Cannabis extract concentrates

Abstract

Liquid composition, comprising: a primary cannabis extract containing a total of at least 50% by weight of cannabinoids, wherein the primary cannabis extract is included in such an amount that the total cannabinoid content is in the range of 40% to 75% by weight, based on 100% by weight of the total liquid composition; an oily medium consisting of triglycerides in which at least 95% of the acid residues are saturated fatty acids with a chain length of 8 and / or 10 carbon atoms; and an ascorbate ester in which the ascorbate ester is a fatty acid with a chain length in the range of 8 to 22 carbon atoms, contained in an amount of 0.01 to 1 wt.%, based on a total weight of the oily medium and the ascorbate ester.

Description

[0001] The invention relates generally to stabilized compositions, in particular to pharmaceutical compositions from cannabis extracts.

[0002] Cannabis (hemp), along with the genus Humulus (hops), belongs to the Cannabaceae family, although Humulus does not contain cannabinoids. Within the genus Cannabis, a botanical and chemotaxonomic differentiation occurs, namely into the species Cannabis sativa Linnaeus, Cannabis indica LAM, and Cannabis ruderalis, or into the "collective species" Cannabis sativa L., consisting of the subspecies Cannabis sativa ssp. sativa and ssp. indica.

[0003] Furthermore, cannabis is divided into drug hemp and fiber hemp, with the distinction being made based on the quantitative ratio of the main cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) (INN: dronabinol). Fiber hemp (also known as industrial hemp) is primarily used for industrial fiber production and may have a maximum Δ9-THC content of 0.2% (e.g., in Germany, among others), while the drug type can have a Δ9-THC content of approximately 5-35% (marijuana, hashish).

[0004] Cannabis sativa L. contains over 400 different compounds, of which more than 60 belong to the class of cannabinoids. Cannabinoids occur in the hemp plant Cannabis sativa in the form of their carboxyl derivatives, the cannabinoid carboxylic acids, from which the so-called "neutral cannabinoids" are formed by decarboxylation, i.e., the release of CO2. For example, cannabidiol (CBD-(I)) is formed by the decarboxylation of cannabidiolic acid (CBD-(II)). (-) -CBD 2-((1R,6R)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol Cannabidiolic acid (CBDS) 2,4-Dihydroxy-3-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-6-pentylbenzoic acid

[0005] Δ 9 -Tetrahydrocannabinol (Δ 9 -THC-Dronabinol (III)) is formed by decarboxylation from the positional isomers Δ 9 -Tetrahydrocannabinolic acids, the Δ 9 -Tetrahydrocannabinolic acid-A (THCS-A-(IV)) (IV)) and the Δ 9 -Tetrahydrocannabinolic acid-B (THCS-B-(V)). (-)-A 9 -THC (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol Δ 9- Tetrahydrocannabinolic acid-A (THCS-A) (6aR,10aR)-1-Hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-2-carboxylic acid, Δ 9- Tetrahydrocannabinolic acid-B (THCS-B) (6aR,10aR)-1-Hydroxy-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene-4-carboxylic acid)

[0006] Cannabigerol (VI) is formed in this way from cannabigerolic acid (CBGS-(VII)). Cannabigerol (CBG) (Z)-2-(3,7-Dimethylocta-2,6-dienyl)-5-pentylbenzene-1,3-diol Cannabigerolic acid (CBGS) (Z)-3-(3,7-Dimethylocta-2,6-dienyl)-2,4-dihydroxy-6-pentylbenzoic acid

[0007] In the case of a closed pyran ring as in the Δ 9For THC (III), two positional isomers of the carboxylic acids -A and -B are possible. Both forms occur naturally (cf., for example, R. Mechoulam et al., Tetrahedron, 1965, 21, 1223; F. Korte et al., Angew. Chem. Internatl. Ed., 1965, 4, 872 and R. Mechoulam et al., Tetrahedron Letters, 1969, 2339).

[0008] Cannabidiol, dronabinol, and their homologues are of medical interest due to their pharmacological properties. Cannibinoids can be obtained in high purity (e.g., ≥ 95%, ≥ 98%, or even ≥ 99%) for use as active pharmaceutical ingredients (APIs) through extraction from plant material, chemical synthesis, and / or semi-synthetic processes in which intermediates (e.g., the cannabinoid acid derivatives described above) are extracted from plants and subsequently converted and purified into the desired cannabinoid(s).

[0009] In addition to compositions using purified cannabinoids, cannabis extracts are increasingly being used as the basis for pharmaceutical compositions. Such cannabis extracts typically contain a variety of substances, in particular several cannabinoids and, where appropriate, other compound classes such as terpenes and terpenoids. The cannabinoid(s) is / are usually the main component of the extract. Furthermore, one cannabinoid may be present in greater quantities than the other cannabinoids, depending on the type of plant used to produce the extract (e.g., medical cannabis or industrial hemp), the plant's growth conditions, and / or the extraction method.

[0010] One obstacle in the production of pharmaceutical preparations of the aforementioned compounds is their relatively high sensitivity to oxidation. To effectively counteract a loss of activity, the preparations must therefore either be freshly prepared or require complex galenic preparation to mitigate the negative effects of light, air, and heat. Proper storage (cool and dark) is not always guaranteed, especially when the preparations are given to the patient to take home.

[0011] DE 10 2012 105 063 B4 discloses stabilized cannabinoid formulations in which the cannabinoid(s) and palmitoyl ascorbate (as an excipient) are dissolved in an oily medium. Possible oily media include, in particular, medium-chain triglyceride mixtures containing capric and caprylic acid.

[0012] While the selection of medium-chain triglycerides and palmitoy ascorbate disclosed in DE 10 2012 105 063 B4 resulted in a cannabinoid composition with increased stability, such compositions may occasionally exhibit an increase in the degradation products of the active ingredient over time. For example, after 12 months or longer of storage of a 25 mg / ml solution of dronabinol in medium-chain triglycerides (e.g., Miglyol 812) mixed with 0.05 wt% palmitoy ascorbate (e.g., prepared according to New Formulation Formulary 22.8), an increase in the cannabinol concentration (a degradation product formed by oxidation of dronabinol) and / or a tripling of the sum of the total impurities may be observed, for example, by HPLC analysis.While the observed stability of these preparations is sufficient for a shelf life of approximately six months, it may be desirable to further improve the stability in order to ensure a higher quality of the accepted substances and possibly extend the shelf life.

[0013] The object of the present invention is therefore to provide cannabinoid compositions with increased stability. In some embodiments, the improved stability is assessed based on the observed increase in one or more degradation products of the cannabinoid selected as the pharmaceutical active ingredient.

[0014] The present invention solves this problem by providing compositions of cannabis extracts containing cannabinoids such as Δ 9-THC and cannabidiol, wherein in these compositions the amount of cannabinoids with respect to the oily medium and the excipient is increased compared to compositions according to the prior art.

[0015] According to the invention, it was surprisingly found that the stability of these compounds and their preparations is greatly improved by increasing the cannabinoid concentration, even without a corresponding increase in the amount of the stabilizing excipient. Intake of the cannabinoids as part of an extract also appears to be beneficial.

[0016] In particular, the invention relates to a liquid composition comprising a primary cannabis extract containing one or more cannabinoids, an ascorbate ester as an excipient, and an oily medium in which the ascorbate is dissolved, wherein the total concentration of cannabinoids is at least 40% by weight, based on the total liquid composition. Preferably, the liquid composition consists of the cannabis extract, the ascorbate ester, and the oily medium. < Cannabis Extract>

[0017] In principle, any known cannabinoid can be included as an active ingredient. The active ingredient is the cannabinoid that is responsible for the desired therapeutic effect of the composition.

[0018] Natural cannabinoids include, for example, plant cannabinoids (phytocannabinoids). Over 60 cannabinoids are known. These can be divided into different types: cannabigerol type, cannabichromene type, cannabidiol type, tetrahydrocannabinol and cannabinol type, cannabielsoin type, iso-tetrahydrocannabinol type, cannabicyclol type, and cannabicitran type. These differ primarily in the type of cyclization of the precursor compound cannabigerol.

[0019] Well-known natural cannabinoids are tetrahydrocannabinol (dronabinol, Δ9-THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), or cannabigerol monoethyl ether (CBGM). The cannabis extract contained in the composition may contain one or more of the above-mentioned cannabinoids. Preferably, the active ingredient is derived from Δ 9 -THC and cannabidiol are selected. The most preferred active ingredient is Δ9-THC.

[0020] The extract of the present invention is a primary extract (full cannabis extract) that can be obtained directly from dried and (ground) plant material, especially cannabis flowers, by extraction with supercritical CO2, short-chain alcohols (e.g., with fewer than 6 carbon atoms), or lipophilic organic solvents (e.g., alkanes or cycloalkanes). If an organic solvent that is not suitable for humans or animals is used, the solvent is removed. Preferably, the solvent extracts primarily lipophilic components such as cannabinoids, terpenes, and terpenoids. A thermal decarboxylation step can also be performed. Those skilled in the art are familiar with the techniques for obtaining primary cannabis extracts.

[0021] Since the extract is a primary extract, it contains other substances such as terpenes and terpenoids in addition to the cannabinoids as active ingredients. Cannabinoids are generally present in the extract in an amount of at least 50% by weight, but no more than 90% by weight, preferably between 60 and 80% by weight, and even more preferably between 70 and 80% by weight. In addition to the cannabinoids, the extract contains approximately 10-15% by weight of terpenes and terpenoids; the remainder of the extract is made up of waxes, fats / oils, flavonoids, and other secondary metabolites.

[0022] The extract content in the liquid composition is selected based on the target concentration of the one or more cannabinoids acting as active ingredient(s). The active ingredient may be present in the liquid composition in an amount of 40% to 75% by weight, preferably 40% to 60% by weight, and more preferably 45% to 55% by weight, such as about 50% by weight, relative to 100% by weight of the liquid composition. For example, if the extract contains the main cannabinoid at a concentration of 80% by weight and the target concentration for the main cannabinoid in the liquid composition is 50% by weight, the amount of extract in the liquid composition will be 62.5% by weight.

[0023] The active ingredient can be, for example, Δ 9-THC, which is contained in the liquid composition in an amount ranging from 45 to 55% by weight, e.g., about 50% by weight. The primary cannabis extract can, for example, contain 60 to 80% by weight of Δ 9 -THC. In some other embodiments, the active ingredient may be cannabidiol, which may be present in the liquid composition in the range of 40 to 60 wt.%. The primary cannabis extract may, for example, contain 60 to 80 wt.% cannabidiol. < Ascorbate esters >

[0024] An ascorbate ester is included as an excipient. The ester is preferably formed with the hydroxy group at the 6-position of the ascorbate molecule. The acid residue forming the ester is preferably a medium- or long-chain acid, with the chain length being chosen to impart sufficient solubility to the ascorbate ester in the oily medium. The acid residue can, for example, be a fatty acid with a chain length in the range of 8 to 22 carbon atoms, preferably 12 to 18 carbon atoms, more preferably 14 to 16 carbon atoms, and even more preferably 16 carbon atoms. The most preferred excipient is ascorbyl palmitate.

[0025] The pharmaceutically accepted L-isomer is preferably used as the ascorbate. Without being bound or limited by any theory, it is possible that the ascorbate stabilizes the composition primarily through its action as an antioxidant. In this case, it can be assumed that the D-isomer may also be effective for preserving the composition. Therefore, in some alternative embodiments, the composition contains ascorbate as the D-isomer or as any mixture of D- and L-isomers.

[0026] The excipient may be present in the liquid composition in a concentration ranging from 0.003 to 0.6 wt%, based on 100 wt% of the liquid composition, preferably in a concentration of from 0.008 wt% to 0.06 wt%, more preferably in a concentration of from 0.01 to 0.03 wt%, for example in a concentration of 0.015 wt%. In some embodiments, the excipient is dissolved in the oily medium in a concentration of from 0.01 to 1 wt%, preferably from 0.03 wt% to 0.7 wt%, more preferably from 0.04 wt% to 0.06 wt%, such as 0.05 wt%, based on 100 wt% of the oily medium and the excipient. < Oily medium >

[0027] The pharmaceutical preparation according to the invention comprises a lipophilic medium. The excipient is dissolved in this medium. The oily medium according to the invention preferably comprises or consists of triglycerides, in particular triglycerides that predominantly contain fatty acids with a chain length of 8 and / or 10 carbon atoms. For example, the oily medium can consist of triglycerides in which at least 95% of the acid residues are saturated fatty acids with a chain length of 8 and / or 10 carbon atoms. Acid residues with other chain lengths can be present to a limited extent. For example, the oily medium can contain up to 2.0% caproic acid and / or up to 1.0% lauric acid and / or up to 1.0% myristic acid and / or up to 1.0% fatty acids with a chain length of 16 carbon atoms or more. The fatty acids that are not saturated fatty acids with a C8 or C10 chain length are preferably within all of the above-mentioned ranges.In some embodiments, the oily medium may consist of medium-chain triglycerides, for example, as defined in the European Pharmacopoeia, 10th edition 2020. Preferred oily media include Myritol 318 PH (also known as Kollisolv MCT 70) and Miglyol 812. The preferred oily medium is Miglyol 812. < Preparation of the liquid composition >

[0028] A liquid composition according to the invention can be prepared, for example, as follows.

[0029] Cannabis plant material (e.g., medical cannabis, Cannabis sativa), preferably flowers, is collected and dried. The dried plant material is then contacted and mixed with an extractant, which can be, for example, CO2, a short-chain alcohol (e.g., ethanol or butanol), or a lipophilic organic solvent (e.g., alkanes or cycloalkanes). After sufficient contact time, the extract is separated from solid residues (e.g., by filtration) and concentrated under mild conditions to largely, preferably completely, remove the extractant. The primary extract is then thermally decarboxylated in the usual manner.

[0030] The primary extract thus obtained is brought into a viscous state, if necessary by heating. During heating, the temperature is adjusted so that the extract reaches the desired viscous state without (or essentially not at all) thermal decomposition of the main cannabinoid. For example, if it is an extract of medical cannabis and Δ 9 If THC is included as the (main) active ingredient, the heating temperature can be in the range of 60 °C to 90 °C, preferably around 70 °C. In the viscous state, the desired amount of the extract is transferred into a flask.

[0031] The desired amount of the oily medium, in which the excipient may already be dissolved, is then added to the cannabis extract. In some embodiments, the amount of oily medium can be determined based on the estimated or measured concentration of the active ingredient in the cannabis extract. For example, if the cannabis extract contains 80 wt.% Δ 9-THC and the target concentration in the liquid composition is 50 wt%, approximately 62.5 g of extract are mixed with 37.5 g of stabilized oily medium per 100 g of liquid composition. In some embodiments, if the oily medium and excipient are premixed, the oily medium can be added to a weighted amount of the excipient (e.g., about 0.05 g) up to a desired total weight (e.g., up to 100 g). The mixture is then stirred and heated until the excipient is completely dissolved. The heating temperature of the heating bath can, for example, be in the range of 70°C to 100°C, e.g., about 85°C. In some alternative embodiments, the oily medium, cannabis extract, and excipient can be mixed in a different order than that described above.

[0032] The mixture is then homogenized, e.g., by connecting the flask to a rotary evaporator and gently heating and rotating the flask containing the mixture until it appears streak-free upon visual inspection. The heating temperature for homogenization can range from 40 °C to 90 °C, preferably from 50 °C to 70 °C.

[0033] After homogenization, the liquid composition is allowed to cool (e.g., to room temperature, approximately 25°C). At this point, the titer of the main cannabinoid can be re-determined, e.g., by HPLC. If the titer is too far from the target value, the concentration of the main cannabinoid can be adjusted (e.g., by adding purified cannabinoid if it is too diluted, or by diluting with additional oily medium if it is too concentrated). Homogenization can be repeated if necessary. Conventional filling procedures known to those skilled in the art can then be carried out.

[0034] The composition thus prepared can be stored in (sealed) vials for distribution to local distributors (e.g., pharmacies), where it can be further diluted before being dispensed to patients according to their prescription. Accordingly, the liquid composition can be considered a finished galenic form (e.g., a liquid dosage form). In some alternative embodiments, the liquid composition can be used to manufacture capsules, such as hard capsules. For this purpose, the liquid preparation is mixed with, for example, a suitable hard fat, adjusted to the target potency, and filled into capsules.

[0035] In some embodiments, the liquid composition consists of the cannabis extract, the ascorbate ester, and the oily medium. Those skilled in the art will understand that "consisting of" means that only the cannabis extract, the oily medium, and the ascorbate esters are included as components, but this does not exclude impurities that may be introduced or generated by the components themselves. <bespiel>

[0036] Preparation of the oily medium with excipient. Palmitoyl ascorbate (0.05 g) was weighed into a flask, to which Miglyol 812 was added to a total weight of 100 mg. The mixture was stirred at approximately 85 °C for approximately 1 hour until the palmitoyl ascorbate was completely dissolved.

[0037] Preparation of the ternary mixture: A cannabis extract (Example 1: 71 g, Δ9-THC content 70 wt%) or dronabinol (Comparative Example 1: 50 g; Comparative Example 2: 2.5 g; purity 99%) was weighed into a round-bottom flask under an inert atmosphere (oxygen content <100 ppm). The mixed oily medium and the excipient (Example 1: 29 g; Comparative Example 1: 50 g; Comparative Example 2: 92.2 g) were then added to the cannabis extract (or dronabinol) under an inert atmosphere. The flask containing the mixture was then connected to a rotary evaporator, and the mixture was homogenized until free of streaks.

[0038] The solution was cooled and filled into glass syringes to measure long-term stability. The stability of the composition was assessed by HPLC analysis after storage in sealed glass syringes at 25°C and a relative humidity of 60%. Stability was determined by monitoring the amount of cannabinol (a degradation product of Δ9-THC) formed over time. The increase in cannabinol in Example 1 was monitored using chromatographic conditions according to the method described in the German Pharmacopoeia, 2021, for the adjusted cannabis extract. The HPLC analysis conditions for the comparative examples were taken from the entry for dronabinol in US Pharmacopoeia, UPS 41, 2018 edition: reversed phase, polar end-capped C18, 4 µm, 250 x 4.6 mm; MeOH / H2O / THF / MeCN 45 / 25 / 20 / 10 v / v / v / v, 1 ml / min.

[0039] Surprisingly, although slightly more cannabinol (0.2% and 0.1%, respectively) was detected in the formulation of Example 1 and Comparative Example 1 than in Comparative Example 2 (<0.1%), after twelve months of storage a 5-10-fold increase (0.5%) was observed in the formulation of Comparative Example 2, a slight increase (0.2%) was observed in the formulation of Comparative Example 1, while no change was observed in the formulation of Example 1.

[0040] From the above examples, it can be seen that, although the amount of excipient in the formulation of Example 1 is lower (both absolute and relative to the cannabinoid) than in Comparative Example 2, a surprisingly improved long-term stability was observed. Comparison with the result of Comparative Example 1 shows a further unexpected increase in stability when the cannabinoid is delivered as a primary plant extract rather than as a purified compound.

[0041] While essentially no reduction in the A9-THC concentration was observed in the composition of Example 1, in the formulation containing the cannabis extracts, the oily medium and the ascorbate ester, prepared according to the above procedure, but in which the initial total content of Δ 9 -THC was 5 wt%, a reduction of over 5% of the original Δ9-THC concentration was observed. QUOTES CONTAINED IN THE DESCRIPTION

[0000] This list of documents submitted by the applicant was generated automatically and is included solely for the convenience of the reader. This list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions. Cited patent literature

[0000] DE 10 2012 105 063 B4 [0011, 0012] Cited non-patent literature

[0000] R. Mechoulam et al., Tetrahedron, 1965, 21, 1223

[0007] F. Korte et al., Angew. Chem. Internatl. Ed., 1965, 4, 872

[0007] R. Mechoulam et al., Tetrahedron Letters, 1969, 2339

[0007] < / bespiel>

Claims

[1] Liquid composition comprising: a primary cannabis extract containing at least 50% by weight of cannabinoids in total, wherein the primary cannabis extract is present in an amount such that the total cannabinoid content is in a range of 40 to 75% by weight, based on 100% by weight of the total liquid composition; an oily medium consisting of triglycerides in which at least 95% of the acid residues are saturated fatty acids with a chain length of 8 and / or 10 carbon atoms; and an ascorbate ester in which ascorbate ester the acid residue is a fatty acid having a chain length in the range of 8 to 22 carbon atoms, contained in an amount of 0.01 to 1 wt.% based on a total weight of the oily medium and the ascorbate ester. [2] Liquid composition according to claim 1, wherein the total content of cannabinoids in the primary extract is in the range of 50 wt% to 90 wt%, preferably 60 to 80 wt% and more preferably 70 to 80 wt%. [3] A liquid composition according to any one of claims 1 or 2, wherein the primary extract is present in an amount such that a first cannabinoid is present in an amount ranging from 40% to 60% by weight, preferably from 45% to 55% by weight, and most preferably about 50% by weight, with respect to 100% by weight of the liquid composition. [4] The liquid composition of claim 3, wherein the first cannabinoid is selected from the group consisting of: tetrahydrocannabinol (Δ9-THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclol (CBL), cannabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromvarin (CBCV), cannabigerovarin (CBGV) and cannabigerol monoethyl ether (CBGM), preferably Δ 9 -THC or cannabidiol and even more preferably Δ 9 -THC is. [5] A liquid composition according to any one of the preceding claims, wherein the primary cannabis extract is obtained from dried flowers of medicinal cannabis. [6] A liquid composition according to any one of the preceding claims, wherein the primary cannabis extract further contains 10-15% by weight of terpenes and terpenoids. [7] A liquid composition according to any one of the preceding claims, wherein the acid residue of the ascorbate is a fatty acid having a chain length of 12 to 18 carbon atoms, preferably 14 to 16 carbon atoms, and more preferably 16 carbon atoms. [8] A liquid composition according to any one of the preceding, wherein the ascorbate ester is ascorbyl palmitate. [9] A liquid composition according to any one of the preceding claims, wherein the ascorbate ester is present in the liquid composition in an amount ranging from 0.003 to 0.6% by weight based on 100% by weight of the liquid composition, preferably in a concentration of from 0.008% to 0.06% by weight, more preferably in a concentration of from 0.01 to 0.03% by weight. [10] A liquid composition according to any one of the preceding claims, wherein the ascorbate ester is present in an amount of from 0.03% to 0.7% by weight, more preferably from 0.04% to 0.06% by weight, such as 0.05% by weight, based on the total weight of the oily medium and the ascorbate ester. [11] Liquid composition according to any one of the preceding claims, wherein of the acid residues of the triglycerides of the oily medium, up to 2.0% are caproic acid and / or up to 1.0% are lauric acid and / or up to 1.0% are myristic acid and / or up to 1.0% are fatty acids having a chain length of 16 or more carbon atoms. [12] A liquid composition according to any one of the preceding claims, wherein the oily medium is medium chain triglycerides, preferably selected from Myritol 318 PH and Miglyol 812, and more preferably the oily medium is Miglyol 812. [13] A liquid composition according to any one of the preceding claims, wherein the liquid composition comprises: 60 to 80% by weight of the primary cannabis extract, based on 100% by weight of the liquid composition, wherein the cannabis extract contains a first cannabinoid in an amount of 65 to 80% by weight, based on the cannabis extract; and 20 to 40% by weight of a mixture of the oily medium and the ascorbate ester. [14] A liquid composition according to any one of the preceding claims, wherein the liquid composition consists essentially of the cannabis extract, the ascorbate ester and the oily medium. [15] Liquid dosage form consisting of the liquid composition according to any one of the preceding claims.