Cannabinoid solution in oil

Abstract

A cannabinoid solution in oil, comprising one or more cannabinoids, wherein the cannabinoid solution is contained in a storage container that inhibits the effect of oxygen from the environment on the solution, and wherein the solution is free of added preservatives.

Description

[0001] Bernd Störmer-Talleur Mittelstraße 2, 31249 Hohenhameln, Cannabinoid solution in oil The present invention relates to a cannabinoid solution in oil, comprising one or more cannabinoids, wherein the cannabinoid solution is in a storage container that prevents the effect of ambient oxygen on the solution, and wherein the solution is free from added preservatives, radical scavengers, compounds with phenolic groups and compounds with basic properties. The invention further relates to a process for producing a stable cannabinoid solution in oil. Various pharmacological effects of cannabinoids from the hemp plant Cannabis sativa are known. Accordingly, there is a high demand for formulations comprising cannabinoids that can either serve as the basis for an administrable formulation or that are already available in an administrable form.Of particular interest in this context is the cannabinoid dronabinol ((-)-Δ). 9-THC (6aR,10aR)-6,6,9-Trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol, hereinafter also referred to as THC). However, other cannabinoids are also of increased interest. Unfortunately, it has been found that cannabinoid formulations that are easy to handle are generally not sufficiently stable with regard to their active ingredients. This applies to cannabinoids in general and dronabinol in particular. To date, THC raw substances or THC isolates have been available on the market as a resinous, very viscous, honey-like, yellowish mass, which are filled into pre-filled glass syringes (e.g., 250 mg, 500 mg, and 1000 mg) for the production and further processing into a solution. This requires heating to approximately 70°C, and then dilution with oils is possible. However, these solutions must be used very quickly to avoid degradation of the cannabinoids they contain, especially dronabinol.As an alternative, there is currently a ready-made solution on the market that uses palmithoylascorbic acid to stabilize cannabinoids, and in particular THC. A similar approach can be found in DE 102012105063 B4, which also states that certain additives are necessary to stabilize the cannabinoids. In principle, however, it is desirable to have as few additives as possible in solutions intended for medicinal use or for other approaches on humans or in the human body in order to avoid undesirable side effects and cross-reactions. However, according to the current state of the art, such additives have previously been considered necessary, particularly for oil-containing solutions. Based on this initial situation, the object of the present invention was to provide a stabilized cannabinoid solution that requires as few additives as possible.This object is achieved by a cannabinoid solution in oil, comprising one or more cannabinoids, wherein the cannabinoid solution is contained in a storage container that prevents the effect of ambient oxygen on the solution, and wherein the solution is free of added preservatives. Surprisingly, and contrary to the prejudice of the expert community, it has been found that it is only necessary to ensure the greatest possible exclusion of oxygen to ensure good stability of the cannabinoids in an oily solution. Cannabinoids within the meaning of the present invention are the following groups a)-l) and m.: a) Cannabigerol-like (CBG). Cannabinerolic Acid A Cannabigerovarin Cannabigerolic acid A Cannabigerolic acid A monomethyl ether Cannabigerovanic acid A b) Cannabichromene-like (CBC) ±)-Cannabichromene (±)-Cannabichromenic acid A (±)-Cannabichromevarin Cannabichromevarinic acid A c) Cannabidiol-like (CBD) (−)-Cannabidiol Cannabidiol monomethyl ether Cannabidiolic acid Cannabidivarinic acid Cannabidiorcol d) Cannabinodiol-like (CBND) e) Tetrahydrocannabinol-like (THC) Δ 9 -Tetrahydrocannabinol-C5 Δ 9 -Tetrahydrocannabinol-C4 Δ 9 Tetrahydrocannabivarin Δ 9 -Tetrahydrocannabinol Δ 9 -Tetrahydro- cannabinolic acid A Δ 9 -Tetrahydro-cannabinolic acid B Δ 9 -Tetrahydro-cannabinolic acid-C4Δ 9 -Tetrahydro- cannabivarinic acid AA and / or B Δ 9 -Tetrahydro- (−)-Δ 8 -trans-(6aR,10aR)- Δ 8 -Tetrahydrocannabinol cannabiorcolic acid A and / or B (−)-Δ 8 -trans-(6aR,10aR)- (−)- -Δ 9 -Tetrahydrocannabinol Tetrahydrocannabinolic acid A f) Cannabinol-artige ( CBN) Cannabiorcol Cannabinolsäure A Ńannabinolmethylether

[0002] g) Cannabitriol-artige (CBT)

[0003] tetrahydrocannabinol Cannabitriolester (−)-(6aR,9S,10S,10aR)- 9,10-Dihydroxy- hexahydrocannabinol, Cannabiripsol - 10-Oxo-Δ 6a(10a) - Δ 9 -tetrahydrocannabinol tetrahydrocannabinol

[0004] h) Cannabielsoinartige ( CBE) Cannabielsoin - C3-Cannabielsoin B

[0005] Cannabifuran Dehydrocannabifuran Cannabiglendol-C3 i) Isocannabinoide - - Isotetrahydrocannabinol (±)-Δ 7 -1,2-cis- (1R,3R,6S / 1S,3S,6R)- (−)-Δ 7 -trans-(1R,3R,6R)- Isotetrahydro- Isotetrahydrocannabivarin cannabivarin

[0006] j) Cannabicyclol-artige (CBL) (±)-(1aS,3aR,8bR,8cR)- (±)-(1aS,3aR,8bR,8cR)- (±)-(1aS,3aR,8bR,8cR)- Cannabicyclol Cannabicyclolsäure A Cannabicyclovarin k) Cannabicitran-artige (CBT) Cannabicitran

[0007] l) Cannabichromanon-artige (CBCN) Cannabichromanon Cannabichromanon-C3Cannabicoumaronon

[0008] m.) Synthetische Cannabinoide Tetrahydrocannabiphorol Tetrahydrocannibidiol. The cannabinoid solution according to the invention within the meaning of this text is always to be understood as the combination of oily cannabinoid solution with the corresponding storage container, unless the context clearly indicates otherwise. Added agents here within the meaning of this text are those that have been added to a solution or formulation. Added agents are not those that originate from natural extracts from the hemp plant Cannabis Sativa, provided these extracts serve to enrich the cannabinoids. Preservatives within the meaning of the present invention are substances that are added to food, cosmetics, or pharmaceuticals to prevent their bacterial or chemical degradation. The core of the present invention is therefore that it is surprisingly possibleCannabinoid solutions can be provided in a stable manner without the addition of stabilizing agents by means of a suitable storage container. A cannabinoid solution according to the invention is preferred (this also includes the storage container to be used according to the invention), wherein the storage container prevents the effect of UV light from the environment. Even if the exclusion of the effect of oxygen is an essential reason for the stabilizing effect, the stabilization of the cannabinoids in the oil solution is further supported by the exclusion of UV light. A cannabinoid solution according to the invention is preferred, wherein the solution is additionally free of added radical scavengers, compounds with phenolic groups and / or compounds with basic properties. A cannabinoid solution according to the invention that is free of one, several or all of the following substances (stabilizers, emulsifiers, radical initiators,Complexing agent and / or antioxidant), selected from the group consisting of cresol (methylphenol), 2-tert.-butylphenol, 4-tert.-butylphenol, 2,4-di-tert.-butylphenol, 2-methyl-4-tert.-butylphenol, 2-tert.-butyl-4-methylphenol, 2,6-di-tert.-butyl-4-methylphenol, 4-tert.-butyl-2,6-dimethylphenol, 2,3,6-trimethylphenol, 2,4,5-trimethylphenol, 2,4,6-trimethylphenol, 6-tert.-butyl-2,4-dimethylphenol, quinones, in particular hydroquinone, hydroquinone monomethyl ether, 2-methylhydroquinone, 2,5-di-tert.-butylhydroquinone, benzoquinone and / or Hydroquinone monomethyl ether; 4-hydroxy-3-methoxybenzaldehyde (vanillin), 4-hydroxy-3-ethoxybenzaldehyde (ethylvanillin), 3-hydroxy-4-methoxybenzaldehyde (isovanillin), 1-(4-hydroxy-3-methoxyphenyl)ethanone (acetovanillon), eugenol, dihydroeugenol, isoeugenol, tocopherols, in particular alpha-, beta-, gamma-, delta- and epsilon-tocopherol and / or alpha-tocopherol hydroquinone; compounds containing acidic protons,in particular carboxylic acids, hydroxyls and / or thiols and / or the corresponding salts of the deprotonated compound, very particularly carboxylic acid salts, phenolates or thiolates, preferably with potassium, sodium, ammonium or calcium as cations, as concrete examples salicylic acid, salicylates such as sodium salicylate; aromatic carboxylic acids with at least one phenolic hydroxyl group, amino, alkylamino, dialkylamino group or thiol group, as well as their salts and / or esters, including corresponding compounds with several carboxylic acid groups and / or ester groups; compounds with at least two groups selected from hydroxyl, thiol and / or amino groups, in particular also "enediol" compounds; lecithin; nitriloacetic acid, ethylenediaminetetraacetic acid (EDTA) and their salts; in particular carboxylic acids with at least one or two or more than two olefinic double bonds such as linolenic acid, arachidonic acid,and their salts and esters; ascorbic acid and its salts and esters such as sodium L-ascorbate, calcium L-ascorbate, 6-palmitoyl-L-ascorbic acid; alginic acid, glucuronic acid, mannuronic acid, their salts and esters, propylene glycol alginate; vitamin E such as natural tocopherols, synthetic α-, γ-, δ-tocopherol; butylated hydroxyanisoi (BHA) and its salts; butylated hydroxytoluene (BHT) and its salts; 2,6-di-tertiary-butyl-p-cresol and its salts; 2,6-di-tertiary-butylphenol and its salts; hydroxy-, dihydroxy- and trihydroxybenzoic acids, their esters and salts such as propyl gallate, octyl gallate, dodecyl gallate; nimesulide; as well as sulfhydryls (SH) and mercaptides and their salts, in particular sodium, potassium, ammonium, calcium salts of the above-mentioned compounds, or esters with glycerol and propylene glycol, derivatives of ascorbic acid, such as calcium L-ascorbate or palmitoyl L-ascorbic acid, bentonite, carrageenan, celluloses such as methylcellulose, cetyl alcohol,Cetylstearyl alcohol, cholesterol, emulsifying cetylstearyl alcohol, fatty alcohols, gelatin, glycerol monostearate, laureth-2, laureth-4, lecithin (e.g. egg yolk, soy), magnesium stearate, macrogol stearate, milk proteins and other proteins, mono- and diglycerides of fatty acids (especially E 471), sodium cetylstearyl sulfate, sodium lauryl sulfate (SLS), oleyl alcohol, phospholipids, poloxamers, polysorbates (e.g. polysorbate 20, 40, polysorbate 60, polysorbate 80), sucrose esters such as sucrose monopalmitate, sorbitan monolaurate (Span 20), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), Sorbitan monooleate (Span 80), stearyl alcohol, and triethanolamine with fatty acids. (End of the list of the above-mentioned group of preferentially excluded compounds.) Avoiding such additives makes sense for the same reasons as avoiding added preservatives. Surprisingly, it turns out thatthat, despite the omission of these additives, stable cannabinoid solutions in oil are possible. It is preferred that, in addition to the extract of Cannabis Sativa, no further additives other than oil are added to the cannabinoid solution according to the invention. In some cases, it may be preferred that the cannabinoid solution according to the invention comprises terpenes and / or essential oils and preferably no other additives. These essential oils / terpenes, with suitable selection and concentration, can lead to an enhancement of the effect of the cannabinoids, in particular THC (dronabinol). It will of course be clear to the person skilled in the art that the solvent (the oil, see also below) is not among the excluded additives. A cannabinoid solution according to the invention is preferred, wherein the cannabinoids are ≥ 50 wt%, preferably ≥ 70 wt%, more preferably ≥ 85 wt% and particularly preferably ≥ 95 wt%, preferably dronabinol,based on the total weight of the cannabinoids present in the solution. A high proportion of dronabinol among the cannabinoids contained in the cannabinoid solution according to the invention is desirable for many medical applications. As is generally the case, the cannabinoid can originate from natural sources, which can be full-spectrum extracts from a cannabis plant or corresponding extracts with subsequent enrichment in certain ingredients, in particular dronabinol, but it can also be artificially produced cannabinoids within the meaning of the present invention. A cannabinoid solution according to the invention is preferred, wherein the gas in the storage container is an inert gas, preferably selected from the group consisting of noble gases and nitrogen. As a rule, it will be expedient to provide a gas phase in the storage container to be used according to the invention. In this case, it is expedient within the meaning of the inventionAn oxygen-free gas should be selected, whereby the inert gases mentioned have proven to be particularly easy to handle. A cannabinoid solution according to the invention is preferred, wherein the storage container contains ≤ 1 wt%, preferably ≤ 0.5 wt% O2, based on the weight of the cannabinoids contained in the solution. To ensure a long shelf life, it may be useful to control the proportion of dissolved oxygen. In particular, it is possible for the solvent (oil) to still contain oxygen. Before dissolving the cannabinoids to be used according to the invention in the oil, measures can be taken to reduce or remove any oxygen that may still be present. A number of options are available to the person skilled in the art for this purpose; preferred options are the application of a vacuum, thermal degassing, the addition of defoamers such as dimethicone,Simethicone or ultrasound treatment. The oil to be used according to the invention is preferably a mono-, di-, or triglyceride. It can preferably be a natural or synthetic oil. Examples of such oils are rapeseed oil, hydrogenated palm oil, hydrogenated soybean oil, peanut oil, olive oil, sunflower oil, avocado oil, jojoba oil, wheat germ oil, macadamia nut oil, apricot kernel oil, hemp oil, rosemary oil, chamomile oil, sage oil, calendula oil, lavender oil, St. John's wort oil, lemon balm oil, sea buckthorn oil, cedarwood oil, cypress oil, evening primrose oil, blackcurrant seed oil, rosehip oil, fish oil, safflower oil, moringa seed oil, castor oil, sweet almond oil, corn germ oil, canola oil, argan oil, amaranth seed oil, and / or components of these oils. The term components of these oils includes in particular those oil fractions which are characterized by a uniform and standardized structure,by their degree of saturation and / or by the number of double bonds. It should be noted that, contrary to common definitions, propylene glycol and glycerin are also considered oils for the purposes of this text. However, for the preferred, narrower definition of oil within the meaning of this text, these two solvents are excluded. The oil to be used for the cannabinoid solution according to the invention is preferably a synthetic or natural triglyceride, particularly preferably a triglyceride in which C8-C10 or C12 carboxylic acids (in particular C8, C10 and / or C12 carboxylic acids) are esterified with glycerin. These oils are also referred to as MCT oils or neutral oils. Accordingly, a cannabinoid solution according to the invention is particularly preferred, wherein the oil comprises or consists of an MTC oil. Particularly preferred natural oils within the meaning of the present invention are selected from the group consisting of hemp oil, coconut oil, almond oil, borage seed oil, sesame oil,Carob seed oil, linseed oil, palm oil, soybean oil, and argan oil. The oil used preferably meets the requirements of the pharmaceutical specifications of current pharmaceutical standards and pharmacopoeias, preferably at least one, preferably all of the following: DAB (German Pharmacopoeia), EuAB (European Pharmacopoeia), and their codices (DAC). Of course, the oil used can also be a mixture of different oils, or only a single type of oil can be used. A cannabinoid solution according to the invention is preferred, wherein the oil to be used comprises castor oil components and / or terpenoids and / or terpenes in general, wherein the terpenes preferably originate from hemp plants and / or hops. Particularly preferred oil components to be used are triglycerides, monoglycerides, and / or diglycerides with hydroxylated fatty acid chains.e.g., with a 9-hydroxyoleic acid residue. Preferred terpenes, particularly from hemp plants, are: alpha-pinene, camphene, beta-pinene, beta-myrcene, delta-3-carene, alpha-terpinene, p-isopropyltoluene, d-limonene, ocimene, gamma-terpinene, valencene, terpinolene, linalool, isopulegol, geraniol, beta-caryophyllene, alpha-humulene, nerodiol, guajol, alpha-bisabolol, borneol, and cineole. Also preferred is a mixture of at least one or / and more triglycerides (oils) as described above and the above-described terpenes from the cannabis plant or terpenes obtained from other plants or synthetically produced from the group of monoterpenes, sesquiterpenes, and / or mixtures thereof. The preferred components, especially terpenes (essential oil components) especially from hemp plants are used for the entourage effect (i.e. a modulating, partially enhancing effect of the main active ingredient,(especially THC) of cannabis extracts. According to the invention, it is preferred that the cannabinoid solution according to the invention contains only oil and oil-soluble components. This also means that preferably no solid components are present and that the cannabinoid solution according to the invention has not been subjected to a homogenization step. A cannabinoid solution according to the invention is preferred, wherein the storage container is a vial, preferably a brown glass vial or violet glass vial. Preferred storage containers according to the invention, in particular the preferred vials mentioned, but also the special vessels described below,have a preferred size of 10 ml - 1000 ml (for multiple doses) or are designed as a single dose. Preferably, the storage containers to be used according to the invention can be easily and almost completely emptied using a suitable commercially available withdrawal system. In particular, the storage means to be used according to the invention, and especially the vials, can be provided with a suitable closure plug, preferably pierceable by a withdrawal device, wherein the closure plug can be either Teflon-free or Teflon-coated. The closure plug must also ensure extremely low gas diffusion or even the exclusion of gas diffusion from or into the storage container. A preferred object of the invention was furthermore to provide a cannabinoid solutionwhich exhibits high stability even upon repeated removal from the storage vessel. Particularly for this preferred application, a storage (and application) container may be preferred over the storage means specifically described so far (for the cannabinoid solution according to the invention or as part of it, provided the storage means is included) that is part of a withdrawal system for preventing oxygen backflow during withdrawal. Such systems for preventing oxygen backflow during withdrawal within the meaning of this text result in a very greatly reduced oxygen backflow, preferably a completely prevented oxygen backflow, when the cannabinoid solution according to the invention is withdrawn from the storage container. Such withdrawal systems generally function bythat the volume of the actual storage container is reduced during withdrawal by the volume of the withdrawn cannabinoid solution according to the invention, wherein a backflow prevention device, for example in the form of a valve, is preferably present at the same time. Examples of such withdrawal systems are known, for example, from the company PACKSYS GmbH, Feldafing, where they are offered as an airless bottle, either as an "Airless Bag-In-Bottle System" or as a "trailing piston system." An alternative, equally suitable system is offered by GAPLAST GmbH, Saul-Altenau, e.g., under the product line "AirlessMotion," which enables both spray and drip functions. Another alternative, equally suitable system is offered by URSATEC, Tholey,offered under the system name COMFORT. These withdrawal systems are typically used for hydrophilic solutions. A new development is the use of oily cannabinoid-THC-containing solutions. According to the invention, the inner bag of the bag-in-bottle system preferably consists of a three-layer system consisting of Surlyn 1601 or 1650 or another oil-compatible Surlyn (ionomer) as the inner bag, EVOH as the oxygen barrier as the middle layer of the inner bag, and PE (polyethylene) as the outer layer of the inner bag. For the closure, polypropylene / polyethylene and a stainless steel ball are preferably used as the riser tube, and polyethylene or EVA ethynyl vinyl acetate is used as the sealing material for the closure cap in order to provide external protection against air (oxygen) influences. Depending on the application, the caps can be spray caps without a snorkel, spray caps with a snorkel, spray caps with a vertical cone to use them as mouth spray, nasal spray,Ear spray and / or dermal spray. A combination of these containers with oily solutions, in this case, an oxidation-sensitive cannabinoid dronabinol solution, makes the use of a preservative-free THC solution possible. Surprisingly, it has been found that the inventive cannabinoid solution in oil is stable even during normal use, i.e., when removed from the corresponding containers, e.g., by the end user. Stable in this context means that when removed three times a day in the form of two sprays or 20 drops (depending on the system), a discoloration of the inventive cannabinoid solution in the storage container is not visible to the naked eye after a period of use of 3 weeks, preferably 4 weeks, more preferably 6 weeks, even more preferably 8 weeks.and particularly preferably 3 months. Furthermore, despite the described withdrawal regime, the general stability criteria described below are also preferably met. This high level of stability – even in combination with the corresponding withdrawal – was not previously expected by experts, otherwise a corresponding approach would have been implemented long ago given the constant demand for preservative-free cannabinoid solutions. An optimal filling size, preferably for pharmacies, with the exclusion of oxygen and UV light, are brown glass vials in vial volumes of 10 ml - 40 ml in filling concentrations of 1-10%, preferably 2.5% (2.5 mg / ml), 5% (5 mg / ml) of the cannabinoid solution according to the invention.also from isolates of the cannabis plant. This ensures an optimal filling quantity in a dispensing container for the end user in accordance with the current Narcotics Prescription Ordinance (maximum 500 mg dronabinol for 30 days' supply for one patient). Due to the absence of preservatives, the cannabinoid solution according to the invention prevents reactions with other forms of drug administration that come into contact with this oily solution, in particular finished medicinal products of any form, preferably soft gelatin capsules, implant containers, TTS (Transermal Therapeutic Systems), dermatological, preferably liquid and semi-solid preparations. According to the invention, a cannabinoid solution according to the invention is preferred, wherein the solution is eye drops, a nasal oil,or a concentrate for the production of orally administrable solutions. Thus, the cannabinoid solution according to the invention is preferably either ready for use or also accessible for further preparatory steps. Such an additional step could preferably also be the filling of soft gelatin capsules according to the invention. According to the invention, a cannabinoid solution is preferred, wherein the solution is stable at 25°C and with exclusion of UV light for ≥ 3 months, preferably for ≥ 6 months. Stable in the sense of the present invention means that at 25°C and with exclusion of UV light, the solution (in its storage container to be used according to the invention) has lost less than 5% of the cannabinoids originally contained in it through degradation after time x (for which it is to be assessed as stable). Preferably, stability according to the specification according to DAC D-100, EU GMP Guide ICH,A particularly preferred application form within the meaning of the invention is the combination of propylene glycol and glycerol as a hydrophilic solvent with THC (dronabinol) produced entirely without the use of additives for use in or around the lungs. A particular advantage here is that pneumonia and even death caused by the inhalation of preservatives, antioxidants, and / or emulsifiers cannot occur. The invention also includes a process for producing a stable cannabinoid solution as described above, particularly in the preferred variants, comprising the following steps: a) Providing a cannabinoid-containing extract or one or more (partially) synthetic cannabinoids, preferably as defined in more detail above, b) Providing an oil, preferably as defined in more detail above, c) Providing a storage container,as defined in more detail above. Surprisingly, it has been found that the process according to the invention can effectively provide a stable cannabinoid solution in oil. This also overcomes an advantage in the professional world, where such an approach has not been pursued to date. In the process according to the invention, cannabinoid-containing extracts from exclusively natural sources, in an oil-soluble state, as is understandable to the person skilled in the art, or artificially produced cannabinoids or corresponding mixtures can of course be used in step a). A process according to the invention is preferred, wherein substances provided in step a) and / or step b) have been subjected to a degassing treatment. This serves in particular to minimize the oxygen content in the solution or to completely avoid oxygen in the solution. In principle, it should be noted thatthat, within the scope of the invention, the preferred cannabinoid is dronabinol; however, full-spectrum extracts from cannabis plants are included under the term "cannabinoid solutions," as are extracts enriched with individual ingredients, particularly THC (dronabinol). Examples Example 1 Manufacturing recipe for a 2.5% oily dronabinol solution: Dronabinol pure substance is a viscous, honey-resin-like substance at room temperature with a slightly creamy white to slightly white-yellow color. a) Withdrawal of 2.5g of dronabinol, synthetic or isolate, from an oxygen-tight, gas-tight container (usually a glass syringe as primary packaging or vial, by applying heat at 70 degrees to liquefy or to reduce the viscosity by means of hot air or other suitable heat sources under exclusion of oxygen (vacuum), and / or inert gas atmosphere (nitrogen, argon,other noble gases) and under exclusion of UV light, in this case dronabinol from Echo Pharmaceuticals, Leiden, Netherlands. b) Weighing (in this case emptying the syringes with the correct amount of THC) according to a) into a container (e.g. beaker or industrial apparatus for mixing oily liquids), in this case MCT Miglyol812N (manufacturer: IOI Oleo GmbH Hamburg), using heat at -70 degrees Celsius under exclusion of oxygen (vacuum) and / or inert gas atmosphere (nitrogen, argon, other noble gases). Adjust to 2.5g dronabinol per 100ml of solution. Addition of medium-chain triglycerides (here: Miglyol 812N, density 0.93-0.96, according to b) with an average density of 0.954, 0.93-0.96 at 20 °C) to 100 parts by mass (100g, corresponding to 94.7g Miglyol 812 at normal temperature), here MCT Miglyol812N according to point b), using heat at 70 degrees Celsius, also under exclusion of oxygen (vacuum) and / or inert gas atmosphere (nitrogen,Argon other noble gases) and under UV light exclusion. For this purpose, the required amount / mass of the weighed dronabinol is heated to 70 degrees Celsius and added to the oil used, which has also been heated to 70 degrees Celsius, and stirred for approximately 10 minutes until the dronabinol is completely dissolved. Mixing is carried out at a slow stirring speed using a magnetic stirrer or stirring rod or stirring equipment from Groninger. This finished, clear to slightly yellowish solution, the fully dissolved recipe concentrate, is then filled into brown or violet glass, also under oxygen exclusion (vacuum) and / or inert gas atmosphere (nitrogen, argon other noble gases) and with a sealing plug, and closed and stored protected from light (UV protection). The formulation components m / V must be adjusted according to the recognized pharmaceutical rules according to their density (m / V_ mass / volume / temperature) and calculated exactly to the THC content, so that the result is a 2,5% (w / v), corresponding to 25 mg / ml. However, the amount of THC in mass / volume mg / ml must be stated. The density of the final solution is only slightly altered by THC at concentrations between 0.5% and 10%. This solution is stable for ≥ 6 months under the conditions described above. Example 2: Stability under conditions of use: A dronabinol solution was prepared as follows: - The required amount of MCT oil (medium chain triglycerides oil) was weighed and filled into glass vials under normal ambient conditions. - The vials were sonicated in an ultrasonic bath to degas. - The material for the dronabinol solution was transferred to a glove box. - The glove box was filled with nitrogen until the oxygen content was 0% as measured by the detector. - The MCT oil was purged with nitrogen.to remove residual oxygen. - The dronabinol (Echo Pharma) was heated until it was a flowable liquid. - The dronabinol was added to the bottle containing the MCT oil. - The dronabinol solution was heated and mixed to create a homogeneous solution. - The solution thus prepared was purged again with nitrogen and then filled into 20 ml brown glass vials or 20 ml PE bottles (URSATEC COMFORT System; Ursatec Comfort Airless and Gaplast Airless) within the glove box. - The top of each container was purged again with nitrogen before the cap was sealed. - The bottles were labeled and stored in stability chambers. Withdrawal: Once daily, 100 μl of solution was withdrawn from a container under standard conditions (25% C, room temperature). In glass vials, this was done by rapid pipette withdrawal.in the case of the PE vials, using the designated spray head. The respective samples were then analyzed by HPLC. Results: It was found that the dronabionol solution contained in glass vials underwent a relatively steady degradation, so that after eight days only 75% of the original dronabionol remained. In contrast, it was surprisingly found that the degradation within the PE bottles was already significantly reduced in the first few days (compared to the glass vials) and remained essentially stable from day four onwards at around 90% of the original dronabionol concentration until day eight. The results show that the PE bottles used (URSATEC COMFORT System) exhibit significantly improved stability even under normal withdrawal conditions. The extent of the increase in stability is surprising. Furthermore, it is assumed that the degradation,which became apparent in the PE bottles during the first three days, is due to residual contamination with oxygen.

Claims

Claims:

1. A cannabinoid solution in oil comprising one or more cannabinoids, wherein the cannabinoid solution is contained in a storage container that prevents the effect of ambient oxygen on the solution, and wherein the solution is free of added preservatives.

2. The cannabinoid solution according to claim 1, wherein the storage container prevents the effect of ambient UV light.

3. The cannabinoid solution according to claim 1 or 2, wherein the solution is additionally free of added radical scavengers, compounds with phenolic groups, and / or compounds with basic properties.

4. Cannabinoid solution according to one of the preceding claims, wherein the cannabinoids are ≥ 50 wt.%, preferably ≥ 70 wt.%, more preferably ≥ 85 wt.%, and particularly preferably ≥ 95 wt.%, preferably dronabinol, based on the total weight of the cannabinoids present in the solution. 5.Cannabinoid solution according to one of the preceding claims, wherein the gas in the storage container is an inert gas, preferably selected from the group consisting of noble gases and nitrogen.

6. Cannabinoid solution according to one of the preceding claims, wherein ≤ 1 wt%, preferably ≤ 0.5 wt% O2 is present in the storage container, based on the weight of the cannabinoids contained in the solution.

7. Cannabinoid solution according to one of the preceding claims, wherein the oil comprises or consists of an MTC oil.

8. Cannabinoid solution according to one of the preceding claims, wherein the storage container is a vial, preferably an amber glass or violet glass vial, or part of a withdrawal system for preventing oxygen backflow during withdrawal.

9. The cannabinoid solution according to any one of the preceding claims, wherein the solution is eye drops, nasal oil, or a concentrate for the preparation of orally administrable solutions.

10. The cannabinoid solution according to any one of the preceding claims, wherein the amount of the solution corresponds to a single dose.

11. The cannabinoid solution according to any one of the preceding claims, wherein the solution is stable at 25°C and under UV light exclusion for ≥ 3 months, preferably for ≥ 6 months.

12. A method for producing a stable cannabinoid solution in oil according to any one of claims 1-11, comprising the following steps: a) providing a cannabinoid-containing extract or one or more (partially) synthetic cannabinoids, preferably as defined in more detail in claim 4, b) providing an oil, preferably as defined in more detail in claim 7, c) providing a storage container as defined in more detail in claim 1 or 8.d) mixing the substances provided in steps a) and b) in the absence of oxygen; e) filling the mixture produced in step d) into the storage container in the absence of oxygen; and f) closing the filled storage container so that no oxygen from the environment can enter the container. 13.) The method according to claim 12, wherein the substances provided in step a) and / or step b) have been subjected to a degassing treatment.

Images