A self-emulsifying solid composition comprising a cannabinoid

Abstract

The present disclosure relates to a solid formulation comprising: an oil phase which comprises one or more dissolved cannabinoid compounds; a surfactant system; and a water-soluble solid carrier phase, wherein the oil phase is present in the form of discrete droplets associated with surfactant, said droplets being at least partially encapsulated by the water-soluble carrier phase. The solid formulation can self-emulsify when contacted with an aqueous solution. A method of producing a formulation, comprising freeze-drying an oil- in-water emulsion which comprises: an oil phase which comprises one or more dissolved cannabinoid compounds; a surfactant system; and an aqueous phase comprising a dissolved carrier material.

Description

[0001]TITLE A self-emulsifying solid composition comprising a cannabinoid TECHNICAL FIELD The present disclosure relates to a self-emulsifying solid composition comprising a cannabinoid. It can be made by freeze-drying a cannabinoid-containing oil-in-water emulsion. The solid formulation can be made into an emulsion by addition of a solvent. The composition can for example be used to manage pain. BACKGROUND Cannabinoids have been known for many centuries to be useful active compounds, which can be used to treat various diseases. For example, these compounds can be used for pain relief. Cannabis plants or extracts from the cannabis plant have been historically used as a natural medicine. More recently, there have been efforts to develop cannabinoid-based medicaments, focusing on their incorporation into modern conventional products for oral use such as solutions, tablets, lozenges etc. Such formulation efforts are complicated by the fact that the cannabinoids are highly lipophilic and thus difficult to formulate for oral administration by conventional drug delivery technologies. Conventional tablets require dissolution of the active pharmaceutical ingredient to facilitate permeation across the gastro-intestinal tract and ultimately transport the drug to therapeutic receptor targets via the blood stream. A well- characterized cannabinoid like cannabidiol (CBD) has a reported water solubility of 0.7 µg / mL and an intestinal permeability that collectively render the cannabinoid a Class II drug of the Biopharmaceutical Classification System (BCS). Its poor water solubility presents a significant hurdle to the preparation of an oral delivery formulation which results in acceptable bioavailability of the active ingredients. In addition, first-pass metabolism imposed by the liver after entering the portal vein is known also to eliminate a significant fraction of the drug further restricting bioavailability. Cannabinoid oil formulations are known to have poor bioavailability when administered orally. In addition, for drug delivery systems targeting the endocannabinoid system (ECS), high drug loads are needed to increase the likelihood of a therapeutic response for a given disease indication. The ECS is an endogenous multifunctional pro-homeostatic signaling system being almost ubiquitously distributed within the body. The system is generally recognized to consist of three main parts 1) receptors: G protein-coupled receptors (GPCRs); cannabinoid receptor 1 (CB1R) and 2 (CB2R), 2) endocannabinoids: the body´s own signaling molecules regulating the ECS through the cannabinoid receptors, including N-arachidonylethanolamine (anandamide i.e., AEA) and 2-arachidonoylglycerol (2-AG) and 3) the enzymes: responsible for the metabolism and regulation of endocannabinoids available at a given time. In line with the development of research in the field, additional components have been discovered being part of the ECS. This including 1) receptors: GPCRs (e.g., GPR18, GPR55 and GPR119), ion channels (e.g., Transient Receptor Potential Vanilloid 1 (TRPV1) and nuclear receptors (e.g., Peroxisome Proliferator-activated receptor gamma (PPAR-y), 2) endocannabinoid-like compounds: e.g., Palmitoylethanolamide (PEA) and Oleoylethanolamine (OEA) and 3) synthesizing and degradative enzymes and transport proteins of the endocannabinoids and alike ligands. The ECS acts locally at the various body parts it is localized within, where it responds to and is activated by disturbances occurring within these systems, with the aim to recover and maintain homeostasis. Use of exogenous cannabinoids to target a specific disease caused by an imbalance in ECS homeostasis, is complicated by a dose-dependent effect on the receptor response observed in vivo. That is, the level of cannabinoid available at the receptor site induces either advantageous or deleterious effects, for example for cognitive functions where low doses of the CB1 agonist, Δ9-THC, in mice improved cognitive performance whereas high doses impaired these functions (DOI:10.3390 / ijms21082778). A drug delivery system intended for delivery of multiple cannabinoids that collectively aim to establish homeostasis in the ECS, must incorporate a broad dose range to accommodate the difference in receptor binding (and ultimately modulation) of the included cannabinoids. Finally, in order to achieve good compliance, it is important to provide the cannabinoids in a form which is easy and convenient for users to take. The above problems are addressed by the present invention, which seeks to develop a cannabinoid-containing solid formulation which is capable of being converted into an emulsion when it is brought into contact with a suitable solvent. This way, one or more cannabinoids can be administered orally in the form of e.g. a tablet or a capsule. Once such a formulation has been swallowed and mixed with gastric fluid, an emulsion is formed in the stomach. This allows easy delivery of the cannabinoid, while avoiding the above-mentioned disadvantages of cannabinoid oil formulations. Other objectives include the ability to allow an adequate amount of the active to be contained and delivered, and that the composition must have good chemical stability, in particular reducing chemical degradation of the active over time. Chemical stability is inherently improved by the transformation from a liquid to a solid and provides better means to store the active ingredients, compared to their pure or solubilized state. It is also an objective for the compositions to be safe and for side-effects to be minimized, and ideally avoided. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a flow diagram illustrating the product of a cannabinoid-based emulsification system. Figure 2 shows the DLS particle size distribution of Example emulsion A1. Figure 3 shows stability data of emulsions. Figure 4 shows pictures of the emulsions.Figure 5 shows the ^^FLUX setup membrane used in in vitrotesting.Figure 6 shows in vitro data relating to flux of cannabinoidsin the emulsions through the PAMPA membrane.Figure 7 shows in vivo pharmacokinetic (PK) data relating tobioavailability of cannabinoids in the emulsions following GI administration. Figure 8 shows the freeze-dried samples X1-X6. Figure 9 shows the reconstituted emulsions made from samples X3 (40% mannitol) and X6 (40% sucrose) at selected timepoints relative to reconstitution. Figure 10 shows the ground material of X3 (40% mannitol) and X6 (40% sucrose) subject to particle size analysis. Figure 11 shows the DLS particle size distribution of reconstituted Example freeze-dried sample X5 (30% sucrose). DESCRIPTION Summary of the Invention The present invention relates to a solid formulation comprising: an oil phase which comprises one or more dissolved cannabinoid compounds; a surfactant system; and a water-soluble solid carrier phase, wherein the oil phase is present in the form of discrete droplets associated with surfactant, said droplets being at least partially encapsulated by the water-soluble carrier phase. The invention also relates to methods of making said compositions, and to their uses in therapeutic methods. The Solid Formulation The present invention formulates cannabinoids in a solid form. This formulation is designed to self-emulsify when the solid carrier phase is dissolved in water or another aqueous solvent such as gastric fluid. The self-emulsifying properties arise from the spatial arrangement of the various components in the solid formulation. In particular, when the solid formulation is prepared from an oil-in-water emulsion by a technique such as freeze drying, it is believed that it is possible to substantially maintain the micelles present in the emulsion (i.e. small droplets of oil-based material surrounded by surfactant) also in the resulting solid composition, or to at least have the surfactant and oil in a relative configuration so that the micelles can be re-formed on reconstitution. This requires the surfactant and the oil phase to be associated with each other in the solid formulation of the present invention. Then, when the liquid formulation is reconstituted by dissolving the solid carrier material, it is possible to generate an emulsion having the same or similar properties as the one which existed prior to freeze-drying, because the micelles are already effectively formed. The structure of the solid formulations of the present invention may be in the form of powder. The solid formulation has a solid carrier matrix comprising internal droplets of oil phase with cannabinoid. The solid formulations are preferably substantially free of water, i.e. the water content is preferably less than 5 wt.% by weight of the formulation, more preferably less than 2 wt.%. The claimed solid formulations are associated with many technical advantages: Firstly, the use of the solid form of the invention (as opposed to e.g. an oil or oil-in-water emulsion) is associated with improved chemical stability of the cannabinoid. Key cannabinoid degradation mechanisms proceed more quickly in liquids. The presently claimed formulations have better storage stability and activity is retained for longer. Secondly, the use of the solid form of the invention removes the risk of phase separation (as compared to e.g. an oil-in- water emulsion). Although oil-in-water emulsions can be formulated to be relatively stable, micelles will eventually merge. This can lead to an increase in droplet size over time, and even to a phase separation. When making use of the solid form of the present invention, physical stability is improved as these mechanisms are prevented due to fixation of the oil phase in the solid carrier. Thirdly, the advantages associated with the use of oil-in- water emulsions (as compared to oils) can be maintained, in particular the improved bioavailability. It has previously been proposed to dissolve cannabinoids in coconut oil or similar medium chain triglycerides, and to administer these compositions directly. A cannabinoid dissolved in such oils is not effectively absorbed by the human body due to hepatic clearance. The presently claimed formulations have improved bioavailability compared to oils. Fourthly, when the solid formulations of the present invention are formed by freeze-drying, the result is a flowable powder which is well-suited for further processing into a pharmaceutical product such as a tablet or a capsule. Such dosage forms are appreciated by many users, and are often considered more convenient than liquid formulations. This can lead to e.g. improved compliance. Fifthly, it is possible to produce the formulations of the present invention in a manner so that the active ingredient is homogenously distributed in the solid material. This can e.g. be achieved when using freeze-drying. The Reconstituted Emulsion As explained above, the solid formulations of the present invention are self-emulsifying, i.e. they form an emulsion when put into contact with an aqueous solvent so that the solid carrier dissolves. It is not necessary to apply techniques normally associated with the formation of emulsions, i.e. intensive mixing, ultrasonication, homogenization etc. In a preferred embodiment, the particle size characteristics of the droplets in the reconstituted emulsion are as similar as possible to those of a base emulsion which is freeze-dried to make the solid formulation of the invention. When the solid formulations of the present invention are administered orally, the self-emulsifying action will take place within the stomach, with the gastric fluid acting as the aqueous phase of the reconstituted emulsion. The reconstituted emulsion will then enable absorption in the gastro-intestinal tract. Accordingly, long-term stability of the reconstituted emulsion is not so important. It is preferred to avoid phase separation for at least one hour after reconstitution to align with the onset of GI-tract absorption.It is also possible to reconstitute the emulsion ex vivoprior to oral administration. It is however preferred thatthe reconstitution takes place in vivo in the stomach.For the purpose of verifying self-emulsification by visual inspection, the following procedure is followed: Pre-treatment of solid formulation from the vial by crushing the freeze-dried material to finer particles. Addition of a quantity of water to the vial. The quantity of water is not decisive. For example, an amount of water equivalent to the quantity of water phase in the base emulsion can be used. If the amount of water is now known, a suitable amount of water can be used to dissolve the solid carrier, for example it is possible to use trial and error to arrive at a reconstituted emulsion in which the oil phase makes up 10 wt.% of the reconstituted emulsion. Generally, the exact amount of water used to reconstitute the emulsion is usually not decisive. It is possible for quick test purposes to simply use 10 ml water per gram of the solid formulation. The water is temperature controlled at physiological temperature, 37^C in order to reflect physiological conditions in the stomach. Gentle shaking of the vial to observe immediate formation of emulsion (homogenous, yellow liquid). For the purposes of characterization of a reconstituted emulsion made by allowing the solid formulations of the present invention to self-emulsify in water, the following method is followed: Pre-treatment of solid formulation from the vial by crushing the freeze-dried material to finer particles. Addition of water to the solid material. Shaking of the vial and verification of complete emulsification. Particle size measurements by DLS within 1 hr after reconstitution. DLS measurements were temperature controlled at 25^C. Droplet Size / Particle Size In the present disclosure, the expression “particle size” is used to characterize the size of the oil droplets / micelles, even though these are not solid particles. This is because the techniques for characterizing the droplet sizes is the same as that used in measuring particle sizes in dispersions. According to the present invention, it is important that the reconstituted emulsion has an appropriate particle size. The present inventors have found that the absorption of the cannabinoids varies with the particle size. The present inventors have identified that there is particularly good absorption when the particle size is around 100-400nm, more preferably around 250nm. When the particles are within the range, the absorption is maximized compared to similar formulations which use larger or smaller oil droplets / micelles. According to the present invention, the D50 value of the reconstituted emulsion is in the range 100-400nm. The D50 value is the particle size value where 50% of the particles are larger than said value, and 50% are smaller, i.e. it represents the median particle size value. In addition, it is preferred that the D10 value of the reconstituted emulsion is higher than or equal to 50nm. It is also preferred that the D90 value is lower than 700nm. Preferably, all of the above D50, D90 and D10 values are simultaneously fulfilled. As is conventional, the D10 value is the particle size where 10% of the particles are smaller than this threshold value. Similarly, the D90 value is the threshold value where 90% of the particles are smaller than this value. It is preferred for as many droplets as possible to be as close to 250nm as possible. In the presently disclosed emulsions, it is reasonable to assume that the oil droplets / micelles are spherical. The D10, D50 and D90 values can be determined directly using well-known test methods. According to the present disclosure, the particle size of the oil droplets / micelles are determined by Dynamic Light Scattering (DLS), which is considered the best way to measure particles in the nano- range. Measurement of droplet sizes is carried out in accordance with ISO 22412:2017. For testing of the base emulsion (prior to freeze drying), 1 mL of emulsion sample is used. It is diluted 60 times in water to maximize dispersion of particles thereby minimizing risk of overlapping particles that cannot be separated. The measurement is repeated three times, and the average taken to yield particle size results. DLS measurements can e.g. be performed on a Malvern Zetasizer Nano ZS. The measurements are made at 25°C and using an equilibration time of 1 minute. Prior to measurement, measures are taken to remove bubbles, e.g. inversion and redispersion of the sample. Such equipment and methods are suitable to measure particle sizes in the range 1 nm to 10 µm. The reconstituted emulsion is tested as described above, but without dilution prior to analysis. The above preferences and test methods relate both to a base emulsion which is converted into the solid formulation of the present invention by freeze drying, and to a reconstituted emulsion obtained by contacting the solid formulation of the present invention with an aqueous solvent to dissolve the solid carrier. As explained above, the particle size characteristics of the droplets in the reconstituted emulsion are as similar as possible to those of a base emulsion which is freeze dried to make the solid formulation of the invention. Zeta Potential The zeta potential of the droplets in an emulsion is related to the overall stability because particles that are highly charged (either positively or negatively) will repel each other in solution and thus be less likely to aggregate and eventually separate out of dispersion. On the other hand, droplets that are relatively uncharged or neutral are more likely to interact with each other rather than the solvent leading to larger particles or complete separation back into two phases. Thus, ensuring optimal droplet zeta potential is helpful to ensure that the emulsion will be stable over time. The base emulsion (prior to freeze drying) preferably has a zeta potential which is close to zero but slightly negative, e.g. in the range -40 mV to -1 mV. Measurement of zeta potential is carried out in accordance with ISO 13099-1:2012. The zeta potential can be measured using e.g. the Malvern Zetasizer Nano ZS, i.e. the same device useable for measuring particle size. For testing, 1 mL of emulsion sample is used. It is diluted 60 times in water to maximize dispersion of particles Zeta potential measurements can e.g. be performed on a Malvern Zetasizer Nano ZS. The measurements are made at 25°C and using an equilibration time of 420 seconds. Prior to measurement, measures are taken to remove bubbles, e.g. inversion and redispersion of the sample. Zeta potential is not measured on the reconstituted sample, as physical stability is less of a concern than for the base emulsion, the latter potentially requiring storage prior to freeze drying. The Water Phase According to the present disclosure, the emulsion comprises a water phase. This relates both to a base emulsion which is converted into the solid formulation of the present invention by freeze- drying, and to a reconstituted emulsion obtained by contacting the solid formulation of the present invention with an aqueous solvent to dissolve the solid carrier. The water phase preferably contains no other solvent than water, although trace amounts of solvents may be present. The water phase may contain at least 90 wt.% water, preferably at least 95 wt.% water and more preferably at least 98 wt.% water. The addition of solvents which may help to dissolve cannabinoids in the water phase are preferably absent. In particular, ethanol is preferably absent (although trace amounts may be tolerated). This is because it is desired to keep the cannabinoid in the oil phase. It is a Pharmacopeial requirement (Ph. Eur. 5.4) to test for residual organic solvents used in the production of said emulsion. Ethanol is often used as extraction solvent for phytocannabinoids as well as cleaning detergent in the emulsion production process, which justifies the test for residual ethanol. The maximum amount of ethanol present in the emulsions of the present invention is preferably set to 0.5 wt.% based on the entire emulsion. In addition to water, the water phase may contain various additives. These are discussed below. It is also possible that surfactant is contained in the water phase. However, for the purposes of the present disclosure, the surfactant system is not included as part of either the water phase or the oil phase when calculating relative amounts. As regards the reconstituted emulsion, the water phase may be gastric fluid, if administered orally to the GI tract, or saliva, if administered as orodispersible tablet. The Solid Carrier Phase The solid compositions of the present invention comprise a water-soluble solid carrier phase. The present inventors have found that when an oil-in-water emulsion comprising a cannabinoid is freeze-dried and reconstituted, then it is not possible to avoid that the oil droplets coalesce to a significant degree. In order to address this problem, a solid carrier phase has been introduced. The solid carrier phase comprises soluble materials which are dissolved in the aqueous phase of the emulsion prior to freeze-drying. The water-solubility of the soluble materials comprised in the carrier phase are preferably at least 400 mg / mL, more preferably at least 500 mg / mL at 20°C. Proceeding this way, it is possible to substantially avoid the above-mentioned problem of a partial or complete collapse of the emulsion on reconstitution, and / or avoid that a significant increase in the measured particle size of the droplets in the emulsion and measured e.g. by the aforementioned D50, D10 and / or D90 values. The present inventors have also found that the selection of the solid carrier is important, and that the use of sucrose leads to particularly good results. Accordingly, the solid carrier phase of the solid formulations of the present invention preferably comprises sucrose, although other carrier agents may be incorporated, e.g. sorbitol. Experiments have revealed that using sucrose leads to a flowable powder in which the cannabinoid is evenly distributed. Both in terms of flowability and homogeneity, it was surprisingly found that using sucrose as a carrier is technically superior to using mannitol. It was also found that the use of sucrose leads to a more stable reconstituted dispersion, which is relatively resistant to phase separation. Sucrose preferably makes up at least 50 wt.% of the solid carrier phase, and more preferably the solid carrier substantially consists of sucrose, or even consists of sucrose. The amount of solid carrier phase has also been found by the present inventors to be important. When the amount of solid carrier phase is too low, the present inventors have found that freeze-drying does not proceed in an acceptable way due to problems with flash- boiling. According to the present invention, the concentration of solid carrier phase by weight in the freeze dried powder is preferably 60 to 90 wt.%, more preferably 65 to 80 wt.%. The Oil Phase According to the present invention, the formulation comprises an oil phase. The cannabinoid is present in this phase. The oil phase acts as a carrier for the cannabinoid, and the cannabinoid is soluble in it. Any oil can in principle be used, as long as the cannabinoid can be dissolved in it. The oil phase preferably comprises one or more long chain triglycerides (LCT) or very long chain triglycerides (VLCT). Triglycerides are tri-esters derived from the condensation reaction of glycerol with three fatty acids. The three fatty acids may be the same or different, and they may each be saturated or unsaturated. An LCT is defined as a triglyceride in which the average carbon number of the fatty acid-derived groups is in the range C12-C15. For example, all three of the fatty acid- derived groups can have a carbon number in the range C12-C15. Analogously, a VLCT has an average carbon number of the fatty acid-derived groups in the range C16-C22. For example, all three of the fatty acid-derived groups can have a carbon number in the range C16-C22. LCT / VLCT oils have been found by the present inventors to result in greater absorption of the cannabinoid(s) in an emulsion when it is taken orally. The inclusion of LCTs and / or VLCTs is believed to result in a higher fraction of the dose reaching the systemic circulation, when compared to a similar emulsion based on medium-chain triglycerides (MCTs). LCTs and VLCTs are significantly more viscous than MCTs. Perhaps for this reason, it is conventional to use MCTs for dissolving cannabinoids. The present inventors have surprisingly found that the advantages of using LCTs and VLCTs outweigh any predicted disadvantages. Preferably, the total amount of LCT and VLCT in the oil phase is in the range 45 to 75 wt.%, more preferably 55 to 65 wt.% based on the total weight of the oil phase. Examples of triglycerides which can be comprised in the oil phase include: OLL: 1-oleyl-2-linoleyl-3-linolenoylglycerol; OOL: 1,2-dioleyl-3-linolenoylglycerol; PLL: 2,3-dilinoleyl-1palmitoylglycerol; POL: 1-palmitoyl-2-oleyl-3-linoleylglycerol; OOO: 1,2,3-trioleylglycerol; POO: 2,3-dioleyl-1-palmitoylglycerol; SOO: 2,3-dioleyl-1-stearoylglycerol. The use of MCTs is preferably substantially avoided, or at least minimized, in the present invention. Preferably, the oil phase comprises no more than 10 wt.% MCTs, preferably no more than 5 wt.% MCTs. In a particularly preferred embodiment, the oil phase comprises olive oil and / or rapeseed oil. Preferably, both of these are contained, preferably in a weight ratio of olive oil:rapeseed oil which is in the range 1:6 to 1:2, preferably around 1:4. The fatty acids present in the triglycerides in olive oil and rapeseed oil are set out in Table 1 below: Table 1: Overview of fatty acid composition of olive oil and rapeseed oil listed in their respective monograph in Ph. Eur. (European Pharmacopoeia). S = Saturated, US = Unsaturated. Composition Fatty acid Type IUPAC name FormulaRapeseed Olive oil oil Palmitic Hexadecanoic SC16H32O2 7.5-20.0% 2.5-6.0%acid acid Palmitoleic (Z)-hexadec-9- USC H O ≤ 3.5% N / Aacid enoic acid Stearic Octadecanoic S C H O 0.5-5.0% ≤ 3.0% acid acid (Z)-octadec-9- 56.0- 50.0- Oleic acid USC H O enoic acid 85.0% 67.0% (9Z,12Z)- Linoleic 16.0- US octadeca-9,12- C H O 3.5-20.0% acid 30.0% dienoic acid (9Z,12Z,15Z)- Linolenic octadeca- 6.0- US C H O ≤ 1.2% acid 9,12,15- 14.0% trienoic acid Arachidic SIcosanoic acid C H O ≤ 0.7% N / Aacid Eicosenic (Z)-icos-11- USC H O ≤ 0.4% ≤ 5.0%acid enoic acid Behenic SDocosanoic acid C H O ≤ 0.2% N / Aacid (Z)-docos-13- Erucic acid US C H O N / A ≤ 2.0%enoic acid Lignoceric Tetracosanoic SC H O ≤ 0.2% N / Aacid acid In addition, the oil phase may contain various additives. These are discussed below. It is also possible that surfactant is contained in the oil phase. However, for the purposes of the present disclosure, the surfactant system is not included as part of either the water phase or the oil phase when calculating relative amounts. The Cannabinoid The presently claimed formulation comprises one or more cannabinoid compounds, which is / are present in the oil phase. According to the present invention, the cannabinoid is dissolved in the oil. The cannabinoid compound(s) may be provided in the form of acannabinoid concentrate, e.g. an extract from the Cannabissativa L. plant (phytocannabinoids). The cannabinoid(s) may also be synthetically derived by means of organic chemistry for example to resemble the body’s own cannabinoids (endocannabinoids), phytocannabinoids or structural analogues thereof. Cannabinoids may also be produced by biosynthesis for example by fermentation technology. Cannabis sativa L. is an annual herbaceous flowering plant. Indigenous to Eastern Asia, the plant is now of cosmopolitan distribution due to widespread cultivation. It has been cultivated throughout recorded history and used as a source of industrial fiber, seed oil, food, and medicine. Although the main psychoactive constituent of Cannabis is tetrahydrocannabinol (THC), the plant is known to contain more than 500 compounds, among them at least 113 cannabinoids; however, most of these “minor” cannabinoids are only produced in trace amounts. Besides THC, another cannabinoid produced in high concentrations by some plants is cannabidiol (CBD). CBD is a phytocannabinoid discovered in 1940. It accounts for up to 40% of the plant’s extract. CBD is a herbal dietary supplement. CBD does not have the same psychoactivity as THC, and can modulate the psychoactive effects of THC on the body if both are present. Unlike THC, which acts on the cannabinoid receptor type 1 (CB1) as a partial agonist, CBD instead is a negative allosteric modulator of CB1 receptors. Material types from the plant are distinguished from their degree of purification and thus concentration of the major cannabinoid: extracts (cannabinoid 45-75% w / w), distillates (60-95 % w / w) and isolates (≥95% w / w). The use of a plant-based extract as model compound for the invention does not restrict its applicability to synthetic and biosynthetic cannabinoids. It is also possible to use e.g. synthetic CBD and / or synthetic THC. As for their phytocannabinoids counterparts, these are poorly water- soluble and they can therefore be dissolved in a carrier oil in the same way as a cannabinoid plant-based extract. When a cannabinoid plant-based extract is used, this is preferably included in the oil phase in an amount of 15 to 55 wt.%, preferably 25 to 45 wt.% based on the weight of the oil phase. The amount of cannabinoid plant-based extract in the base emulsion (prior to freeze drying) is preferably 1 to 10 wt.%, preferably 2 to 8 wt.%. The same preferred amounts apply also to the use of synthetic cannabinoids such as CBD and THC; the total amounts of cannabinoids in the oil phase should in that case preferably be 15 to 55 wt.%, more preferably 25 to 45 wt.% based on the weight of the oil phase.Process for Extracting Cannabinoids from Cannabis Sativa L.Various solvents have been used for the extraction ofcannabinoids as the main bioactive compounds of Cannabissativa L. Common organic solvents can be used, althoughsupercritical CO2is preferred for larger-scale preparative applications. Alcohols such as ethanol (EtOH) and methanol (MeOH) are widely employed, and their usage has been warranted by previous research findings. EtOH presents the additional advantage of low toxicity, besides the reported efficiency for cannabinoids. Production of a cannabis extraction involves the following steps: The cannabis plant material is harvested, i.e. some or all of the stalks, stems and leaves of the plant. The plant material is then dried and chopped. The chopped material is placed in a vessel together with the solvent. The solvent (contained dissolved cannabinoids taken up from the plant material) is then separated from the solid plant material, e.g. by filtration, and the filtrate collected. The solvent is then removed from the filtrate e.g. by evaporation. The resulting composition is the cannabinoid extract. Further steps may be included, such as removal of waxes, removal of terpenes and decarboxylation. Cannabinoid extraction processes are described further in US9987567B1. The composition of the cannabinoid extract, i.e. which cannabinoids are contained in which relative amounts, is dependent on various factors, including the choice of plant material and the solvent used. Conditions applied in the extraction process may also play a role, for example temperature and extraction time. According to the present invention, the cannabinoid(s) is / are dissolved in the oil phase. It is not contemplated that the cannabinoids in the claimed emulsions are present in the form of solid particles of cannabis plant material which contain the cannabinoid(s). In particular, the present inventors have realized that the use of dissolved cannabinoids in the oil phase leads to advantages relative to the inclusion of cannabis plant material. Firstly, when the cannabinoid(s) is / are dissolved in the oil phase, bioavailability is improved as compared to the use of solid cannabis material. Secondly, it is believed that safety is improved because it is uncertain how the body may react to the ingestion of solid, insoluble material with a small particle size. The Surfactant System A surfactant system is needed to reduce the interfacial surface tension between oil and water and ultimately improve the physical stability of the emulsion. It is also needed to ensure that droplets of oil do not coalesce upon reconstitution. Furthermore, the surfactant system is needed in order to render the outside surface of the oil droplets much more hydrophilic, in order to allow these droplets (or micelles, as they are in the presence of the surfactant system) to be bioavailable. The HLB number (hydrophilic-lipophilic-balance) of the selected surfactant system is preferably selected to approximately match that of the disperse phase, i.e. the oil phase in the present invention. Most preferably, the surfactant system comprises non-ionic surfactants. It is preferably to use a blend of hydrophilic and hydrophobic non-ionic surfactants. Preferred surfactants which can be included in the surfactant system in the emulsion of the present invention include non- ionic surfactants such as: Sorbitan esters, such as sorbitan monooleates, sorbitan monolaurates, sorbitan monopalmitates, sorbitan monostearates, sorbitan tristearates, sorbitan trioleates. Preferably, the sorbitan monooleate is used, most preferably the specific surfactant Span® 80. This is a lipophilic surfactant. Polysorbates including polyoxyethylene sorbitane monolaurates, monopalmitates, monostearates, monooleates, tristearates, trioleates and preferably mono-oleates. A particularly preferred surfactant is polyoxyethylene sorbitan mono-oleate (Tween® 80). This is a hydrophilic surfactant. Preferably, the surfactant system comprises both Span® 80 and Tween® 80. If both Span® 80 and Tween® 80 are contained, the weight ratio between them is preferably in the range 1:3 to 1:0.50. The selected ratio may depend on how much oil phase is contained in the emulsion. For large amounts of oil, say ca. 25 wt.%, then the ratio of Span® 80 and Tween® 80 may be in the range 1:0.50 to 1:1, preferably around 1:0.75. For more moderate amounts of oil, say ca. 10 wt.%, then the ratio of Span® 80 and Tween® 80 may be in the range 1:3 to 1:1.50, preferably around 1:2. If both Span® 80 and Tween® 80 are contained, they preferably together make up at least 50 wt.% of the surfactant system, preferably 60 to 100 wt.% of the surfactant system, preferably at least 80 wt.% or at least 90 wt.%. In a preferred embodiment, the surfactant system consists of Span® 80 and Tween® 80. The amount of the surfactant system, relative to the weight of the emulsion as a whole used, can be calculated in view of the desire to form micelles. The concentration therefore has to be selected to be above the critical micelle concentration (CMC). This may be applied to the base emulsion which is freeze-dried. For example, when the oil phase constitutes 10 wt.% of the emulsion, then the total amount of surfactant would typically be 6 wt.%, with the remainder of the base emulsion being the water phase. At least some surfactant will be contained at the interface between the oil phase and the water phase. Additionally, surfactant may also be contained in the water phase and / or the oil phase. For the purposes of the present disclosure, the surfactant system is considered to be a separate part of the composition to the oil phase and the water phase, so that it is not included for the purposes of calculating the total amount of either of these phases, which is needed e.g. for calculating relative amounts of the two phases in the base emulsion, and for calculating relative amounts of ingredients in each of these two phases. Antioxidants It is preferred that the compositions of the present invention comprise one or more antioxidants. The antioxidant primarily serves to prevent oxidation of the cannabinoid. It can also help to prevent oxidation of triglycerides which are contained in the oil phase – in particular, unsaturated triglycerides are prone to oxidation. In a preferred embodiment of the present disclosure, the base emulsion comprises antioxidant components in both the oil phase and in the water phase. In that case, the antioxidant in the oil phase has to be soluble therein, and the antioxidant in the water phase has to be soluble therein. The antioxidant in the oil phase may e.g. be Vitamin E. The antioxidant in the water phase may e.g. be Vitamin C. Suitable amounts of antioxidant are e.g. 0.05 to 2 wt.% based on the emulsion, preferably 0.50 to 1 wt.%. Upon freeze-drying, any antioxidant present in the aqueous phase of the base emulsion will be incorporated into the solid carrier phase of the solid formulation of the invention. Upon reconstitution, that anti-oxidant will dissolve and again enter the aqueous phase. Further Ingredients Further ingredients may be contained in the formulation. For example, a preservative may be included. If included, the preservative may be potassium sorbate and / or sodium benzoate. Alternatively, preservatives such as benzalkonium chloride, cetylpyridinium chloride, thiomersal, benzoic acid, and propylene glycol. Less preferred preservatives include biguanides (e.g. chlorhexidine), phenols, benzyl alcohols, methyl parabens, ethyl parabens, and propyl parabens. The formulation may also contain a pH-modifier. The preferred pH of the emulsions of the present invention is in the range 4-6, preferably around 5. Addition of a pH-modifier may be necessary if the pH of the base emulsion at the end of the emulsification process is outside this preferred range. Such pH modifying agents may be e.g. known buffers, e.g. citric acid. In another preferred embodiment, the formulation may contain a pH-modifier such as lactic acid or a lactate, phosphoric acid or a phosphate, hydrochloric acid, or a hydroxide salt. The amount added is determined based on the pH of the base emulsion at the end of the emulsification process and the target pH. If the emulsion resulting immediately from the emulsification process has a pH within the preferred range, then there may be no need to add a pH-modifier. A taste-masking agent may also be included, especially in cases where the resulting solid material is to be further formulated into an orodispersible tablet. A preferred taste- masking agent is menthol. Menthol is poorly water-soluble, so that it will primarily be found in the oil phase of the formulations of the present invention. The formulation of the present disclosure may further comprise an osmotic agent, preferably selected from the group consisting of glycerin, glucose, sucrose, sorbitol, sodium phosphate and any combination thereof. Processing Technology – Forming the Base Emulsion Formation of nano-sized droplets requires introduction of energy and / or application of mechanical force to break apart the oil phase into droplets. Ultrasonication and high- pressure homogenization are preferred ways to achieve this in present invention. Ultrasonication, as the name implies, applies ultrasonic waves (frequency greater than 20 kHz). The mechanical vibration creates acoustic cavitation resulting in the formation of droplets. High-pressure homogenization uses a high-pressure piston pump to mechanically reduce the size of dispersed oil droplets. Several cycles of homogenization may be introduced to further reduce the size of the droplets so as to arrive at an emulsion which has the recited D50 value of 100nm to 400nm. Processing Technology – Forming the Solid Formulations According to the present invention, the solid formulations are preferably made by freeze-drying a base emulsion. Freeze-drying is a gentle drying process, resulting in less product damage as compared to other drying methods that utilize high temperatures. To effectively freeze-dry a product, it must be completely frozen (i.e. below its eutectic temperature) before the sample is submitted to the freeze drier. If the sample is not completely frozen, expansion of the unfrozen components when placed under vacuum may disrupt the integrity of the sample, resulting in a destroyed product. Freeze-drying is based on sublimation (going directly from solid to gaseous state), where the ice crystals formed under the freezing process turns into vapor and leave small holes and gaps in the product, maintaining the integrity of the sample throughout the process and facilitate easy rehydration Medical Uses The formulations of the present invention have many potential uses. They can be used in palliative care, and / or in the treatment or alleviation of a disease, preferably wherein the disease is selected from the group consisting of pain, in particular acute or chronic pain, somatic pain, visceral pain, neuropathic pain, cancer pain, chronic back pain, chronic central nervous pain; neurological disorders, neurodegenerative diseases, insomnia, psychiatric disorders, nausea, anorexia, vomiting and nausea caused by chemotherapy, diabetic polyneuropathy, fibromyalgia, Tourette-Syndrome, multiple sclerosis, spasm at multiple sclerosis, anxiety disorders, schizophrenia, social phobia, sleep disorder, skin related diseases like psoriasis and neurodermatitis, glaucoma, restless leg syndrome, epilepsy, Alzheimer disease, movement disease like Dystonias, Huntington‘s disease, Parkinson’s disease, bipolar diseases, as well as other medical indications which are affected by the endocannabinoid system and which are affected by any other receptors affected by cannabinoids (e.g. GPR18, GPR119, GPR55). Uses for further processing The formulation may be mixed with other ingredients and converted into a final dosage form. For example, the formulation can be made into tablets or capsules using conventional pharmaceutically acceptable ingredients and conventional methods. Examples of a tablet formulation and a capsule formulation are set out below: Table 2: Example of a tablet formulation. Tablet size is 500 Component Load (wt.%) Weight (mg)Freeze dried powder40 200with 8% active Microcrystalline54 270cellulose Croscarmellose5 25sodium Magnesium stearate 1 5Total N / A 500Table 3: Example of a tablet formulation. Tablet size is 500 mg. Component Load (wt.%) Weight (mg)Freeze dried powder100 505with 8% active Magnesium stearate 1 5Total N / A 510Administration The formulations of the present invention are designed to be optimized for oral administration. As discussed above, the emulsions may be formulated to optimize cannabinoid absorption when the solid formulation is swallowed. For example, when preferred oils are used, the uptake is improved and elimination of the cannabinoid in the liver is reduced. The formulations are primarily intended to be administered in solid form, but may also be administered to the user as an oral solution e.g. by reconstituting the emulsion prior to use. Examples Example 1 – Preparation of the Oil-in-water Emulsion Oil-in-water emulsions were prepared. The oil phase consists of a cannabis extract dissolved in carrier oils (olive and rapeseed oil), lipophilic antioxidant, and taste masking agent (menthol). A lipophilic surfactant (low-HLB) is mixed with the ingredients of the oil phase. The water phase consists of preservative and hydrophilic antioxidant dissolved in WFI water. A hydrophilic surfactant (high-HLB) is mixed with the ingredients of the oil phase. A blank emulsion was also created for the lowest oil phase concentration (10 wt.%). The blank emulsion is prepared in the same manner as the cannabinoid emulsions (see step-wise description below), except that no cannabinoid extract was added. The following manufacturing steps were used: A. Water phase premix• The water phase ingredients are mixed.B. Oil phase premix• The cannabinoid extract is weighed in a container ofsuitable size and liquified by the application of heat (up to 60°C). using either a water bath or heat plate.• All other ingredients are weighed separately and addedto the extract-container under mixing. C. Addition of oil phase to the water phase under ultrasonication (1. Emulsification)• Water phase is weighed in a container of suitable size.• The tip of an ultrasonic probe is installed into thewater phase and turned on.• The oil phase is added in a controlled manner using apump while mixing and under ultrasonication.• Mixing and ultrasonication continues after addition ofoil phase. The total ultrasonication time is 60 min at a batch size of 25 L (25 kg) (approx. 700 W). D. High-pressure homogenization (2. Emulsification)• The ultrasonicated emulsion is subjected to finalemulsification using a high-pressure homogenizer.• The batch is processed through the homogenizer at apressure of at least 100 MPa.• Two cycles of homogenization are performed.E. pH adjustment• The pH is measured, and if necessary, the emulsion is pHadjusted to 4.9 – 5.1 using HCl / NaOH. F. Filtration to single use storage bags• The finished emulsion is filtered through a 0.45 ^mfilter to a single use bag (closed system).• The pressure under filtration is continuously monitoredand the filter is replaced if the pressure exceeds 1 bar. Using the above preparation method, the emulsions of Table 2 below were produced. Refined olive oil was chosen as LCT and refined rapeseed oil as VLCT and mixed together in a 1:4 ratio in the oil phase. A lipophilic antioxidant, all-rac-^- Tocopheryl acetate (Vitamin E acetate), was added in 1.2 wt.% concentration relative to the oil phase. A hydrophilic antioxidant, ascorbic acid (Vitamin C), and a preservative, potassium sorbate, were added to the water phase in 1.2 wt.% and 0.1 wt.% concentration relative to the water phase, respectively. All emulsifications, except D1, were successfully completed. D1 did not result in homogenous emulsion and remained phase separated, confirming the edge of failure of the formulation design. Pictures of emulsions B1, C2 and the failed D1 are provided in Fig. 2A, 2B, and 2C, respectively: Table 4: Formulation design for emulsions. Lab scale is less than 5 L emulsion; pilot scale is between 5 and 30 L emulsion * = Extract from CBD chemovar; ** = Extract from THC chemovar ; *** = 1:1 mix of CBD and THC emulsions Oil Water Surfactant system (relative to Extract phase phase emulsion) (wt.% (wt.% ID Scalerelative (wt.% of Tween of oil Span 80Total HLBto wateremulsion) 80 phase) surfactant phase) blend (wt.%) (wt.%) (wt.%)A1 Pilot 31* 10.0 85.4 2.1 4.0 6.1 11.3A2 Lab 31* 10.0 85.4 2.1 4.0 6.1 11.3A3 Pilot 31** 10.0 85.4 2.1 4.0 6.1 11.3A4 Lab 31** 10.0 85.4 2.1 4.0 6.1 11.3A5 Pilot 31*** 10.0 85.4 2.1 4.0 6.1 11.3A6 Pilot 0 10.0 85.4 2.1 4.0 6.1 11.3A7 Lab 0 10.0 85.4 2.1 4.0 6.1 11.3B1 Lab 42* 20.7 76.4 4.2 3.6 7.8 9.2C1 Lab 40* 27.8 71.0 5.3 4.0 9.3 8.9C2 Lab 42* 27.6 71.7 5.3 3.4 8.6 8.5D1 Lab 40* 35.4 66.9 6.3 3.1 9.4 7.9Example 2 – Particle size measurements and zeta potential DLS measurements were performed on the emulsions A1-A4, A6-A7 and C1 which were produced in Example 1. D10, D50 and D90 values were measured, as well as the zeta potential. The size measurements were performed using a Malvern Zetasizer Nano ZS (Table 3) in accordance with ISO 22412:2017. Measurements of zeta potential were carried out on the same equipment in accordance with ISO 13099-1:2012. The test parameters were as shown in below tables: Table 5: DLS size method details Item DescriptionDisposable cuvette (base Cell emulsion) DTS0012 (reconstituted emulsion) Refractive index of dispersant 1.34 (base emulsion) Mixture of water & oil 1.33 (reconstituted emulsion) emulsion Material (RI / absorbance) 1.450 / 0.001Dispersant viscosity 1.0366 (base emulsion) (cP) 0.8872 (reconstituted emulsion)Display range 0.6 – 6000 nmDetector angle (°) 173Temperature (°C) 2560 (base emulsion) Equilibration time (sec) 120 (reconstituted emulsion) Number of measurements 3Number of sample 2 preparations per sample Table 6: DLS zeta potential method details Item DescriptionCell Disposable folded capillary cellsRefractive index 1.450 / 0.001 (RI / absorbance) Viscosity 1.0366Dielectric constant 78.5Model value 1.50Temperature (°C) 25.0Equilibration time (s) 420 Number of measurements 1 Number of sample 2 preparations The results are shown in Table 7 below: Table 7: Measured particle size distributions and zeta potential of the emulsions Surfactant system (relative to emulsion) ID D10 D50 D90 ZP (mV) (nm) (nm) (nm) A1 67.1 117 214 -10.80A2 68.4 128 240 -6.60A3 82.8 160 360 -15.20A4 68.3 146 389 -5.10A6 58.1 107 194 -9.44A7 63.1 119 219 -7.30C1 113 175 279 -35.00The droplet size distribution is robust towards changes in the extract load of the oil phase (A1-A4 compared to the blank emulsions, A6-A7). The droplet size increases slightly for the highest loaded formulation, C1, but it is still well within the target ranges for droplet size. The droplet size distribution of sample A1 is shown in Figure 3. Example 3 – Stability evaluation 12-month stability testing was performed on emulsion A5 which was produced in Example 1. Stability was tested under ICH Q1 conditions: Refrigerated, intermediate (30°C / 65 %RH) and accelerated (40°C / 75 %RH). The samples were packed in 30 mL HDPE bottles with screw caps and stored in qualified climate chambers. Analyses are summarized in below table 8: Table 8: Analyses conducted per condition and time point. Condition Compendial5 ^CAnalysis30 ^C / 65 %RH 40 ^C / 75 %RHreference (refriger (intermediate) (accelerated) ated) Cannabinoid T0,T3,T6, DAB All time pointsassay (T9,T12) Ph. Eur. T0,T3,T6, MicrobiologyT0,T6,T12 T0,T6,T125.1.4-1 (T9) Residual Ph. Eur. T0 T0 T0solvents 2.4.24 Ph. Eur. pH All time points 2.2.3 Peroxide Ph. Eur. All time points value 2.5.5 Visual All time points N / A appearance The results were: Visual appearance All samples – at any time point and condition – appeared yellow and milky and showed no sign of phase separation. Cannabinoids Cannabinoid stability data are illustrated in Figure 4A-C for the three conditions. The following is observed: ^Under refrigerated conditions, the emulsion remainsfully stable throughout the 12 months test period. No incipient signs of cannabinoid degradation are observed (Figure 4A). ^Degradation of THC is observed at T12 under intermediateconditions (Figure 4B) and at T9 under accelerated conditions (Figure 4C), i.e. degradation starts somewhere between T9 and T12 at 30^C and somewhere between T6 and T9 at 40^C. ^No critical degradation products were detected, as CBNremains below its specification limit (<0.1 %; not shown) and with no quantifiable ^8-THC formationassessed for 40^C at T9 (not shown). Microbiology & pH Microbiological purity is within specification at any condition and at all time points. This is backed-up by the pH which remains in the range 4.8-5.8, considering that bacterial growth (or chemical degradation) can impact the pH of the product. Table 9: pH measurements from QC. The emulsion is adjusted to a pH of approx. 5 during production. 5^C 30 ^C / 65 %RH 40 ^C / 75 %RHConditions (refrigerated) (intermediate) (accelerated) T0 5.2 5.2 5.2T3 5.1 5.6 5.8T6 5.3 5.7 5.5T9 5.3 5.5 5.0T12 5.4 5.1 4.8Peroxide value (“oil rancidity”) Peroxide values are provided in Table 8.The peroxide value IP is the number that expresses inmilliequivalents of active oxygen the quantity of peroxide contained in 1 kg of the substance. It is used to evaluate the rancidity of the oil phase in the emulsion. Rancidity can impact the taste and smell of the product and thus patient compliance. The peroxide value at which oxidation of oils can be detected as an off-flavour varies widely depending on the nature of the oil. Samples of olive oil may not be perceived as rancid till the peroxide value reaches 20 meq / kg according to literature. It is not surprising to see an increase in the peroxide value at the harshest condition after nine months, 2.0 meq / kg, increasing very slightly to 2.1 after 12 months. Peroxide levels are slightly elevated to 1.3 after 12 months for the 30 / 65 condition. However, peroxide values in this range (< 2 meq / kg) are well below the 20 meq / kg threshold of rancidity for pure oils and is therefore not expected to impact taste and smell of the product. Table 10: Peroxide values. 5^C 30 ^C / 65 %RH 40 ^C / 75 %RHConditions (refrigerated) (intermediate) (accelerated) T0 < 0.04 < 0.04 < 0.04T3 < 0.04 < 0.04 < 0.04T6 < 0.04 < 0.04 0.8T9 < 0.08 < 0.08 2T12 < 0.08 1.3 2.1Example 4 – In vitro and in vivo experiments on bioavailability Drug delivery performance of the emulsion technology was tested at a 10% oil phase relative to water phase, loaded with THC and CBD extracts. The tests were performed using the emulsion A5 of example 1 designated Formulation #1 in the experiment (see tables 11 and 12). Formulation #2 of tables 11 and 12) was a simple mixture of extract and MCT oil. Formulation #3 of table 11 was only included in the in vitro experiment. It was prepared from a commercially available EtOH-PG (ethanol and propylene glycol) based formulation with CBD and THC, which was diluted with EtOH-PG to provide a final cannabinoid concentration similar to Formulation #1 and #2 (0.85 wt.% of each cannabinoid). A comparison was made relative to other types of cannabinoid formulation technologies. This is covered by an in vitro and in vivo part with the following aims:• In vitro: To evaluate the transport of CBD and THC fromthree different formulations over an artificial membrane, designed to mimic the oral mucosa, using the µFLUX setup.• In vivo: To elucidate the pharmacokinetic (PK) profileof CBD and THC after oral administration in rats. Table 11: Summary of experimental setup of the in vitro flux (1) o / w emulsion (A5) Formulations (2) MCT-based (3) EtOH-PG based (1): THC and CBD extracts standardized in the final delivery system to approx. 0.85 wt.% of each cannabinoid in the emulsion. (2) THC and CBD extracts standardized in the final delivery system to approx. 0.85 wt.% of each cannabinoid using MCT as Active diluent compounds (3): THC and CBD of an intermediate product diluted in the final delivery system to approx. 0.85 wt.% of each cannabinoid using a 0.43:0.57 mixture of ethanol (EtOH) and propylene glycol (PG) by weight as diluent - Concentrations of all three equalized Parameters (see above), to eliminate any bias from difference in concentration gradients. - Flux through an artificial membrane and artificial saliva (PAMPA = Parallel Artificial Membrane Permeability assay) - Receptor media assayed at specific timepoint using UV-HPLC In vitro: µFLUX experimentsThe in vitro permeation experiments were performed using aµFLUX™ setup from Pion Inc. (Billerica, MA, USA) consisting of two 20 mL compartments separated by a horizontal barrier with an absorptive area of 1.0 cm2. A schematic overview of the µFLUX setup is shown in Figure 5. The barrier of the setup comprised a PAMPA-membrane prepared by the addition of 25 µL phosphatidylcholine solution (20% w / v in dodecane) to a hydrophobic 0.45 µm PVDF filter. An additional hydrophilic 0.45 µm PVDF filter was introduced to act as a physical boundary between the PAMPA-membrane and the donorcompartment. To mimic the in vivo situation, artificialsaliva (Orthana Saliva) 12 mL was added to the donor side along with 3 mL formulation and 20 mL acceptor sink buffer (ASB); 20 mM HEPES, 1% w / v SLS adjusted to pH 7.4 was added to the receiver side. Both donor and receptor compartments were maintained at 37 °C and stirred using 20 mm cross-shaped magnetic stirrers operating at 250 rpm. Samples of 100 μL were taken from the receptor compartments at t = 15, 30, 60, 90, and 120 min and replaced with 100 μL ASB. The samples were diluted with 100 μL methanol and centrifuged before the resulting supernatant was assayed for CBD and THC using HPLC- UV. All treatments were done in triplicate. In vivo: GI tract absorption in rodents Table 12: Summary of experimental setup of the in vivo PK experiments. (1) o / w emulsion Formulations (2) MCT-based (1): THC and CBD extracts standardized in the final delivery system to approx. 0.85 wt% of each cannabinoid in the emulsion. Active (2) THC and CBD extracts standardized in compounds the final delivery system to approx. 0.85 wt% of each cannabinoid using MCT as diluent - Fasted rats (n=4 per cohort) dosed by oral gavage - Blood samples taken from the tail vein Parameters at timepoints: 0.5, 1, 1.5, 2, 3, 4, 6 and 24 h - THC / CBD in supernatant of blood samples assayed by LC-MS Detailed description of rat studies Male Sprague-Dawley rats from Janvier Labs (Le Genest-Saint- Isle, France) were used for the study which was carried out in agreement with the Danish law on animal experiments as approved by the Danish Animal Experiments Inspectorate in accordance with the EU directive 2010 / 63 / EU under license number 2019-15- 0201-00262. THC and CBD strengths were determined for both formulations prior to the in vivo study. The formulations were diluted 1000x in MeOH and analysed by HPLC-UV relative to standards diluted in MeOH.The rats were fasted overnight with ad libitum access towater during their inactive period, by adjusting the day / night rhythm, so that the rats had their inactive period during the night. Four rats were dosed with the emulsion and four rats were dosed with the MCT-based formulation. All rats were dosed by oral gavage with a volume of 3 mL / kg (51 mg / kg, CBD+THC). Blood samples (100-150 µL) were taken from the tail vein at the timepoints: 0.5, 1, 1.5, 2, 3, 4, 6 and 24 h (8 h sample was excluded due to insufficient blood flow from the tail vein) and the plasma collected by centrifugation at 10,000 × g at 4 °C for 10 min. The rats were killed prior to the 24 h sample which was taken from the heart prior to harvesting of the brains. Both plasma samples and brains were stored at -20 °C until the day of LC-MS analysis. Precipitation of plasma proteins was done prior to analysis by mixing 50 µL plasma with 200 µL methanol followed by vortex, 10 min storage at -20 °C and centrifugation. The supernatant was analysed by LC-MS and quantified relative to standards prepared in the same way, yet by mixing 50 µL of blank plasma with 200 µL of CBD / THC solutions in methanol. The difference in dilution factor between samples and standards was accounted for during the data treatment. The brains were each homogenized in 10 mL methanol and the homogenate centrifuged at 5500 × g for 5 min. The supernatant was evaporated to dryness and resuspended in 500 µL MeOH followed by centrifugation and LC-MS analysis. Results Results from the µFLUX studies are shown in Figure 6A and 6B, for CBD and THC flux, respectively. Results from the in vivo study in rats are shown in Figure 7A and 7B, for CBD and THC, respectively. •Permeation through the PAMPA membrane is superior forthe emulsion and almost non-existent for other formulations high likelihood of sublingualabsorption. The poor flux from the EtOH-PG based formulation is believed to be explained partially by precipitation of the poorly soluble cannabinoids from the EtOH-PG solution upon contact with artificial saliva, the latter acting as an anti-solvent to the cannabinoids. Precipitation was visually observed when dispersing the EtOH-PG formulation with artificial saliva. •Significantly faster onset of absorption and highexposure of emulsion following administration to the GI tract compared to the MCT-based formulation. •The combined pre-clinical package establishes theeffectiveness of the emulsion as an enabling drug delivery technology. In addition to sublingual permeation, the fraction of dose, which is inevitably lost to the GI tract, is still absorbed to a high extent. Example 5 – Preparation of the solid formulation by freeze- drying and appearance 6 samples of cannabinoid oil-in-water emulsion as prepared in Example 1 were modified by addition of sucrose or mannitol in different amounts as outlined in the table below. The base emulsion used had the composition shown in Table 13. Between 1 to 3 g of base emulsion was added to each vial and mixed with a quantity of solid carrier providing the intended concentration shown in Table 14. Table 13: Composition of base emulsion. Oil Water Surfactant system (relative to emulsion) phase phase Cannabinoid (wt.% (wt.% Extract relative of (wt.% ofSpan 80 Tween 80 Total HLB surfactantto wateremulsio oil phase) blend phase) n) (wt.%) (wt.%) (wt.%)31 10.0 85.4 2.1 4.0 6.1 11.3Table 14: Final emulsions with added sucrose and / mannitol Solid Amount (wt.% based Sample # Carrier on final emulsion) X1 Mannitol 20X2 Mannitol 30X3 Mannitol 40X4 Sucrose 20X5 Sucrose 30X6 Sucrose 40In a first experiment, it was investigated whether pre- freezing to -78^C provides any advantage in terms of avoiding flash boiling. In addition, the suitability of the two solid carriers was investigated. Samples X1 to X6 were included in this experiment. The experimental conditions, including settings of the freeze dryer, are provided in Table 15: Table 15: Composition of base emulsion. Parameter ValuePre-freezing temperature (°C) ~ -78Sample amount (ml) ~1Product temperature when ~ -78 loading (°C) Chamber pressure (mbar) 0.5Shelf loading temperature (°C) 35 Drying chamber temperature (°C) 50* Number of drying cycles 1Observations from the trial are provided below: Samples X1 and X4 (20% solid carrier): Photographs of the freeze dried samples are shown in Figure 8A. Both samples (mannitol and sucrose) did not seem completely dry. Furthermore, flash-boiling occurred to some extent in both vials, especially in the sample containing mannitol, where displacement of the sample towards the top of the vial is observed. Samples X2 and X5 (30% solid carrier): Photographs of the freeze dried samples are shown in Figure 8B. Both samples appeared dry and uniform. Flash-boiling was more prominent with mannitol as observed from the displaced content of the vial, although some flash-boiling was also observed in the sucrose sample (however without leaving the vial). Samples X3 and X6 (40% solid carrier): Photographs of the freeze dried samples and ground material are shown in Figure 8C. Both samples appeared dry. In the freeze-dried sucrose sample (X3) the colour is uniform, while the mannitol sample (X6) shows visible differences in colour in different regions, suggesting that the cannabinoid / oil phase is not evenly distributed in the solid composition. The inhomogeneity can be seen because the oil containing the cannabinoid has a yellow-orange colour, while both mannitol and sucrose are white. The sucrose material was easily removed from the vial and ground, while the mannitol seemed sticky, reminiscent of an amorphous substance, and could not be properly ground to fine particles. Sucrose was easily ground to a crystalline powder. Example 6 – Mass-balance calculations of samples X5 and X6 (30% and 40% sucrose) The loss of material of during freeze drying for samples X5 and X6 was considered and compared to knowledge on the water content of each base emulsion. The weight loss should approximate the amount of water in the base emulsion. The comparison is calculated as follows: Weight loss / water content * 100 % A value of 100% suggests that all the water has been removed during freeze drying. Values for duplicate measurements of X5 and duplicate measurements of X6 are shown in the table below. The calculations confirm that most or all of the water has been removed from the samples. Table 16: Mass-balance between weight loss after freeze drying and water content of the base emulsion. Sample Vial A Vial BX5 (30% sucrose) 103 % 99 %X6 (40% sucrose) 100 % 100 % Example 7 – Reconstitution of emulsion from the freeze-dried solids and assessment of stability The ground freeze-dried samples X3 (40% mannitol) and X6 (40% sucrose) produced in Example 5 were reconstituted as follows: Water was added to the vial with freeze dried powder in a quantity so that the approximate volume of the base emulsion (incl. solid carrier) was reached. The water was 37^C at the start of reconstitution. The vial was shaken gently to observe immediate formation of emulsion (homogenous, yellow liquid). The resulting liquid formulations were photographed and inspected at selected timepoints relative to the time of reconstitution (Figure 9A: 40% mannitol; Figure 9B: 40% sucrose). The results were as follows: Table 17: Stability of reconstituted X3 (40% mannitol) Timepoint relative to Phase separation? reconstitution 0mins NoInitial separation 8 mins visible More separation 13 mins visible Clear phase 42 mins separation Table 18: Stability of reconstituted X6 (40% sucrose) Timepoint relative to Phase separation? reconstitution 0mins No8 mins No13 mins No42 mins No65 mins NoInitial separation 77 mins visible More separation 152 min visible Example 8 – Particle size measurements performed on the reconstituted emulsions Fresh samples of 30% (X5) and 40% sucrose (X6) formulations were prepared and ground for the assessment of particle size distribution. Photographs of the ground material are shown in Figure 10. Two vials of material were sent for particle size analysis. Particle size measurements were performed by DLS according tothe procedure described previously. Samples were analysed intriplicate. The particle size results are summarized in Table 19. The particle size distribution intensity plot for one of the measurements are shown in Figure 11. Although all are acceptable, there appears to be an impact of the sucrose load, with a higher load yielding larger particles. Table 19: Particle size results of reconstituted samples X5 and X6. Sample Vial no. D10 (nm) D50 (nm) D90 (nm)1 140 259 517X5 (30% sucrose) 2132 275 5271 175 336 640X6 (40% sucrose) 2175 309 654

Claims

CLAIMS 1. A solid formulation comprising: an oil phase which comprises one or more dissolved cannabinoid compounds; a surfactant system; and a water-soluble solid carrier phase, wherein the oil phase is present in the form of discrete droplets associated with surfactant, said droplets being at least partially encapsulated by the water-soluble carrier phase.

2. A formulation according to claim 1, which is self- emulsifying so that it forms an emulsion when contacted with an aqueous solution to allow the solid carrier phase to dissolve.

3. A formulation according to claim 2, wherein the formulation forms an oil-in-water emulsion when simulated gastric fluid is added to it, said emulsion having a D50 particle size of the oil phase droplets as measured by dynamic light scattering in the range 100nm to 400nm.

4. A formulation according to claim 2 or claim 3, wherein the formulation forms an oil-in-water emulsion when simulated gastric fluid is added to it, said emulsion having (i) a D10 value higher than or equal to 50nm and / or (ii) a D90 value lower than 600nm, wherein the D10 and D90 values are measured by dynamic light scattering.

5. A formulation according to any preceding claim, wherein the solid carrier phase comprises sucrose, and preferably consists of sucrose.

6. A formulation according to any preceding claim, which is obtained by freeze-drying an oil-in-water base emulsion in which the oil phase comprises the cannabinoid, said baseemulsion having a D50 particle size of the oil phase droplets as measured by dynamic light scattering in the range 100nm to 400nm.

7. A formulation according to any preceding claim, wherein the oil phase comprises long-chain triglycerides (LCT) and / or very long chain triglycerides (VLCT).

8. A formulation according to claim 7, wherein the total amount of LCT and VLCT in the oil phase is in the range 45 to 75 wt.%, preferably 55 to 65 wt.%, based on the total weight of the oil phase.

9. A formulation according to any preceding claim, wherein the surfactant system comprises a lipophilic surfactant and a hydrophilic surfactant, which are preferably a sorbitan ester and a polysorbate, more preferably Span 80 and Tween 80.

10. A formulation according to any preceding claim, wherein the total amounts of cannabinoids in the oil phase is 15 to 55 wt.%, preferably 25 to 45 wt.%, based on the weight of the oil phase.

11. A formulation according to any preceding claim, wherein the weight ratio of solid carrier phase to oil phase is in the range 2:1 to 8:

1.

12. A formulation according to any preceding claim, wherein the weight ratio of solid carrier phase to oil phase is in the range 3:1 to 7:

1.

13. A formulation according to any preceding claim, wherein the formulation is substantially free of water-insoluble solid particles, preferably free of water-insoluble solid particles.

14. A formulation according to any preceding claim, for use in treating one or more of: ^pain (preferably acute or chronic pain, somatic pain,visceral pain, neuropathic pain, cancer pain, chronic back pain, chronic central nervous pain); ^neurological disorders;^ neurodegenerative diseases;^ insomnia;^ psychiatric disorders;^ nausea;^ anorexia;^ obesity;^ vomiting and / or nausea caused by chemotherapy;^ diabetic polyneuropathy;^ fibromyalgia;^ Tourette-Syndrome;^ multiple sclerosis;^ spasms related to multiple sclerosis;^ anxiety disorders;^ schizophrenia;^ social phobias;^ sleep disorders;^ skin related diseases (preferably psoriasis and / orneurodermatitis); ^glaucoma;^ restless leg syndrome;^ epilepsy;^ Alzheimer disease; and^ movement diseases (preferably Dystonias orHuntington‘s disease).

15. A formulation for use according to claim 14, wherein pain is treated.

16. A formulation for use according to claim 14 or claim 15, wherein the treatment comprises oral administration of the formulation.

17. A method of producing a formulation according to any preceding claim, comprising freeze-drying an oil-in-water emulsion which comprises: an oil phase which comprises one or more dissolved cannabinoid compounds; a surfactant system; and an aqueous phase comprising a dissolved carrier material.

18. A method according to claim 17, wherein the emulsion which is freeze-dried has a D50 particle size of the oil phase droplets as measured by dynamic light scattering in the range 100nm to 400nm.

19. A method according to claim 17 or claim 18, wherein the emulsion which is freeze-dried has (i) a D10 value higher than or equal to 50nm and / or (ii) a D90 value lower than 700nm, wherein the D10 and D90 values are measured by dynamic light scattering.

20. A method according to any of claims 17-19, wherein the emulsion which is freeze-dried is obtainable by: (i) Preparing an oil phase by dissolving one or morecannabinoid compounds in a carrier oil; (ii) Preparing a water phase which comprises a dissolvedcarrier material; and (iii) Mixing the oil phase and the water phase byultrasonication and / or high-pressure homogenization so that the D50 particle size of the oil phase droplets as measured by dynamic light scattering is in the range 100nm to 400nm,wherein the emulsion also comprises a surfactant system, whose components are present in (a) the oil phase and / or (b) the water phase and / or (c) the mixture of the oil phase and the water phase.

21. A method according to any of claims 17-20 wherein the oil-in-water emulsion, prior to freeze-drying, comprises 15 to 40 wt.% dissolved carrier material, preferably 20 to 30 wt.% dissolved carrier material.

22. A method according to any of claims 17-21, wherein the solid carrier material comprises sucrose, preferably wherein the solid carrier material consists of sucrose.

23. A capsule or tablet comprising a formulation according to any of claims 1-16.

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