Composition

Abstract

The present invention relates to orally administrable compositions comprising at least one cannabinoid, methods for their preparation, and their use as pharmaceutical or nutraceutical products. In particular, the present invention relates to orally administrable gelled oil-in-water emulsions that are self-supporting viscoelastic solids having a gelled aqueous phase and an oil phase that comprises one or more physiologically acceptable lipids and at least one cannabinoid.

Description

[Technical Field]

[0001] The present invention relates to compositions for oral administration comprising at least one cannabinoid, methods for their preparation, and their use as pharmaceutical or nutraceutical products. More particularly, the invention relates to such compositions in the form of gelled oil-in-water emulsions. [Background technology]

[0002] Cannabinoids are compounds derived from cannabis that interact with receptors in the brain and body to produce various effects. Cannabis is a genus of plants in the Cannabaceae family, including Cannabis sativa, Cannabis indica, and Cannabis ruderalis. All cannabis plants produce active cannabinoid compounds, which are monocyclic to tetracyclic C21 or C22 meroterpenoids, but each variety produces these compounds in varying concentrations and ratios that depend not only on the genomic background but also on growing conditions and climate. Over 100 different cannabinoids can be isolated from Cannabis sativa, but perhaps the most notable is the psychoactive compound delta-9-tetrahydrocannabinol (THC). Other pharmacologically important cannabinoids include cannabidiol (CBD), cannabinol (CBN), cannabinoid acids, cannabigerol, and cannabivarin. CBD can be extracted from plant parts of the Cannabis sativa plant and is often administered as CBD-containing hemp oil, which contains varying amounts of other cannabinoids. CBD can also be isolated to provide a higher-value product, for example, for pharmaceutical applications where a purified and well-defined active ingredient is required. The need for highly pure CBD can also be met through chemical synthesis of the compound.

[0003] Recently, there has been renewed interest in the therapeutic potential of cannabinoids, particularly cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), and the regulatory landscape for cannabinoids is rapidly changing. While THC is generally considered a narcotic, it has been permitted for medical use in some countries. Certain CBD formulations have already been approved for pharmaceutical use, and as further clinical studies confirm the use of this particular group of compounds, more products are expected to gain regulatory approval. Cannabinoid drugs approved for medical use include Nabiximols (Sativex®), an oromucosal spray containing THC and CBD in ethanol for use in alleviating moderate to severe spasticity due to multiple sclerosis in adults and as an analgesic in the relief of cancer pain; Nabilone (Cesamet™), an oral capsule containing a synthetic cannabinoid similar to THC for use in controlling nausea and vomiting associated with cancer chemotherapy; and Dronabinol (Marinol®), an oral capsule or oral solution containing synthetic THC for appetite stimulation and treatment of chemotherapy-induced nausea in AIDS patients. Epidiolex, a liquid formulation of CBD solution, was also recently approved in the United States for the treatment of seizures associated with two rare and severe forms of epilepsy.

[0004] Cannabinoid-containing extracts can be obtained from cannabis using a variety of extraction methods (e.g., using supercritical CO2, hydrocarbons, alcohols, etc.) and can be further purified, for example, by precipitation with alcohol, distillation, or chromatographic separation. The resulting cannabinoids are highly lipophilic and practically insoluble in water, making them difficult to deliver using many conventional pharmaceutical delivery methods. A common challenge is administration that can provide controllable and / or systemic bioavailability of the active cannabinoid compounds.

[0005] To date, oral delivery of cannabinoids has generally been achieved in the form of solid dosage formulations or oral solutions. However, due to variable absorption and extensive first-pass metabolism (i.e., absorption by the liver), the bioavailability of such orally delivered cannabinoids is low. This means that significant doses are required to achieve the desired effect. Oral delivery of cannabinoids in lipid formulations has been proposed and is generally thought to increase absorption. However, cannabinoids are absorbed very slowly from the gastrointestinal tract, with maximum plasma concentrations achieved 1–6 hours after administration. Delivery to the gastrointestinal tract also does not address the first-pass metabolic effects that reduce blood levels. For example, sublingual delivery in the form of a sublingual spray or aerosol has also been proposed. While this offers faster absorption and a reduced first-pass effect compared to other oral delivery routes, it can be difficult to control the delivered dose, and this delivery method is not convenient for all patients, particularly children and the elderly.

[0006] Alternative delivery routes are being investigated. These include pulmonary delivery by smoking cannabinoid-containing plant parts or by vaporizing solid or liquid extracts (which can be partially or highly purified) by applying heat. Pulmonary delivery is highly effective at rapidly delivering active substances systemically to the bloodstream, but it is not without its problems. One problem with heating cannabinoids is that their composition can be altered (e.g., from an acidic to a non-acidic form). For example, it can convert THC acid into the non-acidic form tetrahydrocannabinol, which is substantially more psychoactive. In the case of CBD, which is not psychoactive, cannabidiolic acid, a structurally different acidic version of the substance, exhibits increased in vivo activity compared to CBD itself. These methods also offer poor control over the dosage of the active substance. For example, when delivered by smoking, heavy, experienced smokers exhibit more than twice the systemic bioavailability of cannabinoids as light, occasional smokers, due to the greater efficiency of inhalation techniques. Therefore, the use of smoking and vaporization as delivery methods is generally considered disadvantageous.

[0007] The use of metered-dose inhalers (MDIs), which deliver pressurized aerosol compositions containing cannabinoids directly to the lungs, has also been proposed, but this often results in coughing, which can cause irritation of the upper respiratory tract and affect the efficiency of the inhalation process and the resulting bioavailability. The delivery of the exact dose of cannabinoids is also difficult to control, as it depends on the depth and length of inhalation.

[0008] Cannabinoids, being highly lipophilic molecules, are susceptible to degradation by light and temperature, as well as autoxidation, especially when present in solution. Therefore, formulation plays an important role in enhancing the bioavailability and physicochemical stability of the compound. Packaging of formulations containing active compounds also affects the physicochemical stability of the product. Strategies employed to address these issues include salt formation (pH adjustment), the use of cosolvents (e.g., ethanol), nano- and microemulsification, lipid-based formulations (e.g., liposomes), and encapsulation in nanoparticles. While delivery of cannabinoids in the form of lipid nanoparticles has been suggested, these tend to reaggregate, i.e., aggregate, when used in solution. Summary of the Invention [Problem to be solved by the invention]

[0009] Therefore, there is a need for other delivery forms of cannabinoids, particularly those that have at least one of the following attributes: the ability to deliver a defined dose of the active cannabinoid component, the ability to provide rapid delivery of the active cannabinoid to the bloodstream to substantially avoid first-pass metabolic effects, and ease of administration to ensure high levels of patient compliance, particularly in elderly and pediatric patients. The latter is important because many of the conditions currently being investigated for treatment with cannabinoids are most commonly encountered in children (e.g., Dravet syndrome, ADHD, autism, etc.) or elderly patients (e.g., Alzheimer's disease, dementia, Parkinson's disease, etc.). [Means for solving the problem]

[0010] Applicants propose that cannabinoids may be orally administered in the form of "gelled" oil-in-water emulsions as described herein. Specifically, Applicants propose delivery of lipophilic cannabinoids as components of the oil phase of such emulsions.

[0011] Providing the active cannabinoids in an oil-in-water emulsion that is "gelled" as described herein provides a stable emulsion that effectively prevents (or at least minimizes) aggregation of the oil droplets, and also helps protect the cannabinoids from light and air (i.e., oxygen), thereby reducing their potential oxidation.

[0012] In at least certain embodiments, the use of "gelled" oil-in-water emulsions described herein also allows for the provision of formulations containing micro- and / or nanoparticles of oil carrying highly lipophilic cannabinoid material. Oil droplets in this size range, particularly nanoscale oil droplets, can significantly enhance oral mucosal delivery (sublingually or buccally) of active cannabinoids and reduce first-pass metabolic effects.

[0013] The good organoleptic properties (i.e., pleasant taste and mouthfeel) of the "gelled" oil-in-water emulsions described herein have the advantage of promoting retention of the product in the mouth, further aiding in oral mucosal delivery of the active cannabinoid material.

[0014] In one aspect, the present invention provides an orally administrable gelled oil-in-water emulsion that is a self-supporting viscoelastic solid having a gelled aqueous phase and an oil phase comprising one or more physiologically acceptable lipids and at least one cannabinoid.

[0015] In another aspect, the present invention provides a method for preparing a gelled oil-in-water emulsion as defined herein, the method comprising forming an oil phase comprising one or more physiologically acceptable lipids and at least one cannabinoid, forming an aqueous phase comprising a physiologically acceptable gelling agent, combining the oil and aqueous phases to form an oil-in-water emulsion, and gelling the emulsion.

[0016] In another aspect, the present invention provides a method for preparing a gelled oil-in-water emulsion as defined herein, the method comprising the steps of forming an oil phase comprising one or more physiologically acceptable lipids, forming an aqueous phase comprising a physiologically acceptable gelling agent, combining the oil phase, the aqueous phase and at least one cannabinoid to form an oil-in-water emulsion, and gelling the emulsion.

[0017] In a further aspect, the present invention provides a gelled oil-in-water emulsion as defined herein for oral pharmaceutical or therapeutic use.

[0018] In another aspect, the present invention provides a gelled oil-in-water emulsion which is a self-supporting viscoelastic solid having a gelled aqueous phase and an oil phase comprising one or more physiologically tolerable lipids and a cannabinoid, for oral use to treat a cannabinoid-responsive condition.

[0019] In another aspect, the present invention provides the use of a cannabinoid in the manufacture of a medicament for oral use in the treatment of a cannabinoid-responsive condition, the medicament being provided in the form of a gelled oil-in-water emulsion, which is a self-supporting viscoelastic solid having a gelled aqueous phase and an oil phase comprising one or more physiologically acceptable lipids and a cannabinoid.

[0020] In another aspect, the present invention provides a method of treating a human or non-human animal subject (e.g., a patient) for addressing a cannabinoid-responsive state, the method comprising orally administering to the subject a pharmaceutically effective amount of a cannabinoid in the form of a gelled oil-in-water emulsion as defined herein.

[0021] In another aspect, the present invention provides the use of a gelled oil-in-water emulsion as defined herein as a nutritional supplement. [Brief explanation of the drawings]

[0022] [Figure 1] Droplet size distribution of emulsions prepared in Examples 24-27 [Figure 2] Droplet size distribution of the emulsions of Examples 24 and 27, which have the same composition except for the mixing speed used in their preparation. [Figure 3] Effect of mixing speed of the Ultra-turrax® unit on the mean volume-based (D[4,3]) droplet size of emulsions of Examples 24-27. DETAILED DESCRIPTION OF THE INVENTION

[0023] definition The term "gel" refers to a form of matter intermediate between a solid and a liquid. The formation of a "gel" typically involves linking or cross-linking polymer chains to form a three-dimensional network within which solvent (e.g., water) is trapped or immobilized to form a sufficiently rigid structure that resists flow at ambient temperatures, i.e., temperatures below about 25°C, preferably below about 20°C. In rheological terms, a "gel" can be defined according to its storage modulus (or "elastic modulus") G', which describes the elasticity (energy storage) of the material, and its loss modulus (or "viscous modulus") G'', which describes the viscosity (energy loss) of the material. Their ratio, tan δ (equal to G" / G'), also known as the "loss tangent," measures how out of phase stress and strain are with each other.

[0024] A material that is "viscoelastic" is characterized by rheological properties that resemble in part the rheological behavior of a viscous fluid and in part the rheological behavior of an elastic solid.

[0025] The gelled oil-in-water emulsions according to the present invention are "self-supporting viscoelastic solids." This is intended to mean that they exhibit properties intermediate between those of solids and liquids, but have predominantly solid behavior, i.e., they have rheological properties more similar to those of solids than to those of liquids. The "predominant solid behavior" cannot be diluted (i.e., destroyed) by adding more solvent. In contrast, in the case of weak (or entangled) gels lacking stable (i.e., long-lived) intermolecular crosslinks, the entangled network structure of the gel can be removed by adding solvent and can be easily destroyed even at very low shear rates / shear stresses.

[0026] The gelled oil-in-water emulsions of the present invention exhibit mechanical rigidity, but, in contrast to solids, they are deformable. Specifically, the gelled emulsions described herein have a storage modulus G' that is greater than their loss modulus G" (i.e., G' > G") over a wide frequency range, e.g., 0.001 to 10 Hz, when measured at ambient temperature (i.e., a temperature in the range of 18°C ​​to 25°C, e.g., 20°C) and 0.1% strain.

[0027] The storage and loss moduli can be measured using known methods, for example, using a Kinexus Ultra+ Rheometer applying a C4 / 40 measurement geometry. The values ​​of the storage and loss moduli are not expected to differ when measured using other types of rheometers within the linear viscoelastic range.

[0028] More specifically, the gelled oil-in-water emulsions described herein will have the following properties: G'>G'' over the frequency range of 0.001-10 Hz at 0.1% strain, and a storage modulus (G') at ambient temperature (i.e., a temperature in the range of 18°C ​​to 25°C, e.g., 20°C) in the range of 10-200,000 Pa, preferably 100-100,000 Pa, and more preferably 500-50,000 Pa.

[0029] Weak gels will typically have a loss tangent with tan δ > 0.1. For strong, or fully developed, gels, G' >> G'' and lower tan δ values ​​(< 0.1) are observed. The gelled oil-in-water emulsions described herein will generally be considered "strong gels" at ambient temperatures, i.e., temperatures in the range of 18°C ​​to 25°C, e.g., 20°C.

[0030] As used herein, the term "gelation" refers to the formation of a "gel." This term is used herein in reference to both the physical properties of the aqueous phase of an emulsion and the physical properties of an oil-in-water emulsion. As will be understood, oil droplets behave more or less like a solid when dispersed throughout the gelled aqueous phase of the oil-in-water emulsions that are the subject of the present invention. Thus, the "gelling" property of the aqueous phase is also characteristic of the oil-in-water emulsion, i.e., may also be considered "gelling" as described herein.

[0031] Unless otherwise defined, the term "liquid" as used herein refers to a substance that is free-flowing and maintains a constant volume. This includes thick and viscous liquids that flow. A "liquid" has a loss modulus (G") greater than its storage modulus (G') and a loss tangent (tan δ) greater than 1.

[0032] As used herein, the term "cannabinoid" refers to compounds that act on one or more cannabinoid receptors, which are part of the endocannabinoid system found in cells in the brain, altering neurotransmitter release.Cannabinoid receptors include type 1 and type 2, called CB1 and CB2.The class of cannabinoids includes all major and minor cannabinoids found in natural cannabis and hemp materials, which can be isolated or synthetically produced, i.e., manufactured.Also included are natural or synthetic derivatives (e.g., acid derivatives) of such compounds, including metabolites.Pharmaceutically acceptable salts of such compounds are also included.

[0033] As used herein, the term "fatty acid" refers to an unbranched or branched, preferably unbranched, hydrocarbon chain having a carboxylic acid (-COOH) group at one end, conventionally referred to as the α (alpha) end. The hydrocarbon chain may be saturated or (mono- or poly-)unsaturated. By convention, the carbon atoms are numbered starting from the α end, with the carbon atom of the carboxylic acid group being carbon atom number 1. The other end is usually a methyl (-CH3) group, conventionally referred to as the ω (omega) end, with the terminal carbon atom being the ω-carbon. Any double bonds present may be in a cis or trans configuration. The nomenclature "ω-x" is used to indicate that the double bond is on the xth carbon-carbon bond, counting from the terminal carbon (i.e., the ω-carbon) toward the carbonyl carbon.

[0034] "Physiologically acceptable" means any component suitable for administration to the human or non-human animal body, in particular suitable for oral administration.

[0035] "Medicine" means any product intended for medical purposes, e.g., to treat or prevent a disease, condition, or disorder of the human or non-human animal body, or to prevent its recurrence, or to reduce or eliminate any of the symptoms of such disease, condition, or disorder. The use and production of products as "medicines" may be heavily regulated by government agencies. Products may be prescribed by a physician, but need not be. For example, products may be available "over the counter," i.e., without a prescription.

[0036] "Treatment" or "treating" includes any therapeutic application that can benefit a human or non-human animal (e.g., a non-human mammal). While both human and animal treatments are within the scope of the present invention, the present invention is primarily directed to human treatment. Veterinary treatment includes treatment of livestock and domestic animals (e.g., pets such as cats, dogs, rabbits, etc.). Treatment may be for an existing disorder or may be prophylactic.

[0037] In contrast to pharmaceuticals, "nutraceuticals" are not required to be subject to regulatory approval. The term "nutraceutical" is used herein to refer to products generally considered to be beneficial for maintaining or enhancing the health and / or general well-being of a human or non-human animal subject. Such substances include, in particular, nutritional supplements such as vitamins and minerals intended to enhance the health of a subject (e.g., a human subject).

[0038] As will be appreciated, some substances may be considered both "drugs" and "dietary supplements." The classification of a substance as either, or indeed both, may vary from country to country depending on local regulations related to pharmaceuticals. It may also depend on the recommended daily dosage of a particular substance. For example, a higher daily dosage of a particular vitamin, such as vitamin D, may be regulated as a drug, while a lower daily dosage may be considered a dietary supplement.

[0039] By "pharmaceutical composition" is meant a composition in any form suitable for use for pharmaceutical purposes.

[0040] "Dietary supplement composition" means a composition in any form suitable for use in a dietary supplement.

[0041] A "pharmaceutically effective amount" refers to an amount that will produce the desired pharmacological and / or therapeutic effect, i.e., an amount of an agent effective to achieve its intended medical purpose. While the needs of individual patients may vary, determination of optimal ranges of effective amounts of any active agent is within the ability of one skilled in the art.

[0042] A "nutraceutical effective amount" refers to an amount that will produce the desired nutraceutical effect, i.e., an amount of an agent that is effective to achieve its intended nutraceutical purpose. While the individual needs of a subject may vary, determining the optimal range of effective amounts of any active agent is within the ability of one skilled in the art.

[0043] The term "capsule" is used herein to refer to a unitary dosage form having a casing or coating (referred to herein as a "capsule shell") that encloses a gelled oil-in-water emulsion as defined herein.

[0044] As used herein, "water activity" is the partial vapor pressure of water in a composition at a particular temperature divided by the standard partial vapor pressure of water at the same temperature. Thus, water activity serves as a measure of the amount of free (i.e., unbound) water in a composition. Water activity can be measured by methods known in the art, for example, by using a Rotronic Hygrolab instrument.

[0045] In a first aspect, the present invention provides an orally administrable gelled oil-in-water emulsion that is a self-supporting viscoelastic solid having a gelled aqueous phase and an oil phase comprising one or more physiologically acceptable lipids and at least one cannabinoid.

[0046] The oil phase of the emulsion will comprise a physiologically tolerable lipid or a mixture of different physiologically tolerable lipids that act as a carrier for the lipophilic cannabinoid material, which will generally be soluble in the oil phase.

[0047] The cannabinoids that can be used in the present invention include any known cannabinoid found in the Cannabis genus, particularly Cannabis sativa, or a combination of known cannabinoids, or any synthetically produced cannabinoid. Any derivative of such cannabinoids, including but not limited to acid derivatives, can also be used in the present invention.

[0048] Cannabinoids for use in the present invention can be extracted from cannabis, or they can be synthetically produced.Extraction methods are well known in the art, including, for example, the use of supercritical CO2, hydrocarbons, and alcohol.After extraction, a mixture of active cannabinoids will typically be produced.Depending on the extraction method used (e.g., the nature of the solvent used for extraction), this material can be used without further purification, i.e., as an "extract," or can be further purified by distillation or chromatographic separation using known methods such as precipitation in alcohol.Purification can be carried out, for example, to provide a clearly defined product for pharmaceutical use.

[0049] The cannabinoid may be selected from any of the known cannabinoids, including, but not limited to, tetrahydrocannabinol and its isomers (including delta-9-tetrahydrocannabinol and its isomers, such as trans(-)-delta-9-tetrahydrocannabinol), tetrahydrocannabinolic acid and its isomers (delta-9-tetrahydrocannabinolic acid and its isomers, such as trans(-)-delta-9-tetrahydrocannabinolic acid), cannabidiol, cannabidiolic acid, cannabigerol, cannabigerolic acid, cannabigerovarin, cannabigerolic acid, cannabichromene, cannabichromenic acid, cannabidivarin, cannabidivaric acid, cannabivarin, cannabivarin, cannabivarin acid, tetrahydrocannabivarin, tetrahydrocannabivarinic acid, cannabinol, cannabinolic acid, cannabinodiol, cannabielsoin, cannabicyclol, and cannabicitran, and their isomers, and any mixtures thereof.

[0050] When a mixture of cannabinoids is used, the major component will typically be selected from one or more of delta-9-tetrahydrocannabinol, delta-9-tetrahydrocannabinolic acid, cannabidiol, cannabidiolic acid, cannabichromate, cannabigerolic acid, cannabidivarin, cannabivarinic acid, tetrahydrocannabinolic acid, tetrahydrocannabivarin, and cannabigerol. More preferably, the major component will be one or more of delta-9-tetrahydrocannabinol, delta-9-tetrahydrocannabinolic acid, cannabidiol, and cannabidiolic acid. Even more preferably, the major component may be cannabidiol or an acid variant thereof. The major cannabinoid component may be present in an amount of 80 to 100% by weight (based on the total weight of all cannabinoids present), for example, 85 to 99% by weight, preferably 90 to 98% by weight, for example, 95 to 98% by weight. The use of highly pure cannabinoid material is beneficial when controlled dosage is required, such as in compositions intended for pharmaceutical use.

[0051] In one embodiment, the active cannabinoid material for use in the present invention will comprise a mixture of at least two (e.g., two) cannabinoids selected from the group consisting of tetrahydrocannabinol (e.g., delta-9-tetrahydrocannabinol), tetrahydrocannabinolic acid (e.g., delta-9-tetrahydrocannabinolic acid), cannabidiol, and cannabidiolic acid. Small amounts of other cannabinoids may be present, but they will generally be present in amounts less than 20% by weight (based on the total weight of all cannabinoids present), preferably less than 10% by weight, more preferably less than 5% by weight, for example less than 2% by weight.

[0052] In one set of embodiments, the cannabinoid material for use in the present invention comprises tetrahydrocannabinol (e.g., delta-9-tetrahydrocannabinol) and / or cannabidiol. Mixtures of these cannabinoids in substantially purified form may be used. Thus, the cannabinoid material for use in the present invention may consist of tetrahydrocannabinol (e.g., delta-9-tetrahydrocannabinol) and / or cannabidiol. The use of a combination of tetrahydrocannabinol (e.g., delta-9-tetrahydrocannabinol) and cannabidiol forms a preferred embodiment.

[0053] Any known synthetic and semi-synthetic forms of cannabinoids can also be used in the present invention.Examples of such drugs include dronabinol, a synthetic delta-9 THC sold under the trade name Marinol®.Other synthetic cannabinoids include nabilone (a THC-like synthetic cannabinoid sold under Cesamet®), dexanabinol (a synthetic non-psychotropic cannabinoid that blocks NMDA receptors and COX-2 cytokines and chemokines (manufactured by Solvay Pharmaceuticals)), cannabinol (formerly PRS-211,375) (a synthetic cannabinoid that specifically binds to CB2 (manufactured by Pharmos)), HU308 (a synthetic cannabinoid that specifically binds to CB2 (manufactured by Pharmos)), HU331 (a synthetic cannabinoid manufactured by Cayman Chemical) and CT-3 (adulemic acid) (a more potent analogue of THC metabolite THC-11-acid).

[0054] The amount of active cannabinoid material present in the compositions of the present invention will vary; for example, it will depend on the type of cannabinoid, the intended use of the composition (whether as a medicine or a dietary supplement), the intended recipient, etc. It can vary as needed, and appropriate amounts can be readily determined by one of skill in the art. When the compositions are provided in unit dosage form, the amount of cannabinoid per unit dose can be selected based on the daily dose required to treat a particular condition or for use as a dietary supplement. It can be, for example, in the range of 5 to 350 mg, preferably 10 to 300 mg, e.g., 20 to 200 mg. For dietary supplement use, the amount of cannabinoid will generally be at the lower end of these ranges, e.g., 5 to 50 mg, preferably 7 to 20 mg, more preferably 10 to 15 mg per unit dose.

[0055] A wide variety of different lipids are known for oral use in pharmaceutical and / or nutraceutical products, and any of these can be used in the oil phase of the emulsions described herein. Lipid sources include, but are not limited to, vegetable oils such as rapeseed oil, sunflower oil, corn oil, olive oil, sesame oil, palm kernel oil, coconut oil, nut oil (e.g., almond oil or peanut oil), and hemp oil.

[0056] Lipids derived from natural sources typically comprise a mixture of different lipid components.Therefore, in one embodiment, the oil phase will comprise a mixture of different lipids.For example, the oil phase may comprise a mixture of lipids with different chain lengths and / or different degrees of saturation.

[0057] Lipids for use in the present invention may be liquid, solid, or semi-solid at ambient temperature (i.e., a temperature of about 18°C ​​to about 25°C). Those that are liquid at such temperatures are generally preferred. Any combination of liquid, solid, and semi-solid lipids may also be used. Solid lipids having a melting point below about 100°C, preferably below about 70°C, e.g., below about 50°C, may be used in the present invention. Solid lipids that may be used include butter, cocoa fat, and the like. If desired, the overall melting point of the lipids constituting the oil phase may be adjusted by blending different lipids, e.g., by blending solid lipids (egg butter) with liquid oil. An overall melting point in the range of 45-50°C may be desirable.

[0058] Lipids for use in the present invention include, in particular, fatty acids and their derivatives. These include both naturally occurring fatty acids and their derivatives, as well as synthetic analogs. In one embodiment, the oil phase may contain a mixture of different fatty acids or fatty acid derivatives.

[0059] The hydrocarbon chain of a fatty acid or fatty acid derivative can be saturated or unsaturated, and it can be unbranched or branched. Preferably, it will be unbranched. Typically, the hydrocarbon chain will contain 4 to 28 carbon atoms, generally an even number of carbons. Fatty acids vary in chain length and can be classified as "short," "medium," "long," or "very long" chain fatty acids. Those with hydrocarbon chains of 5 or fewer carbon atoms are called "short-chain fatty acids," those with hydrocarbon chains of 6 to 12 carbon atoms are called "medium-chain fatty acids," those with hydrocarbon chains of 13 to 21 carbon atoms are called "long-chain fatty acids," and those with hydrocarbon chains of 22 or more carbon atoms are called "very long-chain fatty acids." Any of these may be used in the present invention.

[0060] In one embodiment, the oil phase will comprise a saturated fatty acid or a derivative of a saturated fatty acid, including, but not limited to, any of the derivatives described herein. Medium-chain saturated fatty acids and their derivatives find particular use in the present invention. Particularly preferred are those having 8 to 12 carbon atoms in the hydrocarbon chain, e.g., 8, 10, or 12 carbon atoms, i.e., caprylic acid (C8), capric acid (C10), or lauric acid (C12), and any derivatives thereof.

[0061] The saturated fatty acids and their derivatives for use in the present invention can be naturally occurring or they can be synthetically produced. Most typically, they will be naturally occurring and can be used in the form of a mixture of different fatty acids and / or different fatty acid derivatives. Sources of saturated fatty acids and their derivatives include, for example, coconut oil and palm kernel oil.

[0062] In another embodiment, the oil phase may contain unsaturated fatty acids or derivatives thereof whose carbon chains contain one or more carbon-carbon double bonds. The double bonds may be in the cis or trans configuration, or any combination thereof in which one or more double bonds are present. Those in which the double bonds are in the trans configuration are generally less preferred due to the need to reduce consumption of so-called "trans fats" as part of a healthy diet. Therefore, fatty acids with cis-configured double bonds and their derivatives are preferred. Mono- and polyunsaturated fatty acids and their derivatives are well known in the art. Such fatty acids typically contain 12 to 26 carbons, more commonly 16 to 22 carbons, and have mono- or polyunsaturated hydrocarbon chains. These include, in particular, polyunsaturated fatty acids (PUFAs), such as essential fatty acids.

[0063] Particularly important essential fatty acids include omega-3, omega-6, and omega-9 fatty acids. Examples of omega-3 fatty acids include alpha-linolenic acid (ALA), stearidonic acid (SDA), eicosatetraenoic acid (ETE), eicosatetraenoic acid (ETA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), docosahexaenoic acid (DHA), tetracosapentaenoic acid, and tetracosahexaenoic acid. Examples of omega-6 fatty acids include linoleic acid, gamma-linolenic acid, eicosadienoic acid, dihomo-gamma-linolenic acid (DGLA), arachidonic acid (AA), docosatetraenoic acid, adrenic acid, docosapentaenoic acid, and calendic acid. Examples of omega-9 fatty acids include oleic acid, eicosenoic acid, mead acid, erucic acid, and nervonic acid.

[0064] The sources of unsaturated fatty acids and their derivatives include oils obtained from various animal, fish, plant, algae and microbial sources.Particularly important sources are fish oil, algae oil and vegetable oil, which are rich in omega-3, omega-6 and omega-9 fatty acids.Fish oil can be obtained from anchovy, sardine and mackerel, for example.

[0065] Any known derivative of fatty acid can be used in the present invention. These include, in particular, carboxylic acid esters, carboxylic acid anhydrides, glycerides (i.e., mono-, di-, or triglycerides) and phospholipids. As used herein, the term "derivative" in the context of fatty acids also encompasses any pharmaceutically acceptable salt of fatty acid. Suitable salts are well known to those skilled in the art and include, but are not limited to, lithium, sodium, potassium, ammonium, meglumine, and diethylamine salts.

[0066] Examples of carboxylic acid esters of fatty acids include those in which R is a straight or branched alkyl group, typically a short chain alkyl, preferably selected from, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and n-hexyl. 1-6 Examples include compounds with a terminal -CO2R group that is an alkyl group.

[0067] When the fatty acid derivative is a carboxylic acid anhydride, it is preferably a C 11 in which R is a straight or branched alkyl group, typically a short chain alkyl, preferably selected from, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl and n-hexyl. 1-6 It may contain a terminal -CO2COR group which is an alkyl group.

[0068] Glycerides are esters derived from glycerol and up to three fatty acids. The fatty acids present can be any of those described herein, and therefore, for example, they can be saturated or unsaturated. In the case of diglycerides and triglycerides, the fatty acid components can be the same or different. For example, they can be of different chain lengths.

[0069] In one embodiment, the lipid carrier for use in the present invention can comprise medium-chain triglycerides (MCT).MCT is a triglyceride containing two or three medium-chain fatty acids, which may be the same or different.Sources of MCT include, for example, coconut oil and palm kernel oil.The fatty acids present in MCT are typically saturated medium-chain fatty acids.For example, the MCT in coconut oil contains C 6-12 Fatty acids, mainly C8 and C 10 A typical fatty acid composition of MCT oil obtained from coconut oil may include, for example, 0.1% by weight of caproic acid (C6:0), 55% by weight of caprylic acid (C8:0), 44.8% by weight of caproic acid (C10:0), and 0.1% by weight of lauric acid (C12:0).

[0070] Phospholipids generally consist of a glycerol molecule attached to a hydrophilic "head" group consisting of two fatty acids ("tail" groups) and a phosphate group. The phosphate group may be modified by attachment to choline, ethanolamine, or serine. In one embodiment, the oil phase may be composed entirely or partially of phospholipids, particularly marine (e.g., pelagic seafood, e.g., krill) phospholipids.

[0071] The amount of oil present in the compositions of the present invention depends on factors such as the nature of the oil, the nature of the cannabinoid, and the desired loading level, and can be varied as needed. The oil phase containing the selected cannabinoid agent may, for example, comprise 5-85%, 10-75%, 15-65%, 20-60%, 30-50%, or 40-50% by weight of the gelled oil-in-water emulsion. High loading levels of oil can be readily achieved in the gelled emulsions described herein.

[0072] As will be appreciated, in the compositions of the present invention, the oil containing the cannabinoid material provides a discontinuous phase within the continuous aqueous phase that is gelled. Thus, the oil is dispersed throughout the gelled aqueous phase in the form of oil droplets (also referred to herein as oil "particles"). The gelling of the aqueous phase provides a stable emulsion that prevents the oil droplets from aggregating, for example, due to the prevention of physical collisions between the droplets.

[0073] The size of the oil particles in the gelled oil-in-water emulsion is not particularly limited. For example, oil particles having a volumetric size within the range of about 10 nm to about 100 μm, preferably about 50 nm to about 50 μm, particularly about 100 nm to about 10 μm, such as about 750 nm to about 3 μm, can be provided. The volumetric average particle size can be in the range of about 100 nm to about 10 μm, preferably about 500 nm to about 2 μm. As used herein, "volume average" refers to the volume moment average or De Brouckere mean diameter (also known as the "D[4,3]" value). This reflects the size of the particles that make up the majority of the sample volume and is most sensitive to the presence of large particles within the size distribution.

[0074] An essentially uniform size distribution of the oil particles may be desirable. 90 The value indicates the size that 90% of the oil particles in all the oil droplets meet. 90 The value may range from 500 nm to 50 μm, preferably from 1 μm to 20 μm, and in particular from 1 μm to 5 μm. 50 and D 10 The values ​​indicate the size values ​​that 50% and 10% of the oil droplets meet among the total of all oil droplets. 50 The value may range from 0.1 to 5 μm, in particular from 0.3 to 2 μm, for example from 0.5 to 1.5 μm. 10 The value may range from 0.1 to 1 μm, in particular from 0.2 to 0.5 μm.

[0075] The size and size distribution of lipid droplets can be determined using conventional methods and equipment in the art, for example, a Malvern Mastersizer 3000 (Worcestershire, UK) connected to a Hydro MV wet dispersion unit (Malvern, Worcestershire, UK). Data analysis can be performed using the manufacturer's software (Mastersizer 3000, v1.0.1). Tests can be performed by dissolving and diluting the gelled emulsion in a suitable solvent (1:100) at 50°C. Suitable solvents include Milli-Q water and 10% (v / v) HCl solution (the latter may minimize aggregation during testing). The refractive indices of water and corn oil are set to 1.33 (solvent) and 1.47 (dispersed phase), respectively, and the absorbance of the dispersed droplets is set to 0.01. To avoid multiple scattering or low intensity of scattered light, add the dissolved emulsion to the dispersion unit (containing approximately 125 mL of water) until approximately 10% obscuration is obtained.

[0076] This can be beneficial because the size and size distribution of oil particles can vary. For example, if they have smaller particle sizes, enhanced absorption of oil particles in the mouth (and therefore improved bioavailability of active cannabinoid materials) can be achieved. Without wishing to be bound by theory, it is believed that improved bioavailability is related to the direct uptake of smaller oil particles by cells without the need for lipolysis. For use in enhancing oral mucosal (i.e., sublingual or buccal) delivery, nano-range oil particles (i.e., nanoparticles) are preferred. The use of certain lipid carrier materials as described herein can also enhance uptake into the circulatory system. For example, medium-chain triglycerides (MCTs) can be directly ingested through either the oral mucosa or the intestine without lipolysis.

[0077] Oil particle size reduction can be achieved by a variety of different means, such as mechanical processes, chemical processes involving the selection of smaller lipid molecules, or indeed a combination of these approaches. Mechanical reduction involves the use of shear forces to break down large oil droplets into small nanoscale particles. Thus, smaller particles can be generated by appropriate adjustments to the method used to generate the emulsion, for example, by varying the shear force and / or the duration of mixing of the oil and aqueous phases. Using higher shear forces and / or longer mixing times produces smaller oil particles. Suitable shear can be achieved using conventional homogenizers, such as rotor-stator mixers, e.g., Ultra-Turrax® homogenizers. A problem often encountered with mechanical processes for producing oil-in-water emulsions is particle reagglomeration (i.e., aggregation), which is addressed in the present invention by the use of a gelled aqueous phase, which helps stabilize the emulsion.

[0078] Chemical methods suitable for achieving oil particle size reduction may involve the selection of a specific type of lipid (or combination of lipids) that can form smaller oil droplets. For example, certain oils, such as MCT, tend to produce a finer dispersion of oil droplets. Chemical methods may also involve the use of stabilizers, typically surfactants or other emulsifiers, which reduce the energy required for emulsification (by reducing interfacial tension) and protect the droplets from re-agglomeration. When chemical methods are used, the use of mechanical energy may be more limited.

[0079] The oil droplets present in the gelled aqueous phase of the emulsion described herein will have a relatively high LaPlace pressure. Therefore, they will behave like a solid rather than a liquid in the final gelled emulsion. Therefore, the physical state of the oil particles will be essentially solid, especially when they exist in nanoscale dimensions. Such particles can be called, for example, "solid lipid nanoparticles."

[0080] The aqueous phase of the emulsion comprises water and at least one physiologically acceptable gelling agent. The aqueous phase may comprise a single gelling agent or may comprise a mixture of different gelling agents.

[0081] Suitable gelling agents include hydrocolloids that can form gels. These are composed of long-chain polymers such as polysaccharides and proteins. Gelling-type hydrocolloids that can be used in the present invention include, but are not limited to, alginate, pectin, carrageenan (kappa and iota), gelatin, gellan gum, and agar.

[0082] Gelling agents suitable for use in the present invention are well known in the food, pharmaceutical, and nutraceutical industries; some are described, for example, in Phillips et al. (eds.) "Handbook of Hydrocolloids," Woodhead Publishing, Cambridge, UK, 2000, the contents of which are incorporated herein by reference. A gelling agent, or combination of gelling agents, for use in the emulsions described herein can be readily selected by one of skill in the art, taking into consideration factors such as the need for compatibility with the remaining components of the composition, the need for compatibility with oral delivery, and the need for physiological acceptability.

[0083] A gelling agent can be a material that can undergo a sol-gel transformation (i.e., transition from a liquid to a gel) under the influence of a change in a physicochemical parameter such as temperature, pH, or the presence of a metal ion (e.g., a group I or II metal ion).

[0084] Suitable gelling agents include, but are not limited to, sugars (e.g., oligosaccharides and polysaccharides), proteins, and glycoproteins. Examples of gelling agents include, but are not limited to, gelatin or a mixture of gelatin and polysaccharides, or gellan, or alginates (e.g., sodium alginate), or a mixture of alginate and glucono-delta-lactone (GDL). Alginates can be used alone to provide alginate gels, or can be used in combination with CaCO to provide ionically crosslinked gels.

[0085] Gelatin will melt easily when exposed to body temperature for a sufficient period of time. Thus, for example, when held in the mouth at about 37°C, a gelatin-based composition will melt over time. This can be advantageous for providing the desired release of oil droplets in the mouth and thus enhancing the uptake of the cannabinoid material into the oral mucosa (e.g., sublingually or buccally). Melting of gelatin in the mouth can be aided by gently moving the dose in the mouth, for example, under the tongue or in the buccal cavity.

[0086] The gelatin used as a gelling agent in the composition of the present invention can be produced from any mammal or any aquatic species (for example, fish) collagen.In one embodiment, gelatin can be obtained from the collagen of saltwater fish, for example, warm-water fish.Collagen from birds can also provide gelatin for use in the present invention.

[0087] Gelatin having an imino acid content of 5 to 25% by weight, more specifically, gelatin having an imino acid content of 10 to 25% by weight, is preferred. The gelatin will typically have a weight-average molecular weight in the range of 10 to 250 kDa, preferably 75 to 220 kDa, and particularly 80 to 200 kDa. Gelatin having a Bloom value of 60 to 300, particularly 90 to 260, is preferred.

[0088] Both Type A and Type B gelatin can be used. "Type A gelatin" refers to gelatin obtained from acid-treated raw materials, often from pig skin collagen or fish collagen, although it can also be obtained from bovine sources. Gelatin obtained from acid-treated warm-water fish collagen is particularly preferred. "Type B gelatin" refers to gelatin obtained from alkali-treated raw materials, typically from collagen contained in bovine hide and bone. Due to their more rapid dissolution, compositions containing Type B gelatin typically have a much faster drug release profile than corresponding compositions containing Type A gelatin of the same bloom strength. This effect is particularly pronounced at high bloom strengths, typically above 200. Therefore, the use of Type B gelatin is preferred when immediate or very rapid release of cannabinoids after administration is required. The selection of Type B gelatin may also be desirable to minimize re-agglomeration of oil particles during gel dissolution, i.e., after administration.

[0089] The size of the lipid droplets can be influenced by the choice of gelatin type. Therefore, the appropriate choice of gelatin type can also take into account the desired lipid droplet size and distribution.

[0090] As described herein, gelatin will be present in the aqueous phase in an amount appropriate to provide the desired degree of gelation. The amount will vary somewhat depending on the type of gelatin, but can be readily determined by one skilled in the art. Typically, gelatin will be present in the aqueous phase at a concentration of 1 to 50% by weight, preferably 2 to 35% by weight, particularly 5 to 25% by weight, e.g., 7 to 20% by weight or 8 to 15% by weight, e.g., about 10% by weight (i.e., based on the weight of the aqueous phase).

[0091] When polysaccharides are used as gelling agents, natural, synthetic, or semi-synthetic polysaccharides can be used, such as polysaccharides from plants, fish, terrestrial mammals, algae, bacteria, and their derivatives and fragmentation products. Typical marine polysaccharides include carrageenan, alginate, agar, and chitosan. Typical plant polysaccharides include pectin. Typical microbial polysaccharides include gellan and scleroglucan. The use of charged, e.g., electrostatically charged and / or sulfated polysaccharides is preferred. The use of marine polysaccharides, particularly carrageenan and alginate, especially carrageenan, is also generally preferred.

[0092] The carrageenan family, including lambda, iota, and kappa carrageenans, is a family of linear sulfated polysaccharides produced by red algae. The repeating disaccharide units in kappa carrageenan are β-D-galactose-4-sulfate and 3,6-anhydro-α-D-galactose, while the repeating disaccharide units in iota carrageenan are β-D-galactose-4-sulfate and 3,6-anhydro-α-D-galactose-2-sulfate. Both kappa and iota carrageenans are used in food preparation and find use as gelling agents in the present invention.

[0093] The use of alginate, carrageenan, and pectin involves cation-mediated gelation of negatively charged polysaccharides. For example, carrageenan gelation is generally promoted by the inclusion of group I or group II ions, such as sodium, potassium, or calcium ions. Both iota-carrageenan and kappa-carrageenan form salt- or cold-setting, reversible gels in aqueous environments. Coil-helix transitions and helical aggregation form the gel network. Kappa-carrageenan has specific binding sites for monovalent cations, such as Cs. + >K + >>Na + >Li +This leads to gel formation with a decrease in shear modulus and elastic modulus in the order of 100 mM to 100 mM. In principle, increasing salt concentration improves the elastic modulus and setting and melting temperatures of kappa-carrageenan gels. When kappa-carrageenan is used in accordance with the present invention, for example, at concentrations up to 100 mM, more particularly up to 50 mM, the use of water-soluble potassium, rubidium, or cesium compounds, especially potassium compounds, and especially naturally occurring compounds (e.g., salts), is preferred. Salt-dependent conformational transitions are also found for iota-carrageenan. The molecule also exhibits a Ca 2+ It is also known to undergo a coil-helix transition accompanied by strong helix stabilization in the presence of multivalent cations such as Calcium, Strontium, Barium, Iron, or Aluminum. The use of water-soluble calcium, strontium, barium, iron, or aluminum compounds, especially calcium compounds, and especially naturally occurring compounds (e.g., salts), is preferred when iota-carrageenan is used according to the present invention, for example, at concentrations of up to 100 mM.

[0094] The polysaccharide gelling agents used in accordance with the present invention will typically have a weight-average molecular weight of 5 kDa to 2 MDa, preferably 10 kDa to 1 MDa, most preferably 100 kDa to 900 kDa, and particularly 400 to 800 kDa. They will typically be used at a concentration of 0.01 to 5 wt. % in the aqueous phase (i.e., based on the total weight of the aqueous phase of the emulsion), preferably 0.1 to 2.5 wt. %, and particularly 0.2 to 2 wt. %. When monovalent or polyvalent cations, typically Group I or Group II metal ions, are included in the aqueous phase, they will typically be present at a concentration in the range of 2.5 to 100 mM, particularly 5 to 50 mM.

[0095] When pectin is used as the only gelling agent in the aqueous phase, the pectin is not alkoxylated / esterified and contains Ca 2+Although pectin can be gelled with ions, it is preferably alkoxylated, e.g., methoxylated or ethoxylated, when a large amount of solids is present and / or at low pH values. Such alkoxylated / esterified pectins, e.g., highly alkoxylated / highly esterified, e.g., highly methoxylated (HM) or highly ethoxylated (HE) pectins, are commercially available. Highly alkoxylated refers to a degree of esterification of at least 50%. Pectin will typically be used at a concentration of 0.01 to 5 wt. %, preferably 0.1 to 2.5 wt. %, and especially 0.2 to 2 wt. % in the aqueous phase (i.e., based on the total weight of the aqueous phase of the emulsion). Alternatively, pectin, e.g., non-alkoxylated pectin, can be used in combination with an additional non-proteinaceous gelling agent, e.g., a polysaccharide, e.g., alginate, carrageenan, or, preferably, agar.

[0096] Mixtures of polysaccharides and gelatin may be used as gelling agents, in which case the weight ratio of gelatin to polysaccharide in the aqueous phase will typically be 50:1 to 5:1, preferably 40:1 to 9:1, especially 20:1 to 10:1.

[0097] In one embodiment, the aqueous phase may have a gelling temperature in the range of 10 to 45°C, more preferably 20 to 35°C. In one embodiment, it may have a melting temperature in the range of 30 to 80°C, preferably 32 to 60°C, for example 35 to 50°C. If a particular melting temperature is desired, the type of gelling agent may be selected accordingly. Particularly suitable gelling agents for achieving the desired melting temperature include, but are not limited to, any of the gelatins described herein.

[0098] The aqueous phase of the gelled oil-in-water emulsion may comprise 15-95%, 25-90%, 30-80%, 35-75%, 40-75%, 45-70%, 45-65%, or 50-60% by weight of the composition.

[0099] In addition to water, gelling agents, and any necessary gelation initiators, other physiologically acceptable materials may also be present in the aqueous phase, such as emulsifiers, emulsion stabilizers, pH adjusters (e.g., buffers), viscosity adjusters (e.g., buffers), thickeners, plasticizers, sweeteners, bulking agents (i.e., fillers), aromas, flavors, and colorants. The nature and concentrations of such materials can be readily determined by one skilled in the art.

[0100] The presence of a bulking agent (i.e., a filler) in the aqueous phase helps reduce microbial growth by lowering the water activity. The water activity can be reduced, for example, to less than about 0.8, e.g., in the range of 0.5 to 0.8, or 0.6 to 0.75, or 0.65 to 0.75, e.g., 0.7 to 0.75. The amount and type of bulking agent can be readily selected by those skilled in the art. Suitable examples include, but are not limited to, sugar alcohols such as sorbitol and xylitol, and mixtures thereof. These may constitute 45 to 70% by weight, preferably 50 to 65% by weight, e.g., 55 to 60% by weight, based on the aqueous phase. In some cases, the selected bulking agent may also function as a sweetener, depending on its concentration. For example, the compositions of the present invention may contain xylitol, e.g., 0.5 to 50% by weight, preferably 1 to 40% by weight, e.g., 15 to 40% by weight, to improve taste and mouthfeel.

[0101] If the aqueous phase contains a sweetener, it is typically selected from natural sweeteners such as sucrose, fructose, glucose, reduced glucose, maltose, xylitol, maltitol, sorbitol, mannitol, lactitol, isomalt, erythritol, polyglycitol, polyglucitol, glycerol, and stevia, and artificial sweeteners such as aspartame, acesulfame-κ, neotame, saccharin, and sucralose. The use of non-cariogenic sweeteners is preferred.

[0102] Thickeners that may be present in the aqueous phase include starch, modified starch, xanthan, galactomannans (guar gum and locust bean gum), karaya gum, tragacanth gum, gum arabic, and other hydrocolloids such as cellulose derivatives (e.g., methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), and carboxymethylcellulose (CMC)), and any combination thereof. The thickening effect of such materials depends on the type and concentration of the hydrocolloid used, other ingredients, and the pH of the formulation, but the appropriate amount can be easily determined.

[0103] Emulsifiers can also be present in the aqueous phase.Suitable agents are well known in the food industry and in pharmaceutical and nutritional supplement products.Any known emulsifier or emulsifiers can be selected for use in the emulsion of the present invention, keeping in mind the need for compatibility with the remaining components of the emulsion and the requirement that they should be suitable for oral delivery.Non-limiting examples of suitable emulsifiers include proteins, such as soy protein, and amphiphilic polysaccharides, such as HM pectin.Gum arabic, which is a mixture of glycoproteins and polysaccharides, can also be used. Other emulsifiers suitable for use in gelling emulsions include lecithin, monoglycerides, polysorbates (e.g., Polysorbate 65, Polysorbate 80, Polysorbate 20), Cremophor EL, Solutol HS15, poloxamers (e.g., Poloxamer 407, Poloxamer 188), and cellulose derivatives (e.g., methylcellulose (MC), hydroxypropylmethylcellulose (HPMC)).

[0104] Flavoring agents may be present in the composition to help mask the taste of certain lipids, such as those containing omega-3 fatty acids. Suitable flavors include, but are not limited to, citrus flavors, such as orange or lemon oil.

[0105] Suitable buffers are well known in the art and include, for example, sodium citrate, malic acid, etc. The pH of the aqueous phase of the emulsion may be adjusted to within the range of 2 to 9, particularly 3 to 7.5, for example 4 to 7.

[0106] In one set of embodiments, the gelled oil-in-water emulsion may further comprise an oral mucosal uptake enhancer to aid in delivery of the cannabinoid active substance in the oral cavity, whether via sublingual or buccal delivery. The term "oral mucosal uptake enhancer" refers to any substance that enhances uptake of the active substance through the oral mucosal surface, e.g., via the buccal and / or sublingual surfaces in the mouth. This substance may be, but is not necessarily, an oral mucosal adhesion enhancer, such as a mucoadhesive agent. The term "mucoadhesive agent" refers to a substance that exhibits an affinity for the mucosal surface, i.e., adheres to the surface through the formation of bonds that are generally non-covalent in nature. The oral mucosal uptake enhancer is typically provided in the aqueous phase.

[0107] Mucoadhesives suitable for use in the gelled emulsions described herein are well known in the art and can be readily selected. Non-limiting examples include natural materials such as agarose, chitosan, gelatin, hyaluronic acid, and various gums (e.g., guar gum, hawthorn gum, xanthan gum, gellan gum, carrageenan gum, pectin gum, and sodium alginate gum), as well as synthetic materials such as cellulose derivatives and poly(acrylic acid)-based polymers.

[0108] Other materials suitable for use as oral mucosal uptake enhancers are known in the art and can be readily selected. As will be appreciated, such substances must be compatible with the remaining components of the emulsion and suitable for oral delivery (i.e., they must be safe, non-toxic, non-irritating, and non-allergenic). Ideally, they will be pharmacologically and chemically inert and, in particular, provide an acceptable taste. Such substances may act in a variety of different ways. For example, they may enhance adsorption on the oral mucosa by altering mucus rheology, increasing the fluidity of lipid bilayer membranes, acting on components at tight junctions, and / or overcoming enzymatic barriers.

[0109] Suitable oral mucosal uptake enhancers include, for example, surfactants (anionic surfactants such as sodium lauryl sulfate; cationic surfactants such as cetylpyridinium chloride; and nonionic surfactants such as poloxamers; Brij, Span, Myrj, Tween, etc.); cyclodextrins (including alpha, beta, gamma cyclodextrin, and methylated beta cyclodextrin); chelating agents (e.g., EDTA, citric acid, sodium salicylate, methoxysalicylic acid); terpenes (which may be found in essential oils, e.g., peppermint oil (menthol)); bile salts (e.g., Examples include sodium glycol deoxycholate, sodium glycocholate, sodium taurodeoxycholate, and sodium taurocholate; positively charged polymers (e.g., chitosan, trimethylchitosan, polyacrylic acid); cationic compounds / amino acids (e.g., poly-L-arginine); mono- or polyols (e.g., ethanol, isopropanol, propylene glycol, polyethylene glycol, glycerol, and propanediol); sulfoxides (e.g., dimethyl sulfoxide (DMSO)); urea and its derivatives, and any combination thereof. In one embodiment, the oral mucosal uptake enhancer may be selected from citric acid, glycerol, menthol, and any combination of these agents.

[0110] Fatty acids can also enhance absorption into oral mucosa.The enhancement of absorption will vary depending on the length and concentration of fatty acid.Medium-chain fatty acids are considered to be particularly suitable.For longer chain fatty acids, unsaturated ones are considered to be particularly beneficial.Examples of fatty acids that can be present to enhance absorption through oral mucosa include oleic acid, caprylic acid, lauric acid, lysophosphatidylcholine, and phosphatidylcholine.Lecithin, for example, can be used as a source of phosphatidylcholine.

[0111] Particularly suitable for use as oral mucosal uptake enhancers in the present invention are cationic polymers such as chitosan and chitosan derivatives, especially acetylated chitosan. Acetylated chitosan having a degree of acetylation in the range of 30-60% may be preferred.

[0112] If present, any oral mucosal uptake enhancer may be present in an amount of 0.1 to 2% by weight, based on the total weight of the composition.

[0113] In addition to lipids and active cannabinoid agents, the oil phase of the emulsion may also contain physiologically tolerable lipid-soluble materials, such as antioxidants (e.g., vitamin E), flavorings, and coloring agents, if desired.

[0114] In some embodiments, other physiologically active agents may also be present in the gelled emulsions described herein. These may be provided in the aqueous and / or oily phases, and may be dissolved and / or dispersed in one or both of these phases. Other active agents that may be present in the oily phase include lipophilic active agents.

[0115] Examples of other physiologically active agents that may be included in the compositions of the present invention include anti-inflammatory agents such as, for example, NSAIDs (e.g., diclofenac), vitamin D, melatonin, and magnesium (e.g., magnesium carbonate).

[0116] In one embodiment, a gelled oil-in-water emulsion according to the present invention may comprise, consist essentially of, or consist of the following components: (a) water, (b) one or more physiologically tolerable lipids; (c) at least one cannabinoid; (d) one or more physiologically tolerable gelling agents; (e) one or more bulking agents; (f) one or more buffering agents; (g) optionally, one or more viscosity modifiers (e.g., thickeners or plasticizers); (h) optionally, one or more oral mucosal uptake enhancers; and (i) Optionally, one or more additional physiologically active agents.

[0117] By "consisting essentially of" it is intended that the emulsions will be substantially free (e.g., free of) other ingredients that would materially affect their properties. By "consisting of" it is intended that the emulsions will be substantially free (e.g., free of) ingredients other than those listed.

[0118] In one set of embodiments, the compositions of the present invention may be provided in the form of a dosage unit. By "dose unit," it is intended that the composition be orally ingested by the subject "as received" (e.g., administered to a patient), i.e., not broken or cut up prior to oral delivery. The weight of the dosage unit will therefore be such that it is suitable for delivering the composition in this manner. For example, it may have a total weight in the range of 50 to 3,000 mg, e.g., 250 to 3,000 mg or 500 to 2,500 mg, particularly 100 to 2,000 mg, e.g., 750 to 2,000 mg, particularly 100 to 1,500 mg, more particularly 400 to 1,500 mg, particularly 400 to 1,000 mg.

[0119] In one set of embodiments, the dosage units will generally be very large, for example, having a mass of 400 to 3,000 mg, for example, 600 to 1,500 mg. The total dosage unit weight can be selected as needed. For example, the dosage unit can be scaled up or down depending on the properties of the selected active ingredients and their intended doses, for example, the dosage unit can be determined according to the desired dose of cannabinoid.

[0120] Each dosage unit will contain one "core" of the gelled oil-in-water emulsion described herein. Each core may be formed from a larger portion of the gelled emulsion that has been divided, for example, by cutting. More typically, however, each core is formed by extrusion or molding of the dosage unit from a liquid emulsion or incompletely gelled emulsion prior to gelation (i.e., above the gelling temperature of the selected gelling agent or prior to the addition of any gelation initiator).

[0121] The composition of the present invention typically consists of a gelled oil-in-water emulsion core. As will be understood, in this case, the core will only contain a defined oil phase and an aqueous phase, i.e., will not contain any other components. However, as will be discussed, in other embodiments, the core may be provided with a coating of a physiologically acceptable coating material. Such coatings may be conventional in the pharmaceutical and nutraceutical industry and may be applied by any conventional means, such as dipping or spraying.

[0122] In one set of embodiments, the gelled oil-in-water emulsions described herein may be provided with a coating. For example, they may be provided within a capsule shell that dissolves in the mouth. Viewed from another aspect, therefore, the invention provides an orally administrable capsule comprising a capsule shell encapsulating a gelled oil-in-water emulsion described herein.

[0123] In the capsules of the present invention, the shell may be any physiologically acceptable material, but typically will be a sugar, biopolymer, or synthetic or semi-synthetic polymer that is soluble or degradable in saliva or fluids in the gastrointestinal tract. The shell may be flexible, but is preferably substantially rigid. Particularly desirable is a capsule with a "jelly bean" consistency. The shell is preferably of a material and thickness that protects the contents from oxidation. The shell may comprise sugar, gelatin, or cellulose, particularly sugar or gelatin, such as sorbitol or gelatin. The use of sugar, gelatin, and cellulose as capsule shell materials is well known in the pharmaceutical and nutraceutical fields. Gelatin may be obtained from any of the sources described herein, including non-mammalian sources.

[0124] Thus, the capsule shell material will typically be a sugar such as sucrose, fructose, maltose, xylitol, maltitol, or sorbitol, but may further include hydrocolloid materials such as, for example, gelatin, carrageenan, alginate, pectin, cellulose, modified cellulose, starch, modified starch, gum arabic, etc. The capsule shell may include other ingredients such as, for example, artificial sweeteners, colors, fillers, flavors, antioxidants, etc.

[0125] The capsule shell can be preformed so that the oil-in-water emulsion can be filled into the shell as a liquid or once solidified. Alternatively, a shell precursor (e.g., a solution) can be coated onto the hardened emulsion, for example, using standard coating techniques. If desired, the capsule can be further coated, for example, with a wax.

[0126] The preparation of the gelled oil-in-water emulsion described herein can be carried out by emulsifying the aqueous phase and oil phase components. It will be understood that the emulsification is carried out under conditions in which the aqueous phase is liquid (e.g., viscous liquid), i.e., before the formation of a gel. The emulsification conditions depend on the type of gelling agent selected. For example, if the gelling agent undergoes a sol-gel transition, the emulsification is carried out at a temperature higher than the sol-gel transition temperature. Subsequent cooling of the emulsion below the sol-gel temperature will yield the desired gelled emulsion.

[0127] Prior to emulsification, the selected cannabinoid may be added to the oil phase. This may be accomplished by dissolving the cannabinoid in the selected oil. For example, CBD has a melting point of 67.5°C and is a crystalline solid at ambient temperature. Dissolving the CBD in the oil phase without heating ensures that the active substance is not undesirably degraded. Alternatively, the selected cannabinoid may be added to a mixture of the aqueous and oil phase components prior to emulsification. During the emulsification process, lipophilic cannabinoid materials typically migrate to the oil phase.

[0128] The formation of the emulsion can be achieved by conventional techniques and by using known equipment, for example, homogenizers based on the rotor-stator principle. The speed and duration of stirring can be adjusted as needed, for example, varied to achieve the desired shear force and provide the desired droplet size.

[0129] Emulsification is generally carried out under a controlled atmosphere to avoid oxidative degradation of lipids and / or active cannabinoid materials.For example, emulsification can be carried out in the presence of a non-oxidizing gas such as nitrogen.Degassing to remove air bubbles can also be carried out during the manufacturing process, for example, before mixing the emulsion components, after the liquid emulsion is formed, before packaging the hardened emulsion, etc.This is carried out using conventional means, such as applying a vacuum or sparging with a non-oxidizing gas (e.g., nitrogen).

[0130] After emulsification and gelation, the emulsion can be dried to reduce the water content, however, when dried, it will still retain a continuous gelled water phase as described herein and a water content within the ranges defined herein.

[0131] The gelled oil-in-water emulsion will typically be provided in the form of a dosage unit as described herein. Individual dosage units can be formed by methods such as molding, extrusion, or cutting. However, typically, dosage units can be formed by filling the liquid emulsion into molds, such as individual molds in a blister pack that are then sealed. The dosage units are preferably in the form of tablets or lozenges. However, for children, they can be conveniently presented in shapes that appeal to children, such as geometric shapes such as sticks, strips, and tubes, or in the shape of animals, dolls, or vehicles.

[0132] In one set of embodiments, the core may be shaped to promote retention of the composition in the mouth and aid in oral mucosal (e.g., sublingual or buccal) delivery of the cannabinoid. Disk-shaped cores are suitable for this purpose. Rod-shaped cores may also be suitable for placement under the tongue when sublingual delivery is desired.

[0133] The methods for preparing gelled oil-in-water emulsions described herein form a further aspect of the present invention. Viewed from a further aspect, therefore, the present invention provides a method for preparing an orally administrable gelled oil-in-water emulsion, comprising forming an oil phase containing one or more physiologically acceptable lipids and one or more active cannabinoids, forming an aqueous phase containing one or more physiologically acceptable gelling agents, combining the oil and aqueous phases to form an oil-in-water emulsion, and gelling the emulsion. If desired, the emulsion can be divided into individual dosage units before or after gelling.

[0134] The dosage units are preferably individually packaged in airtight containers, for example, sealed wrappers, or more preferably in blisters of blister packs.Therefore, in another aspect, the present invention provides a package comprising an airtight and lighttight compartment containing a dosage unit of the composition according to the present invention.By excluding both air (i.e., oxygen) and light from the packaged dosage units, the long-term stability of the active cannabinoid material is improved.

[0135] The package according to the present invention is preferably provided in the form of a blister pack containing at least two dosage units, e.g., 2 to 100, preferably 6 to 30 dosage units. Blister packs generally comprise a metal or metal / plastic laminate sheet base having molded cavities into which the dosage forms are placed. The pack is usually sealed with a foil, typically a metal or metal / plastic laminate foil, e.g., by heating the area between the cavities. The use of metal or metal / plastic laminate to form the blister pack helps to prevent air (i.e., oxygen), light, and moisture from penetrating the contents of the blister pack, thus enhancing the stability of the cannabinoid material.

[0136] Packages according to the invention are preferably filled under a non-oxidizing gas atmosphere (eg nitrogen) or flushed with such a gas before sealing.

[0137] The gelled oil-in-water emulsions of the present invention find use both as pharmaceuticals, i.e., for therapeutic purposes, and as dietary supplements. The gelled form of the compositions described herein and their favorable organoleptic properties (i.e., mouthfeel and taste) make them particularly suitable for holding in the mouth without immediate swallowing. For example, the product can be held under the tongue (for sublingual delivery) or in the buccal cavity (for intrabuccal delivery). The exact timing of holding in the mouth before dissolution depends on the specific formulation, but it is envisioned that the product can be held in the mouth for up to several minutes, e.g., 1 to 15 minutes, before completely dissolving. Upon inhalation, the gelled emulsion slowly dissolves, delivering the active agent directly to the circulatory system via the oral cavity. Sublingual or intrabuccal delivery of cannabinoids minimizes first-pass metabolic effects.

[0138] For example, when used as a nutritional supplement, the compositions described herein can be used as a supplement (for example, a nutritional supplement) to maintain the general health and / or well-being of the target.The use examples of nutritional supplements include, but are not limited to, alleviating anxiety symptoms, alleviating menopausal symptoms, treating insomnia, alleviating menstrual symptoms (for example, menstrual cramps), preventing nausea, stimulating appetite, and as a muscle relaxant.Other uses of nutritional supplements include recreational use, such as enhancing sexual pleasure.

[0139] The gelled oil-in-water emulsions described herein find use in the treatment or prevention of a range of conditions responsive to a selected cannabinoid agent. As will be appreciated, the nature of such conditions will depend on the selected cannabinoid (and any other active pharmaceutical ingredients, if present), but can be readily determined by one of ordinary skill in the art. For example, the gelled emulsions may be used to treat or prevent any of the following conditions: pain (e.g., cancer pain, arthritis pain), inflammation, neurological disorders, mood disorders (e.g., anxiety), epilepsy, sleep disorders, symptoms of multiple sclerosis, anorexia (i.e., to increase appetite), schizophrenia, inflammatory bowel disease (i.e., Crohn's disease and ulcerative colitis), and chemotherapy-induced nausea. More specifically, the gelled oil-in-water emulsions may be used to treat chronic pain (e.g., musculoskeletal pain) and chronic inflammatory diseases (e.g., rheumatoid arthritis and osteoarthritis).

[0140] Viewed from another aspect, therefore, the present invention provides a gelled oil-in-water emulsion as described herein for use in therapy.

[0141] Viewed from yet another aspect, the present invention provides a gelled oil-in-water emulsion which is a self-supporting viscoelastic solid having a gelled aqueous phase and an oil phase comprising one or more physiologically acceptable lipids and a cannabinoid, for oral use in the treatment of a condition responsive to said cannabinoid.

[0142] In another aspect, the present invention provides the use of a cannabinoid in the manufacture of a medicament for oral use in the treatment of a cannabinoid-responsive condition, the medicament being provided in the form of a gelled oil-in-water emulsion, which is a self-supporting viscoelastic solid having a gelled aqueous phase and an oil phase comprising one or more physiologically acceptable lipids and a cannabinoid.

[0143] Corresponding medical methods of treatment form further aspects of the invention. Viewed from yet another aspect, the present invention therefore provides a method of treating a human or non-human animal subject (e.g., a patient) for addressing a cannabinoid-responsive state, the method comprising orally administering to the subject a pharmaceutically effective amount of a cannabinoid in the form of a gelled oil-in-water emulsion as described herein.

[0144] In another aspect, the present invention provides the use of a gelled oil-in-water emulsion as described herein as a dietary supplement. Corresponding methods of administering the gelled oil-in-water emulsion to achieve a dietary supplement effect also form part of the invention.

[0145] Viewed from another aspect, therefore, the present invention provides a method of administering a cannabinoid to a human or non-human animal subject to enhance and / or maintain the health or well-being of the subject, the method comprising orally administering to the subject a nutritionally effective amount of a cannabinoid in the form of a gelled oil-in-water emulsion as described herein.

[0146] The invention described herein is primarily directed to cannabinoid formulations, however, the benefits of using MCT oil as described herein may extend to other gelled oil-in-water emulsions containing other active ingredients.

[0147] Thus, in a broader aspect, the present invention provides an orally administrable gelled oil-in-water emulsion that is a self-supporting viscoelastic solid, the emulsion having a gelled aqueous phase and an oil phase containing at least one physiologically acceptable saturated fatty acid or derivative of a saturated fatty acid and at least one active agent. In this aspect of the invention, the saturated fatty acid or derivative thereof can be selected from any of the materials described herein. In one embodiment, it can be a medium-chain triglyceride (MCT). The active agent is typically one that can be dissolved in the oil phase.

[0148] [Brief description of the drawing] The present invention will now be further described with reference to the following non-limiting examples and accompanying figures. [Figure 1] Droplet size distribution of emulsions prepared in Examples 24 to 27. [Figure 2] Droplet size distribution of emulsions of Examples 24 and 27, which have the same composition except for the mixing speed used in their preparation. [Figure 3] Effect of mixing speed of the Ultra-turrax® unit on the mean volume-based (D[4,3]) droplet size of emulsions of Examples 24-27.

[0149] [Example] material: Unless otherwise specified, the gelatin is Type A or Type B gelatin. Unless otherwise specified, the gelatin may have a Bloom value of 150.

[0150] The MCT oil was based on coconut oil from Cocos nucifera, supplied by Henry Lamotte Oils GmbH, and had the following fatty acid composition (wt%):

[0151] [Table 1]

[0152] "Hemp Oil" is CBD-standardized hemp oil supplied by Hempro Int GmbH & Co. KG, containing 3.832% CBD by weight and 99.5% purity by HPLC (THC content <0.25).

[0153] Examples 1-4 - Gelled oil-in-water emulsions containing CBD A gelled oil-in-water emulsion with the composition listed in Table 1 was made by adding gelatin to water and heating the solution to 70°C with stirring for 10 minutes. Sorbitol and xylitol were added to the mixture in stages, followed by sodium citrate. Heating and stirring were continued during each addition to ensure complete dissolution, maintaining the temperature between 50 and 75°C. After approximately 15 minutes, the resulting solution was degassed under vacuum to remove air bubbles. At a temperature of approximately 55°C, malic acid was added and dissolved in the mixture. Colorants and flavoring agents, as well as oil containing CBD, were added to the resulting aqueous phase with stirring, and the mixture was homogenized using a commercially available Ultra-Turrax® unit. The resulting emulsion was again degassed under vacuum to remove air bubbles. While still liquid, the warm emulsion was filled into preformed cavities of an appropriate fill material, sealed, and allowed to harden at room temperature to form a gel.

[0154] [Table 2]

[0155] Example 5 - Gelled oil-in-water emulsion with 10% by weight oil phase Water: 25.35% by weight Gelatin: 9% by weight Sorbitol: 15% by weight Xylitol: 36.57% by weight Trisodium citrate: 2.7% by weight Malic acid: 1.38% by weight MCT oil containing 10mg of CBD: 10% by weight

[0156] The gelatin is added to the water, and the solution is then heated to approximately 70°C for 10 minutes while stirring. The sorbitol and xylitol are then added incrementally to the mixture, followed by trisodium citrate. Heating and stirring are continued between each addition to ensure complete dissolution, maintaining the temperature between 50 and 75°C. The resulting solution is degassed under vacuum to remove air bubbles. At approximately 55°C, malic acid is added and dissolved in the mixture.

[0157] The CBD-containing MCT oil is added to the resulting aqueous phase with stirring, and the mixture is homogenized using a commercially available Ultra-Turrax unit. The resulting emulsion is again degassed under vacuum to remove air bubbles.

[0158] While still liquid, the warm emulsion is filled into a preformed cavity of suitable filling material, sealed, and allowed to harden at room temperature to form a gel.

[0159] Example 6 - Gelled oil-in-water emulsion with 20% by weight oil phase A gelled oil-in-water emulsion having the following composition is prepared as in Example 5: Water: 22.53% by weight Gelatin: 8% by weight Sorbitol: 13.33% by weight Xylitol: 32.51% by weight Trisodium citrate: 2.4% by weight Malic acid: 1.23% by weight MCT oil containing 10mg of CBD: 20% by weight

[0160] Example 7 - Gelled oil-in-water emulsion with 30% by weight oil phase A gelled oil-in-water emulsion having the following composition is prepared as in Example 5: Water: 19.72% by weight Gelatin: 7% by weight Sorbitol: 11.67% by weight Xylitol: 28.44% by weight Trisodium citrate: 2.1% by weight Malic acid: 1.07% by weight MCT oil containing 10mg of CBD: 30% by weight

[0161] Example 8 - Gelled oil-in-water emulsion with 40% by weight oil phase A gelled oil-in-water emulsion having the following composition is prepared as in Example 5: Water: 16.9% by weight Gelatin: 6% by weight Sorbitol: 10% by weight Xylitol: 24.38% by weight Trisodium citrate: 1.8% by weight Malic acid: 0.92% by weight MCT oil containing 10mg of CBD: 40% by weight

[0162] Example 9 - Gelled oil-in-water emulsion with 50% by weight oil phase A gelled oil-in-water emulsion having the following composition is prepared as in Example 5: Water: 14.08% by weight Gelatin: 5% by weight Sorbitol: 8.33% by weight Xylitol: 20.32% by weight Trisodium citrate: 1.5% by weight Malic acid: 0.77% by weight MCT oil containing 10mg of CBD: 50% by weight

[0163] Example 10 - Gelled oil-in-water emulsion with 50 wt% oil phase and higher CBD loading A gelled oil-in-water emulsion having the following composition can be prepared similarly to Example 5: Water: 14.08% by weight Gelatin: 5% by weight Sorbitol: 8.33% by weight Xylitol: 20.32% by weight Trisodium citrate: 1.5% by weight Malic acid: 0.77% by weight 20-300mg of CBD 1 MCT oil containing: 50% by weight 1 The amount of CBD can vary between 20 and 300 mg depending on the intended use of the composition.

[0164] Example 11 - Gelled oil-in-water emulsion containing 20% ​​by weight of oil phase and mucoadhesive A gelled oil-in-water emulsion having the following composition can be prepared similarly to Example 5, except for the following initial steps: chitosan is first dissolved in weakly acidic water (water + acetic acid), and once completely dissolved, an alkaline buffer (typically a phosphate salt) is added. Gelatin is then added to the resulting aqueous solution, and the temperature is raised to 70°C with stirring for 10 minutes. The remaining procedure of Example 5 is then followed. Water: 22.53% by weight Gelatin: 8% by weight Sorbitol: 13.33% by weight Xylitol: 32.51% by weight 20-300mg of CBD 1 MCT oil containing: 20% by weight Acetylated chitosan (mucoadhesive): 1% by weight Acetic acid: as needed Alkaline buffer (pH 7.5): 2.63% by weight 1 The amount of CBD can vary between 20 and 300 mg depending on the intended use of the composition.

[0165] Example 12 - Gelled oil-in-water emulsions containing other oral mucosal uptake enhancers A gelled oil-in-water emulsion having the composition set forth in Table 2 may be prepared similarly to Example 5, with the following modifications: glycerol is added after xylitol / sorbitol, citric acid and peppermint essential oil are added and dissolved before the oil, and lecithin is added towards the end of the homogenization step. A cannabinoid (e.g., CBD) may be included as part of the oil phase.

[0166] [Table 3]

[0167] Example 13 - Gelled oil-in-water emulsion containing 20% ​​oil phase by weight containing CBD + dronabinol A gelled oil-in-water emulsion having the following composition can be prepared similar to Example 5. Dronabinol is added to the oil phase along with the CBD. Water: 22.53% by weight Gelatin: 8% by weight Sorbitol: 13.33% by weight Xylitol: 32.51% by weight Trisodium citrate: 2.4% by weight Malic acid: 1.23% by weight 20-300mg of CBD 1 and 2.5 to 10 mg of dronabinol 2 MCT oil containing: 20% by weight 1 The amount of CBD can vary between 20 and 300 mg depending on the intended use of the composition. 2 The amount of dronabinol can vary between 2.5 and 10 mg depending on the intended use of the composition.

[0168] Example 14 - Gelled oil-in-water emulsion containing 20% ​​by weight oil phase containing CBD + NSAID (diclofenac) A gelled oil-in-water emulsion having the following composition may be prepared similarly to Example 5. Diclofenac may be added to the water phase or the oil phase prior to mixing and homogenization of these phases. Water: 21% by weight Gelatin: 8% by weight Sorbitol: 13% by weight Xylitol: 31.05% by weight Trisodium citrate: 2.4% by weight Malic acid: 1.22% by weight MCT oil containing 20-300mg of CBD 1 :20% by weight Diclofenac (50 mg): 3.33% by weight 1 The amount of CBD can vary between 20 and 300 mg depending on the intended use of the composition.

[0169] Example 15 - Gelled oil-in-water emulsion containing 20% ​​by weight oil phase with CBD + other active agents Gelled oil-in-water emulsions based on MCT oil and containing, in addition to CBD, either vitamin D, melatonin (0.5-5 mg), and magnesium carbonate (40 mg to approximately 10% of the RDA) can be prepared as in Example 14. The gelled emulsions can be used as dietary supplements.

[0170] Example 16 - Gelling Oil-in-Water Emulsion with Agar as Gelling Agent A gelled oil-in-water emulsion having the following composition can be prepared similarly to Example 5, except for the following initial step: agar is added to water, and the solution is then heated to approximately 90°C with stirring for 30 minutes or until completely dissolved. The temperature is then reduced to 70°C, and the citrate ester (emulsifier) ​​is added along with the sugar alcohol, following the procedure from Example 5. Water: 26% by weight Agar: 2% by weight Citric acid ester (Grinsted Citrem N 12): 1% by weight Sorbitol: 14% by weight Xylitol: 28% by weight Trisodium citrate: 2.4% by weight Malic acid: 1.6% by weight MCT oil containing 10mg of CBD: 25% by weight

[0171] Example 17 - Gelling Oil-in-Water Emulsion Using Agar as Gelling Agent A gelled oil-in-water emulsion having the following composition may be prepared similarly to Example 5, except for the following initial step: agar and locust bean gum are added to water, and the solution is then heated to approximately 90°C with stirring for 30 minutes or until completely dissolved. The temperature is then reduced to 70°C, and the citrate ester is added along with the sugar alcohol, following the procedure from Example 5. Water: 26% by weight Agar: 1.8% by weight Citric acid ester (Grinsted Citrem N 12): 1% by weight Locust bean gum: 0.2% by weight Sorbitol: 14% by weight Xylitol: 28% by weight Trisodium citrate: 2.4% by weight Malic acid: 1.6% by weight MCT oil containing 10mg of CBD: 25% by weight

[0172] Example 18 - Gelling Oil-in-Water Emulsion with κ-Carrageenan as Gelling Agent A gelled oil-in-water emulsion having the following composition may be prepared similarly to Example 5, except for the following initial step: add κ-carrageenan to water and heat the solution to approximately 80°C with stirring for 15 minutes or until completely dissolved. The temperature is then reduced to 70°C and the soy protein and potassium salt are added along with the sugar alcohol according to the procedure from Example 5. Water: 26% by weight κ-carrageenan: 1.5% by weight KCl: 0.4% by weight Citric acid ester (Grinsted Citrem N 12): 1% by weight Sorbitol: 14% by weight Xylitol: 28% by weight Trisodium citrate: 2.5% by weight Malic acid: 1.6% by weight MCT oil containing 10mg of CBD: 25% by weight

[0173] Example 19 - Gelling Oil-in-Water Emulsion with Io-Carrageenan as Gelling Agent A gelled oil-in-water emulsion having the following composition can be prepared similarly to Example 5, except for the following initial step: ι-carrageenan is added to water and the solution is heated to about 80°C with stirring for 15 minutes or until completely dissolved. The temperature is then reduced to 70°C and the soy protein and calcium salt are added along with the sugar alcohol according to the procedure from Example 5. Water: 26% by weight Io-carrageenan: 1.5% by weight CaCl2: 0.4% by weight Citric acid ester (Grinsted Citrem N 12): 1% by weight Sorbitol: 14% by weight Xylitol: 28% by weight Trisodium citrate: 2.5% by weight Malic acid: 1.6% by weight MCT oil containing 10mg of CBD: 25% by weight

[0174] Example 20 - Gelled oil-in-water emulsion containing HM pectin as gelling agent Water: 27% by weight HM pectin: 1.5% by weight Sorbitol: 16.75% by weight Xylitol: 29.75% by weight 50% citric acid solution: as needed (depending on the desired pH) MCT oil containing 10mg of CBD: 25% by weight pH 3.0-3.1

[0175] A dry mixture of HM pectin and sugar alcohol is prepared and dispersed in water. The resulting solution is boiled with stirring until the pectin is completely dissolved. While still at a temperature above 95°C, the CBD-containing MCT oil is added with stirring. The mixture is homogenized using a commercially available Ultra-Turrax unit to produce an emulsion. Citric acid is added, if necessary, to achieve the recommended pH range. While still liquid, the warm emulsion is filled into preformed cavities of the appropriate fill material, sealed, and allowed to harden at room temperature to form a gel.

[0176] Example 21 - Gelled oil-in-water emulsion with LM pectin as gelling agent Water: 26% by weight LM pectin: 1.5% by weight Calcium citrate: 0.2% by weight Citric acid ester (Grinsted Citrem N 12): 1% by weight Trisodium citrate: 0.25% by weight Sorbitol: 16.75% by weight Xylitol: 29.3% by weight 50% citric acid solution: as needed (depending on desired pH) MCT oil containing 10mg of CBD: 25% by weight pH 3.4-3.7

[0177] A dry mixture of LM pectin, sugar alcohol, and calcium citrate is prepared and dispersed in water. The resulting solution is boiled with stirring until the pectin is completely dissolved. While still at or above 95°C, the CBD-containing MCT oil is added with stirring. The mixture is homogenized using a commercially available Ultra-Turrax unit to produce an emulsion. Citric acid is added as needed to achieve the recommended pH range. While still liquid, the warm emulsion is filled into preformed cavities of the appropriate fill material, sealed, and allowed to harden at room temperature to form a gel.

[0178] Example 22 - Gelling Oil-in-Water Emulsion with Alginate as Gelling Agent Water: 26% by weight Alginate: 1.5% by weight Calcium sulfate: 0.3% by weight Sodium pyrophosphate: 0.03% by weight Citric acid ester (Grinsted Citrem N 12): 1% by weight Sorbitol: 16.75% by weight Xylitol: 29.4% by weight MCT oil containing 10mg of CBD: 25% by weight

[0179] A dry mixture of alginate, sugar alcohol, soy protein, and sodium pyrophosphate is prepared and dispersed in water at 20°C until dissolved. While still at room temperature, the CBD-containing MCT oil is added with stirring. The mixture is homogenized using a commercially available Ultra-Turrax unit to create an emulsion. Calcium sulfate is then added with vigorous stirring. While still liquid, the warm emulsion is filled into preformed cavities of suitable fill material, sealed, and allowed to harden at room temperature to form a gel.

[0180] Example 23 - Gelling oil-in-water emulsion containing alginate as gelling agent Water: 26% by weight Alginate: 1.5% by weight Calcium carbonate: 0.06% by weight Glucono-δ-lactone: 0.2% by weight Citric acid ester (Grinsted Citrem N 12): 1% by weight Sorbitol: 16.75% by weight Xylitol: 29.4% by weight MCT oil containing 10mg of CBD: 25% by weight

[0181] A dry mixture of alginate, sugar alcohol, soy protein, and calcium carbonate is prepared and dispersed in water at 20°C. While still at room temperature, the CBD-containing MCT oil is added with stirring. The mixture is homogenized using a commercially available Ultra-Turrax unit to create an emulsion. Glucono-δ-lactone is then added with vigorous stirring. While still liquid, the warm emulsion is filled into preformed cavities of suitable fill material, sealed, and allowed to harden at room temperature to form a gel.

[0182] Examples 24-27 - Effect of Mixing Speed ​​on Oil Droplet Size The compositions shown in Table 3 are prepared similarly to the compositions of Examples 1-4.

[0183] [Table 4]

[0184] Droplet size and size distribution were measured using a Malvern Mastersizer 3000 (Worcestershire, UK) connected to a Hydro MV wet dispersion unit (Malvern, Worcestershire, UK). Data analysis was performed using the manufacturer's software (Mastersizer 3000, v1.0.1). Tests were performed by dissolving and diluting the gelled emulsions in a 10% (v / v) HCl solution (1:100) at 50 °C. The refractive indices of water and corn oil were set to 1.33 (solvent) and 1.47 (dispersed phase), respectively, and the absorbance of the dispersed droplets was set to 0.01. To avoid multiple scattering or low intensity of scattered light, each dissolved emulsion was added to the dispersion unit (containing approximately 125 mL of water) until approximately 10% obscuration was achieved.

[0185] The droplet size distributions of the different emulsions are shown in Figures 1-3. Figure 1 shows the droplet size distributions achieved by varying the mixing speed. High-Standard-Medium-Low corresponds to the Ultra-Turrax® unit and mixing time settings shown in Table 3. Figure 2 compares the droplet size distribution results of emulsions from Examples 24 and 27, which have the same composition and differ only in mixing speed. Figure 3 shows the effect of the Ultra-Turrax® unit mixing speed on the average volumetric (D[4,3]) droplet size.

[0186] Example 28 - Packaging Blister pack: Prior to curing, the emulsions produced in any of Examples 1-23 can be filled into blister trays made from metal / plastic laminates to which the plastic / metal foil laminate has been heat sealed.

[0187] Small piece: Prior to curing, the emulsions produced in any of Examples 1-23 can be extruded into individual pieces, which, once cured, are then sealed into individual plastic / metal foil laminate pouches. Alternatively, the single extruded piece, once set, can be cut into individual pieces as needed prior to packaging.

[0188] Example 29 - Coated Gelled Emulsion The hardened emulsion produced in any of Examples 1-23 can be coated with a sorbitol solution containing sorbitol (80% by weight), lemon flavor (0.15% by weight), yellow color (0.5% by weight), and water (ad 100% by weight). The coating solution can be cured at 99-95°C for 4-5 hours before application. Coating can be done by dipping or panning at 20-45°C. Several layers of coating material can be applied, with drying between each layer, until the final composite layer is hardened.

[0189] Alternatively, prior to hardening, the liquid emulsions prepared in any of Examples 1-23 can be filled into soft capsule shells, such as commercially available gelatin capsule shells. This can be done using a conventional soft gel machine. Typically, such capsule shells contain gelatin (40% by weight), glycerol (30% by weight), lemon flavor (0.15% by weight), yellow color (0.5% by weight), and water (ad 100% by weight).

Claims

1. 1. An orally administrable gelled oil-in-water emulsion in unit dosage form, comprising: The orally administrable gelled oil-in-water emulsion is a self-supporting viscoelastic solid having a gelled aqueous phase and an oil phase comprising one or more physiologically acceptable lipids and at least one cannabinoid; the one or more physiologically acceptable lipids are medium chain triglycerides; the oil phase comprising 40-60% by weight of the gelled oil-in-water emulsion; An orally administrable gelled oil-in-water emulsion.

2. 2. The orally administrable gelled oil-in-water emulsion of claim 1, wherein the at least one cannabinoid is selected from tetrahydrocannabinol, tetrahydrocannabinolic acid, cannabidiol, cannabidiolic acid, cannabigerol, cannabigerophosphate, cannabigerovarin, cannabigerovaric acid, cannabichromene, cannabichromene acid, cannabidivarin, cannabidivaric acid, cannabivarin, cannabivarin acid, tetrahydrocannabivarin, tetrahydrocannabivaric acid, cannabinol, cannabinolic acid, cannabinodiol, cannabielsoin, cannabicyclol, cannabicitran, and mixtures thereof.

3. 3. An orally administrable gelled oil-in-water emulsion according to claim 1 or claim 2, wherein the at least one cannabinoid is selected from tetrahydrocannabinol and / or cannabidiol.

4. 4. An orally administrable gelled oil-in-water emulsion according to any one of claims 1 to 3, wherein the one or more physiologically acceptable lipids are derived from palm kernel oil or coconut oil.

5. 5. The orally administrable gelled oil-in-water emulsion of any one of claims 1 to 4, wherein the medium chain triglyceride has two or three medium chain fatty acids which may be the same or different and have 8 or 10 carbons.

6. 6. The orally administrable gelled oil-in-water emulsion of claim 1, wherein the oil phase is dispersed in the gelled aqueous phase in the form of oil droplets having diameters in the range of 10 nm to 100 μm.

7. 7. The orally administrable gelled oil-in-water emulsion of claim 6, wherein the oil droplets have an average diameter in the range of 100 nm to 1 μm.

8. 8. The orally administrable gelled oil-in-water emulsion of claim 1, wherein the aqueous phase comprises a physiologically acceptable gelling agent selected from alginate, pectin, carrageenan, gelatin, gellan gum and agar.

9. 9. The orally administrable gelled oil-in-water emulsion of claim 8, wherein the gelling agent is gelatin.

10. 10. The orally administrable gelled oil-in-water emulsion of claim 9, wherein the gelatin is present in the aqueous phase at a concentration of 5 to 25% by weight based on the weight of the aqueous phase.

11. 11. The orally administrable gelled oil-in-water emulsion of any one of claims 1 to 10, wherein the aqueous phase further comprises one or more bulking agents.

12. 12. The orally administrable gelled oil-in-water emulsion of claim 11, wherein the bulking agent is a sugar alcohol.

13. 13. An orally administrable gelled oil-in-water emulsion according to claim 11 or 12, wherein the bulking agent is present in a concentration of 45 to 70% by weight based on the aqueous phase.

14. 14. The orally administrable gelled oil-in-water emulsion of any one of claims 1 to 13, further comprising an oral mucosal uptake enhancer.

15. 15. The orally administrable gelled oil-in-water emulsion of claim 14, wherein the oral mucosal uptake enhancer is a cationic polymer.

16. 16. The orally administrable gelled oil-in-water emulsion of claim 15, wherein the cationic polymer is chitosan or a chitosan derivative.

17. 17. The orally administrable gelled oil-in-water emulsion of any one of claims 1 to 16, wherein said unit dosage form is uncoated.

18. A package comprising an airtight and lighttight compartment containing a single dosage unit of a gelled oil-in-water emulsion according to any one of claims 1 to 17.

19. 18. A method for preparing an orally administrable gelled oil-in-water emulsion in unit dosage form according to any one of claims 1 to 17, comprising the steps of: The method comprises: forming an oil phase comprising one or more physiologically acceptable lipids which are medium chain triglycerides and at least one cannabinoid; forming an aqueous phase containing a physiologically acceptable gelling agent; combining the oil phase and the aqueous phase to form an oil-in-water emulsion; Gelling the emulsion; A method comprising:

20. 18. A method for preparing an orally administrable gelled oil-in-water emulsion in unit dosage form according to any one of claims 1 to 17, comprising the steps of: The method comprises: forming an oil phase comprising one or more physiologically acceptable lipids which are medium chain triglycerides; forming an aqueous phase containing a physiologically acceptable gelling agent; combining the oil phase, the aqueous phase, and at least one cannabinoid to form an oil-in-water emulsion; Gelling the emulsion; A method comprising:

21. 18. A gelled oil-in-water emulsion according to any one of claims 1 to 17 for oral pharmaceutical or therapeutic use.

22. 18. A gelled oil-in-water emulsion according to any one of claims 1 to 17 for oral use in the treatment of cannabinoid responsive conditions.

23. 23. A gelling oil-in-water emulsion for use according to claim 22, wherein said condition is selected from pain, inflammation, neurological disorders, mood disorders, epilepsy, sleep disorders, symptoms of multiple sclerosis, anorexia, schizophrenia, inflammatory bowel disease, and chemotherapy-induced nausea.

24. 23. A gelled oil-in-water emulsion for use according to claim 22, wherein the condition is selected from chronic pain and chronic inflammatory diseases.

25. 23. A gelled oil-in-water emulsion according to claim 22 for relieving symptoms of anxiety, relieving menopausal symptoms, treating insomnia, relieving menstrual symptoms, preventing or treating nausea, stimulating appetite or for use as a muscle relaxant.

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