Oral cannabinoid formulations

Abstract

The present invention relates to a cannabinoid containing oral solution. Preferably the oral solution comprises a cannabinoid, a lipid solvent, a sweetener and ethanol, characterised in that the sweetener is an ultrahigh potency sweetener.

Claims

1. A pharmaceutical formulation for oral administration comprising: cannabidiol (CBD); a lipid solvent; an ultrahigh potency sweetener; and ethanol, wherein ethanol has a concentration of less than about 3% v/v.

2. The pharmaceutical formulation of claim 1, wherein the ultrahigh potency sweetener has a sweetness intensity that is 1000x greater than sucrose.

3. The pharmaceutical formulation of claim 1, wherein the ultrahigh potency sweetener has a sweetness intensity that is 5000x greater than sucrose.

4. The pharmaceutical formulation of claim 1, wherein the ultrahigh potency sweetener is (N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1- methyl ester) (Neotame).

5. The pharmaceutical formulation of claim 1, wherein the ultrahigh potency sweetener is N-[n-3-(3-hydroxy-4methoxyphenyl)propyl-α-L-aspartyl] -L-phenylalanine 1-methyl ester) (Advantame).

6. The pharmaceutical formulation of claim 1, further comprising a flavorant.

7. The pharmaceutical formulation of claim 1, wherein the CBD is present in an amount of from 5 to 40% (w/v), ethanol is present in an amount of less than 2% (v/v), ultrahigh potency sweetener is present in less than 0.05% (w/v), flavorant is present in an amount of less 0.2% (w/v) and lipid solvent is q.s. to 100%.

8. The pharmaceutical formulation of claim 7, wherein the ultrahigh potency sweetener is Neotame, the flavorant is strawberry flavor and the lipid solvent is sesame oil.

9. The pharmaceutical formulation of claim 1, wherein the formulation is stable in climatic zones I and II for up to 24 months at 25° C.

10. The pharmaceutical formulation of claim 1, wherein the formulation is stable in climatic zones III and IV for up to 18 months at 30° C.

11. The pharmaceutical formulation of claim 1, wherein the solution lacks a stabilizing agent.

12. The pharmaceutical formulation of claim 8, wherein the formulation is stable in climatic zones I and II for up to 24 months at 25° C.

13. The pharmaceutical formulation of claim 8, wherein the formulation is stable in climatic zones III and IV for up to 18 months at 30° C.

14. The pharmaceutical formulation of claim 8, wherein the solution lacks a stabilizing agent.

15. The pharmaceutical formulation of claim 1, the ultrahigh potency sweetener is Neotame, and the lipid solvent is sesame oil.

16. The pharmaceutical formulation of claim 1, wherein the concentration of ethanol is less than about 2% (v/v).

17. The pharmaceutical formulation of claim 1, wherein the concentration of ethanol ranges from about 0.5% (v/v) to 3% (v/v).

18. The pharmaceutical formulation of claim 1, wherein the lipid solvent is sesame oil.

19. The pharmaceutical formulation of claim 1, wherein: the CBD is present in an amount ranging from 5 to 40% (w/v); the ethanol is present in an amount ranging from 0.5% (v/v) to 2% (v/v); the ultrahigh potency sweetener is present in an amount ranging from 0.01% (w/v) to 0.0025% about; flavorant is present in an amount of less 0.2% (w/v); and sesame oil is q.s. to 100%.

20. The pharmaceutical formulation of claim 1, wherein the CBD is present in an extract.

Description

DETAILED DESCRIPTION

(1) The Applicant initially sought to replace the ethanol in their oral lipid formulation with an alternative pharmaceutically acceptable solvent, such as propylene glycol, polyethylene glycol or glycerin but found their miscibility with sesame oil, across a range of concentrations (0.5-10%) tested, was not satisfactory.

(2) They then looked at substituting the sweetener they used, sucralose, with an alternative pharmaceutically acceptable sweetener, such as, for example, sucrose, aspartame, saccharin, dextrose, mannitol or xylitol without success due to for example, taste profile or physical stability.

(3) When these two approaches failed they, unconventionally, tried ultrahigh potency sweeteners, which whilst approved by the FDA in foods, are not generally considered as sweeteners for use in pharmaceuticals. The two tested, Advantame and Neotame proved surprisingly effective and formulations containing these sweeteners did not require stabilizing with anti-oxidants and chelating agents as is common in cannabinoid containing formulations. The Examples that follow describe the development of the claimed formulations which show good stability.

EXAMPLE 1

Selection of Alternative Sweeteners

(4) Alternative sweeteners to sucralose (comparator) were selected as shown in Table 1 below.

(5) TABLE-US-00001 TABLE 1 Acceptable Multiplier of Sweetness Daily Intake Intensity Compared to Sweetener (mg/kg/day)* Table Sugar (Sucrose) Sucralose 5     600 x Saccharin 15 200-700 x Saccharin Dihydrate 15 200-700 x Aspartame 50     200 x Neotame 0.3 7,000-13,000 x   Advantame 32.8  20,000 x *Acceptable daily intake values derived from FDA website: http://www.fda.gov/Food/IngredientsPackagingLabeling/FoodAdditivesIngredients/ucm397725.htm#SummaryTable

(6) Batches using these sweeteners were prepared as shown in Table 2 below, with the concentrations of each sweetener being selected based on its relative sweetness compared to sucralose.

(7) TABLE-US-00002 TABLE 2 Batch Batch Batch Batch Batch Ingredients ET03/049C ET03/049D ET03/049A ET03/049B ET03/012I Saccharin 0.05% w/v — — — — Saccharin Dihydrate — 0.05% w/v — — — Aspartame — — 0.15% w/v — — Neotame — — — 0.005% w/v — Advantame — — — — 0.0025% w/v Anhydrous Ethanol 10% v/v 10% v/v 10% v/v 10% v/v 2% v/v Strawberry Flavour 0.10% w/v 0.10% w/v 0.10% w/v 0.10% w/v 0.10% w/v Refined Sesame Oil q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100% q.s. to 100%

(8) Four of the five formulations were clear solutions with the exception of Aspartame which did not completely solubilise in ethanol.

(9) The Formulations made with Saccharin and Saccharin dihydrate produced an unpleasant taste, and also had a lingering bitter after taste.

(10) On the other hand, the Formulations made with Neotame and Advantame both had a good taste profile, with no bitter after taste.

(11) Therefore Neotame and Advantame were both considered suitable candidates for further development.

EXAMPLE 2

Evaluation of an Advantame Formulation

(12) An experiment (ET03/015) was carried out to determine the lowest ethanol concentration required to solubilise Advantame. Table 3 details the batches made with various ethanol concentrations ranging from 0.5% to 3.0% v/v.

(13) TABLE-US-00003 TABLE 3 Batch Batch Batch Batch Batch E Batch Ingredients ET03/015 A ET03/015 B ET03/015 C ET03/015 D T03/015 E ET03/015 F Advantame 0.0025% w/v Strawberry Flavour  0.10% w/v Anhydrous Ethanol 0.5% v/v 1.0% v/v 1.5% v/v 2.0% v/v 2.5% v/v 3.0% v/v Refined Sesame Oil q.s. to 100%

(14) These batches were stored at 25° C./60% RH and 40° C./75% RH for up to 4 weeks and observed for any signs of precipitation. There was no precipitation observed over the period assessed. Therefore it was concluded that Advantame can be used as a sweetener and can be solubilised at ethanol concentration of at least as low as 0.5% v/v. i.e. the concentration of ethanol required in the formulation can be reduced by a factor of 20 compared to a sucralose containing formulation.

EXAMPLE 3

Preparation of Neotame Formulations

(15) In an experiment (ET03/127), various formulations were prepared with different levels of CBD (25 mg/ml, 100 mg/ml and 200 mg/ml), Neotame (0.005 and 0.01% w/v) and ethanol (0.5 to 3.0% v/v).

(16) The objective of the experiment was to determine the physical stability of the formulations with different concentrations of CBD, Neotame and ethanol. Tables 4 to 6 below detail the compositions of the formulations.

(17) TABLE-US-00004 TABLE 4 (CBD 25 mg/ml) Batch Batch Batch Batch Batch Batch Batch Batch Ingredients A/25 B/25 C/25 D/25 E/25 F/25 G/25 H/25 Cannabidiol  2.5% w/v Neotame 0.005% 0.01% 0.005% 0.01% 0.005% 0.01% 0.005% 0.01% w/v w/v w/v w/v w/v w/v w/v w/v Anhydrous Ethanol 0.5% 0.5% 1.0% 1.0% 2.0% 2.0% 3.0% 3.0% v/v v/v v/v v/v v/v v/v v/v v/v Flavour 0.10% w/v q.s. to 100%

(18) TABLE-US-00005 TABLE 5 (CBD 100 mg/ml) Batch Batch Batch Batch Batch Batch Batch Batch Ingredients A/100 B/100 C/100 D/100 E/100 F/100 G/100 H/100 Cannabidiol 10.0% w/v Neotame 0.005% 0.01% 0.005% 0.01% 0.005% 0.01% 0.005% 0.01% w/v w/v w/v w/v w/v w/v w/v w/v Anhydrous Ethanol 0.5% 0.5% 1.0% 1.0% 2.0% 2.0% 3.0% 3.0% v/v v/v v/v v/v v/v v/v v/v v/v Flavour 0.10% w/v Refined Sesame Oil q.s. to 100%

(19) TABLE-US-00006 TABLE 6 (CBD 200 mg/ml) Batch Batch Batch Batch Batch Batch Batch Batch Ingredients A/200 B/200 C/200 D/200 E/200 F/200 G/200 H/200 Cannabidiol 20.0% w/v Neotame 0.005% 0.01% 0.005% 0.01% 0.005% 0.01% 0.005% 0.01% w/v w/v w/v w/v w/v w/v w/v w/v Anhydrous Ethanol 0.5% 0.5% 1.0% 1.0% 2.0% 2.0% 3.0% 3.0% v/v v/v v/v v/v v/v v/v v/v v/v Flavour 0.10% w/v Refined Sesame Oil q.s. to 100%

EXAMPLE 4

Testing of Neotame Formulations for Physical Stability

(20) The 25 mg/ml and 100 mg/ml batches were tested for physical stability by opening the bottles and allowing them to stand for 2 weeks to let the ethanol evaporate. This was done as a worst case in-use scenario where the bottle is repeatedly opened and closed multiple times during use. The batches were monitored for any signs of precipitation and the ethanol content measured. The results are provided in Table 7.

(21) TABLE-US-00007 TABLE 7 CBD Assay Appearance of Ethanol Content (mg/ml) Solution (% v/v) Batch Initial Initial Day 14 Target Initial Day 14 A/25 24.6 Clear Clear 0.5 0.6 0.03 B/25 24.6 Clear Clear 0.5 0.6 0.02 C/25 24.9 Clear Clear 1.0 1.1 0.04 D/25 24.4 Clear Clear 1.0 1.0 0.05 E/25 24.3 Clear Clear 2.0 2.0 0.09 F/25 24.8 Clear Clear 2.0 2.1 0.14 G/25 24.3 Clear Clear 3.0 3.4 0.14 H/25 24.3 Clear Clear 3.0 3.0 0.12 A/100 98.9 Clear Clear 0.5 0.6 0.04 B/100 99.2 Clear Clear 0.5 0.7 0.05 C/100 100.0 Clear Clear 1.0 1.2 0.10 D/100 100.1 Clear Clear 1.0 1.1 0.15 E/100 100.1 Clear Clear 2.0 2.1 0.20 F/100 97.4 Clear Clear 2.0 2.1 0.18 G/100 99.9 Clear Clear 3.0 3.3 0.25 H/100 100.4 Clear Clear 3.0 3.3 0.29

(22) All 25 mg/ml and 100 mg/ml batches were clear without any signs of precipitation. The ethanol content dropped significantly at day 14 for all batches; however there were no signs of precipitation of Neotame even after the ethanol content had dropped by more than 85% of its initial concentration. This indicates that Neotame can be physically solubilised at concentrations up to 0.01% w/v in ethanol.

(23) As Neotame is freely soluble in ethanol at room temperature only a small quantity of ethanol is required to keep Neotame solubilised in the formulation. Accordingly it was decided to use Neotame in a formulation at 0.008% w/v concentration for optimum sweetness with ethanol at a concentration of 1% v/v (0.79% w/v).

EXAMPLE 5

Long Term Stability Testing

(24) 100mg/ml and 200mg/ml formulations were made up as per Table 8 below>

(25) TABLE-US-00008 TABLE 8 Quantitative Composition Reference to CBD 100 CBD 200 Quality mg/ml oral mg/ml oral Component Function standard solution solution Cannabidiol Active In-house 10.0% w/v 20.0% w/v Anhydrous Ethanol Sweetener Ph Eur & 0.79% w/v.sup.† 0.79% w/v.sup.† solubilizer USP/NF Neotame Sweetener USP/NF 0.008% w/v 0.008% w/v Strawberry Flavour Flavour In-house 0.10% w/v 0.10% w/v Refined Sesame Oil Solubilizer Ph Eur & q.s. to 100% q.s. to 100% USP/NF Note: .sup.†0.79% w/v is equivalent to 1% v/v of anhydrous ethanol

(26) The method of manufacture comprised solubilising the CBD in sesame oil. The sweetener and flavour were mixed in ethanol and the ethanolic phase was then mixed with the sesame oil phase containing dissolved CBD.

(27) The long term stability testing was according to ICH guideline (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2 Guideline.pdf) with different CBD strengths as detailed in Table 9 below.

(28) TABLE-US-00009 TABLE 9 Study Formula Storage Reference Description Ingredients Composition Conditions DSP-15-10-02 CBD 100 mg/ml CBD 10.0% w/v 25° C./60% RH oral solution Anhydrous Ethanol 0.79% w/v 30° C./65% RH Neotame 0.008% w/v 40° C./75% RH Strawberry Flavour 0.10% w/v Refined Sesame Oil q.s. to 100% CBD 200 mg/ml CBD 20.0% w/v 25° C./60% RH oral solution Anhydrous Ethanol 0.79% w/v 30° C./65% RH Neotame 0.008% w/v 40° C./75% RH Strawberry Flavour 0.10% w/v Refined Sesame Oil q.s. to 100%

(29) The tests shown in Table 10 below were used to determine the stability of the formulations.

(30) TABLE-US-00010 TABLE 10 Test Test method Appearance of Solution Visual check CBD Content Ultra-Performance Liquid Degradants: Chromatography CBE I (UPLC) CBE II OH-CBD Total Degradants Microbial: Pharmacopoeial TAMC TYMC E. coli

(31) The results from illustrated in Tables 11 to 15 for the 100mg/ml CBD formulation and 16 to 20 for the 200 mg/ml CBD formulation.

(32) TABLE-US-00011 TABLE 11 Stability data for CBD 100 mg/ml Oral Solution Batch ET04/126-B 25° C. ± 2° C./60% RH ± 5% RH, Vertical Time-point (months) Test Specification 0 2 3 6 Appearance A clear, A clear solution A clear solution A clear solution A clear solution of Solution colorless to free from visible free from visible free from visible free from visible yellow solution particulates particulates particulates particulates CBD 90.0-110.0 mg/ml 99.5 mg/ml 101.3 mg/ml 99.9 mg/ml 98.9 mg/ml Content (90.0-110.0% LC) (99.5%) (101.3%) (99.9%) (98.9%) Degradants CBE I NMT 0.2% ND ND ND ND CBE II NMT 0.2% ND ND ND ND OH-CBD NMT 0.2% 0.03% ND 0.02% 0.05% Total NMT 1.0% 0.03% ND 0.02% 0.05% Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with Complies with Complies with Complies with TYMC NMT 10.sup.2 cfu/g pharmacopoeial pharmacopoeial pharmacopoeial pharmacopoeial E. coli Absent in 1 g requirements requirements requirements requirements ND = Not Detected

(33) TABLE-US-00012 TABLE 12 Stability data for CBD 100 mg/ml Oral Solution Batch ET04/126-B 30° C. ± 2° C./65% RH ± 5% RH, Vertical Time-point (months) Test Specification 0 2 3 6 Appearance A clear, A clear solution A clear solution A clear solution A clear solution of Solution colorless to free from visible free from visible free from visible free from visible yellow solution particulates particulates particulates particulates CBD 90.0-110.0 mg/ml 99.5 mg/ml 100.8 mg/ml 99.1 mg/ml 99.0 mg/ml Content (90.0-110.0% LC) (99.5%) (100.8%) (99.1%) (99.0%) Degradants: CBE I NMT 0.2% ND ND ND ND CBE II NMT 0.2% ND ND ND ND OH-CBD NMT 0.2% 0.03% ND 0.02% 0.05% Total NMT 1.0% 0.03% ND 0.02% 0.05% Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with Complies with Complies with Complies with TYMC NMT 10.sup.2 cfu/g pharmacopoeial pharmacopoeial pharmacopoeial pharmacopoeial E. coli Absent in 1 g requirements requirements requirements requirements ND = Not Detected

(34) TABLE-US-00013 TABLE 13 Stability data for CBD 100 mg/ml Oral Solution Batch ET04/126-B 40° C. ± 2° C./75% RH ± 5% RH, Vertical Time-point (months) Test Specification 0 2 6 Appearance A clear, A clear solution A clear solution A clear solution of Solution colorless to free from visible free from visible free from visible yellow solution particulates particulates particulates CBD 90.0-110.0 mg/ml 99.5 mg/ml 100.8 mg/ml 98.8 mg/ml Content (90.0-110.0% LC) (99.5%) (100.8%) (98.8%) Degradants CBE I NMT 0.2% ND ND 0.05% CBE II NMT 0.2% ND ND ND OH-CBD NMT 0.2% 0.03% ND 0.06% Total NMT 1.0% 0.03% ND 0.11% Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with Complies with Complies with TYMC NMT 10.sup.2 cfu/g pharmacopoeial pharmacopoeial pharmacopoeial E. coli Absent in 1 g requirements requirements requirements ND = Not Detected

(35) TABLE-US-00014 TABLE 14 Stability data for CBD 100 mg/ml Oral Solution Batch ET04/126-B In-Use 25° C. ± 2° C./60% RH ± 5% RH, Vertical Time-point (Initial) Test Specification 8 weeks Appearance of A clear, colorless to A clear solution free from Solution yellow solution visible particulates CBD Content 90.0-110.0 mg/ml 100.3 mg/ml (90.0-110.0% LC) (100.3%) Degradants: CBE I NMT 0.2% ND CBE II NMT 0.2% ND OH-CBD NMT 0.2% ND Total NMT 1.0% ND Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with pharmacopoeial TYMC NMT 10.sup.2 cfu/g requirements E. coli Absent in 1 g ND = Not Detected

(36) TABLE-US-00015 TABLE 15 Stability data for CBD 100 mg/ml Oral Solution Batch ET04/126-B In-Use 30° C. ± 2° C./65% RH ± 5% RH, Vertical Time-point (Initial) Test Specification 8 weeks Appearance of A clear, colorless to A clear solution free from Solution yellow solution visible particulates CBD Content 90.0-110.0 mg/ml 99.7 mg/ml (90.0-110.0% LC) (99.7%) Degradants: CBE I NMT 0.2% ND CBE II NMT 0.2% ND OH-CBD NMT 0.2% ND Total NMT 1.0% ND Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with pharmacopoeial TYMC NMT 10.sup.2 cfu/g requirements E. coli Absent in 1 g ND = Not Detected

(37) TABLE-US-00016 TABLE 16 Stability data for CBD 200 mg/ml Oral Solution Batch ET04/126-C 25° C. ± 2° C./60% RH ± 5% RH, Vertical Time-point (months) Test Specification 0 2 3 6 Appearance A clear, colorless A clear solution A clear solution A clear solution A clear solution of Solution to yellow solution free from visible free from visible free from visible free from visible particulates particulates particulates particulates CBD 180.0-220.0 mg/ml 199.5 mg/ml 202.3 mg/ml 198.2 mg/ml 198.3 mg/ml Content (90.0-110.0% LC) (99.7%) (101.2%) (99.1%) (99.1%) Degradants: CBE I NMT 0.2% ND ND ND ND CBE II NMT 0.2% ND ND ND ND OH-CBD NMT 0.2% 0.04% ND 0.02% 0.04% Total NMT 1.0% 0.04% ND 0.02% 0.04% Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with Complies with Complies with Complies with TYMC NMT 10.sup.2 cfu/g pharmacopoeial pharmacopoeial pharmacopoeial pharmacopoeial E. coli Absent in 1 g requirements requirements requirements requirements ND = Not Detected

(38) TABLE-US-00017 TABLE 17 Stability data for CBD 200 mg/ml Oral Solution Batch ET04/126-C 30° C. ± 2° C./65% RH ± 5% RH, Vertical Time-point (months) Test Specification 0 2 3 6 Appearance A clear, colorless A clear solution A clear solution A clear solution A clear solution of Solution to yellow solution free from visible free from visible free from visible free from visible particulates particulates particulates particulates CBD 180.0-220.0 mg/ml 199.5 mg/ml 201.8 mg/ml 199.4 mg/ml 198.0 mg/ml Content (90.0-110.0% LC) (99.7%) (100.9%) (99.7%) (99.0%) Degradants: CBE I NMT 0.2% ND ND ND ND CBE II NMT 0.2% ND ND ND ND OH-CBD NMT 0.2% 0.04% ND 0.01% 0.04% Total NMT 1.0% 0.04% ND 0.01% 0.04% Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with Complies with Complies with Complies with TYMC NMT 10.sup.2 cfu/g pharmacopoeial pharmacopoeial pharmacopoeial pharmacopoeial E. coli Absent in 1 g requirements requirements requirements requirements ND = Not Detected

(39) TABLE-US-00018 TABLE 18 Stability data for CBD 200 mg/ml Oral Solution Batch ET04/126-C 40° C. ± 2° C./75% RH ± 5% RH, Vertical Time-point (months) Test Specification 0 2 6 Appearance A clear, colorless A clear solution A clear solution A clear solution of Solution to yellow solution free from visible free from visible free from visible particulates particulates particulates CBD 180.0-220.0 mg/ml 199.5 mg/ml 202.3 mg/ml 197.9 mg/ml Content (90.0-110.0% LC) (99.7%) (101.2%) (99.0%) Degradants: CBE I NMT 0.2% ND ND 0.04% CBE II NMT 0.2% ND ND ND OH-CBD NMT 0.2% 0.04% ND 0.05% Total NMT 1.0% 0.04% ND 0.09% Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with Complies with Complies with TYMC NMT 10.sup.2 cfu/g pharmacopoeial pharmacopoeial pharmacopoeial E. coli Absent in 1 g requirements requirements requirements ND = Not Detected

(40) TABLE-US-00019 TABLE 19 Stability data for CBD 200 mg/ml Oral Solution Batch ET04/126-C In-Use 25° C. ± 2° C./60% RH ± 5% RH, Vertical Time-point (Initial) Test Specification 8 weeks Appearance A clear, colorless to A clear solution free from of Solution yellow solution visible particulates CBD Content 180.0-220.0 mg/ml 198.7 mg/ml (90.0-110.0% LC) (99.4%) Degradants: CBE I NMT 0.2% ND CBE II NMT 0.2% ND OH-CBD NMT 0.2% ND Total NMT 1.0% ND Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with pharmacopoeial TYMC NMT 10.sup.2 cfu/g requirements E. coli Absent in 1 g ND = Not Detected

(41) TABLE-US-00020 TABLE 20 Stability data for CBD 200 mg/ml Oral Solution (Re-formulation) Batch ET04/126-C In-Use 30° C. ± 2° C./65% RH ± 5% RH, Vertical Time-point (initial) Test Specification 8 weeks Appearance A clear, colorless to A clear solution free from of Solution yellow solution visible particulates CBD Content 180.0-220.0 mg/ml 199.2 mg/ml (90.0-110.0% LC) (99.6%) Degradants: CBE I NMT 0.2% ND CBE II NMT 0.2% ND OH-CBD NMT 0.2% ND Total NMT 1.0% ND Degradants Microbial: TAMC NMT 10.sup.3 cfu/g Complies with pharmacopoeial TYMC NMT 10.sup.2 cfu/g requirements E. coli Absent in 1 g ND = Not Detected

(42) Conclusions

(43) From these data it can be concluded that both the 100 mg/ml and the 200 mg/ml CBD containing formulations are stable up to 6 months under both normal and accelerated conditions and the inference is that the formulations will support shelf life of at least: Climatic Zone I and II—24 months, Store below 25° C. Climatic Zone III and IV—18 month, Store below 30° C.

EXAMPLE 6

Safety Levels

(44) The Neotame containing, formulations of Table 8 illustrate the fact that both levels of Neotame and ethanol are well below recommended guidelines when the CBD is used at a dose of 20 mg/kg.

(45) Neotame.

(46) Assuming a maximum CBD dose of 20 mg/kg/day, the maximum Neotame dose at 0.008% w/v concentration in the formulation would be 0.016 mg/kg/day with the 100 mg/ml CBD formulation and 0.008 mg/kg/day with the 200 mg/ml CBD formulation. These are well below the acceptable daily intake limits for Neotame of 0.3 mg/kg/day, as per the FDA guidelines for food.

(47) Ethanol

(48) According to European Medicine Agency draft guideline (EMA/CHMP/507988/2013), for 2-6 years old children a theoretical limit for Blood Alcohol Concentration (BAC) following a single administration of formulation containing alcohol is not more than 0.01 g/L (10 mg/L), and ethanol intake should be exceed 6 mg/kg/day.

(49) The theoretical BAC and maximum ethanol intake for proposed formulations containing 1% v/v ethanol, assuming a max CBD dose of 20 mg/kg/day are detailed in Table 21 below.

(50) TABLE-US-00021 TABLE 21 Formulation Theoretical BAC Ethanol intake CBD 100 mg/ml solution  0.001 g/L 1.58 mg/kg/day CBD 200 mg/ml solution 0.0005 g/L 0.79 mg/kg/day

(51) It is evident that they are well below the specified limits.