METHOD FOR SOLUBILIZING NATURAL, ENDOGENOUS AND SYNTHETIC CANNABINOIDS

Abstract

The present invention relates to a method for solubilizing phytogenic, endogenous and synthetic cannabinoids, to the solubilisate produced by this method and respective uses as a pharmaceutical dosage form. A MCT oil- and non-hydrogenated phosphatidylcholine-based solubilization method is disclosed.

Claims

1. A method for solubilizing a cannabinoid, comprising the following steps: a) providing a first composition comprising at least one cannabinoid in the overall range of 10% to 45% per weight of the first composition and at least one medium-chained triglyceride in the overall range of 55% to 90% per weight of the first composition, wherein said at least one cannabinoid and said at least one medium-chained triglyceride are mixed under stirring in a temperature range of 15° C. to 40° C. and the relative weight percentages of the first composition add up to 100%; b) providing a second composition comprising at least one non-hydrogenated phosphatidylcholine in the overall range of 60% to 85% per weight of the second composition, at least one non-hydrogenated lysophosphatidylcholine in the overall range of 5% to 30% per weight of the second composition, at least one C.sub.2-C.sub.4 alcohol in the overall range of 3% to 30% per weight of the second composition and at least one of glyceryl stearate or a saturated or unsaturated C.sub.14 to C.sub.20 fatty acid in the overall range of 1% to 15% per weight of the second composition, wherein said ingredients are mixed under stirring at room temperature, the weight ratio of said at least one non-hydrogenated phosphatidylcholine to said one non-hydrogenated lysophosphatidylcholine is in the range of 15:1 to 2:1 and the relative weight percentages of the second composition add up to 100%; c) mixing said first composition and said second composition under stirring and the use of ultrasonic treatment in a frequency range of 20 kHz to 1 MHz and a power range of 50 W to 40 KW, wherein the weight ratio of said first composition to said second composition is in the range of 9:1 to 3:2; d) heating the mixture of step c) by continuously increasing the temperature with a temperature increment of 0.5° C./min to 5° C./min until a final temperature of 100° C. to 130° C. is reached, and f) letting the resulting solubilisate cool down to room temperature, wherein no polysorbate or polyethylene glycol is used for the method.

2. The method according to claim 1, wherein said at least one saturated or unsaturated C.sub.14 to C.sub.20 fatty acid is oleic acid.

3. The method according to claim 1, wherein said at least one C.sub.2 to C.sub.4 alcohol is ethanol.

4. The method according to claims 1, wherein additionally in step b) at least one antioxidant in the overall range of 0.01% to 10% per weight is added, said at least one antioxidant being a food additive and/or a pharmaceutically acceptable excipient.

5. The method according to claim 4, wherein said at least one antioxidant is ascorbyl palmitate and/or at least one tocopherol.

6. A solubilisate of at least one cannabinoid, produced by a method as defined in claim 1.

7. The solubilisate as defined in claim 6 for use in medicine.

8. The solubilisate for use according to claim 7 for masking the smell or taste of the at least one cannabinoid.

9. The solubilisate according to claim 7, in which the solubilisate of the at least one cannabinoid enhances the resorption or bioavailability of at least one cannabinoid.

10. The solubilisate according to claim 6, in which the at least one cannabinoid is cannabidiol.

11. A finished solution, wherein a solubilisate as defined in claim 6 is solved in an aqueous solution.

12. A pharmaceutical composition containing at least one cannabinoid formulated in a solubilisate as defined in claim 6 and at least one pharmaceutically acceptable excipient, respectively.

13. A pharmaceutical composition according to claim 12, wherein said at least one pharmaceutically acceptable excipient is selected from a group comprising carriers, binding agents, lubricants, glidants, disintegrants, colorants, buffers, preservatives, emulsifiers, permeation enhancers, antioxidants, diluents, pH-regulators, fat liquors, solvents, consistency enhancers, hydrotropes, sweeteners, acidifiers, thickening agents, anti-adherents, fillers, flavors, sweeteners, opacifiers, flavoring substances and aromatic substances.

14. A pharmaceutical composition according to claim 12 for use in medicine.

15. A pharmaceutical composition according to claims 12, wherein the at least one cannabinoid is Δ.sup.9-tetrahydrocannabinol or (-)-cannabidiol.

16. The method of claim 1 further comprising step e) maintaining the final temperature of step d) for a time range of 1 hour to 2 hours.

17. A pharmaceutical composition containing at least one cannabinoid formulated in a finished solution as defined in claim 11 and at least one pharmaceutically acceptable excipient, respectively.

18. The pharmaceutical composition of claim 17, wherein said at least one pharmaceutically acceptable excipient is selected from a group comprising carriers, binding agents, lubricants, glidants, disintegrants, colorants, buffers, preservatives, emulsifiers, permeation enhancers, antioxidants, diluents, pH-regulators, fat liquors, solvents, consistency enhancers, hydrotropes, sweeteners, acidifiers, thickening agents, anti-adherents, fillers, flavors, sweeteners, opacifiers, flavoring substances and aromatic substances.

19. A pharmaceutical composition according to claim 17 for use in medicine.

20. A pharmaceutical composition according to claim 17 wherein the at least one cannabinoid is Δ.sup.9-tetrahydrocannabinol or (-)-cannabidiol.

Description

EXAMPLES

[0200] In the ensuing examples the relative quantities of the solubilizing agents can be changed inside the margins indicated for each component in the method according to the invention. The addition of tocopherol is optional.

[0201] The resulting solubilisate can be diluted with an aqueous solution in order to obtain a finished solution. The volume of the aqueous solution can vary according to the desired volume of the finished solution.

[0202] It is possible to upscale or downscale the indicated amounts according to the desired absolute amount of the agent to be solubilized in the solubilisate. The solubilisate can be portioned according to the desired final amount of the agent that shall be administered to a patient in need thereof.

[0203] In general, the afforded solubilisates produced according to the method of the invention had a specific gravity of 0.92-0.94.

[0204] Standard chemicals were purchased from Sigma-Aldrich, Darmstadt, Germany.

Example 1: Solubilization of Δ.SUP.9.-tetrahydrocannabinol

[0205] Ca. 100 ml of a solubilisate of Δ.sup.9-tetrahydrocannabinol were generated by the following procedure:

[0206] 40 g Δ.sup.9-tetrahydrocannabinol (Ashanoa, Austria; purity >98%) were mixed with 50 ml MCT oil (Azelis, Moers, Germany) under stirring for 10 min at room temperature and atmospheric pressure to generate a first composition.

[0207] 8 g 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC; Lipoid GmbH, Ludwigshafen, Germany),), 1 g L-alpha-lysophosphatidylcholine (Lipoid GmbH, Ludwigshafen, Germany), 500 pl ethanol, 300 μl oleic acid and 200 mg glyceryl stearate were mixed under stirring for 5 min at room temperature and atmospheric pressure to generate a second composition.

[0208] The first composition and the second composition were mixed under stirring for 10 min at room temperature and atmospheric pressure. During the mixing ultrasound was applied to the joint composition via a BANDELIN SONOPULS HD 2070.2 (generator: GM 2070.2; ultrasonic converter: UW 2070; stepped standard horn SH 70 G; microtip MS 73, 3 mm; BANDELIN electronics GmbH & Co. KG, Berlin, Germany) at 100 W and 20 kHz.

[0209] Then the joint composition was heated under continuous stirring with an approximate temperature increment of 4° C./min. Thus, a clear solubilisate according to the invention was obtained after ca. 20 min at a final temperature of ca. 100° C. Then the heating and the stirring was stopped and the resulting solubilisate was allowed to cool down to room temperature. The solubilisate stayed clear and stable over min. 1 month.

[0210] Upon being diluted into an aqueous finished solution (10 ml solubilisate; bidest. water ad 100 ml) under stirring the finished solution became quickly clear and had an ivory to light brownish appearance. The taste of the finished solution was neutral.

Example 2: Solubilization of (-)-cannabidiol

[0211] Ca. 100 ml of a solubilisate of (-)-cannabidiol were generated by the following procedure:

[0212] 40 g (-)-cannabidiol (Ashanoa, Austria; purity >98%) were mixed with 50 ml MCT oil (Azelis, Moers, Germany) under stirring for 10 min at room temperature and atmospheric pressure to generate a first composition.

[0213] 7 g dimyristoyl phosphatidylcholine (DMPC; Lipoid GmbH, Ludwigshafen, Germany), 1.5 g of a mixture of 1-lysophosphatidylcholine and 2-lysophosphatidylcholine (weight ratio: 1:1; Lipoid GmbH, Ludwigshafen, Germany), 700 μl ethanol, 400 μl oleic acid, 200 mg glyceryl stearate and 200 mg alpha-tocopherol were mixed under stirring for 5 min at room temperature and atmospheric pressure to generate a second composition.

[0214] The first composition and the second composition were mixed under stirring for 10 min at room temperature and atmospheric pressure. During the mixing ultrasound was applied to the joint composition via a BANDELIN SONOPULS HD 2070.2 (generator: GM 2070.2; ultrasonic converter: UW 2070; stepped standard horn SH 70 G; microtip MS 73, 3 mm; BANDELIN electronics GmbH & Co. KG, Berlin, Germany) at 100 W and 20 kHz.

[0215] Then the joint composition was heated under continuous stirring with an approximate temperature increment of 5° C./min. Thus, a clear solubilisate according to the invention was obtained after ca. 20 min at a final temperature of ca. 120° C. Then the heating and the stirring was stopped and the resulting solubilisate was allowed to cool down to room temperature. The solubilisate stayed clear and stable over min. 6 weeks.

[0216] Upon being diluted into an aqueous finished solution (10 ml solubilisate; bidest. water ad 100 ml) under stirring the finished solution became quickly clear and had an ivory to light brownish appearance. The taste of the finished solution was neutral. The unpleasant taste of cannabidiol was completely covered.

Example 3: Solubilization of a Cannabis sativa Extract

[0217] Ca. 100 ml of a solubilisate of a Cannabis sativa extract were generated by the following procedure:

[0218] 40 g Cannabis sativa extract (Ashanoa, Austria) were mixed with 50 ml MCT oil (Azelis, Moers, Germany) under stirring for 15 min at room temperature and atmospheric pressure to generate a first composition.

[0219] 8 g non-hydrogenated soy bean PC and POPC (weight ratio: 1:1; Lipoid GmbH, Ludwigshafen, Germany), 1 g L-alpha-lysophosphatidylcholine (Lipoid GmbH, Ludwigshafen, Germany), 500 μl ethanol, 300 μl oleic acid and 200 mg ascorbyl palmitate were mixed under stirring for 5 min at room temperature and atmospheric pressure to generate a second composition.

[0220] The first composition and the second composition were mixed under stirring for 15 min at room temperature and atmospheric pressure. During the mixing ultrasound was applied to the joint composition via a BANDELIN SONOPULS HD 2070.2 (generator: GM 2070.2; ultrasonic converter: UW 2070; stepped standard horn SH 70 G; microtip MS 73, 3 mm; BANDELIN electronics GmbH & Co. KG, Berlin, Germany) at 100 W and 20 kHz.

[0221] Then the joint composition was heated under continuous stirring with an approximate temperature increment of 3° C./min. Thus, a clear solubilisate according to the invention was obtained after ca. 33 min at a final temperature of ca. 120° C. Then the heating and the stirring was stopped and the resulting solubilisate was allowed to cool down to room temperature. The solubilisate stayed clear and stable over min. one month.

[0222] Upon being diluted into an aqueous finished solution (10 ml solubilisate; bidest. water ad 100 ml) under stirring the finished solution became quickly clear and had an ivory to light brownish appearance. The taste of the finished solution was neutral. The grassy taste of Cannabis extracts was completely covered.

Reference Example 4: Solubilization of (-)-cannabidiol: Variation I

[0223] The experiment was conducted with the same ingredients and relative percentages as Example 2. The difference was that (-)-cannabidiol was not included in the first but in the second composition (the phosphatidylcholine composition).

[0224] The result was that (-)-cannabidiol was not solved properly in the phosphatidylcholine phase. Upon joining the first composition and the second composition, as provided in step c) of the process of the disclosure, the solubilization process did not properly work. Neither temperature increase nor sonification led to a clear solubilisate. This approach was not further pursued.

Reference Example 5: Solubilization of (-)-cannabidiol: Variation II

[0225] The experiment was conducted with the same ingredients and relative percentages as Example 2. The difference was that that there was no separation in a first and a second composition but all ingredients were added in one step and the method of the disclosure starts with step c).

[0226] The result was that the solubilization process took more time (>30 minutes) until the solution became clear. The temperature increase, however, was likewise stopped at 120° C. A problem showed with the stability. After 3-7 days substances from the solubilisate started to build a precipitate at the bottom of the vial. Simple agitation could not solve the precipitate again. As long-term stability is needed for a commercial product this approach was not further pursued.

Reference Example 6: Solubilization of (-)-cannabidiol: Variation III

[0227] The experiment was conducted with the same ingredients and relative percentages as Example 2. The difference was that the mixing ratio of the first composition to the second composition in step c) of the method of the disclosure was 20:1.

[0228] The result was that the solubilization process according to the disclosure did not work. The solubilization process according to the disclosure did not work. Neither temperature increase nor sonification led to a clear solubilisate.

Reference Example 7: Solubilization of (-)-cannabidiol: Variation IV

[0229] The experiment was conducted with the same ingredients and relative percentages as Example 2. The difference was that the mixing ratio of the first composition to the second composition in step c) of the method of the disclosure was 1:1.

[0230] The result was that the solubilization process according to the disclosure did not work. The mixture started to solidify at room temperature. Neither temperature increase nor sonification led to a clear solubilisate.

Reference Example 8: Solubilization of (-)-cannabidiol: Variation V

[0231] The experiment was conducted with the same ingredients and relative percentages as Example 2. The difference was that no ultrasonic treatment was used for the mixture of the first composition and the second composition, as provided in step c) of the method of the disclosure.

[0232] The result was that the awarded solubilisate did not become completely clear. Moreover, upon solving the solubilisate in an aqueous solution so called zebra-striping occurred. The sonification step seems therefore necessary for the method of the invention.

Reference Example 9: Solubilization of (-)-cannabidiol: Variation VI

[0233] The experiment was conducted with the same ingredients and relative percentages as Example 2. The difference was that the mixture of the first composition and the second composition of step c) of the method of the disclosure was not cautiously heated, as provided in step d) of the method of the disclosure, but was heated immediately to over 100° C.

[0234] The result was that the solubilization process according to the disclosure yielded a clear solution. But shortly after cooling down a crystallization process started. Crystals (apparently of (-)-cannabidiol) started to precipitate in a considerable degree. The cautious heating step seems therefore necessary for the method of the invention.