carrier oil is used as a solvent for extracting cannabinoid species from plant sources. Since the trichomes of the oil-filled inflorescences are lipophilic, natural vegetable oils are an effective method for extracting a mixture of cannabinoid species from the plant's cannabinoid-containing resin.

[0007] Another commonly used method is extraction with an organic solvent that dissolves the cannabinoids. Such extraction requires adjusting the solvent for effective extraction and often results in low-yield extractions. Furthermore, it is difficult to remove trace amounts of the solvent from the final product, reducing the purity and safety of the resulting extract.

[0008] A further method used for extracting various compounds from various plant sources is supercritical CO2 extraction. In the CO2 extraction process, CO2 is used under supercritical conditions (i.e., high temperature and high pressure) for extracting cannabinoid species. Although relatively effective for extracting various compounds from plant sources, this technique is more complex and very expensive compared to liquid extraction.

[0009] There are various methods for extracting cannabinoids, but all of them have a common drawback of low extraction yields and low (or no) selectivity. That is, the extraction methods known to date extract various types of cannabinoids from plant sources, often resulting in mixtures of CBD and THC in various concentrations and ratios, hindering the subsequent use of CBD in formulations and pharmaceutical compositions.

[0010] The bioavailability of orally, topically or ophthalmically administered cannabinoids in commercially available products has often been found to be poor and insufficient, thereby resulting in inadequate therapeutic effects. Improved solubility or solubilization and enhanced bioavailability and absorption by delivery systems other than smoking are needed.

SUMMARY OF THE INVENTION

[0011] In the present disclosure, solubilization of cannabinoids is provided rather than using a unique formulation. As will be described in more detail herein, the formulations of the present disclosure have the ability to incorporate a large amount of various cannabinoids. Furthermore, the present disclosure provides a method for obtaining such cannabinoid-incorporated formulations, and various pharmaceutical compositions and dosage forms containing such formulations.

[0012] In one aspect, the present disclosure provides a cannabinoid-incorporated formulation comprising at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and / or one co-solvent, and at least 0.1% by weight of a cannabinoid.

[0013] The formulations of the present disclosure are usually in the form of microemulsions. Microemulsions (ME) are well-known media for intravenous drug delivery due to their spontaneous formation, high solubilization capacity and physical stability [1]. A particular type of microemulsion is the spontaneously formed microemulsion characterized by a nanoscale droplet size, which is a new and advanced category of delivery vehicles. These microemulsions have been studied before and have been demonstrated to have the ability to solubilize insoluble drugs and nutraceuticals [2-7]. This formulation is a self-assembled microemulsion system of nanodroplets containing a surfactant and an oil. The system of the present disclosure comprises at least one oil, at least one hydrophilic surfactant and at least one solvent, and may further contain additional components such as co-surfactants, co-solvents and phospholipids, as will be further described herein. In the present disclosure, the term microemulsion means such a formulation unless otherwise defined, and the terms "microemulsion" and "formulation" are used interchangeably.

[0014] The formulations of the present disclosure are in the form of concentrates that are substantially water-free (containing a maximum of 10% by weight of water) and can be completely and progressively diluted in the aqueous phase to form microemulsions. The concentrated forms of the present disclosure, as will be further explained, are completely dilutable with water, in contrast to conventional microemulsions known in the art. The diluted formulations (diluted microemulsions) have a nano-sized uniform (monodisperse) structure and exhibit an interfacial tension that behaves like a zero Newtonian fluid between the oil and aqueous phases. This formulation self-organizes to form water-free inverse micelles when the surfactant and oil are mixed. Dilution with water or an aqueous solution forms water-swelled micelles or oil-in-water nano-droplets, which can be converted to a co-continuous intermediate phase in the presence of an aqueous phase such as water. Further dilution results in inversion (umbrella type) to oil-in-water droplets. Further dilution results in inversion (umbrella type) to oil-in-water droplets.

[0015] While not wishing to be bound by theory, these systems are composed of oil-solvated clusters or short domains of the surfactant, but are different from classical inverse micelles. Mixing with a small amount of aqueous medium forms hydrated and solvated surfactants, and further dilution in the aqueous phase easily transforms them into oil-in-water (O / W) nano-droplets, confining the extracted cannabinoid molecules in their core. This transformation to the O / W microemulsion is spontaneous, i.e., no shear force, mechanical force, or excessive heating conditions are required. The cannabinoid is confined in the core of the inverse micelle and remains at the interface between the oil and aqueous phases when diluted in the co-continuous region. Thereafter, once the O / W microemulsion is formed, the cannabinoid molecules are located at the center of the droplets. The interaction (physical complex formation) between CBD and the surfactant (and co-surfactant if used) enables the extracted cannabinoid to be maintained within the oil core through the structural transformation from the co-continuous region of the inverse micelle and ultimately to the O / W microemulsion. Thus, the formulation is stable and prevents the unwanted release of cannabinoids from the oil core before administration (i.e., during storage).

[0016] The formulations of the present disclosure provide thermodynamically stable microemulsions, have nanosized droplets, and can be safely stored for a long time without aggregation, coalescence, or phase separation. The formulations of the present invention are also characterized by a substantially uniform and stable droplet size, typically a narrow size distribution on the nanometer scale. The stability of the droplet size is important because once administered, a change in droplet size can impair the release of cannabinoids. Furthermore, cannabinoid-containing formulations lack water when not in a diluted form and thus do not support (or minimally support) the growth of microorganisms. Additionally, due to their high stability and small droplet size, these formulations can be sterilized by various methods such as heat sterilization, filtration through a 0.22 μm filter, UV, and other methods known in the art without the risk of self-contamination and without damaging the beneficial structure of the medium.

[0017] In the present disclosure, the formulations are designed to solubilize cannabinoids from various sources, and the cannabinoid-containing formulations (cannabinoid-containing microemulsions) are substantially water-free, can be easily diluted, or even "on demand" and adjusted according to the application or administration route in any type of aqueous solution (buffer, water for injection, saline, isotonic mixture, etc.).

[0018] Thus, in some embodiments, the microemulsion is substantially water-free. The expression substantially water-free means a formulation containing up to 10% by weight of water. In other embodiments, the formulation is water-free.

[0019] Cannabinoids are a group of psychoactive and non-psychoactive compounds that act on cannabinoid receptors within cells to suppress the release of neurotransmitters in the brain. This term is meant to include cannabinoids obtained from natural sources. Cannabinoids include cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol (CBG), cannabigerol monomethyl ether (CBGM), cannabigerovaleric acid (CBGVA), cannabigeroval (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevaleric acid (CBCVA), cannabichromeval (CBCV), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylethyl (CBDM), cannabidiol-C4 (CBD-C4) 、 cannabidivarinic acid (CBDVA), cannabidiocanol (CBD-C1), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9-tetrahydrocannabinol-C4 (THCA-C4), delta-9-tetrahydrocannabivarinic acid (THCVA), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabiolic acid (THCA-C1), delta-9-tetrahydrocannabiocanol (THC-C1), delta-7-cis-iso-tetrahydrocannabivarin, delta-8-tetrahydrocannabinolinic acid A (Δ 8 -THCA), delta-8-tetrahydrocannabinol (Δ 8-THC), cannabicyclolic acid (CBLA), cannabinol (CBL), cannabinocyclovaline (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielsoin (CBE), cannabinolic acid (CBNA), cannabinol (CBN), cannabinol methyl ether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabinol-C2 (CBN-C2), cannabinol-C1 (CBN-C1), cannabinodiol (CBND), cannabinodibarin (CBVD), cannabinotriol (CBT), 10-ethoxy-9-hydroxy-delta-6A-tetrahydrocannabinol, 8,9-dihydroxy-delta-6A-tetrahydrocannabinol, cannabinotriol valine (CBTV), ethoxy cannabinotriol valine (CBTVE), dehydrocannabifuran (DCBF), cannabifuran (CBF), cannabinochromanone (CBCN), cannabicitran (CBT), 10-oxo-delta-6A-tetrahydrocannabinol (OTHC), delta-9-cis-tetrahydrocannabinol (cis-THC), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-benzoxocin-5-methanol (OH-iso-HHCV), cannabilipsool (CBR), trihydroxy-delta-9-tetrahydroxycannabinol (triOH-THC), and any other cannabinoid, or one or more thereof.

[0020] In some embodiments, the desired cannabinoid is CBD or CBDA.

[0021] In some embodiments, the cannabinoid is THC.

[0022] In some embodiments, the cannabinoid-added formulation contains from about 0.1 to 12% by weight of cannabinoid. In other embodiments, the cannabinoid-added formulation contains from about 0.1 to 10% by weight of cannabinoid, from 0.1 to 9% by weight of cannabinoid, or from about 0.1 to 8% by weight of cannabinoid. In some other embodiments, the cannabinoid-added formulation can contain from about 0.5 to 12% by weight of cannabinoid, from about 1 to 12% by weight of cannabinoid, from about 1.5 to 12% by weight of cannabinoid, from about 2 to 12% by weight of cannabinoid. In further embodiments, the cannabinoid-added formulation contains from about 0.5 to 11% by weight of cannabinoid, from about 1 to 10% by weight of cannabinoid, from 1.5 to 9% by weight of cannabinoid, or from about 2 to 8% by weight of cannabinoid.

[0023] As described above, the formulations of the present disclosure contain at least one oil, at least one hydrophilic surfactant, at least one co-surfactant, and at least 0.1% by weight of at least one cannabinoid, and optionally further contain at least one co-solvent.

[0024] The formulations of the present disclosure may be further adjusted to solubilize other components that may be present in cannabinoid sources such as terpenes, essential oils, and the like.

[0025] In the context of the present disclosure, the term oil refers to a natural or synthetic oil in which the cannabinoid is dissolved. The oil used in the microemulsions of the present disclosure should be approved for administration to a subject and includes mineral oil, paraffinic oil, vegetable oil, glyceride, fatty acid ester, liquid hydrocarbon, and the like.

[0026] According to some embodiments, this oil can be selected from medium-chain triglycerides (MCT), olive oil, soybean oil, canola oil, cottonseed oil, palm olein, sunflower oil, corn oil, rapeseed oil, grapeseed oil, hemp oil, pomegranate oil, avocado oil, peppermint oil, tomato oil, isopropyl myristate, oleyl lactate, coco-caprylo-caprate, hexyl laurate, oleyl amine, oleic acid, oleyl alcohol, linoleic acid, linoleyl alcohol, ethyl oleate, hexane, heptane, nonane, decane, dodecane, D-limonene, neem oil, peppermint oil, anise oil, rosemary oil, sage oil, hibiscus oil, berry oil (any type), menthol, capsaicin, grape seed oil, pumpkin oil, hemp oil, and similar essential oils and mixtures thereof.

[0027] According to some embodiments, this oil is present in the formulation in an amount of about 0.5 to 20% by weight. According to other embodiments, this oil is present in the formulation in an amount of about 1 to 10% by weight.

[0028] This formulation contains at least one hydrophilic surfactant. The term hydrophilic surfactant means an ionic or non-ionic surfactant that is hydrophilic, i.e., a surfactant that has an affinity for water. Exemplary surfactants are polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, and polyoxyethylene esters of saturated and unsaturated castor oils, ethoxylated monoglycerol esters, ethoxylated fatty acids, ethoxylated fatty acids of short-chain, medium-chain, and long-chain fatty acids, etc.

[0029] In some embodiments, at least one hydrophilic surfactant is selected from polyoxyethylenes, ethoxylated (20 EO) sorbitan monolaurate (T20), ethoxylated (20 EO) sorbitan monostearate / palmitate (T60), ethoxylated (20 EO) sorbitan monooleate / linoleate (T80), ethoxylated (20 EO) sorbitan trioleate (T85), ethoxylated (20 EO - 40 EO) castor oil; ethoxylated (20 - 40 EO) hydrogenated castor oil, ethoxylated (5 - 40 EO) monoglyceride stearate / platinumate, polyoxyl 35 castor oil. According to other embodiments, the hydrophilic surfactant is selected from Solutol HS15 (polyethylene glycol (15)-hydroxystearate), polyoxyl 35 castor oil, polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 80 (Tween 80), Mirj S40, oleoyl macrogol glyceride, polyglyceryl-3 dioleate, ethoxylated hydroxystearic acid, decaglycerol laurate, decaglycerin monooleate, hexaglycerin monooleate, hexaglycerol monolaurate and other polyglycerol esters, sucrose monooleate, sucrose monolaurate, etc.

[0030] In some embodiments, this formulation may contain about 30 to 85% by weight of the hydrophilic surfactant. According to some other embodiments, this formulation may contain about 35 to 80% by weight of the hydrophilic surfactant.

[0031] The term co-surfactant should be understood to encompass any agent different from the hydrophilic surfactant that can reduce the interfacial tension between the oil phase and the water phase (together with the hydrophilic surfactant) to almost zero (or zero), and when the formulation is mixed with an aqueous liquid, a homogeneous mixture is formed. According to some embodiments, the co-surfactant is selected from polyols, diglycerides, polyoxyethylene, etc.

[0032] The co-surfactant is at least one polyol, i.e., an alcohol containing at least two hydroxyl groups, such as alcohols including ethylene glycol, glycerol, polyethylene glycol, polypropylene glycol, sorbitol, mannitol, lactitol, xylitol, etc.

[0033] In some embodiments, the co-surfactant is selected from glycerol, polypropylene glycol, polyethylene glycol, ethoxylated hydrogenated castor oil, saturated or unsaturated fatty acid sorbitan esters (Spans), phospholipids, waxes (carnauba, beeswax, candelilla). In some embodiments, the co-surfactant is present in the formulation in an amount of about 1 to 50% by weight. In other embodiments, the co-surfactant may be present in the formulation in an amount of about 5 to 45% by weight.

[0034] The co-solvent is a polyol such as propylene glycol, glycerol, xylitol, or a short-chain alcohol such as ethanol, propanol, isopropanol.

[0035] The formulations described herein are spontaneously formed microemulsions, which are characterized by an energy balance with substantially zero interfacial tension. Such a balance is obtained by a combination of a surfactant and a co-surfactant. Thus, in some embodiments, the ratio between the hydrophilic surfactant and the co-surfactant is between about 1:1 and 6:1 (wt / wt). In other embodiments, the ratio between the hydrophilic surfactant and the co-surfactant may be about 1:1 - 4:1 (wt / wt).

[0036] The formulation may further contain additional ingredients. In some embodiments, the formulation further contains at least one solvent. The term "solvent" refers to an organic compound different from oil that is miscible with oil and forms a homogeneous oil phase that dissolves and stabilizes cannabinoids together with the oil. The solvent can be selected from, for example, liquid hydrocarbons, alcohols, etc. according to some embodiments. According to some embodiments, the solvent can be selected from ethanol, propanol, isopropyl alcohol, acetic acid, propionic acid, fumaric acid, tartaric acid and its derivatives, lactic acid, maleic acid, malic acid, etc.

[0037] In some embodiments, the solvent is present in the formulation in an amount of about 0.1 to 25% by weight. In some other embodiments, the formulation contains about 0.1 to 15% by weight of the solvent.

[0038] According to some embodiments, other additional ingredients in the formulation are at least one phospholipid. For example, soybean lecithin, rapeseed lecithin, corn or sunflower lecithin, egg lecithin, Epicorn200, Forzal 50PG, dioleoylphosphatidylcholine (DOPC), oleyl palmitoyl phosphatidylcholine (POPC), and corresponding phospholipids such as serine, ethanolamine, glycerol, etc. can be used. According to such embodiments, the formulation may contain about 1 to 10% by weight of phospholipids.

[0039] In further embodiments, the formulations described herein may further contain at least one additive selected from antioxidants (tocopherol), preservatives, membrane permeants, membrane permeation promoters (e.g., transcutol, isosorbide, oleic acid, propylene glycol, maltodextrin, cyclodextrin, etc.), oil / water-soluble vitamins, BHA, BHT, TBHQ, propionic acid and its derivatives, and others.

[0040] In some embodiments, the formulation comprises at least one co-surfactant selected from: (i) at least one cannabinoid, (ii) at least one oil selected from medium-chain triglycerides (MCT), glycerin, glycerol, castor oil, R(+)-limonene, isopropyl myristate, ethyl laurate, ethyl caprate, olive oil, oleic acid, and triacetin, (iii) at least one hydrophilic surfactant selected from polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor castor oil), MirjS40, HECO40 (ethoxylated 40 hydrogenated castor oil), labrasol (oleoyl macrogol glyceride), glycerol, and sucrose mono / dilaurate, (iv) polypropylene glycol (PG), and Plurol Oleique CC497 (polyglyceryl-3 dioleate), and optionally at least one phospholipid and / or at least one solvent selected from oleic acid, transcutol, acetic acid, ethanol, and isopropyl alcohol.

[0041] In other embodiments, the formulation is selected from the following formulations: - at least one cannabinoid (e.g., CDB), medium-chain triglycerides (MCT), polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor castor oil), polypropylene glycol (PG), ethanol, and at least one phospholipid; or - at least one cannabinoid (e.g., CDB), medium-chain triglycerides (MCT), polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor castor oil), polypropylene glycol (PG), ethanol, and at least one phospholipid; or - at least one cannabinoid (e.g., CDB), medium-chain triglycerides (MCT), oleic acid, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor castor oil), polypropylene glycol (PG), ethanol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), R-(+)-limonene, polysorbate 80 (Tween80), propylene glycol (PG), and ethanol; or - At least one cannabinoid (e.g., CDB), R-(+)-limonene, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), and propylene glycol (PG); or - At least one cannabinoid (e.g., CDB), medium-chain triglyceride (MCT), polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), and propylene glycol (PG). Or - At least one cannabinoid (e.g., CDB), isopropyl myristate, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), and propylene glycol (PG); or - At least one cannabinoid (e.g., CDB), ethyl laurate, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), and propylene glycol (PG); or - At least one cannabinoid (e.g., CDB), MCT, glycerol, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), propylene glycol (PG), and ethanol; or - At least one cannabinoid (e.g., CDB), MCT, glycerol, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), propylene glycol (PG), ethanol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), MCT, glycerol, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), propylene glycol (PG), ethanol, transcutol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), MCT, glycerol, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), polypropylene glycol (PG), ethanol, oleic acid, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), MCT, glycerol, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), polypropylene glycol (PG), ethanol, transcutol, oleic acid, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), R(+)-limonene, polysorbate 80 (Tween80), polypropylene glycol (PG), and ethanol; or - At least one cannabinoid (e.g., CDB), castor oil, polysorbate 80 (Tween80), MirjS40, polypropylene glycol (PG), ethanol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), MCT, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), polypropylene glycol (PG), ethanol, oleic acid, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), ethyl caprylate, polysorbate 80 (Tween80), polypropylene glycol (PG), ethanol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), ethyl caprylate, HECO 40, polyglyceryl-3 dioleate (CC497), polypropylene glycol (PG), acetic acid, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), olive oil, Labrasol (oleoyl macrogol glyceride), polyglyceryl-3 dioleate (CC497), and ethanol; or - At least one cannabinoid (e.g., CDB), olive oil, polysorbate 80 (Tween80), polypropylene glycol (PG), ethanol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), MCT, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), polypropylene glycol (PG), and at least one phospholipid. Or - At least one cannabinoid (e.g., CDB), MCT, oleic acid, polysorbate 80 (Tween80), polyoxyl 35 castor oil (Cremophor EL), glycerol, polypropylene glycol (PG), ethanol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), limonene, polysorbate 80 (Tween80), polypropylene glycol (PG), and ethanol; or - At least one cannabinoid (e.g., CDB), triacetin, polysorbate 80 (Tween80), polypropylene glycol (PG), and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), triacetin, Labrasol (oleoyl macrogol glyceride), polyoxyl 35 castor oil (Cremophor EL), polypropylene glycol (PG), isopropanol, and at least one phospholipid; or - At least one cannabinoid (e.g., CDB), MCT, sucrose mono / dilaurate, polypropylene glycol (PG), isopropanol, and at least one phospholipid.

[0042] As demonstrated herein, cannabinoid-added formulations stabilize cannabinoids in an acidic environment, particularly gastric juice. If the cannabinoid is CBD, the formulation may reduce the rate of conversion of CBD to THC.

[0043] As described above, the formulations of the present disclosure are composed of surfactant short domains distributed in a nanometer-sized substantially uniform oil solvate cluster or a water-free continuous phase. In some embodiments, the formulation has an oil droplet size of about 5 to 100 nanometers, preferably 10 to 30 nm.

[0044] The droplet size refers to the arithmetic mean of the measured droplet diameters, and the diameters are in the range of ±15% from the average value.

[0045] In one aspect thereof, the present disclosure provides a method for preparing a cannabinoid-added formulation described herein, comprising the step of mixing a microemulsion with a cannabinoid source.

[0046] The mixing can be carried out by any suitable known method that does not include shear mixing, such as manual mixing, magnetic stirring, pedal mixing, etc. In some embodiments, the mixing is carried out for about 2 to 60 minutes. In other embodiments, the mixing is carried out at a temperature of about 15 to 60 °C.

[0047] The cannabinoid source means any source containing the desired cannabinoid, referring to natural, semi-synthetic or synthetic sources. In some embodiments, the cannabinoid source is selected from substantially pure cannabinoids (e.g., pure CBD), crystalline forms of cannabinoids, natural cannabinoid sources (e.g., cannabis plant parts), and cannabinoid extracts (obtained by any known extraction method).

[0048] When the source is a cannabinoid extract, the extract is obtained by oil extraction, solvent extraction, and / or CO2 extraction.

[0049] When the cannabinoid source is a natural cannabinoid source, in some embodiments, it may be a plant from the genus Cannabis. This plant can be selected from Cannabis sativa, Cannabis indica, Cannabis ruderalis, and any mixture thereof. This plant may be any natural strain, any horticultural variety, cultivated strain or engineered strain classified in the genus Cannabis.

[0050] The methods of the present disclosure can be implemented using any part of a plant source containing cannabinoids. That is, in some embodiments, the plant source is selected from the flowers, inflorescences, buds, fruits, pericarp, seeds, leaves, stems, petioles, roots, and any mixture thereof of cannabis.

[0051] The plant source can be provided in any desired form, for example, minced, and the plant source can be provided as, for example, powder, granules, pellets, tablets, flakes, shredding, or plant parts (e.g., intact leaves, seeds, intact inflorescences, etc.). The plant source is provided in a fresh, frozen, freeze-dried, semi-dried or dried state.

[0052] When using a plant as the source of cannabinoids, the cannabinoids can be extracted from the plant source by using the formulations of the present disclosure. The term "extraction" or its linguistic variations means the transfer of the desired cannabinoids from the plant source to the solubilized oil phase of the formulation. The weight ratio (wt / wt) of the plant source to the formulation in such embodiments is from 1:5 to 1:100.

[0053] Extraction is usually carried out by stirring or thoroughly mixing the formulation and the cannabinoid source, for example, at 50 to 6000 rpm.

[0054] In other embodiments, the cannabinoid source is not a natural source in its natural form (i.e., not a plant part), but is a substantially pure cannabinoid (e.g., pure CBD), a crystalline form of a cannabinoid, or a cannabinoid extract (obtained by any known extraction method).

[0055] When enhancing the solubilization of cannabinoids in a formulation, the formulation can be homogenized after mixing the cannabinoid source with the other components of the formulation. Homogenization, or any linguistic variation thereof, refers to the process of applying shear force to the mixture to form intimate contact that solubilizes the desired cannabinoids from the source. Homogenization can be carried out by suitable means including, but not limited to, a homogenizer and high-speed mechanical agitation. Note that since the formulations used in the processes of the present disclosure have nanostructured sizes, homogenization has little effect on the size and / or structure of the micelles.

[0056] In some embodiments, homogenization is carried out over a period of about 1 to 60 minutes. In other embodiments, homogenization may be carried out for about 1 to 45 minutes, about 1 to 30 minutes, or even about 1 to 20 minutes. In some other embodiments, homogenization can be carried out for about 5 to 60 minutes, about 10 to 60 minutes, about 15 to 60 minutes, or about 20 to 60 minutes.

[0057] In some embodiments, homogenization can be carried out at a temperature of about 5 to 70 °C. In other embodiments, homogenization can be carried out at a temperature of about 15 to 70 °C, about 20 to 70 °C, about 25 to 70 °C, or about 30 to 70 °C. In some other embodiments, homogenization can be carried out at a temperature of about 10 to 65 °C, about 10 to 60 °C, about 10 to 55 °C, about 10 to 50 °C, about 10 to 45 °C, or even about 10 to 40 °C. In further embodiments, homogenization can be carried out at a temperature of about 15 to 60 °C, about 20 to 50 °C, or about 25 to 45 °C.

[0058] Additional addition of cannabinoids from the cannabinoid source can be carried out by using additional solubilization cycles, thereby maximizing the yield obtained from a given amount of the cannabinoid source.

[0059] The formulations of the present disclosure can be used as such, i.e., as cannabinoids in a concentrated form that is substantially free of water, or they can be diluted or further formulated into various pharmaceutical compositions. Thus, according to another aspect, the present disclosure provides a pharmaceutical composition or a dietary supplement composition comprising the cannabinoid-added formulations described herein.

[0060] The concentrates and diluted forms of the present disclosure significantly improve the stability of the formulations over time, reduce the risk of contamination, and expand their scope of application to a wide variety of concentrations (various dosages) and dilution forms, while allowing medical professionals to make decisions on how, when, and which formulations to prepare prior to use.

[0061] The term "concentrate" (or its linguistic variants) means an oil-based structured oil / surfactant system that is substantially free of water, where the surfactant tails are solubilized with the cannabinoid in a surfactant / cosurfactant system, facilitating any complete dilution with a diluent aqueous phase (dilutable) to form a diluted formulation for administration. In other words, the concentrate is designed to be rapidly and completely diluted with a suitable diluent, usually water for injection or physiological saline, to form a diluted formulation as described below. When diluted with a suitable diluent, the concentrate of the present invention spontaneously forms a microemulsion, which is a "surfactant's ill-defined solvation domain (or cluster)" mesophase that initially forms water-in-oil nanodroplets at minor dilution (about 20 - 30 wt%); and upon further dilution, it changes to a bicontinuous mesophase and becomes oil-in-water (O / W) nanodroplets. Here, the diluent forms the continuous phase, while the oil phase is in the form of discrete droplets of nanometer size (i.e., the diluted formulation). As described above, the diluted formulation is formed spontaneously from the concentrate, i.e., without the need to apply any shear, cavitation, or homogenization process.

[0062] In addition to providing flexibility in adjusting cannabinoid dosages and better control, the concentrates produced by the methods described herein are substantially free of water, i.e., lacking in water. When water is absent from the formulation (i.e., when it is at most 10% by weight water), the concentrate lacks an environment to sustain the growth of microorganisms (e.g., fungi or bacteria), allowing for long-term storage without (or at a minimum) the risk of contamination. Without wishing to be bound by theory, one reason that little bacterial contamination is observed in such concentrates is the absence of unbound water, thereby limiting microbial growth and substantially extending the shelf life of the cannabinoid-containing formulation.

[0063] The ratio between the concentrate and the diluent depends on the desired final concentration of the cannabinoid in the formulation. According to some embodiments, the diluted formulation contains about 75 to 98% by weight of the diluent.

[0064] In some embodiments, the composition can be adjusted for lyophilization by adding to the formulation at least one sugar, such as dextrin, lactose, mannitol, maltodextrin, erythritol, sorbitol, or other suitable lyophilization additives.

[0065] In some embodiments, the pharmaceutical composition may include at least one pharmaceutically acceptable carrier. The "pharmaceutically acceptable carriers" described herein, such as vehicles, adjuvants, excipients, or diluents, are well known to those skilled in the art and are readily available. The pharmaceutically acceptable carrier is preferably one that is chemically inert to the active compound and that has no adverse side effects or toxicity under the conditions of use.

[0066] The choice of carrier is determined in part by the active agent (i.e., the cannabinoid) and by the particular method used for administration of the composition. Accordingly, there are a wide variety of suitable compositions for the pharmaceutical compositions of the present invention.

[0067] The aqueous diluent can be selected from water, water for injection, saline, dextrose solution, water / alcohol mixtures, aqueous solutions (such as sugar and sweetener solutions and water-alcohol mixtures), or a buffer solution with a pH of 3 to 9, or other isotonic solutions, or flavored water.

[0068] The cannabinoid is stably contained (i.e., solubilized) in the oil droplets and is controllably released to the appropriate administration target. Without wishing to be bound by theory, the cannabinoid-oil-surfactant system forms strong reversible molecular interactions, thus enabling the solubilization of the cannabinoid within the oil droplets of the microemulsion.

[0069] Depending on the route of administration and / or the desired formulation characteristics, the pharmaceutical composition may contain various additional components such as aqueous and non-aqueous diluents, isotonic sterile injections, antioxidants, buffers, bacteriostatic agents, suspending agents, solubilizing agents, thickening agents, gelling agents, skin softeners, moisturizing agents, stabilizers, preservatives, buffers, coloring agents, fragrances, flavoring agents, flavor masking agents, absorbents, filters, electrolytes, proteins, chelating agents, etc.

[0070] In some embodiments, the pharmaceutical composition is in a form selected from gels, lotions, oils, soaps, sprays, emulsions, creams, ointments, capsules, soft gel capsules, chewing gums, patches, buccal patches, and various other foods and supplements, or solutions.

[0071] In other embodiments, the formulation can be adapted to deliver the cannabinoid to the circulatory system of the subject via various routes of administration such as topical administration, oral administration, rectal administration, vaginal administration, subcutaneous administration, intravenous administration, intramuscular administration, transdermal administration, intranasal administration, inhalation administration, intraocular administration, parenteral administration, etc.

[0072] Compositions suitable for oral administration include: (a) a compound or a composition containing it, such as a solution of an effective amount of a compound dissolved in a diluent such as water, saline, or juice (e.g., orange juice); (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient in solid or granular form; (c) powders; (d) suspensions in a suitable liquid; (e) concentrates or diluted microemulsions; (f) sprays; (g) inhalations. Liquid formulations may contain water and a diluent such as an alcohol, e.g., ethanol, benzyl alcohol, and polyethylene alcohol, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms may be of the ordinary hard or soft gelatin type, containing, for example, a surfactant, a lubricant, and an inert additive containing, for example, lactose, sucrose, calcium phosphate, and corn starch. Tablet forms may contain one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, coloring agents, diluents, buffering agents, disintegrants, wetting agents, preservatives, flavoring agents, and a pharmacologically compatible carrier. Lozenge forms may contain the active ingredient in a flavoring agent, usually sucrose and gum arabic or tragacanth gum, and, in addition to the active formulation, may contain an active formulation and a carrier known in the art in an inert base such as gelatin and glycerin, or sucrose and acacia.

[0073] Another aspect of the present disclosure is for the treatment of symptoms selected from pain-related disorders (as analgesics), inflammatory disorders and symptoms (as anti-inflammatories), apatite suppression or stimulation (as anorectic or appetite stimulants), vomiting or nausea (as antiemetics), intestinal disorders, anxiety-related disorders and symptoms (as anxiolytics), psychosis-related disorders and symptoms (as antipsychotics), seizures and / or spasm-related disorders and symptoms (as antiepileptics or antispasmodics), sleep disorders and symptoms (as hypnotics), disorders and symptoms requiring immunosuppressive treatment, disorders and symptoms associated with elevated blood glucose levels (as antidiabetic agents), disorders and symptoms associated with deterioration of the nervous system (as neuroprotective agents), inflammatory skin disorders and symptoms (such as psoriasis), disorders and symptoms associated with arterial occlusion (as anti-ischemic agents), disorders and symptoms associated with bacterial infections, disorders and symptoms associated with fungal infections, proliferative disorders and symptoms, disorders and symptoms associated with inhibition of bone growth, post-traumatic disorders, etc. The present disclosure provides a cannabinoid-added preparation or pharmaceutical composition.

[0074] A further aspect provides a method of treating a subject suffering from a condition selected from pain-related disorders, inflammatory disorders and symptoms, apatite suppression or stimulation, symptoms of vomiting and nausea, intestinal disorders, anxiety-related disorders and symptoms, psychosis-related disorders and symptoms, sleep disorders and symptoms, seizures and / or spasm-related disorders and symptoms, disorders and symptoms requiring immunosuppressive treatment, disorders and symptoms associated with elevated blood glucose levels, disorders and symptoms associated with deterioration of the nervous system, disorders and symptoms associated with arterial occlusion, disorders and symptoms associated with bacterial infections, disorders and symptoms associated with fungal infections, proliferative disorders and symptoms, and disorders and symptoms associated with inhibition of bone growth, post-traumatic disorders, etc. The method comprises administering to the subject an effective amount of the cannabinoid-added preparation or pharmaceutical composition of the present disclosure.

[0075] The formulations described herein can be used by themselves to elicit at least one effect, such as a therapeutic effect, or can be associated with at least one cannabinoid capable of eliciting, enhancing, preventing, or reducing at least one effect by treating or preventing an undesirable condition or disease in a subject. This at least one agent (substance, molecule, element, compound, entity, or combination thereof) can be selected from a therapeutic agent, i.e., an agent capable of eliciting or modulating a therapeutic effect when administered in a therapeutically effective amount, and a non-therapeutic agent, i.e., an agent that does not itself elicit or modulate a therapeutic effect but can impart selected desired properties to a pharmaceutical composition.

[0076] The pharmaceutical compositions of the present disclosure can be selected to treat, prevent, or ameliorate a medical condition or symptom. As used herein, the term "treatment," or linguistic variations thereof, means, whether in concentrated form or in diluted formulation, preventing the manifestation of such symptoms before they occur, retarding the progression of the disease, retarding the exacerbation of symptoms, promoting the onset of remission, retarding irreversible damage occurring in the progressive chronic phase, retarding the onset of the progressive stage, reducing the severity, or curing the disease, improving survival rate or more rapid recovery, or preventing the occurrence of the disease, or a combination of two or more of the above, by administering a therapeutically effective amount of the compositions or systems described herein.

[0077] As is known, the effective amount for the purposes described herein can be determined by considerations known in the art. This effective amount is usually determined in appropriately designed clinical trials (dose range trials), and the method for appropriately conducting such trials to determine the effective amount is obvious to those skilled in the art. As is generally known, this effective amount is determined by various factors including pharmacokinetic parameters such as the distribution profile in the body, half-life in the body, and, if any, undesirable side effects, age, gender, and others.

[0078] The term "subject" refers to a mammal, human, or non-human.

[0079] The terms "range" between a first and a second denoted number and "range" from a first denoted number to a second denoted number are used interchangeably herein and are meant to include the first and second denoted numbers and all decimal and integer digits therebetween. Where various embodiments are described using a given range, the range is so displayed merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges as well as individual numerical values within that range.

[0080] As used herein, the term "about" means including a ±10% deviation from the specifically stated value of a parameter such as temperature, pressure, concentration, etc. [Brief explanation of the drawings]

[0081] For a better understanding of the subject matter disclosed herein, and to illustrate how it may be carried out in practice, embodiments will now be described, by way of non-limiting example, with reference to the accompanying drawings, in which:

Figure 1

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DETAILED DESCRIPTION OF THE INVENTION

[0082] Formulations and Preparation Exemplary microemulsions described herein are provided in Tables 1-1 through 1-5. As described above, the formulations are self-assembled systems that form spontaneously. Thus, some of the compositions of the formulations were prepared by simply mixing the components at 25 to 70 °C. An exemplary method of preparing the formulations comprises mixing together an oil, a surfactant, and a co-surfactant (and, if applicable, a solvent, a co-solvent, and / or a phospholipid as well) until a homogeneous and clear (transparent) mixture is obtained. If the surfactant or the oil is solid at room temperature, it can be heated with mixing to dissolve completely and form an empty formulation.

[0083] The formulation is then slowly added to a cannabinoid source, such as a plant part or a pure cannabinoid, to properly wet it, and then mixed and / or homogenized. Another variation of this method comprises adding the cannabinoid source stepwise to an empty (unadded) formulation until a homogeneous slurry is obtained.

[0084] Solubilization was carried out under heating and / or an inert atmosphere, thereby solubilizing the desired cannabinoid, in this case CBD, in the formulation.

[0085] TIFF0007716071000001.tif87170

[0086] TIFF0007716071000002.tif84170

[0087] TIFF0007716071000003.tif77170

[0088] TIFF0007716071000004.tif56170

[0089] TIFF0007716071000005.tif104170

[0090] Features of CBD-added formulations The empty CBD-doped (1 wt%) 5CS system was characterized using several methods to elucidate the structural changes and the effect of CBD on the formulation. Conductivity, rheological measurements, differential scanning calorimetry, and dynamic light scattering were used to identify molecular-level phase transitions and changes within the system.

[0091] Dilutability The CBD-spiked 5CS system was diluted by mixing with up to 9% water, as shown in Figure 1. The system remained clear and was completely dilutable without phase separation.

[0092] Conductivity measurement The structural transition of the system as a result of dilution was followed by measuring the conductivity. To facilitate the measurement, the 5CS system was diluted with 0.01 M NaCl solution. Measurements were performed at room temperature (23 ± 2 °C) using a conductivity meter 730 (Metler Toledo GmbH, Switzerland) equipped with a 180 × 65 mm / 0.61 kg electrode (conductivity range 0.04 S / cm to 1000 mS / cm). The results are shown in Figure 2.

[0093] As shown in Figure 2 depicting the conductivity of the empty system and the CBD-added system with respect to water content, no significant effect is observed as a result of the solubilization of CBD. These results indicate that cannabinoids, in this case CBD, can be uniquely formulated to capture them at the interface of the formulation or in the oil core. Figure 2 also demonstrates that the incorporation of CBD into the system does not affect the stability, disruption, or physical changes of the system throughout the entire dilution process (ratio).

[0094] Furthermore, Figure 2 confirms that at low water content (about 20 wt% water), the system is W / O nano-droplets, which change to a bicontinuous phase (a sharp increase in conductivity) and convert to O / W droplets as a result of the dilution effect (a sharp decrease in conductivity).

[0095] Viscosity measurement Viscosity measurements as a function of dilution were performed at room temperature (25 ± 0.1 °C) using a Thermo Haake Rheo Scope 1 equipped with a C60 / °l cone and a glass plate (the distance between the cone and the plate during measurement was 0.022 mm). In each measurement, an increasing shear rate (from 0 to 100 s -1 ) was applied for 6 minutes.

[0096] As shown in Figure 3, when W / O nano-droplets are formed (up to about 20 wt% water), CBD is located at the outer interface close to the oil and does not interfere with the entanglement of the surfactant tails. Similarly, when the system converts to O / W nano-droplets, CBD does not affect the entanglement of the surfactant because most of the surfactant is in the oil core.

[0097] However, a significant difference in viscosity has been confirmed between the CBD-added system and the empty system between 30 and 50 wt% water. Without wishing to be bound by theory, in the bicontinuous region where the system is composed of interfaces that mostly weaken these interactions, CBD molecules interfere with the entanglement between the lipophilic tails of the surfactant, resulting in a lower viscosity compared to the empty (additive-free) formulation.

[0098] Differential scanning calorimetry (DSC) The melting / freezing temperature of water varies depending on the molecular environment of the water. Therefore, these temperature changes can be used to characterize the interactions of water molecules with other species in the system. To track these changes, subzero calorimetry was performed. Samples of 8-12 mg 5CS systems at different water dilutions, both unadded and with low wt% CBD, were cooled from 25°C to -100°C and then returned to 25°C at a rate of 5°C / min (using a Mettler Toledo DSC 822). Between cooling and heating, the samples were kept isothermally at -100°C for 20 minutes. All measurements were performed on an empty perforated pan as a reference. The melting temperatures and transition enthalpies for the various samples are shown in Table 3.

[0099] TIFF0007716071000006.tif54170

[0100] Above 30 wt% water, no endothermic peaks appeared. This means that the water is tightly bound and is found primarily in the core of the droplet. Above 30% water, the melting temperature and enthalpy increase as water is released from the droplet. At high water concentrations (i.e., highly dilute solutions), very little water remains. Nevertheless, it is clear from the ΔHm values that even at 90 wt% water, not all of the water is free, as the ΔHm for free water is approximately -280 J / g.

[0101] The thermal behavior of this system shows that at low water contents (0-40%), water binds to the surfactant and freezes at temperatures between -30 and -20°C. At higher water contents, the water scale becomes more free and freezes at temperatures approaching 0°C (greater than 60% water by weight). This means that above 60% water by weight, water is the continuous phase. At lower water contents (30-50%), water creates continuous domains along with the oil-continuous domains, creating a so-called bicontinuous mesophase. Beyond a dilution of 30% by weight, water becomes tightly bound to the polyethoxylated head groups of the surfactant. The primary difference between the empty and loaded systems reflects the mobility of water: when CBD is entrapped within the core, water attaches to the surfactant head groups, resulting in more free movement of water molecules.

[0102] Dynamic light scattering (DLS) The oil droplet size of the water-diluted formulations was determined by DLS measurements and analysis of the oil-in-water droplet diffusion coefficient. The results of the DLS measurements are shown in Table 4.

[0103] TIFF0007716071000007.tif39170

[0104] Typically, solubilization of guest molecules in a formulation causes droplets to swell, increasing their diameter. In the 5CS system, the effect of solubilization was not significant. This is due to the relatively low concentration of CBD in the microemulsion.

[0105] The diffusion coefficient of the system at different dilutions is correlated with the droplet size, with larger diameters resulting in slower droplet diffusion coefficients.

[0106] Self-diffusion NMR (SD-NMR) Self-diffusion NMR analysis was performed to determine the structure of the oil droplets (or micelles) of the formulation. SD-NMR can locate each component in the NSSL through measurement of its diffusion coefficient. Rapid diffusion (>100×10 -11 m 2 s -1) is characteristic of small molecules, dissociating in solution, but with slow diffusion coefficients (<0.1 × 10 -11 m 2 s -1 ) suggests low mobility of macromolecules or bound / aggregated molecules.

[0107] NMR measurements were performed on a Bruker AVII500 spectrometer equipped with a GREAT 1 / 10 gradient, a 5 mm BBO probe, and a 5 mm BBI probe, z-gradient coils, and maximum gradient strengths of 0.509 and 0.544 Tm. -1 Diffusion was measured using both asymmetric bipolar longitudinal eddy current delay (bpLED) experiments and / or asymmetric bipolar stimulated echo (known as one-shot) experiments with convection compensation and a 20% asymmetry factor, ramped in 32 steps from 2 to 95% of maximum intensity. The spectra were processed using Bruker TOPSPIN software. NMR spectra were recorded at 25 ± 0.2 °C. Components were identified by chemical shifts in 1H NMR.

[0108] Figures 4A and 4B show the diffusion coefficients (Dx) of the various components for the neat and 1 wt% formulations, respectively.

[0109] As described above, the formulations of the present disclosure consist of oil droplets that solubilize CBD, surrounded by surfactant and co-surfactant. When in concentrated form (i.e., in the absence of water), this system is arranged in an inverted micellar structure, and when mixed with a small amount of aqueous medium, hydrated and solvated surfactants are formed. Further dilution results in the formation of aqueous phase oil-in-water (O / W) nanodroplets that are confined in the oil core. If the diffusion coefficients of CBD and surfactant are similar (as measured in a microemulsion system), CBD will remain confined within the oil core throughout the structural change of the system (i.e., dilution-induced structural change). This is the result of interactions (physical complexation) between CBD and surfactant and / or co-surfactant, thereby stabilizing the formulation and preventing undesired release of CBD from the oil core. Release of CBD from the formulation occurs upon interaction of the droplets with target biological membranes after administration to a treated subject.

[0110] Figures 3A and 3B show that the mobility of all components is not significantly affected by the solubilization of CBD in the nanodroplets. While the chemical shift of CBD was not detectable by this NMR technique, the fact that no changes were measured in all other components indicates that CBD is completely solubilized throughout the dilution process. The mobility of the surfactant is very low, indicating that CBD interacts with the surfactant and is in close proximity to it at the interface.

[0111] Stability of plant-derived CBD formulations 5CS and In9(6) formulations (see Table 5-1) were spiked with 5% CBD by weight and incubated under different conditions (unprotected, with 600 ppm α-tocopherol acetate, and under nitrogen atmosphere) at three different temperatures (4, 25, and 40°C). Both concentrates and diluted microemulsions (80% water) were tested.

[0112] TIFF0007716071000008.tif84170

[0113] The visual appearance of the samples was recorded after 30 days of incubation, and the results are shown in Table 5-2.

[0114] TIFF0007716071000009.tif57170

[0115] As can be seen from the table, the CBD-spiked formulations were stable across a wide variety of conditions, with the majority of samples tested remaining clear without any signs of phase separation or precipitation.

[0116] Stability of pure CBD solubilized in AX-1 and 5CS formulations Crystalline CBD was solubilized to a concentration of 5% by weight in the AX-1 and 5CS formulations under various conditions: with the addition of 1000 ppm vitamin E acetate, under passive nitrogen diffusion, or without any special treatment. All samples were maintained at three different temperatures: 4°C, 25°C, and 40°C. Four samples of each formulation / treatment were retained for testing at four time points, including 0 (initial), 15, 30, and 60 days. All samples (2 mL) were retained in correspondingly labeled 4 mL vials. Some samples were passively purged with nitrogen. At designated sampling times, appropriate samples were examined for appearance and analyzed by HPLC to determine CBD concentration and the presence / absence of degradation products.

[0117] As can be seen in Figures 5A and 5B, respectively, no significant changes in CBD concentrations were detected in the AX1 and 5CS concentrates after 60 days at all storage temperatures.

[0118] Stability LumiFuge TM test To determine the long-term stability of the formulation, LUMiFuge TMRapid measurements were performed using analytical centrifugation. The LUMiFuge analysis can predict the shelf life of a formulation at its original concentration, even in the case of slow destabilization processes such as sedimentation, aggregation, complexation, and fractionation. During LUMiFuge measurements, the sample cell in the centrifugal force field is irradiated with parallel light; the transmitted light is detected by sensors arranged linearly along the entire length of the sample cell. Local changes in particles or droplets are detected by changes in light transmission over time. The results are presented as a graph plotting the percentage of transmitted light (% transmittance) against the local position (mm), and the corresponding transmittance profile becomes apparent over time. The concentrated form and the AX1 formulation with 85% water-diluted CBD were tested in comparison with the commercial product "PlusCBD Oil" from CS Science (the formulations were tested as received without further treatment).

[0119] Figures 6A through 6C show the change in sample transmittance as a function of time. As shown in the figures, in both AX-1 formulations (concentrated and diluted forms), the samples were stable throughout the entire analysis time and showed no change in transmittance (Figures 6A and 6B, respectively). The "Plus CBD" product already showed phase separation at the initial stage of the measurement (Figure 6C) and was accompanied by significant precipitation.

[0120] Therefore, CBD in oil formulations is not stable and is predicted to separate and fractionate over time, while the formulations of the present disclosure are stable even after centrifugation at 3000 rpm for 17 hours. These conditions assume storage for at least two years.

[0121] In vivo studies Retraction test The response to pain and anti-inflammatory activity of the CBD-added formulations of the present disclosure in mice were evaluated by oral administration of a 5CS formulation containing 5 wt% CBD, compared with CBD dispersed in olive oil.

[0122] Various doses of CBD were administered in the range of 5, 10, 25, and 50 mg / kg per dose. Paw withdrawal was evaluated by pricking the paws of mice at various added amounts, and the withdrawal reflex response was recorded. Figure 7 shows the paw withdrawal threshold in mice for the 5%-CBD 5CS formulation compared to CBD in olive oil. Figure 8 shows the paw thickness of the inflamed paw in mice for the 5%-CBD 5CS formulation compared to the CBD olive oil extract.

[0123] As seen in Figure 7, at all doses tested, mice administered the CBD-added formulation of the present disclosure showed higher tolerance to pain immediately after administration (2 and 24 hours), at least equivalent tolerance to pain, and at least comparable tolerance to pain compared to the tolerance in the oil sample at 6 hours after administration. This demonstrates the improved release, penetration, and performance of CBD in the system after administration.

[0124] Furthermore, as seen in Figure 8, mice administered the formulation of the present disclosure showed a more significant decrease in paw thickness at all doses tested compared to CBD in the same dose of olive oil. That is, the formulation of the present disclosure has improved anti-inflammatory activity compared to standard CBD in oil.

[0125] Delayed-type hypersensitivity (DTH) CBD has been shown to reduce the inflammatory response and the effect of pain due to the inflammatory response. Without wishing to be bound by theory, the reduction of inflammation is achieved by various mechanisms including the decrease in levels of inflammatory cytokines and chemokines such as IL-2, IL-4, TNF-α, MCP-1, and agonist and antagonist binding to CB1 receptors, adenosine receptors, and other GPCRs.

[0126] The therapeutic effect of oral administration of the CBD-added formulation of the present disclosure as an anti-inflammatory agent. The effect of CBD was evaluated using an inflammatory rat model - a delayed hypersensitivity (DHT) model. In this test, inflammation was induced and the reduction in ear swelling after treatment was measured.

[0127] The abdomen of male rats (average body weight 250 g) was shaved and challenged 10 times with 500 μl of 2% oxazolone (400 mg of oxazolone dissolved in 16 ml of acetone and 4 ml of mineral oil). The next day (referred to as day 1 in this specification), 500 μl of CBD formulation was orally administered by forced gavage. On day 6, the ear thickness of the rats was measured using calipers.

[0128] The rats were challenged with another dose of 50 μl of 0.5% oxazoline, and 2 hours after the challenge, a second oral treatment with 500 μl of the CBD formulation was performed. The ear thickness was measured again 12 and 24 hours after the challenge, and blood samples were collected for serum preparation.

[0129] Sample composition: Crystalline CBD in AX-1 was administered at doses of 24 mg / kgBW and 48 mg / KgBW (BW = body weight) compared to controls of naive rats and DTH-induced rats without any treatment.

[0130] As seen in Figures 9 and 10A through 10D, a significant decrease in ear thickness and inflammatory appearance (erythema and edema) as a result of treatment with crystalline CBD solubilized in AX-1 was obtained compared to DTH-induced rats that were not treated. The anti-inflammatory effect of crystalline CBD solubilized in AX-1 was more prominent than that seen for ethanol extraction using both dosing regimens. Naive rats did not show erythema or swelling, while DTH-induced rats without treatment showed inflammatory and swelling responses. Rats treated with AX-1 showed a relatively significant decrease in swelling and erythema of the treated rats.

[0131] Pharmacokinetic Profile - 1 The pharmacokinetics of the CBD profile in the blood of rats after oral administration were evaluated at various doses of 10, 25, 50 mg CBD / kg body weight compared to CBD dispersed in olive oil. As shown in Table 6, 60 male rats (SD) weighing 230 - 250 g were randomly assigned to the test groups. The test formulation was orally administered to the rats by forced gavage.

[0132] TIFF0007716071000010.tif88170

[0133] As seen in Figures 10A-10C, within 30 minutes of oral administration, CBD levels in the blood from formulations 5CS and In9(6) were up to 16-fold higher than those obtained from the oil dispersion. These results demonstrate very rapid absorption and high levels of penetration. After 4 hours, CBD absorption in oil reaches its maximum level (Tmax). It can also be seen that when CBD is dispersed in the required oil, a significantly higher dose is required to achieve the same blood levels, whereas the low CBD (10 mg / kg) formulations of the present disclosure achieve robust penetration.

[0134] Pharmacokinetic profile - 2 Additional formulation PK evaluations were performed for the formulations detailed in Tables 7-1 and 7-2.

[0135] TIFF0007716071000011.tif50170

[0136] TIFF0007716071000012.tif72170

[0137] A PK study in rats was conducted to measure the levels of CBD in the bloodstream after oral administration of 25 mg / kg body weight (BW) and compare AX1 to formulation AX-1(B). As seen in Figure 12A, the PK profiles of CBD showed similar kinetics for both formulations. Therefore, D-limonene and EtOH can be replaced with less bitter, pharmacologically acceptable ingredients to improve patient compliance.

[0138] Similarly, a PK study was conducted in rats to measure CBD levels in the bloodstream after oral administration of OR210SE or OR103(2) at 25 mg / kg BW compared with 5CS and AX-1.

[0139] As seen in Figure 12B, OR210SE shows a better PK profile and absorbs a much higher level of CBD into the bloodstream after oral administration compared to the AX-1 and 5CS (both administered in concentrated form) formulations. The Cmax after OR210SE administration was observed at a relatively high concentration at the 30-minute time point compared to AX-1 (approximately 900 ng / mL vs. 550 ng / mL, respectively). Formulation OR103(2) shows a more delayed absorption of CBD with a Cmax from 2 to 4 hours after administration. This formulation also shows a relatively high level of CBD reaching the bloodstream. Thus, OR103(2) and OR210SE are suitable for delayed-release formulations.

[0140] Stability of CBD in Stimulated Gastric Fluid (SGF) Since oral administration of CBD is known to show cases of side effects that may contribute to the degradation of CBD to THC when exposed to gastric fluid, the CBD stability when solubilized in AX(1) and 5CS was tested in a simulation of the gastric fluid environment.

[0141] Stock solutions of 3% CBD in MeOH, AX1, and 5CS were prepared. The medium for stimulated gastric fluid (SGF) was prepared by dissolving sodium chloride (0.2 w / v%) and hydrochloric acid (0.1 M) in DDW and incubated at 37 °C.

[0142] For the MeOH solution, sodium dodecyl sulfate (1 w / v%) was added to the SGF. 500 ml of the SGF medium was placed in an appropriate Erlenmeyer flask. 0 to 1 ml of each CBD stock solution was added to the SGF. The mixture was vigorously shaken in a water bath warmed to 37 °C, and immediately 1 ml of the solution was sampled and exchanged with an equal volume of pre-warmed SGF medium. Similarly, the same volume was sampled at 5, 10, 15, 20, 30, 45, 60, 75, 90, 120, 150, and 180 minutes. Each 1 mL sample was neutralized to pH 7 to 9 with 980 μL of 0.1 M sodium hydroxide and 3 ml of MeOH, and the pH level was tested. All samples were kept at 4 °C until HPLC analysis.

[0143] For the MeOH solution and AX1 system, additional samples were taken every 30 minutes and injected directly into the HPLC without further treatment. This was to evaluate that acclimation does not affect the observed profile. The measured CBD concentrations were divided by the initial concentration (C / Co) at each time point.

[0144] Figures 13A and 13B are graphs showing the change in CBD content over time in both neutralized and non-neutralized samples. CBD in MeOH as a suspension medium showed significant degradation over time. The degradation started very early and had already started after 5 minutes. 68% of the molecules were degraded within 30 minutes, and less than 4% of CBD remained after 2 hours. The degradation of CBD resulted in 7 peaks detected using HPLC-UV analysis. Four unknown peaks called "Unk" and 3 peaks were identified as Δ8-THC, Δ9-THC, and CBN. However, when CBD was added to both 5CS and AX1, no degradation was observed (C / Co remained at 1). The CBD level was stable and constant, and no degradation products were shown even 3 hours after measurement. Samples measured after neutralization or immediately after sampling showed similar results, indicating the accuracy of this method.

[0145] According to previous reports, in an acidic environment, CBD mainly degrades into THC and some additional minor related cannabinoids. HPLC analysis showed a total of 7 degradation products including Δ 9 -THC, Δ 8 -THC and CBN detected at different time points.

[0146] Figure 13C shows the tendency for the CBD peak area to decrease. At the same time, the peak areas of the related degradation products increase, and some of these products appear to be degraded within the time (compound "unk2"), while others start to rise at that point ("unk5" and "unk3").

[0147] From these results, it is expected that the administration of CBD in methanol would result in a very rapid conversion of CBD to THC due to the acidic environment, which could lead to undesirable psychoactive and harmful effects. In contrast, CBD solubilized in the 5CS and In9(6) systems is well protected against conversion to THC even after 180 minutes of exposure to acidic gastric juice.

[0148] As a comparison, the CBD profiles in SGF were evaluated using a commercial product (RSHO™ containing CBD dissolved in vegetable oil) and CBD dissolved in pure olive oil. The RSHO profile of degradation in SGF is shown in Figure 14A, and the CBD profile of degradation in olive oil in SGF is shown in Figure 14B.

[0149] In contrast to AX-1 and 5CS, where CBD remains stable when exposed to SGF for 180 minutes, CBD in commercial products or olive oil degrades relatively rapidly within 30 minutes after exposure. Thus, the formulations described herein provide a "protective shield" such that CBD is directly absorbed when orally administered into the bloodstream, rather than its degradation products such as THC or other cannabinoids.

[0150] Formulation Freeze-drying and resuspension As detailed below, the CBD-containing formulations 5CS and AX-1 were formulated for lyophilization.

[0151] Concentrated samples of 2.5 wt% CBD-added AX1 and 5 wt% CBD-added 5CS formulations were diluted (10-fold) with the following solutions. Dextrin (10 - 20 w / v%) Lactose (10 - 20 w / v%) Mannitol (10 - 20 w / v%) Maltodextrin (10 - 20 w / v%) Erythritol (10 - 30 w / v%) Sorbitol (20 - 70 w / v%)

[0152] The diluted sample was frozen in liquid nitrogen and lyophilized for at least 24 hours. After lyophilization, a powder of solid particles was obtained (Figure 15A).

[0153] Next, the CBD-added particles were redispersed in water (10 to 90% WT) to obtain a reconstituted microemulsion (Figure 15B). This formulation had completely regained its original clear and homogeneous appearance, and no phase separation or precipitation of CBD was observed.

[0154] To determine whether the nano-sized droplets retained their structure and size, the reconstituted powder of 5CS diluted with mannitol was measured for droplet size using a DLS instrument as shown in Table 8.

[0155] TIFF0007716071000013.tif41170

[0156] Similar droplet sizes were observed before lyophilization (original formulation) and after reconstitution at different water ratios.

[0157] The lyophilized powder was introduced into capsules (TROPAC CAPSULES) customized to its size for oral administration to rats. After oral administration, CBD in the bloodstream was evaluated compared to the concentrated formulation at the same dose of 10 mg / kgBW. The PK profiles of the lyophilized powder and the liquid concentrated formulation were similar as shown in Figure 16A and did not show the effect of the lyophilized 5CS as predicted by the DLS results.

[0158] Furthermore, the lyophilized powder and its reconstituted sample showed similar kinetic profiles and CBD amounts reaching the bloodstream (Figure 16B). This result indicates that the hydration of this powder has no effect on the performance and / or bioavailability of CBD.

[0159] Since lyophilization and reconstitution did not interfere with the properties of the formulation, it is possible to administer the formulation in powder or liquid form according to the preferences of the end-user / patient.

[0160] Co-solubility with other active ingredients Docohexanoic acid (DHA): DHA is an omega-3 fatty acid that occurs naturally throughout the body, most abundant in the cerebral cortex, retina, and heart. DHA is therefore essential for brain growth and functional development and has been shown to improve learning ability, cognitive behavior, and depression. Decreased DHA consumption has been associated with cognitive decline during aging and the development of sporadic Alzheimer's disease.

[0161] Additionally, DHA helps reduce blood triglycerides, reduces blood clots, and prevents cardiac arrhythmias. Epidemiological studies have shown a strong correlation between consumption of fish with high concentrations of DHA and a reduction in sudden death from myocardial infarction.

[0162] The opposite effects of DHA have also been observed and studied in inflammation, particularly in rheumatoid arthritis (RA) and asthma. DHA has favorable effects on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes, myocardial infarction, thrombosis, and some cancers.

[0163] DHA can be obtained from our diet, primarily from fish oils and algae, but because its bioavailability is very limited, it should be consumed at a high level and intensity to reach sufficient levels in the body.

[0164] Solubilizing CBD and DHA is not easy. Using the 5CS and AX-1 formulations, a relatively high concentration of both CBD and DHA (50 mg / mL CBD and 50 mg / mL or more DHA) can be achieved in a 1:1 ratio, resulting in a clear, stable formulation containing nano-sized droplets. This system "carries" a very large amount of the total active molecule while remaining fully dilutable. This system can solubilize the desired CBD:DHA ratio. This dual-molecule system may provide multifunctional therapeutic effects. Furthermore, the DHA added to the composition is a polyunsaturated long-chain fatty acid and may act as a bioavailability enhancer, improving CBD delivery.

[0165] Curcumin: Curcumin is a small molecule and a prototype "curcuminoid" with effects similar to other polyphenols. It is known as a very powerful anti-inflammatory and anti-cancer molecule. It has also been shown as a molecule that reduces cognitive decline associated with aging, reduces the levels of lipids and plaques in arteries, and supports the reduction of the risk of diabetes. However, its oral bioavailability is very poor. Combining both CBD and curcumin increases the anti-inflammatory effect and brings about an additional dual beneficial therapeutic effect. Both curcumin and CBD are successfully co-solubilized in the 5CS formulation at a concentration of 60 mg / mL of CBD and 50 mg / mL of curcumin, and solubilized in the AX-1 formulation at a concentration of 50 mg / mL of CBD and 15 mg / mL of curcumin. The resulting formulations are transparent and contain both active molecules, showing an orange appearance (curcumin coloring effect), and showing no phase separation or precipitation.

[0166] Seasonings The 2.5% CBD-added formulation was tested for the possibility of adding flavoring agents such as mint, lemon tea, tropical, citrus, cranberry-pomegranate, etc. The diluted formulation was clear and stable after preparation.

[0167] Furthermore, the AX1 sample was prepared using monk fruit (Siraitia grosvenorii) powder and monk fruit juice and flavoring agents (oil-based and water-based). Both the monk fruit powder and the monk fruit juice were compatible with the AX1 concentrate. In the case of flavors, the addition of oil-based flavors kept the sample clear and stable, and in contrast, resulted in phase separation compared to water-based flavors.

[0168] For 5CS, samples were prepared using monk fruit powder and monk fruit juice and fragrances (oil-based and water-based). Only the monk fruit powder resulted in a stable system, but additional PG was added (10% of the final product) to completely dissolve the powder. Both water-based and oil-based flavors were compatible.

[0169] Thus, the addition of flavorings and other additives does not adversely affect the formulation and can mask the bitter taste in both diluted and concentrated forms.

[0170] Encapsulation in soft gel capsules To allow for an alternative form of oral administration, the 5CS formulation was encapsulated in soft gel capsules. The soft gels were found to remain intact after extended storage with no evidence of leakage or damage to the coating, and no weight loss or moisture occurred within the bottle.

Claims

1. A cannabinoid - added pharmaceutical or dietary supplement in micro - emulsion form, free of water, comprising: At least one oil selected from the group consisting of mineral oil, paraffin oil, vegetable oil, glyceride, fatty acid ester, liquid hydrocarbon, and mixtures thereof, in an amount of about 0.5 to 20% by weight; At least one hydrophilic surfactant present in the formulation in an amount of about 30 to 85% by weight, selected from polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, and polyoxyethylene esters of saturated and unsaturated castor oils, ethoxylated monoglycerol esters, ethoxylated fatty acids, and ethoxylated fatty acids of short - chain, medium - chain, and long - chain fatty acids; At least one co - surfactant present in the formulation in an amount of about 1 to 50% by weight, which is propylene glycol, and containing at least 0.1% by weight of at least one cannabinoid, said cannabinoid being cannabigerolic acid (CBGA), cannabigerolic acid monomethyl ether (CBGAM), cannabigerol (CBG), cannabigerol monomethyl ether (CBGM), cannabigerovalinic acid (CBGVA), cannabigerovaline (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevalinic acid (CBCVA), cannabichromevaline (CBCV), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethyl ether (CBDM), cannabidiol-C ４ (CBD-C ４ ), cannabidiovalinic acid (CBDVA), cannabidiocol (CBD-C １ ), delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinol (THC), delta-9-tetrahydrocannabinolic acid-C ４ (THCA-C ４ ), delta-9-tetrahydrocannabinol-C ４ (THCA-C ４ ), delta-9-tetrahydrocannabivarinic acid (THCVA), delta-9-tetrahydrocannabivarin (THCV), delta-9-tetrahydrocannabiolic acid (THCA-C １ ), delta-9-tetrahydrocannabiocol (THC-C １ ), delta-7-cis-iso-tetrahydrocannabivarin, delta-8-tetrahydrocannabinolic acid A (Δ ８ -THCA), delta-8-tetrahydrocannabinol (Δ ８ -THC), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovaline (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEA-B), cannabielso (CBE), cannabinolic acid (CBNA), cannabinol (CBN), cannabinol methyl ether (CBNM), cannabinol-C ４ (CBN-C ４ ), cannabvarin (CBV), cannabinol-C ２ (CBN-C ２ ), cannabinol (CBN-C １ ), cannabinodiol (CBND), cannabinodivarine (CBVD), cannabinotriol (CBT), 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol, 8,9-dihydroxy-delta-6a-tetrahydrocannabinol, cannabinotriol valine (CBTV), ethoxy-cannabinotriol valine (CBTVE), dehydrocannabifuran (DCBF), cannabifuran (CBF), cannabinochromanon (CBCN), cannabicitran (CBT), 10-oxo-delta-6a-tetrahydrocannabinol (OTH), delta-9-cis-tetrahydrocannabinol (cis-THC), 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol (OH-iso-HHCV), cannabiripsol (CBR), trihydroxy-delta-9-tetrahydroxycannabinol (triOH-THC), or at least one thereof, characterized in that it is a pharmaceutical or nutritional supplement preparation with added cannabinoids.

2. The cannabinoid - added pharmaceutical or dietary supplement according to claim 1, wherein the cannabinoid is CBD, CBD - A, THC, or a mixture thereof.

3. The cannabinoid - added pharmaceutical or dietary supplement according to claim 1, wherein the at least one oil is selected from medium - chain triglycerides (MCT), olive oil, soybean oil, canola oil, cottonseed oil, palm olein, sunflower oil, corn oil, rapeseed oil, grapeseed oil, hemp oil, pomegranate oil, avocado oil, peppermint oil, tomato oil, isopropyl myristate, oleyl lactate, coco - caprylic / capric acid, hexyl laurate, oleyl amine, oleic acid, oleyl alcohol, linoleic acid, linoleyl alcohol, ethyl oleate, hexane, heptane, nonane, decane, dodecane, D - limonene, neem oil, lavender oil, peppermint oil, anise oil, rosemary oil, sage oil, hibiscus oil, berry oil (all kinds), menthol, capsaicin, grapeseed oil, pumpkin oil, hemp oil, and similar essential oils or triglycerides or fatty acid esters, and mixtures thereof.

4. In the cannabinoid-added pharmaceutical or nutritional supplement according to any one of claims 1 to 3, the ratio of the hydrophilic surfactant to the co-surfactant is about 1:1 to 6:1 (wt / wt), and the cannabinoid-added pharmaceutical or nutritional supplement is characterized thereby.

5. In the cannabinoid-added pharmaceutical or nutritional supplement according to any one of claims 1 to 4, (a) at least one solvent selected from ethanol, propanol, isopropyl alcohol, acetic acid, propionic acid, fumaric acid, tartaric acid, lactic acid, maleic acid, malic acid, and mixtures thereof, and the at least one solvent is present in the formulation in an amount of about 0.1 to 25% by weight; and / or (b) at least one phospholipid present in the formulation in an amount of about 1 to 10% by weight The cannabinoid-added pharmaceutical or nutritional supplement is further characterized by comprising.

6. In the cannabinoid-added pharmaceutical or nutritional supplement according to any one of claims 1 to 5, the cannabinoid-added pharmaceutical or nutritional supplement is characterized by containing about 0.1 to 12% by weight of the cannabinoid.

7. In the cannabinoid-added pharmaceutical or nutritional supplement according to any one of claims 1 to 6, the oil droplet size is about 5 to about 30 nanometers, and / or the cannabinoid is incorporated in the oil, and the cannabinoid-added pharmaceutical or nutritional supplement is characterized thereby.

8. A method for preparing a cannabinoid-added pharmaceutical or nutritional supplement according to any one of claims 1 to 7, the method comprising a cannabinoid source, at least one oil selected from mineral oil, paraffin oil, vegetable oil, glyceride, fatty acid ester, liquid hydrocarbon, and mixtures thereof, in an amount of about 0.5 to 20% by weight, at least one hydrophilic surfactant selected from polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monooleate, and polyoxyethylene esters of saturated and unsaturated castor oil, ethoxylated monoglycerol esters, ethoxylated fatty acids, and ethoxylated fatty acids of short-chain, medium-chain, and long-chain fatty acids, present in the formulation in an amount of about 30 to 85% by weight, and At least one co-surfactant present in the formulation in an amount of about 1 to 50% by weight and which is propylene glycol Comprising mixing with a water-free formulation in the form of a microemulsion, thereby obtaining a cannabinoid-added formulation that is water-free and in the form of a microemulsion, wherein the cannabinoid source is selected from pure cannabinoids, crystalline forms of cannabinoids, and cannabinoid extracts from plant sources. A method characterized by that.

9. The method according to claim 8, wherein the mixing is carried out for about 2 to 30 minutes and / or at a temperature of about 15 to 60 °C. A method characterized by that.

10. A composition comprising a cannabinoid-added pharmaceutical or nutritional supplement formulation according to any one of claims 1 to 7, wherein the composition is a pharmaceutical composition or a nutritional supplement composition, and the composition optionally further comprises a pharmaceutically acceptable carrier and / or diluent. A composition characterized by that.

11. The composition according to claim 10, wherein the composition is in a form selected from gels, lotions, oils, soaps, sprays, emulsions, creams, ointments, capsules, soft gel capsules, patches, or solutions, and optionally the composition is configured to deliver the cannabinoid locally, orally, by inhalation, nasally, transdermally, intravitreally, or parenterally to the circulation system of a subject. A composition characterized by that.

12. In the cannabinoid-added pharmaceutical or nutritional supplement formulation according to any one of claims 1 to 7, the formulation is for use in the treatment of conditions selected from pain-related disorders, inflammatory disorders and symptoms, anxiety-related disorders and symptoms, psychiatric-related disorders and symptoms, disorders and symptoms related to seizures and / or spasms, sleep disorders and symptoms, and post-traumatic disorders. A cannabinoid-added pharmaceutical or nutritional supplement formulation characterized by that.

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