TOPICAL COMPOSITION

Abstract

There is disclosed a composition for topical application of a cannabinoid as active ingredient comprising a solution of the cannabinoid in an excipient formulation comprising a polyhydric alcohol as partition coefficient enhancer, a saturated long-chain fatty acid or alcohol thereof as diffusion coefficient enhancer, and a co-solvent, wherein the saturated long-chain fatty acid or alcohol has a carbon chain length of from C10 to C16. The composition can be used in the treatment of a variety of conditions.

Claims

1. A composition for topical application of a cannabinoid as active ingredient comprises a solution of the cannabinoid in an excipient formulation comprising a polyhydric alcohol as partition coefficient enhancer, a saturated long-chain fatty acid or alcohol thereof as diffusion coefficient enhancer, and a co-solvent, wherein the saturated long-chain fatty acid or alcohol has a carbon chain length of from C10 to C16.

2. A composition according to claim 1, wherein the long-chain fatty acid or alcohol has a carbon chain length of from C12 to C14.

3. A composition according to claim 1, wherein the long-chain fatty acid or alcohol is myristic acid or myristyl alcohol.

4. A composition according to claim 1, wherein the long-chain fatty acid or alcohol is myristyl alcohol.

5. A composition according to claim 1, wherein the co-solvent comprises a lower alcohol and/or a glycol ether.

6. A composition according to claim 5, wherein the lower alcohol is isopropyl alcohol.

7. A composition according to claim 5, wherein the glycol ether is a diethylene glycol ether.

8. A composition according to claim 1, wherein the co-solvent is a lower alcohol such as isopropyl alcohol.

9. A composition according to claim 1, wherein the polyhydric alcohol comprises one or more glycols.

10. A composition according to claim 1, wherein the polyhydric alcohol comprises propylene glycol, optionally together with butylene glycol.

11. A composition according to claim 1, wherein the composition further comprises water.

12. A composition according to claim 1, wherein the composition further comprises glycerol, sorbitol or a second polyhydric alcohol having three or more hydroxy groups.

13. A composition according to claim 1, wherein the composition is in a single phase.

14. A composition according to claim 1, wherein the composition is in the form of a gel.

15. A composition according to claim 1, wherein the composition does not include a silicone fluid.

16. A composition according to claim 1, wherein the composition comprises, in percentages by weight: TABLE-US-00012 cannabinoid 1-5 polyhydric alcohol 20-50 fatty acid/alcohol 2-5 co-solvent 20-50 water .sup. 0-30.

17. A composition according to claim 1, wherein the composition comprises, in percentages by weight: TABLE-US-00013 cannabinoid 2-3 polyhydric alcohol 30-45 fatty acid/alcohol 2.5-4.5 co-solvent 25-40 water .sup. 0-25.

18. A composition according to claim 1, wherein the composition comprises, in percentages by weight: TABLE-US-00014 cannabinoid 1-3 polyhydric alcohol 30-40 fatty acid/alcohol 2-3 co-solvent 30-40 water  20-30.

19. A composition according to claim 1, wherein the cannabinoid is selected from cannabidiol; non-acidic, naturally occurring and synthetic derivatives such as cannabidorcol, nor-cannabidiol (CBD-C4), cannabidivarin and cannabidiol monomethyl ether; and other cannabis plant secondary metabolites derived from cannabigerolic acid and their decarboxylated products such as A9-tetrahydrocannabinol, cannabinol, cannabigerol, cannabichromene, cannabicyclol, cannabivarin, A9-tetrahydrocannabivarin, cannabichromevarin, cannabigerovarin, cannabigerol monomethyl ether, cannabielsoin and cannabicitran.

20. A composition according to claim 1, wherein the cannabinoid is cannabidiol.

21-23. (canceled)

24. A method of treatment comprising applying an effective amount of the composition of claim 1 to a target site on a human or animal body.

25. The method of claim 24, wherein the method is for the treatment of pain; inflammation; skin conditions such as dry skin, itchy skin, rashes, acne, eczema, dermatitis and psoriasis; damaged skin such as cuts, bruises, abrasions, blisters and wounds; baldness; alopecia; hair loss; and muscle spasms.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0033] The invention will now be described in detail by way of example only with reference to the figures in which:

[0034] FIG. 1 is a graph showing the results of in vitro permeation and penetration (IVPT) studies for the compositions of the invention compared to an existing commercially available CBD formulation. The graph shows the mean cumulative amount of CBD (nmol/cm.sup.2) delivered to the receptor solution 24 h post-application of the 7 formulations. Data points represent the cumulative amount of CBD from 3-5 replicates and 1 donor. Formulations listed in rank order. Outliers removed.

[0035] FIG. 2 is a graph showing the results of in vitro permeation and penetration (IVPT) studies for the compositions of the invention compared to an existing commercially available CBD formulation. The graph shows the mean amount of CBD (ng) delivered to the epidermis 24 h post-application of the 7 formulations. Data points represent the cumulative amount of CBD from 4-5 replicates and 1 donor. Error bars represent one standard error from the mean. Outliers removed.

EXAMPLES

[0036] Exemplary solvent systems for compositions according to the invention are set out in the table below, together with a comparative formulation (SOL 1) based on the disclosure of WO2016/132159. The values given are percentages by weight.

TABLE-US-00005 TABLE 1 SOL 1 SOL 3 SOL 5 SOL 12 CBD 2.0 2.0 2.0 2.0 Propylene glycol 30.56 42.31 35.00 35.00 Transcutol 14.09 — — — Isopropyl alcohol 46.59 26.75 35.75 35.75 Water 5.00 24.75 24.75 24.75 Isopropyl myristate 1.76 — — — Lauric Acid —  4.19 — — Myristic Acid — — —  2.50 Myristyl Alcohol — —  2.50 — By Weight 100% 100% 100% 100%

[0037] The pH of all the formulations above was in the range 4-5.

[0038] Solvent systems such as those disclosed in the above table may be converted to gel formulations according to the invention by addition of one or more antioxidants and antinucleating agents.

[0039] Compositions as set out above may be prepared by mixing the various ingredients, in a manner known to those skilled in then art.

[0040] The Table below sets out exemplary solvent systems and corresponding gel formulations for compositions according to the invention:

TABLE-US-00006 TABLE 2 Composition (% w/w) Gels Solvent systems Excipient SOL12A SOL8 SOL3 SS SOL12A SS SOL8 SS SOL3 Cannabidiol (CBD) 2.00 2.00 2.00 2.00 2.00 2.00 Propylene glycol 35.00 35.00 42.31 35.00 35.00 42.31 Isopropyl alcohol (IPA) 22.55 22.55 13.55 25.55 25.55 16.55 Water 24.75 24.75 24.75 24.75 24.75 24.75 Myristyl alcohol — 2.50 — — 2.50 — Myristic acid 2.50 — — 2.50 — — Lauric acid — — 4.19 — — 4.19 Butylated hydroxyanisole (BHA) 0.10 0.10 0.10 0.10 0.10 0.10 Butylated hydroxytoluene (BHT) 0.10 0.10 0.10 0.10 0.10 0.10 Hydroxy propylcellulose (HPC MF) 3.00 3.00 3.00 N/A Total 90.00 90.00 90.00 90.00 90.00 90.00 pH adjustment solution to pH 4-5 Final Q.S. to 100% with IPA 100.00 100.00 100.00 100.00 100.00 100.00

[0041] The SS SOL8 and SOL8 gel formulations above are based on the SOL 5 formulation from Table 1.

[0042] Skin Permeation and Penetration

[0043] The above compositions from Table 2 were tested for skin penetration efficacy against commercially-available CBDol Topical CBD Salve (manufactured by CBDistillery™) according to the following conditions:

TABLE-US-00007 TABLE 3 SETUP FULL SCALE IVPT Skin type: Epidermal Membrane No. skin donors 1 Receptor solution: PBS, pH 7.4 + 0.01% Brij 98 + 30 mM glutathione + 30 mM EDTA No. formulations: 7 No. replicates: 5 No. skin blanks: 1 Dose amount: 10 mg/cm.sup.2 Flow rate: 8 μl/min RS collection times: Every 3 hours for 24 hours SKIN PENETRATION SAMPLE PROCESSING* Extraction fluid: 90:10 v/v acetonitrile:water + 0.1% BHT Surface of skin: Residual formulation was cleaned from the surface of the skin with 3 cotton swabs, one dry, one wetted with extraction fluid and an additional dry one. Cotton swabs used to clean the skin were then discarded. Stratum corneum: No tape stripping was conducted, epidermis + stratum corneum was analyzed together. Extraction procedure No separation prior to processing. Epidermis (SC & Epidermis): and stratum corneum was homogenized in extraction fluid and shaken for 0.5-1 hour.

[0044] Epidermal membrane was prepared by heat separating epidermis and dermis from dermatomed frozen human abdominal skin (from elective abdominoplasty), with the epidermal membrane being prepared on top of filter paper. The epidermal membrane from a single skin donor was mounted onto the MedFlux-HT® flow through diffusion cell system using a receptor solution of PBS pH 7.4 with 0.01% Brij 98, 30 mM glutathione and 30 mM EDTA, employing a flow rate of 8 μL/min. The formulation was applied as a single dose to the skin surface at 10 mg/cm.sup.2 and receptor solution samples were collected every 3 hours over a 24 hour period.

[0045] Following completion of the experiment, the tissue was removed from the MedFlux-HT® flow through diffusion cell system. The surface of the tissue was cleaned with three cotton swabs (one dry, one wetted with 90:10 v/v acetonitrile:water with 0.1% BHT, and an additional dry cotton swab). Cotton swabs used to clean the surface of the skin were discarded. The tissue sample was then homogenised with 90:10 v/v acetonitrile:water with 0.1% BHT and shaken for approximately 0.5-1 hour. CBD amounts in the receptor solution and tissue were quantified by LC-MS/MS analysis.

[0046] The results are shown in Tables 4 and 5 below and graphically in FIGS. 1 and 2.

[0047] Receptor Solution—Tabulated Data (AUC and API Flux) Mean cumulative amount of CBD (nmol/cm.sup.2) and API flux (nmol/cm.sup.2/hr) delivered to the receptor solution at 24 h, following application of the 7 formulations. Outliers removed.

TABLE-US-00008 TABLE 4 Cumulative Amt (nmol/cm.sup.2) API Flux (nmol/cm.sup.2/hr) Std Std Std Std Formulation N Mean Dev Err N Mean Dev Err SS-SOL 12A 3 0.88 0.72 0.42 3 0.053 0.029 0.017 SS-SOL 8 5 0.68 0.57 0.25 5 0.034 0.018 0.008 SOL 12A Gel 5 0.28 0.13 0.06 5 0.028 0.013 0.006 SOL 8 Gel 5 0.27 0.21 0.09 5 0.022 0.016 0.007 SS-SOL 3 4 0.21 0.07 0.03 4 0.021 0.007 0.004 SOL 3 Gel 5 0.15 0.02 0.01 5 0.015 0.003 0.001 CBDol 4 0.00 0.00 0.00 4 0.000 0.000 0.000 Topical Salve

[0048] Epidermis Tabulated Data (ng)

[0049] Mean amount of CBD (ng) delivered to the epidermis at 24 h, following application of the 7 formulations. Outliers removed.

TABLE-US-00009 TABLE 5 Epidermis (ng) Formulation N Mean Std Dev Std Err SOL 12A Gel 5 25850 21576 9649 SS-SOL 12A 5 24200 8197 3666 SS-SOL 3 5 20800 8338 3729 SOL 3 Gel 4 20200 8078 4039 SS-SOL 8 5 14354 4265 1908 SOL 8 Gel 5 13630 8160 3649 CBDol Topical Salve 5 1698 537 240

[0050] It was found that all compositions tested outperformed the commercially-available product and delivered between about 14,000 and 26,000 ng of CBD to the skin, an 8-15-fold increase over CBDol Topical Salve. Compositions according to the invention delivered between 0.15-0.88 nmol/cm.sup.2 to the receptor solution, whereas receptor solution samples for the comparator product were below the limit of quantification (lower limit of quantification=0.25 ng/mL). SS SOL12A and SS SOL8 delivered the highest amount of CBD to the receptor solution over 24 hours.

[0051] Stability

[0052] A known issue for CBD or other cannabinoid formulations is that there is a tendency towards instability, especially under oxidative stress and where the pH values lie outside the range approximately of pH 3 to 7. Further, certain excipients can cause cannabinoids to degrade. Therefore, over time, the CBD or other cannabinoid breaks down, affecting the shelf life of the composition. It has been shown that the compositions of the invention provide improved cannabinoid stability compared to commercially available formulations such as CBDol Topical CBD Salve. This means that the compositions maintain their potency over the course of their shelf life. Of the exemplary compositions described above, in stability testing, both SS SOL8 and SS SOL12A show no significant reduction in potency following storage at 25° C. and 40° C. for up to three months. SS SOL8 performed better than SS SOL12A in terms of recovery of and peak purity of CBD.

[0053] Data for the recovery of and peak purity of CBD for the SOL3, SOL8 and SOL12A formulations at after 1, 2, and 3 months is given in Tables 6 and 7 below.

TABLE-US-00010 TABLE 6 CBD percentage recovery (%) of the SOL3, SOL8 and SOL12A formulations at t = 0, 1, 2 and 3-month. Percentage recovery (%) of CBD t = 1 month t = 2 month t = 3 month 25° C./ 40° C./ 25° C./ 40° C./ 25° C./ 40° C./ Formulation Pack t = 0 60% RH 75% RH 60% RH 75% RH 60% RH 75% RH SOL3 Tube 101.50 93.96 93.51 97.43 96.16 101.35 95.42 2% w/w CBD Vial 98.16 96.77 99.58 94.99 98.62 96.01 SOL8 Tube 98.97 100.29 98.90 99.94 99.80 102.87 102.30 2% w/w CBD Vial 100.39 98.32 100.92 99.99 100.07 98.32 SOL12A Tube 101.94 98.42 94.47 97.96 96.68 98.77 96.94 2% w/w CBD Vial 98.34 97.01 97.80 94.47 98.39 95.24

TABLE-US-00011 TABLE 7 Peak purity (% area) of the SOL3, SOL8 and SOL12A formulations at t = 0, 1, 2 and 3-month. Peak purity (% area) t = 1 month t = 2 month t = 3 month 25° C./ 40° C./ 25° C./ 40° C./ 25° C./ 40° C./ Formulation Pack t = 0 60% RH 75% RH 60% RH 75% RH 60% RH 75% RH SOL3 Tube 99.35 98.51 96.04 98.15 94.27 97.64 91.99 2% w/w CBD Vial 99.00 97.26 98.54 95.03 97.78 93.66 SOL8 Tube 99.25 99.04 98.90 99.23 98.75 99.19 98.37 2% w/w CBD Vial 99.25 98.96 99.24 97.87 98.63 96.58 SOL12A Tube 99.23 98.55 96.10 98.38 94.77 97.88 92.43 2% w/w CBD Vial 98.89 96.43 98.52 94.40 98.05 92.88