Pharmaceutical compositions of cannabinoids

Abstract

Liquid composition, comprising: at least 40% by weight of a cannabinoid, 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 pharmaceutical compositions, of cannabinoids, preferably dronabinol.

[0002] 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 produced by decarboxylation, i.e., splitting off of CO2. For example, cannabidiol (CBD-(I)) is produced by decarboxylation of cannabidiolic acid (CBDS-(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

[0003] 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)

[0004] 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

[0005] In the case of a closed pyran ring as in the Δ 9 For 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).

[0006] Cannabinoids can be obtained in high purity (e.g., ≥ 95%, preferably ≥ 98%, and more preferably ≥ 99%) for use as active pharmaceutical ingredients (APIs) by extraction from plant materials, 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 into the desired cannabinoid(s) and purified. Methods known to those skilled in the art for obtaining highly pure cannabinoids include, for example,described in WO 2019 / 063848 A1 (purification of dronabinol by short-path vacuum distillation), WO 2017 / 055619 A1 (purification of cannabidiol by vacuum distillation), WO 2018 / 233991 A1 and WO 2016 / 135346 A1 (purification of cannabinoids by sequential centrifugal partition chromatography), EP 2314580 B1 (synthetic production of cannabinoids), EP 1896389 (production of dronabinol from cannabidiol) and EP 1409474 A1 (semi-synthetic production of dronabinol) and the references cited therein. Biosynthetic approaches are also being explored, see, for example, Carvalho Â. et al., FEMS Yeast Research, 2017, 17, fox037.

[0007] Cannabidiol, dronabinol, and their homologues are of medical interest due to their pharmacological properties. US 2009 / 0181080, US 2008 / 0112895, and US 2011 / 0306660 describe cannabinoid formulations in which a cannabinoid is present in an aqueous composition. AT 509 000 describes water-soluble preparations of cannabinoids and cannabis preparations containing a polar solvent, as well as their applications. US 2007 / 104741 describes compositions capable of self-forming emulsions in an aqueous environment (SEDDS). These compositions require a high concentration of a surfactant in the medium to create the SEDDS matrix. US 2011 / 0092583 describes oral dosage forms of cannabinoids in such a self-regulating system. WO 2008 / 005992 describes compositions comprising THC, a solvent selected from oils and C1-C4 alcohols, and an acid.

[0008] 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.

[0009] WO 2006 / 063109 A2 discloses stable dronabinol formulations in an oily medium, particularly sesame oil. 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.

[0010] While the selection of medium-chain triglycerides and palmitoy ascorbate, as described in DE 10 2012 105 063 B4, results in a cannabinoid composition with increased stability, such compositions may nevertheless 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 dronabinol oxidation) and / or a tripling of the sum of the total impurities may be observed, for example, by HPLC analysis.While this stability of the 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 substances received and possibly extend the shelf life.

[0011] The aim 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 pharmaceutically active ingredient.

[0012] The present invention solves the above problem by providing compositions of cannabinoids such as dronabinol and cannabidiol in which the amount of the cannabinoid via the oily medium and the excipient is increased compared to the prior art compositions.

[0013] 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.

[0014] In particular, the invention relates to a liquid composition comprising a cannabinoid as the active ingredient, an ascorbate ester as the excipient, and an oily medium in which the ascorbate is dissolved, wherein the total concentration of the cannabinoid as the active ingredient is at least 40% by weight, based on the total liquid composition. Preferably, the liquid composition consists of the cannabinoid, the ascorbate ester, and the oily medium. < Active ingredient / cannabinoid>

[0015] In principle, any known cannabinoid can be included as an active ingredient. The active ingredient is the cannabinoid responsible for the desired therapeutic effect of the composition. Such a cannabinoid is generally present in the composition with a purity of at least 95.0% by weight, preferably 98.0% by weight, and even more preferably with a purity of 99.0% by weight or higher. For example, a purity of 95% of the active ingredient means that in the starting material, the ratio between the mass of the components that are not part of the active ingredient and the mass of the cannabinoid contained as the active ingredient is 0.05:0.95. This ratio can also be reflected in the final product, namely in relation to the total mass of the composition without the oily medium and the excipient. As long as the active ingredient is of sufficient purity, it can be obtained using any suitable method known to the person skilled in the art, such as:Extraction from plant materials, chemical synthesis or semi-synthesis processes, e.g. according to any of the teachings described above.

[0016] 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.

[0017] Well-known natural cannabinoids include tetrahydrocannabinol (dronabinol, THC), cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabicyclovir (CBL), cannabivarol (CBV), tetrahydrocannabivarin (THCV), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), or cannabigerol monoethyl ether (CBGM). The active ingredient is preferably selected from dronabinol and cannabidiol. The most preferred active ingredient is dronabinol.

[0018] For the purposes of the invention, cannabinoids also include derivatives and homologues of natural cannabinoids, which may contain additional functional groups or have been obtained by derivatizing natural cannabinoids. For example, esters of cannabinoids can be obtained by reaction with carboxylic acids, e.g., THC hemisuccinate (THC-HS).

[0019] The active ingredient may be present in the liquid composition at at least 40% by weight, and preferably at least 45% by weight. In some embodiments, the active ingredient is present in the composition in the range of 40% to 75% by weight, preferably 40% to 60% by weight, more preferably 45% to 55% by weight, such as about 50% by weight, relative to 100% by weight of the liquid composition.

[0020] For example, the active ingredient may be dronabinol with a purity of at least 98% by weight, present in the liquid composition in an amount ranging from 45 to 55% by weight, such as 50% by weight. In some other embodiments, the active ingredient may be cannabidiol with a purity of at least 95% by weight, present in an amount ranging from 40 to 70% by weight. < Ascorbate esters >

[0021] An ascorbate ester is included as an excipient in the composition according to the invention. The pharmaceutically acceptable L-isomer is preferably used as the ascorbate. 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, 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 in its L-isomer form.

[0022] 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.

[0023] The excipient may be present in the liquid composition at a concentration ranging from 0.005 to 0.6 wt.%, based on 100 wt.% of the liquid composition, preferably at a concentration of 0.01 wt.% to 0.06 wt.%, more preferably at a concentration of 0.02 to 0.04 wt.%, for example at a concentration of 0.025 wt.%. In some embodiments, the excipient is dissolved in the oily medium at a concentration of 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 >

[0024] The pharmaceutical preparation according to the invention comprises a lipophilic medium. The additives are 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. <Zubereitung der flüssigen Zusammensetzung >

[0025] A liquid composition according to the invention can be prepared, for example, as follows.

[0026] The cannabinoid (e.g., dronabinol) is brought into a viscous state by heating, if necessary. During heating, the temperature is adjusted so that the cannabinoid can reach the desired viscous state without thermal decomposition (or substantially without thermal decomposition). When oily cannabinoids such as dronabinol are used as the 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 cannabinoid (e.g., 250 mg) is transferred into a flask. For solid cannabinoids (e.g., cannabidiol, which is a crystalline powder, or cannabigerol, which is also a powder), the powders can first be mixed with the oily medium and then heated until they dissolve.

[0027] A desired amount of the oily medium, in which the excipient may already be dissolved, is then mixed with the cannabinoid. In some embodiments, the same weighted mass as the cannabinoids can be added to the mixed oily medium and excipient (e.g., 250 mg of the mixed oily medium and excipient is added to 250 mg of cannabinoid). In some embodiments, if the oily medium and excipient are premixed, the oily medium can be added to a weighted amount of 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, the cannabinoid, and the excipient may be mixed in a different order than that described above.

[0028] 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 free of streaks upon visual inspection. The heating temperature for homogenization can range from 60 °C to 90 °C, preferably around 70 °C.

[0029] After homogenization, the liquid composition is allowed to cool (e.g., to room temperature, approximately 25 °C). Conventional filling procedures familiar to those skilled in the art can then be carried out.

[0030] The composition thus prepared can be stored in (sealed) vials or glass syringes 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.

[0031] In some embodiments, the liquid composition consists essentially of the cannabinoid, the ascorbate ester, and the oily medium. Those skilled in the art will appreciate that "essentially" means that only the cannabinoid, the oily medium, and the ascorbate esters are included as ingredients, but this does not exclude impurities (such as traces of other cannabinoids) that may be introduced or generated from the ingredients themselves. <bespiel>

[0032] 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.

[0033] Preparation of the ternary mixture: Dronabinol (Example 1: 50 g; Comparative Example 1: 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: 50 g; Comparative Example 1: 92.2 g) were then added to dronabinol under an inert atmosphere. The flask containing the mixture was then connected to a rotary evaporator, and the mixture was homogenized by stirring (at approximately 100 rpm) until free of streaks.

[0034] The solution was cooled and filled into glass syringes to measure long-term stability. The stability of the composition was assessed by HPLC-DAD analysis after storage in sealed containers at 25°C and 60% relative humidity. The HPLC analysis conditions were taken from the entry for dronabinol in the US Pharmacopoeia, UPS 41, 2018 edition: reverse-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. Stability was assessed by monitoring the amount of cannabinol (a degradation product of dronabinol) formed over time, as well as the amount of total impurities present (estimated from the areas of peaks other than dronabinol in the chromatogram). Surprisingly, the formulation of Example 1 contained slightly more cannabinol (0.1% in relation to the dronabinol content, estimated as the ratio of the respective peak areas) than Comparative Example 1 (e.g.B. <0.1% with respect to dronabinol content), but after twelve months of storage only a slight increase was observed for the formulation of Example 1 (0.2%), whereas a 5-10-fold increase (0.5%) was observed for the formulation of Comparative Example 1.

[0035] Similar conclusions were reached when considering the total amount of impurities. For the formulation of Comparative Example 1, the total impurities detected after 12 months were 3.5 times higher than the total impurities detected immediately after preparation. In contrast, for Example 1, the total impurities detected after 12 months were only 1.2 times higher than the total impurities detected immediately after preparation.

[0036] From the above examples, it can be seen that although in the formulation of Example 1 the amount of excipient is lower (both absolute and relative to the cannabinoid) than in Comparative Example 1, a surprisingly improved long-term stability 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] WO 2019 / 063848 A1

[0006] WO 2017 / 055619 A1

[0006] WO 2018 / 233991 A1

[0006] WO 2016 / 135346 A1

[0006] EP 2314580 B1

[0006] EP 1896389

[0006] EP 1409474 A1

[0006] US 2009 / 0181080

[0007] US 2008 / 0112895

[0007] US 2011 / 0306660

[0007] AT 509 000

[0007] US 2007 / 104741

[0007] US 2011 / 0092583

[0007] WO 2008 / 005992

[0007] WO 2006 / 063109 A2

[0009] DE 10 2012 105 063 B4 [0009, Zitierte Nicht-Patent Literature

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

[0005] F. Short et al., Angew. Chem. Internatl. Ed., 1965, 4, 872

[0005] R. Mechoulam et al., Tetrahedron Letters, 1969, 2339

[0005] Carvalho Â. et al., FEMS Yeast Research, 2017, 17, fox037

[0006] < / bespiel>

Claims

[1] Liquid composition comprising: at least 40% by weight of a cannabinoid, 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 cannabinoid is present in an amount of at least 45% by weight with respect to 100% by weight of the total liquid composition. [3] A liquid composition according to any one of claims 1 or 2, wherein the cannabinoid is present in an amount ranging from 40% to 75% by weight, preferably from 40% to 60% by weight, and more preferably from 45% to 55% by weight, most preferably about 50% by weight, with respect to 100% by weight of the liquid composition. [4] A liquid composition according to any one of the preceding claims, wherein the cannabinoid is present at a purity of at least 95%, preferably at least 98%, and more preferably 99% or higher. [5] A liquid composition according to any one of the preceding claims, wherein the cannabinoid is selected from the group consisting of: tetrahydrocannabinol (dronabinol, 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), and preferably is dronabinol or cannabidiol and even more preferably is dronabinol. [6] 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. [7] A liquid composition according to any one of the preceding claims, wherein the ascorbate ester is ascorbyl palmitate. [8] 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 0.005 to 0.6% by weight based on 100% by weight of the liquid composition, preferably in a concentration of from 0.01% to 0.06% by weight, more preferably in a concentration of from 0.02 to 0.04% by weight. [9] 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 0.07% 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. [10] 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. [11] 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. [12] A liquid composition according to any one of the preceding claims, wherein the composition comprises: 40 to 75% by weight of the cannabinoid, preferably 50% by weight; and 25 to 60 wt.% of a mixture of the oily medium and the ascorbate ester. [13] A liquid composition according to any one of the preceding claims, wherein the liquid composition consists of the cannabinoid, the ascorbate ester and the oily medium. [14] Liquid dosage form consisting of the liquid composition according to any one of the preceding claims.