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WO2025188185A1 - New method for delivering compounds of interest - Google Patents

New method for delivering compounds of interest

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Publication number
WO2025188185A1
WO2025188185A1 PCT/NL2025/050110 NL2025050110W WO2025188185A1 WO 2025188185 A1 WO2025188185 A1 WO 2025188185A1 NL 2025050110 W NL2025050110 W NL 2025050110W WO 2025188185 A1 WO2025188185 A1 WO 2025188185A1
Authority
WO
WIPO (PCT)
Prior art keywords
delivery system
oil
acid
mixture
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/NL2025/050110
Other languages
French (fr)
Other versions
WO2025188185A8 (en
Inventor
Rients Pieter BEINTEMA
George Peter JOUBERT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biogntx R&d BV
Original Assignee
Biogntx R&d BV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biogntx R&d BV filed Critical Biogntx R&d BV
Publication of WO2025188185A1 publication Critical patent/WO2025188185A1/en
Publication of WO2025188185A8 publication Critical patent/WO2025188185A8/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/348—Cannabaceae
    • A61K36/3482—Cannabis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • Nanoparticles NPs
  • nanocarrier (NC) formulations of highly lipophilic drugs enable the delivery of compounds that previously could not be administered at therapeutic levels by conventional formulations.
  • Complex NC constructs such as liposomes, nanocapsules, polymeric NPs, micelles and polymersomes can improve the observed therapeutic effect of drug compounds by increasing solubility, improving pharmacokinetics or altering biodistribution.
  • Metallic, organic, inorganic and polymeric (nano- or micro- )structures, including dendrimers, micelles, and liposomes are frequently considered in designing the target-specific drug delivery systems. In particular, those drugs having poor solubility with less absorption ability are tagged with these particles.
  • compositions with lipophilic substances are usually provided in the form of a solution in an oily solvent wherein the lipophilic compounds, such as cannabidiol (CBD) and tetrahydrocannabinol (THC) dissolve, allowing a rather concentrated content.
  • CBD cannabidiol
  • THC tetrahydrocannabinol
  • Most of the known compositions are oil-based, i.e. an oily solution wherein the lipophilic compounds are dissolved, or a water-in oil dispersion, wherein the lipophilic compounds are in the oily phase.
  • the oily solvent needs to be food grade and acceptable for oral administration.
  • the composition is defined as oily or oil-based when more than half of the volume of the composition is an oil, and in case of a dispersion, the oily phase should be the continuous phase.
  • Ingestion of oil is however cumbersome and since the ingestion volume is limited, the cannabinoid compositions known in the art are highly concentrated, e.g. in concentrations of 5 w/w% to 60 w/w%. Such high concentrated composition are however difficult to dose properly and often, undesired side effects are observed. Furthermore, the bioavailability of lipophilic compounds from oily preparations is low, which means that much of the ingested active compound is not utilized.
  • most methods for delivering cannabis components use an oily solution. This is far from ideal.
  • the present invention which provides an aqueous composition containing particles of at least two different size classes, is advantageously suited for comprising such a compound of interest, which may preferably be a lipophilic compound, but which is also suitable for the delivery of amphiphilic or hydrophilic compounds.
  • a compound of interest which may preferably be a lipophilic compound, but which is also suitable for the delivery of amphiphilic or hydrophilic compounds.
  • These kinds of particle based delivery systems have been a big step forward in getting lipophilic drugs, like some components of cannabis, into the body. They have helped drugs work better by making them dissolve more easily, getting them to the right places in the body, and changing how they spread out once they are there.
  • One big issue is finding a way to create aqueous compositions of particles that are stable for a long time and are easy to apply, especially for drugs that do not like water.
  • the present invention provides a delivery system comprising of a first aqueous composition prepared by the steps of a . Providing an emulsifier or a blend of emulsifiers in powder form; b.
  • a second sonication treatment while keeping the mixture cold, and a second aqueous composition prepared by the steps of i .
  • oils at a temperature above 40°C where all oils have become liquid, wherein said oils differ in melting temperature, wherein the oil mixture comprises at least one oil with a melting point above 50°C and which mixture comprises at least a sufficient amount of an oil of a low melting point, p referably medium chain triglycerides, to enable the composition formed in step n to have a partly liquid oil phase at temperatures around about 4°C, preferably wherein the oils and the weight ratio between them is identical to the oils and weight ratio used in step b); k . Adding the compound of interest in any suitable hydrophobic solvent to the oil mixture; l . Optionally letting the mixture cool down to room temperature; m.
  • the emulsifier is a blend of emulsifiers, preferably wherein said emulsifiers are non-toxic emulsifiers, more preferably wherein said blend comprises sugar-based emulsifiers, such as sucrose ester and/or cyclodextrin, while more preferably the emulsifier is a blend comprising sucrose ester, cyclodextrin and lecithin, preferably sunflower lecithin, preferably wherein the amount of lecithin is such, that in the final sonified mixture from step g and/or the final composition obtained in step n).
  • the concentration of lecithin is less than 5% by weight, preferably less than 2%, more preferably less than 1%.
  • a delivery system as descriebd above, wherein the amount by weight of sugar-based emulsifiers is at least two times the amount of lecithin, preferably at least four times. Also preferred is a delivery system wherein the weight ratio between sucrose ester, cyclodextrin and lecithin is 2 : 2 : 1.
  • the oil mixture comprises oils or fats that are non toxic and also preferred is when the oil mixture comprises at least one oil with a melting point above 60°C and/or wherein the oil mixture comprises an oil with a melting point in between room temperature and body temperature.
  • the oil mixture comprises stearic acid, coconut oil and medium chain triglycerides.
  • the oil mixture when mixed with the hydrophobic compound, comprises the components in a weight ratio of stearic acid : coconut oil : medium chain triglycerides : solvent with hydrophobic compound of 1 : 2 : 3 : 5.
  • a non-toxic antioxidant is added to the oil mixture, preferably wherein said antioxidant is a blend of antioxidants, more preferably wherein said antioxidant or blend of antioxidants in total in weight does not exceed the amount of 10% of the oil mixture, preferably not exceed the amount of 5% of the oil mixture.
  • said blend of antioxidants comprises linseed oil, hempseed oil, tocopherol and/or rosemary extract; preferably where it comprises linseed oil, hempseed oil, tocopherol and rosemary extract, preferably in a weight ratio of 2 : 2 : 2 : 1.
  • a further part of the invention is a delivery system as described above, wherein the weight ratio of oil to emulsifiers in both the method to prepare the first and the second aqueous composition is from 3.0 to 5.0, more preferable from 3.2 to 4.0, more preferably about 3.5.
  • the water is food-grade water.
  • a lso part of the invention is a delivery system as described above, wherein the particles in the first aquoes composition will have a mean particle size of 10 – 600 nm, preferably of 50 – 150 nm and more preferably of 80 – 130 nm, most preferably about 110 nm expressed as D50 determined in accordance with ISO 9276-2. Further preferred in the present invention is a delivery system wherein glycerol is added to the final composition, more preferably wherein the concentration of glycerol is more than 20%, preferably more than 25% by weight.
  • At least one of the compounds of interest is a plant-based extract in oil, preferably wherein the plant-based extract is an extract of Cannabis sativa, preferably, wherein said extract comprises a cannabinoid, more preferably, wherein said extract comprises a cannabinoid chosen from the group consisting of ⁇ 9- tetrahydrocannabinol (THC), ⁇ 9-tetrahydrocannabinolic acid ( ⁇ 9-THCA or THCA), ⁇ 9- tetrahydrocannabiorolic acid ( ⁇ 9-THCA-C1 or THCA-C1), ⁇ 9-tetra-hydrocannabiorcol ( ⁇ 9- THCO-C1 or THCO-C1), ⁇ 9-tetrahydrocanna-biorcolic acid ( ⁇ 9-THCOA or THCOA), ⁇ 9- tetra-hydrocannabivarin ( ⁇ 9-THCV or THCV), ⁇ 9-te
  • a delivery system as described above, wherein the first and second aqueous compositions are blended into a cream.
  • an aqueous cream base is provided, through which the second aqueous composition is mixed with low shear, whereafter the first aqueous composition is gently added and mixed with very low shear, more preferably wherein the cream base comprises water, coconut oil, shea butter, medium chain triglycerides and sucrose ester.
  • F urther part of the invention is a delivery system as described above, wherein optionally after storage of the first and/or second aqueous composition, water is added to either or both of the first and second aqueous composition to obtain a diluted composition, preferably, wherein the composition is diluted with water, more preferably wherein the composition is diluted in such a way that the dilution comprises between 0.001% and 5% of the compound of interest, preferably between 0.005% and 1%, more preferably between 0.01% and 0.5%, more preferably between 0,02 % and 0.1%, more preferably wherein the water is food-grade and further preferably wherein a stabiliser is added to the composition, preferably wherein said stabiliser is a food grade stabiliser, more preferably wherein said stabiliser is a gum, more preferably wherein said stabiliser comprises guar gum and/or xanthan gum, more preferably wherein the concentration of guar gum and/or xanthan gum in the diluted composition is between 0.01 and 0.05%,
  • the invention comprises a delivery system as described above, wherein further a preservative is added to the delivery system, preferably wherein said preservative is a food grade preservative, more preferably, wherein said preservative is chosen from the group consisting of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbicate, citric acid, sorbic acid, calcium sorbate, benzoic acid, potassium benzoate, acetic acid, erythorbic acid, sodium erythorbate, ethyl lauroyl arginate, long-chain glycolipids from Dacryopinax spathularia MUCL 53181, methyl-p-hydroxybenzoate, nisin, sulphurous acid, dimethyl dicarbonate, ascorbyl palmitate and blends thereof.
  • a preservative is added to the delivery system, preferably wherein said preservative is a food grade preservative, more preferably, wherein said preservative is chosen from
  • said preservative preferably comprises ascorbic acid, citric acid or sorbic acid or a blend thereof, preferably wherein the ascorbic acid, if present, is present at a concentration between 0.01% and 0,1% by weight, preferably about 0.05%, and wherein the citric acid, if present, is present at a concentration between 0.005% and 0.05% by weight, preferably at about 0.01%, and wherein the sorbic acid, if present, is present at a concentration between 0.05% and 0.5%, preferably about 0,1%.
  • Also part of the invention is a delivery system as described above, wherein further a flavouring compound is added to the first or second aqueous composition or to the delivery system or to the cream, preferably a food grade flavouring compound.
  • F urther part of the invention is a delivery system wherein the first and/or second aqueous composition are stored before mixing them to obtain the delivery system, preferably, wherein either the first aqueous composition is stored as powder by lyophilisation and/or wherein the second aqueous composition is stored as powder by lyophilisation.
  • the freeze-dried powder is preferably reconstituted in water.
  • FIGURES F ig. 1 shows a comparison of a solid particle and a particle of a composition according to the invention that comprises an oil phase where part of the oil phase is liquid.
  • Fig. 2 shows particle size distributions of first (nano) and second (micro) aqueous compositions according to the invention as prepared and measured as described in Example 5 and 6.
  • Fig. 3 Fluorescence induced by release of nile red in C. elegans over time.
  • the y-axis represents corrected total fluorescence
  • the x-axis represents compounds
  • the facets on the x-axis represent recovery times after exposure for 2 hours to the compounds.
  • Fig. 4 Schematic representation of fluorescence induced by release of nile red in C. elegans over time.
  • Light blue scale zone indicates levels of fluorescence in untreated nematodes.
  • LC-MS Heat map of neurotransmitter and amino acid metabolites
  • Heat map showing normalized and scaled (z-values) of metabolite levels. Red shading indicates low values, while blue shading indicates high values. Metabolites were measured and are represented as rows in the heat map.
  • Fig.9 Levels of the amino acid aspartic acid in CBD-treated nematodes Left: The y-axis represents the normalized micromolar concentration for the metabolite detected in the treated nematodes. Each dot represents one replicate measurement, and the bar graph indicates the mean. Aspartic acid is increased upon CBD treatment and levels decrease over time after nano-CBD treatment and increase over time in micro-CBD treatment. Right: Visual representation of aspartic acid levels over time in nano- (x) and micro-CBD (O) treated nematodes. Light blue scale zone indicates metabolite levels in untreated nematodes.
  • Fig.10 Levels of the amino acid glutamic acid(+) in CBD-treated nematodes Left: The y-axis represents the normalized micromolar concentration for the metabolite detected in the treated nematodes. Each dot represents one replicate measurement, and the bar graph indicates the mean. Aspartic acid is increased upon CBD treatment and levels decrease over time after nano-CBD treatment and increase over time in micro-CBD treatment. Right: Visual representation of glutamic acid levels over time in nano- (x) and micro-CBD (O) treated nematodes. Light blue scale zone indicates metabolite levels in untreated nematodes.
  • the invention consists of the preparation of two separate compositions that each may be characterised containing particles having an oil phase where part of the oil phase is liquid (see Fig. 1).
  • the main difference between the first and second composition is in the average size of the particles, which is smaller in the first composition since for that composition a sonication treatment is used to lower the average particle size.
  • the particle size of the particles in the first composition is ranging from 10 nm to 600 nm, preferably of 50 – 150 nm and more preferably of 80 – 130 nm, most preferably about 110 nm, expressed as D50 determined in accordance with ISO 9276-2.
  • the average particle size in the second composition which only very shortly has been exposed to a sonication treatment, or, preferably, has been mixed with high shear, e.g. by microfluidising, is in the range of 300 nm – 100 ⁇ m, more preferable between 500 nm and 10 ⁇ m, more preferably between 750 nm and 5 ⁇ m, even more preferably around 1 ⁇ m.
  • the size of the particles may be determined by the pore filter that is used in the apparatus and the mixing advantageously takes place for such a long time that the particles have the same size.
  • These compositions may or may not harbour the same compound of interest and may or may not have identical ingredients, i.e. the same emulsifier(s), the same oils and identical further additives.
  • a first aqueous composition is made by emulsifying an oil composition comprising a hydrophobic or amphiphilic compound of interest with water by adding an emulsifier, after which the emulsion is sonicated to produce an aqueous nanoparticle solution.
  • a first step in the present invention for preparing the first aqueous particle composition of the present invention is to provide an emulsifier or, preferably, a blend of emulsifiers.
  • the goal of these emulsifiers is to provide a system from which small particles may be produced and for this purpose, the emulsifier should be able to provide a sufficient stability. Further, since it is highly likely that eventually the composition is taken orally, it should also have a sufficient safety profile and it should also provide for an acceptable taste.
  • lecithin is lecithin, this in itself already being a blend of glycerophospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid.
  • the lecithin may be derived from various sources, such as soybean, rapeseed, cotton seed or sunflower.
  • Lecithin is a food-grade product, has GRAS status and is also admitted in Europe as food additive E322. However, due to its off-flavour, it is desirable that the amount of lecithin in the final composition is relatively low.
  • the concentration of lecithin is less than 5%, preferably less than 2%, more preferably less than 1% of the final sonified first composition as obtained in the process according to the present claims.
  • sugar-based emulsifiers are preferred, since they provide a sweet taste. Any sugar- based emulsifier that is non-toxic and which has a sweet taste can be used, such as sucrose esters, cyclodextrin, sucralose esters, sophorolipids, and the like.
  • the concentration of these sugar-based emulsifiers is at least two times the concentration of lecithin and preferably at least four times.
  • the most preferable combination of emulsifiers is a blend of sunflower lecithin, sucrose ester (e.g. RyotoTM sugar ester P- 1670 obtainable from Mitsubishi Chemical Corporation) and ⁇ -cyclodextrin, most preferably in a weight or molar ratio of 1:2:2. This blend also shows a lower toxicity profile than traditional emulsifiers or emulsifier blends with a lower formation of harmful free radicals and degradation products.
  • cyclodextrin means that the size of the small particles will be approximately 110 nm, which size is determined by the internal bond angles of cyclodextrin encouraging particle sizes of this diameter. Particles below 110nm that incorporate beta-cyclodextrin do so with torsion energy supplied by sonication (provided in a later step) which is an thermodynamically unstable arrangement. It is expected that these particles will spontaneously reform themselves over time to a larger, more stable and energetically favourable conformation of about 110 nm.
  • O ther emulsifiers that are preferred are mono- or diglycerides (also known as E471), such as glycerol monostearate, glycerol monopalmitate, glycerol monooleate, glycerol monolaurate and glycerol monoricinoleate.
  • mono- and di-esters known as E305 of ascorbic acid, such as ascorbylstearate and ascorbylpalmitate.
  • E305 mono- and di-esters of ascorbic acid, such as ascorbylstearate and ascorbylpalmitate.
  • a mixture of oils is provided, which mixture may consist of two oils, but can also have 3, 4 or more different oil constituents. Similar to the blend of emulsifiers, also for the oil mixture only oils should be included which are non-toxic and food-grade. Further, in order to be able to regulate the viscosity and stability of the particle solution oils of different melting temperatures should be used. For obtaining a good stability of the nanoparticles at least one oil with a melting temperature of more than 50°C, preferably more than 60°C, should be used, such as myristic acid, palmitic acid, stearic acid or arachidic acid.
  • stearic acid that has a melting point of nearly 70°C
  • Stearic acid is one of the most common saturated fatty acids found in nature and in the food supply and it is often used in (nonalcoholic) beverages.
  • Stearic acid is preferably used since it advantageously stabilises the small particles that will be formed in the process.
  • Further preferred in the oil mix is an oil that has a melting point that lies between room temperature and body temperature.
  • Such an oil may for example be chosen from coconut oil, cocoa butter, palm kernel oil, peanut oil and babassu oil.
  • Preferable is coconut oil since this is cheap and easily commercially obtainable.
  • the oil mixture should also contain a component that would provide for a low melting point, such that the oil phase in the final nanocarrier emulsion still comprises oils that are liquid at about 4°C.
  • the advantage of having an oil phase in the nanoparticles that is at least partly liquid is that the lipophilic compound that is contained in these nanoparticles is more readily available for absorption and uptake into the body. The characteristics of such a small particle are shown in Fig. 1, where it can be seen that the oil phase of the particle comprises both liquid and solid oil.
  • MCT medium chain triglycerides
  • MCTs Medium-chain triglycerides
  • MCFAs medium-chain fatty acids
  • MCTs are triglycerides with two or three fatty acids having an aliphatic tail of 6 – 12 carbon atoms, i.e. medium-chain fatty acids (MCFAs).
  • MCTs are used since these are completely saturated, which means that they are unlikely to react during sonication or mixing. Further MCTs are stable over a wide temperature range through all processing conditions.
  • C8 MCT caprylic acid MCT
  • the oil mixture is prepared by adding all components at a temperature at which all the oils/fats are liquid (and which is below the boiling temperature of any of the present components). To this oil mixture the hydrophobic or amphiphilic compound of interest is added which may or may not be present in a hydrophobic solvent.
  • any cannabinoid compound may be included, such as selected from the group of ⁇ 9-tetrahydrocannabinol (THC), ⁇ 9- tetrahydrocannabinolic acid ( ⁇ 9-THCA or THCA), ⁇ 9-tetrahydrocannabiorolic acid ( ⁇ 9- THCA-C1 or THCA-C1), ⁇ 9-tetra-hydrocannabiorcol ( ⁇ 9-THCO-C1 or THCO-C1), ⁇ 9- tetrahydrocanna-biorcolic acid ( ⁇ 9-THCOA or THCOA), ⁇ 9-tetra-hydrocannabivarin ( ⁇ 9- THCV or THCV), ⁇ 9-tetrahydrocannabivarinic acid ( ⁇ 9-THCVA or THCVA), trihydroxy- ⁇ 9- tetrahydro-cannabinol (TRIOH-THC), ⁇ 10-tetrahydro-cannabinol (
  • An increase in the amount of oils with a low melting point causes a larger part of the oil phase in the nanoparticle to be in liquid form, which provides a more rapid release, while an increase in the amount of oils with a high melting point causes a larger part of the oil phase in the particle to be solid, which provides for a retarded release of the hydrophobic or amphiphilic compound.
  • the ratio of components that provides a very stable particle composition with the desired release properties may be achieved by mixing stearic acid, coconut oil, medium chain triglycerides and solvent with hydrophobic compound in a weight ratio of approximately 1 : 2 : 3 : 5. However, depending on the nature and melting points of the individual components other ratios may be equally applicable.
  • the skilled person will know how to vary the parameters involved in preparing the oil mixture to obtain the desired release characteristics. It is especially advantageous to ensure that the (solid) particles that will be formed after the emulsifying and sonication steps will melt at body temperature so that the particle becomes unstable and will disintegrate. Also the use of lecithin in the emulsion may lead to instability of the particle in situations with a low pH. If thus an aqueous particle composition is desired that is able to safely pass the stomach after ingestion care should be taken not to use too much lecithin in the emulsifier mixture.
  • one or more antioxidants may be added to the oil mixture. However, in order to maintain the antioxidant activity of such compounds, these should only be added when the oil mixture is cooled down to about RT.
  • Antioxidants prevent free radical induced damage of cell and biological targets by preventing the formation of radicals, scavenging them, or by promoting their decomposition. Moreover, antioxidants prevents the oxidative reaction which is responsible for rancid odors and flavors within fats and oils which reduces nutritional quality of foods. Thus, antioxidants play an important role to enable a long-term storage of compositions comprising oils and fats and also act advantageously in the body. Fortunately, there are sufficient hydrophobic or amphiphilc compounds that may be added to the oil mixture that can function as antioxidant (see e.g. Papas AM. Oil-Soluble Antioxidants in Foods. Toxicology and Industrial Health.
  • antioxidants used to protect the active hydrophobic ingredient during sonication without presenting a toxicity threat to the user of the composition.
  • all of the mentioned antioxidants as a single component or as a blend may be added in such an amount to achieve the desired protection, we found that a mixture of linseed oil, hempseed oil, tocopherol and rosemary extract provided sufficient antioxidant protection in the process of the invention.
  • Tocopherol also enhances tissue absorption of the compound of interest.
  • a further component to be added to the oil mixture is panthenol, which is a provitamin of vitamin B5. It is a moisturizer and humectant that is often found in shampoos and skin care products.
  • the present invention enhances the binding of the small particles to water, i.e. it increases the Zeta potential of the particle solution. Because of this, it enhances tissue absorption rates of the compound of interest.
  • Other additions may be pyridoxal 5’- phosphate or pyridoxine hydrochloride (vitamin B6) or melatonin.
  • the oil mixture is mixed with the emulsifier (blend) and water at a slightly elevated temperature (about 30 - 40°C). Normally on 1 litre of the oil mixture a total of 25 grams of the emulsifier (blend) is used and 500 ml water.
  • the water preferably is food-grade water.
  • the mixture is optionally homogenised to obtain an emulsion in which the oil droplets are uniformly dispersed in the continuous phase.
  • homogenisation can be performed with any type of mixing apparatus, such as a high-speed blender, a homogenizer, an immersion blender, an overhead stirrer, a magnetic stirrer or even a kitchen mixer or whisk (for small batches). It is also possible to obtain homogenisation through (micro)fluidisation.
  • H omogenisation is not optional and microfluidisation is especially preferred for the preparation of the second aqueous composition (in which the next step of sonication is omitted).
  • a microfluidizer is similar to a homogenizer in terms of shearing forces except that a high-pressure pump drives the liquids through an inline homogenizer to produce the coarse emulsion. This emulsion is then driven through microchannels designed within an interaction chamber. The flow and impingement of the emulsion results in size reduction of dispersed phase droplets, thereby yielding the small particle emulsion.
  • a microfluidizer the distributions of produced particle sizes appear to be narrower and smaller than the products of traditional homogenization.
  • microfluidization over high-pressure homogenization is that it is less prone to clogging as it functions at a constant shear rate.
  • this method provides better reproducibility due to fixed geometry.
  • the interaction chamber is available in two different types that are Y-type and Z- type.
  • Y-type chamber divides the feed into two microstreams where it experiences very high velocity and then these microstreams collide with each other and with the wall, thereby leading to droplet disruption.
  • Z-type chamber has zigzag microchannel through which feed is forced at high pressure where it experiences particle–particle and particle–wall collision thereby causing breakdown of droplets. Both types may be used in the present invention and the shape of these microchannels largely determines the average particle size of the resulting dispersion.
  • the product stream is acted upon by two primary forces which bring about the desired results.
  • First is the ‘shear force’, which acts between the product streams and walls of the channel at high velocity and second is the ‘impact force’ that is collision that occurs when the high-velocity product stream impinges upon itself.
  • a heat exchanger brings the product stream to ambient temperature.
  • Microfluidizer treatment may produce stable emulsions with uniform particle size distribution and droplet size up to ⁇ 0.1 ⁇ m, but in the present invention preferably average particle sizes of 300 nm to 100 ⁇ m, more preferably between 500 nm and 10 ⁇ m, even more preferably between 750 nm and 5 ⁇ m and even more preferably around 1 ⁇ m expressed as D50 determined in accordance with ISO 9276-2, are obtained. Since the so-produced emulsions have a uniform particle size distribution, it is irrelevant whether the average particle size is measured through surface area, volume or number. After this step of homogenisation (optional in the preparation of the first aqueous composition) the process of sonication is started.
  • the oil droplets in the emulsion will fall apart into smaller droplets, finally resulting into small particles with a size ranging from 10 – 600 nm ,preferably 50 – 150 nm and more preferably 80 -130 nm, most preferably about 110 nm.
  • the result is an aqueous medium in which small-size oil droplets loaded with the compound of interest are available, i.e. the droplets are a mixed solid and liquid composition (as depicted in Fig. 1).
  • the nature and the amounts and ratios of the oils determine largely the distribution of the solid and liquid oil in the particles and with this the release characteristics of the particles.
  • the sonication process may be performed with any commercially available sonicator and should be continued until the moment that the average particle size of the nanoparticles no longer decreases, i.e. until the mean particle size of the nanoparticles is stable. Since, similar to the process of microfluidisation, also here a composition is obtained where the size of the particles follows a Gauss distribution, the average particle size may be measured according to surface are, number or volume and would yield a D50 in accordance with ISO 9276-2.
  • the nanoparticles will have a mean particle size of 10 – 600 nm, preferably of 50 – 150 nm and more preferably of 80 – 130 nm, most preferably about 110 nm. Calculation of the mean particle size may be expressed as D50 determined in accordance with ISO 9276-2 (14th Edition, September 4, 2019) or with tuneable resistive pulse sensing (TRPS) such as obtainable by using an Izon ExoidTM apparatus. Other methods of measuring the droplet size in a nano-emulsion may be used, such as dynamic light scattering, nanoparticle tracking analysis, transmission electron microscopy, scanning electron microscopy or laser diffraction.
  • Monitoring the particle size during the sonication is preferably achieved by TRPS on samples taken during sonication Care should be taken not to overheat the sonicated mixture.
  • the sonication process itself produces heat which may jeopardize the formation and stability of the droplets formed. Cooling can be performed by external cooling of the container in which the sonication process takes place, but a better way is to immediately cool down the formed first aqueous small particle solution at the moment that the sonication process is (nearly) completed.
  • the cooled composition preferably should be shortly sonicated to prevent coalescence of the small particles.
  • the cooling preferably can be achieved by putting the solution on ice, which can be done already during the sonication process, alternatively glycerol may be added in an amount up to 25% of the particle solution.
  • glycerol has the additional advantage that it (further) crystallizes the particles, thereby increasing the shelf life of the product and glycerol thus may be added when long term storage of the first aqueous particle composition is needed. If the first aqueous composition is not directly used to prepare the delivery system of the present invention, it may also be stored using freeze-drying.
  • a powder is obtained which may later be reconstituted by adding water.
  • a filter with a cut-off at e.g 200 nm is used.
  • Several filter types may be used, such as polyetherculfone (PES) filter, polyvinylidene fluoride (PVDF) filters, polytetrafluoroethylene (PTFE) filters, mixed cellulose ester (MCE) filters, polypropylene (PP) filters or nylon filters.
  • PES polyetherculfone
  • PVDF polyvinylidene fluoride
  • PTFE polytetrafluoroethylene
  • MCE mixed cellulose ester
  • PP polypropylene
  • the first aqueous composition may also be stored using freeze-drying. In that case, a powder is obtained which may later be reconstituted by adding water.
  • the second aqueous composition may be prepared according to the same process as described above, but with the exception of the sonication step (although a very short sonication may be performed) and with the obligatory presence of the homogenisation step, preferably provided by microfluidisation. This second aqueous composition may also be freeze-dried for long term storage or it may be further processed into the delivery system of the invention directly after preparation.
  • the first aqueous composition may be gently mixed with the second aqueous composition to obtain the delivery system of the present invention. Possibly either or both of the compositions may be diluted with food-grade water before use. In any case care should be taken to not vigorously mix the compositions in order not to provoke coalescence of the particles.
  • the presence of the small-sized oil droplets in the first aqueous composition enables a controlled release of the compound of interest: there will be a fraction of solid lipid and a fraction of liquid lipid dependent on the temperature to which the aqueous solution is exposed. This enables the function of a controlled release as when the particles crystallize they displace the compound of interest from the core into the surrounding medium.
  • the presence of the larger (‘micro’) particles in the second aqueous composition has a different release profile, in which the compound of interest will be released later and more gradually.
  • a compound of interest may be provided to a person in need thereof, where the relatively small particles of the first aqueous solution provide a rapid onset of the release with a high peak effect, while the relatively large particles of the second aqueous composition provide a delayed onset with a slower more stable release. Further finetuning of the release properties of the particles of both the first and the second aqueous compositions may be provide by altering the oil compositions of the particles. This is also what differentiates the presently claimed system from earlier drug delivery particle systems.
  • a solid base solid lipid nanoparticles, SLN
  • a liquid base nano-emulsion
  • the partial crystallisation which is dependent on the melting temperature of the oils used in the oil mixture, gives stability to the particles that resist flocculation without sacrificing the ability to load the particles with high amounts of hydrophilic or amphiphilic compounds and maintain encapsulation efficiency.
  • a further aspect that aids in the stability is the zeta potential.
  • a first aqueous particle composition as e.g. prepared according to the examples herein has a Zeta potential of -47 mV. Zeta potentials of less than -30 mV or greater than +30 mV typically indicate indefinite colloidal stability. Thus, the observed instability, if any, wouldn't arise from particle agglomeration, as our nanoparticles inherently resist flocculation. Importantly, a strong negative zeta potential has been documented to more effectively facilitate the overcoming of biological barriers like the blood-brain barrier (BBB), gastrointestinal (GI) tract, and cellular membranes (e.g., p-GP efflux pumps and other charged surface proteins).
  • BBB blood-brain barrier
  • GI gastrointestinal
  • cellular membranes e.g., p-GP efflux pumps and other charged surface proteins.
  • the product For shelfing the product obtained according to the above-described process, the product should be packaged in a sterile packaging, which can be of any inert material, such as glass or vacuum packaging materials, which are normally used for airtight packaging of food products. When packaged in such a way the shelf life of the separate first and second aqueous composition is extremely long and when needed, they can be restituted and mixed to form the delivery system.
  • a sterile packaging which can be of any inert material, such as glass or vacuum packaging materials, which are normally used for airtight packaging of food products.
  • the stabiliser is a gum, such as guar gum (E412), arabic gum (E414), xanthan gum (E415), alginic acid (E400), carrageenan (E407), ghatti gum, tragacanth gum (E413), karaya gum (E416), locust bean gum (E410), dammar gum, glucomannan (E425), tara gum (E417), gellan gum or beta-glucan.
  • guar gum E412
  • arabic gum E414
  • xanthan gum E415)
  • alginic acid E400
  • carrageenan E407
  • ghatti gum ghatti gum
  • tragacanth gum E413
  • karaya gum E416
  • locust bean gum E410
  • dammar gum glucomannan (E425), tara gum (E417), gellan gum or beta-glucan.
  • Preservatives may be chosen from the group consisting of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbicate, citric acid, sorbic acid, calcium sorbate, benzoic acid, potassium benzoate, acetic acid, erythorbic acid, sodium erythorbate, ethyl lauroyl arginate, long-chain glycolipids from Dacryopinax spathularia MUCL 53181, methyl- p-hydroxybenzoate, nisin, sulphurous acid, dimethyl dicarbonate, ascorbyl palmitate and blends thereof.
  • a combination of ascorbic acid, citric acid and sorbic acid provides the desired result when the ascorbic acid, if present, is present at a concentration between 0.01% and 0,1%, preferably about 0.05%, and when the citric acid, if present, is present at a concentration between 0.005% and 0.05%, preferably at about 0.01%, and when the sorbic acid, if present, is present at a concentration between 0.05% and 0.5%, preferably about 0,1%.
  • Most preservatives are weak acids, which means that preferably the pH of the first and or second aqueous compositions needs to be lowered by adding an acid such as citric acid or by adding a buffer, such as SlimpieTM syrup.
  • flavouring compound that can be used in food, including drinks, may be added, such as flavouring essences. These are readily available in any taste and the skilled person will know how to apply these and which concentration is needed for the flavouring to provide a pleasant taste.
  • compositions as exemplified herein it was found that a superior system was made that surpasses the stability, flavor, and safety profiles of existing counterparts currently in the market and which retains very favourable release characteristics of the compound(s) of interest delivered with the system.
  • the chosen co- emulsifiers (sunflower lecithin, beta-cyclodextrin, and sucrose ester) interact synergistically to enhance particle stability, offering a robust formulation capable of maintaining product quality under various storage conditions.
  • the combination also enhances the flavor profile of the beverage, ensuring an enjoyable consumption experience.
  • the blend exhibits a lower toxicity profile compared to traditional emulsifiers, thus preventing the formation of harmful free radicals and degradation products during high-intensity processing.
  • the thermal process results in a more efficient procedure with minimized energy requirements and side reactions, especially since a natural antioxidant blend is employed to shield the active ingredients, mitigating potential oxidative damage to consumers.
  • some molecules tocopherol, vitamin B5 precursor
  • the formulation allows precise manipulation of drug release kinetics, offering a customizable delivery experience, which is unknown for at least cannabinoids.
  • the unique temperature-responsive release mechanism in the particles ensures a stable product at room temperature that allows controlled release upon ingestion.
  • the formulation is versatile and allows for ultra-stable particles capable of being loaded with a variety of hydrophobic and/or amphiphilic drugs, expanding potential applications beyond cannabinoid delivery.
  • the optimized particle sizes in the formulation support efficient tissue penetration and help in overcoming drug resistance mechanisms.
  • the unique combination of emulsifiers, lipid vehicles, and natural antioxidants in the formulation not only provides a safe and stable cannabinoid delivery system but also enhances bioavailability and release kinetics.
  • the tested formulation offered enhanced bioavailability of cannabinoids with a second, prolonged effect, being up to 10 times more bioavailable than normal cannabinoid oil and showing effects in minutes but lasting for hours.
  • the release kinetics of compounds from the particles can be programmed to suit the needs of different consumers, ranging from rapid to delayed release, but especially a combination of both types of release.
  • the delivery system of the present invention makes it possible to easy combine the delivery of different compounds of interest, even where these would normally be unable to be combined in one dosage form (e.g. because of pH preferences, buffer incompatibilities and the like) thereby facilitating the compliance with the treatment.
  • the system is especially well suited to combine compounds of interest that benefit from a different release profile.
  • One example for this is in cancer therapy where cytotoxic cocktails are used where one compound should be administered first and a second at a later moment.
  • chemotherapeutic drugs are used in combination with immunotherapy, where some chemotherapeutic drugs are known to sensitize cells for immune effector cells.
  • time-dependent chemotherapy drugs e.g. paclitaxel and topotecan
  • interleukines such as IL-18
  • cytotoxic drugs with anti-PD-1 monoclonal antibodies
  • the technology also supports the targeted delivery of cannabinoids or other therapeutic agents specifically inside tumors, providing a valuable tool for personalized medicine.
  • Targeting moieties may be attached to the outer surface of the particles with technology that is available to the skilled person.
  • the design supports potential sequential release of multiple therapeutic agents, facilitating a coordinated treatment approach.
  • the technology can be extended to controlled-release drug delivery systems, improving patient compliance and therapeutic outcomes. F urther, the particles and especially the small particles are transdermally bioavailable, expanding the delivery routes for therapeutic agents.
  • the technology can be applied to improve the efficacy of cosmetic formulations, potentially enabling better skin penetration and longer-lasting effects.
  • a cream is made by adding to a cream base first the second aqueous composition by low shear mixing and secondly adding the first aqueous composition with minimal mixing.
  • the cream base preferably is an aqueous cream base, more preferably a composition comprising water, coconut oil, shea butter oils, preferably MCT, and sucrose ester.
  • a paste can be made, preferably an edible paste. Both to the cream and to the paste additional compounds such as preservatives, odorants, flavorants, and the like.
  • the particle design allows for encapsulation and preservation of volatile or sensitive substances, extending shelf-life and maintaining compound efficacy.
  • the formulation enables the loading and delivery of hydrophilic, amphiphilic, or charged bioactive compounds, expanding potential applications.
  • the technology can be used to improve oral delivery of drugs with low bioavailability due to first-pass metabolism.
  • Incorporation of bio-essential compounds can potentially improve the stability and bioavailability of probiotics or other beneficial gut microflora and thus co-administered with these.
  • the formulation can also potentially protect and enhance the delivery of probiotics, supporting their survival during transit through the harsh stomach environment.
  • the nanoparticles also allow for penetration through the blood-brain barrier, providing potential solutions for neurological conditions.
  • the particle design might further allow for cell-specific targeting of therapeutics by incorporating specific ligands or antibodies on the surface of the particles.
  • the particle design could potentially enable the delivery of genes or RNA therapies, extending the potential applications to the burgeoning field of gene therapy.
  • the formulation can further potentially improve the delivery and efficacy of vaccines by protecting the antigen and providing adjuvant effects.
  • the potential applications of the technology extend to animal health, potentially improving the delivery and absorption of veterinary therapeutics.
  • the major advantage of the present delivery system with small (nano-) and/or larger (micro-)particles with different release characteristics is that it enables for a fine-tuning in the bioavailability of the compound of interest.
  • a further advantage is that it is now possible to provide a combination of substances of interest.
  • compositions in which the second compound influences the effects of the first compound are a mixture of the first aqueous particle composition as described above, where the compound of interest is THC and of a second aqueous composition comprising CBD.
  • the amounts of CBD and THC are present in a ratio of 2 : 1.
  • Such a mixture can be made according to the methods described herein wherein the THC is provided from a plant extract of a high-THC producer plant, where the CBD may be provided from a different plant source (obtained from a low-THC producer) or the CBD may be obtained as a commercially available distillate.
  • the effect of such a composition is a rapid onset of the THC effect followed by a second peak of the THC activity. Initially the uptake speed is dependent on the size of the particles in the composition. This means that the smaller (i.e. nano-) particles that contain the THC as active compound are taken up first. In the case that the composition is ingested orally, this intake takes place via the gut, but if the composition is e.g.
  • the uptake is transdermally.
  • the most rapidly taken up smaller particles will be transported into the blood vessels first where the THC is released from the oil phase of the particles.
  • the THC When the THC is released, it will be bound to proteins present in the blood (such as albumin) or fatty acid binding proteins (FABPs) that are present in the inter- and intracellular fluids. There will then be an equilibrium of bound THC versus free THC, where the free THC is providing the pharmacological effect.
  • the uptake of THC is followed by the slower uptake of the larger particles that harbor the CBD.
  • the CBD is released from the oil phase in the larger particles it will replace the THC that is bound to the blood proteins and FABPs.
  • aqueous particle compositions as described above can be used for various other embodiments in which delivery of hydrophobic or amphiphilic substances may be influenced by a second substance.
  • a second substance can be a compound that may act agonistically or antagonistically and the second compound may even be identical to the first compound. In this latter situation one would be obtaining a prolonged pharmacological effect of the compound.
  • the second compound is inert or that the second particle solution contains particles that are not loaded with an active compound.
  • a specific embodiment for the delivery system of the present invention is the embodiment in which pharmaceutical compounds that are normally given in a combination preparation or as a combined therapy are combined in the present delivery system.
  • One example for this is the combination of anticonceptives, such as ethinylestradiol in combination with desogestrel, gestodeen or flevogestrel.
  • sulfomethoxazol or sulfametrol in combination with trimethoprim, artemether with lumefantrine, atovaquon with proguanil, flumetason with clioquinol, daunorubicine with cytarabine, ezetimibe with atorvastatine, rosuvastatine or simvastatine, pravastatine with phenophibrate, pyridoxine with meclizine or doxylamine and even combinations with three pharmaceutical compounds such as hydrocortisone/oxytetracycline/polymyxine B, colistine/bacitracine/hydrocortisone or fludrocortison/neomycine/polymyxine B.
  • hydrophilic compounds may be delivered.
  • the distribution of these hydrophilic compounds over the oil and water phases of the aqueous compositions described herein depends largely on the solubility of the compound and thus this determines the encapsulation efficiency. Nevertheless, even if the hydrophilic substances are not taken up by the particles in the aqueous compositions, they will remain solved in the water phase of the composition.
  • hydrophilic substances it is possible to conjugate hydrophilic substances to the particles when the aqueous compositions have been prepared.
  • Such conjugation may be achieved by using gold, or e.g. carbodiimide coupling (see for an overview of coupling methodologies Hawthorne, D. et al. J. Drug Deliv, Sci. Technol. 78, 103936, 2022).
  • the terms hydrophobic and hydrophilic have their generally accepted meaning, which means that hydrophobic compounds are poorly soluble in water but are soluble in polar solvents, while hydrophilic compounds are soluble in water and badly soluble in polar solvents. The exact solubility depends on temperature and pressure of the circumstances, but also on the charge distribution in the compounds itself.
  • amphiphilic or amphoteric compounds are compounds that have both a part (moiety) that reacts hydrophilic and a part (moiety) that reacts hydrophobic. It will depend on the number of the hydrophilic and hydrophobic moieties and their level of hydrophobicity/hydrophilicity and the distribution of these moieties over the molecule if the molecule will be more hydrophilic or more hydrophobic. Examples of these amphiphilic molecules are proteins, like enzymes, antibodies, antibody fragments, and the like, nucleic acids and various small molecules.
  • optionally vitamin B6 and melatonin are added to the oil phase during preparation of the emulsions.
  • Example 1 Preparation of an aqueous nanoparticle cannabinoid first composition
  • a mixture of emulsifiers was prepared by combining 10g beta cyclodextrin (Landor Trading Comp.), 10g sucrose ester (Ryoto TM P-1670 from Mitsubishi Chemical Company), and 5g sunflower lecithin (buXtrade). This mixture was then diluted to 800ml with purified water at 25°C.
  • an oily mixture was prepared by melting 10g stearic acid, 50g natural cannabis sativa extract, 20g coconut oil (Ekoplaza), 30g C8 MCT (Lus Health Ingredients), 2g hempseed oil (Holland and Barrett), 2g linseed oil (Holland and Barrett), 1g natural tocopherols concentrate (soapqueen.nl), and 1g rosemary extract in order of descending melting point, using a heated stirrer. The temperature during this process did not exceed 75°C and the total process lasted for approximately 30 minutes. The oily phase and emulsifier solution were then combined using a mixer until the mixture was visibly homogeneous.
  • This mixture was then further processed with 600W of sonication power (U.S. SOLID sonicator) in a 1L beaker, with a cycle of 10 seconds on and 2 seconds off for 7 minutes and 30 seconds.
  • the mixture was cooled to room temperature (approximately 20°C) using a water and ice bath before being sonicated for a further 2 minutes with the same conditions.
  • the final product was filtered using a 200nm filter to remove any larger particles.
  • the resulting filtrate had a mean particle size of 114.8 nm (measured using a Izon Science Apparatus (using TPRS) and a THC concentration of 50 mg/ml.
  • the filtrate could be preserved using 25% glycerol if not intended for immediate use.
  • Example 2 Preparation of a dosage form of the composition from Example 1
  • a strawberry-flavored preparation was made by adding 20ml of the THC filtrate from Example 1, 200ml of strawberry syrup BP, 1g of potassium sorbate, 0.5g Guar Gum (buXtrade), 150mg Ascorbic Acid (buXtrade), and 50mg Citric Acid (buXtrade) to 1L of water. After thorough mixing it was divided into dosage forms containing 25 cl of the preparation. The preparation should be consumed within 2 days of preparation.
  • Example 3 Preparation of an aqueous nanoparticle first composition with auxin as compound of interest
  • a mixture of emulsifiers was prepared by combining 1.25 g beta cyclodextrin (Landor Trading Comp.), 1.36 g sucrose ester (Ryoto TM P-1670 from Mitsubishi Chemical Company), and 0.87 g sunflower lecithin (buXtrade). This mixture was then diluted to 102 ml with purified water at 25°C.
  • an oily mixture was prepared by melting 1 g stearic acid, 5.11 g auxin (indole- 3-acetic acid, Sigma Aldrich), 2 g coconut oil (Ekoplaza), 3g C8 MCT (Lus Health Ingredients), 0.2 g hempseed oil (Holland and Barrett), 0.2 g flackseed (Holland and Barrett), 0.1 g natural tocopherols concentrate (soapqueen.nl), and 0.1g rosemary extract in order of descending melting point, using a heated stirrer. The temperature during this process did not exceed 75°C and the total process lasted for approximately 30 minutes. The oily phase and emulsifier solution were then combined using a mixer until the mixture was visibly homogeneous.
  • This mixture was then further processed with 600W of sonication power (U.S. SOLID sonicator) in a 1L beaker, with a cycle of 10 seconds on and 2 seconds off for 7 minutes and 30 seconds.
  • the mixture was cooled to room temperature (approximately 20°C) using a water and ice bath before being sonicated for a further 2 minutes with the same conditions. Residual clumps were removed by sonication for an additional minute.
  • the final product was filtered using a 2 ⁇ m polypropylene filter (woven, nonbinder from VWF) to remove any larger particles.
  • Example 4 Preparation of the first and second aqueous compositions with reduced sonication requirements (taking nile red A or CBD as compound of interest) A.
  • First aqueous composition An oil blend is prepared by mixing 5 g stearic acid (melting point ⁇ 69 °C), 10 g coconut oil (solid below ⁇ 25 °C), 15 g medium-chain triglycerides (MCT) and 1 g Nile Red A (pure compound).
  • the warmed oil phase is slowly introduced into the emulsifier solution under moderate stirring ( ⁇ 300 rpm) to form a coarse pre-emulsion.
  • the combined mixture is kept at approximately 40 °C during this blending step.
  • the pre-emulsion is passed through a bench-scale microfluidizer at 100 bar for three passes. After the first pass, the coarse droplets are reduced in size to roughly 2–3 ⁇ m. By the third pass, the mean droplet diameter approaches 1 ⁇ m (D50 ⁇ 1.0–1.2 ⁇ m).
  • the emulsion temperature is maintained at ⁇ 35–40 °C to avoid excessive heating.
  • a sonication step is applied for 20 KW ⁇ s (100 % amplitude, continuous mode, Hielscher UP400St). This brief ultrasound treatment helps refine the size distribution and eliminates any remaining large droplets without producing significant free radicals.
  • the emulsion is cooled to ambient temperature ( ⁇ 20 °C).
  • Particle size analysis e.g., via laser diffraction or TRPS
  • D50 volume-weighted median diameter
  • ⁇ 0.2 PDI narrow size distribution
  • An antioxidant assay confirms negligible oxidative degradation, correlating with the reduced sonication time.
  • Nile Red A emulsion exhibits good stability over at least 3 months of storage at 4 °C, with no creaming or droplet coalescence.
  • This example illustrates how the microfluidizer-to-sonication approach can load a pure fluorescent dye (Nile Red A) into a partially solidified lipid carrier, yielding submicron droplets suitable for analytical or imaging applications.
  • B. Second aqueous composition An oil blend is prepared by mixing 10 g stearic acid (melting point ⁇ 69 °C), 20 g coconut oil (solid below ⁇ 25 °C), 30 g medium-chain triglycerides (MCT) and 50 g broad-spectrum cannabis distillate (82 % CBD content, plus minor cannabinoids/terpenes).
  • the combined mixture is kept at approximately 40 °C during this blending step.
  • the pre-emulsion is passed through a bench-scale microfluidizer at 100 bar for three passes. After the first pass, the coarse droplets are reduced in size to roughly 2–3 ⁇ m. By the third pass, the mean droplet diameter approaches 1 ⁇ m (D50 ⁇ 1.0–1.2 ⁇ m). Throughout microfluidization, the emulsion temperature was maintained at ⁇ 35–40 °C to avoid excessive heating. Following microfluidization, a sonication step is applied for 50 KW ⁇ s (100 % amplitude, continuous mode, Hielscher UP400St).
  • This brief ultrasound treatment helps refine the size distribution and eliminates any remaining large droplets without producing significant free radicals.
  • the emulsion is cooled to ambient temperature ( ⁇ 20 °C).
  • Particle size analysis e.g., laser diffraction or TRPS
  • D50 volume-weighted median diameter
  • ⁇ 0.2 PDI narrow size distribution
  • Antioxidant assays confirms negligible degradation of the active cannabinoids or minor terpenes, correlating with minimized sonication time.
  • the resulting broad-spectrum CBD emulsion remains stable for at least 3 months at 4 °C, displaying minimal creaming or droplet coalescence.
  • This approach demonstrates how broad-spectrum cannabinoid distillate can be formulated into a stable, partially solidified lipid emulsion, preserving minor cannabinoids and terpenes.
  • microfluidization and a short ultrasonic burst free-radical formation is limited, protecting the plant-derived actives and achieving a submicron particle size.
  • microfluidizer processing prior to a brief sonication significantly reduces total ultrasonic energy exposure, thereby minimizing oxidative stress on sensitive actives.
  • the partial crystallization from stearic acid further enhances physical stability and can help modulate release characteristics.
  • Example 5 Particle distribution
  • First and second aqueous compositions according to the present invention were made with the dye Nile Red as compound of interest.
  • an oil phase was prepared by melting together approximately 5 g of stearic acid (melting point ⁇ 69 °C), 10 g of coconut oil (solid below ⁇ 25 °C), 15 g of medium-chain triglycerides (MCT), and 1 g of Nile Red A (pure compound).
  • the warmed oil phase was gradually introduced into the emulsifier solution under moderate stirring ( ⁇ 300 rpm) to create a coarse pre-emulsion.
  • the combined mixture was maintained at about 40 °C to ensure sufficient fluidity and ease of mixing.
  • the pre-emulsion was then subjected to sonication for a total of approximately 51 kW ⁇ s at 100% amplitude in continuous mode (using a Hielscher UP400St). This sonication step facilitated droplet size reduction to the desired submicron range.
  • the emulsion was allowed to cool to ambient temperature ( ⁇ 20 °C).
  • Particle size analysis (e.g., via laser diffraction on a Shimadzu SALD-2300, reference index 1.55–0.05i) indicated a volume-weighted median diameter (D50) of about 0.346 ⁇ m, with a narrow size distribution (PDI ⁇ 0.195).
  • D50 volume-weighted median diameter
  • PDI narrow size distribution
  • a small-emulsion demonstrated stability for at least three weeks at 4 °C, exhibiting no significant creaming or droplet coalescence.
  • a second micro-emulsion batch was prepared under the same conditions described above, except no sonication energy was applied.
  • Example 6 In vivo uptake of compound of interest Nile red fat staining in vivo to study the release from small particles. Nile Red is commonly used as a fixative-based stain to quantify the main fat stores in C. elegans (Brooks et al, 2009, O’ Rourke et al, 2009).
  • C. elegans can take up nutrients from their environment by feeding, with bacteria being their primary food source.
  • a size range of 0.5-3 ⁇ m is considered as optimal, although nematodes can ingest smaller and larger particles. Further, processing is rapid, with uptake within 15 minutes time as shown with fluorescent particles (Kiyama et al, 2012).
  • Nematode handling Nematode populations (wild-type N2) were synchronized by hypochlorite treatment of gravid adult hermaphrodites to isolate individual eggs. Eggs were incubated in M9 buffer overnight to allow hatching of L1 larvae in the absence of food. Synchronized L1 larvae were cultured on NGM agar plates seeded with OP50 bacteria at 20° for 72 hours. Nematodes were then transferred to vial containing S-medium and OP50 and grown at 20° for 24 hours before addition of small particle suspension. 6.4.
  • Small particle treatment Small particle nile red was added to the vials to a final concentration of 0.4 or 2 ⁇ g/ml and incubated for 2 hours at at 20 °C. Nematodes were subsequently washed to rinse away excess small particles from the medium, and further incubated for 30, 60 or 135 minutes in vials to allow for digestion of remaining small particles in the nematodes. 6.5. Microscopy For analysis and quantification, nematodes were collected in centrifuge tubes and gently centrifuged. 3.7 ⁇ l of worm pellet was added to 1 ⁇ l 50mM sodium azide on 3% agarose slides.
  • this fluorescence may at least in part be the result of unprocessed particles present in the nematodes.
  • nematodes were allowed to recover for 30, 60 or 135 minutes after exposure to allow for clearance and dissociation of the residual particles. Analysis of the corrected total GFP intensity confirmed that both nano-nile red and micro- nile red were able to induce a significant increase in fluorescence in nearly all conditions tested, indicating that particles are taken up by the nematodes ( Figure 3).
  • the signal in the nano-nile red treated nematodes remained higher over time, strongly indicating a more efficient uptake of nile red upon treatment with nano-nile red.
  • Differently sized particles appeared to have different behavioral dynamics when they were exposed to C. elegans.
  • the fluorescence of nano-nile red decreased, but visually always remained higher than the comparable concentration of micro-nile red.
  • the stronger initial increase of fluorescence followed by a subsequent decline suggests a peak like behavior, in which particles are accumulated and dissociated efficiently until supply runs out (Figure 4).
  • fluorescence appeared more stable over time in micro-nile red treated nematodes. Combined, this suggests that the nile red is released from the particles in different phases depending on the size of the particles.
  • This data supports a 2-phase system in which particles in the nanometer size range and micrometer size range dissociate at different rates, leading to different peaks in activity of the encapsulated compounds.
  • Micro CBD particle composition and small particle CBD nano composition were prepared as follows: An oil phase was prepared by melting together approximately 10 g of stearic acid (melting point ⁇ 69 ⁇ °C), 20 g of coconut oil (solid below ⁇ 25 ⁇ °C), 30 g of medium-chain triglycerides (MCT), and 50 g of a broad- spectrum cannabis distillate (nominally 82% CBD content, with minor cannabinoids and terpenes). While maintaining the temperature at about 50 ⁇ °C, 2 g of rosemary extract (antioxidant) and 1 g of tocopherol (vitamin E) were added. The mixture was stirred until a homogeneous solution resulted.
  • MCT medium-chain triglycerides
  • an aqueous phase was prepared by dissolving approximately 10 g of sucrose ester (e.g., RyotoTM P-1670), 10 g of ⁇ -cyclodextrin, and 5 g of sunflower lecithin in 800 mL of purified water, maintained at 35–40 ⁇ °C. This solution was stirred until all components were completely dissolved and free of visible particulates. The warmed oil phase was slowly introduced into the emulsifier solution under moderate stirring ( ⁇ 300 ⁇ rpm), forming a coarse pre-emulsion. The blend was maintained at approximately 40 ⁇ °C to ensure adequate fluidity during mixing.
  • a sonication step was applied for about 200 kW ⁇ s at 100% amplitude in continuous mode (e.g., using a Hielscher UP400St) to reduce droplet size and improve emulsion uniformity.
  • a Hielscher UP400St a Hielscher UP400St
  • 30 g of erythritol was added to serve as a cryoprotectant.
  • the treated emulsion was then poured into six pre-chilled trays (cooled over dry ice) to rapidly freeze the product. The trays were subsequently placed in a Harvest RightTM Large Freeze Dryer.
  • the freeze-dryer was programmed with an initial freezing temperature of ⁇ 28 ⁇ °C, 0:00 extra freeze ⁇ me, afinishing temperature of 21 ⁇ °C, and an additional drying time of 24 ⁇ hours. Upon completion of the freeze-drying cycle, a stable, dry product was obtained. Particle size analysis (e.g., by laser diffraction or TRPS) on the reconstituted (rehydrated) emulsion showed a volume-weighted median diameter (D50) of approximately 0,288 ⁇ m, with a narrow size distribution.
  • D50 volume-weighted median diameter
  • the resulting freeze-dried formulation when stored at 4 ⁇ °C post-rehydration, demonstrated excellent colloidal stability for at least three months, showing no significant creaming or droplet coalescence.
  • Lyophilized small particle CBD nano powder contained 40% CBD and was dissolved in 6 times concentrated OP50 bacteria to a final concentration of 2.5 mg/ml for LC-MS metabolomics.
  • Small particle CBD micro was prepared by mixing 1.875g of emulsifier mix (consisting of sucrose ester, ⁇ - cyclodextrin and sunflower lecithin in a 2:2:1 weight ratio) in 60 ml of water and mixed vigorously to dissolve the emulsion mix. 5.44 g of micro-CBD oil paste (the oil fraction with CBD obtained exactly according to the protocol described with the preparation of the nano-particles) was added and frothed extensively to emulsify the oil.
  • the resulting suspension is calculated to contain 5 mg/ml micro-CBD, and was mixed in a 1:1 ratio with 12 times concentrated OP50 bacteria for a final concentration of 2.5 mg/ml for LC-MS metabolomics.
  • 1.2. Strains and culture C. elegans nematodes were cultured on NGM plates seeded with OP50 bacteria and generally maintained at 20°C using standard methods (Brenner 1974). Genotypes of the strain used in this study is N2 wild type. Strains used in this study were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440).
  • Nematode populations (wild-type N2) were synchronized by hypochlorite treatment of gravid adult hermaphrodites to isolate individual eggs. Eggs were incubated in M9 buffer overnight to allow hatching of L1 larvae in the absence of food. Synchronized L1 larvae were cultured on NGM agar plates seeded with OP50 bacteria at 20° for 52 hours, where the bacterial food source was supplemented small particle CBD. Small particle CBDs used were fast nano and micro. Small particle CBDs were given to the nematodes at a 2.5 mg/ml final concentration mixed in the food.
  • Nematodes were grown on NGM plates with OP50 and subsequently exposed for either 4 or 24 hours on NGM plates with OP50 mixed with small particle CBD before collection, keeping the 52-hour growth period consistent between all conditions.
  • Sample preparation LC-MS Nematodes were collected from plates by washing, and were freeze-dried, homogenized, and processed separately for each triplicate (Molenaars et al.2021). Extracts were made with methanol and chloroform phases, and the methanol phase was kept and used for analysis. Samples were processed at a clinical health laboratory in Bunnik, the Netherlands and tested against a panel of 6 neurotransmitters, as well as a panel of 46 amino acids.
  • Metabolomics was pioneered in the 1990s and allows measurement of metabolites, the substances that are used during metabolism, and offers a highly sensitive method to detect changes in organisms in disease, and upon exposure to nutrients or compounds (Oliver et al. 1998, Nicholson et al.1999, German et al.2005).
  • This method relies on different analytical techniques with each having their specific advantages and includes techniques such as nuclear magnetic resonance (NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) (Roberts et al, 2013).
  • NMR nuclear magnetic resonance
  • GC-MS gas chromatography-mass spectrometry
  • LC-MS liquid chromatography-mass spectrometry
  • Nanoparticles are classified by their size that ranges from as small as 1nm to up to 500 nm when referring to scientific literature and nomenclature (Harish et al.2022). In the laws of the European Union only particles smaller than 100 nm are officially classified as nanoparticles (Rasmussen et al.2024), however, to provide distinction, this report references to scientific literature with nano particles categorized as sizes up to 500 nm.
  • nano-CBD a suspension with a median size of the particles of 280nm
  • micro-CBD a micro suspension of particles with a median size of several micrometers
  • Phase Preparation Aqueous Phase (W-Phase) Preparation • Disperse Xanthan Gum (2 g) and Saccharose Ester (10 g) in about 100 g of the total water portion (kept at ⁇ 40–50 °C). • Stir thoroughly until all solids dissolve. • Add remaining water to reach the total W-phase amount (538 g). • Dissolve Potassium Sorbate (10 g) and Glycerin (50 g) into the same solution. Maintain temperature at ⁇ 40 °C to keep the gum well-hydrated. 2.
  • W-Phase Preparation • Disperse Xanthan Gum (2 g) and Saccharose Ester (10 g) in about 100 g of the total water portion (kept at ⁇ 40–50 °C). • Stir thoroughly until all solids dissolve. • Add remaining water to reach the total W-phase amount (538 g). • Dissolve Potassium Sorbate (10 g) and Glycerin (50 g) into the same solution. Maintain temperature
  • Controlled Cannabinoid Delivery • Incorporation of “WS” form enables a multi-phase release profile for CBD. • The result is both immediate and sustained release of active compound when applied to the skin. 4. High Biocompatibility & Sensory Profile • Shea Butter, Argan Oil, and Rosehip Oil add emolliency and nutritional benefits, while Tocopherol aids in antioxidant protection. • The final cream is non-greasy with a pleasant after-feel. Summary: Using a microfluidizer allows for a gentle yet effective method of emulsifying multiple oils and cannabinoids into a stable cream. The final cream base leverages slow-release and immediate-release cannabinoid fractions, providing enhanced therapeutic and cosmetic benefits.

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Abstract

The present invention provides a delivery system comprising of a first aqueous composition harbouring small particles and a second aqueous composition harbouring larger particles in which the particles of the first and second aqueous compositions may comprise the same or a different compound of interest, wherein said compound of interest preferably is a hydrophobic or amphiphilic compound. In both cases the small particles comprise a partly liquid oil phase at temperatures around about 4°C.

Description

New method for delivering compounds of interest BACKGROUND Nanoparticles (NPs) and nanocarrier (NC) formulations of highly lipophilic drugs enable the delivery of compounds that previously could not be administered at therapeutic levels by conventional formulations. Complex NC constructs, such as liposomes, nanocapsules, polymeric NPs, micelles and polymersomes can improve the observed therapeutic effect of drug compounds by increasing solubility, improving pharmacokinetics or altering biodistribution. Metallic, organic, inorganic and polymeric (nano- or micro- )structures, including dendrimers, micelles, and liposomes are frequently considered in designing the target-specific drug delivery systems. In particular, those drugs having poor solubility with less absorption ability are tagged with these particles. However, the efficacy of these structures as drug delivery vehicles varies depending on the size, shape, and other inherent biophysical/chemical characteristics. For these reasons, there is still need for a new, stable composition comprising a compound of interest enabling long-term storage and easy application for producing a pharmaceutical composition comprising the compound of interest. In the co-pending application PCT/NL2024/050344 already compositions and a method for producing these have been described in which the compound of interest is delivered in a stable mesoparticle composition, wherein a mesoparticle is defined as a particle with a mean particle size of 10-600 nm, expressed as D50 determined in accordance with ISO 9276-2. In practice, (oral) compositions with lipophilic substances, such as cannabinoid compositions are usually provided in the form of a solution in an oily solvent wherein the lipophilic compounds, such as cannabidiol (CBD) and tetrahydrocannabinol (THC) dissolve, allowing a rather concentrated content. Most of the known compositions are oil-based, i.e. an oily solution wherein the lipophilic compounds are dissolved, or a water-in oil dispersion, wherein the lipophilic compounds are in the oily phase. For oral administration, the oily solvent needs to be food grade and acceptable for oral administration. The composition is defined as oily or oil-based when more than half of the volume of the composition is an oil, and in case of a dispersion, the oily phase should be the continuous phase. Ingestion of oil is however cumbersome and since the ingestion volume is limited, the cannabinoid compositions known in the art are highly concentrated, e.g. in concentrations of 5 w/w% to 60 w/w%. Such high concentrated composition are however difficult to dose properly and often, undesired side effects are observed. Furthermore, the bioavailability of lipophilic compounds from oily preparations is low, which means that much of the ingested active compound is not utilized. Right now, most methods for delivering cannabis components use an oily solution. This is far from ideal. It is not easy to ingest, and the body does not absorb much of the drug. It also takes a long time (about 3.5 hours) for the drug to start working, and the dose (and thus the effects) can be unpredictable. Moreover, these methods usually have a high concentration of the drug, which can make dosing difficult and cause unwanted side effects. They also go through a process in the body called first pass metabolism, which can increase the drug's interaction with other substances in the body, complicating things further. In more recent times many approaches have been published to provide water-based compositions comprising lipophilic or amphiphilic substances, such as cannabinoids. The present invention, which provides an aqueous composition containing particles of at least two different size classes, is advantageously suited for comprising such a compound of interest, which may preferably be a lipophilic compound, but which is also suitable for the delivery of amphiphilic or hydrophilic compounds. These kinds of particle based delivery systems have been a big step forward in getting lipophilic drugs, like some components of cannabis, into the body. They have helped drugs work better by making them dissolve more easily, getting them to the right places in the body, and changing how they spread out once they are there. However, there are still some problems to solve. One big issue is finding a way to create aqueous compositions of particles that are stable for a long time and are easy to apply, especially for drugs that do not like water. Therefore in the present invention water soluble nano- or micro-carriers have been developed in which the oil phase still is partly liquid. SUMMARY OF THE INVENTION The present invention provides a delivery system comprising of a first aqueous composition prepared by the steps of a. Providing an emulsifier or a blend of emulsifiers in powder form; b. Mixing two or more oils at a temperature above 40°C where all oils have become liquid, wherein said oils differ in melting temperature, wherein the oil mixture comprises at least one oil with a melting point above 50°C and which mixture comprises at least a sufficient amount of an oil with a low melting point, preferably medium chain triglycerides, to enable the composition formed in step g to have a partly liquid oil phase at temperatures around about 4°C; c. Adding the compound of interest in any suitable hydrophobic solvent to the oil mixture; d. Optionally letting the mixture cool down to room temperature; e. Adding the emulsifier powder and water to the oil mixture and letting the mixture emulsify, under optional agitation and heating to 30-40°C; f. Subjecting the emulsified mixture to a sonication and optionally mixing or fluidisation treatment until the average particle size of the mixture remains stable; g. Cooling down the sonicated mixture allowing sufficient time for crystallisation; and h. Optionally, a second sonication treatment while keeping the mixture cold, and a second aqueous composition prepared by the steps of i. Providing an emulsifier or a blend of emulsifiers in powder form, where preferably the emulsifier is identical to the emulsifier provided in step a); j. Mixing two or more oils at a temperature above 40°C where all oils have become liquid, wherein said oils differ in melting temperature, wherein the oil mixture comprises at least one oil with a melting point above 50°C and which mixture comprises at least a sufficient amount of an oil of a low melting point, preferably medium chain triglycerides, to enable the composition formed in step n to have a partly liquid oil phase at temperatures around about 4°C, preferably wherein the oils and the weight ratio between them is identical to the oils and weight ratio used in step b); k. Adding the compound of interest in any suitable hydrophobic solvent to the oil mixture; l. Optionally letting the mixture cool down to room temperature; m. Adding the emulsifier powder and water to the oil mixture and letting the mixture emulsify, under optional agitation and heating to 30-40°C; n. Cooling down the mixture allowing sufficient time for crystallisation; wherein said first and second aqueous compositions are mixed to obtain the delivery system. Preferably in said delivery system the emulsifier is a blend of emulsifiers, preferably wherein said emulsifiers are non-toxic emulsifiers, more preferably wherein said blend comprises sugar-based emulsifiers, such as sucrose ester and/or cyclodextrin, while more preferably the emulsifier is a blend comprising sucrose ester, cyclodextrin and lecithin, preferably sunflower lecithin, preferably wherein the amount of lecithin is such, that in the final sonified mixture from step g and/or the final composition obtained in step n). the concentration of lecithin is less than 5% by weight, preferably less than 2%, more preferably less than 1%. Also part of the invention is a delivery system as descriebd above, wherein the amount by weight of sugar-based emulsifiers is at least two times the amount of lecithin, preferably at least four times. Also preferred is a delivery system wherein the weight ratio between sucrose ester, cyclodextrin and lecithin is 2 : 2 : 1. In a further embodiment the oil mixture comprises oils or fats that are non toxic and also preferred is when the oil mixture comprises at least one oil with a melting point above 60°C and/or wherein the oil mixture comprises an oil with a melting point in between room temperature and body temperature. In a preferred embodiment the oil mixture comprises stearic acid, coconut oil and medium chain triglycerides. Further it is preferred when the oil mixture, when mixed with the hydrophobic compound, comprises the components in a weight ratio of stearic acid : coconut oil : medium chain triglycerides : solvent with hydrophobic compound of 1 : 2 : 3 : 5. Also part of the invention is a delivery system as described above, wherein a non-toxic antioxidant is added to the oil mixture, preferably wherein said antioxidant is a blend of antioxidants, more preferably wherein said antioxidant or blend of antioxidants in total in weight does not exceed the amount of 10% of the oil mixture, preferably not exceed the amount of 5% of the oil mixture. More preferably, said blend of antioxidants comprises linseed oil, hempseed oil, tocopherol and/or rosemary extract; preferably where it comprises linseed oil, hempseed oil, tocopherol and rosemary extract, preferably in a weight ratio of 2 : 2 : 2 : 1. A further part of the invention is a delivery system as described above, wherein the weight ratio of oil to emulsifiers in both the method to prepare the first and the second aqueous composition is from 3.0 to 5.0, more preferable from 3.2 to 4.0, more preferably about 3.5. In a preferred embodiment of the present invention, the water is food-grade water. Also part of the invention is a delivery system as described above, wherein the particles in the first aquoes composition will have a mean particle size of 10 – 600 nm, preferably of 50 – 150 nm and more preferably of 80 – 130 nm, most preferably about 110 nm expressed as D50 determined in accordance with ISO 9276-2. Further preferred in the present invention is a delivery system wherein glycerol is added to the final composition, more preferably wherein the concentration of glycerol is more than 20%, preferably more than 25% by weight. In a preferred embodiment at least one of the compounds of interest is a plant-based extract in oil, preferably wherein the plant-based extract is an extract of Cannabis sativa, preferably, wherein said extract comprises a cannabinoid, more preferably, wherein said extract comprises a cannabinoid chosen from the group consisting of Δ9- tetrahydrocannabinol (THC), Δ9-tetrahydrocannabinolic acid (Δ9-THCA or THCA), Δ9- tetrahydrocannabiorolic acid (Δ9-THCA-C1 or THCA-C1), Δ9-tetra-hydrocannabiorcol (Δ9- THCO-C1 or THCO-C1), Δ9-tetrahydrocanna-biorcolic acid (Δ9-THCOA or THCOA), Δ9- tetra-hydrocannabivarin (Δ9-THCV or THCV), Δ9-tetrahydrocannabivarinic acid (Δ9- THCVA or THCVA), trihydroxy-Δ9-tetrahydro-cannabinol (TRIOH-THC), Δ10-tetrahydro- cannabinol (Δ10-THC), tetrahydro-cannabiphorol (THCP), THC-O acetate (THCO), hexa- hydrocannabinol (HHC), 10-oxo- Δ6a-tetrahydrocannabinol (OTHC), Δ8-tetra- hydrocannabinol (Δ8-THC), Δ8-tetrahydrocannabinolic acid (Δ8-THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiorcol (CBDC1), cannabidiol-C4 (CBDC4), cannabidiol dimethyl ether (CBDD), cannabidiol monomethyl ether (CBDM), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), nabilone, nabiximol, anandamide, cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerolic acid A monomethykether (CBGAM), canna- bigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabigerol mono-methylether (CBGM), cannabinol (CBN), cannabinolic acid (CBNA), cannabdiorcol (CBN-C1), cannabinol-C2 (CBN-C2), cannabivarin (CBN-C3), cannabinol-C4 (CBN-C4), cannabinodivarin (CBNDC3), cannabinol methylether (CBNM-C5), cannabichromene (CBC), cannabichromenc acid (CBCA), cannabichromanon (CBCN-C5), cannabicoumaronone (CBCON-C5), cannabi-chromanone-C3 (CBCN-C3), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabielsoin (CBE- C5), cannabigelndol-C3 (OH-iso-HHCVC3), C3-canna-bielsoicacid B (CBEA-C3 B), cannabifuran (CBF), dehydrocannabifuran (DCBF-C5), cannabifuran (CBF-C5), dehydrocannabifuran (DCBF or CBFD), cannabicyclol (CBL-C5), cannabicyclovarin (CBLV- C3), cannabitriol (CBT), cannabitriolvarin (CBTV), cannabiripsol (CBR), cannabinodivarin (CBV or CBVD), 2-arachidonoylglycerol (2-AG), 2-arachidonoylglycerol ether (2-AGE), isotetra-hydrocannabinol, isotetrahydrocannabivarin, palmitoylethanolamide, epigallo- catechin (EGC), (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG), even more preferred wherein said extract comprises THC or a blend with THC. Also part of the invention is a delivery system as described above, wherein the first and second aqueous compositions are blended into a cream. Preferably, wherein an aqueous cream base is provided, through which the second aqueous composition is mixed with low shear, whereafter the first aqueous composition is gently added and mixed with very low shear, more preferably wherein the cream base comprises water, coconut oil, shea butter, medium chain triglycerides and sucrose ester. Further part of the invention is a delivery system as described above, wherein optionally after storage of the first and/or second aqueous composition, water is added to either or both of the first and second aqueous composition to obtain a diluted composition, preferably, wherein the composition is diluted with water, more preferably wherein the composition is diluted in such a way that the dilution comprises between 0.001% and 5% of the compound of interest, preferably between 0.005% and 1%, more preferably between 0.01% and 0.5%, more preferably between 0,02 % and 0.1%, more preferably wherein the water is food-grade and further preferably wherein a stabiliser is added to the composition, preferably wherein said stabiliser is a food grade stabiliser, more preferably wherein said stabiliser is a gum, more preferably wherein said stabiliser comprises guar gum and/or xanthan gum, more preferably wherein the concentration of guar gum and/or xanthan gum in the diluted composition is between 0.01 and 0.05%, more preferably about 0.02%. In another embodiment the invention comprises a delivery system as described above, wherein further a preservative is added to the delivery system, preferably wherein said preservative is a food grade preservative, more preferably, wherein said preservative is chosen from the group consisting of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbicate, citric acid, sorbic acid, calcium sorbate, benzoic acid, potassium benzoate, acetic acid, erythorbic acid, sodium erythorbate, ethyl lauroyl arginate, long-chain glycolipids from Dacryopinax spathularia MUCL 53181, methyl-p-hydroxybenzoate, nisin, sulphurous acid, dimethyl dicarbonate, ascorbyl palmitate and blends thereof. In such a delivery system said preservative preferably comprises ascorbic acid, citric acid or sorbic acid or a blend thereof, preferably wherein the ascorbic acid, if present, is present at a concentration between 0.01% and 0,1% by weight, preferably about 0.05%, and wherein the citric acid, if present, is present at a concentration between 0.005% and 0.05% by weight, preferably at about 0.01%, and wherein the sorbic acid, if present, is present at a concentration between 0.05% and 0.5%, preferably about 0,1%. Also part of the invention is a delivery system as described above, wherein further a flavouring compound is added to the first or second aqueous composition or to the delivery system or to the cream, preferably a food grade flavouring compound. Further part of the invention is a delivery system wherein the first and/or second aqueous composition are stored before mixing them to obtain the delivery system, preferably, wherein either the first aqueous composition is stored as powder by lyophilisation and/or wherein the second aqueous composition is stored as powder by lyophilisation. In such a system the freeze-dried powder is preferably reconstituted in water. Also part of the present invention is a delivery system as described above, in which panthenol is added to the oil mixture, preferably wherein panthenol is added to an amount between 0.5 and 5% of the oil mixture, more preferably an amount between 1 and 3% of the oil mixture. FIGURES Fig. 1 shows a comparison of a solid particle and a particle of a composition according to the invention that comprises an oil phase where part of the oil phase is liquid. Fig. 2 shows particle size distributions of first (nano) and second (micro) aqueous compositions according to the invention as prepared and measured as described in Example 5 and 6. Fig. 3 Fluorescence induced by release of nile red in C. elegans over time. Bar graphs showing fluorescence values (AU) of different exposure times and concentrations of nano- nile red or micro-nile red over time. The y-axis represents corrected total fluorescence, the x-axis represents compounds, the facets on the x-axis represent recovery times after exposure for 2 hours to the compounds. Fig. 4 Schematic representation of fluorescence induced by release of nile red in C. elegans over time. Visual representation of fluorescence levels over time in nematodes treated with 2 µg/ml nano- (X) or micro- (O) nile red (NR). Light blue scale zone indicates levels of fluorescence in untreated nematodes. Fig. 5 Heat map of neurotransmitter and amino acid metabolites (LC-MS). Heat map showing normalized and scaled (z-values) of metabolite levels. Red shading indicates low values, while blue shading indicates high values. Metabolites were measured and are represented as rows in the heat map. Fig.6 Levels of the neurotransmitter serotonin in CBD-treated nematodes Left: The y-axis represents the normalized micromolar concentration for the metabolite serotonin detected in the treated nematodes. Each dot represents one replicate measurement, and the bar graph indicates the mean. Serotonin is increased in CBD treatment and levels increase over time. Right: Visual representation of serotonin levels over time in nano- (x) and micro-CBD (O) treated nematodes. Light blue scale zone indicates metabolite levels in untreated nematodes. Fig. 7 Levels of the neurotransmitter dopamin in CBD-treated nematodes Left: The y-axis represents the normalized micromolar concentration for the metabolite dopamine detected in the treated nematodes. Each dot represents one replicate measurement, and the bar graph indicates the mean. Dopamin is increased in CBD treatment and levels increase over time. Right: Visual representation of dopamin levels over time in nano- (x) and micro-CBD (O) treated nematodes. Light blue scale zone indicates metabolite levels in untreated nematodes. Fig.8 Levels of the amino acid beta-alanine in CBD-treated nematodes Left: The y-axis represents the normalized micromolar concentration for the metabolite detected in the treated nematodes. Each dot represents one replicate measurement, and the bar graph indicates the mean. Beta-alanine is increased upon CBD treatment and levels decrease over time after nano-CBD treatment and increase over time in micro-CBD treatment. Right: Visual representation of beta-alanine levels over time in nano- (x) and micro-CBD (O) treated nematodes. Light blue scale zone indicates metabolite levels in untreated nematodes. Fig.9 Levels of the amino acid aspartic acid in CBD-treated nematodes Left: The y-axis represents the normalized micromolar concentration for the metabolite detected in the treated nematodes. Each dot represents one replicate measurement, and the bar graph indicates the mean. Aspartic acid is increased upon CBD treatment and levels decrease over time after nano-CBD treatment and increase over time in micro-CBD treatment. Right: Visual representation of aspartic acid levels over time in nano- (x) and micro-CBD (O) treated nematodes. Light blue scale zone indicates metabolite levels in untreated nematodes. Fig.10 Levels of the amino acid glutamic acid(+) in CBD-treated nematodes Left: The y-axis represents the normalized micromolar concentration for the metabolite detected in the treated nematodes. Each dot represents one replicate measurement, and the bar graph indicates the mean. Aspartic acid is increased upon CBD treatment and levels decrease over time after nano-CBD treatment and increase over time in micro-CBD treatment. Right: Visual representation of glutamic acid levels over time in nano- (x) and micro-CBD (O) treated nematodes. Light blue scale zone indicates metabolite levels in untreated nematodes. DETAILED DESCRIPTION As can be derived from the description of the invention as provided above, the invention consists of the preparation of two separate compositions that each may be characterised containing particles having an oil phase where part of the oil phase is liquid (see Fig. 1). However, the main difference between the first and second composition is in the average size of the particles, which is smaller in the first composition since for that composition a sonication treatment is used to lower the average particle size. In a preferred embodiment of the present invention, the particle size of the particles in the first composition is ranging from 10 nm to 600 nm, preferably of 50 – 150 nm and more preferably of 80 – 130 nm, most preferably about 110 nm, expressed as D50 determined in accordance with ISO 9276-2. If the claimed method is followed, the distribution of the particles according to size, whether it is the particle size as measured by the surface area, volume or number, will follow a Gauss curve, which means that all of the indicated measurement methods would yield the same result. The average particle size in the second composition, which only very shortly has been exposed to a sonication treatment, or, preferably, has been mixed with high shear, e.g. by microfluidising, is in the range of 300 nm – 100 μm, more preferable between 500 nm and 10 μm, more preferably between 750 nm and 5 μm, even more preferably around 1 μm. When microfluidising is used, the size of the particles may be determined by the pore filter that is used in the apparatus and the mixing advantageously takes place for such a long time that the particles have the same size. These compositions may or may not harbour the same compound of interest and may or may not have identical ingredients, i.e. the same emulsifier(s), the same oils and identical further additives. In the present invention a first aqueous composition is made by emulsifying an oil composition comprising a hydrophobic or amphiphilic compound of interest with water by adding an emulsifier, after which the emulsion is sonicated to produce an aqueous nanoparticle solution. A first step in the present invention for preparing the first aqueous particle composition of the present invention is to provide an emulsifier or, preferably, a blend of emulsifiers. The goal of these emulsifiers is to provide a system from which small particles may be produced and for this purpose, the emulsifier should be able to provide a sufficient stability. Further, since it is highly likely that eventually the composition is taken orally, it should also have a sufficient safety profile and it should also provide for an acceptable taste. One preferred emulsifier is lecithin, this in itself already being a blend of glycerophospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, and phosphatidic acid. The lecithin may be derived from various sources, such as soybean, rapeseed, cotton seed or sunflower. Lecithin is a food-grade product, has GRAS status and is also admitted in Europe as food additive E322. However, due to its off-flavour, it is desirable that the amount of lecithin in the final composition is relatively low. So, care should be taken that the concentration of lecithin is less than 5%, preferably less than 2%, more preferably less than 1% of the final sonified first composition as obtained in the process according to the present claims. Next to this low amount, it is also deemed advantageous to include further emulsifiers that would be able to mask the bad taste of lecithin. For this purpose sugar-based emulsifiers are preferred, since they provide a sweet taste. Any sugar- based emulsifier that is non-toxic and which has a sweet taste can be used, such as sucrose esters, cyclodextrin, sucralose esters, sophorolipids, and the like. For an optimal taste masking effect the concentration of these sugar-based emulsifiers is at least two times the concentration of lecithin and preferably at least four times. The most preferable combination of emulsifiers is a blend of sunflower lecithin, sucrose ester (e.g. Ryoto™ sugar ester P- 1670 obtainable from Mitsubishi Chemical Corporation) and β-cyclodextrin, most preferably in a weight or molar ratio of 1:2:2. This blend also shows a lower toxicity profile than traditional emulsifiers or emulsifier blends with a lower formation of harmful free radicals and degradation products. Also, the presence of cyclodextrin means that the size of the small particles will be approximately 110 nm, which size is determined by the internal bond angles of cyclodextrin encouraging particle sizes of this diameter. Particles below 110nm that incorporate beta-cyclodextrin do so with torsion energy supplied by sonication (provided in a later step) which is an thermodynamically unstable arrangement. It is expected that these particles will spontaneously reform themselves over time to a larger, more stable and energetically favourable conformation of about 110 nm. Other emulsifiers that are preferred are mono- or diglycerides (also known as E471), such as glycerol monostearate, glycerol monopalmitate, glycerol monooleate, glycerol monolaurate and glycerol monoricinoleate. Also equally applicable in the present invention are mono- and di-esters (known as E305) of ascorbic acid, such as ascorbylstearate and ascorbylpalmitate.The adavantage of E305 is that it is not applicable as emulsifier, but that it also has antioxidant properties. In a second step of the method of preparing the first aqueous composition a mixture of oils is provided, which mixture may consist of two oils, but can also have 3, 4 or more different oil constituents. Similar to the blend of emulsifiers, also for the oil mixture only oils should be included which are non-toxic and food-grade. Further, in order to be able to regulate the viscosity and stability of the particle solution oils of different melting temperatures should be used. For obtaining a good stability of the nanoparticles at least one oil with a melting temperature of more than 50°C, preferably more than 60°C, should be used, such as myristic acid, palmitic acid, stearic acid or arachidic acid. Preferably stearic acid (E570), that has a melting point of nearly 70°C, is used. Stearic acid is one of the most common saturated fatty acids found in nature and in the food supply and it is often used in (nonalcoholic) beverages. Stearic acid is preferably used since it advantageously stabilises the small particles that will be formed in the process. Further preferred in the oil mix is an oil that has a melting point that lies between room temperature and body temperature. Such an oil may for example be chosen from coconut oil, cocoa butter, palm kernel oil, peanut oil and babassu oil. Preferable is coconut oil since this is cheap and easily commercially obtainable. Lastly, the oil mixture should also contain a component that would provide for a low melting point, such that the oil phase in the final nanocarrier emulsion still comprises oils that are liquid at about 4°C. The advantage of having an oil phase in the nanoparticles that is at least partly liquid is that the lipophilic compound that is contained in these nanoparticles is more readily available for absorption and uptake into the body. The characteristics of such a small particle are shown in Fig. 1, where it can be seen that the oil phase of the particle comprises both liquid and solid oil. For this ingredient an oily substance with a very low melting point (below room temperature) should be taken, such as olive oil, rapeseed oil, sunflower oil, soybean oil, castor oil, tung oil, cotton seed oil, or medium chain triglycerides (MCT). Medium-chain triglycerides (MCTs) are triglycerides with two or three fatty acids having an aliphatic tail of 6 – 12 carbon atoms, i.e. medium-chain fatty acids (MCFAs). Preferably, medium chain triglycerides are used since these are completely saturated, which means that they are unlikely to react during sonication or mixing. Further MCTs are stable over a wide temperature range through all processing conditions. Also, it is a cheap source of oil and safely, rapidly metabolized by the body into known, safe metabolites with an extremely favourable safety profile. Also, they produce a small particle size that easily sonicates and MCTs can easily be obtained in high purity. In a further preferred embodiment, C8 MCT (caprylic acid MCT) is used. The oil mixture is prepared by adding all components at a temperature at which all the oils/fats are liquid (and which is below the boiling temperature of any of the present components). To this oil mixture the hydrophobic or amphiphilic compound of interest is added which may or may not be present in a hydrophobic solvent. If such a hydrophobic solvent is used, care should be taken that the solvent is nontoxic and acceptable in food applications, at least at a concentration at which it will be available in the final product. Suitable hydrophobic solvents are food-grade oils. Preferably the hydrophobic or amphiphilic compound in a solvent is a plant extract in oil, preferably an extract from hemp (Cannabis sativa) comprising one or more cannabinoids, more preferably comprising at least THC (Δ9-tetrahydrocannabinol). However, any cannabinoid compound may be included, such as selected from the group of Δ9-tetrahydrocannabinol (THC), Δ9- tetrahydrocannabinolic acid (Δ9-THCA or THCA), Δ9-tetrahydrocannabiorolic acid (Δ9- THCA-C1 or THCA-C1), Δ9-tetra-hydrocannabiorcol (Δ9-THCO-C1 or THCO-C1), Δ9- tetrahydrocanna-biorcolic acid (Δ9-THCOA or THCOA), Δ9-tetra-hydrocannabivarin (Δ9- THCV or THCV), Δ9-tetrahydrocannabivarinic acid (Δ9-THCVA or THCVA), trihydroxy-Δ9- tetrahydro-cannabinol (TRIOH-THC), Δ10-tetrahydro-cannabinol (Δ10-THC), tetrahydro- cannabiphorol (THCP), THC-O acetate (THCO), hexa-hydrocannabinol (HHC), 10-oxo- Δ6a- tetrahydrocannabinol (OTHC), Δ8-tetra-hydrocannabinol (Δ8-THC), Δ8- tetrahydrocannabinolic acid (Δ8-THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiorcol (CBDC1), cannabidiol-C4 (CBDC4), cannabidiol dimethyl ether (CBDD), cannabidiol monomethyl ether (CBDM), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), nabilone, nabiximol, anandamide, cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerolic acid A monomethykether (CBGAM), canna-bigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabigerol mono-methylether (CBGM), cannabinol (CBN), cannabinolic acid (CBNA), cannabdiorcol (CBN-C1), cannabinol-C2 (CBN-C2), cannabivarin (CBN-C3), cannabinol-C4 (CBN-C4), cannabinodivarin (CBNDC3), cannabinol methylether (CBNM-C5), cannabichromene (CBC), cannabichromenc acid (CBCA), cannabichromanon (CBCN-C5), cannabicoumaronone (CBCON-C5), cannabi-chromanone- C3 (CBCN-C3), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabielsoin (CBE-C5), cannabigelndol-C3 (OH-iso-HHCVC3), C3-canna-bielsoicacid B (CBEA-C3 B), cannabifuran (CBF), dehydrocannabifuran (DCBF-C5), cannabifuran (CBF- C5), dehydrocannabifuran (DCBF or CBFD), cannabicyclol (CBL-C5), cannabicyclovarin (CBLV-C3), cannabitriol (CBT), cannabitriolvarin (CBTV), cannabiripsol (CBR), cannabinodivarin (CBV or CBVD), 2-arachidonoylglycerol (2-AG), 2-arachidonoylglycerol ether (2-AGE), isotetra-hydrocannabinol, isotetrahydrocannabivarin, palmitoylethanolamide, epigallo-catechin (EGC), (-)-epicatechin gallate (ECG) and (-)- epigallocatechin gallate (EGCG). The hydrophobic or amphiphilic compound may be added to the oil mixture in the form as is, i.e. in the hydrophobic solvent, but, if available, it may also be added in dry or semi-dry form. It has been found that a mixture with stearic acid, coconut oil and medium chain triglycerides is yielding excellent results with respect to the production of stable particles in which the oil phase in the particles is at least partly liquid at a temperature of 4°C. The ratio between the oils/fats with different melting points enables control of the melting behaviour of the particles and thereby release of the hydrophobic or amphiphilic compound associated with these particles after entering the human body. An increase in the amount of oils with a low melting point causes a larger part of the oil phase in the nanoparticle to be in liquid form, which provides a more rapid release, while an increase in the amount of oils with a high melting point causes a larger part of the oil phase in the particle to be solid, which provides for a retarded release of the hydrophobic or amphiphilic compound. The ratio of components that provides a very stable particle composition with the desired release properties may be achieved by mixing stearic acid, coconut oil, medium chain triglycerides and solvent with hydrophobic compound in a weight ratio of approximately 1 : 2 : 3 : 5. However, depending on the nature and melting points of the individual components other ratios may be equally applicable. The skilled person will know how to vary the parameters involved in preparing the oil mixture to obtain the desired release characteristics. It is especially advantageous to ensure that the (solid) particles that will be formed after the emulsifying and sonication steps will melt at body temperature so that the particle becomes unstable and will disintegrate. Also the use of lecithin in the emulsion may lead to instability of the particle in situations with a low pH. If thus an aqueous particle composition is desired that is able to safely pass the stomach after ingestion care should be taken not to use too much lecithin in the emulsifier mixture. Optionally one or more antioxidants may be added to the oil mixture. However, in order to maintain the antioxidant activity of such compounds, these should only be added when the oil mixture is cooled down to about RT. Antioxidants prevent free radical induced damage of cell and biological targets by preventing the formation of radicals, scavenging them, or by promoting their decomposition. Moreover, antioxidants prevents the oxidative reaction which is responsible for rancid odors and flavors within fats and oils which reduces nutritional quality of foods. Thus, antioxidants play an important role to enable a long-term storage of compositions comprising oils and fats and also act advantageously in the body. Luckily, there are sufficient hydrophobic or amphiphilc compounds that may be added to the oil mixture that can function as antioxidant (see e.g. Papas AM. Oil-Soluble Antioxidants in Foods. Toxicology and Industrial Health. 1993;9(1-2):123-149; Fan L and Micheal Eskim NA, The Use of Antioxidants in the Preservation of Edible oils, In: Handbook of Antioxidants for Food Preservation, Woodhead Publishing Series in Food Science, Technology and Nutrition, 2015, 373-388. ). Many plant oils, such as olive oil, rapeseed oil, linseed oil, peanut oil, sunflower oil, carrot seed oil, palm oil, corn oil, hempseed oil or cottonseed oil can be used, but also other plant derived components, such as vitamin E (tocopherol), extracts from rosemary, sage, thyme, and the like. As indicated above, also ascorbylpalmitate or ascorbylstearate may be used as antioxidants. The main purpose of adding these antioxidants to the oil mixture is to protect the active hydrophobic ingredient during sonication without presenting a toxicity threat to the user of the composition. Although all of the mentioned antioxidants as a single component or as a blend may be added in such an amount to achieve the desired protection, we found that a mixture of linseed oil, hempseed oil, tocopherol and rosemary extract provided sufficient antioxidant protection in the process of the invention. Tocopherol also enhances tissue absorption of the compound of interest. A further component to be added to the oil mixture is panthenol, which is a provitamin of vitamin B5. It is a moisturizer and humectant that is often found in shampoos and skin care products. In the present invention it enhances the binding of the small particles to water, i.e. it increases the Zeta potential of the particle solution. Because of this, it enhances tissue absorption rates of the compound of interest. Other additions may be pyridoxal 5’- phosphate or pyridoxine hydrochloride (vitamin B6) or melatonin. The oil mixture is mixed with the emulsifier (blend) and water at a slightly elevated temperature (about 30 - 40°C). Normally on 1 litre of the oil mixture a total of 25 grams of the emulsifier (blend) is used and 500 ml water. The water preferably is food-grade water. The addition of these three components results in an emulsion with discontinuous oil droplets containing a load of the compound of interest dispersed in the continuous aqueous medium. T For the preparation of the first aqueous composition, the mixture is optionally homogenised to obtain an emulsion in which the oil droplets are uniformly dispersed in the continuous phase. Such homogenisation can be performed with any type of mixing apparatus, such as a high-speed blender, a homogenizer, an immersion blender, an overhead stirrer, a magnetic stirrer or even a kitchen mixer or whisk (for small batches). It is also possible to obtain homogenisation through (micro)fluidisation. Homogenisation is not optional and microfluidisation is especially preferred for the preparation of the second aqueous composition (in which the next step of sonication is omitted). A microfluidizer is similar to a homogenizer in terms of shearing forces except that a high-pressure pump drives the liquids through an inline homogenizer to produce the coarse emulsion. This emulsion is then driven through microchannels designed within an interaction chamber. The flow and impingement of the emulsion results in size reduction of dispersed phase droplets, thereby yielding the small particle emulsion. By using a microfluidizer the distributions of produced particle sizes appear to be narrower and smaller than the products of traditional homogenization. One further advantage of microfluidization over high-pressure homogenization is that it is less prone to clogging as it functions at a constant shear rate. In addition, this method provides better reproducibility due to fixed geometry. The interaction chamber is available in two different types that are Y-type and Z- type. Y-type chamber divides the feed into two microstreams where it experiences very high velocity and then these microstreams collide with each other and with the wall, thereby leading to droplet disruption. Z-type chamber has zigzag microchannel through which feed is forced at high pressure where it experiences particle–particle and particle–wall collision thereby causing breakdown of droplets. Both types may be used in the present invention and the shape of these microchannels largely determines the average particle size of the resulting dispersion. The product stream is acted upon by two primary forces which bring about the desired results. First is the ‘shear force’, which acts between the product streams and walls of the channel at high velocity and second is the ‘impact force’ that is collision that occurs when the high-velocity product stream impinges upon itself. Upon exiting the interaction chamber, a heat exchanger brings the product stream to ambient temperature. Microfluidizer treatment may produce stable emulsions with uniform particle size distribution and droplet size up to < 0.1 µm, but in the present invention preferably average particle sizes of 300 nm to 100 µm, more preferably between 500 nm and 10 µm, even more preferably between 750 nm and 5 µm and even more preferably around 1 µm expressed as D50 determined in accordance with ISO 9276-2, are obtained. Since the so-produced emulsions have a uniform particle size distribution, it is irrelevant whether the average particle size is measured through surface area, volume or number. After this step of homogenisation (optional in the preparation of the first aqueous composition) the process of sonication is started. By this process, the oil droplets in the emulsion will fall apart into smaller droplets, finally resulting into small particles with a size ranging from 10 – 600 nm ,preferably 50 – 150 nm and more preferably 80 -130 nm, most preferably about 110 nm. The result is an aqueous medium in which small-size oil droplets loaded with the compound of interest are available, i.e. the droplets are a mixed solid and liquid composition (as depicted in Fig. 1). As indicated above, the nature and the amounts and ratios of the oils determine largely the distribution of the solid and liquid oil in the particles and with this the release characteristics of the particles. The sonication process may be performed with any commercially available sonicator and should be continued until the moment that the average particle size of the nanoparticles no longer decreases, i.e. until the mean particle size of the nanoparticles is stable. Since, similar to the process of microfluidisation, also here a composition is obtained where the size of the particles follows a Gauss distribution, the average particle size may be measured according to surface are, number or volume and would yield a D50 in accordance with ISO 9276-2. Depending on the sonication equipment used and the components that were used in the oil mixture and emulsifier blend the nanoparticles will have a mean particle size of 10 – 600 nm, preferably of 50 – 150 nm and more preferably of 80 – 130 nm, most preferably about 110 nm. Calculation of the mean particle size may be expressed as D50 determined in accordance with ISO 9276-2 (14th Edition, September 4, 2019) or with tuneable resistive pulse sensing (TRPS) such as obtainable by using an Izon Exoid™ apparatus. Other methods of measuring the droplet size in a nano-emulsion may be used, such as dynamic light scattering, nanoparticle tracking analysis, transmission electron microscopy, scanning electron microscopy or laser diffraction. Monitoring the particle size during the sonication is preferably achieved by TRPS on samples taken during sonication Care should be taken not to overheat the sonicated mixture. The sonication process itself produces heat which may jeopardize the formation and stability of the droplets formed. Cooling can be performed by external cooling of the container in which the sonication process takes place, but a better way is to immediately cool down the formed first aqueous small particle solution at the moment that the sonication process is (nearly) completed. The cooled composition preferably should be shortly sonicated to prevent coalescence of the small particles. Thereafter, it should be left for some time (couple of hours) to allow for crystallization of the formed small particles, which would prevent re-aggregation of the particles during further processing. The cooling preferably can be achieved by putting the solution on ice, which can be done already during the sonication process, alternatively glycerol may be added in an amount up to 25% of the particle solution. The addition of glycerol has the additional advantage that it (further) crystallizes the particles, thereby increasing the shelf life of the product and glycerol thus may be added when long term storage of the first aqueous particle composition is needed. If the first aqueous composition is not directly used to prepare the delivery system of the present invention, it may also be stored using freeze-drying. In that case, a powder is obtained which may later be reconstituted by adding water. After sonication, but before glycerol may be added or before further processing, the mixture is preferably filtered to remove larger particles and microorganisms, such as bacteria. For such a filtration, a filter with a cut-off at e.g 200 nm is used. Several filter types may be used, such as polyetherculfone (PES) filter, polyvinylidene fluoride (PVDF) filters, polytetrafluoroethylene (PTFE) filters, mixed cellulose ester (MCE) filters, polypropylene (PP) filters or nylon filters. All such filters may be pre-sterilized or can be sterilized by the user and these are readily commercially available. If the first aqueous composition is not directly used to prepare the delivery system of the present invention, it may also be stored using freeze-drying. In that case, a powder is obtained which may later be reconstituted by adding water. The second aqueous composition may be prepared according to the same process as described above, but with the exception of the sonication step (although a very short sonication may be performed) and with the obligatory presence of the homogenisation step, preferably provided by microfluidisation. This second aqueous composition may also be freeze-dried for long term storage or it may be further processed into the delivery system of the invention directly after preparation. The first aqueous composition may be gently mixed with the second aqueous composition to obtain the delivery system of the present invention. Possibly either or both of the compositions may be diluted with food-grade water before use. In any case care should be taken to not vigorously mix the compositions in order not to provoke coalescence of the particles. The presence of the small-sized oil droplets in the first aqueous composition enables a controlled release of the compound of interest: there will be a fraction of solid lipid and a fraction of liquid lipid dependent on the temperature to which the aqueous solution is exposed. This enables the function of a controlled release as when the particles crystallize they displace the compound of interest from the core into the surrounding medium. The presence of the larger (‘micro’) particles in the second aqueous composition has a different release profile, in which the compound of interest will be released later and more gradually. By the combination of the two particle composition into one delivery system, it has become possible that a compound of interest may be provided to a person in need thereof, where the relatively small particles of the first aqueous solution provide a rapid onset of the release with a high peak effect, while the relatively large particles of the second aqueous composition provide a delayed onset with a slower more stable release. Further finetuning of the release properties of the particles of both the first and the second aqueous compositions may be provide by altering the oil compositions of the particles. This is also what differentiates the presently claimed system from earlier drug delivery particle systems. These either use a solid base (solid lipid nanoparticles, SLN) which suffers from low encapsulation efficiency and poor drug release kinetics, a liquid base (nano-emulsion) which suffers from poor shelf stability as the nanoparticles just coalesce with each other and fuse to stop being nanoparticles, and/or delivery systems with microparticles which show instability and leakage of the compound of interest. The partial crystallisation, which is dependent on the melting temperature of the oils used in the oil mixture, gives stability to the particles that resist flocculation without sacrificing the ability to load the particles with high amounts of hydrophilic or amphiphilic compounds and maintain encapsulation efficiency. A further aspect that aids in the stability is the zeta potential. It appears that a first aqueous particle composition as e.g. prepared according to the examples herein has a Zeta potential of -47 mV. Zeta potentials of less than -30 mV or greater than +30 mV typically indicate indefinite colloidal stability. Thus, the observed instability, if any, wouldn't arise from particle agglomeration, as our nanoparticles inherently resist flocculation. Importantly, a strong negative zeta potential has been documented to more effectively facilitate the overcoming of biological barriers like the blood-brain barrier (BBB), gastrointestinal (GI) tract, and cellular membranes (e.g., p-GP efflux pumps and other charged surface proteins). This represents an unexpected and beneficial aspect of our formulation, and prior to our work, it wasn't predictable that this ingredient combination would have a strong negative charge that would confer such desirable attributes. For shelfing the product obtained according to the above-described process, the product should be packaged in a sterile packaging, which can be of any inert material, such as glass or vacuum packaging materials, which are normally used for airtight packaging of food products. When packaged in such a way the shelf life of the separate first and second aqueous composition is extremely long and when needed, they can be restituted and mixed to form the delivery system. The first aqueous composition that is obtained according to the claimed method as described above is a highly stable solution/dispersion of nanostructured lipid particles, loaded with the hydrophobic or amphiphilic compound of interest, herein also called small particles. It has a very high shelf life of many years without any noticeable change in the composition. Further, it is a highly concentrated source of the compound of interest. Before mixing with the second aqueous composition, this product can be diluted to decrease the amount of active ingredient in order to obtain a suitable dose form. Dilution normally will be done by adding (food-grade) water. When diluting, or when obtained as delivery system in a final mix of the first and second aqueous compositions, additionally stabilizers, colourants, preservatives and/or flavourants may be added. For stabilizers preferably a food grade stabiliser is chosen. Preferably the stabiliser is a gum, such as guar gum (E412), arabic gum (E414), xanthan gum (E415), alginic acid (E400), carrageenan (E407), ghatti gum, tragacanth gum (E413), karaya gum (E416), locust bean gum (E410), dammar gum, glucomannan (E425), tara gum (E417), gellan gum or beta-glucan. We have found that addition of a combination of guar gum and xanthan gum works well as a stabilizer when it is applied in a concentration in the diluted composition of between 0.01 and 0.05%, more preferably about 0.02%. Preservatives may be chosen from the group consisting of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbicate, citric acid, sorbic acid, calcium sorbate, benzoic acid, potassium benzoate, acetic acid, erythorbic acid, sodium erythorbate, ethyl lauroyl arginate, long-chain glycolipids from Dacryopinax spathularia MUCL 53181, methyl- p-hydroxybenzoate, nisin, sulphurous acid, dimethyl dicarbonate, ascorbyl palmitate and blends thereof. In the present invention it was found that a combination of ascorbic acid, citric acid and sorbic acid provides the desired result when the ascorbic acid, if present, is present at a concentration between 0.01% and 0,1%, preferably about 0.05%, and when the citric acid, if present, is present at a concentration between 0.005% and 0.05%, preferably at about 0.01%, and when the sorbic acid, if present, is present at a concentration between 0.05% and 0.5%, preferably about 0,1%. Most preservatives are weak acids, which means that preferably the pH of the first and or second aqueous compositions needs to be lowered by adding an acid such as citric acid or by adding a buffer, such as Slimpie™ syrup. The latter addition also provides a pleasant taste to the aqueous composition or delivery system. Although the composition as produced according to the above described method already has an acceptable, if not pleasant taste, a further flavouring compound may be added, if desired. Any flavouring compound that can be used in food, including drinks, may be added, such as flavouring essences. These are readily available in any taste and the skilled person will know how to apply these and which concentration is needed for the flavouring to provide a pleasant taste. In the products that were obtained in which the hydrophobic compound of interest was a cannabinoid a dilution of 1:8 was made, which resulted in a product that comprised approximately 8 mg of the cannabinoid in 25 ml of product (used as a dosage form), which is a concentration of about 0.04% (meaning that the undiluted product had a concentration of about 0.3%). However, it has appeared that in the current system concentrations up to 5% of the compound of interest may be reached, of course depending on the nature of the hydrophobic or amphiphilic compound, the concentration of the hydrophobic or amphiphilic compound in the solvent in which it is added to the oil mixture, the amount of oil mixture and the amount of water that is used in the emulsifying reaction, etc. With the specific compositions as exemplified herein it was found that a superior system was made that surpasses the stability, flavor, and safety profiles of existing counterparts currently in the market and which retains very favourable release characteristics of the compound(s) of interest delivered with the system. The chosen co- emulsifiers (sunflower lecithin, beta-cyclodextrin, and sucrose ester) interact synergistically to enhance particle stability, offering a robust formulation capable of maintaining product quality under various storage conditions. The combination also enhances the flavor profile of the beverage, ensuring an enjoyable consumption experience. Further, the blend exhibits a lower toxicity profile compared to traditional emulsifiers, thus preventing the formation of harmful free radicals and degradation products during high-intensity processing. The thermal process, as exemplified herein, involving a hot emulsion phase followed by cooling before homogenization, results in a more efficient procedure with minimized energy requirements and side reactions, especially since a natural antioxidant blend is employed to shield the active ingredients, mitigating potential oxidative damage to consumers. Further, some molecules (tocopherol, vitamin B5 precursor) have been incorporated to enhance tissue absorption rates and facilitate efficient drug release kinetics. By adjusting the solid-to-liquid lipid ratios, the formulation allows precise manipulation of drug release kinetics, offering a customizable delivery experience, which is unknown for at least cannabinoids. The unique temperature-responsive release mechanism in the particles ensures a stable product at room temperature that allows controlled release upon ingestion. The formulation, however, is versatile and allows for ultra-stable particles capable of being loaded with a variety of hydrophobic and/or amphiphilic drugs, expanding potential applications beyond cannabinoid delivery. The optimized particle sizes in the formulation support efficient tissue penetration and help in overcoming drug resistance mechanisms. The unique combination of emulsifiers, lipid vehicles, and natural antioxidants in the formulation not only provides a safe and stable cannabinoid delivery system but also enhances bioavailability and release kinetics. The tested formulation offered enhanced bioavailability of cannabinoids with a second, prolonged effect, being up to 10 times more bioavailable than normal cannabinoid oil and showing effects in minutes but lasting for hours. Nevertheless, the release kinetics of compounds from the particles can be programmed to suit the needs of different consumers, ranging from rapid to delayed release, but especially a combination of both types of release. Further, the delivery system of the present invention makes it possible to easy combine the delivery of different compounds of interest, even where these would normally be unable to be combined in one dosage form (e.g. because of pH preferences, buffer incompatibilities and the like) thereby facilitating the compliance with the treatment. The system is especially well suited to combine compounds of interest that benefit from a different release profile. One example for this is in cancer therapy where cytotoxic cocktails are used where one compound should be administered first and a second at a later moment. This is especially the case when chemotherapeutic drugs are used in combination with immunotherapy, where some chemotherapeutic drugs are known to sensitize cells for immune effector cells. This is especially the case for so-called time-dependent chemotherapy drugs, e.g. paclitaxel and topotecan, in combination with interleukines, such as IL-18 (Alagkiozidis, I. et al., J. Transl. Med.9, 77 (2011)) and for the combination of cytotoxic drugs with anti-PD-1 monoclonal antibodies (Bailly, C. et al., NAR Cancer, 2020 Feb 17;2(1):zcaa002). The technology also supports the targeted delivery of cannabinoids or other therapeutic agents specifically inside tumors, providing a valuable tool for personalized medicine. Targeting moieties may be attached to the outer surface of the particles with technology that is available to the skilled person. The design supports potential sequential release of multiple therapeutic agents, facilitating a coordinated treatment approach. The technology can be extended to controlled-release drug delivery systems, improving patient compliance and therapeutic outcomes. Further, the particles and especially the small particles are transdermally bioavailable, expanding the delivery routes for therapeutic agents. The technology can be applied to improve the efficacy of cosmetic formulations, potentially enabling better skin penetration and longer-lasting effects. For transdermal treatment preferably a cream is made by adding to a cream base first the second aqueous composition by low shear mixing and secondly adding the first aqueous composition with minimal mixing. When mixing these ingredients care should be taken that the particles do not coalesce. The cream base preferably is an aqueous cream base, more preferably a composition comprising water, coconut oil, shea butter oils, preferably MCT, and sucrose ester. In the same manner, but replacing the cream base with a paste base, also a paste can be made, preferably an edible paste. Both to the cream and to the paste additional compounds such as preservatives, odorants, flavorants, and the like. Also, the particle design allows for encapsulation and preservation of volatile or sensitive substances, extending shelf-life and maintaining compound efficacy. The formulation enables the loading and delivery of hydrophilic, amphiphilic, or charged bioactive compounds, expanding potential applications. For instance, the technology can be used to improve oral delivery of drugs with low bioavailability due to first-pass metabolism. Incorporation of bio-essential compounds can potentially improve the stability and bioavailability of probiotics or other beneficial gut microflora and thus co-administered with these. The formulation can also potentially protect and enhance the delivery of probiotics, supporting their survival during transit through the harsh stomach environment. Next to the transdermal delivery, the nanoparticles also allow for penetration through the blood-brain barrier, providing potential solutions for neurological conditions. The particle design might further allow for cell-specific targeting of therapeutics by incorporating specific ligands or antibodies on the surface of the particles. The particle design could potentially enable the delivery of genes or RNA therapies, extending the potential applications to the burgeoning field of gene therapy. The formulation can further potentially improve the delivery and efficacy of vaccines by protecting the antigen and providing adjuvant effects. The potential applications of the technology extend to animal health, potentially improving the delivery and absorption of veterinary therapeutics. The major advantage of the present delivery system with small (nano-) and/or larger (micro-)particles with different release characteristics is that it enables for a fine-tuning in the bioavailability of the compound of interest. A further advantage is that it is now possible to provide a combination of substances of interest. These substances may have independent pharmacological results, but they may also be chosen in such a way that the second compound influences the effect of the first compound. Next to the above described possibilities in cancer therapy, a further good example of such a composition in which the second compound influences the effects of the first compound is a mixture of the first aqueous particle composition as described above, where the compound of interest is THC and of a second aqueous composition comprising CBD. Preferably in the final mixture the amounts of CBD and THC are present in a ratio of 2 : 1. Such a mixture can be made according to the methods described herein wherein the THC is provided from a plant extract of a high-THC producer plant, where the CBD may be provided from a different plant source (obtained from a low-THC producer) or the CBD may be obtained as a commercially available distillate. The effect of such a composition is a rapid onset of the THC effect followed by a second peak of the THC activity. Initially the uptake speed is dependent on the size of the particles in the composition. This means that the smaller (i.e. nano-) particles that contain the THC as active compound are taken up first. In the case that the composition is ingested orally, this intake takes place via the gut, but if the composition is e.g. applied as a crème on the skin, the uptake is transdermally. In both cases the most rapidly taken up smaller particles will be transported into the blood vessels first where the THC is released from the oil phase of the particles. When the THC is released, it will be bound to proteins present in the blood (such as albumin) or fatty acid binding proteins (FABPs) that are present in the inter- and intracellular fluids. There will then be an equilibrium of bound THC versus free THC, where the free THC is providing the pharmacological effect. The uptake of THC is followed by the slower uptake of the larger particles that harbor the CBD. When the CBD is released from the oil phase in the larger particles it will replace the THC that is bound to the blood proteins and FABPs. This then causes a second peak of free THC and thus a second peak of the pharmacological effect. While the above described embodiment is dedicated to cannabinoids and more specifically THC and CBD, it will be apparent to the skilled person that the aqueous particle compositions as described above can be used for various other embodiments in which delivery of hydrophobic or amphiphilic substances may be influenced by a second substance. Such a second substance can be a compound that may act agonistically or antagonistically and the second compound may even be identical to the first compound. In this latter situation one would be obtaining a prolonged pharmacological effect of the compound. It would also be possible that the second compound is inert or that the second particle solution contains particles that are not loaded with an active compound. A specific embodiment for the delivery system of the present invention is the embodiment in which pharmaceutical compounds that are normally given in a combination preparation or as a combined therapy are combined in the present delivery system. One example for this is the combination of anticonceptives, such as ethinylestradiol in combination with desogestrel, gestodeen or flevogestrel. Other possible combinations are sulfomethoxazol or sulfametrol in combination with trimethoprim, artemether with lumefantrine, atovaquon with proguanil, flumetason with clioquinol, daunorubicine with cytarabine, ezetimibe with atorvastatine, rosuvastatine or simvastatine, pravastatine with phenophibrate, pyridoxine with meclizine or doxylamine and even combinations with three pharmaceutical compounds such as hydrocortisone/oxytetracycline/polymyxine B, colistine/bacitracine/hydrocortisone or fludrocortison/neomycine/polymyxine B. Next to delivery systems for oral delivery, it is also possible to mix the nano-/micro- particle delivery system in which two or more compounds are combined with a generic aqueous cream BP or a similar emollient preparation. In this case when such a cream is applied to the skin, the uptake of the particles takes place via the skin, but the combination effect as discussed above may occur on the identical principles. Creams or lotions that can be made according to this invention could especially be useful in dermatological applications where combinations of hydrocortisone with e.g. clioquinol, bethamethason, tetracycline, oxytetracycline, ketoconazole or triamcinolone may be used. Also cannabinoids can be used in such creams. It would also be possible to even add a further active compound as a powder mixed into the cream. In that case the powder particles act as the largest particles with a relatively very slow uptake and thus a possibility to have a further delayed effect. Whereas the delivery system of the present invention is especially advantageous for the delivery of hydrophobic and/or amphiphilic compounds, also hydrophilic compounds may be delivered. The distribution of these hydrophilic compounds over the oil and water phases of the aqueous compositions described herein depends largely on the solubility of the compound and thus this determines the encapsulation efficiency. Nevertheless, even if the hydrophilic substances are not taken up by the particles in the aqueous compositions, they will remain solved in the water phase of the composition. Secondly, it is possible to conjugate hydrophilic substances to the particles when the aqueous compositions have been prepared. Such conjugation may be achieved by using gold, or e.g. carbodiimide coupling (see for an overview of coupling methodologies Hawthorne, D. et al. J. Drug Deliv, Sci. Technol. 78, 103936, 2022). It should be understood that in the present invention the terms hydrophobic and hydrophilic have their generally accepted meaning, which means that hydrophobic compounds are poorly soluble in water but are soluble in polar solvents, while hydrophilic compounds are soluble in water and badly soluble in polar solvents. The exact solubility depends on temperature and pressure of the circumstances, but also on the charge distribution in the compounds itself. Further, amphiphilic or amphoteric compounds are compounds that have both a part (moiety) that reacts hydrophilic and a part (moiety) that reacts hydrophobic. It will depend on the number of the hydrophilic and hydrophobic moieties and their level of hydrophobicity/hydrophilicity and the distribution of these moieties over the molecule if the molecule will be more hydrophilic or more hydrophobic. Examples of these amphiphilic molecules are proteins, like enzymes, antibodies, antibody fragments, and the like, nucleic acids and various small molecules. In a further embodiment of the invention in the combined delivery system of the present invention optionally vitamin B6 and melatonin are added to the oil phase during preparation of the emulsions. Then preferably 20% of the amount of B6 and melatonin is added to the oil mixture used for (nano-)emulsion of the first compound, while 80% of the B6 and melatonin is added to the oil mixture for the preparation of the second nano- or micro-emulsion. Example 1 Preparation of an aqueous nanoparticle cannabinoid first composition A mixture of emulsifiers was prepared by combining 10g beta cyclodextrin (Landor Trading Comp.), 10g sucrose ester (Ryoto TM P-1670 from Mitsubishi Chemical Company), and 5g sunflower lecithin (buXtrade). This mixture was then diluted to 800ml with purified water at 25°C. Separately, an oily mixture was prepared by melting 10g stearic acid, 50g natural cannabis sativa extract, 20g coconut oil (Ekoplaza), 30g C8 MCT (Lus Health Ingredients), 2g hempseed oil (Holland and Barrett), 2g linseed oil (Holland and Barrett), 1g natural tocopherols concentrate (soapqueen.nl), and 1g rosemary extract in order of descending melting point, using a heated stirrer. The temperature during this process did not exceed 75°C and the total process lasted for approximately 30 minutes. The oily phase and emulsifier solution were then combined using a mixer until the mixture was visibly homogeneous. This mixture was then further processed with 600W of sonication power (U.S. SOLID sonicator) in a 1L beaker, with a cycle of 10 seconds on and 2 seconds off for 7 minutes and 30 seconds. The mixture was cooled to room temperature (approximately 20°C) using a water and ice bath before being sonicated for a further 2 minutes with the same conditions. The final product was filtered using a 200nm filter to remove any larger particles. The resulting filtrate had a mean particle size of 114.8 nm (measured using a Izon Science Apparatus (using TPRS) and a THC concentration of 50 mg/ml. The filtrate could be preserved using 25% glycerol if not intended for immediate use. Example 2 Preparation of a dosage form of the composition from Example 1 A strawberry-flavored preparation was made by adding 20ml of the THC filtrate from Example 1, 200ml of strawberry syrup BP, 1g of potassium sorbate, 0.5g Guar Gum (buXtrade), 150mg Ascorbic Acid (buXtrade), and 50mg Citric Acid (buXtrade) to 1L of water. After thorough mixing it was divided into dosage forms containing 25 cl of the preparation. The preparation should be consumed within 2 days of preparation. Example 3 Preparation of an aqueous nanoparticle first composition with auxin as compound of interest A mixture of emulsifiers was prepared by combining 1.25 g beta cyclodextrin (Landor Trading Comp.), 1.36 g sucrose ester (Ryoto TM P-1670 from Mitsubishi Chemical Company), and 0.87 g sunflower lecithin (buXtrade). This mixture was then diluted to 102 ml with purified water at 25°C. Separately, an oily mixture was prepared by melting 1 g stearic acid, 5.11 g auxin (indole- 3-acetic acid, Sigma Aldrich), 2 g coconut oil (Ekoplaza), 3g C8 MCT (Lus Health Ingredients), 0.2 g hempseed oil (Holland and Barrett), 0.2 g flackseed (Holland and Barrett), 0.1 g natural tocopherols concentrate (soapqueen.nl), and 0.1g rosemary extract in order of descending melting point, using a heated stirrer. The temperature during this process did not exceed 75°C and the total process lasted for approximately 30 minutes. The oily phase and emulsifier solution were then combined using a mixer until the mixture was visibly homogeneous. This mixture was then further processed with 600W of sonication power (U.S. SOLID sonicator) in a 1L beaker, with a cycle of 10 seconds on and 2 seconds off for 7 minutes and 30 seconds. The mixture was cooled to room temperature (approximately 20°C) using a water and ice bath before being sonicated for a further 2 minutes with the same conditions. Residual clumps were removed by sonication for an additional minute. The final product was filtered using a 2μm polypropylene filter (woven, nonbinder from VWF) to remove any larger particles. An identical batch of was made but now with an oil mixture of 4 g stearic acid, 2 g coconut oil and 2 g medium chain triglycerides to which 5.11 g auxin was added. Example 4 Preparation of the first and second aqueous compositions with reduced sonication requirements (taking nile red A or CBD as compound of interest) A. First aqueous composition An oil blend is prepared by mixing 5 g stearic acid (melting point ~69 °C), 10 g coconut oil (solid below ~25 °C), 15 g medium-chain triglycerides (MCT) and 1 g Nile Red A (pure compound). While maintaining a temperature of about 50 °C, 2 g hempseed oil, 2 g linseed oil, 1 g rosemary extract (antioxidants) and 1 g tocopherol (vitamin E) are added. The mixture is stirred until a homogeneous solution is formed. A separate aqueous phase is prepared by dissolving 5 g sucrose ester (Ryoto™ P-1670), 5 g β-cyclodextrin, and 2.5 g sunflower lecithin in 400 mL of purified water at 35–40 °C. This emulsifier solution is stirred until fully dissolved, ensuring no visible particulate matter remains. The warmed oil phase is slowly introduced into the emulsifier solution under moderate stirring (~300 rpm) to form a coarse pre-emulsion. To maintain fluidity, the combined mixture is kept at approximately 40 °C during this blending step. The pre-emulsion is passed through a bench-scale microfluidizer at 100 bar for three passes. After the first pass, the coarse droplets are reduced in size to roughly 2–3 µm. By the third pass, the mean droplet diameter approaches 1 µm (D50 ~1.0–1.2 µm). Throughout microfluidization, the emulsion temperature is maintained at ~35–40 °C to avoid excessive heating. Following microfluidization, a sonication step is applied for 20 KW·s (100 % amplitude, continuous mode, Hielscher UP400St). This brief ultrasound treatment helps refine the size distribution and eliminates any remaining large droplets without producing significant free radicals. The emulsion is cooled to ambient temperature (~20 °C). Particle size analysis (e.g., via laser diffraction or TRPS) shows a volume-weighted median diameter (D50) of ~0.110 µm, with a narrow size distribution (< 0.2 PDI). An antioxidant assay confirms negligible oxidative degradation, correlating with the reduced sonication time. The resulting Nile Red A emulsion exhibits good stability over at least 3 months of storage at 4 °C, with no creaming or droplet coalescence. This example illustrates how the microfluidizer-to-sonication approach can load a pure fluorescent dye (Nile Red A) into a partially solidified lipid carrier, yielding submicron droplets suitable for analytical or imaging applications. B. Second aqueous composition An oil blend is prepared by mixing 10 g stearic acid (melting point ~69 °C), 20 g coconut oil (solid below ~25 °C), 30 g medium-chain triglycerides (MCT) and 50 g broad-spectrum cannabis distillate (82 % CBD content, plus minor cannabinoids/terpenes). While maintaining a temperature of about 50 °C, 2 g rosemary extract (antioxidants) and 1 g tocopherol (vitamin E) are added. The mixture is stirred until a homogeneous solution is formed. A separate aqueous phase is prepared by dissolving 10 g sucrose ester (Ryoto™ P-1670), 10 g β-cyclodextrin, and 5 g sunflower lecithin in 800 mL of purified water at 35–40 °C. This emulsifier solution is stirred until fully dissolved, ensuring no visible particulate matter remains. The warmed oil phase is slowly introduced into the emulsifier solution under moderate stirring (~300 rpm) to form a coarse pre-emulsion. To maintain fluidity, the combined mixture is kept at approximately 40 °C during this blending step. The pre-emulsion is passed through a bench-scale microfluidizer at 100 bar for three passes. After the first pass, the coarse droplets are reduced in size to roughly 2–3 µm. By the third pass, the mean droplet diameter approaches 1 µm (D50 ~1.0–1.2 µm). Throughout microfluidization, the emulsion temperature was maintained at ~35–40 °C to avoid excessive heating. Following microfluidization, a sonication step is applied for 50 KW·s (100 % amplitude, continuous mode, Hielscher UP400St). This brief ultrasound treatment helps refine the size distribution and eliminates any remaining large droplets without producing significant free radicals. The emulsion is cooled to ambient temperature (~20 °C). Particle size analysis (e.g., laser diffraction or TRPS) shows a volume-weighted median diameter (D50) of ~0.110 µm, with a narrow size distribution (< 0.2 PDI). Antioxidant assays confirms negligible degradation of the active cannabinoids or minor terpenes, correlating with minimized sonication time. The resulting broad-spectrum CBD emulsion remains stable for at least 3 months at 4 °C, displaying minimal creaming or droplet coalescence. This approach demonstrates how broad-spectrum cannabinoid distillate can be formulated into a stable, partially solidified lipid emulsion, preserving minor cannabinoids and terpenes. By combining microfluidization and a short ultrasonic burst, free-radical formation is limited, protecting the plant-derived actives and achieving a submicron particle size. In both examples, microfluidizer processing prior to a brief sonication significantly reduces total ultrasonic energy exposure, thereby minimizing oxidative stress on sensitive actives. The partial crystallization from stearic acid further enhances physical stability and can help modulate release characteristics. The final submicron emulsions (D50 ~0.110 µm) resist coalescence and oxidative degradation, providing long-term storage stability for a wide range of potential applications. Example 5 Particle distribution First and second aqueous compositions according to the present invention were made with the dye Nile Red as compound of interest. For preparing a first aqueous composition an oil phase was prepared by melting together approximately 5 g of stearic acid (melting point ~69 °C), 10 g of coconut oil (solid below ~25 °C), 15 g of medium-chain triglycerides (MCT), and 1 g of Nile Red A (pure compound). While maintaining the temperature at approximately 50 °C, 2 g of hempseed oil, 2 g of linseed oil, 1 g of rosemary extract (providing antioxidants), and 1 g of tocopherol (vitamin E) were added. The resulting mixture was stirred until a homogeneous solution formed. In a separate container, an aqueous phase was prepared by dissolving about 5 g of sucrose ester (e.g., Ryoto™ P-1670), 5 g of β-cyclodextrin, and 2.5 g of sunflower lecithin in 400 mL of purified water, maintained at 35–40 °C. This aqueous solution was stirred until all components were fully dissolved, ensuring the absence of visible particulate matter. The warmed oil phase was gradually introduced into the emulsifier solution under moderate stirring (~300 rpm) to create a coarse pre-emulsion. During this blending step, the combined mixture was maintained at about 40 °C to ensure sufficient fluidity and ease of mixing. The pre-emulsion was then subjected to sonication for a total of approximately 51 kW·s at 100% amplitude in continuous mode (using a Hielscher UP400St). This sonication step facilitated droplet size reduction to the desired submicron range. Following sonication, the emulsion was allowed to cool to ambient temperature (~20 °C). Particle size analysis (e.g., via laser diffraction on a Shimadzu SALD-2300, reference index 1.55–0.05i) indicated a volume-weighted median diameter (D50) of about 0.346 µm, with a narrow size distribution (PDI ~0.195). The resulting Nile Red A small-emulsion demonstrated stability for at least three weeks at 4 °C, exhibiting no significant creaming or droplet coalescence. A second micro-emulsion batch was prepared under the same conditions described above, except no sonication energy was applied. Particle size analysis (e.g., via laser diffraction on a Shimadzu SALD-2300, reference index 1.50–0.05i) showed a volume-weighted median diameter (D50) of approximately 30.355 µm and a multimodal, wider size distribution (PDI ~0.753). The particle distribution of these compositions are show in Figure 2. Example 6 In vivo uptake of compound of interest Nile red fat staining in vivo to study the release from small particles. Nile Red is commonly used as a fixative-based stain to quantify the main fat stores in C. elegans (Brooks et al, 2009, O’ Rourke et al, 2009). To stain fat in nematodes, permeabilization with a fixative is required as the cuticle, the C. elegans skin, protects it from the environment (Page and Johnstone, 2006). The small particle technology of the invention allows to circumvent this permeabilization, as it in theory can deliver its contents through feeding and subsequent dissociation in vivo. C. elegans can take up nutrients from their environment by feeding, with bacteria being their primary food source. A size range of 0.5-3 µm is considered as optimal, although nematodes can ingest smaller and larger particles. Further, processing is rapid, with uptake within 15 minutes time as shown with fluorescent particles (Kiyama et al, 2012). Once ingested, particles pass through the pharynx and reach the intestine (Avery and You, 2012). Here, contents of the intestine are rapidly absorbed and secreted by defecation in a manner of minutes (Ghafouri and McGhee, 2007). 6.1. Preparation of small particle nile red suspension. The compositions made according to Example 5 were used in this experiment. 6.2. C. elegans strains and culture C. elegans nematodes were cultured on NGM plates seeded with OP50 bacteria and generally maintained at 20°C using standard methods (Brenner 1974). Genotypes of the strain used in this study is N2 wild type. Strains used in this study were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). 6.3. Nematode handling Nematode populations (wild-type N2) were synchronized by hypochlorite treatment of gravid adult hermaphrodites to isolate individual eggs. Eggs were incubated in M9 buffer overnight to allow hatching of L1 larvae in the absence of food. Synchronized L1 larvae were cultured on NGM agar plates seeded with OP50 bacteria at 20° for 72 hours. Nematodes were then transferred to vial containing S-medium and OP50 and grown at 20° for 24 hours before addition of small particle suspension. 6.4. Small particle treatment Small particle nile red was added to the vials to a final concentration of 0.4 or 2 µg/ml and incubated for 2 hours at at 20 °C. Nematodes were subsequently washed to rinse away excess small particles from the medium, and further incubated for 30, 60 or 135 minutes in vials to allow for digestion of remaining small particles in the nematodes. 6.5. Microscopy For analysis and quantification, nematodes were collected in centrifuge tubes and gently centrifuged. 3.7 µl of worm pellet was added to 1 µl 50mM sodium azide on 3% agarose slides. Images were obtained with a LD A-Plan 20X/0.30 Ph1 lens on a Zeiss Axioplan 2 microscope with an exposure time of 400 milliseconds. 6.6. Quantification Images were analyzed using ImageJ software by selecting regions of interest corresponding with the nematode or background. Area, Mean, StDev, Min, Max, INTDEN and RAWINTDEN values were collected from ImageJ. The corrected total fluorescence intensity was calculated by subtracting the integrated density of the tissue with the total background fluorescence intensity of an equally sized area. 6.7 Results When small particle nile red was supplemented to the food of C. elegans, fluorescence became apparent in the nematodes, indicating it that the small particles are being ingested. As the small particles are fluorescent by themselves, this fluorescence may at least in part be the result of unprocessed particles present in the nematodes. Thus, to minimize the contribution of these residuals and allow for digestion of particles and incorporation of nile red into the C. elegans body fat, nematodes were allowed to recover for 30, 60 or 135 minutes after exposure to allow for clearance and dissociation of the residual particles. Analysis of the corrected total GFP intensity confirmed that both nano-nile red and micro- nile red were able to induce a significant increase in fluorescence in nearly all conditions tested, indicating that particles are taken up by the nematodes (Figure 3). Fluorescence was higher in nematodes treated with the higher dose of 2.0 µg/ml of small particles compared to 0.4 µg/ml. The signal produced by 2.0 µg/ml of nano-nile red was significantly higher than that of micro-nile red of the same concentration. This could have several explanations. The in vitro experiments showed that nano-nile red was more fluorescent, which could be the cause of the difference in the nematodes. However, with the clearance rate of the intestine, it is expected that most of the small particles will have been expelled during the initial 30 minutes of recovery, and free particles would be severely diluted in the recovery medium to prevent effective re-ingestion. Furthermore, the signal in the nano-nile red treated nematodes remained higher over time, strongly indicating a more efficient uptake of nile red upon treatment with nano-nile red. Differently sized particles appeared to have different behavioral dynamics when they were exposed to C. elegans. Over time, the fluorescence of nano-nile red decreased, but visually always remained higher than the comparable concentration of micro-nile red. The stronger initial increase of fluorescence followed by a subsequent decline suggests a peak like behavior, in which particles are accumulated and dissociated efficiently until supply runs out (Figure 4). In contrast, fluorescence appeared more stable over time in micro-nile red treated nematodes. Combined, this suggests that the nile red is released from the particles in different phases depending on the size of the particles. This data supports a 2-phase system in which particles in the nanometer size range and micrometer size range dissociate at different rates, leading to different peaks in activity of the encapsulated compounds.
Example 7 Metabolomics study 1. 1.1. Preparation of small particle CBD suspension Micro CBD particle composition and small particle CBD nano composition were prepared as follows: An oil phase was prepared by melting together approximately 10 g of stearic acid (melting point ~69^°C), 20 g of coconut oil (solid below ~25^°C), 30 g of medium-chain triglycerides (MCT), and 50 g of a broad- spectrum cannabis distillate (nominally 82% CBD content, with minor cannabinoids and terpenes). While maintaining the temperature at about 50^°C, 2 g of rosemary extract (antioxidant) and 1 g of tocopherol (vitamin E) were added. The mixture was stirred until a homogeneous solution resulted. In a separate container, an aqueous phase was prepared by dissolving approximately 10 g of sucrose ester (e.g., Ryoto™ P-1670), 10 g of β-cyclodextrin, and 5 g of sunflower lecithin in 800 mL of purified water, maintained at 35–40^°C. This solution was stirred until all components were completely dissolved and free of visible particulates. The warmed oil phase was slowly introduced into the emulsifier solution under moderate stirring (~300^rpm), forming a coarse pre-emulsion. The blend was maintained at approximately 40^°C to ensure adequate fluidity during mixing. A sonication step was applied for about 200 kW·s at 100% amplitude in continuous mode (e.g., using a Hielscher UP400St) to reduce droplet size and improve emulsion uniformity. Following sonication, and while the emulsion was still hot (above ~40^°C), 30 g of erythritol was added to serve as a cryoprotectant. The treated emulsion was then poured into six pre-chilled trays (cooled over dry ice) to rapidly freeze the product. The trays were subsequently placed in a Harvest Right™ Large Freeze Dryer. The freeze-dryer was programmed with an initial freezing temperature of −28^°C, 0:00 extra freeze ^me, afinishing temperature of 21^°C, and an additional drying time of 24^hours. Upon completion of the freeze-drying cycle, a stable, dry product was obtained. Particle size analysis (e.g., by laser diffraction or TRPS) on the reconstituted (rehydrated) emulsion showed a volume-weighted median diameter (D50) of approximately 0,288 µm, with a narrow size distribution. The resulting freeze-dried formulation, when stored at 4^°C post-rehydration, demonstrated excellent colloidal stability for at least three months, showing no significant creaming or droplet coalescence. Lyophilized small particle CBD nano powder contained 40% CBD and was dissolved in 6 times concentrated OP50 bacteria to a final concentration of 2.5 mg/ml for LC-MS metabolomics. Small particle CBD micro was prepared by mixing 1.875g of emulsifier mix (consisting of sucrose ester, β- cyclodextrin and sunflower lecithin in a 2:2:1 weight ratio) in 60 ml of water and mixed vigorously to dissolve the emulsion mix. 5.44 g of micro-CBD oil paste (the oil fraction with CBD obtained exactly according to the protocol described with the preparation of the nano-particles) was added and frothed extensively to emulsify the oil. The resulting suspension is calculated to contain 5 mg/ml micro-CBD, and was mixed in a 1:1 ratio with 12 times concentrated OP50 bacteria for a final concentration of 2.5 mg/ml for LC-MS metabolomics. 1.2. Strains and culture C. elegans nematodes were cultured on NGM plates seeded with OP50 bacteria and generally maintained at 20°C using standard methods (Brenner 1974). Genotypes of the strain used in this study is N2 wild type. Strains used in this study were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). Nematode populations (wild-type N2) were synchronized by hypochlorite treatment of gravid adult hermaphrodites to isolate individual eggs. Eggs were incubated in M9 buffer overnight to allow hatching of L1 larvae in the absence of food. Synchronized L1 larvae were cultured on NGM agar plates seeded with OP50 bacteria at 20° for 52 hours, where the bacterial food source was supplemented small particle CBD. Small particle CBDs used were fast nano and micro. Small particle CBDs were given to the nematodes at a 2.5 mg/ml final concentration mixed in the food. Nematodes were grown on NGM plates with OP50 and subsequently exposed for either 4 or 24 hours on NGM plates with OP50 mixed with small particle CBD before collection, keeping the 52-hour growth period consistent between all conditions. 1.4. Sample preparation LC-MS Nematodes were collected from plates by washing, and were freeze-dried, homogenized, and processed separately for each triplicate (Molenaars et al.2021). Extracts were made with methanol and chloroform phases, and the methanol phase was kept and used for analysis. Samples were processed at a clinical health laboratory in Bunnik, the Netherlands and tested against a panel of 6 neurotransmitters, as well as a panel of 46 amino acids. For the LC-MS experiment, micromolar values of each metabolite were obtained and were normalized based on the dried nematode pellet mass that was used for the extraction. Filtering of the data was applied, and metabolites with > 3 missing values among the replicates were removed from the analysis (Sun and Xia 2024). Heat maps were made by graphing the z-score transformed data. Statistical analysis of individual metabolites was done by two-sided t-tests for each metabolite. All combinations of comparisons between the small particle CBD treatments were tested and compared to control. 2. 2.1. Metabolomics as a measure of in vivo release from small particles Metabolism is the combination of all chemical processes that occur in organisms that allow normal function and life. This includes the breakdown of nutrients from food sources, as well as processes that build and repair bodily features. Metabolomics was pioneered in the 1990s and allows measurement of metabolites, the substances that are used during metabolism, and offers a highly sensitive method to detect changes in organisms in disease, and upon exposure to nutrients or compounds (Oliver et al. 1998, Nicholson et al.1999, German et al.2005). This method relies on different analytical techniques with each having their specific advantages and includes techniques such as nuclear magnetic resonance (NMR) spectroscopy, gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) (Roberts et al, 2013). While these techniques all detection of any metabolite, targeted metabolomics, in which the metabolic profiles are compared to a library of known metabolites, is particularly powerful in detecting changes in organism upon disease or compound exposure. Thus, we employed metabolomics to determine the release of the compound CBD from small particles. To quantitatively determine the release of compounds from small particles in a living organism, we aimed to study the changes in metabolites in the nematode C. elegans upon release of CBD. Cannabinoids have been shown to alter the behavior of C. elegans as reflected in traits such as motility, appetite and cognition (Oakes et al.2019, Van Es-Remers et al.2022). Underlying this altered behavior are changes in metabolites and molecular pathways which include signaling through neurotransmitters such as dopamine and serotonin (Oakes et al.2019). Upon release of CBD from small particles, dopamine and serotonin release is expected to increase, resulting in higher levels of these metabolites. By exposing nematodes to different sizes of small particles, we expect different peaks in release of these neurotransmitters, which can be measured using targeted metabolomics. 2.3. Heatmaps of samples Visualization of the datasets was performed to produce heat maps of the measured neurotransmitters and amino acids (Figure 5). Due to the more limited number of data points available, hierarchical clustering was not used to cluster the groups of treatments. Instead, the more targeted approach of LC- MS, (which was done here), is more useful for looking at the levels of particular health-related metabolites and is shown in the following sections. To study the effect of CBD release from small particles, nematodes were exposed to CBD-containing small particles of different sizes. Nanoparticles are classified by their size that ranges from as small as 1nm to up to 500 nm when referring to scientific literature and nomenclature (Harish et al.2022). In the laws of the European Union only particles smaller than 100 nm are officially classified as nanoparticles (Rasmussen et al.2024), however, to provide distinction, this report references to scientific literature with nano particles categorized as sizes up to 500 nm. To test both nano and micro particle sizes, a suspension with a median size of the particles of 280nm (hereafter annotated as nano-CBD), and a micro suspension of particles with a median size of several micrometers (hereafter annotated as micro-CBD) were prepared. Nematodes were exposed for 4 or 24 hours with either of these suspensions mixed in the food, or to free CBD in the growth medium. Afterwards, metabolites were extracted from the nematodes and targeted LC-MS analysis was performed against a panel of 6 neurotransmitters as well as a panel of 46 amino acids. Analysis of the levels of the metabolite serotonin confirmed that serotonin levels were significantly increased in small particle CBD-treated nematodes compared to untreated controls (Figure 6). This increase in neurotransmitter response depended on the presence of CBD, as treatment with free CBD similarly led to a modest but not significant increase in serotonin levels. Treatment with CBD encapsulated in small particles resulted in a stronger increase of serotonin levels than free CBD, although the method of administration does not allow for direct comparison. Free CBD in the solid growth medium might rely on diffusion into the food source or nematodes, while the small particles could be mixed in the food and therefore be delivered more directly to the nematodes. This makes direct comparison complicated, and therefore, for further analysis exposure to free CBD was excluded. However, the increase in serotonin levels in nematodes treated with small particle encapsulated CBD clearly confirms that CBD is released from the particles in vivo, resulting in an increase in levels of this neurotransmitter. Further analysis of serotonin levels revealed a more potent increase upon treatment with nano-CBD compared to micro-CBD. Although after 4 hours serotonin levels were increased for both nano and micro particles, the average increase for nano-CBD was slightly higher at 2.6-fold than for micro-CBD at a 2.0-fold increase compared to controls. This effect was more pronounced after 24 hours of exposure, with serotonin levels increasing to 4.6-fold for nano-CBD and 2.6-fold for micro-CBD compared to untreated controls. This indicates that particles in the nanometer size range release their contents quicker and are more potent in their release than micrometer sized particles. The prolonged effect on serotonin levels probably indicates that both for the nano-CBD and the micro-CBD the maximum effect had not yet been reached. The increased potency of nano-CBD was further confirmed by the dopamine levels (Figure 7). Treatment with both nano and micro particles resulted in a strong increase of dopamine after 4 hours of respectively 4.8-fold and 3.7-fold compared to controls, although this effect was only statistically significant for nano-CBD. After 24 hours, dopamine levels continued to rise in nematodes treated with nano-CBD, resulting in a significant 5.9-fold increase of metabolite levels. The effect of micro-CBD on dopamine levels remained identical between 4 and 24 hours, showing a positive upwards trend in statistics. Together, these results show that CBD is released from the particles in vitro, resulting in increased levels of dopamine and serotonin. The nano-CBD form at 280nm median size released its contents faster, and with greater effect, indicating a difference in release timing and potency between particles of different sizes. Particles of different sizes are expected to dissociate at different rates. In theory, as a results metabolite levels should increase, peak in intensity, and eventually decline as the particles have dissociated and their contents are metabolized. These patterns may depend on specific metabolites, as some metabolites will be further processed while other remain stable over time. When analyzing the data we did not observe a decline in dopamine and serotonin levels upon prolonged exposure to small particle CBD. However, upon examination of the remaining metabolites detected, we observed at least 20 out of the total panel of amino acids that displayed a behavior in which an increase in the metabolite levels after 4 hours was followed by a decline at the 24-hour timepoint (Examples shown for beta-alanine in Figure 8, aspartic acid in Figure 9 and glutamic acid(+) in Figure 10). For each of these metabolites, this time-dependent decline was specific for the nano-CBD. In contrast, in the micro-CBD samples the metabolite levels showed an inverse response, with no or mild increase in metabolite levels after 4 hours of exposure, and a strong increase after 24 hours. These results further enforce the observation that particles of different sizes have different release dynamics. Here, nano particles seem able to dissociate and release their compounds quicker than micro particles, resulting in a quicker rise of metabolites, but also faster depletion of the particles and available CBD, resulting in a decline in metabolite levels over time. Micrometer sized particles appear to release slower and more gradually, causing a peak in metabolite levels at a later time after more prolonged exposure. This data confirms the notion that small particles of different sizes have different release dynamics, which would indicate that a more prolonged release of compound occurs when mixing small particles of different sizes. 3. Brenner, Sydney.1974. “The Genetics of Caenorhabditis Elegans.” Genetics 77 (1): 71–94. German, J Bruce, Hammock, Bruce, Watkins, Steven. ‘Metabolomics: building on a century of biochemistry to guide human health’. Metabolomics.2005 Mar;1(1):3-9. doi: 10.1007/s11306-005-1102-8. PMID: 16680201; PMCID: PMC1457093. Harish V, Tewari D, Gaur M, Yadav AB, Swaroop S, Bechelany M, et al. Review on Nanoparticles and Nanostructured Materials: Bioimaging, Biosensing, Drug Delivery, Tissue Engineering, Antimicrobial, and Agro-Food Applications.Nanomaterials (Basel).2022;12(3). Molenaars, Marte, Bauke V. Schomakers, Hyung L. Elfrink, Arwen W. Gao, Martin A. T. Vervaart, Mia L. Pras-Raves, Angela C. Luyf, et al.2021. ‘Metabolomics and Lipidomics in Caenorhabditis Elegans Using a Single-Sample Preparation’. Disease Models & Mechanisms 14 (4): dmm047746. https://doi.org/10.1242/dmm.047746. Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica.1999 Nov;29(11):1181-9. doi: 10.1080/004982599238047. PMID: 10598751. Oakes M, Law WJ, Komuniecki R. Cannabinoids Stimulate the TRP Channel-Dependent Release of Both Serotonin and Dopamine to Modulate Behavior in C. elegans. J Neurosci. 2019 May 22;39(21):4142-4152. doi: 10.1523/JNEUROSCI.2371-18.2019. Epub 2019 Mar 18. PMID: 30886012; PMCID: PMC6529862. Oliver SG, Winson MK, Kell DB, Baganz F. Systematic functional analysis of the yeast genome. Trends Biotechnol.1998 Sep;16(9):373-8. doi: 10.1016/s0167-7799(98)01214-1. Erratum in: Trends Biotechnol 1998 Oct;16(10):447. PMID: 9744112. Rasmussen K, Riego Sintes J, Rauscher H. How nanoparticles are counted in global regulatory nanomaterial definitions. Nature Nanotechnology.2024;19(2):132-8. Roberts LD, Souza AL, Gerszten RE, Clish CB. Targeted metabolomics. Curr Protoc Mol Biol.2012 Apr;Chapter 30:Unit 30.2.1-24. doi: 10.1002/0471142727.mb3002s98. PMID: 22470063; PMCID: PMC3334318. Sun, Jun, and Yinglin Xia. 2024. Data for Statistical Analysis’. Genes & Diseases 11 (3): 100979. Van Es-Remers, M., Spadaro, J. A., Poppelaars, E., Kim, H. K., van Haaster, M., de Wit, M., ILiopoulou, E., Wildwater, M., & Korthout, H. (2022). C. elegans as a test system to study relevant compounds that contribute to the specific health- related effects of different cannabis varieties. Journal of Cannabis Research, 4(1), 53. https://doi.org/10.1186/s42238- 022-00162-9 Example 8 Preparation of a Cream Base Below is a representative method for producing 1 kg of a cream base that incorporates cannabinoids (CBD, CBG) in both Nano ("WS") and Micro forms using a microfluidizer for homogenization. 1. Formulation Table (1 kg Total) Phase Ingredient Amount (%) W-Phase Water 20 - 60 Xanthan Gum 0.5 - 5 Saccharose 0.1 - 5 Ester Potassium Sorbate 0.1 - 2 Glycerin 0 - 20 Oil-Phase Stearic Acid 0.5- 5 Cetyl Alcohol 0.5 - 5 Shea Butter 10 - 20 Coconut Oil (C12) 1 - 20 MCT Oil (C8) 1 - 20 Tocopherol 0.1 - 10 Argan Oil 1 - 20 Rosehip Oil 1 - 20 Hemp Seed Oil 1 - 20 Phenoxyethanol 0.1 - 2 W-Phase (Fast / Nano Additions) CBD 5% WS 0 - 60 W-Phase (Slow / Micro) CBD 5% WS 0 - 60 Concentrate CBG 0 - 40 Total (Check) 1000.0 Notes: • “WS” indicates water-soluble (or water-dispersed) forms of the cannabinoids. 2. Phase Preparation 1. Aqueous Phase (W-Phase) Preparation • Disperse Xanthan Gum (2 g) and Saccharose Ester (10 g) in about 100 g of the total water portion (kept at ~40–50 °C). • Stir thoroughly until all solids dissolve. • Add remaining water to reach the total W-phase amount (538 g). • Dissolve Potassium Sorbate (10 g) and Glycerin (50 g) into the same solution. Maintain temperature at ~40 °C to keep the gum well-hydrated. 2. Oil Phase Preparation • Combine Stearic Acid (10 g), Cetyl Alcohol (30 g), Shea Butter (100 g), Coconut Oil (C12) (50 g), MCT Oil (C8) (50 g), and the designated cannabinoids (CBC 2 g, CBD 2 g, CBG 1 g). • Add Tocopherol (5 g), Argan Oil (10 g), Rosehip Oil (10 g), Hemp Seed Oil (10 g), and Phenoxyethanol (8 g). • Heat to 70–75 °C with gentle stirring until the fats fully melt and a uniform oil mixture is formed. 3. Emulsion Formation 1. Pre-Emulsion • Heat the W-phase to ~70 °C so that both aqueous and oil phases are at similar temperatures. • Transfer the oil phase into the W-phase under moderate agitation (e.g., 300–400 rpm) to form a coarse emulsion. 2. Microfluidizer Processing • Pass the coarse emulsion through a microfluidizer at ~80–100 bar for 1–2 passes. • The resulting droplet size typically approaches 1–2 µm. • Maintain the temperature at ~60–65 °C during microfluidization to prevent premature solidification of high-melting components (e.g., Stearic Acid). 3. Cooling & Final Cream 1. Cooling • After microfluidization, cool the cream base to ~30–35 °C, stirring gently. • During cooling, ensure a uniform texture is maintained; the Stearic Acid and Shea Butter will begin to solidify, giving the cream its desired viscosity and structure. 2. Incorporate Remaining Heat-Sensitive Additives • While cooling, add the WS Cannabinoids, add them below ~40  °C. • The final amount of finely-ground raw CBG concentrate may also be introduced here if not already included, ensuring thorough dispersion. 3. Quality Checks • Viscosity & Texture: Evaluate the cream consistency once fully cooled to ambient temperature. • Particle Size: Laser diffraction or microscopy can confirm the targeted droplet size (~1–2 µm range). • Stability & Phase Separation: Observe over 24–48 h to ensure no creaming or visible oil separation occurs. 4. Packaging • Fill into jars or tubes under aseptic conditions, if required. • Store at ~25 °C (room temperature). Properly preserved, the cream maintains stability and potency for several months. 4. Key Advantages 1. Reduced Free-Radical Formation • By relying primarily on microfluidization to achieve micron-scale droplets, the recipe minimizes oxidative stress on cannabinoids and oils. 2. Enhanced Stability & Texture • The combined oil blend (Stearic Acid, Shea Butter, MCTs, etc.) solidifies partially upon cooling, creating a rich, stable cream texture that resists phase separation. 3. Controlled Cannabinoid Delivery • Incorporation of “WS” form enables a multi-phase release profile for CBD. • The result is both immediate and sustained release of active compound when applied to the skin. 4. High Biocompatibility & Sensory Profile • Shea Butter, Argan Oil, and Rosehip Oil add emolliency and nutritional benefits, while Tocopherol aids in antioxidant protection. • The final cream is non-greasy with a pleasant after-feel. Summary: Using a microfluidizer allows for a gentle yet effective method of emulsifying multiple oils and cannabinoids into a stable cream. The final cream base leverages slow-release and immediate-release cannabinoid fractions, providing enhanced therapeutic and cosmetic benefits.

Claims

CLAIMS 1. A delivery system comprising of a first aqueous composition prepared by the steps of o. Providing an emulsifier or a blend of emulsifiers in powder form; p. Mixing two or more oils at a temperature above 40°C where all oils have become liquid, wherein said oils differ in melting temperature, wherein the oil mixture comprises at least one oil with a melting point above 50°C and which mixture comprises at least a sufficient amount of an oil with a low melting point, preferably medium chain triglycerides, to enable the composition formed in step g to have a partly liquid oil phase at temperatures around about 4°C; q. Adding the compound of interest in any suitable hydrophobic solvent to the oil mixture; r. Optionally letting the mixture cool down to room temperature; s. Adding the emulsifier powder and water to the oil mixture and letting the mixture emulsify, under optional agitation and heating to 30-40°C; t. Subjecting the emulsified mixture to a sonication and optionally mixing or fluidisation treatment until the average particle size of the mixture remains stable; u. Cooling down the sonicated mixture allowing sufficient time for crystallisation; and v. Optionally, a second sonication treatment while keeping the mixture cold, and a second aqueous composition prepared by the steps of w. Providing an emulsifier or a blend of emulsifiers in powder form, where preferably the emulsifier is identical to the emulsifier provided in step a); x. Mixing two or more oils at a temperature above 40°C where all oils have become liquid, wherein said oils differ in melting temperature, wherein the oil mixture comprises at least one oil with a melting point above 50°C and which mixture comprises at least a sufficient amount of an oil of a low melting point, preferably medium chain triglycerides, to enable the composition formed in step n to have a partly liquid oil phase at temperatures around about 4°C, preferably wherein the oils and the weight ratio between them is identical to the oils and weight ratio used in step b); y. Adding the compound of interest in any suitable hydrophobic solvent to the oil mixture; z. Optionally letting the mixture cool down to room temperature; aa. Adding the emulsifier powder and water to the oil mixture and letting the mixture emulsify, under optional agitation and heating to 30-40°C; bb. Cooling down the mixture allowing sufficient time for crystallisation; wherein said first and second aqueous compositions are mixed to obtain the delivery system. 2. Delivery system according to claim 1, wherein the emulsifier is a blend of emulsifiers, preferably wherein said emulsifiers are non-toxic emulsifiers, more preferably wherein said blend comprises sugar-based emulsifiers, such as sucrose ester and/or cyclodextrin. 3. Delivery system according to claim 2, wherein the emulsifier is a blend comprising sucrose ester, cyclodextrin and lecithin, preferably sunflower lecithin. 4. Delivery system according to claim 3, wherein the amount of lecithin is such, that in the final sonified mixture from step g and/or the final composition obtained in step n). the concentration of lecithin is less than 5% by weight, preferably less than 2%, more preferably less than 1%. 5. Delivery system according to claim 2, 3 or 4, wherein the amount by weight of sugar- based emulsifiers is at least two times the amount of lecithin, preferably at least four times. 6. Delivery system according to any of claims 3-6, wherein the weight ratio between sucrose ester, cyclodextrin and lecithin is 2 : 2 : 1. 7. Delivery system according to any of the previous claims, wherein the oil mixture comprises oils or fats that are non toxic. 8. Delivery system according to any of the previous claims, wherein the oil mixture comprises at least one oil with a melting point above 60°C. 9. Delivery system according to any of the previous claims, wherein the oil mixture comprises an oil with a melting point in between room temperature and body temperature. 10. Delivery system according to any of the previous claims, wherein the oil mixture comprises stearic acid, coconut oil and medium chain triglycerides.
11. Delivery system according to any of the previous claims, wherein the oil mixture, when mixed with the hydrophobic compound comprises the components in a weight ratio of stearic acid : coconut oil : medium chain triglycerides : solvent with hydrophobic compound of 1 : 2 : 3 : 5. 12. Delivery system according to any of the previous claims, wherein a non-toxic antioxidant is added to the oil mixture, preferably wherein said antioxidant is a blend of antioxidants, more preferably wherein said antioxidant or blend of antioxidants in total in weight does not exceed the amount of 10% of the oil mixture, preferably not exceed the amount of 5% of the oil mixture. 13. Delivery system according to claim 12, wherein said blend of antioxidants comprises linseed oil, hempseed oil, tocopherol and/or rosemary extract; preferably where it comprises linseed oil, hempseed oil, tocopherol and rosemary extract, preferably in a weight ratio of 2 : 2 : 2 : 1. 14. Delivery system according to any of the previous claims, wherein the weight ratio of oil to emulsifiers in both the method to prepare the first and the second aqueous composition is from 3.0 to 5.0, more preferable from 3.2 to 4.0, more preferably about 3.5 15. Delivery system according to any of the previous claim, wherein the water is food-grade water. 16. Delivery system to any of the previous claims, wherein the particles in the first aquoes composition will have a mean particle size of 10 – 600 nm, preferably of 50 – 150 nm and more preferably of 80 – 130 nm, most preferably about 110 nm expressed as D50 determined in accordance with ISO 9276-2. 17. Delivery system according to any of the previous claims, wherein glycerol is added to the final composition, more preferably wherein the concentration of glycerol is more than 20%, preferably more than 25% by weight. 18. Delivery system according to any of the previous claim, wherein at least one of the compounds of interest is a plant-based extract in oil. 19. Delivery system according to claim 17, wherein the plant-based extract is an extract of Cannabis sativa, preferably, wherein said extract comprises a cannabinoid, more preferably, wherein said extract comprises a cannabinoid chosen from the group consisting of Δ9-tetrahydrocannabinol (THC), Δ9-tetrahydrocannabinolic acid (Δ9- THCA or THCA), Δ9-tetrahydrocannabiorolic acid (Δ9-THCA-C1 or THCA-C1), Δ9- tetra-hydrocannabiorcol (Δ9-THCO-C1 or THCO-C1), Δ9-tetrahydrocanna-biorcolic acid (Δ9-THCOA or THCOA), Δ9-tetra-hydrocannabivarin (Δ9-THCV or THCV), Δ9- tetrahydrocannabivarinic acid (Δ9-THCVA or THCVA), trihydroxy-Δ9-tetrahydro- cannabinol (TRIOH-THC), Δ10-tetrahydro-cannabinol (Δ10-THC), tetrahydro- cannabiphorol (THCP), THC-O acetate (THCO), hexa-hydrocannabinol (HHC), 10-oxo- Δ6a-tetrahydrocannabinol (OTHC), Δ8-tetra-hydrocannabinol (Δ8-THC), Δ8- tetrahydrocannabinolic acid (Δ8-THCA), cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidiorcol (CBDC1), cannabidiol-C4 (CBDC4), cannabidiol dimethyl ether (CBDD), cannabidiol monomethyl ether (CBDM), cannabidivarin (CBDV), cannabidivarinic acid (CBDVA), nabilone, nabiximol, anandamide, cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerolic acid A monomethykether (CBGAM), canna-bigerovarin (CBGV), cannabigerovarinic acid (CBGVA), cannabigerol mono-methylether (CBGM), cannabinol (CBN), cannabinolic acid (CBNA), cannabdiorcol (CBN-C1), cannabinol-C2 (CBN-C2), cannabivarin (CBN-C3), cannabinol-C4 (CBN-C4), cannabinodivarin (CBNDC3), cannabinol methylether (CBNM-C5), cannabichromene (CBC), cannabichromenc acid (CBCA), cannabichromanon (CBCN-C5), cannabicoumaronone (CBCON-C5), cannabi-chromanone-C3 (CBCN-C3), cannabichromevarin (CBCV), cannabichromevarinic acid (CBCVA), cannabielsoin (CBE-C5), cannabigelndol-C3 (OH- iso-HHCVC3), C3-canna-bielsoicacid B (CBEA-C3 B), cannabifuran (CBF), dehydrocannabifuran (DCBF-C5), cannabifuran (CBF-C5), dehydrocannabifuran (DCBF or CBFD), cannabicyclol (CBL-C5), cannabicyclovarin (CBLV-C3), cannabitriol (CBT), cannabitriolvarin (CBTV), cannabiripsol (CBR), cannabinodivarin (CBV or CBVD), 2-arachidonoylglycerol (2-AG), 2-arachidonoylglycerol ether (2-AGE), isotetra- hydrocannabinol, isotetrahydrocannabivarin, palmitoylethanolamide, epigallo-catechin (EGC), (-)-epicatechin gallate (ECG) and (-)-epigallocatechin gallate (EGCG). 20. Delivery system according to claim 18 or 19, wherein said extract comprises THC or a blend with THC. 21. Delivery system according to any of the previous claims, wherein the first and second aqueous compositions are blended into a cream. 22. Delivery system according to claim 21, wherein an aqueous cream base is provided, through which the second aqueous composition is mixed with low shear, whereafter the first aqueous composition is gently added and mixed with very low shear. 23. Delivery system according to claim 22, wherein the cream base comprises water, coconut oil, shea butter, medium chain triglycerides and sucrose ester.
24. Delivery system according to any of the previous claims, wherein optionally after storage of the first and/or second aqueous composition, water is added to either or both of the first and second aqueous composition to obtain a diluted composition, preferably, wherein the composition is diluted with water, more preferably wherein the composition is diluted in such a way that the dilution comprises between 0.001% and 5% of the compound of interest, preferably between 0.005% and 1%, more preferably between 0.01% and 0.5%, more preferably between 0,02 % and 0.1%. 25. Delivery system according to claim 24, wherein the water is food-grade. 26. Delivery system according to claim 24 or 25 wherein further a stabiliser is added to the composition, preferably wherein said stabiliser is a food grade stabiliser, more preferably wherein said stabiliser is a gum, more preferably wherein said stabiliser comprises guar gum and/or xanthan gum, more preferably wherein the concentration of guar gum and/or xanthan gum in the diluted composition is between 0.01 and 0.05%, more preferably about 0.02%. 27. Delivery system according to any of the previous claims, wherein further a preservative is added to the delivery system, preferably wherein said preservative is a food grade preservative, more preferably, wherein said preservative is chosen from the group consisting of ascorbic acid, sodium ascorbate, isoascorbic acid, sodium isoascorbicate, citric acid, sorbic acid, calcium sorbate, benzoic acid, potassium benzoate, acetic acid, erythorbic acid, sodium erythorbate, ethyl lauroyl arginate, long-chain glycolipids from Dacryopinax spathularia MUCL 53181, methyl-p-hydroxybenzoate, nisin, sulphurous acid, dimethyl dicarbonate, ascorbyl palmitate and blends thereof. 28. Delivery system according to claim 26 or 27, wherein said preservative comprises ascorbic acid, citric acid or sorbic acid or a blend thereof, preferably wherein the ascorbic acid, if present, is present at a concentration between 0.01% and 0,1% by weight, preferably about 0.05%, and wherein the citric acid, if present, is present at a concentration between 0.005% and 0.05% by weight, preferably at about 0.01%, and wherein the sorbic acid, if present, is present at a concentration between 0.05% and 0.5%, preferably about 0,1%. 29. Delivery system according to any of the previous claims, wherein further a flavouring compound is added to the first or second aqueous composition or to the delivery system or to the cream or paste, preferably a food grade flavouring compound. 30. Delivery system according to claim 1, where the first and/or second aqueous composition are stored before mixing them to obtain the delivery system.
31. Delivery system according to claim 30, wherein the first aqueous composition is stored as powder by lyophilisation. 32. Delivery system according to claim 30, wherein the second aqueous composition is stored as powder by lyophilisation. 33. Delivery system according to claim 31 or 32, wherein the powder is reconstituted in water. 34. Delivery system according to any of the previous claims in which panthenol is added to the oil mixture, preferably wherein panthenol is added to an amount between 0.5 and
PCT/NL2025/050110 2024-03-07 2025-03-07 New method for delivering compounds of interest Pending WO2025188185A1 (en)

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