CANNABINOID EMULSIONS

Abstract

The technology disclosed in this specification pertains to an emulsion comprising (i) a continuous aqueous phase, (ii) an disperse oil phase comprising a cannabinoid, and (iii) an emulsifier which is gum arabic, wherein the weight ratio of gum arabic to said disperse oil phase is ≥1:1. The emulsion may have a relatively small particle size with a relatively high oil load in combination. The emulsion may also have a small particle size without requiring a polysorbate or any co-surfactant.

Claims

1. An emulsion comprising (i) a continuous aqueous phase, (ii) an disperse oil phase comprising a cannabinoid, and (iii) an emulsifier which is gum arabic, wherein the weight ratio of gum arabic to said disperse oil phase is at least 1:1.

2. The emulsion according to claim 1, wherein the weight ratio of gum arabic to said disperse oil phase is at least 1.5:1.

3. The emulsion according to claim 1, wherein the weight ratio of gum arabic to said disperse oil phase is at least 3:1.

4. The emulsion according to claim 1, wherein the weight ratio of gum arabic to said disperse oil phase is from 1.1 to 6:1.

5. The emulsion according to claim 1, wherein the weight fraction of the disperse oil phase in the emulsion is from 1 to 20 wt. % based on the weight of the emulsion.

6. The emulsion according to claim 1, wherein said disperse oil phase has a median particle size (d50) of 500 nm.

7. The emulsion according to claim 1, wherein the weight fraction of the disperse oil phase in the emulsion is from 2 to 8 wt. % based on the weight of the emulsion; wherein the weight ratio of gum arabic to said disperse oil phase is greater than 3:1; and wherein the disperse oil phase has a median particle size (d50) of 250 nm or less.

8. (canceled)

9. (canceled)

10. The emulsion according to claim 1, wherein the weight fraction of the disperse oil phase in the emulsion is from 8 to 20 wt. % based on the weight of the emulsion; wherein the weight ratio of gum arabic to said disperse oil phase is from 1:1 to 3:1; wherein said disperse oil phase has a median particle size (d50) from 200 to 500 nm.

11. (canceled)

12. (canceled)

13. The emulsion according to claim 1, wherein said cannabinoid is a) one or more of tetrahydrocannabinol (THC) and cannabidiol (CBD) or is b) selected from the group consisting of tetrahydrocannabinol (THC) and cannabidiol (CBD) cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabielsoin (CBE), iso-tetrahydrocannabinol (iso-THC), cannabicyclol (CBL), cannabicitran (CBT), cannabivarin (CBV), tetrahydrocannabivarin (THCV), THCP (tetrahydrocannabiphorol), cannabidivarin (CBDV), cannabichromevarin (CBCV), cannabigerovarin (CBGV), cannabigerol monomethyl ether (CBGM), tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA) or mixtures thereof.

14. The emulsion according to claim 1, wherein, the disperse oil phase comprises a vegetable oil.

15. The emulsion according claim 1, wherein said vegetable oil is selected from the group consisting of medium chain triglyceride (MCT) oil, coconut oil, corn oil, cottonseed oil, olive oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil and canola oil.

16. The emulsion according to claim 1, wherein the weight ratio of said cannabinoid to vegetable oil is between 1:0.1 and 1:9.

17. The emulsion according to claim 1, wherein said gum arabic is the sole emulsifier in the emulsion.

18. (canceled)

19. A method comprising admixing an emulsion comprising (i) a continuous aqueous phase, (ii) an disperse oil phase comprising a cannabinoid, and (iii) an emulsifier which is gum arabic, wherein the weight ratio of gum arabic to said disperse oil phase is greater than 1:1 and a second ingredient to make a beverage.

20. (canceled)

21. (canceled)

22. A method comprising: i. providing an aqueous phase comprising water and an emulsifier which is gum arabic ii. providing an oil phase comprising an oil and a cannabinoid extract, iii. mixing said aqueous phase and said oil phase to create a pre-emulsion; and iv. homogenizing said pre-emulsion to obtain the emulsion. wherein the weight ratio of gum arabic to said disperse oil phase is greater than 1:1.

23. The method of claim 22 wherein the emulsion has an oil disperse phase and wherein the weight fraction of the disperse is from 1 to 20 wt. % based on the weight of the emulsion.

24. The method of claim 22 wherein the weight fraction of the disperse oil phase in the emulsion is from 2 to 8 wt. % based on the weight of the emulsion; wherein the weight ratio of gum arabic to said disperse oil phase is greater than 3:1.

25. The method of claim 22 wherein the wherein the weight fraction of the disperse oil phase in the emulsion is from 8 to 20 wt. % based on the weight of the emulsion; wherein the weight ratio of gum arabic to said disperse oil phase is from 1:1 to 3:1.

26. The method of claim 22, wherein said cannabinoid is one or more of tetrahydrocannabinol (THC) and cannabidiol (CBD).

27. The method of claim 22, wherein the weight ratio of said cannabinoid to vegetable oil is between 1:0.1 and 1:9.

Description

EXAMPLES

Examples 1-6, Reference Experiment A

[0065] All examples and comparative experiments described herein involved the use of gum arabic from Acacia senegal (TIC Pretested® Gum Arabic Spray Dry Powder).

[0066] Nanoemulsions comprising gum arabic as the emulsifier and CBD isolate powder ((>98% purity) purchased from Treehouse Biotech (Longmont, Colo.) as the cannabinoid source were prepared according to the following formulations (Table 1). All percentages are given in wt. %.

TABLE-US-00001 TABLE 1 Gum MCT CBD Citric Ascorbic Potassium Sodium Ratio Gum arabic Oil Isolate acid acid Sorbate Benzoate Water arabic:oil Example (%) (%) (%) (%) (%) (%) (%) (%) phase 1 20.0 3.0 2.0 0.2 0.2 0.1 0.1 74.4 5:1 2 25.0 3.0 2.0 0.2 0.2 0.1 0.1 69.4 5:1 3 20.0 6.0 4.0 0.2 0.2 0.1 0.1 69.4 2:1 4 25.0 6.0 4.0 0.2 0.2 0.1 0.1 64.4 2.5:1.sup.  5 20.0 7.2 4.8 0.2 0.2 0.1 0.1 67.4 1.67:1   6 20.0 7.2 4.8 0.4 — — 0.05 67.55 1.67:1   A (ref) 10.0 12.0 8.0 0.2 0.2 0.1 0.1 69.4 0.5:1.sup. 

[0067] Citric acid, ascorbic acid, sodium benzoate and potassium sorbate were dissolved in room temperature deionized water via overhead mixing for 5 minutes. The gum arabic was added to the solution and allowed to mix for 30 minutes. Simultaneously in a separate beaker, the MCT (medium chain triglyceride) oil was heated on a hot plate to 65° C. The CBD isolate powder was added to the MCT oil and mixed (via magnetic stirrer bar) until fully dissolved. The CBD oil solution was allowed to cool to room temperature.

[0068] A pre-emulsion was made by adding the oil phase into the aqueous phase under high shear mixing conditions (10,000 rpm) for 2 minutes in a homogenizer (Manufacturer: Ross, Model: HSM-LCI-T).

[0069] The pre-emulsion was further processed using a Microfluidizer (Microfluidics, Model: M-110EH). The interaction chamber used was the F12Y-H30Z. The mixtures were processed at a pressure of 10000 PSI, or 689.48 bar.

[0070] The particle size of the emulsion is immediately tested using a laser diffraction particle size analyzer (Manufacturer: Malvern Mastersizer 2000) where the median particle size (d50), as well as d10, d90, and d[4,3] are recorded. For emulsions with a median particle size (d50) under 100 nm, particle size measurements were taken by dynamic light scattering (DLS) using a Malvern Zetasizer Nano-S and reported as Z-average particle size. Table 2 shows the particle sizes taken after various passes.

[0071] The emulsions obtained in examples 1 and 2 have were found to have a median particle size (d50) of below 200 nm. The emulsions obtained in examples 3 to 6 were found to have a median particle size (d50) below 400 nm for emulsions wherein the weight fraction of the disperse phase was as high as 12 wt. %.

TABLE-US-00002 TABLE 2 Example Pass d10 (nm) d50 (nm) d90 (nm) d[4, 3] (nm) 1 1 151.85 235.91 349.18 246.11 3 106.86 172.19 255.62 177.95 5 108.21 175.55 262.26 181.63 2 1 119.54 198.88 302.51 206.44 3 100.5 158.88 236.09 164.32 5 98.78 156.51 232.65 161.99 3 1 144.96 247.24 375.06 256.15 3 186.15 296.68 422.28 301.51 5 227.7 349.33 486.59 354.14 4 1 152.65 255.57 377.67 262.04 2 190.59 281.43 387.54 287.07 3 135.3 226.18 335.35 232.02 5 1 188.33 305.92 462.69 319.55 2 201.77 326.5 478.85 335.09 3 238.02 378.62 539.93 385.66 6 2 229.5 372.11 557.76 385.48 A (Ref) 1 558.5 983.43 1352.70 975.42 2 676.56 993.13 1307.28 991.22 3 687.69 994.09 1305.77 994.66

Examples 1.a-6.a, Reference Experiment A.a

[0072] Beverage stability was evaluated by diluting the nanoemulsions, obtained after the final pass, to a CBD content of 25 mg per 355 g of beverage, such as according to Table 3. The citric acid and sodium benzoate are added to room temperature deionized water and mixed via magnetic stir bar for 5 minutes. The CBD nanoemulsion is added to the solution and lightly mixed. A 12 oz bottle is filled with the solution and capped. The bottle is store horizontally at room temperature without manipulation for 21 days. After 21 days, the beverage is visually examined without manipulation for the presence of a white ring at the top of the beverage (creaming of the CBD emulsion). The beverage can also be examined for sedimentation.

TABLE-US-00003 TABLE 3 Ingredient % (w/w) Emulsion (2% CBD isolate; 4%; 4.8%; 8%) 0.35; 0.7; 0.84; 1.4 Sodium Benzoate 0.1 Citric acid 0.3 Water Balance

[0073] Table 4 provides the beverage stability and TSI of the emulsions.

TABLE-US-00004 TABLE 4 Example Beverage Stability TSI (Global) 1.a Stable 0.9 2.a Stable 1.3 3.a Stable 0.8 4.a Stable 0.5 5.a Stable 0.9 6.a Stable 0.8 A.a  Not Stable 2.7

Reference Experiment B

[0074] A nanoemulsion using polysorbate 80 as the emulsifier was prepared according to Table 5. The polysorbate nanoemulsion was processed at a pressure of 30000 PSI. The particle size measurement was taken by dynamic light scattering (DLS) using a Malvern Zetasizer Nano-S and reported as Z-average particle size. The results have been presented in Table 6.

TABLE-US-00005 TABLE 5 Experiment B Polysorbate MCT CBD Citric Ascorbic Potassium Sodium 80 Oil Isolate Acid Acid Sorbate Benzoate Water (%) (%) (%) (%) (%) (%) (%) (%) 25.0 7.5 5.0 0.2 0.2 0.1 0.1 61.9

TABLE-US-00006 TABLE 6 Experiment B d10 d50 d90 Mean Beverage TSI Pass (nm) (nm) (nm) (nm) Stability (Global) 1 84.44 133.34 199.07 138.59 — — 3 — — — 42.24 (Z-avg) — — 4 — — — 39.78 (Z-avg) Stable 24.5

Bioavailability

[0075] The bioavailability of the emulsions B, 2 and 5 was determined, and compared to single intravenous cannabidiol (CBD solid) and non-emulsified oil (CBD in MCT oil).

[0076] Plasma pharmacokinetics following single intravenous cannabidiol (CBD solid) or oral administration (4 emulsions+1 non-emulsified oil) was investigated in male Sprague-Dawley rats. Rats were used for this study because they are an accepted model for characterization of pharmacokinetics of formulations being developed for humans. Twelve (12) single-catheterized rats (275-300 g, jugular vein catheter) were obtained from Envigo and divided into 6 groups of 2 animals each. Rats were acclimated for 5 days; the temperature was controlled from 68-79° F., the humidity was controlled from 20% to 70% and the light source was fluorescent lamps with a light/dark cycle of 12/12 hours on/off. No concurrent medication was administered during the study, and all rats had access (ad-libitum) to Tekland Rodent Chow 2018 (Envigo) and tap water throughout the live phase. All animals were randomly placed. Post acclimation, all animals received a single IV (tail vein injection) or oral treatment of one of the nanoemulsions, a non-emulsified oil, or a positive control based on Table 7. Group 1 animals received a single IV injection while Groups 2-6 received a single oral administration. The non-emulsified oil is CBD isolate dissolved in MCT oil. WFI=sterile water for injection. Dosing and dose volume are in mg/mg (body weight) and mL/kg (body weight) respectively.

TABLE-US-00007 TABLE 7 Emulsion/ CBD Dose Dose Volume product Vehicle (mg/kg) (mL/kg) Route CBD solid 20% DMSO + 2 5 IV WFI Non-emulsified MCT Oil 10 10 PO oil B WFI 10 10 PO 2 WFI 10 10 PO 5 WFI 10 10 PO

[0077] The CBD concentration in blood plasma samples obtained at various collection times (15, 30, 60, 120, 180, 240, 480 minutes and 24 hr) was determined. The results are reported in Table 8 below.

TABLE-US-00008 TABLE 8 Sample Time (min) Concentration (ng/mL) CBD Isolate Pre-Dose ND 5 1560.0 30 481.0 60 341.0 120 178.0 180 89.2 240 44.2 480 10.6 24 hr 5.2 Non-emulsified oil Pre-Dose ND 5 ND 30 ND 60 ND 120 BLQ 180 BLQ 240 6.6 480 13.6 24 hr BLQ B Pre-Dose ND 5 86.2 30 185.0 60 310.0 120 131.0 180 67.7 240 45.1 480 21.6 24 hr 5.4 2 Pre-Dose ND 5 107.0 30 583.0 60 262.0 120 103.0 180 85.8 240 66.9 480 35.5 24 hr 5.0 5 Pre-Dose ND 5 87.5 30 294.0 60 270.0 120 142.0 180 88.2 240 71.7 480 48.5 24 hr BLQ

[0078] The following pharmacokinetic parameters were determined: Bioavailability absolute (Fabs), Bioavailability relative to non-emulsified (Frel), the time at maximum concentration, the maximum concentration, and half-life (T.sub.1/2). See Table 9.

TABLE-US-00009 TABLE 9 AUClast AUC.sub.inf Sample F.sub.abs F.sub.rel T.sub.max C.sub.max T.sub.1/2 (ng*h/mL) (ng*h/mL) CBD solid 0.25 1560 N.D. 1984 2013 Non-emulsified oil 2.04% 100% 8.0 13.6 N.D. 202 276 B 9.01% 443% 1.0 310 6.89 894 948 2 12.0% 589% 0.5 583 5.43 1190 1230 3 8.48% 416% 0.5 294 6.11 841 1270

[0079] It can thus be observed that the nanoemulsions achieved maximum concentration faster compared to the polysorbate and non-emulsified oil. They further achieved much higher bioavailability than the emulsified oil.