Cannabinoid solubilizate

Abstract

In order to quickly provide the highest possible bioavailability of cannabinoids, which in particular are in the form of an isolate, with a stable formulation, the invention provides a solubilizate containing: at least one cannabinoid, in particular cannabinoid isolate; at least one emulsifier having an HLB value in the range of less than 18, preferably between 13 and 18, in particular polysorbate 80 or polysorbate 20 or at least one sugar ester of edible fatty acids or a mixture of at least two emulsifiers selected from the group comprising polysorbate 20, polysorbate 80 and sugar esters of edible fatty acids; and medium-chain triglycerides.

Description

[0001] CANNAB INO ID SOLUB ILI SAT

[0002] The invention relates to a solubilisate with cannabinoids and medium-chain triglyceride according to claim 1. Furthermore, the invention relates to a product containing such a solubilisate, a capsule filled with such a solubilisate and a process for its preparation and the use of the solubilisate for use in the treatment of and / or prevention of sleep disorders (insomnia), depression and / or anxiety states.

[0003] Unsatisfactory sleep duration or quality impairs well-being and performance during the day and can lead to considerable suffering for those affected.

[0004] Such a sleep disorder, which is also known as "insomnia", is present when the symptoms occur three times a week for three months, or when shorter phases occur over several years (see "International Classification of Sleep Disorders" ICSD-3). In these cases, those affected have the impression of insufficient sleep or do not feel rested after the usual amount of sleep.

[0005] The prevalence of insomnia in Germany is between 10 and 50%, with 25 to 30% of the total population affected by occasional insomnia and 10 to 13% by chronic insomnia. Chronic insomnia is associated with, among other things, psychiatric disorders. The risk of depression is increased by 2.6 times. Likewise, the risk of myocardial infarction (heart attack) and stroke is increased by up to 70%. Furthermore, affective disorders / bipolar disorders, anxiety disorders, panic disorders, post-traumatic stress disorders (PTSD), alcohol abuse (alcohol dependence), borderline disorders, dementia, eating disorders and schizophrenia are associated with sleep disorders (information as of December 29, 2022 in http : / / www . gesundheits- lex ikon . com / Schlaf- Schlafs toerungen / Schlaf s toerungen- Insomnie / ).

[0006] A current therapeutic approach for sleep disorders is cannabinoid use. Clinical interest in the therapeutic potential of cannabinoids in treating sleep disorders is increasing. Growing evidence suggests that the endocannabinoid system plays a role in regulating the circadian sleep-wake cycle (see, for example, Isobel Lavender et al., "Cannabinoids, Insomnia, and Other Sleep Disorders" in: Sleep: CHEST Reviews, Volume 162, Issue 2, P452-465, August 1, 2022, https: / / doi.org / 10.1016 / j.chest.2022.04.151.)

[0007] Cannabinoids are transformation products and synthetic analogues of some terpene phenols found primarily in hemp plants (cannabis). The term "hemp plant" or "cannabis plant" encompasses the wild-type Cannabis sativa and its variants, including cannabis chemovars that naturally contain varying amounts of the various cannabinoids, Cannabis sativa subspecies indica, and plants that are the result of genetic crosses, self-crosses, or hybrids. The cannabis plant contains at least 113 cannabinoids from the group of terpene phenols. Some of these cannabinoids are Delta9-Tetrahydrocannabinol (THC), Delta8-Tetrahydrocannabinol, Cannabidiol (CBD), Cannabichromene (CBC), Cannabigerol (CBG), Cannabinol (CN), Delta9-Tetrahydrocannabivarin (THCV), Cannabicyclol (CBL), Cannabielsoin (CBE) , cannabitriol (CBT) and cannabinodiol (CBND) .

[0008] Tetrahydrocannabinol (THC) is a psychoactive substance, primarily responsible for the intoxicating effects of cannabis products. THC naturally occurs in the plant in the form of two THC acids, which are converted into THC when the plant material is heated. Cannabidiol (CBD) is a non-psychoactive cannabinoid that, among other things, also has antispasmodic, anxiolytic, and neuroprotective effects. Cannabichromene (CBC), like CBD, does not have an intoxicating effect. It is primarily thought to have an antidepressant effect. Cannabinol (CBN) is an oxidation product of THC and has an intoxicating effect, as well as pain-relieving, antispasmodic, and sedative effects. Cannabigerol (CBG) is non-psychoactive and is thought to have a greater pain-relieving effect than THC. Tetrahydrocannabivarin (THCV) has a lower psychoactive effect compared to THC and has, among other things, appetite-suppressing and metabolism-stimulating effects.

[0009] Cannabis also contains a variety of non-cannabinoids with diverse pharmacological properties. There is evidence that cannabinoids such as cannabinol (CBN), cannabidiol (CBD), and others modify the effects of α9-THC. Artificial cannabinoids can be produced both semi-synthetically, i.e., from natural cannabinoids, and fully synthetically from simple raw materials. Other plants can also produce active substances that act in the human body via the same mechanisms as the cannabinoids of the hemp plant. For the purposes of this application, the term "cannabinoid" encompasses both natural and artificial cannabinoids.

[0010] To enter the bloodstream after oral administration, the active ingredient must cross the small intestinal blood barrier. It is then metabolized in the liver and excreted as a bioavailable portion in the hepatic vein. The remainder of the total active ingredient ingested and released into the body is either microbially degraded in the intestine or eliminated with the feces or bile.

[0011] The inventor therefore set himself the task of providing a formulation which makes the calming and healing properties of cannabinoids, in particular CBD, in relation to sleep disorders (insomnia), depression and / or anxiety accessible to the human or animal organism in an easy-to-use manner.

[0012] In particular, it is an object of the invention to quickly enable the highest possible bioavailability of cannabinoids.

[0013] The inventor recognized that, unlike other plant extracts, the temporal distribution of absorption rate is of great importance for cannabinoids, and especially CBD. With optimized pharmacokinetics, the effects described above can be achieved as quickly as possible and thus in a targeted manner, rather than undesirably delayed and / or over a longer period of time.

[0014] Cannabinoids are available in various forms. A distillate is a highly refined natural extract that has undergone a distillation process. With a CBD content typically of 75% or more, a CBD distillate, for example, is highly concentrated. Other plant compounds such as flavonoids, terpenes, and cannabinoids (including THC) make up the remainder of the CBD distillate.

[0015] An isolate is the technically purest available form of an active ingredient, in this case a cannabinoid, and essentially contains no other components of the source material. For example, CBD isolate is produced using a natural extraction process that uses CBD distillate. This eliminates all components that give hemp its flavor and aroma. The isolate therefore has no taste or odor. CBD isolate is a crystalline solid. A cannabinoid isolate therefore has the technically maximum possible active ingredient content by mass.

[0016] It is a further object of the invention to provide a stable formulation for cannabinoids, in particular for CBD, which are in the form of an isolate. These objects are achieved in a surprisingly simple manner with a solubilisate according to claim 1 and a process for its production. This solubilisate consists of or contains: at least one cannabinoid, in particular cannabinoid isolate, preferably CBD isolate, at least one emulsifier with an HLB value in the range less than 18, preferably between 13 and 18, in particular polysorbate 80 or polysorbate 20 or at least one sugar ester of fatty acids or a mixture of at least two emulsifiers which are selected from the group comprising polysorbate 20, polysorbate 80 and sugar esters of fatty acids, and medium-chain triglycerides (MCT).

[0017] The components of the solubilisate add up to 100 wt. %. If further possible components of the solubilisate according to the invention are mentioned below, this applies accordingly.

[0018] Medium-chain triglycerides (MCTs) are triglycerides that contain medium-chain fatty acids. Medium-chain fatty acids include caproic acid, caprylic acid, capric acid and lauric acid. These are saturated fatty acids that occur naturally in tropical vegetable fats such as coconut oil and palm kernel oil. They are also found in small amounts in milk fat. Pure MCT oil does not exist in nature, but pure MCT oils can be produced synthetically. For the purposes of the invention, individual MCTs or a mixture of different MCTs can be used as medium-chain triglycerides. Surprisingly, it has been found that the composition according to the invention comprising at least one cannabinoid, emulsifier and medium-chain triglycerides (MCT) provides a stable formulation for cannabinoids, even when these are present in the form of an isolate as a starting material.The cannabinoid is present in the solubilisate according to the invention enclosed in micelles. The micelles can be measured as particles using laser light diffraction, for example, in an aqueous dilution of the solubilisate.

[0019] Unlike an emulsion formulation, in which the active ingredient is dissolved in a liquid phase, particularly an oil, in the form of drops dispersed in another liquid, particularly aqueous, phase, the micellar structure of the solubilizate according to the invention is very stable. The invention thus creates a formulation of product micelles loaded with cannabinoid as the active ingredient, so that the active ingredient is protected from environmental influences and, due to the specific structure of the solubilizate, is highly bioavailable. Bioavailability will be discussed in more detail below.

[0020] This provides a solubilisate which is suitable for the oral absorption of a dose of cannabinoids, in particular CBD, by humans or animals such that their calming and even healing properties with regard to sleep disorders (insomnia), depression and / or anxiety are made accessible to the human or animal organism. One reason for this is the comparatively short time in which a comparatively large amount of cannabinoid from the solubilisate according to the invention is absorbed by the organism. The reference point for the comparison is a solution of the isolate in glycerol. This was demonstrated in an animal study which is discussed in more detail below.

[0021] In a preferred embodiment of the invention, the solubilizate comprises medium-chain triglycerides in a proportion of up to 10 wt.%, preferably between 1 wt.% and 8 wt.%, particularly preferably up to 5 wt.%.

[0022] According to a further development of the invention, the solubilisate may contain as a further component up to 10% by weight, preferably between 1% by weight and 8% by weight, particularly preferably up to 5% by weight of glycerol.

[0023] Depending on the field of application, the solubilisate can be prepared within the scope of the invention with at least one antioxidant. For this purpose, the solubilisate contains up to 5 wt.%, preferably between 0.5 wt.% and 3 wt.%, particularly preferably between

[0024] 1 wt.% and 2 wt.% of at least one antioxidant, preferably at least one tocopherol, particularly preferably mixed tocopherol.

[0025] Within the scope of the invention, the use of alpha-tocopherol and / or beta-tocopherol and / or gamma-tocopherol and / or delta-tocopherol or using mixed tocopherols consisting of alpha-tocopherol, beta-tocopherol, gamma-tocopherol and delta-tocopherol is preferred. It has been shown that the use of the same amount of mixed tocopherols imparts a greater antioxidant potential to the solubilizate according to the invention than the use of, for example, alpha-tocopherol alone. A mixture of alpha-tocopherol, beta-tocopherol, gamma-tocopherol and delta-tocopherol is referred to as "mixed tocopherol" in the context of this description and the appended claims.

[0026] Chemical lipophilic antioxidants can be used in addition to or as an alternative to tocopherol within the scope of the invention. Examples include butylhydroxyanisole (BHA; E320), butylhydroxytoluene (BHT, E321), gallates (E310 to E312), or rosemary extract with the active ingredients carnosol and carnosic acid (E392). The so-called "E numbers" refer to the list of food additives approved by the European Union.

[0027] In order to provide stable micelles of the cannabinoid, the emulsifier content, in particular the polysorbate content, can be at least 70 wt.%, preferably in the range between 75 wt.% and 98 wt.%, particularly preferably in the range between 82 wt.% and 93 wt.%, within the scope of the invention.

[0028] The particularly small size of the micelles in the solubilisate according to the invention results in a clear and permanently transparent product. The solubilisates according to the invention have a narrow particle size distribution with small average particle sizes, even under the physiological conditions of gastric passage. Preferably, the diameter distribution of the micelles in a dilution of the solubilisate with distilled water in a ratio of 1:500 at pH 1.1 and 37°C ranges from approximately d0 5 nm to approximately d0 50 nm, particularly preferably from approximately d0 6 nm to approximately d0 50 nm. These values ​​were determined using a volume distribution.

[0029] The particle size analysis of the micelles in an aqueous dilution of the solubilizate according to the invention was carried out according to the principle of dynamic light scattering using the ParticleMetrix NANOFLEX backscattering particle analyzer. Before dilution, the samples were heated to 37 °C in a water bath and redispersed by shaking and stirring. The samples were then diluted 1:500 with distilled water and heated to 37 °C with constant stirring using a magnetic stirrer plate. The pH was then adjusted to approximately 1.1 using 32% HCl. The samples were then measured immediately.

[0030] An indication of the improved bioavailability compared to compositions of a cannabinoid not micelled according to the invention is provided by the significantly easier measurement-based determination of the turbidity of the solubilisate. Due to the formulation according to the invention, the turbidity of the solubilisate is preferably less than 50 FNU, preferably less than 25 FNU, and particularly preferably less than 15 FNU, measured by scattered light measurement with infrared light in accordance with the provisions of ISO 7027 with a dilution of the solubilisate in a ratio of 1:50 in water. The aqueous dilution of the solubilisate in a ratio of 1:50 has a pH in the range from 6 to 8.

[0031] To experimentally determine the turbidity of the solubilizates according to the invention, the turbidity meters are calibrated with a standard suspension. The reading is therefore not in the form of the measured light intensity, but rather as the concentration of the calibration suspension. When measuring any suspension, the reading means that the liquid in question causes the same light scattering as the standard suspension of the indicated concentration. The internationally established turbidity standard is formazin. Among the most common units is "FNU," which stands for "Formazine Nephelometry Units." This is the unit used, for example, in water treatment for measurements at 90°C according to the specifications of standard EN ISO 7027.

[0032] Regarding bioavailability in mammals, the applicant commissioned a study conducted by Charles River Laboratories Den Bosch BV on male and female Wistar Han rats. Among other things, a CBD solubilizate according to the invention in the form of an isolate was compared with a solution of CBD isolate in glycerol with regard to bioavailability.

[0033] During the study, the animals were kept at a temperature range of 18°C ​​to 24°C with an average of 20°C. The air humidity ranged from 40% to 70% with an average of 48% to 40%. The light cycle was set at 12 hours of light and 12 hours of darkness. The animals were fed SM R / MZ from SSNIFF® Spezialitäten GmbH, Soest, Germany in the form of pellets, as well as water from the municipal water supply. The animals were free to consume food and water ad libitum except for the administration of the active ingredient. For this purpose, food intake was stopped the night before the active ingredient was administered for a maximum of 20 hours, although water intake was still permitted. Food intake could be resumed for 4 hours after dosing.

[0034] A single oral dose of 41.1 mg / kg body weight was administered to 10 animals per test group. Blood samples of 0.2 mL in K2EDTA as anticoagulant were collected via jugular vein puncture at 15 min (0.25 hours), 30 min (0.5 hours), 45 min (0.75 hours), 1, 2, 4, 8, and 24 hours after dosing.

[0035] The samples were centrifuged at approximately 2000 g for 10 minutes within 2 hours at a temperature ranging from 4°C to 8°C. The resulting plasma was separated and frozen in polypropylene tubes immediately over dry ice or in a freezer set to -75°C.

[0036] For pharmacokinetics, the parameters explained in Table 1 were determined.

[0037] No mortality and no clinical signs of toxicity of the solubilisate were observed in the study.

[0038] Table 2 presents the results of the study based on the parameters explained in Table 1. Average values ​​are given for the specified AUG and t max and C max from the data for the 10 animals of each group. Table 1: Pharmacokinetic parameters

[0039] Table 2: Values ​​from the study For the solubilisate according to the invention, the ratio of the respective value for the solubilisate to the value for the CBD isolate dissolved in glycerin is given in the right column of Table 2 as "factor to the value of the solution in glycerin". It is precisely this evaluation that shows a great benefit from the invention. On the one hand, a more than twice as high maximum concentration is achieved after administration of the dose (C max of the solubilizate / C max the solution = 2 , 44 ) .

[0040] Within the scope of the invention, however, it is not primarily the absolute value of Cmax that is decisive, but rather the kinetics of absorption and degradation of the cannabinoid, which is enabled by the formulation according to the invention. This kinetics can be influenced by varying the composition within the scope of the invention and is reflected in the temporal course of the AUC after administration of the solubilisate in a significantly increased rate of absorption compared to the solution of the cannabinoid in glycerol, especially in the first hour after administration of the active ingredient ("onset").

[0041] The AUC (area under the curve) of the plasma concentration-time curve measured up to 30 minutes after oral administration of the solubilisate according to the invention has a value which is 17 to 22 times, preferably 19 to 20 times, higher than after oral administration of the same dose of cannabinoid, in particular cannabinoid isolate, dissolved in glycerol.

[0042] The AUC (area under the curve) of the plasma concentration-time curve measured up to 60 minutes after oral administration of the solubilisate according to the invention has a value which is 14 to 19 times higher, preferably 16 to 17 times higher, than after oral administration of the same dose of cannabinoid, in particular cannabinoid isolate, dissolved in glycerol.

[0043] Furthermore, the highest concentration in the animal study was also reached about three times as quickly, i.e. in about one third of the time (t max the solution / t max of the solubilisate = 2.95). The time t maxThe plasma concentration-time curve after oral administration of a dose of cannabinoid, in particular cannabinoid isolate, in glycerol, at which the maximum concentration in the plasma is reached, therefore has, within the scope of the invention, a value in the range of 1.96 times to 4 times, preferably in the range of 2.8 times to 3.1 times, the value after oral administration of the same dose of cannabinoid, in particular cannabinoid isolate, in the form of the solubilisate according to the invention.

[0044] In particular, the invention enables the use of a solubilisate described above as a medicament, in particular in the treatment of and / or prevention of sleep disorders (insomnia), depression and / or anxiety. After ingesting a dose of the solubilisate, the highest concentration of the cannabinoid is reached within the first hour, thus enabling a rapid effect, in particular a rapid, deep sleep. After the first hour, the

[0045] The concentration of the active ingredient decreases again, thus providing a formulation which allows degradation within a sleep period of, for example, up to 8 hours. In this way, side effects such as daytime fatigue can be avoided by the invention. The solubilisate according to the invention is therefore suitable for use as a dietary supplement and / or as a medicament with an effect against sleep disorders (insomnia), depression and / or anxiety. It also allows the production of a dietary supplement and / or medicament for the treatment of and / or prevention of sleep disorders (insomnia), depression and / or anxiety.

[0046] The significantly improved kinetics of the bioavailability of the cannabinoid in the solubilisate according to the invention compared to the form dissolved in glycerol allows a reduction in the amount of cannabinoid, in particular CBD, that a user has to take orally daily in order to achieve the desired effect.

[0047] In order to enable the oral application of the solubilisate according to the invention in a simpler and more pleasant manner for the consumer or patient, the invention also provides a capsule filled with a solubilisate described above, wherein the capsule is designed as a soft gelatin capsule or hard gelatin capsule or as a soft, gelatin-free capsule or as a hard, gelatin-free capsule such as a cellulose capsule.

[0048] Within the scope of the invention, the solubilisate according to the invention can also be incorporated into other products, in particular fluids, in a particularly simple manner. The small micelles filled with the active ingredient are retained. The fluids can be further processed so that the solubilisate can be used in any formulated product. The "product" within the meaning of the invention encompasses fluids and solids, including products for sucking by the consumer, such as coated tablets or gumdrops.

[0049] Thus, the invention also provides a product containing a solubilisate as described above, wherein the product is selected from the group comprising foodstuffs, dietary supplements, beverages, cosmetics, and pharmaceutical products. In particular, within the scope of the invention, the product may comprise an aqueous dilution of the solubilisate.

[0050] The invention also provides a method for the treatment of and / or prevention of sleep disorders (insomnia), depression and / or anxiety states, in which a solubilisate according to the invention, in particular in a capsule or as a fluid, is administered to the food supplement consumer or patient, in particular orally, in particular once a day.

[0051] It has already been shown to be sufficient if the solubilisate is administered to the consumer or patient in a cannabinoid dose in the range of 5 mg / kg body weight to 8.4 mg / kg body weight, preferably with a dose of 6.7 mg / kg body weight, especially once daily. In this case, the findings on dosage obtained in the animal study were multiplied by a factor of

[0052] Dosage for humans / dosage for rats = 0.16. For a 75 kg person, the dosage corresponds to a dose of 500 mg of cannabinoid, for example, CBD.

[0053] The invention further provides a method for producing a solubilizate as described above, comprising the following steps: a) introducing at least one emulsifier having an HLB value in the range of less than 18, preferably between 13 and 18, in particular polysorbate 80 or polysorbate 20 or at least one sugar ester of fatty acids or a mixture of at least two emulsifiers selected from the group comprising polysorbate 20, polysorbate 80 and sugar esters of fatty acids, b) mixing the emulsifier from step a) with at least one cannabinoid, in particular cannabinoid isolate, and at least one medium-chain triglyceride

[0054] (MCT), wherein at least in step b) heating takes place to a temperature in the range from 82°C to 97°C, preferably to a temperature in the range from 83°C to 92°C, particularly preferably to a temperature in the range from 85°C to 89°C.

[0055] In this way, a solubilisate according to the invention can be produced in a surprisingly simple manner. This production method makes it possible to produce a solubilisate that, in aqueous dilution, can form micelles loaded with at least one cannabinoid as the active ingredient. In step b), the at least one cannabinoid can also be added together with other components, depending on the application and the specific intended formulation for the solubilisate. In particular, premixes of the cannabinoid can be prepared with at least one other component of the solubilisate to be produced and then further processed with the emulsifier and, if necessary, additional components.

[0056] In a further development of the method, before step b) a step bl) mixing of the at least one cannabinoid, in particular cannabinoid isolate, with the at least one medium-chain triglyceride (MCT) takes place.

[0057] Depending on the desired loading and particle size distribution, separate premixing of cannabinoid and MCT may be preferable.

[0058] It has further been found to be advantageous for the production of a mixture which is as uniform as possible if, in step a), heating takes place to a temperature at least in the range from 40°C to 62°C, preferably to a temperature in the range from 45°C to 57°C, particularly preferably to a temperature in the range from 48°C to 52°C.

[0059] In a further embodiment of the invention, glycerin is additionally added to the mixture in step b) and / or step b1). Within the scope of the invention, it is also possible to first prepare a premix of glycerin and cannabinoid. For this purpose, a step b1) of mixing at least one cannabinoid, in particular cannabinoid isolate, with glycerin can be carried out before step b) and / or step b1).

[0060] By adding glycerol, the stability of the micelles of the solubilisate can be improved if necessary.

[0061] Depending on the application and production conditions, it may be helpful to protect the cannabinoid from decomposition, especially when processed as an isolate. For this purpose, a further development of the invention provides for the additional addition of at least one antioxidant, preferably tocopherol, particularly preferably mixed tocopherol, in step a).

[0062] The invention is explained in more detail below using an exemplary embodiment. The following components were used.

[0063] Polysorbate 80

[0064] The material "TEGO SMO 80 V FOOD" from Evonik Nutrition & Gare GmbH, Essen, Germany, was used as the source of polysorbate 80. This product complies with EU requirements for food additive E 433. Alternatively, the product Grillet 4 / Tween 80-LQ- (SG) from CRODA GmbH, Nettetal, Germany, can also be used.

[0065] Within the scope of the invention, in addition to or as an alternative to polysorbate 80, polysorbate 20 and / or sugar esters of fatty acids could also be used as an emulsifier. One possible source for polysorbate 20 is, for example, the material "TEGO SML 20 V FOOD" with the specification code "K09 EU-FOOD" from Evonik Nutrition & Care GmbH, Essen, Germany. The product complies with the EU requirements for food additive E 432. As an alternative to the aforementioned TEGO SML 20 from Evonik, Grillet 1 / Tween 20-LQ- (SG) from CRODA GmbH, Nettetal, Germany, can also be used as polysorbate 20 within the scope of the invention. One possible sugar ester of fatty acids is, for example, a sucrose ester with the product name "DUB SE 15 P" from the manufacturer Stearine Dubois. This is

[0066] Approved in the EU as food additive E 473.

[0067] Glycerin

[0068] The glycerol used in the present application was the product "Glycerol 99.5%" from Cremer Oleo GmbH & Co. KG, Hamburg, Germany. Alternatively, the product "Glycamed 99.7%" from Glaconchemie GmbH, Merseburg, Germany, can also be used. According to the manufacturer's information, the glycerol content of this product is at least 99.5%.

[0069] Medium-chain triglycerides

[0070] Medium-chain triglycerides were used as MCT oil ( 70 / 30 )

[0071] Rofetan GTCC 70 / 30 from DHW Deutsche Hydrierwerke Rodleben GmbH, Dessau-Roßlau, Germany, is used. Alternatively, the product Delios S from BTC Europe GmbH, Monheim, Germany, can also be used.

[0072] Mixed tocopherol

[0073] For example, the 70% mixed tocopherol in vegetable oil Vitapherole T-70 Non GMO from the manufacturer VitaeNaturals can be used as mixed tocopherol (E306, CAS numbers 59-02-9, 16698-35-4, 54-28-4 and 119-13-1).

[0074] Example: CBD solubilisate,

[0075] It will

[0076] 33 g CBD isolate cannabidiol at least 99.8%

[0077] (32.9 g CBD)

[0078] 40 g glycerin,

[0079] 40 g MCT oil,

[0080] 15 g mixed tocopherol 70% and

[0081] 872 g of polysorbate 80 is used. The CBD isolate is cannabidiol with CAS number 13956-29-1, which is a whitish to slightly yellowish powder.

[0082] Polysorbate 80 is heated to a temperature in the range of 48°C to 52°C. Mixed tocopherol is added and homogenized while stirring while maintaining the temperature. Stirring is vigorous enough to ensure even distribution of the mixed tocopherol throughout the Polysorbate 80. Glycerin, MCT oil, and CBD isolate are mixed separately and heated to a temperature of 85°C to 89°C. The mixture is homogenized to such a degree that the turbidity of this pre-solution no longer changes upon further stirring while maintaining the temperature. The mixture of glycerin, MCT oil, and CBD isolate is then incorporated into the Polysorbate 8 O-mixed tocopherol mixture while stirring. Stirring is vigorous enough to ensure even distribution while maintaining the temperature in the range of 85°C to 89°C. The product is cooled to a temperature below 60°C and bottled. It is then stored in the dark at a maximum of 25°C.

[0083] When diluted 1:50 in water, this 3% CBD isolate solubilizate has a maximum turbidity of 50 FNU. The measured value for the sample was 10.4, the average of three measurements from three batches, and thus a value well below 15 FNU. It is particularly suitable for administration in capsules or as an additive to beverages.

[0084] The mixed tocopherol serves as an antioxidant in the formulation according to the invention and the exemplary embodiment described above. Depending on the intended use or other components of the formulation of the product in which the solubilisate according to the invention is used, the addition of the mixed tocopherol can be omitted, mixed tocopherol can be used in combination with other substances, or another substance or mixture of substances can be used as an antioxidant. Apart from CBD isolate, cannabinoid solubilisates can be produced and used within the scope of the invention additionally or alternatively with THC oil or isolate and / or with oils or isolates or other sources, including other cannabinoids.The advantage of using an isolate compared to using a cannabinoid oil for the formulation of the solubilisate is that due to the high active ingredient concentration in the isolate, a comparatively small mass of this active ingredient-containing component can be used in the solubilisate and yet a high cannabinoid content can be achieved in the solubilisate.

[0085] It will be apparent to those skilled in the art that the invention is not limited to the examples described above, but rather can be varied in many ways. In particular, the features of the individually presented examples can also be combined with one another or interchanged. This applies in particular to the emulsifier and active ingredient composition of the solubilizate according to the invention.

Claims

AMENDED CLAIMS received by the International Bureau on 9 February 2024 (09.02.2024) 1. Solubilisate containing at least one cannabinoid, in particular cannabinoid isolate, at least one emulsifier with an HLB value in the range of less than 18, preferably between 13 and 18, in particular polysorbate 80 or polysorbate 20 or at least one sugar ester of fatty acids or a mixture of at least two emulsifiers selected from the group comprising polysorbate 20, polysorbate 80 and sugar esters of fatty acids, and medium-chain triglycerides, characterized in that the solubilisate comprises medium-chain triglycerides in a proportion of up to 10% by weight, preferably between 1% by weight and 8% by weight, particularly preferably up to 5% by weight.

2. Solubilisate according to claim 1, characterized in that the solubilisate contains as a further component up to 10 wt.%, preferably between 1 wt.% and 8 wt.%, particularly preferably up to 5 wt.% glycerol.

3. Solubilisate according to one of the preceding claims, characterized in that the solubilisate contains as a further component up to 5 wt.%, preferably between 0.5 wt.% and 3 wt.%, particularly preferably between 1 wt.% and 2 wt.% of at least one antioxidant, preferably at least one AMENDED SHEET (ARTICLE 19) Tocopherol, particularly preferably mixed tocopherol.

4. Solubilisate according to one of the preceding claims, characterized in that the emulsifier content, in particular the polysorbate content, is at least 70% by weight, preferably in the range between 75% by weight and 98% by weight, particularly preferably in the range between 82% by weight and 93% by weight.

5. Solubilisate according to one of the preceding claims, characterized in that the diameter distribution of the micelles in a dilution of the solubilisate with distilled water in a ratio of 1:500 under physiological conditions (pH 1.1 and 37°C) ranges from about d 0 o = 5 nm to about d 0 o = 20 nm, preferably in the range from d 0 o = 6 nm to about d 0 o = 13 nm.

6. Solubilisate according to one of the preceding claims, characterized in that the turbidity of the solubilisate is less than 50 FNU, preferably less than 25 FNU, particularly preferably less than 15 FNU, measured by scattered light measurement with infrared light according to the provisions of standard ISO 7027 with a dilution of the solubilisate in a ratio of 1:50 in water.

7. Solubilisate according to one of the preceding claims, characterized in that the AUG ("area under the curve") of the plasma concentration-time curve measured up to 30 AMENDED SHEET (ARTICLE 19) Minutes after oral administration of a solubilisate according to one of the preceding claims, the value is 17 to 22 times higher, preferably 19 to 20 times higher, than after oral administration of the same dose of cannabinoid, in particular cannabinoid isolate, dissolved in glycerol.

8. Solubilisate according to one of the preceding claims, characterized in that the AUG ("area under the curve") of the plasma concentration-time curve measured up to 60 minutes after oral administration of a solubilisate according to one of the preceding claims has a value 14 to 19 times higher, preferably 16 to 17 times higher, than after oral administration of the same dose of cannabinoid, in particular cannabinoid isolate, dissolved in glycerol.

9. Solubilisate according to one of the preceding claims, characterized in that the time tmax of the plasma concentration-time curve after oral administration of a dose of cannabinoid, in particular cannabinoid isolate, dissolved in glycerol, at which the maximum concentration in the plasma is reached, has a value in the range of 1.96 times to 4 times, preferably in the range of 2.8 times to 3.1 times, the value after oral administration of the same dose of cannabinoid, in particular cannabinoid isolate, in a solubilisate according to one of the preceding claims.

10. Solubilisate according to one of the preceding claims AMENDED SHEET (ARTICLE 19) for use as a medicine, particularly in the treatment and / or prevention of sleep disorders (insomnia), depression and / or anxiety.

11. Solubilisate according to one of the preceding claims for use as a food supplement and / or as a medicament having an effect against sleep disorders (insomnia), depression and / or anxiety states.

12. Solubilisate according to one of the preceding claims for the manufacture of a food supplement and / or medicament for the treatment of and / or prevention of sleep disorders (insomnia), depression and / or anxiety.

13. Capsule filled with a solubilisate according to one of the preceding claims, characterized in that the capsule is designed as a soft gelatin capsule or hard gelatin capsule or as a soft, gelatin-free capsule or as a hard, gelatin-free capsule, for example as a cellulose capsule.

14. Product containing a solubilisate according to any one of claims 1 to 13, characterized in that the product is selected from the group comprising food, food supplements, beverages, cosmetics and pharmaceutical products.

15. Product according to claim 14, AMENDED SHEET (ARTICLE 19) characterized in that the product comprises an aqueous dilution of the solubilizate .

16. A method for the treatment of and / or prevention of sleep disorders (insomnia), depression and / or anxiety states, characterized in that a solubilisate according to one of claims 1 to 12, in particular in a capsule according to claim 13 or as a product according to one of claims 14 or 15, is administered to the food supplement consumer or patient, in particular orally. 17 . Method according to claim 16, characterized in that the solubilisate is added to the food supplement Consumers or patients are administered a cannabinoid dose in the range of 5 mg / kg body weight to 8.4 mg / kg body weight, preferably with a dose of 6.7 mg / kg body weight, in particular once daily. 18 . A process for producing a solubilisate according to one of claims 1 to 12, comprising the following steps: a) introducing at least one emulsifier having an HLB value in the range of less than 18, preferably between 13 and 18, in particular polysorbate 80 or polysorbate 20 or at least one sugar ester of fatty acids or a mixture of at least two emulsifiers selected from the group consisting of AMENDED SHEET (ARTICLE 19) Polysorbate 20, polysorbate 80 and sugar esters of fatty acids, b) mixing the emulsifier from step a) with at least one cannabinoid, in particular cannabinoid isolate, and at least one medium-chain triglyceride (MCT), wherein the medium-chain triglyceride is used in a proportion of up to 10 wt.%, preferably between 1 wt.% and 8 wt.%, particularly preferably up to 5 wt.%, wherein at least in step b) heating to a temperature in the range from 82°C to 97°C, preferably to a temperature in the range from 83°C to 92°C, particularly preferably to a temperature in the range from 85°C to 89°C takes place.

19. The method according to claim 18, wherein prior to step b) a step bl) of mixing at least one cannabinoid, in particular cannabinoid isolate, with at least one medium-chain triglyceride (MCT) takes place.

20. The method according to claim 18 or 19, wherein in step a) heating takes place to a temperature at least in the range from 40°C to 62°C, preferably to a temperature in the range from 45°C to 57°C, particularly preferably to a temperature in the range from 48°C to 52°C.

21. The process according to any one of claims 18 to 20, wherein glycerol is additionally added in step b) and / or in step bl). AMENDED SHEET (ARTICLE 19) 22. The method according to any one of claims 18 to 20, wherein before step b) and / or before step bl) a step bll) of mixing at least one cannabinoid, in particular cannabinoid isolate, with glycerol takes place.

23. Method according to one of claims 18 to 22, wherein in step a) additionally at least one Antioxidant, preferably tocopherol, particularly preferably mixed tocopherol, is added. AMENDED SHEET (ARTICLE 19)

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