Cannabinoid preparations

Abstract

The present invention relates to a novel formulation comprising a large amount of at least one cannabinoid, wherein the cannabinoid is in an amorphous form.

Description

Detailed Description of the Invention

[0001] The present invention relates to a novel formulation containing a large amount of at least one cannabinoid in an amorphous form.

[0002] Cannabinoids are compounds of several structural classifications that are found mainly in the cannabis plant and most animal organisms, or as synthetic compounds. To date, at least 113 cannabinoids have been isolated from the cannabis plant.

[0003] There are many different cannabinoids and terpenoids in cannabis samples, but so far only the main cannabinoids have been associated with pharmacological activity.

[0004] The main types of cannabinoids are as follows: Cannabidiol (CBD), Tetrahydrocannabinol (THC), Cannabinol (CBN), Cannabigerol (CBG), Cannabichromene (CBC), Cannabicyclol (CBT), Cannabinodivarin (CBV), Cannabiripsol (CBR), Hexahydrocannabinol (HHC), Delta-9-Tetrahydrocannabivoral (THCP), Tetrahydrocannabivarin (THCV), Endocannabinoid (Anandamide), and Endocannabinoid (2-AG).

[0005] Cannabinoids are known to have health benefits shown in medical research, such as lowering blood pressure, reducing inflammation, preventing relapse of drug and alcohol dependence, treating anxiety disorders, treating gastrointestinal (GI) disorders, and preventing seizures.

[0006] Cannabinoids can be administered in multiple ways, such as by inhalation of cannabis smoke or vapor, oral administration in the form of tablets or capsules, and as an aerosol spray to the cheek.

[0007] Crystalline cannabinoids have been shown to have low oral bioavailability. For example, it is estimated that only 6% of an orally administered dose of crystalline cannabinoids was bioavailable under fasting conditions. On the other hand, lipid-soluble cannabinoids have been reported to show approximately four times greater bioavailability.

[0008] The problems with cannabinoid formulations, particularly in high-dose forms, are their low water solubility and the limited solubility of cannabinoids in various oils. This makes it difficult to provide liquid or solid dosage forms containing large quantities of one or more cannabinoids, especially amorphous forms to improve bioavailability.

[0009] Therefore, an object of the present invention was to provide a formulation in which at least one cannabinoid is formulated in large quantities and at least one cannabinoid is substantially in an amorphous form (and remains storable).

[0010] Furthermore, this formulation should be usable for manufacturing further application forms (such as powders, tablets, and capsules) that are storage stable.

[0011] Furthermore, the particle size of oil droplets containing at least one cannabinoid must be small, especially to ensure a homogeneous distribution in the final dosage form.

[0012] Surprisingly, it was found that using specific ratios of vitamin E and at least one cannabinoid could yield a stable emulsion containing large amounts of at least one cannabinoid (particularly in a dissolved amorphous form).

[0013] This liquid formulation (emulsion / dispersion) can then be used as is, or it can be converted into a solid formulation (such as a powder) that contains at least one cannabinoid in an amount of up to approximately 45 wt-%, but is substantially amorphous, i.e., a more bioavailable form.

[0014] Therefore, the present invention relates to a liquid formulation (LF), (i) 5 to 85% by weight (wt-%) of at least one cannabinoid based on the total weight of the liquid formulation, (ii) Based on the total weight of the liquid preparation, 2 to 25 wt-% of vitamin E, (iii) At least one emulsifier in an amount of 1 to 50 wt-% based on the total weight of the liquid formulation, (iv) 12-55 wt-% water based on the total weight of the liquid preparation It contains, and at least 50 wt-% of the total weight of cannabinoids, at least one cannabinoid, is in an amorphous form, and This relates to liquid formulations (LF) in which the ratio of at least one cannabinoid to vitamin E is 2:1 to 4:1.

[0015] In this invention, the total proportion of the formulation is always 100 wt-%.

[0016] In relation to the present invention, preferred cannabinoids are selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivarin, cannabilipsol, hexahydrocannabinol, delta-9-tetrahydrocannabihoral, tetrahydrocannabivarin, endocannabinoids, and endocannabinoids.

[0017] More preferred cannabinoids are selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, and delta-9-tetrahydrocannabihoral.

[0018] Particularly preferred cannabinoids are selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, and cannabigerol (cannabidiol being the most preferred).

[0019] In all embodiments of the present invention, the most preferred use is cannabidiol.

[0020] Accordingly, the present invention relates to a liquid formulation (LF1) in which at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, delta-9-tetrahydrocannabihoral, tetrahydrocannabivarin, endocannabinoids, and endocannabinoids.

[0021] Therefore, the present invention relates to a liquid formulation (LF1') in which at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, and delta-9-tetrahydrocannabihoral.

[0022] Therefore, the present invention relates to a liquid formulation (LF) in which at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, and cannabigerol (cannabidiol being the most preferred), and is a liquid formulation (LF1'').

[0023] The amount of at least one cannabinoid in the liquid formulation according to the present invention is 5 to 85 wt-% based on the total weight of the liquid formulation.

[0024] Preferably, the amount of at least one cannabinoid in the liquid formulation according to the present invention is 10 to 85 wt-% based on the total weight of the liquid formulation.

[0025] More preferably, the amount of at least one cannabinoid in the liquid formulation according to the present invention is 10 to 80 wt-% based on the total weight of the liquid formulation.

[0026] Even more preferably, the amount of at least one cannabinoid in the liquid preparation according to the present invention is 15 to 80 wt-% based on the total weight of the liquid preparation.

[0027] Most preferably, in all embodiments of the present invention, the amount of at least one cannabinoid in the liquid preparation according to the present invention is selected in the range of 7.5 to 50 wt-%, particularly 10 to 50 wt-%, most particularly 15 to 50 wt-%. Further suitable ranges are selected in the range of 15 to 40 wt-%, 15 to 35 wt-%, 15 to 30 wt-%, 20 to 45 wt-%, 20 to 40 wt-%, 20 to 35 wt-%, 20 to 30 wt-%, 25 to 45 wt-%, 25 to 40 wt-%, 30 to 45 wt-%, 30 to 40 wt-%, 35 to 45 wt-%, and 35 to 40 wt-% based on the total weight of the liquid preparation.

[0028] Therefore, the present invention relates to a liquid preparation (LF), (LF1), (LF1') or (LF1''), and a liquid preparation (LF2) in which the amount of at least one cannabinoid in the preparation according to the present invention is 10 to 85 wt-% based on the total weight of the liquid preparation.

[0029] Therefore, the present invention relates to a liquid preparation (LF), (LF1), (LF1') or (LF1''), and a liquid preparation (LF2') in which the amount of at least one cannabinoid in the preparation according to the present invention is 10 to 80 wt-% based on the total weight of the liquid preparation.

[0030] Therefore, the present invention relates to a liquid preparation (LF), (LF1), (LF1') or (LF1'), and a liquid preparation (LF2'') in which the amount of at least one cannabinoid in the preparation according to the present invention is 15 to 80 wt-% based on the total weight of the liquid preparation.

[0031] As described above, at least 50 wt-% of one cannabinoid based on the total weight of the cannabinoid is in an amorphous form.

[0032] More preferably, in all embodiments of the present invention, at least 55 wt-% of the total weight of cannabinoids is in an amorphous form.

[0033] More preferably, in all embodiments of the present invention, at least 60 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0034] More preferably, in all embodiments of the present invention, at least 70 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0035] More preferably, in all embodiments of the present invention, at least 75 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0036] More preferably, in all embodiments of the present invention, at least 80 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0037] More preferably, in all embodiments of the present invention, at least 85 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0038] More preferably, in all embodiments of the present invention, at least 90 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0039] More preferably, in all embodiments of the present invention, at least 95 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0040] More preferably, in all embodiments of the present invention, at least 98 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0041] More preferably, in all embodiments of the present invention, at least 99 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0042] More preferably, in all embodiments of the present invention, 100 wt-% of the total weight of cannabinoids is in an amorphous form.

[0043] In all embodiments of the present invention, at least one cannabinoid is most advantageous in substantially amorphous form and more preferably dissolved in vitamin E.

[0044] In relation to the present invention, the term "crystalline" is understood to mean a homogeneous physical property, in particular a homogeneous melting range and a coherent or non-coherent portion of one or more components having long-range order. It is well understood that a crystal is a solid, i.e., a solid state of aggregation.

[0045] In relation to the present invention, the term "amorphous" is understood to mean a coherent or non-coherent portion of one or more components that lacks homogeneous physical properties, particularly a homogeneous melting range and long-range order.

[0046] In all embodiments of the present invention, most advantageously, the amorphous cannabinoid is liquid, i.e., exists in a liquid (e.g., dissolved) state of aggregation, particularly dissolved in vitamin E. More preferably, the amorphous cannabinoid is not amorphous or substantially amorphous, but is not dissolved.

[0047] In relation to the present invention, the term "long-range order" is understood to mean the regular and periodic spacing of molecules or atoms (in this case, at least one cannabinoid) in a crystalline solid. Therefore, the precise positions of some molecules or atoms can be advantageously used to determine the positions of all molecules or atoms in the crystalline solid.

[0048] The content of at least one cannabinoid in crystalline form in the liquid and solid formulations according to the present invention can be measured using a commonly known method such as differential scanning calorimetry (DSC).

[0049] In relation to the present invention, DSC was used to determine the amount of at least one cannabinoid in crystalline form in liquid and solid formulations, respectively, in accordance with the present invention, by following standard methods in the art, i.e., by using each crystalline cannabinoid as an external standard.

[0050] Therefore, in all embodiments of the present invention, the crystallinity (%) is preferably determined by DSC using each crystalline cannabinoid as an external standard.

[0051] The DSC method used in this invention is as follows:

[0052] Liquid or powder (solid) formulations (approximately 8-10 mg) were placed in aluminum pans and sealed. An empty pan was used as a reference sample. Approximately 1-2 mg of the sample was used (external standard) to investigate the bulk cannabinoid material (i.e., each crystalline cannabinoid). Each sample was heated from 10°C to 90°C at 10°C / min and cooled to 10°C at 10°C / min. During heating, thermal transition peaks were determined (observed) for crystalline cannabinoid compounds, and for CBD, it was determined to be approximately 68°C, due to the melting of cannabidiol crystals. The crystallinity of the sample could be determined by analyzing the DSC thermogram and measuring the peak area. The peak area of ​​the DSC peak corresponds to the amount of heat released during crystallization / heat consumed during melting and is proportional to the crystallinity of the sample. To determine the crystallinity %, the peak area of ​​the sample was referenced to the peak area of ​​the crystalline cannabinoid. Next, the amount of crystalline cannabinoids present in each sample can be calculated, and this is then used to determine the degree of crystallinity (%) based on the total amount of known cannabinoids present in the sample.

[0053] Accordingly, the present invention relates to a liquid formulation (LF3) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2'') in which at least 55 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0054] Accordingly, the present invention relates to a liquid formulation (LF4) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2''), wherein at least 60 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0055] Accordingly, the present invention relates to a liquid formulation (LF5) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2'') in which at least 65 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0056] Accordingly, the present invention relates to a liquid formulation (LF6) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2''), wherein at least 70 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0057] Accordingly, the present invention relates to a liquid formulation (LF7) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2''), wherein at least 75 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0058] Accordingly, the present invention relates to a liquid formulation (LF8) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2''), wherein at least 80 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0059] Accordingly, the present invention relates to a liquid formulation (LF9) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2''), wherein at least 85 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0060] Accordingly, the present invention relates to a liquid formulation (LF10) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2''), wherein at least 90 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0061] Accordingly, the present invention relates to a liquid formulation (LF11) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2'') in which at least 95 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0062] Accordingly, the present invention relates to a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2'') in which at least 98 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids (LF12).

[0063] Accordingly, the present invention relates to a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), or (LF2'') in which 100 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids (LF13).

[0064] The liquid formulation according to the present invention contains vitamin E.

[0065] Vitamin E is a group of eight lipid-soluble compounds, including four tocopherols ((α)-tocopherol, (β)-tocopherol, (γ)-tocopherol, and (δ)-tocopherol) and four tocotrienols ((α)-tocotrienol, (β)-tocotrienol, (γ)-tocotrienol, and (δ)-tocotrienol). Mixtures of these compounds, such as (all-rac)-α-tocopherol, can also be used. In relation to the present invention, (all-rac)-α-tocopherol is preferred in all embodiments. It is commercially available, for example, by DSM Nutritional Products Ltd, as dl-α-tocopherol or all-rac-α-tocopherol.

[0066] Accordingly, the present invention relates to a liquid formulation (LF14) which is (LF1), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), or (LF13), wherein vitamin E is (all-rac)-α-tocopherol.

[0067] The liquid formulation according to the present invention contains 2 to 25 wt-% of vitamin E based on the total weight of the liquid formulation.

[0068] Preferably, the amount of vitamin E is selected in the range of 3 to 20 wt-% based on the total weight of the liquid preparation.

[0069] Accordingly, the present invention relates to a liquid formulation (LF15) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), or (LF14), wherein the amount of vitamin E is selected in the range of 3 to 20 wt-% based on the total weight of the liquid formulation.

[0070] Most preferably, in all embodiments of the present invention, the amount of vitamin E in the liquid formulation according to the present invention is selected to be in the range of 5 to 20 wt-%, for example, particularly 5 to 15 wt-%, based on the total weight of the liquid formulation.

[0071] As described above, the ratio of cannabinoids to vitamin E in the liquid formulation according to the present invention is 2:1 to 4:1.

[0072] Preferably, the ratio of at least one cannabinoid to vitamin E is 2:1 to 3.5:1.

[0073] More preferably, the ratio of at least one cannabinoid to vitamin E is 2.2:1 to 3.5:1.

[0074] Another preferred ratio of at least one cannabinoid to vitamin E is 3-4, for example, the ratio being approximately 4.

[0075] Accordingly, the present invention relates to a liquid formulation (LF16) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), or (LF15), wherein the ratio of cannabinoid to vitamin E is 2:1 to 3.5:1.

[0076] Accordingly, the present invention also relates to liquid formulations (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), or (LF15), and to liquid formulations (LF16') having a cannabinoid to vitamin E ratio of 2.2:1 to 3.5:1.

[0077] Furthermore, the liquid formulation according to the present invention contains at least one emulsifier. Commonly known and used emulsifiers can be used. A single emulsifier or a mixture of emulsifiers can be used.

[0078] Suitable emulsifiers include processed (food) starch, vitamin E TPGS, ascorbyl palmitate, pectin, alginic acid, carrageenan, furceran, dextrin derivatives, cellulose and cellulose derivatives (e.g., cellulose acetate, methylcellulose, hydroxypropyl methylcellulose), lignosulfonates, polysaccharide gums (e.g., acacia gum (= acacia gum), modified acacia gum, TIC gum, flaxseed gum, ghati gum, tamarind gum and arabinogalactan), gelatin (beef, fish, pork, poultry), and vegetable protein. These include proteins (e.g., peas, soybeans, castor beans, cotton, potatoes, sweet potatoes, manioc, rapeseed, sunflower, sesame, flaxseed, safflower, lentils, nuts, wheat, rice, corn, barley, rye, oats, lupin, and sorghum), animal proteins including milk or whey protein, lecithin, polyglycerol esters of fatty acids, monoglycerides of fatty acids, diglycerides of fatty acids, sorbitan esters, and sugar esters (and derivatives thereof).

[0079] Preferred emulsifiers in all embodiments of the present invention are modified (food) starch (OSA starch), vitamin E TPGS, polysaccharide gum, gelatin (beef, fish, pork, poultry), plant protein, and mixtures thereof.

[0080] Starch can be modified physically and chemically. Pregelatinized starch is an example of physically modified starch. Acid modification, oxidation, crosslinking, starch esters, starch ethers, and cationic starch are examples of chemically modified starch. A particularly suitable starch in all embodiments of the present invention is octenyl succinate starch (OSA starch), which is commercially available, for example, as Cleargum from Roquette or as Capsul HS from Ingredion.

[0081] Therefore, the present invention relates to a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), or (LF16'), wherein at least one emulsifier is modified (food) starch, vitamin E TPGS (CAS No. 9002-96-4), ascorbyl palmitate, pectin, alginic acid, carrageenan, furceran, dextrin derivatives, cellulose and cellulose derivatives (e.g., cellulose acetate, methylcellulose, hydroxypropyl methylcellulose), lignosulfonates, polysaccharide gums (e.g., acacia gum (= acacia gum), modified acacia gum, TIC gum, flaxseed gum, ghati gum, tamarind gum and arabinogalactan), gelatin (beef, fish, pork, poultry), vegetable protein (e.g.) The present invention relates to a liquid formulation (LF17) selected from the group consisting of peas, soybeans, castor beans, cotton, potatoes, sweet potatoes, manioc, rapeseed, sunflower, sesame, flaxseed, safflower, lentils, nuts, wheat, rice, corn, barley, rye, oats, lupin, and sorghum), animal proteins including milk or whey protein, lecithin, polyglycerol esters of fatty acids, monoglycerides of fatty acids, diglycerides of fatty acids, sorbitan esters, and sugar esters (and derivatives thereof).

[0082] Accordingly, the present invention also relates to liquid formulations (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), or (LF16'), wherein at least one emulsifier is selected from the group consisting of denatured (food) starch, vitamin E TPGS, polysaccharide gum, gelatin (bovine, fish, pig, poultry), and plant protein (LF17'). In all embodiments of the present invention, the use of gelatin is preferred.

[0083] The liquid formulation according to the present invention contains at least one emulsifier in an amount of 1 to 50 wt-% based on the total weight of the liquid formulation.

[0084] Preferably, the liquid formulation according to the present invention contains at least one emulsifier in an amount of 5 to 50 wt-% based on the total weight of the liquid formulation.

[0085] Accordingly, the present invention relates to a liquid formulation (LF18) which is a liquid formulation (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), (LF16'), (LF17), or (LF17'), and contains at least one emulsifier in an amount of 5 to 50 wt-% based on the total weight of the liquid formulation.

[0086] Most preferably, in all embodiments of the present invention, the amount of at least one emulsifier in the liquid formulation according to the present invention is selected from the range of 10 to 50 wt-%, particularly 15 to 50 wt-%, for example, most particularly 20 to 50 wt-%. Further suitable ranges are selected from 15 to 45 wt-%, 15 to 40 wt-%, 15 to 35 wt-%, 20 to 45 wt-%, 20 to 40 wt-%, and 20 to 35 wt-%, based on the total weight of the liquid formulation.

[0087] In all embodiments of the present invention, the liquid formulation according to the present invention preferably comprises vitamin E TPGS and at least one other emulsifier (other than vitamin E TPGS). This is preferable because it further reduces the particle size of the oil droplets.

[0088] Particularly suitable emulsifiers in all embodiments of the present invention are gelatin, a mixture of gelatin and vitamin E TPGS, or a mixture of OSA starch and vitamin E TPGS, preferably in the absence of any other emulsifier. Most preferably in all embodiments of the present invention is the use of gelatin, more preferably in combination with vitamin E TPGS, and most preferably in the absence of any further emulsifier.

[0089] Vitamin E TPGS (TPGS stands for tocopherol polyethylene glycol succinate), also known as yocofersolan or tocophersolan, is a synthetic water-soluble form of vitamin E.

[0090] The IUPAC name is α-hydro-ω-{[4-oxo-4-({(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydro-2H-1-benzopyran-6yl}oxy)butanoyl]oxy}poly(oxyethylene). The CAS number is 9002-96-4.

[0091] Vitamin E TPGS is a compound with the following formula: [ka]

[0092] Preferably, in all embodiments of the present invention, the liquid formulation according to the present invention contains 0.1 to 10 wt-% of vitamin E TPGS based on the total weight of the liquid formulation, and 0.9 to 40 wt-% of at least one other emulsifier (other than vitamin E TPGS), for example, particularly gelatin or OSA starch, most preferably gelatin, based on the total weight of the liquid formulation.

[0093] More preferably, in all embodiments of the present invention, the liquid formulation according to the present invention comprises 0.1 to 8 wt-% of vitamin E TPGS based on the total weight of the liquid formulation, and 0.9 to 42 wt-% of at least one other emulsifier (other than vitamin E TPGS), such as gelatin or OSA starch, based on the total weight of the liquid formulation.

[0094] In all embodiments of the present invention, the ratio (w / w) of gelatin and OSA starch to vitamin E TPGS, respectively, is preferably selected within the range of 90:~1:1, preferably 90~2.5:1, and most preferably 90:1~5:1. Further suitable ranges are 50:1~5:1, 25:1~5:1, and 10:1~5:1.

[0095] The liquid formulation according to the present invention contains 12 to 55 wt-% water based on the total weight of the liquid formulation.

[0096] Preferably, the liquid formulation according to the present invention contains 15 to 55 wt-% water based on the total weight of the liquid formulation.

[0097] Preferably, the liquid formulation according to the present invention contains 20 to 55 wt-% water based on the total weight of the liquid formulation.

[0098] Accordingly, the present invention relates to a liquid formulation (LF19) comprising (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), (LF16'), (LF17), (LF17'), and (LF18), wherein the amount of water is 15 to 55 wt-% based on the total weight of the liquid formulation.

[0099] Therefore, the present invention also relates to liquid formulations (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), (LF16'), (LF17), (LF17'), (LF18), and liquid formulations (LF19') in which the amount of water is 20-55 wt-% based on the total weight of the liquid formulation.

[0100] Most preferably, in all embodiments of the present invention, the amount of water in the liquid formulation according to the present invention is selected from 15 to 50 wt-%, particularly 15 to 45 wt-%, for example, most particularly 15 to 40 wt-%, based on the total weight of the liquid formulation.

[0101] The liquid formulation according to the present invention may optionally contain at least one further auxiliary agent. Such auxiliary agents may be dyes, thickeners (such as maltodextrin or glucose syrup), fillers, binders, flavors, antioxidants (other than vitamin E), or pH buffers.

[0102] The content of these additives can be up to 40 wt-% based on the total weight of the liquid formulation.

[0103] Accordingly, the present invention also relates to liquid formulations (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), (LF16'), (LF17), (LF17'), (LF18), (LF19), or (LF19'), wherein the liquid formulation comprises at least one auxiliary agent selected from the group consisting of dyes, thickeners (such as maltodextrin and (dried) glucose syrup), fillers, binders, flavors, antioxidants (other than vitamin E), and pH buffers (LF20).

[0104] Therefore, the present invention relates to a liquid formulation (LF20') in which the amount of at least one auxiliary agent is up to 40 wt-% based on the total weight of the liquid formulation.

[0105] Particularly suitable adjuvants present in the liquid or solid formulation according to the present invention are selected from the group consisting of glucose syrup, additional antioxidants (other than vitamin E), ascorbic acid, pH buffers, flavors and / or dyes, preferably from the group consisting of glucose syrup and / or ascorbic acid.

[0106] Suitable antioxidants for use in the formulations according to the present invention are sulfites, such as (SO2(E220);Na2SO3(E221), NaHSO3(E222);Na2S2O5(E223);(K2S2O5(E224);CaSO3(E226);Ca(HSO3)2(E227);KHSO3(E228)) and ascorbic acid. These are most preferred in all embodiments of the present invention.

[0107] Suitable (dried) glucose syrups and maltodextrins for use in accordance with the present invention include, but are not limited to, Glucidex® products commercially available from Roquette, Glycodry Dried Glucose Syrup from Tereos, and Glycodry 385 from Henley Bridge.

[0108] Preferably, in all embodiments of the present invention, the liquid formulation contains glucose syrup, more preferably in an amount selected from 2 to 15 wt-%, and more preferably from 3 to 10 wt-%, based on the total weight of the liquid formulation.

[0109] If the liquid formulation contains ascorbic acid, the amount is preferably selected in the range of 0.5 to 5 wt-%, more preferably in the range of 0.75 to 3 wt-%, and most preferably in the range of 1 to 2 wt-%, based on the total weight of the liquid formulation.

[0110] The liquid formulation according to the present invention can be manufactured using generally known methods.

[0111] Generally, the liquid formulation (emulsion / dispersion) according to the present invention is manufactured as follows. (i) Preparation of the lipid phase, (ii) Preparation of the aqueous phase And dispersion / emulsification of the lipid phase into the aqueous phase.

[0112] Therefore, in a preferred embodiment, the present invention is a method for preparing a liquid formulation according to the present invention, (i) Preparation of the lipid phase by solubilizing at least one cannabinoid in vitamin E at a temperature preferably 60-100°C, more preferably 65-90°C, and most preferably 70-80°C, and optionally thereafter adding vitamin E TGPS (if present). (ii) Preparation of the aqueous phase by solubilizing at least one emulsifier (other than vitamin E TGPS) and, if present, an auxiliary agent in water, then, (iii) Emulsification of the lipid phase into the aqueous phase at a temperature preferably 60-100°C, more preferably 65-90°C, and most preferably 70-85°C, to form an emulsion. This also relates to methods that include this.

[0113] The aqueous phase is prepared appropriately at high temperature according to methods well known in this art. It is even more preferable to heat the aqueous phase to approximately the same temperature as the lipid phase before dispersion / emulsification.

[0114] It is also possible to convert the liquid formulation according to the present invention into a solid (dry) formulation (powder, beadlets, granules).

[0115] This can be done by commonly known and used techniques such as spray drying and spray granulation. Preferably, the solid formulation according to the present invention is in the form of a spray-dried solid formulation or a beadlet, the beadlet can be obtained by spraying an emulsion onto a fluid bed of solid particles, particularly corn starch, a technique exemplified, for example, in European Patent No. 0285682A1. It is well known to those skilled in the art that drying is carried out in the presence of a carrier, which may be added to the liquid formulation before drying or used in the drying process by spraying the liquid formulation onto a carrier material.

[0116] Particularly suitable carrier materials used in connection with the present invention include maltodextrin (which can also be used as a thickener, i.e., has a dual role), corn starch, and silica.

[0117] Therefore, the present invention relates to a method for preparing a solid formulation according to the present invention, (i) Preparation of the lipid phase by solubilizing at least one cannabinoid in vitamin E at a temperature preferably 60-100°C, more preferably 65-90°C, and most preferably 70-80°C, and optionally thereafter adding vitamin E TGPS (if present). (ii) Preparation of the aqueous phase by solubilizing at least one emulsifier (other than vitamin E TGPS) and, if present, an auxiliary agent in water, and then (iii) Emulsification of the lipid phase into the aqueous phase at a temperature preferably 60-100°C, more preferably 65-90°C, most preferably 70-80°C, to form an emulsion, then (vi) Drying of the emulsion This also relates to methods that include this.

[0118] The solid formulation according to the present invention is prepared by spray drying according to standard methods in the art, preferably using maltodextrin as a carrier (auxiliary / flow) agent. Therefore, step (iv) of the method preferably includes drying the emulsion using maltodextrin as a carrier, more preferably by spray drying. Preferably, maltodextrin is used in an amount of 2.5 to 15 wt-%, more preferably 3 to 10 wt-%, and most preferably 5 to 10 wt-%, based on the total weight of the solid formulation.

[0119] It is understood that all preferences and definitions given herein regarding concentration ranges, etc., also apply to the methods according to the present invention.

[0120] The conversion of a liquid formulation to a solid (dry) formulation according to the present invention means that the amount of water is reduced to 5 wt-% or less based on the total weight of the solid formulation.

[0121] Preferably, in a solid formulation (such as one made from a liquid formulation according to the present invention), the water content is less than 3 wt-% based on the total weight of the solid formulation.

[0122] More preferably, in a solid formulation (such as one made from a liquid formulation according to the present invention), the water content is 2.5 wt-% or less based on the total weight of the solid formulation.

[0123] More preferably, in a solid formulation (such as one made from a liquid formulation according to the present invention), the water content is less than 2 wt-% based on the total weight of the solid formulation.

[0124] It is well understood that removing water will change the amounts (wt-%) of components (i), (ii), and (iii), as well as at least one optional adjuvant, accordingly.

[0125] The definitions and preferences provided herein for all components are also applicable to solid dosage forms.

[0126] Accordingly, the present invention relates to a solid formulation which is any of the formulations (LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), (LF16'), (LF17), (LF17'), (LF18), (LF19), (LF19'), (LF20), or (LF20'), wherein the water content is reduced to 0-5 wt-% based on the total weight of the solid formulation.

[0127] Therefore, the present invention is (i) Based on the total weight of the solid dosage form, at least one cannabinoid in an amount of 5 to 85 wt-%, (ii) Based on the total weight of the solid preparation, 2 to 25 wt-% of vitamin E, (iii) At least one emulsifier in an amount of 1 to 55 wt-% based on the total weight of the solid dosage form, (iv) at least one adjuvant in an amount of up to 40 wt-% based on the total weight of the solid dosage form, (v) less than 5 wt-% water based on the total weight of the solid dosage form It contains, and based on the total amount of cannabinoids, at least 50 wt-% of at least one cannabinoid is in an amorphous form, and This also applies to solid dosage forms (SFs) in which the ratio of at least one cannabinoid to vitamin E is 2:1 to 4:1.

[0128] Therefore, the present invention is (i) Based on the total weight of the solid dosage form, at least one cannabinoid in an amount of 10-75 wt-%, (ii) Based on the total weight of the solid preparation, 5-20 wt-% of vitamin E, (iii) Based on the total weight of the solid dosage form, at least one emulsifier in an amount of 10 to 50 wt-%, (iv) at least one adjuvant in an amount of up to 40 wt-% based on the total weight of the solid dosage form, (v) less than 5 wt-% water based on the total weight of the solid dosage form It contains, and based on the total amount of cannabinoids, at least 50 wt-% of at least one cannabinoid is in an amorphous form, and This also applies to solid dosage forms (SFs) in which the ratio of at least one cannabinoid to vitamin E is 2:1 to 4:1.

[0129] Therefore, the present invention relates to a solid dosage form (SF), and also to a solid dosage form (SF'') in which the water content is less than 3 wt-% based on the total weight of the solid dosage form.

[0130] Therefore, the present invention also relates to a solid dosage form (SF) having a water content of 2.5 wt-% or less, more preferably less than 2 wt-%, based on the total weight of the solid dosage form (SF''').

[0131] Therefore, the present invention also relates to a solid formulation (SF1) which is a solid formulation (SF), (SF'), (SF'') or (SF''') in which at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, delta-9-tetrahydrocannabihoral, tetrahydrocannabivarin, endocannabinoids and endocannabinoids.

[0132] Therefore, the present invention also relates to a solid formulation (SF1') which is a solid formulation (SF) (SF'), (SF'') or (SF''') in which at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, and delta-9-tetrahydrocannabihoral.

[0133] Therefore, the present invention also relates to a solid formulation (SF1'') which is a solid formulation (SF), (SF'), (SF'') or (SF''') in which at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol and cannabigerol (cannabidiol being the most preferred).

[0134] Therefore, the present invention also relates to a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), or (SF1'') in which the amount of at least one cannabinoid in the formulation according to the present invention is 15 to 75 wt-% based on the total weight of the solid formulation (SF2).

[0135] Therefore, the present invention also relates to a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), or (SF1'') in which the amount of at least one cannabinoid in the formulation according to the present invention is 15 to 70 wt-% based on the total weight of the solid formulation (SF2').

[0136] Therefore, the present invention also relates to a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), or (SF1'') in which the amount of at least one cannabinoid in the formulation according to the present invention is 20 to 65 wt-% based on the total weight of the solid formulation (SF2'').

[0137] Accordingly, the present invention relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2''), and also to solid formulations (SF3) in which at least 55 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0138] Therefore, the present invention also relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2'') in which at least 60 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids (SF4).

[0139] Accordingly, the present invention relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2''), and also to solid formulations (SF5) in which at least 65 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0140] Therefore, the present invention also relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2'') in which at least 70 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids (SF6).

[0141] Accordingly, the present invention relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2''), and also to solid formulations (SF7) in which at least 75 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0142] Therefore, the present invention also relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2'') in which at least 80 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids (SF8).

[0143] Accordingly, the present invention also relates to a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2'') in which at least 85 wt-% of one cannabinoid is in an amorphous form, based on the total weight of the cannabinoids (SF9).

[0144] Therefore, the present invention relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2''), and also to solid formulations (SF10) in which at least 90 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0145] Therefore, the present invention relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2''), and also to solid formulations (SF11) in which at least 95 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0146] Therefore, the present invention relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2''), and also to solid formulations (SF12) in which at least 98 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0147] Therefore, the present invention relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), or (SF2''), and also to solid formulations (SF13) in which 100 wt-% of one type of cannabinoid is in an amorphous form based on the total weight of cannabinoids.

[0148] Therefore, the present invention also relates to a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), or (SF13) in which vitamin E is (all-rac)-α-tocopherol, and also to a solid formulation (SF14).

[0149] Therefore, the present invention also relates to a solid preparation (SF15) which is a solid preparation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), or (SF14), wherein the vitamin E content is 8 to 18 wt-% based on the total weight of the solid preparation.

[0150] Therefore, the present invention also relates to a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), or (SF15') a solid formulation (SF16) having a cannabinoid to vitamin E ratio of 2:1 to 3.5:1.

[0151] Therefore, the present invention also relates to solid formulations (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), or (SF15'), and to solid formulations (SF16') having a cannabinoid-to-vitamin E ratio of 2.2:1 to 3.5:1.

[0152] Therefore, the present invention relates to a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), (SF15'), (SF16), or (SF16'), wherein at least one emulsifier is denatured (food) starch, vitamin E TPGS (CAS No. 9002-96-4), ascorbyl palmitate, pectin, alginic acid, carrageenan, furceran, dextrin derivatives, cellulose and cellulose derivatives (e.g., cellulose acetate, methylcellulose, hydroxypropyl methylcellulose), lignosulfonates, polysaccharide gums (e.g., acacia gum (= acacia gum), modified acacia gum, TIC gum, flaxseed gum, ghati gum, tamarind gum and arabinogalactan), gelatin (beef, fish, pork, poultry), vegetable protein (e.g.) The invention also relates to solid formulations (SF17) selected from the group consisting of peas, soybeans, castor beans, cotton, potatoes, sweet potatoes, manioc, rapeseed, sunflowers, sesame, flaxseed, safflower, lentils, nuts, wheat, rice, corn, barley, rye, oats, lupin, and sorghum), animal proteins including milk or whey protein, lecithin, polyglycerol esters of fatty acids, monoglycerides of fatty acids, diglycerides of fatty acids, sorbitan esters, and sugar esters (and derivatives thereof).

[0153] Accordingly, the present invention also relates to a solid formulation (SF) (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), (SF15'), (SF16) or (SF16') wherein at least one emulsifier is selected from the group consisting of denatured (food) starch, vitamin E TPGS, polysaccharide gum, gelatin (bovine, fish, pig, poultry) and plant protein (SF17').

[0154] Therefore, the present invention also relates to a solid formulation (SF18) which is a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), (SF15'), (SF16), (SF16'), (SF17), or (SF17'), wherein the amount of at least one emulsifier is 15 to 50 wt-% based on the total weight of the solid formulation.

[0155] Accordingly, the present invention also relates to a solid formulation (SF19) which is a solid formulation (SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), (SF15'), (SF16), (SF16'), (SF17), (SF17'), or (SF18), wherein the solid formulation contains at least one auxiliary agent selected from the group consisting of dyes, thickeners (such as maltodextrin and glucose syrup), fillers, binders, flavors, antioxidants (other than vitamin E), and pH buffers.

[0156] Therefore, the present invention relates to a solid formulation (SF19) in which the amount of at least one auxiliary agent is up to 35 wt-% based on the total weight of the solid formulation (SF19').

[0157] Particularly suitable adjuvants present in the solid formulation according to the present invention are selected from the group consisting of (dried) glucose syrup, maltodextrin, ascorbic acid, pH buffers, flavors, and / or dyes, preferably from the group consisting of (dried) glucose syrup, maltodextrin, and / or ascorbic acid.

[0158] In all embodiments of the present invention, it is particularly preferable that the liquid and / or solid formulations contain an emulsifier, vitamin E TPGS, and at least one other emulsifier (other than vitamin E TPGS), such as gelatin in particular.

[0159] In all embodiments of the present invention, the use of gelatin having a Bloom value of less than 200, such as in the range of 100 to 200, is particularly preferred.

[0160] In all embodiments of the present invention, it is particularly preferable that the liquid and solid formulations according to the present invention do not contain any further oils after vitamin E, i.e., vitamin E is the only oil used in the preparation process to solubilize at least one cannabinoid present in the formulation according to the present invention.

[0161] Therefore, a particularly preferred formulation according to the present invention is as follows:

[0162] Essentially, (i) 7.5 to 50 wt-%, preferably 10 to 40 wt-%, and most preferably 15 to 30 wt-%, of the total weight of the liquid formulation, (ii) 3 to 20 wt-%, preferably 3 to 15 wt-%, most preferably 3 to 10 wt-%, of vitamin E based on the total weight of the liquid preparation, (iii) 0-5 wt-%, preferably 0-4 wt-%, most preferably 0-3.5 wt-%, vitamin E TPGS, (iv) At least one emulsifier in an amount of 15-50 wt-%, preferably 20-40 wt-%, and most preferably 20-35 wt-%, based on the total weight of the liquid formulation, (v) A glucose syrup in an amount of 1-15 wt-%, preferably 2.5-12 wt-%, most preferably 4-10 wt-%, (vi) 0-5 wt-%, preferably 0-4 wt-%, most preferably 0-3 wt-%, of at least one auxiliary agent selected from the group consisting of antioxidants (other than vitamin E), pH buffers, flavors and / or dyes, (vii) 12 to 55 wt-%, preferably 15 to 50 wt-%, most preferably 15 to 45 wt-%, of water based on the total weight of the liquid formulation It consists of, and based on the total weight of cannabinoids, at least 50 wt-% of at least one cannabinoid is in an amorphous form, and A liquid formulation (A) having a ratio of at least one cannabinoid to vitamin E of 2:1 to 4:1.

[0163] It should be fully understood that all preferences and definitions described herein also apply to liquid formulations (A), in particular, as follows: (a) The emulsifier is selected from gelatin or OSA starch, more preferably the emulsifier is gelatin or a mixture of gelatin and vitamin E TPGS, and / or (b) Vitamin E is (all-rac)-α-tocopherol and / or (c) Gelatin has a Bloom value selected in the range of 100 to 200, and / or (d) At least 75 wt-% of the cannabinoids are in an amorphous form, and / or (e) At least one cannabinoid is CBD, and / or (f) An additional antioxidant (other than vitamin E) is ascorbic acid.

[0164] Essentially, (i) At least one cannabinoid in an amount of 10-40 wt-%, preferably 15-35 wt-%, and most preferably 20-30 wt-%, based on the total weight of the liquid formulation, (ii) Based on the total weight of the liquid preparation, 3 to 20 wt-%, preferably 4 to 15 wt-%, and most preferably 5 to 15 wt-%, of vitamin E, (iii) 0-5 wt-%, preferably 0-4 wt-%, most preferably 0-3.5 wt-%, vitamin E TPGS, (iv) 15-50 wt-%, preferably 20-40 wt-%, most preferably 20-35 wt-% of gelatin based on the total weight of the liquid formulation, (v) A glucose syrup in an amount of 1-15 wt-%, preferably 2.5-12 wt-%, most preferably 4-10 wt-%, (vi) 0-5 wt-%, preferably 0-4 wt-%, most preferably 0-3 wt-%, of at least one auxiliary agent selected from the group consisting of antioxidants (other than vitamin E), pH buffers, flavors and / or dyes, (vii) 12 to 45 wt-%, preferably 15 to 40 wt-%, most preferably 15 to 35 wt-%, of water based on the total weight of the liquid formulation It consists of, and based on the total weight of cannabinoids, at least 50 wt-% of at least one cannabinoid is in an amorphous form, and A liquid formulation (B) having a ratio of at least one cannabinoid to vitamin E of 2:1 to 4:1.

[0165] Again, it should be fully understood that all preferences and definitions described herein also apply to liquid formulations (B), in particular, as follows: (g) The emulsifier is a mixture of gelatin and vitamin E TPGS, and / or (h) at least 75 wt-%, preferably at least 85 wt-%, most preferably at least 95 wt-%, for example at least 99 wt-%, of the cannabinoids is in an amorphous form, and / or (i) Vitamin E is (all-rac)-α-tocopherol and / or (j) Gelatin has a selected Bloom value in the range of 100 to 200, and / or (k) At least one cannabinoid is CBD, and / or (l) An additional antioxidant (other than vitamin E) is ascorbic acid.

[0166] Essentially, (i) At least one cannabinoid in an amount of 10-50 wt-%, preferably 20-45 wt-%, and most preferably 30-40 wt-%, based on the total weight of the solid formulation, (ii) Based on the total weight of the solid formulation, 3 to 20 wt-%, preferably 3 to 15 wt-%, and most preferably 5 to 15 wt-%, of vitamin E, (iii) 0 to 7.5 wt-%, preferably 0 to 7 wt-%, most preferably 0 to 5.5 wt-%, of vitamin E TPGS based on the total weight of the solid formulation, (iv) At least one emulsifier (other than vitamin E TPGS) in an amount of 15-50 wt-%, preferably 20-40 wt-%, and most preferably 20-35 wt-%, based on the total weight of the solid formulation, (v) 1 to 20 wt-%, preferably 5 to 20 wt-%, most preferably 5 to 15 wt-%, of glucose syrup based on the total weight of the solid formulation, (vi) 0 to 5 wt-%, preferably 0 to 4 wt-%, most preferably 0 to 3 wt%, of the total weight of the solid formulation, at least one auxiliary agent selected from the group consisting of antioxidants (other than vitamin E), pH buffers, flavors and / or dyes, (vii) Based on the total weight of the solid formulation, 0 to 15 wt-%, preferably 2.5 to 10 wt-%, most preferably 5 to 10 wt-%, of the carrier, (viii) Less than 5 wt-% of water, preferably 0 to 3.5 wt-% of the total weight of the solid formulation and It consists of, and based on the total weight of cannabinoids, at least 50 wt-% of at least one cannabinoid is in an amorphous form, and A solid formulation (C) having a ratio of at least one cannabinoid to vitamin E of 2:1 to 4:1.

[0167] It should be fully understood that all preferences and definitions described herein also apply to solid formulations (C), in particular, as follows: (a) The emulsifier is selected from gelatin or OSA starch, more preferably the emulsifier is gelatin or a mixture of gelatin and vitamin E TPGS, and / or (b) Vitamin E is (all-rac)-α-tocopherol and / or (c) Gelatin has a Bloom value selected in the range of 100 to 200, and / or (d) The carrier is maltodextrin, corn starch, or silica, and / or (e) At least 75 wt-% of the cannabinoids are in an amorphous form, and / or (f) At least one cannabinoid is CBD, and / or (g) The additional antioxidant (other than vitamin E) is ascorbic acid, and / or (h) The solid dosage form is a spray-dried solid dosage form.

[0168] Essentially, (i) At least one cannabinoid in an amount of 10-50 wt-%, preferably 20-45 wt-%, and most preferably 30-40 wt-%, based on the total weight of the solid formulation, (ii) Based on the total weight of the solid formulation, 3 to 20 wt-%, preferably 4 to 15 wt-%, and most preferably 5 to 15 wt-%, of vitamin E, (iii) 0 to 5.5 wt-%, preferably 1 to 5.5 wt-%, most preferably 2.5 to 5.5 wt-%, of the total weight of the solid formulation, and (iv) At least one type of gelatin in an amount of 15-50 wt-%, preferably 20-40 wt-%, and most preferably 20-35 wt-%, based on the total weight of the solid formulation, (v) A glucose syrup in an amount of 1 to 15 wt-%, preferably 2.5 to 12 wt-%, most preferably 4 to 10 wt-%, based on the total weight of the solid formulation, (vi) 0 to 5 wt-%, preferably 0 to 4 wt-%, most preferably 0 to 3 wt%, of the total weight of the solid formulation, at least one auxiliary agent selected from the group consisting of antioxidants (other than vitamin E), pH buffers, flavors and / or dyes, (vii) Based on the total weight of the solid formulation, 0 to 15 wt-%, preferably 3 to 10 wt-%, and most preferably 5 to 10 wt-%, of the carrier, (viii) Less than 5 wt-% of water, preferably 0 to 3.5 wt-% of the total weight of the solid formulation and It consists of, and based on the total weight of cannabinoids, at least 50 wt-% of at least one cannabinoid is in an amorphous form, and A solid formulation (D) having a ratio of at least one cannabinoid to vitamin E of 2:1 to 4:1.

[0169] Again, it should be fully understood that all preferences and definitions described herein also apply to solid formulations (D), in particular, as follows: (a) The emulsifier is a mixture of gelatin and vitamin E TPGS, and / or (b) at least 75 wt-%, preferably at least 85 wt-%, most preferably at least 95 wt-%, for example at least 99 wt-%, of which at least cannabinoids are in an amorphous form, and / or (c) Vitamin E is (all-rac)-α-tocopherol and / or (d) Gelatin has a Bloom value in the range of 100 to 200, and / or (e) The carrier is maltodextrin, corn starch or silica, and / or (f) At least one cannabinoid is CBD, and / or (g) The additional antioxidant (other than vitamin E) is ascorbic acid, and / or (h) The solid dosage form is a spray-dried solid dosage form.

[0170] In all embodiments of the present invention, a further advantage is essentially that (i) Based on the total weight of the solid formulation, 30-45 wt-% CBD, (ii) Based on the total weight of the solid preparation, 5-15 wt-% of vitamin E, (iii) Based on the total weight of the solid formulation, 0-5.5 wt-% of vitamin E TPGS, (iv) 20-35 wt-% gelatin based on the total weight of the solid formulation, (v) Based on the total weight of the solid formulation, 4-10 wt-% glucose syrup, (vi) 0 to 3 wt% of additional antioxidants (other than vitamin E) based on the total weight of the solid formulation, preferably ascorbic acid and (vii) Based on the total weight of the solid formulation, 0-10 wt-% maltodextrin, (viii) less than 5 wt-% water based on the total weight of the solid formulation This is a solid formulation (E) consisting of the following.

[0171] In all embodiments of the present invention, the most preferred is essentially, (i) Based on the total weight of the solid formulation, 35-42 wt-% CBD, (ii) Based on the total weight of the solid preparation, 5-15 wt-% of vitamin E, (iii) Based on the total weight of the solid formulation, 2.5 to 5.5 wt-% of vitamin E TPGS, (iv) 25-35 wt-% gelatin based on the total weight of the solid formulation, (v) Based on the total weight of the solid formulation, 4-10 wt-% glucose syrup, (vi) 0 to 3 wt% of additional antioxidants (other than vitamin E) based on the total weight of the solid formulation, preferably ascorbic acid and (vii) Based on the total weight of the solid formulation, 0-10 wt-% maltodextrin, (viii) less than 5 wt-% water based on the total weight of the solid formulation This is a solid formulation (F) consisting of the following.

[0172] Another advantageous solid formulation according to the present invention is essentially, (i) Based on the total weight of the solid formulation, 35-42 wt-% CBD, (ii) Based on the total weight of the solid preparation, 5-15 wt-% of vitamin E, (iii) Based on the total weight of the solid formulation, 2.5 to 5.5 wt-% of vitamin E TPGS, (iv) 25-35 wt-% gelatin based on the total weight of the solid formulation, (v) Based on the total weight of the solid formulation, 4-10 wt-% glucose syrup, (vi) 1 to 3 wt% of additional antioxidants (other than vitamin E) based on the total weight of the solid formulation, preferably ascorbic acid and (vii) Based on the total weight of the solid formulation, 0-10 wt-% maltodextrin, (viii) less than 5 wt-% water based on the total weight of the solid formulation It is a solid formulation (G) consisting of the following.

[0173] When used in connection with the present invention, the term "essentially consisting of" means that the addition of wt-% of the listed components is limited to a total of 100 wt-%. However, it cannot be ruled out that small amounts of impurities may be present, such as less than 5 wt-%, preferably less than 3 wt-%, introduced by the raw materials or processes used.

[0174] The term "less than 5 wt-% water" refers to any amount selected within the range of 0 to <5 wt-%, for example, 0 to 4.999 wt-%, based on the total weight of the solid formulation. Particularly advantageous formulations according to the present invention contain 1 to <5 wt-%, 2 to <5 wt-%, or 2.5 to <5 wt-%, based on the total weight of the solid formulation, of water.

[0175] The solid formulation according to the present invention is preferably in the form of particles having a particle size of less than 1.5 mm, and more preferably less than 1 mm. The particle size of the solid formulation can be determined, for example, by sieving using a standard method in the art.

[0176] In another preferred embodiment, the solid formulation according to the present invention is incorporated into a dosage form suitable for oral administration, such as tablets (e.g., orally dispersible tablets, chewable tablets, film-coated tablets, immediate-release tablets, extended-release tablets, or sustained-release tablets), capsules, orally dispersible films, or gummies.

[0177] The amount of the solid formulation of the present invention incorporated into such an oral dosage form is preferably selected in the range of 10 mg to 500 mg.

[0178] To prepare a solid dosage form according to the present invention, the solid dosage form according to the present invention may be mixed with excipients known in the art, such as the following: • Diluents, such as lactose, starch, microcrystalline cellulose, sorbitol, mannitol, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate, sucrose-based diluents, and mixtures thereof; • Binders, such as acacia, cellulose derivatives, gelatin, glucose, polyvinylpyrrolidone, starch, sucrose, sorbitol, tragacanth, sodium alginate, and mixtures thereof; • Disintegrants, such as microcrystalline cellulose and cellulose derivatives, starch and its derivatives, alginic acid and its derivatives, ion exchange resins, cross-linked sodium carboxymethylcellulose, sodium starch glycolate, cross-linked polyvinylpyrrolidone, and formaldehyde-casein; Lubricants, anti-adhesion agents and lubricants, such as magnesium stearate, calcium and sodium stearate, stearic acid, hydrogenated castor oil, talc, water, polyethylene glycol, sodium lauryl sulfate, magnesium lauryl sulfate, and silica.

[0179] Liquid formulations according to the present invention, for example, liquid formulations [(LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), (LF16'), (LF17), (LF17'), (LF18), (LF19), (LF19'), (LF20) or (LF20')], and solid formulations according to the present invention [(SF), (SF'), (SF' (SF''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), (SF15'), (SF16), (SF16'), (SF17), (SF17'), (SF18), (SF19), or (SF19') can be used in a variety of application areas such as food, feed, nutritional supplements, pharmaceuticals, and personal care products.

[0180] These formulations can be in any form (e.g., solid, liquid, or gel-like).

[0181] At least one liquid formulation according to the present invention, for example, a liquid formulation [(LF), (LF1), (LF1'), (LF1''), (LF2), (LF2'), (LF2''), (LF3), (LF4), (LF5), (LF6), (LF7), (LF8), (LF9), (LF10), (LF11), (LF12), (LF13), (LF14), (LF15), (LF16), (LF16'), (LF17), (LF17'), (LF18), (LF19), (LF19'), (LF20 or (LF20')] and / or at least one solid formulation according to the present invention. Foods, feeds, nutritional supplements, pharmaceuticals, and personal care products containing [(SF), (SF'), (SF''), (SF'''), (SF1), (SF1'), (SF1''), (SF2), (SF2'), (SF2''), (SF3), (SF4), (SF5), (SF6), (SF7), (SF8), (SF9), (SF10), (SF11), (SF12), (SF13), (SF14), (SF15), (SF15'), (SF16), (SF16'), (SF17), (SF17'), (SF18), (SF19), or (SF19')] are preferred.

[0182] The present invention also relates to the following embodiments.

[0183] 1. (i) Based on the total weight of the solid formulation, at least one cannabinoid in an amount of 10-50 wt-% (ii) Based on the total weight of the solid preparation, 3 to 20 wt-% of vitamin E, (iii) Based on the total weight of the solid formulation, 0-7.5 wt-% of vitamin E TPGS, (iv) Based on the total weight of the solid formulation, at least one emulsifier (other than vitamin E TPGS) in an amount of 15-50 wt-%, (v) At least one adjuvant in an amount of 1 to 40 wt-% based on the total weight of the solid dosage form, (vi) less than 5 wt-% water based on the total weight of the solid formulation It contains, and at least 50 wt-% of the total weight of cannabinoids is in an amorphous form, and A solid formulation having a ratio of at least one cannabinoid to vitamin E of 2:1 to 10:1, preferably 2:1 to 4:1.

[0184] 2. (i) Based on the total weight of the solid formulation, at least one cannabinoid in an amount of 10-50 wt-% (ii) Based on the total weight of the solid preparation, 3 to 20 wt-% of vitamin E, (iii) Based on the total weight of the solid formulation, 0-7.5 wt-% of vitamin E TPGS, (iv) Based on the total weight of the solid formulation, at least one emulsifier (other than vitamin E TPGS) in an amount of 15-50 wt-%, (v) At least one adjuvant in an amount of 1 to 40 wt-% based on the total weight of the solid dosage form, (vi) less than 5 wt-% water based on the total weight of the solid formulation It contains, and at least 50 wt-% of the total weight of cannabinoids is in an amorphous form, and A solid formulation according to Embodiment 1, wherein the ratio of at least one cannabinoid to vitamin E is 2:1 to 10:1, preferably 2:1 to 4:1.

[0185] 3. A solid formulation according to Embodiment 2, wherein the formulation essentially consists of components (i) to (vi).

[0186] 4. A solid formulation according to any one of Embodiments 1 to 3, wherein the amount of at least one cannabinoid is selected in the range of 20 to 45 wt-%, preferably in the range of 30 to 45 wt-%, and most preferably in the range of 35 to 40 wt-%, based on the total weight of the solid formulation.

[0187] 5. A solid formulation according to any one of Embodiments 1 to 3, wherein the amount of vitamin E is selected in the range of 3 to 15 wt-%, preferably 5 to 15 wt-%, based on the total weight of the solid formulation.

[0188] 6. A solid formulation according to any of Embodiments 1 to 5, wherein the amount of vitamin E TPGS is selected from 0 to 7 wt-%, preferably from 0 to 5.5 wt-%, and more preferably from 2 to 5.5 wt-%, based on the total weight of the solid formulation.

[0189] 7. A solid formulation according to any one of Embodiments 1 to 6, wherein the amount of emulsifier is selected in the range of 20 to 40 wt-%, preferably 20 to 35 wt-%, based on the total weight of the solid formulation.

[0190] 8. A solid formulation according to any of Embodiments 1 to 6, wherein the amount of at least one auxiliary agent is selected in the range of 5 to 34 wt-%, preferably in the range of 5 to 28 wt-%.

[0191] 9. A solid formulation according to any of Embodiments 1 to 8, wherein the amount of water is selected in the range of 0 to less than 5 wt-% based on the total weight of the solid formulation.

[0192] 10. A solid formulation according to any one of Embodiments 1 to 9, wherein at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, delta-9-tetrahydrocannabihoral, tetrahydrocannabivarin, endocannabinoids, and endocannabinoids.

[0193] 11. A solid formulation according to any one of Embodiments 1 to 10, wherein at least one cannabinoid is cannabidiol.

[0194] 12. A solid formulation according to any of Embodiments 1 to 11, wherein vitamin E is (all-rac)-α-tocopherol.

[0195] 13. A solid formulation according to any of Embodiments 1 to 12, wherein the emulsifier is gelatin (bovine, fish, pig, poultry, preferably pig) or modified (OSA) starch.

[0196] 14. A solid formulation according to Embodiment 13, wherein the gelatin has a Bloom value of less than 200, preferably selected in the range of 100 to 200.

[0197] 15. A solid formulation according to any of Embodiments 1 to 14, wherein at least one auxiliary agent is selected from the group consisting of dyes, thickeners, carriers, fillers, binders, flavors, antioxidants (other than vitamin E), and pH buffers.

[0198] 16. A solid formulation according to any of Embodiments 1 to 15, wherein at least one auxiliary agent is selected from the group consisting of thickeners, carriers, and antioxidants (other than vitamin E).

[0199] 17. A solid formulation according to Embodiment 16, wherein the thickener is selected from the group consisting of (dried) glucose syrup, maltodextrin, and mixtures thereof.

[0200] 18. A solid formulation according to Embodiment 16 or 17, wherein the carrier is selected from the group consisting of maltodextrin, corn starch, and / or silica.

[0201] 19. A solid formulation according to Embodiment 17, 18, or 19, wherein an additional antioxidant is selected from the group of sulfites and / or ascorbic acid, preferably the additional antioxidant is ascorbic acid.

[0202] 20. A solid formulation according to any one of Embodiments 1 to 19, wherein at least one auxiliary agent comprises at least one thickener and at least one antioxidant (other than vitamin E), more preferably at least one thickener, at least one carrier and at least one antioxidant (other than vitamin E).

[0203] 21. A solid formulation according to any of Embodiments 17 to 20, wherein the amount of glucose syrup in the solid formulation is selected from 1 to 20 wt-%, preferably 5 to 20 wt-%, and most preferably 5 to 15 wt-%, based on the total weight of the solid formulation.

[0204] 22. A solid formulation according to any of Embodiments 17 to 21, wherein the amount of maltodextrin in the solid formulation is selected from 2.5 to 15 wt-%, preferably 3 to 10 wt-%, and most preferably 5 to 10 wt-%, based on the total weight of the solid formulation.

[0205] 23. A solid formulation according to any of Embodiments 17 to 22, wherein the amount of an additional antioxidant in the solid formulation, preferably ascorbic acid, is selected in the range of 1 to 3 wt-% based on the total weight of the solid formulation.

[0206] 24. A solid formulation according to any one of Embodiments 1 to 23, wherein the solid formulation is a spray-dried solid formulation.

[0207] 25. A solid formulation according to any of Embodiments 1 to 24, wherein at least 75 wt-% of the cannabinoid is in an amorphous form.

[0208] 26. Use of solid formulations in any of Embodiments 1 to 25 in foods, feed products, nutritional supplements, pharmaceutical compositions, and personal care products.

[0209] 27. Use of a formulation according to any of Embodiments 1 to 25 in a pharmaceutical product.

[0210] 28. Foods, feed products, nutritional supplements, pharmaceuticals and personal care products comprising a formulation according to any of Embodiments 1 to 27.

[0211] 29. A pharmaceutical product according to Embodiment 28, which is in the form of a tablet, capsule, oral dispersion film, or gummy, preferably a tablet or capsule.

[0212] 30. Use of vitamin E, preferably (all-rac)-α-tocopherol, to enhance the bioavailability of at least one cannabinoid, preferably cannabidiol, in the form of a solid formulation, most preferably according to any one of Embodiments 1 to 25.

[0213] 31. Use of vitamin E to reduce or inhibit crystal formation of at least one cannabinoid, preferably cannabidiol, in the form of a solid formulation, most preferably one of Embodiments 1 to 25.

[0214] 32. A method for preparing a solid formulation according to any of Embodiments 1 to 25, (i) Solubilizing at least one cannabinoid in vitamin E, followed by optionally adding vitamin E TGPS to form a lipid phase, (ii) The step of solubilizing at least one emulsifier (other than vitamin E TGPS) and one or more auxiliary agents optionally in water to form an aqueous phase, followed by, (iii) The step of emulsifying the lipid phase in the aqueous phase, followed by, (vi) The step of drying the emulsion Methods that include...

[0215] 33. A method according to Embodiment 32, wherein step (i) is performed at a temperature selected in the range of 60 to 100°C, preferably 65 to 90°C, and most preferably 70 to 80°C.

[0216] 34. A method according to Embodiment 32 or 33, wherein emulsification is performed at a temperature selected in the range of 60 to 100°C, more preferably 65 to 90°C, and most preferably 70 to 80°C.

[0217] 35. A method according to any of Embodiments 32 to 34, wherein drying is by spray drying, and preferably maltodextrin is used as an auxiliary (carrier) agent.

[0218] 36. A solid formulation, as per any one of the above claims, in which the degree of crystallinity (%) is determined by DSC using crystalline cannabinoids as an external standard.

[0219] It is understood that all definitions and preferences outlined herein also apply to embodiments 1 to 35.

[0220] A more preferred embodiment is as follows:

[0221] 1a. (i) Based on the total weight of the liquid formulation, at least one cannabinoid in an amount of 5 to 85 wt-%, (ii) Based on the total weight of the liquid preparation, 2 to 25 wt-% of vitamin E, (iii) At least one emulsifier in an amount of 1 to 50 wt-% based on the total weight of the liquid formulation, (iv) 12-55 wt-% water based on the total weight of the liquid preparation It contains, and at least 50 wt-% of the total weight of cannabinoids, at least one cannabinoid, is in an amorphous form, and A liquid formulation having a ratio of at least one cannabinoid to vitamin E of 2:1 to 4:1.

[0222] 2a. A liquid formulation according to Embodiment 1a, wherein at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, delta-9-tetrahydrocannabihoral, tetrahydrocannabivarin, endocannabinoids, and endocannabinoids.

[0223] 3a. A liquid formulation according to Embodiment 1a or Embodiment 2a, wherein the amount of at least one cannabinoid in the formulation according to the present invention is 10 to 85% by weight based on the total weight of the liquid formulation.

[0224] 4a. A liquid formulation according to any of the above embodiments (1a to 3a), wherein at least 55 wt-% of one type of cannabinoid is in an amorphous form, based on the total weight of the cannabinoids.

[0225] 5a. A liquid formulation according to any of the above embodiments (1a to 4a), wherein vitamin E is (all-rac)-α-tocopherol.

[0226] 6a. A liquid formulation according to any of the above embodiments (1a to 5a), wherein the vitamin E content is 3 to 20 wt.-% based on the total weight of the liquid formulation.

[0227] 7a. At least one emulsifier is used in processed (food) starch, vitamin E TPGS, ascorbyl palmitate, pectin, alginic acid, carrageenan, furceran, dextrin derivatives, cellulose and cellulose derivatives (e.g., cellulose acetate, methylcellulose, hydroxypropyl methylcellulose), lignosulfonates, polysaccharide gums (e.g., acacia gum (= acacia gum), modified acacia gum, TIC gum, flaxseed gum, ghati gum, tamarind gum and arabinogalactan), gelatin (beef, fish, pork, poultry), and vegetable protein (e.g., pea, soybean, hi). A liquid formulation according to any of the above embodiments (1a to 6a), selected from the group consisting of mash, cotton, potato, sweet potato, manioc, rapeseed, sunflower, sesame, flaxseed, safflower, lentil, nuts, wheat, rice, corn, barley, rye, oat, lupin, and sorghum), animal protein including milk or whey protein, lecithin, polyglycerol esters of fatty acids, monoglycerides of fatty acids, diglycerides of fatty acids, sorbitan esters, and sugar esters (and derivatives thereof).

[0228] 8a. A liquid formulation according to any of the above embodiments (1a to 7a), comprising at least one auxiliary agent selected from the group consisting of dyes, thickeners, fillers, binders, flavors, antioxidants, and pH buffers.

[0229] 9a. A liquid formulation according to Embodiment 8a, wherein the amount of at least one auxiliary agent is up to 40 wt-% based on the total weight of the liquid formulation.

[0230] 10a. (i) Based on the total weight of the solid dosage form, at least one cannabinoid in an amount of 5 to 85 wt-%, (ii) Based on the total weight of the solid preparation, 2 to 25 wt-% of vitamin E, (iii) Based on the total weight of the solid dosage form, at least one emulsifier in an amount of 1 to 50 wt-%, (iv) at least one adjuvant in an amount of up to 40 wt-% based on the total weight of the solid dosage form, (v) less than 5 wt-% water based on the total weight of the solid dosage form It contains, and at least 50 wt-% of the total weight of cannabinoids, at least one cannabinoid, is in an amorphous form, and A solid formulation having a ratio of at least one cannabinoid to vitamin E of 2:1 to 4:1.

[0231] 11a. A solid formulation according to Embodiment 10a, wherein the water content is less than 3 wt-% based on the total weight of the solid formulation.

[0232] 12a. A solid formulation according to Embodiment 10a or Embodiment 11a, wherein at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, and delta-9-tetrahydrocannabihoral.

[0233] 13a. Use of formulations according to any of the above embodiments in food, feed products, nutritional supplements, pharmaceutical compositions and personal care products.

[0234] 14a. Use of a formulation according to any of the above embodiments 1a to 12a in a pharmaceutical composition.

[0235] 15a. Foods, feed products, nutritional supplements, pharmaceuticals, and personal care products comprising a formulation according to any of the embodiments 1a to 12a described above.

[0236] 16a. A pharmaceutical composition comprising a formulation according to any of the embodiments 1a to 12a described above.

[0237] The following examples are provided to further illustrate the compositions and effects of the present invention. These examples are for illustration only and are not intended to limit the scope of the present invention in any way.

[0238] All parts and percentages in the examples are related to weight (unless otherwise specified), and temperatures are in °C (unless otherwise specified).

[0239] [Examples] [General Method] The crystallinity of the solid formulations was measured using a differential scanning calorimeter (DSC) as outlined below.

[0240] External standard: Crystalline CBD (1 - 2 mg) was placed in an aluminum pan and sealed (external standard). An empty pan was used as a reference. Each sample was heated from 10°C to 90°C at 10°C / min and then cooled to 10°C at 10°C / min. Crystalline CBD showed a heat transition peak (melting point) at approximately 68°C.

[0241] Each powder (solid) formulation was measured evenly using approximately 8 - 10 mg of each sample.

[0242] Next, the peak area of each sample was referenced to the peak area of the external standard sample, and the amount of crystals in each sample was calculated as a percentage of the crystallinity of each sample.

[0243] All particle sizes were determined using Beckmann Coulter, Delsa Nano S (dynamic light scattering).

[0244] Bioavailability was tested using the Caco - 2 model as detailed below.

[0245] Figure 1: DSC thermogram of the solid formulation of Example 2 (y - axis: Heat flow (normalized) (W / g); x - axis: Temperature (°C)) Solid line: t = 0 (immediately after manufacture) Dashed line: After storage at 5°C for 12 months Dotted line: After 12 months of storage at 25°C Breaked line: After 12 months of storage at 40°C.

[0246] DSC analysis showed no crystallization peaks even after storage at low temperatures. This demonstrates the excellent stability of the solid formulation according to the present invention.

[0247] [Example 1] (i) For the preparation of the lipid phase, a total of 95 g of CBD was dispersed in 40.5 g of (all-rac)-α-tocopherol at 75°C, stirring until completely dissolved.

[0248] The lipid phase was kept warm until dispersion into the aqueous phase was complete.

[0249] (ii) For the preparation of the aqueous phase, a total of 123 g of porcine gelatin and Bloom 140 were hydrated and dissolved in 167.5 g of warm water (40°C). Then, 23.5 g of dry glucose syrup DE2023 was added, and the solution was heated to the processing temperature of 75°C.

[0250] (iii) The heated aqueous phase was stirred, and the heated lipid phase was slowly added. Homogenization was carried out at a high temperature (approximately 75°C) to form a liquid formulation. No crystals were observed in the liquid formulation (visual evaluation).

[0251] After adjusting the viscosity with water (approximately 440g), the emulsion was spray-dried using maltodextrin as a carrier (approximately 6%) at an inlet temperature of approximately 180°C and an outlet temperature of 80°C.

[0252] A fine, fluid powder containing approximately 2.5% residual water and 32.8% CBD was obtained. DSC analysis revealed that more than 99% of the CBD was in an amorphous form (i.e., no crystals were detected).

[0253] [Example 2] (i) For the preparation of the lipid phase, a total of 95 g of CBD was dispersed in 40.5 g of (all-rac)-α-tocopherol at 75°C, stirring until completely dissolved. Then, 1.51 g of vitamin E TPGS was added to the warm (75°C) CBD / (all-rac)-α-tocopherol mixture and homogenized.

[0254] The lipid phase was kept warm until dispersion into the aqueous phase was complete.

[0255] (ii) For the preparation of the aqueous phase, a total of 123 g of porcine gelatin and Bloom 140 were hydrated and dissolved in warm water (40°C). Subsequently, 31.5% dry glucose syrup DE2023 was added, and the solution was heated to the processing temperature of 75°C.

[0256] (iii) The heated aqueous phase was stirred, and the heated lipid phase was slowly added. Homogenization was carried out at a high temperature of approximately 75°C for 40 minutes to form a liquid formulation. No crystals were observed in the liquid formulation (visual evaluation).

[0257] After adjusting the viscosity with water, the emulsion was spray-dried using maltodextrin as a carrier (approximately 6%) at an inlet temperature of approximately 180°C and an outlet temperature of 80°C.

[0258] A fine, fluid powder containing approximately 2.5% residual water and 32.6% CBD was obtained, and DSC analysis revealed that more than 99% of the CBD was in an amorphous form (i.e., below the detection limit (bld)). As shown in Figure 1, the sample remained stable, meaning it did not show crystal formation even after storage at various temperatures, as determined by DSC measurements after 12 months of storage at 5°C, 25°C, and 40°C.

[0259] [Table 1]

[0260] As can be seen from Table 1, the particle size was significantly reduced by the addition of vitamin E TPGS. Furthermore, no crystal formation was observed in either the liquid or solid form.

[0261] [Example 3] Using the components outlined in Table 2, a 40% CBD powder (solid) formulation was prepared in the same manner as in Example 2. Again, no crystal formation was observed in the liquid formulation (visual evaluation). A fine-flowable powder containing approximately 2.5% residual water and 40.7% CBD was obtained, and when measured by DSC, more than 99% of the CBD was in the amorphous form. The solid powder maintained stable open storage.

[0262]

Table 2

[0263]

Table 3

[0264]

Table 4

[0265] As can be seen from Table 2b, increasing the amount of vitamin E TPGS up to >7 wt-% increases the adhesiveness of the formulation, which is undesirable as it affects the handling properties.

[0266] As can be seen from Table 2c, increasing the ratio up to 7:1 led to crystal formation compared to the solid formulation with a ratio of 4:1 that did not show crystal formation.

[0267] [Example 4] Using the components outlined in Table 3, CBD liquid and powder (solid) formulations were prepared in the same manner as in Example 1, using OSA starch instead of gelatin. Again, no crystal formation was observed in the liquid formulation (visual evaluation).

[0268]

Table 5

[0269] As can be seen from Table 3, in contrast to gelatin, some crystal formation occurred when OSA starch was used.

[0270] [Example 4: Bioavailability] To compare the effect of oil on the bioavailability of CBD, CBD powder (solid) formulations (beadlets) containing approximately 12–16 wt-% CBD and a particle size distribution of approximately 200 nm were prepared using various oils outlined below. Liquid formulations were prepared in the same manner as in Example 1 above. Subsequently, each beadlet was prepared by spraying the liquid formulation into a fluid bed using natural corn starch. The amount of each oil was selected to ensure complete dissolution of CBD in the oil.

[0271] [Table 6]

[0272] Bioavailability was tested using the Caco-2 bioavailability assay outlined below.

[0273] [·Cell culture preparation] Caco-2 ECACC 86010202 (European Collection of Cell Cultures, Salisbury, UK) cells were cultured at 37°C under a 5% CO2 atmosphere in DMEM medium supplemented with 4.5 g / L D-glucose, 4 mM L-glutamine, 1 mM sodium pyruvate, 1% MEM non-essential amino acids, 50 μg / mL gentamicin (Life Technologies Europe BV, Zug, Switzerland), and heat-inactivated FBS (Sigma-Aldrich, Buchs, Switzerland). Subconfluent cells were trypsinized using 0.25% trypsin / EDTA (Life Technologies Europe BV, Zug, Switzerland).

[0274] [Caco-2 Bioavailability Assay] Cells were seeded at a density of 70,000 cells / well in a 12-well cellQART® cell culture insert with a PET membrane, 0.4 μm pore size, and a cell growth area of ​​1.1 cm² / well (SABEU, Northeim, Germany). The culture medium was changed every 2-3 days. After 21 days of culture, the barrier integrity of the differentiated cell monolayer grown on the insert plate was confirmed by measuring transepithelial electrical resistance (TEER) using an EVOM2 voltanmeter (World Precision Instruments, Berlin) equipped with an STX2-PLUS electrode. The TEER value correlates with the airtightness of the confluent monolayer.

[0275] After 21 days, the insert plate was washed twice with HBSS solution (HBSS pH 7.4 containing Ca2+ and Mg2+, 5.5 mM D-(+)-glucose, sodium bicarbonate, 4 mM L-glutamine, and 20 mM HEPES, Life Technologies Europe BV, Zug, Switzerland) and incubated in a CO2 incubator at 37°C for 1 hour. A CBD treatment solution was prepared at a concentration of 15 μM in HBSS solution. The treatment solution was applied to the front chamber (200 μL), and 1.5 mL of 4% BSA in HBSS solution was added to the base chamber. The plate was then incubated in a CO2 incubator on an orbital shaker (80 rpm) at 37°C for 3 hours.

[0276] After incubation, buffer solution was collected from the basal (BL) and tip (API) compartments and diluted with acetonitrile for analysis. The cell layer (CL) was washed once with HBSS solution, and then 500 μL of acetonitrile was added to the tip. Cells were scraped from the membrane using a pipette tip and collected for analysis.

[0277] Cannabidiol was quantified by stable isotope dilution LC-MS using an Agilent 1290 Infinity II UHPLC connected to a Bruker Impact II Q-TOF mass spectrometer. Eight cannabidiol calibration curve solutions covering a concentration range of 2.5 ng / ml to 2000 ng / ml in acetonitrile were prepared. A 500 ng / ml solution of deuterium-labeled d3-cannabidiol (CAS number 1435783-16-6) in acetonitrile was used as the internal standard. Before injection, 250 ml of the calibration curve solution was mixed with 25 ml of the internal standard solution. Similarly, 250 ml of centrifuged CaCO2 compartment sample was combined with 25 ml of the internal standard. The analytical column was a Raptor ARC C18 column (2.1 × 150 mm). The mobile phase was water / acetonitrile 24:76 (V / V) containing 5 mM ammonium formate and 0.1% V / V formic acid. Chromatograms were developed isotropically at a flow rate of 0.4 ml / min and a column temperature of 30°C. The injection volume was 1.5 ml. The column effluent was introduced into a VIP-HESI source (Bruker Daltonik GmbH) operating in positive ionization mode. The mass spectrometer operated in full scan mode, scanning the m / z range of 100–1000 at a spectral rate of 4 Hz. High-resolution chromatograms extracted at m / z 315.2319 and m / z 318.2507 were used for quantification with a width of 5 mDa. Calibration curves were established by least squares by plotting the peak area ratio (area sample vs. area internal standard) against the added concentration. Regression calculations of the quantitative data were performed using TASQ 1.4 software (Bruker Daltonik). Table 5 shows the amount of CBD measured as a percentage of the original CBD content from the tip (API), basal (BL) compartments, and cell layer (CL). The cellular permeability (reflecting bioavailability) of CBD is determined by the sum of the amounts measured in the basal compartment and the cell layer (BL+CL). A higher recovery rate indicates higher cellular permeability of CBD.

[0278] [Table 7]

[0279] As can be seen from Table 5, the product form using VIT.E showed the best bioavailability, as the highest levels of CBD were detectable in both the cell lysate (CL) and the basal portion (BL).

[0280] [Example 5: Pharmaceutical composition including a solid formulation according to the present invention] Tablets and capsules using the ingredients outlined in Tables 6, 7, and 8 are prepared using the respective solid formulations of Examples 1, 2, 3a, 3b, 3c, 4, 5, and 6, according to standard methods in the art.

[0281] [Table 8]

[0282] [Table 9]

[0283] [Table 10] [Brief explanation of the drawing]

[0284] [Figure 1] DSC thermogram of the solid formulation in Example 2

Claims

1. (i) 5 to 85 wt-% of at least one cannabinoid based on the total weight of the solid dosage form, (ii) Based on the total weight of the solid preparation, 2 to 25 wt-% of vitamin E, (iii) Based on the total weight of the solid dosage form, at least one emulsifier in an amount of 1 to 50 wt-%, (iv) at least one adjuvant in an amount of up to 40 wt-% based on the total weight of the solid dosage form, (v) less than 5 wt-% water and based on the total weight of the solid dosage form The cannabinoids include, and at least 50 wt-% of the total weight of the cannabinoids, the at least one cannabinoid is in an amorphous form, and A solid formulation wherein the ratio of at least one cannabinoid to vitamin E is 2:1 to 10:1, preferably 2:1 to 4:

1.

2. (i) 10 to 50 wt-% of at least one cannabinoid based on the total weight of the solid formulation, (ii) Based on the total weight of the solid preparation, 3 to 50 wt-% of vitamin E, (iii) Based on the total weight of the solid formulation, 0 to 7.5 wt-% of vitamin E TPGS and (iv) Based on the total weight of the solid formulation, at least one emulsifier (other than vitamin E TPGS) in an amount of 15 to 50 wt-%, (v) At least one adjuvant in an amount of 1 to 40 wt-% based on the total weight of the solid dosage form, (vi) less than 5 wt-% water and based on the total weight of the solid formulation It contains, and at least 50 wt-% of the total weight of the cannabinoids is in an amorphous form, and The solid formulation according to claim 1, wherein the ratio of at least one cannabinoid to vitamin E is 2:1 to 10:1, preferably 2:1 to 4:

1.

3. A solid formulation according to claim 2, which essentially consists of components (i) to (vi).

4. The solid formulation according to any one of claims 1 to 3, wherein the amount of at least one cannabinoid is selected from 20 to 45 wt-%, preferably from 30 to 45 wt-%, and most preferably from 35 to 40 wt-%, based on the total weight of the solid formulation.

5. The solid preparation according to any one of claims 1 to 4, wherein the amount of vitamin E is selected in the range of 3 to 15 wt-%, preferably 5 to 15 wt-%, based on the total weight of the solid preparation.

6. The solid formulation according to any one of claims 1 to 5, wherein the at least one cannabinoid is selected from the group consisting of cannabidiol, tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclan, cannabinodivaline, cannabilipsol, hexahydrocannabinol, delta-9-tetrahydrocannabihoral, tetrahydrocannabivarin, endocannabinoids, and endocannabinoids, and preferably the at least one cannabinoid is cannabidiol.

7. The solid formulation according to any one of claims 1 to 6, wherein the vitamin E is (all-rac)-α-tocopherol.

8. The solid formulation according to any one of claims 1 to 7, wherein the at least one emulsifier is selected from the group consisting of modified (food) starch, gelatin, and a mixture of gelatin and vitamin E TPGS, and preferably the emulsifier consists of a mixture of gelatin and vitamin E TPGS.

9. The solid formulation according to any one of claims 1 to 8, wherein the at least one auxiliary agent is selected from the group consisting of dyes, thickeners, carriers, fillers, binders, flavors, antioxidants and pH buffers, preferably from the group consisting of thickeners, carriers and antioxidants, and most preferably from the group consisting of glucose syrup, maltodextrin, corn starch and / or ascorbic acid.

10. A solid formulation according to any one of claims 1 to 9, which is a spray-dried solid formulation.

11. Use of the formulation according to any one of claims 1 to 10 in food, feed products, nutritional supplements, pharmaceuticals and personal care products.

12. Foods, feed products, nutritional supplements, pharmaceuticals and personal care products comprising a formulation according to any one of claims 1 to 10.

13. The pharmaceutical product according to claim 12, which is in the form of a tablet, capsule, oral dispersion film, or gummy.

14. Use of vitamin E, preferably (all-rac)-α-tocopherol, to enhance the bioavailability of at least one cannabinoid, preferably cannabidiol, in the form of a solid formulation according to any one of claims 1 to 13.

15. A method for preparing a solid formulation according to any one of claims 1 to 10, (i) Solubilizing at least one cannabinoid in vitamin E, followed by optionally adding vitamin E TGPS to form a lipid phase, (ii) A step of solubilizing at least one emulsifier (other than vitamin E TGPS) and one or more auxiliary agents optionally in water to form an aqueous phase, followed by, (iii) The step of emulsifying the lipid phase in the aqueous phase, and subsequently, (iv) A step of drying the emulsion, preferably by spray drying, and more preferably by using maltodextrin as an auxiliary (carrier) agent. Methods that include...

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