Highly-loaded cannabinoid formulations

Abstract

The present disclosure provides cannabinoid formulations, more particularly pharmaceutical formulations which are highly-loaded with cannabinoids. The formulations are suitable for self-emulsifying into emulsions that are characterized by a stable mono-modal narrow droplet size distribution, and suitable for administration to subjects in need of cannabinoids administration for treatment of various conditions.

Description

[0001] Highly-loaded cannabinoid formulations

[0002] TECHNOLOGICAL FIELD

[0003] The present disclosure provides cannabinoid formulations, more particularly pharmaceutical formulations which are highly-loaded with cannabinoids.

[0004] BACKGROUND ART

[0005] References considered to be relevant as background to the presently disclosed subject matter are listed below:

[0006] [1] PCT patent application publication no. WO 2008 / 058366

[0007] [2] PCT patent application publication no. WO 2003 / 105607

[0008] [3] PCT patent application publication no. WO 2018 / 061007

[0009] [4] US patent application publication no. US2022370531

[0010] [5] PCT patent application publication no. W02020132181

[0011] [6] US patent application publication no. US2021212946

[0012] [7] Tran et al., Journal of Pharmaceutical Investigation 2021, 51, 349-463

[0013] Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

[0014] BACKGROUND

[0015] Cannabinoids have been used for many years for treatment of various medical and psychological indications.

[0016] The cannabis plant contains various cannabinoids, which is a family that includes many active compounds found mainly in the resin-producing pistillate inflorescences of cannabis plants. Although a variety of cannabinoid compounds have been identified in literature thus far, several defined compounds have been the focus of interest for medicinal uses, including cannabidiol (CBD) and tetrahydrocannabinol (THC). While THC is a psychoactive compound with adverse long-lasting effects on the user, CBD is not identified as a psychotropic agent and is considered safe for consumption in various routes of administration.

[0017] Until recently cannabinoids were administered as products derived from a natural source, i.e. administered as extracts, cannabis oil, cannabinoids dispersed in oil, or as dried vegetative product for smoking, however such administration forms do not provide the ability to carefully control the cannabinoid dose and / or composition administered. The cannabinoids’ composition and content can vary significantly between one vegetative source to another, making it nearly impossible to control the actual administrated dose.

[0018] In order to mitigate these problems, various pharmaceutical preparations have been developed, into which isolated or extracted cannabinoids, or combinations of cannabinoids, have been formulated. Still, even when formulating cannabinoids into various pharmaceutical dosage forms, it was found that it is difficult to provide physical and / or chemical stability of the cannabinoids in the administration form. Thus, such formulations do not typically provide sufficient bioavailability, a controlled index of absorption variability, consistency of absorption, and other parameters which significantly impact the efficacy of the administered formulation.

[0019] GENERAL DESCRIPTION

[0020] The present disclosure provides formulations, typically pharmaceutical and / or nutraceutical formulations, that contain high concentrations of cannabinoids, and are tailored for self-emulsification when mixed with aqueous liquids.

[0021] While most known formulations that contain cannabinoids, which are compounds having a lipophilic nature, contain relatively high concentrations of oil or oily components in order to solubilize or dissolve high amounts of cannabinoids into the formulation, the presently disclosed formulations do not contain oils. The present inventors have surprisingly found that in unique combinations of hydrophilic surfactants, lipophilic surfactants and phospholipids, at defined concentration range and weight ratios, some cannabinoids, e.g. CBD, participate in the structural formation of the emulsions, and thus can function as “structure builders”. In other words, the inventors have found that in unique combinations of hydrophilic and lipophilic surfactants, phospholipids and high concentrations of cannabinoids, these components form together a uniform droplets structure, having high stability, unlike classic emulsion in which the cannabinoids are merely solubilized into an oily core. This permits stable loading of high concentrations of cannabinoids into the formulations, with full solubilization of the cannabinoids when in the concentrate (i.e. substantially water-free) form, on the one hand - and on the other hand, instead of being merely solubilized into the formulation when in the emulsion form, the cannabinoid molecules constitute a structural part of the physical structure of the emulsion’s droplets, to both increase the emulsion’s cannabinoid load capability and stabilize the emulsion’s structure.

[0022] Thus, the formulations of this disclosure are tailored to self-emulsify into stable emulsions when mixed with an aqueous liquid (e.g. for administration, or when diluted in stomach fluids after administration), while carrying a relatively high concentration of cannabinoids, with the resulting emulsion having substantially mono-modal droplet size and narrow size distribution, utilizing the cannabinoid as a structure stabilizer.

[0023] Without wishing to be bound by theory, such stability and uniformity in droplet size provides improved control over the release of the cannabinoids from the formulation after administration. Thus, administration of formulations of the present disclosure permit administration of higher doses of cannabinoids, with improved bioavailability, more consistent absorption and significantly lower user-dependent absorption variability.

[0024] As noted, the pharmaceutical formulations of this disclosure are tailored to provide, once mixed with an aqueous liquid, a stable, mono-modal emulsion. The term mono-modal (or mono-modal droplet size distribution) refers to droplet size distribution having only a single size population, i.e. a distribution that has a singular narrow maximum. Thus, mono-modal emulsion as used herein denotes emulsions having a droplet size distribution that is characterized by a single (one) narrow size population.

[0025] By one of its aspects, the disclosure provides a formulation for administration of at least one cannabinoid to a subject in need thereof, the formulation comprising: at least about 10 wt% of at least one cannabinoid, at least one hydrophilic surfactant; at least one lipophilic surfactant selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids, and mixtures thereof; at least one phospholipid; and no more than 1 wt% water; the formulation being in liquid form and forming an emulsion when mixed with an aqueous liquid, the emulsion having a mono-modal droplet size distribution.

[0026] As used herein, the term cannabinoid refers to therapeutically active compounds which are found in plants of the genus Cannabis (e.g. Cannabis sativa or Cannabis indica). The term includes compounds which are obtained and / or isolated from natural sources (e.g. plants), as well as compounds obtained synthetically. The term also encompasses derivative compounds which are the product of chemical modification to a naturally occurring cannabinoid, so long as the product retains its therapeutic activity. The cannabinoid can be a substantially pure cannabinoid (e.g. pure CBD), a cannabinoid in crystalline form, a cannabinoid isolated from a natural source (e.g. extracted or purified from cannabis plant or part thereof), a synthetic cannabinoid (e.g. synthesized by one or more chemical reactions), a cannabinoid extract (e.g. extract obtained by known extraction methods), and mixtures thereof.

[0027] Exemplary cannabinoids for use in the present disclosure include, but are not limited to, cannabigerolic acid (CBGA), cannabigerolic acid monomethylether (CBGAM), cannabigerol (CBG), cannabigerol monomethylether (CBGM), cannabigerovarinic acid (CBGVA), cannabigerovarin (CBGV), cannabichromenic acid (CBCA), cannabichromene (CBC), cannabichromevarinic acid (CBCVA), cannabichromevarin (CBCV), cannabidiolic acid (CBDA), cannabidiol (CBD), cannabidiol monomethylether (CBDM), cannabidiol-C4 (CBD-C4), cannabidivarinic acid (CBDVA), cannabidiorcol (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-tetrahydrocannabiorcolic acid (THCA-C1), delta-9-tetrahydrocannabiorcol (THC-C1), delta-7-cis- isotetrahydrocannabivarin, delta-8-tetrahydrocannabinolic acid A (A8-THCA), delta-8- tetrahydrocannabinol (A8-THC), cannabicyclolic acid (CBLA), cannabicyclol (CBL), cannabicyclovarin (CBLV), cannabielsoic acid A (CBEA-A), cannabielsoic acid B (CBEAB), cannabielsoin (CBE), cannabinolic acid (CBNA), cannabinol (CBN), cannabinol methylether (CBNM), cannabinol-C4 (CBN-C4), cannabivarin (CBV), cannabinol-C2 (CBNC2), cannabiorcol (CBN-C1), cannabinodiol (CBND), cannabinodivarin (CBVD), cannabitriol (CBT), 10-ethoxy-9-hydroxy-delta-6a- tetrahydrocannabinol, 8,9-dihydroxy-delta-6a-tetrahydrocannabinol, cannabitriolvarin (CBTV), ethoxy-cannabitriolvarin (CBTVE), dehydrocannabifuran (DCBF), cannabifuran (CBF), cannabichromanon (CBCN), cannabicitran (CBT), 10-oxo-delta-6a- tetrahydrocannabinol (OTHC), delta-9-cistetrahydrocannabinol (cis-THC), 3, 4,5,6- tetrahtdro-7-hydroxy-a-a-2-trimethyl-9-n-propyl-2,6-methano-2H-l-benzoxocin-5- methanol (OH-iso-HHCV), cannabiripsol (CBR), trihydroxy-delta-9- tetrahydroxycannabinol (triOH-THC), cannabidiol hydroxyquinone (CBDHQ), and any combination thereof.

[0028] In some embodiments, at least one of the cannabinoids is a non-psychoactive cannabinoid. In some embodiments, the at least one cannabinoid is selected from cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabidivarin (CBDV), cannabinol (CBN), or derivatives thereof, and mixtures thereof.

[0029] In some embodiments, the at least one cannabinoid is CBD or a CBD derivative. As used herein, the terms cannabidiol or CBD refer to a non-psychoactive cannabinoid of the same name, having a chemical formula C21H30O2 and an IUPAC name 2-(lR,6R)- 3-methyl-6-prop-l-en-2-ylcyclohex-2-en-l-yl-5-pentylbenzene-l,3-diol. The term also encompasses derivative compounds which are the product of chemical modification to a naturally occurring cannabidiol, so long as the product retains its therapeutic activity.

[0030] In some embodiments, the pharmaceutical formulation comprises no more than 1 wt% tetrahydrocannabinol (THC). In some embodiments, the pharmaceutical formulation comprises less than 0.01 wt% tetrahydrocannabinol (THC). In some embodiments, the pharmaceutical formulation is devoid of THC.

[0031] In some cases, the cannabinoid (e.g. CBD) is a natural cannabinoid, namely one isolated from a cannabinoid-producing plant.

[0032] In some embodiments, the cannabinoid is extracted from a cannabinoid- containing plant or plant part. In some embodiments, the cannabinoid is extracted from a plant of the Cannabis genus. In some embodiments, the cannabinoid is extracted from a Cannabis sativa (hemp) plant.

[0033] In some embodiments, the cannabinoid is a synthetic cannabinoid. In some embodiments, the cannabinoid is a synthetic cannabinoid obtained via chemical synthesis or modification techniques. By some embodiments, the formulation comprises between about 10 wt% and about 25 wt% of said at least one cannabinoid.

[0034] According to other embodiments, the formulation comprises between about 15 wt% and about 22 wt% of said at least one cannabinoid.

[0035] According to some embodiments, the formulation comprises about 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, 20 wt%, 21 wt%, or 22 wt% of said at least one cannabinoid, e.g. CBD.

[0036] As noted, the formulation comprises a combination of hydrophilic surfactants and lipophilic surfactants.

[0037] A surfactant is a molecule having two portions, a lipophilic portion (typically a non-polar lipophilic tail) and a hydrophilic portion (typically a polar or ionic head portion); the specific combination of lipophilic and hydrophilic portions determines the hydrophilicity / lipophilicity of the surfactant.

[0038] As used herein, the term hydrophilic surfactant refers to ionic or non-ionic surfactants having a hydrophilic nature, i.e. a surfactant having an affinity for water. Typically, the hydrophilic surfactant has an HLB value of above about 11.

[0039] The term lipophilic surfactant refers to ionic or non-ionic surfactants having a lipophilic nature, i. e. a surfactant having an affinity for oil or fatty components . Typically, the lipophilic surfactant has an HLB value of less than about 9.

[0040] The term HLB value, or hydrophilic -lipophilic balance, is a value that defines the degree of hydrophilicity or lipophilicity of a surfactant, this value being determined by calculating the proportion of the molecular weight of the hydrophilic portion of the surfactant’s molecule out of the entire molecular weight of the molecule. Typically, the HLB value is calculated according to the following formula: where MWh is the molecular weight (g / mol) of the hydrophilic portion of the molecule, and MW is the molecular weight (g / mol) of the entire molecule. Thus, the HLB value defines a scale of values of 1 to 20, the higher the HLB value the more hydrophilic the surfactant, while the lower the HLB value the more lipophilic the surfactant.

[0041] Exemplary hydrophilic surfactants are polysorbates (polyoxyethylene sorbitan fatty acid esters), polyoxyethylene esters of saturated castor oil, polyoxyethylene esters of unsaturated castor oil, ethoxylated castor oil, hydrogenated ethoxylated castor oil, pegylated-hydrogenated castor oil, ethoxylated monoglycerol esters, ethoxylated fatty acids, ethoxylated fatty alcohols, polyoxylglycerides, and others.

[0042] According to some embodiments, the at least one hydrophilic surfactant is selected from caprylocaproyl polyoxyl-8 glycerides (PEG-8 caprylic / capric glycerides), ethoxylated castor oil, ethoxylated sorbitan monolaurate, ethoxylated sorbitan monostearate / palmitate, ethoxylated sorbitan monooleate / linoleate, ethoxylated sorbitan trioleate, hydrogenated ethoxylated castor oil, pegylated-hydrogenated castor oil, ethoxylated monoglyceride stearate / plamitate, Solutol® HS15 (polyethylene glycol (15)- hydroxystearate), oleoyl macrogolglycerides, ethoxylated hydroxy stearate, polyglycerol esters such as decaglycerol monolaurate, decaglycerol monooleate, hexaglycerol monooleate and hexaglycerol monolaurate, sucrose monooleate, sucrose monolaurate, and mixtures thereof.

[0043] In some embodiments, the at least one hydrophilic surfactant is selected from caprylocaproyl polyoxyl-8 glycerides (PEG-8 caprylic / capric glycerides), ethoxylated castor oil, hydrogenated ethoxylated castor oil, pegylated-hydrogenated castor oil, and mixtures thereof.

[0044] According to some embodiments, the formulation comprises a total amount of hydrophilic surfactants of between about 30 wt% and about 70 wt% of the formulation. By some other embodiments, the formulation comprises a total amount of hydrophilic surfactants of between about 40 wt% and about 60 wt% of the formulation, e.g. a total amount of hydrophilic surfactants of between about 45 wt% and 60 wt%.

[0045] By some embodiments, the lipophilic surfactants are selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids (C12 and longer), and mixtures thereof.

[0046] By some embodiments, the at least one lipophilic surfactant is selected from glyceryl monolinoleate (Maisine® cc), propylene glycol monolaurate (lauroglycol), and mixtures thereof.

[0047] According to preferred embodiments, the at least one lipophilic surfactant is a mixture of glyceryl monolinoleate and propylene glycol monolaurate.

[0048] According to some embodiments, the formulation comprises a total amount of lipophilic surfactants of between about 15 wt% and about 30 wt% of the formulation. By some other embodiments, the formulation comprises a total amount of lipophilic surfactants of between about 18 wt% and about 25 wt% of the formulation. By some embodiments, the weight ratio (weight-to-weight) between the total of hydrophilic surfactants and the total of lipophilic surfactants is between about 3 : 1 and about 1:3. In some embodiments, the weight ratio between the total of hydrophilic surfactants and the total of lipophilic surfactants is between about 3: 1 and about 1: 1.

[0049] As further noted, the formulation comprises at least one phospholipid. Phospholipids are lipidic molecules that comprise at least one phosphate group. Typically, a phospholipid has two lipid tails derived from fatty acids, joined by an alcohol residue (for example a glycerol moiety) and a phosphate group. Hence, in the presently disclosed formulations, the phospholipids function as auxiliary surfactants in structuring of the droplets, once the formulation is mixed with an aqueous liquid to form an emulsion.

[0050] According to some embodiments, the phospholipid is selected from phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine, and mixtures thereof.

[0051] In some embodiments, the phospholipid is phosphatidylcholine.

[0052] By some embodiments, the formulation comprises a total amount of phospholipids of between about 0.5 wt% and about 5 wt% of the formulation.

[0053] In some embodiments, the weight ratio between the total hydrophilic surfactants and the phospholipids ranges between about 15: 1 and about 20: l, e.g. between about 15: 1 and 18: 1.

[0054] In some embodiments, the weight ratio between the total lipophilic surfactants and the phospholipids ranges between about 5: 1 and about 10: 1, e.g. between about 6: 1 and 8: 1.

[0055] As noted above, unlike classic emulsions, the formulations of this disclosure are designed to self-emulsify into emulsions that contain high concentrations of lipophilic cannabinoids without requiring a high concentration of an oil or an oily component (i.e. a nonpolar chemical substance that is composed primarily of hydrocarbons) in order to solubilize the cannabinoid into the formulation. In the present formulations, the combination of hydrophilic surfactants, lipophilic surfactants, and phospholipids permits solubilization of the cannabinoid in the interface of the droplet when mixed with an aqueous phase, and hence do not require oil for obtaining stable cannabinoid solubilization.

[0056] Thus, in some embodiments, the formulations are devoid of oil. The formulations are in concentrate form, that is suitable for mixing with an aqueous liquid in order to form an emulsion. Hence, the formulations are substantially water-free, namely containing less than about 1 wt% of water, e.g. less than 0.5 wt% of water. By some embodiments, the formulation is devoid of water.

[0057] Due to their water-free form, the formulations stably solubilize the high loads of cannabinoids to form a stable concentrate over a prolonged period of time, without providing a microorganisms-supporting environment. Thus, the formulation can have a long shelf-life, without microorganisms’ contamination and with thermodynamic and kinetic stability, in spite of the high concentrations of cannabinoids in the formulation.

[0058] By some embodiments, the formulation is clear (transparent) in the visible spectrum - namely the cannabinoid is fully solubilized in the formulation and no phase separation or cannabinoid exudation is visible.

[0059] According to some embodiments, the formulation can further comprise at least one co-surfactant. The term co-surfactant should be understood to encompass any agent, different from the hydrophilic or lipophilic surfactants, which, when the formulation is mixed with an aqueous liquid, is capable (together with the surfactants) of lowering the interfacial tension between the formulation phase and an aqueous phase to almost zero (or zero) allowing for the formation of a homogeneous emulsion.

[0060] According to some embodiments, the co-surfactant is selected from polyols, polyoxyethylenes, and others; for example ethylene glycol, glycerol, polyethylene glycol, propylene glycol, sorbitol, mannitol, lactitol, xylitol and others.

[0061] In some embodiments, the formulation comprises a total amount of co-surfactants of between about 5 wt% and about 15 wt%, e.g. between about 7 wt% and about 11 wt%.

[0062] In some embodiments, the weight ratio of total lipophilic surfactants to cosurfactants range s between about 1 : 1 and about 4 : 1 , e. g. between about 2 : 1 and 3: 1.

[0063] In some embodiments, the formulation may additionally comprise at least one additive, selected from antioxidants (tocopherols), preservatives, membrane-piercing agents, transmembrane penetrating enhancers (such as transcutol, isosorbide, oleic acid, propylene glycol, maltodextrines, cyclodextrines, etc.), oil / water soluble vitamins, beta hydroxy carboxylic acid (BHA), butylated hydroxytoluene (BHT), tertiary butylhydroquinone (TBHQ), propylate, and others. In some embodiments, the formulation may be adapted for lyophilization, i. e. by adding at least one sugar to the formulation, e.g. dextrin, lactose, mannitol, maltodextrin, erythritol, sorbitol, or any other suitable lyophilization additive.

[0064] By another one of its aspects, the disclosure provides a pharmaceutical formulation for administration of at least one cannabinoid to a subject in need thereof, the formulation comprising: at least about 10 wt% of CBD, at least one hydrophilic surfactant selected from caprylocaproyl polyoxyl-8 glycerides (PEG-8 caprylic / capric glycerides), ethoxylated castor oil, hydrogenated ethoxylated castor oil, pegylated-hydrogenated castor oil, and mixtures thereof; at least one lipophilic surfactant selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids, and mixtures thereof; at least one phospholipid; and no more than 1 wt% water; the weight ratio between the total of hydrophilic surfactants and the total of lipophilic surfactants in the formulation ranging between about 3: 1 and about 1:3, and the formulation being in liquid form and forming an emulsion when mixed with an aqueous liquid, the emulsion having a mono-modal droplet size distribution.

[0065] As noted, once the formulation is mixed into an aqueous liquid, the formulation self-emulsifies to form an emulsion, in which droplets are dispersed in a continuous aqueous phase without requiring application of homogenization or shear forces. In such emulsions, made of formulations of this disclosure, the droplets are structured out of surfactants-phospholipid-cannabinoid mixture. Without wishing to be bound by theory, the inventors have found that, in formulations of this disclosure, the cannabinoid (e.g. CBD) forms a physical complex with the surfactants and / or the phospholipid, such that when mixed with an aqueous phase, such complex re-arranges to form stable droplets with the cannabinoid being a physical part of the structure, and not solubilized in the core of the droplet. In other words, in the formulations of this disclosure, the inventors have found, as will be demonstrated below, that without introduction of at least 10 wt% of cannabinoids, preferably between 10 wt% and 25 wt% of cannabinoids (e.g. CBD), a stable, mono-modal emulsion is not formed. Hence, high concentration of cannabinoid is critical for the formation of a mono-modal stable emulsion from the mixture of the hydrophilic surfactants, lipophilic surfactants, and phospholipids of the presently disclosed formulation.

[0066] The formulations are tailored for self-emulsification to form a mono-modal emulsion when mixed in an aqueous liquid. Namely, when mixed into an aqueous liquid, the formulations spontaneously form structured droplets of surfactants-phospholipid- cannabinoids, without requiring rigorous or aggressive mixing or shearing conditions. This is mainly due to the physical complex formed between the cannabinoids and the surfactants and / or the phospholipid. This physical complex permits formation of dense, well-packed and compacted interfacial layer, resulting from a structural match of the molecules at the interface. Typically, such complexes are formed from two or more of the hydrophilic surfactants and lipophilic surfactants. Without wishing to be bound by theory, in the formulations of this disclosure, once mixed with an aqueous phase, a geometric physical complex is formed between one or more of the surfactants and the phospholipid, such that the longer tails of the phospholipid and / or lipophilic surfactants are entangled with the shorter tails of the hydrophilic surfactants, while the hydrophilic head groups of the hydrophilic surfactant and the phospholipid, together with the cannabinoid, form strong hydrogen bonding to stabilize the structure of the droplet.

[0067] Such matching and formation of a geometrical complex enables the surfactants- phospholipid-cannabinoid combination to self-arrange in uniform structures when mixed into the aqueous phase, with a substantially mono-modal droplet size distribution. The cannabinoids, and particularly CBD, when utilized in concentrations of 10-25 wt% of the formulation, were found to assist in reducing the curvature of the interface between the droplets and the aqueous phase, thereby assisting in controlling the geometry of the interface of the droplet. Thus, the combination of surfactants-phospholipid-cannabinoid, when mixed with an aqueous phase, permits obtaining an emulsion with optimized balance between the surface tension and interfacial tension resulting from the combination of hydrophilic and lipophilic surfactants, and a robust and stable droplet structure obtained from the incorporation of phospholipids and the cannabinoids into the interface structure, leading to an emulsion with a stable, mono-modal droplet size distribution, which is highly loaded with cannabinoids. Thus, the inventors have found that in high concentrations (10-25 wt%) of cannabinoids, e.g. CBD, the cannabinoid functions as a “geometrical kosmotropic agent”, namely a component that contributes to the formation of stable geometrical structure of the droplet’s interface.

[0068] According to some embodiments, the emulsion (that is prepared from mixing a formulation of this disclosure with an aqueous phase) has a mono-modal droplet size distribution. In such embodiments, the droplet size distribution has a polydispersity index (PDI) value of no more than 0.5, preferably no more than 0.3.

[0069] According to some embodiments, the average droplet size of the emulsion prepared from mixing a formulation of this disclosure with an aqueous phase is between about 100 nm and about 500 nm.

[0070] The term average droplet size refers to the arithmetic mean of measured diameters of the droplets. Unless otherwise specifically indicated, the average size denotes a volume -based average size.

[0071] According to some embodiments, the emulsion prepared from mixing a formulation of this disclosure with an aqueous phase is stable for at least 7 days at a temperature of about 25°C, typically up to 30 days. Namely, the emulsion does not show phase separation, significant changes in average droplet size, sedimentation, aggregation, coalescence, or any other phenomenon indicating lack of physical stability.

[0072] By another one of its aspects, the disclosure provides a nutraceutical formulation, the formulation comprising: at least about 10 wt% of at least one cannabinoid, at least one hydrophilic surfactant; at least one lipophilic surfactant selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids, and mixtures thereof; at least one phospholipid; and no more than 1 wt% water, the formulation being in liquid form and forming an emulsion when mixed with an aqueous liquid, the emulsion having a mono-modal droplet size distribution.

[0073] By another one of its aspects, the disclosure provides a nutraceutical formulation comprising: at least about 10 wt% of CBD, at least one hydrophilic surfactant selected from caprylocaproyl polyoxyl-8 glycerides (PEG-8 caprylic / capric glycerides), ethoxylated castor oil, hydrogenated ethoxylated castor oil, pegylated-hydrogenated castor oil, and mixtures thereof; at least one lipophilic surfactant selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids, and mixtures thereof; at least one phospholipid; and no more than 1 wt% water; the weight ratio between the total of hydrophilic surfactants and the total of lipophilic surfactants in the formulation ranging between about 3: 1 and about 1:3, and the formulation being in liquid form and forming an emulsion when mixed with an aqueous liquid, the emulsion having a mono-modal droplet size distribution.

[0074] By another aspect, the disclosure provides an emulsion for administration of at least one cannabinoid to a subject in need thereof, the emulsion comprising: between about 1 wt% and about 15 wt% of a pharmaceutical formulation as disclosed herein; and between about 85 wt% and about 99 wt% of an aqueous liquid.

[0075] By another aspect, the disclosure provides an emulsion for administration of at least one cannabinoid to a subject in need thereof, the emulsion comprising: between about 5 wt% and about 15 wt% of a pharmaceutical formulation as disclosed herein; and between about 85 wt% and about 95 wt% of an aqueous liquid.

[0076] By yet another aspect, the disclosure provides an emulsion for administration of at least one cannabinoid to a subject in need thereof, the emulsion comprising: between about 0.5 wt% and about 3.75 wt% of at least one cannabinoid, between about 1.5 wt% and about 10.5 wt% of at least one hydrophilic surfactant, between about 0.75 wt% and about 4.5 wt% of at least one lipophilic surfactant selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids, and mixtures thereof, between about 0.025 wt% and about 0.75 wt% of at least one phospholipid, and between about 85 wt% and about 95 wt% of an aqueous liquid; the emulsion having a mono-modal droplet size distribution.

[0077] The term aqueous liquid refers to any water-based liquid, such as water, water for injection, saline, dextrose solution, water / alcohol mixtures, aqueous solutions (such as sugar and sweetener solutions and water-alcohol mixtures), buffer having a pH between 3 and 9, isotonic solution, flavored water, etc. The term also means to encompass stomach or bile liquids - such that when the water-free formulation is administered without preliminary dilution, the mixing of the formulation with the stomach liquid forms the emulsion in situ in the stomach.

[0078] When administered in emulsion form, the aqueous liquid may include a variety of additional components, such as anti-oxidants, buffers, bacteriostats, suspending agents, solubilizers, thickening agents, gelling agent, emollients, moisturizers, stabilizers, preservatives, buffers, coloring agents, aromatic agents, flavoring agents, flavor masking agents, electrolytes, proteins, chelating agents, and others.

[0079] The formulation can be administered as such, i. e. in concentrate, water-free form for forming the emulsion in situ in the stomach. Alternatively, the formulation can be mixed with an aqueous liquid for forming an emulsion prior to administration.

[0080] Thus, according to another aspect, the present disclosure provides a process for preparing an emulsion as disclosed herein, the process comprising mixing the pharmaceutical formulation disclosed herein and an aqueous liquid at no more than 500 rpm for a period of time of no more than 15 minutes.

[0081] By some embodiments, mixing is carried out at a temperature of between about 10 °C and about 40 °C.

[0082] Mixing may be carried out by any suitable known method that does not involve sheer-mixing, for example, manual mixing, magnetically stirring, mixing by pedals, shaking, rolling, and others.

[0083] By another aspect, the disclosure provides a dosage form for oral administration comprising the pharmaceutical formulation disclosed herein, or an emulsion prepared from the pharmaceutical formulation.

[0084] By some embodiments, the dosage form is selected from a hard-shell capsule and a soft-gel capsule, a gel, a spray, a cream, a chewing gum, and a buccal patch. Preferably, the dosage form comprises the formulation, i.e. in concentrate, substantially water-free form, or even devoid of water.

[0085] Another aspect of the disclosure provides a pharmaceutical formulation or emulsion of this disclosure, for use in treating a disease or condition in a subject in need thereof.

[0086] By another aspect, use of a pharmaceutical formulation or emulsion of this disclosure, in treating a disease or condition in a subject in need thereof.

[0087] A further aspect provides a method of treating a subject suffering from a disease or condition by administering to said subject a therapeutically effective amount of a pharmaceutical formulation or emulsion of this disclosure.

[0088] By some embodiments, said disease or condition is selected from neuropsychiatric disorders such as general anxiety disorder, social anxiety disorder, post-traumatic stress disorder, disorders and conditions associated with seizures and / or convulsions, epilepsy, childhood epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, psychosis, attention deficit disorder, cognitive deficit disorders, migraine, depression, addictions (including conditions such as opioid use disorder, smoking, alcoholism) and similar related disorders that involve neurology and psychiatry; neurodegenerative disorders, such as Alzheimer’s disease, dementia, encephalopathy, Parkinson’s disease, multiple sclerosis and similar disorders that gradually damage or destroy parts of a person’s nervous system or brain; pain associated disorders; inflammatory disorders and conditions, appetite suppression or stimulation; symptoms of vomiting and nausea, intestine and bowl disorders, sleep disorders and conditions; disorders and conditions which require treatment by immunosuppression; disorders and conditions associated with elevated blood glucose levels; disorders and conditions associated with the nerve system; inflammatory skin disorders; disorders and conditions associated with artery blockage; disorders conditions associated with bacterial infections; disorders and conditions associated with fungal infections; proliferative disorders and conditions; disorders and conditions associated with inhibited bone growth; and others.

[0089] According to some embodiments, said disease or condition is selected from neuropsychiatric disorders, such as general anxiety disorder, social anxiety disorder, post- traumatic stress disorder, disorders and conditions associated with seizures and / or convulsions, epilepsy, childhood epilepsy, Lennox-Gastaut syndrome, Dravet syndrome, psychosis, atention deficit disorder, cognitive deficit disorders, migraine, depression, addictions (including conditions such as opioid use disorder, smoking, alcoholism) and similar related disorders that involve neurology and psychiatry.

[0090] According to other embodiments, said disease or condition is selected from neurodegenerative disorders, such as Alzheimer’s disease, dementia, encephalopathy, Parkinson’s disease, multiple sclerosis and similar disorders that gradually damage or destroy parts of a person’s nervous system or brain.

[0091] By some other embodiments, said disease or condition is selected from pain associated disorders.

[0092] According to some embodiments, said disease or condition is selected from inflammatory disorders and conditions and inflammatory skin disorders.

[0093] By some embodiments, said disease or condition is selected from appetite suppression or stimulation, symptoms of vomiting and nausea, intestine disorders and bowl disorders.

[0094] According to some embodiments, said disease or condition is selected from sleep disorders and condition.

[0095] By some embodiments, said disease or condition is selected from disorders and conditions which require treatment by immunosuppression.

[0096] According to some embodiments, said disease or condition is selected from disorders and conditions associated with elevated blood glucose levels.

[0097] By some embodiments, said disease or condition is selected from disorders and conditions associated with the nerve system.

[0098] According to some embodiments, said disease or condition is selected from disorders and conditions associated with artery blockage.

[0099] By some embodiments, said disease or condition is selected from disorders conditions associated with bacterial infections and fungal infection.

[0100] According to some embodiments, said disease or condition is selected from proliferative disorders and conditions.

[0101] By some embodiments, said disease or condition is selected from disorders and conditions associated with inhibited bone growth.

[0102] The formulations described herein may be used as such to induce at least one effect, e.g. therapeutic effect, or may be associated with at least one cannabinoid, which is capable of inducing, enhancing, arresting or diminishing at least one effect, by way of treatment or prevention of unwanted conditions or diseases in a subject.

[0103] The pharmaceutical formulations of the present disclosure may be selected to treat, prevent or ameliorate any pathology or condition. The term treatment or any lingual variation thereof, as used herein, refers to the administering of a therapeutic amount of the formulation or emulsion described herein, whether in a concentrate form or in am emulsion form, which is effective to ameliorate undesired symptoms associated with a disease, to prevent the manifestation of such symptoms before they occur, to slow down the progression of the disease, slow down the deterioration of symptoms, to enhance the onset of remission period, slow down the irreversible damage caused in the progressive chronic stage of the disease, to delay the onset of said progressive stage, to lessen the severity or cure the disease, to improve survival rate or more rapid recovery, or to prevent the disease from occurring or a combination of two or more of the above.

[0104] As known, the effective amount for purposes herein may be determined by such considerations as known in the art. The effective amount is typically determined in appropriately designed clinical trials (dose range studies) and the person versed in the art will know how to properly conduct such trials in order to determine the effective amount. As generally known, the effective amount depends on a variety of factors including the distribution profde within the body, a variety of pharmacological parameters such as halflife in the body, on undesired side effects, if any, on factors such as age and gender, and others.

[0105] The term subject refers to a mammal, human or non-human.

[0106] As used herein, the singular form a, an and the include plural references unless the context clearly dictates otherwise. For example, the term "a cannabinoid" or "at least one cannabinoid" may independently include a plurality of cannabinoids, including mixtures thereof.

[0107] As used herein, the term about is meant to encompass deviation of ±10% from the specifically mentioned value of a parameter, such as concentration, weight ratio, temperature, etc.

[0108] Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases ranging / ranges between a first indicate number and a second indicate number and between a first indicate number and a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

[0109] Throughout this disclosure, unless the context requires otherwise, the word comprise, and variations such as comprises and comprising, will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any integer or step or group of integers and steps.

[0110] Generally it is noted that the term ... at least one... as applied to any component of a formulation or a composition of this disclosure should be read to encompass one, two, three, four, five, six, seven, eight, nine or ten different occurrences of said component in a formulation or a composition disclosed herein.

[0111] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the disclosure. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0112] BRIEF DESCRIPTION OF THE DRAWINGS

[0113] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0114] Figs. 1A-1C are images of formulations according to this disclosure, in respective concentrate form, immediately after dilution by 90% water, and diluted by 90% water after 25 days, at different concentrations of CBD (left-to-right: 0%, 5 wt%, 10 wt%, 15 wt%, 20 wt% and 25 wt% of CBD).

[0115] Figs. 2A-2D are droplet size distributions (%vol) of formulations with different CBD concentrations: 0 wt%, 10 wt%, 20 wt% and 25 wt% CBD, respectively, at 90% water dilution. Figs. 3A-3E are droplet size distributions (%vol) of the formulations of Table 3 in which different phospholipid concentrations were used: 0 wt%, 3 wt%, 5 wt%, 7 wt% and 10 wt% phospholipids, respectively.

[0116] Figs. 4A-4F are droplet size distributions (%vol) of the formulations of Table 5 in which the phospholipid was replaced by other components.

[0117] Figs. 5A-5B are images of the concentrate of Table 7 in which the ratios between the hydrophilic surfactants and the lipophilic surfactants was modified, without CBD and with 20 wt% CBD, respectively.

[0118] Figs. 6A-6D are optical microscope images of emulsions prepared from formulations Form4B and Form 10 immediately after preparation (Figs. 6A-6B) and 3 hours after preparation (Figs. 6C-6D), respectively.

[0119] Fig. 7 shows droplet size distributions for emulsions prepared from Form4B (solid black line), Forml 1 (gray solid line), and Forml2 (gray dashed line).

[0120] Fig. 8 shows surface tension test results for the vehicle (dark gray line), Form2 (light gray line) and Form4 (Black line) in emulsion form (99% water dilution).

[0121] Fig. 9 shows interfacial tension test results for the vehicle (dark gray line), Form2 (light gray line) and Form4 (Black line) in concentrate form, as measured against mineral oil.

[0122] Figs. 10A-10B show differential scanning calorimetry (DSC) test results for the vehicle and Form4 (20wt% CBD), respectively.

[0123] Figs. 11A-11C are viscosity test results for the vehicle, Form2 and Form4, respectively, diluted by 70% water.

[0124] Figs. 12A-12C are rheological test results for vehicle, Form2 and Form4, respectively, diluted by 70% water.

[0125] DETAILED DESCRIPTION OF EMBODIMENTS

[0126] Effect of cannabinoid concentration

[0127] Formulations with various concentrations CBD were prepared as detailed in Table 1. All components of the formulation, except for the CBD, were initially mixed at room temperature until forming a homogenous mixture. Then the CBD was added and the formulation was further mixed for 30-45 minutes at 45-50 °C. The formulations were then mixed with water to form emulsions (1 part emulsion to 9 parts water, forming a 90% dilution), at a mixing rate of no more than 500 rpm at room temperature. Images of the concentrates, the emulsions immediately after preparation and the emulsions after 25 days at room temperature are provided in Figs. 1A-1C, respectively.

[0128] Table 1: Formulations with different CBD content

[0129] (a) glyceryl monolinoleate

[0130] (b) ethox lated castor oil

[0131] (c) caprylocaproyl polyoxy 1-8 glycerides

[0132] (d) Phosphatidylcholine in sunflower oil, content > 50.0 %

[0133] As can be seen, in the concentrated form, all formulations provide clear and transparent liquids, indicating that CBD was well solubilized into the concentrate formulation. Once diluted in water, no formation of stable emulsion was observed in low content of CDS, while over 10 wt% of CBD the formulation self-assembles into an emulsion. The emulsions remained stable for at least 25 days when maintained at room temperature.

[0134] Particle size analysis was made for the 90% diluted formulations of Table 1, using dynamic light scattering (DLS), as shown in Table 2 and Figs. 2A-2D.

[0135] Table 2: Droplet average size and PPI values for emulsions (90% water dilution) As can be clearly seen, the vehicle, i.e. without CBD, shows a poly-modal droplet size distribution, indicating an emulsion that is likely to have significantly impaired stability. Once CBD is added in 10 wt% and 20 wt%, the resulting emulsion has a mono- modal droplet size distribution, with a relatively low PDI value. Increasing the CBD concentration to 25wt% resulting in disruption of the droplet structure and formation of an emulsion with poly-modal droplet size distribution.

[0136] As can be seen, stable, mono-modal emulsions were obtained for up to 20 wt% CBD, typically 10-20 wt% CBD. As no mono-modal emulsion was formed in the absence of CBD, the significant contribution of CBD (at a defined concentration range) to the formation of a stable mono-modal emulsion is clearly demonstrated.

[0137] Effect of phospholipid concentration

[0138] CBD concentrate formulations (circa 20 wt% CBD) with different phospholipid concentrations were prepared according to Table 3. Particle size analysis was made for the 90% diluted formulations of Table 3, using dynamic light scattering (DLS), as shown in Table 4 and Figs. 3A-3F.

[0139] Table 3: Formulations with different phospholipid content

[0140] Table 4: Droplet average size and PDI values for emulsions made from formulations of

[0141] Table 3 (90% water dilution) As can be seen, absence of phospholipid resulted in an emulsion with poly-modal droplet size distribution. The same effect was observed above 5 wt% of phospholipids, demonstrating disruption of the droplet’s structure when excess phospholipid is added to the formulation.

[0142] The effect of phospholipids on formation of a mono-modal emulsion was also investigated by replacing the phospholipid present in Form4B with one of the surfactants or co-surfactant in the formulation, as shown in Table 5. Particle size analysis was made for the 90% diluted formulations of Table 5, using dynamic light scattering (DLS), as shown in Table 6 and Figs. 4A-4F.

[0143] Table 5: Formulations with no phospholipid

[0144] Table 6: Droplet average size and PPI values for emulsions made from formulations of

[0145] Table 5 (90% water dilution) As evident from the results, the phospholipid is critical for obtaining a mono- modal emulsion, and replacement of phospholipid by one of the surfactants or cosurfactants did not result in a mono-modal emulsion, but rather an emulsion with poly- modal droplet size distribution.

[0146] The effect of the phospholipid on the predicted long-term stability of the emulsion was assessed by LumiSizer™ analysis. LumiSizer analysis permits prediction of long term stability by rapid analytical centrifugation. During LumiSizer measurements, parallel light illuminates the sample cell in a centrifugal field; the transmitted light is detected by sensors arranged linearly along the total length of the sample-cell. Local alterations of particles or droplets are detected due to changes in light transmission over time. Thus, the conditions applied on the sample during this test simulate accelerated aging, and permits prediction of physical stability of the formulation over time.

[0147] Emulsions made by 90% water dilutions of 20 wt% CBD formulation, with 3 wt% phospholipid and without phospholipid were tested by LumiSizer analysis. The sample without phospholipid was observed to be significantly less stable over time compared to the sample with 3 wt% of phospholipid. This attests to the importance of the cannabinoidphospholipid combination in forming a stable physical complex with the surfactants.

[0148] Effect of weight ratio between the hydrophilic and lipophilic surfactants

[0149] CBD concentrate formulations (20 wt% CBD) with different ratios of hydrophilic surfactants to lipophilic surfactants were prepared according to Tables 7-1 and 7-2. The same formulations were prepared while removing CBD from the formulations. Images of the formulations without CBD and with 20 wt% CBD are shown in Figs. 5A-5B, respectively.

[0150] Table 7-1: Formulations with different surfactants ratios without CBD

[0151] * Hydrophilic surfactants to lipophilic surfactants weight ratio Tab e 7-2: Formulations with different surfactants ratios, with 20 wt% CBD

[0152] * Hydrophilic surfactants to lipophilic surfactants weight ratio

[0153] As can be seen, in all formulations, removal of CBD caused immediate destabilization of the formulation, regardless of the ratio between the hydrophilic surfactants and the lipophilic surfactants. Once 20 wt% CBD was introduced, all concentrates were clear and stable, without any indication of phase separation, sedimentation, aggregation, etc.

[0154] Thus, it seems that when in concentrated form, the formulation is less sensitive to the ratio between the hydrophilic and lipophilic surfactants within the range of ratios of 3: 1 and 1:3. This was also observed when the formulations were diluted with 90% water, indicating that as long as there is CBD and phospholipid in the formulation, a stable complex can be obtained with the surfactants, both in the concentrate and emulsion forms.

[0155] These observations were also seen in LumiSizer analysis, in which the emulsions (90% water dilution) of Tables 7-1 and 7-2 showed significant increased stability for formulations containing CBD compared to formulations without CBD, with the different ratios between the hydrophilic and lipophilic surfactants having no significant impact on stability.

[0156] Effect of lipophilic surfactants selection

[0157] CBD concentrate formulations (20 wt% CBD) with different lipophilic surfactant were prepared according to Table 8 to demonstrate the effect of substituting the lipophilic surfactants. Each formulation was then diluted with distilled water (90% dilution). Optical microscope images of the resulting emulsions are provided: immediately after preparation (Figs. 6A-6B) and 3 hours after preparation (Figs. 6C-6D). able 8: Formulations with different lipophilic surfactants

[0158] * polyglyceryl-3 dioleate

[0159] As can be seen, while in the formulation of Form4B the emulsion is homogenous and stable (Figs. 6A,6C), the emulsion prepared from FormlO show high dispersity of droplets size already after preparation and even more so within 3 -hours from preparation (Figs. 6B,6D). Thus, the combination of lipophilic surfactants has a detrimental effect on the formation of stable mono-modal emulsions.

[0160] Effect of oil addition

[0161] CBD concentrate formulations (20 wt% CBD) in which some of the lipophilic surfactants were replaced by oil were prepared according to Table 9 to demonstrate the effect of modifying the lipophilic phase on the resulting emulsions. Each formulation was then diluted with distilled water (90% dilution). Droplet size distribution is provided in Fig. 7. As can be seen, addition of oil to the formulations causes significant loss of monomodality in droplet size distribution (gray solid and dashed line) in comparison to Form4B (solid black line). Thus, addition of oil destabilizes the emulsion formed out of the formulations.

[0162] Surface and interfacial tension measurements

[0163] Surface tension is the tendency of a droplet of liquid to assume the minimal surface area possible, and is obtained by the balance of the inter-molecular cohesive forces (forces acting between molecules of the same type in the formulation) and the adhesive forces (forces acting between molecules of different types in the formulation). The interfacial tension is typically a measure of the balance of inter-molecular forces operating in the droplet of the formulation when mixed into the aqueous phase.

[0164] The function of surfactants in formulations is typically to reduce and adjust the surface and interfacial tension, as to have better control over the curvature of the interface formed between the droplets and the aqueous continuous phase when the formulation is mixed with the aqueous liquid - thereby promoting self-emulsification and increasing the stability of the emulsion.

[0165] In order to assess the impact of CBD on surface and interfacial tension, surface and interfacial tension tests were carried out in a DCAT tensiometer, at ca. 25°C, plate PT11.

[0166] Results of the surface tension measurements for formulations with different CBD content, diluted with 99% water, are provided in Table 10, as well as Fig. 8. Results for interfacial tension are provided in Fig. 9.

[0167] Table 10: Surface tension measurements (99% water dilution)

[0168] As can be seen, the surface tension increases as the concentration of CBD in the formulation increases. Similar behavior is observed for the interfacial tension, in which for both 10 wt% and 20 wt% CBD, the interfacial tension is significantly higher than the interfacial tension of the vehicle formulation.

[0169] This indicates that while CBD is a critical component in forming a stable, mono- modal emulsion when the formulation is mixed with water, it does not function as a surfactant - as no reduction in surface tension is observed when incorporating CBD into the formulation. Thus, while having no surfactant-like behavior, the CBD is a clear structure building molecule, that permits formation of stable physical complex with the surfactants and phospholipids.

[0170] Analysis of the structure of droplets

[0171] In order to determine the structure of the droplets obtained after mixing the formulations with water to form an emulsion, self-diffusion NMR (SD-NMR) analysis was carried out for the vehicle, Form2 and Form4 formulations, in concentrate (water- free) form. SD-NMR is able to locate some of the formulation- components within the droplet via measurements of its diffusion coefficient. Rapid diffusion (>100xl0'nm2 / s) is characteristic of small molecules, free in solution, while slow diffusion coefficients (O.lxlO-11m2 / s) suggest low mobility of macromolecules or bound / aggregated molecules.

[0172] SD-NMR measurements were performed with a Bruker Avance NEO 500 spectrometer equipped with GREAT 1 / 60 gradients, a 5mm diffusion-BBI probe, both with a z-gradient coil and with a maximum gradient strength of 17 T m-1, . Diffusion was measured using a stimulated echo (STE) with a 5 ms longitudinal eddy-current delay (bpLED) experiment, ramping the strongest gradient in 32 steps. The spectrum was processed with the Bruker TOPSPIN and Dynamics Center software. NMR spectra were recorded at 25±0.2°C. The components were identified by their chemical shift in 1H NMR.

[0173] Tables 11-1 and 11-2 show the diffusion coefficients of the vehicle, Form2 and Form 4, as obtained from the SD-NMR analysis, for the concentrate forms and the diluted forms (70% water dilution). Table 11-1: Diffusion coefficients and chemical shifts for CBD, as determined by SD- M R. concentrate

[0174] Table 11-2: Diffusion coefficients and chemical shifts for CBD, as determined by SD-

[0175] NMR, 70% water dilution

[0176] As can be seen, increasing the concentration of the CBD in the formulation causes reduction in the diffusion coefficients and chemical shifts. This indicates that increasing the concentration of CBD in the formulation causes increased interactions between the surfactants, phospholipid and CBD, indicating that CBD is entrapped, or physically complexed, within the interface structure of the droplet formed from the surfactants- phospholipid-CBD combination. These diffusion coefficients clearly demonstrate the interactions (physical complexation) between the CBD, the surfactants and the phospholipids.

[0177] Without wishing to be bound by theory, release of the CBD from the droplet will occur upon interaction of the droplets with target biological membranes after administration to the subject to be treated due to the affinity of CBD to the biological membrane at the target site.

[0178] Differential scanning calorimetry (DSC)

[0179] Differential heating and cooling thermograms of the formulations can be used as indications to the nature of interaction between components in the formulations.

[0180] 15-30 mg samples of the vehicle formulation (No CBD) and Form4 (20 wt% CBD) were heated from 30°C to 90°C and then cooled back to 30°C both at a rate of 10°C / min (using a Mettler Toledo DSC 822). All measurements were carried out against empty perforated pan as a reference. The thermograms are shown in Figs. 10A and 10B, respectively. As can be seen, an endothermic event was observed at 86°C for Form4, attributed to the release of CBD from the formulation. When comparing the thermograms of the vehicle (Fig. 8A) and that of Form4 (Fig. 8B) significant differences are observed between the vehicle and Form4 - the CBD-containing formulation showing significantly higher AH gain between heating and cooling. This indicates that CBD is not merely solubilized in the formulation, but forms physical complexation with the other components (i.e. surfactants and phospholipids) - once CBD is released from the structure, no re-organization into a stable structure is observed.

[0181] Rheological behavior

[0182] Viscosity measurements were carried out at RT (25 ±0.1°C), using Thermo Haake Rheo Scope 1 equipped with C60 / ° 1 cone and plate (the distance between the cone and the plate during the measurements was 0.022mm). At each measurement increasing shear rates (0-60 s'1) were applied for 6 min. Viscosity profiles for the vehicle, Form2 and Form4, at 70% water dilution, are shown in Figs. 11A-11C, respectively.

[0183] As can be seen, the viscosity of emulsions formed from Form2 and Form4 are significantly lower than the viscosity of an emulsion based on the vehicle (i.e. without CBD) under the same testing conditions. This indicates that the structures of the emulsion formed in the absence of CBD and when high loads of CBD are present are significantly different.

[0184] Such differences are even more observable when looking at the shearing stress (r, tau), and the dynamic viscosity (r| ,eta) which quantifies the fluid’s internal friction, as shown in Figs. 12A-12C for the vehicle, Form2 and Form4, respectively, at 70% water dilution. For Form4 (20 wt% CBD), the shearing stress reaches maximum and the internal friction reaches zero very quickly (at very low shearing rates) in comparison to the vehicle and Form2 (10 wt% CBD). This indicates significant modification in interaction forces at the interface of the droplets, showing the significant impact of the presence of CBD on the structure of the interface and the interaction between the other components (surfactants and phospholipid) - once sheer forces are applied to the emulsions formed from the CBD-loaded formulations, CBD is released from the structured droplet ad causes immediate collapse of the structure of the emulsion. Thus, in the formulations described herein, the cannabinoid is a critical component for the formation of structured droplets and their stability. Long term stability of droplet size distribution

[0185] Droplet size distribution was measured by DLS for Form4B (water-free form) and for Form4B encapsulated in softgel capsules, at various timepoints after production, as detailed in Tables 12-1 and 12-2, respectively.

[0186] Table 12-1: Droplet size distribution of Form4B, 25°C, 60% RH

[0187] Table 12-2: Droplet size distribution of Form4B in softgcl capsule

[0188] As can be seen, the mono-modal size distribution of the formulation is maintained over a prolonged period of time, both in non-encapsulated and encapsulated forms, at different storage conditions.

Claims

CLAIMS:

1. A formulation for administration of at least one cannabinoid to a subject in need thereof, the formulation comprising: at least about 10 wt% of at least one cannabinoid, at least one hydrophilic surfactant; at least one lipophilic surfactant selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids, and mixtures thereof; at least one phospholipid; and no more than 1 wt% water; the weight ratio between the total of hydrophilic surfactants and the total of lipophilic surfactants in the formulation ranging between about 3: 1 and about 1:3, and the formulation being in liquid form and forming an emulsion when mixed with an aqueous liquid, the emulsion having a mono-modal droplet size distribution.

2. The formulation of claim 1, wherein said formulation comprises between about 10 wt% and about 25 wt% of said at least one cannabinoid.

3. The formulation of claim 1 or 2, comprising between about 15 wt% and about 22 wt% of said at least one cannabinoid.

4. The formulation of any one of claims 1 to 3, wherein said cannabinoid is selected from cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabidivarin (CBDV), cannabinol (CBN), or derivatives thereof, and mixtures thereof.

5. The formulation of any one of claims 1 to 4, wherein said cannabinoid is cannabidiol (CBD).

6. The formulation of any one of claims 1 to 5, comprising up to 1 wt% tetrahydrocannabinol (THC).

7. The formulation of any one of claims 1 to 6, comprising a total amount of hydrophilic surfactants of between about 30 wt% and about 70 wt% of the formulation.

8. The formulation of any one of claims 1 to 7, wherein said at least one hydrophilic surfactant is selected from caprylocaproyl polyoxyl-8 glycerides (PEG-8 caprylic / capric glycerides), ethoxylated castor oil, ethoxylated sorbitan monolaurate, ethoxylated sorbitan monostearate / palmitate, ethoxylated sorbitan monooleate / linoleate, ethoxylated sorbitan trioleate, hydrogenated ethoxylated castor oil, pegylated-hydrogenated castor oil, ethoxylated monoglyceride stearate / plamitate, Solutol® HS15 (polyethylene glycol (15)- hydroxystearate), oleoyl macrogolglycerides, ethoxylated hydroxy stearate, polyglycerolesters such as decaglycerol monolaurate, decaglycerol monooleate, hexaglycerol monooleate and hexaglycerol monolaurate, sucrose monooleate, sucrose monolaurate, and mixtures thereof.

9. The formulation of any one of claims 1 to 8, comprising a total amount of lipophilic surfactants of between about 15 wt% and about 30 wt% of the formulation.

10. The formulation of any one of claims 1 to 9, wherein said at least one lipophilic surfactant is selected from glyceryl monolinoleate, propylene glycol monolaurate, and mixtures thereof.

11. The formulation of any one of claims 1 to 10, wherein the lipophilic surfactant is a mixture of glyceryl monolinoleate and propylene glycol monolaurate.

12. The formulation of any one of claims 1 to 11, wherein the weight ratio between the total of hydrophilic surfactants and the total of lipophilic surfactants is between about 3 : 1 and about 1: 1.

13. The formulation of any one of claims 1 to 12, comprising a total amount of phospholipids of between about 0.5 wt% and about 5 wt% of the formulation.

14. The formulation of any one of claims 1 to 13, devoid of water.

15. The formulation of any one of claims 1 to 14, devoid of oil.

16. The formulation of any one of claims 1 to 15, further comprising at least one cosurfactant.

17. The formulation of claim 16, comprising a total amount of co-surfactants of between about 8 wt% and about 15 wt%.

18. The formulation of any one of claims 1 to 17, wherein said emulsion is stable for at least 7 days at a temperature of about 25°C.

19. The formulation of any one of claims 1 to 18, wherein the emulsion has an average droplet size of between about 100 nm and about 500 nm.

20. The formulation of any one of claims 1 to 19, wherein the formulation is clear in the visible spectrum.

21. The formulation of any one of claims 1 to 20, being a pharmaceutical formulation.

22. The formulation of any one of claims 1 to 21, being a nutraceutical formulation.

23. An emulsion for administration of at least one cannabinoid to a subject in need thereof, the emulsion comprising: between about 1 wt% and about 15 wt% of a formulation of any one of claims 1 to 22; andbetween about 85 wt% and about 99 wt% of an aqueous liquid; the emulsion having a mono-modal droplet size distribution.

24. The emulsion of claim 23, having an average droplet size of between about 100 nm and about 500 nm.

25. The emulsion of claim 23 or 24, being stable for at least 7 days at a temperature of about 25°C.

26. A process for preparing an emulsion of any one of claims 23 to 25, comprising mixing between about 1 wt% and about 15 wt% of a formulation of any one of claims 1 to 24 and between about 85 wt% and about 99 wt% of an aqueous liquid at no more than 500 rpm for a period of time of no more than 15 minutes.

27. A dosage form for oral administration comprising the formulation of any one of claims 1 to 22.

28. The dosage form of claim 27, being selected from a hard-shell capsule and a soft- gel capsule, a gel, a spray, a cream, a chewing gum, and a buccal patch.

29. A formulation of any one of claims 1 to 21 being a pharmaceutical formulation, or an emulsion of any one of claims 23 to 25, for use in treating a disease or condition in a subject in need thereof.

30. A method of treating a subject suffering from a disease or condition by administering to said subject a therapeutically effective amount of a pharmaceutical formulation of any one of claims 1 to 21 being a pharmaceutical formulation or an emulsion of any one of claims 23 to 25.

31. A nutraceutical formulation comprising: at least about 10 wt% of at least one cannabinoid, at least one hydrophilic surfactant; at least one lipophilic surfactant selected from monoglycerides, propylene glycol mono-esters of long chain fatty acids, and mixtures thereof; at least one phospholipid; and no more than 1 wt% water; the weight ratio between the total of hydrophilic surfactants and the total of lipophilic surfactants in the formulation ranging between about 3: 1 and about 1:3, and the formulation being in liquid form and forming an emulsion when mixed with an aqueous liquid, the emulsion having a mono-modal droplet size distribution.

Images