CANNABINOIDS COMPOSITIONS AND METHODS

Abstract

A composition for administration into the nasal cavity, the rectal cavity and the vaginal cavity, wherein the composition is an essentially non-aqueous composition comprising: not less than 25% by weight of one or more cannabinoid(s); from 25% to 55% by weight one or more phospholipid(s); and optionally one or more antioxidant(s).

Claims

1. A composition for administration into a body cavity selected from the group consisting of the nasal cavity, the rectal cavity and the vaginal cavity, wherein the composition is an essentially non-aqueous composition comprising: not less than 25% by weight of one or more cannabinoid(s); from 25% to 55% by weight one or more phospholipid(s); and optionally one or more antioxidants.

2. A composition according to claim 1, comprising: from 30% to 50% by weight of one or more cannabinoid(s) and from 30% to 50% by weight of one or more phospholipid(s).

3. A composition according to claim 1, wherein the weight ratio cannabinoid(s) to phospholipid(s) is in the range of 1:0.75-1.33.

4. A composition according to claim 3, wherein the weight ratio cannabinoid(s) to phospholipid(s) is in the range of 1:0.8-1.25.

5. A composition according to claim 1, further comprising one or more liquids selected from the group consisting of glycols and vegetable oils.

6. A composition according to claim 1, which is devoid of added liquids.

7. A composition according to claim 1 for nasal administration.

8. A composition according to claim 1 for rectal administration.

9. A composition according to claim 1 for vaginal administration.

10. A composition for nasal administration according to claim 7, comprising not less than 18% by weight of one or more liquids selected from the group consisting of glycols and vegetable oils.

11. A composition for nasal administration according to claim 10, comprising from 25 to 35% by weight of cannabinoid(s), from 25 to 35% of phospholipid(s), from 30 to 40% of propylene glycol and an antioxidant.

12. A composition for nasal administration according to claim 10, comprising from 35 to 45% by weight of cannabinoid(s), from 35 to 45% of phospholipid(s), from 18 to 30% of propylene glycol and an antioxidant.

13. A composition according to claim 7, comprising a vegetable oil selected from the group consisting of black cumin seed oil, hemp seed oil, pomegranate seed oil, sesame seed oil, brassica seed oil and black sesame oil.

14. A composition according to claim 13, comprising pomegranate oil, sesame oil or a mixture thereof.

15. A composition according to claim 13 for nasal administration, comprising from 25 to 35% by weight of cannabinoid(s), from 25 to 50% by weight phospholipids; from 18 to 50% by weight of therapeutically effective oil.

16. A composition according to claim 7, comprising at least one glycol and at least one vegetable oil.

17. A composition according to claim 16, comprising propylene glycol and pomegranate oil.

18. A composition for nasal administration according to claim 16, comprising from 25 to 40% by weight of cannabinoid(s), from 30 to 50% by weight phospholipids, from 10 to 30% of propylene glycol and from 3 to 20% by weight of vegetable oil.

19. A composition according to claim 7, comprising from 25 to 40% by weight of CBD, from 1 to 25% by weight of THC, from 30 to 45% of phospholipids, from 1 to 30% of propylene glycol and from 0.1 to 1.5 of antioxidant.

20. A composition according to claim 7, comprising from 25 to 35% by weight of CBD, from 1 to 15% by weight of THC, from 1 to 15% by weight of CBN, from 30 to 45% of phospholipids, from 1 to 25% of propylene glycol and from 0.1 to 1.5 of antioxidant.

21. A composition according to claim 7, comprising from 35 to 50% by weight one or more cannabinoids and from 35 to 50% by weight phospholipid(s).

22. A composition according to claim 21 for rectal or vaginal administration, wherein the composition is devoid of added liquid.

23. A method of treating a disease and/or condition in a patient, combatting the progress of a disease or relieving symptoms associated therewith, comprising intranasal, rectal or vaginal administration of a composition according to claim 1.

24. A method according to claim 23, comprising intranasal administration of a composition for administration into the nasal cavity of a patient, wherein the composition is an essentially non-aqueous composition comprising: not less than 25% by weight of one or more cannabinoid(s); from 25% to 55% by weight one or more phospholipid(s); and optionally one or more antioxidants.

25. A method according to claim 24, for treating brain and CNS diseases and conditions.

26. A method according to claim 24, wherein the disease and condition is selected from the group consisting of neurological disorder, muscular disturbances, ticks, insomnia, pain, anxiety, migraine, glioma, epilepsy, blastoglioma, cancer, acne, IBD, Chron's disease, loss of appetite, anxiety, distress, panic, tremor, multiple sclerosis, menopause, including symptoms associated with menopause, autism, dementia, Alzheimer, Parkinson, awakens, mood disorders, post-trauma, alcoholic and nonalcoholic fatty liver, hysteria, seizure and types of encephalopathy, including hepatic-encephalopathy, hepatic cancer and cirrhosis, menstrual pain and cramps, premenstrual pain, painful menstrual periods and vaginal mucosa inflammation.

27. A method according to claim 26, for relieving pain in said patient.

28. A method according to claim 23, comprising rectal administration of a composition for administration into the rectal cavity of a patient, wherein the composition is an essentially non-aqueous composition comprising: not less than 25% by weight of one or more cannabinoid(s); from 25% to 55% by weight one or more phospholipid(s); and optionally one or more antioxidants.

29. A method according to claim 28, for the treatment of liver disease selected from the group consisting of hepatic-encephalopathy, hepatic cancer and cirrhosis.

Description

[0123] In the drawings:

[0124] FIG. 1: Representative NIR images for mice brains treated with 10 l CBD nasal composition (right) as compared to brain of untreated mice (left).

[0125] FIG. 2: Representative NIR images for mice brains treated with 10 l CBD nasal composition (right) as compared to the brain of untreated mice (left).

[0126] FIG. 3: Representative NIR images for mice brains treated with 10 l nasal control compositions containing 0.5% w/w ICG (right) as compared to untreated mice (left).

[0127] FIG. 4: Representative multiphoton micrographs for the olfactory region in mice brains treated nasally with 10 l of Composition I or Control Composition, each containing 0.5% w/w FITC. Field of images: height: 818 m, width: 818 m and depth: 200 m; lens 20 (A1-MP microscope NIKON-Japan).

[0128] FIG. 5: Representative multiphoton micrographs for the olfactory region in mice brains treated nasally with 10 l of Composition II or Control Composition, each containing 0.5% w/w FITC. Field of images: 818 m, width: 818 m and depth: 200 m; lens 20 (A1-MP microscope NIKON-Japan).

[0129] FIG. 6: Representative NIR images for mice brains treated nasally with 10 l of Composition III or Control Composition each containing 0.5% w/w ICG as compared to untreated mice.

[0130] FIG. 7: Mean writing counts in mice treated with 50 mg/kg CBD from the rectal formulation of the invention as compared to oral solution, 0.5 and 6 hours prior to IP injection of acetic acid and compared to untreated control mice received IP injection of acetic acid, n=5 for untreated control, n=3 for the rectal formulation and oral solution at 0.5 hour and n=5 for the two treatments after 6 hours. (MeanSD). p<0.05 (considered significant) for the rectal formulation vs. untreated control at 0.5 and 6 hours and vs. oral solution at hours. p>0.05 (considered not significant) for oral solution vs. untreated control at 0.5 and 6 hours, by two-tailed Mann-Whitney.

[0131] FIG. 8: MPE % values in mice treated with 50 mg/kg CBD from the rectal formulation as compared to oral solution, 0.5 and 6 hours prior to IP injection of acetic acid and compared to untreated control mice received IP injection of acetic acid.

EXAMPLES

[0132] Glossary: PLphospholipids; PGpropylene glycol; CBDCannabidiol; THCTetrahydrocannabinol; CBNCannabinol; HSOhemp seed oil; Vit Evitamin E; Fluorescein isothiocyanate: FITC. CBD obtained by extraction from plants, purity 93.7% (Aifame, Switzerland). THC obtained by extraction from plant, purity>90% (BOL pharma, Israel). Lipoid 5100 and Phospholipon 90 G are from Lipoid GmbH, Germany. Pomegranate Oil (organic) manufactured by Bara Herbs, Israel and Hemp Seed Oil (organic) manufactured by Pukka Herbs, UK were used. Lecithin Soya (Fagron, Spain) and Propylene glycol (Tamar) from Tamar, Israel. Olive Oil from Henry Lamotte Oil GmbH, Germany.

Example 1

CBD-Containing Composition

[0133]

TABLE-US-00001 TABLE 1 Ingredients Concentration % w/w CBD 41.3 Phospholipon 90G 41.3 Vitamin E 1.3 Propylene glycol 16.1

[0134] Preparation: PL was mixed well, then CBD was added and mixed well. Vitamin E was added and mixed. Finally, PG was added with mixing. A viscous liquid was obtained.

Example 2

CBD-Containing Composition

[0135]

TABLE-US-00002 TABLE 2 Ingredients Concentration % w/w CBD 39.3 Phospholipon 90G 46.8 Vitamin E 1.4 Hemp seed oil 4.7 Propylene glycol 7.8

[0136] Preparation: PL was mixed well then CBD was added and mixed well. Then Vit E was added, followed by the addition of HSO with mixing. Finally, PG was added and mixed. A viscous liquid was obtained.

Example 3

CBD-Containing Composition

[0137]

TABLE-US-00003 TABLE 3 Ingredients Concentration % w/w CBD 42.1 Phospholipon 90G 42.1 Vitamin E 1.5 Hemp seed oil 4.3 menthol 0.2 Propylene glycol 9.8

[0138] Preparation: PL was mixed well then CBD was added and mixed well. Then Vitamin E was added followed by addition of HSO with mixing. Then menthol was added and mixed well. Finally, PG was added with mixing. A viscous liquid was obtained.

Example 4

CBD-Containing Composition

[0139]

TABLE-US-00004 TABLE 4 Ingredients Concentration % w/w CBD 37.8 Phospholipon 90H 37.8 Vitamin E 1.3 Olive oil 9.5 Propylene glycol 13.6

[0140] Preparation: Phospholipon 90H was mixed well then CBD was added and mixed well. Then Vitamin E was added, followed by olive oil addition with mixing. Finally, PG was added with mixing. A viscous liquid was obtained.

Example 5

CBD-Containing Composition

[0141]

TABLE-US-00005 TABLE 5 Ingredients Concentration % w/w CBD 32 Phospholipon 90G 32 Vitamin E 0.5 Propylene glycol 35.5

[0142] Preparation: PL was mixed well then CBD was added and mixed well. Then Vit E is added and mixed. Finally, PG is added and mixed. A liquid was obtained.

Example 6

CBD-Containing Composition

[0143]

TABLE-US-00006 TABLE 6 Ingredients Concentration % w/w CBD 40 Phospholipon 90G 40 Vitamin E 0.8 Propylene glycol 19.2

[0144] Preparation: PL is mixed well then CBD was added and mixed well. Then Vit E is added with mixing. Finally, PG is added and mixed. A viscous liquid was obtained.

Example 7

CBD-Containing Composition

[0145]

TABLE-US-00007 TABLE 7 Ingredients Concentration % w/w CBD 45 Phospholipon 90G 37.8 Vitamin E 1.3 Olive oil 4 Propylene glycol 11.9

[0146] Preparation: PL was mixed well then CBD was added and mixed well. Then Vit E was added followed by olive oil addition with mixing. Finally, PG was added and mixed.

Example 8

CBD-Containing Composition

[0147]

TABLE-US-00008 TABLE 8 Ingredients Concentration % w/w CBD 40 Lipoid S 40 Vitamin E 0.8 Propylene glycol 19.2

[0148] Preparation: Lipoid was mixed well, then CBD was added and mixed well. Then Vitamin E was added and mixed. Finally, PG was added and mixed. A viscous liquid was obtained.

Example 9

Cannabinoid Mixture (CBD+THC)-Containing Composition

[0149]

TABLE-US-00009 TABLE 9 Ingredients Concentration % w/w CBD 30 THC 10 Lipoid S 40 Vitamin E 0.8 Propylene glycol 19.2

[0150] Preparation: Lipoid was mixed well with CBD and THC. Then Vitamin E was added with mixing. Finally, PG was added and mixed.

Example 10

Cannabinoid Mixture (CBD+THC)-Containing Composition

[0151]

TABLE-US-00010 TABLE 10 Ingredients Concentration % w/w CBD 35 THC 5 Lipoid S 40 Vitamin E 0.8 Propylene glycol 19.2

[0152] Preparation: Lipoid was mixed well with CBD and THC. Then Vitamin E was added with mixing. Finally, PG was added and mixed. A viscous liquid was obtained.

Example 11

Cannabinoid Mixture (CBD+THC)-Containing Composition

[0153]

TABLE-US-00011 TABLE 11 Ingredients Concentration % w/w CBD 39 THC 1 Lipoid S 40 Vitamin E 1 Propylene glycol 19

[0154] Preparation: Lipoid was mixed well with CBD and THC. Vitamin E was added with mixing. Finally, PG was added and mixed.

Example 12

Cannabinoid Mixture (CBD+THC)-Containing Composition

[0155]

TABLE-US-00012 TABLE 12 Ingredients Concentration % w/w CBD 30 THC 20 Phospholipon G 40 Vitamin E 0.8 Propylene glycol 9.2

[0156] Preparation: Phospholipon G was mixed well with CBD and THC. Vitamin E was added with mixing. Finally, PG was added and mixed. A liquid was obtained.

Example 13

Cannabinoid Mixture (CBD+THC)-Containing Composition

[0157]

TABLE-US-00013 TABLE 13 Ingredients Concentration % w/w CBD 30 THC 10 Lipoid S 10 Phospholipon G 20 Vitamin E 0.8 Propylene glycol 29.2

[0158] Preparation: Lipoid and Phospholipon G are mixed well with CBD and THC. Then Vitamin E was added with mixing. Finally, PG was added and mixed. A liquid was obtained.

Example 14

Cannabinoid Mixture (CBD+THC+CBN)-Containing Composition

[0159]

TABLE-US-00014 TABLE 14 Ingredients Concentration % w/w CBD 30 THC 5 CBN 10 Phospholipon G 40 Vitamin E 0.8 Propylene glycol 14.2

[0160] Preparation: Phospholipon G is mixed well with the mixture of drugs (CBD, THC and CBN). Then Vitamin E was added with mixing. Finally, PG was added and mixed.

Examples 15 to 19

Composition of CBD with a Second Pharmaceutically Active Compound

[0161]

TABLE-US-00015 TABLE 15 Exam- Exam- Exam- Exam- Exam- ple 15 ple 16 ple 17 ple 18 ple 19 Ingredient wt % wt % wt % wt % wt % CBD 40 30 30 30 30 Tramadol HCl 1 Diazepam 1 1 Brotizolam 0.25 Butarphenol 0.5 Phospholipon 35 25 30 30 90G Lipoid PC 7 15 5 Phospholipon 15 90H Vitamin E 1 q.s. q.s. 0.75 0.5 Propylene 23 to 100 to 100 39 34 glycol

[0162] The compositions of Examples 15 to 19 set out in Table 15 were prepared using the procedures described in previous examples. Phospholipid(s) are combined with the cannabinoids and mixed well, followed by addition of the other drug with mixing, and addition of the antioxidant and PG under mixing.

Example 20

Nasal Delivery to Brain Tested by Near Infrared (NIR) Imaging

[0163] The delivery of the NIR probe Indocyanin green (ICG) to the cortex in mice brain from CBD nasal composition of the invention was examined by Odyssey Infrared Imaging System (LI-COR, USA). The composition is tabulated in Table 16.

TABLE-US-00016 TABLE 16 Ingredients Concentration % w/w ICG 0.5 CBD 30 Phospholipon G 30 Vitamin E 0.5 Propylene glycol 39

[0164] Preparation: CBD was mixed well with PL and then mixed at intervals of ten minutes over a period of half an hour. Then Vitamin E was added followed by addition of ICG. Finally, PG was added and mixed well. A liquid was obtained.

[0165] Mice were treated with 10 l of the above nasal composition. Thirty minutes after treatment, the animals were sacrificed; brains were removed, washed with normal saline and observed under the imaging system. The scanning was performed using offset 2, resolution 339.6 m, channel 800 nm and intensity 1. The fluorescence intensity of the probe (arbitrary units A.U.) in brain was further assessed using ImageJ software. The results were compared to the brain of untreated mice.

[0166] The NIR images obtained in this experiment (FIG. 1) show that the administration of CBD nasal composition containing ICG yielded a strong fluorescent signal as compared to the brain of untreated mice.

[0167] Semi-quantification of the images and normalization of the fluorescence intensity (by subtracting the auto fluorescence of the untreated brain from the fluorescence intensity of each image) was carried out. A fluorescence of 16.6 A.U. was assessed in the brain of animals treated with the nasal composition of the invention.

Example 21

Nasal Delivery to Brain Tested by Near Infrared (NIR) Imaging

[0168] The delivery of the NIR probe Indocyanin green (ICG) to the cortex in mice brain from CBD nasal composition of the invention was examined by Odyssey Infrared Imaging System (LI-COR, USA). The composition is tabulated in Table 17.

TABLE-US-00017 TABLE 17 Ingredients Concentration % w/w ICG 0.5 CBD 40 Lipoid SPC 40 Vitamin E 0.5 Propylene glycol 19

[0169] Preparation: CBD was mixed well with Lipoid SPC for five minutes; it was then mixed every ten minutes over a period of additional forty min. Then Vitamin E was added and mixed, then ICG was added and mixed. Finally, PG was added and mixed well. A viscous liquid was obtained.

[0170] Mice were treated with 10 l nasal composition presented in Table 17. Thirty minutes after treatment, the animals were sacrificed; brains were removed, washed with normal saline and observed under the imaging system. The scanning was performed using offset 2, resolution 339.6 m, channel 800 nm and intensity 1. The fluorescence intensity (arbitrary units A.U.) in brain was further assessed using ImageJ software.

[0171] The NIR images obtained in this experiment (FIG. 2) show that the administration of nasal composition of the invention yielded a strong fluorescence in the brain. A fluorescence of 20.4 A.U. was assessed in the group treated with nasal composition of this example.

Example 22 (Comparative)

Nasal Delivery to Brain Tested by Near Infrared (NIR) Imaging

[0172] Mice were divided into two control treatment groups and one untreated control group.

TABLE-US-00018 TABLE 18 Ingredients Concentration % w/w ICG 0.5 Propylene glycol To 100

[0173] Preparation: ICG was dissolved in PG with mixing.

[0174] Mice were treated nasally with 10 l of the control composition tabulated in Table 18. Thirty minutes after treatments, the animals were sacrificed; brains were removed, washed with normal saline and observed under the imaging system. The scanning was performed using offset 2, resolution 339.6 m, channel 800 nm and intensity L1. The fluorescence intensity of the probe (arbitrary units A.U.) in brain was further assessed using ImageJ software.

[0175] The NIR images obtained in this experiment (FIG. 3) show that the administration of control nasal compositions containing ICG resulted in only a very weak fluorescent signal as compared to the nasal compositions of the invention presented above.

[0176] Semi-quantification of the images and normalization of the fluorescence intensity (by subtracting the auto fluorescence of the untreated brain from the fluorescence intensity of each image) show a fluorescence of only 4.8 A.U. for the control nasal composition.

Examples 23-25

Cannabinoid(s) and Oil-Containing Compositions

[0177] This set of examples illustrate the incorporation of pomegranate oil into CANNASL formulations; the total concentrations of the cannabinoid(s) and the oil in the illustrated formulations is from 36% to 45% by weight.

TABLE-US-00019 TABLE 19 23 24 25 Ingredient wt % Lipoid S100 50.0 40.0 Phospholipon 90G 35.0 CBD 25.0 29.0 30.0 THC 1.0 CBN 1.0 Pomegranate oil 12.5 15.0 6.0 Propylene glycol 12.5 15.0 27.0

[0178] The compositions set out in Table 19 were prepared by the procedures described above. In Examples 23 and 24, propylene glycol was the last added ingredient: it was slowly added under stirring to the phospholipids, cannabinoid(s) and oil mixture. In Example 25, the order of addition was different: Phospholipon 90G was mixed with the CBD and CBN, followed by the addition of propylene glycol; the pomegranate oil was then added slowly under mixing. In all three cases, homogenous (brownish or yellowish) viscous liquid is obtained.

Examples 26-31

Cannabinoid(s) and Oil(s)-Containing Compositions

[0179] This set of Examples illustrate the incorporation of cannabinoid (either a single cannabinoid or a mixture of two cannabinoids) and therapeutically effective oils into high content phospholipids preparations.

TABLE-US-00020 TABLE 20 26 27 28 29 30 31 % w/w % w/w % w/w % w/w % w/w % w/w Lipoid S100 50.0 40.0 Lecithin soya 33.3 40 44 40 CBD 29.0 29.0 20 30 30 30 THC 1.0 1.5 10 Pomegranate 36.7 18.5 15 10 15 15 oil Black sesame 10 seed oil Olive oil 15 16 Hemp seed 15 5 oil

[0180] The compositions are prepared by first mixing the phospholipids component with the cannabinoid(s), followed by slow or portion wise addition of the oil(s) under mixing. When a mixture of oils is used, such as in Examples 28 to 31, the oils are added either successively (e.g., a portion of one oil is mixed with the phospholipids/cannabinoids, followed by slow addition under mixing of the remaining portion and the other oil, such as in Example 28, or by successive addition of the oils to the phospholipids/cannabinoids with mixing (such as in Examples 29 to 31). Homogeneous brownish liquids or viscous liquids were formed.

Examples 32-33 (of the Invention) and 34 (Comparative) Nasal Delivery to the Brain of Cannabinoid and Oils-Containing Compositions Measured by Multiphoton Imaging

[0181] The compositions tabulated in Table 21 were prepared and then nasally administered to mice; their delivery to the brain via the nasal route was measured by multiphoton imaging.

TABLE-US-00021 TABLE 21 Example 32 Example 33 Example 34 Composition I Composition II (control) % w/w % w/w % w/w Lipoid SPC 25.0 Lecithin soya 30.0 Pomegranate oil 12.5 15.0 20.0 Sesame oil 36.5 24.0 49.0 CBD 25.0 30.0 -tocopherol 0.5 0.5 0.5 FITC 0.5 0.5 0.5 Vaseline 30.0

[0182] Preparation

[0183] Composition I (of Example 32) was prepared in the following way. Lipoid SPC was mixed with CBD, followed by addition of -Tocopherol. Pomegranate oil was added and the mixture was mixed. Then the sesame oil was added slowly under mixing. Lastly, FITC was added under mixing. A liquid was obtained. Composition II (of Example 33) was prepared in the following way. Lecithin was mixed with pomegranate oil, followed by addition of -Tocopherol. Then sesame oil was added gradually under mixing. CBD was added gradually and slowly under mixing. Lastly, FITC was added under mixing. A liquid was obtained. The Control Composition (of Example 34) was prepared in the following way. Vaseline was mixed with pomegranate oil, followed by addition of -Tocopherol. Sesame oil was then added gradually under mixing. Lastly, FITC was added and mixed well.

Experimental Protocol

[0184] Mice were treated with 10 l of Nasal Composition I, II or Control Composition each containing 0.5% w/w FITC. Ten minutes after treatment, the animals were sacrificed; brains were removed, washed with normal saline and the olfactory region in brain was observed under the multiphoton microscope A1-MP microscope (NIKON, Japan). The field of image was 818818200 nm (widthheightdepth), the scanning was performed using objective lens 20, excitation wavelength of 740 nm, laser intensity 6%, scan speed 0.125. The fluorescence intensity of the probe (Arbitrary units, A.U.) in scanned brain region was further analyzed using ImageJ software. The brain of untreated mouse was examined to rule out the auto-fluorescence of the olfactory region.

[0185] Results

[0186] The multiphoton micrographs obtained in this experiment are given in FIGS. 4-5. The results show that the nasal administration of Compositions I and II (containing FITC) yielded a strong fluorescent signal as compared to Control FITC Composition, with highest signal following probe administration from Composition II (FIG. 5). Semi-quantification of the images shows a fluorescent intensity of 63.7 and 77.9 for Composition I and II, respectively. On the other hand, nasal administration of FITC from the Control Composition yielded a fluorescent intensity of only 9.4 A.U.

Examples 35 (of the Invention) and 36 (Comparative)

Nasal Delivery to the Brain of Cannabinoid and Oils-Containing Compositions Measured by NIR Imaging

[0187] The compositions tabulated in Table 22 were prepared and then nasally administered to mice. The delivery of the NIR probe Indocyanin green (ICG) to the cortex in mice brain from nasal compositions of the invention was examined by Odyssey Infrared Imaging System (LI-COR, USA).

TABLE-US-00022 TABLE 22 Example 35 Composition III Example 36 % w/w (Control) Lipoid SPC 40.0 Pomegranate oil 5.0 CBD 35.5 Propylene glycol 18.5 99.5 -tocopherol 0.5 ICG 0.5 0.5

[0188] Composition III (of Example 35) was prepared in the following way. Lipoid SPC was mixed with CBD intermittently over approximately one hour, followed by addition of -Tocopherol. Then pomegranate oil was added and mixed well, followed by slow addition of propylene glycol under mixing. Lastly, ICG was added and mixed well.

[0189] The Control Composition (of Example 36) was prepared by dissolving the ICG in propylene glycol.

[0190] Experimental Protocol

[0191] Mice were treated with 10 l of Nasal Composition III or Control Composition each containing 0.5% w/w ICG as compared to untreated mice. Thirty minutes after treatments, the animals were sacrificed; brains were removed, washed with normal saline and observed under the imaging system. The scanning was performed using offset 2, resolution 339.6 m, channel 800 nm and intensity 1. The fluorescence intensity of the probe (Arbitrary units, A.U.) in brain was further analyzed using ImageJ software.

[0192] Results

[0193] The NIR images obtained in this experiment show that the nasal administration of Composition III containing ICG yielded a strong fluorescent signal as compared to Control ICG Composition (FIG. 6). Semi-quantification of the images and normalization of the fluorescence intensity (by subtracting the auto fluorescence of the untreated brain from the fluorescence intensity of each image) show a fluorescent intensity of 9.7 for Composition III. On the other hand, nasal administration of the Control ICG Composition yielded a fluorescent intensity of only 0.4 A.U.

Examples 37 (of the Invention) and 38 (Comparative)

Antinociceptive Effect of Rectal Administration of CBD from the Composition of the Invention

[0194] The purpose of the study reported herein was to evaluate the onset and the prolonged antinociceptive effect of cannabidiol (CBD) administered rectally from a formulation of the invention, in comparison with oral solution, in mice model of pain. The two tested formulations are set out in Table 23.

TABLE-US-00023 TABLE 23 Example 37 Example 38 Composition III (comparative - oral solution) % w/w % w/w CBD 40.0 20.0 Phospholipon 90 G 50.0 Vit E 10.0 Propylene glycol 40.0 Ethanol absolute 40.0

[0195] Experimental Protocol

[0196] This experiment was performed on twenty five male CD-1 ICR mice (21-25 g). Mice were housed under standard conditions of light and temperature in plastic cages in the specific-pathogen unit (SPF) of the pharmacy school at the Hebrew University. Animals were provided with unlimited access to water and food, and were individually inserted in separated cages with smooth flat floor.

[0197] Twenty mice were divided randomly and equally into four treatment groups to test the rectal and oral treatments at two different time points; the other five mice served for the control (untreated) group. Animals were treated with CBD at a dose of 50 mg/kg in 6-6.5 mg from the formulation of the invention (Example 37) or the oral solution (Example 38). The treatments were administered using Microman (a precision microliter pipette).

[0198] 30 minutes or 6 hours after treatments, the animals were injected intraperitoneally with acetic acid (0.6% v/v) at a dose of (10 ml/kg) (n=5). Five animals were anesthetized with Isoflurane and injected with acetic acid at the same dose without treatment served as untreated control.

[0199] Number of writhing episodes was recorded by counting the number of writhes 5 minutes after acetic acid administration for a period of 20 minutes. Writhes were indicated by the abdominal constriction and stretching of at least one hind limb.

[0200] The analgesic effect of each treatment is expressed by the Maximum Possible Effect (MPE %) of the treatments, which is directly related to the efficiency of the treatment, and is calculated according to the following equation:

MPE %=[Mean writhing in untreated control groupnumber of writhing in treated group]/[Mean writhing in untreated control group]

[0201] Results

[0202] The results of the experiment (onset and prolonged antinociceptive effect of CBD administered in the formulation of the invention as compared to oral solution) are shown in Tables 24 and 25 and are also presented graphically in the form of bar diagrams appended in FIGS. 7 and 8.

[0203] Table 24 shows the number of writhes counted after IP injection of acetic acid, at the two time points (MeanSD at the time points 0.5 h and 6 h). The bars in the diagram of FIG. 7 correspond (from left to right) to the rectal treatment, oral treatment and untreated control.

TABLE-US-00024 TABLE 24 Writhes Count Time point (hours) 0.5 6 New rectal formulation 9.0 2.0 8.0 2.8 Oral solution 25.0 7.8 18.4 8.8 Untreated control 32.5 4.9

[0204] The MPE % values calculated are shown in Table 25 and in FIG. 8 (the left bar represents the rectal treatment and the right bar the oral treatment).

TABLE-US-00025 TABLE 25 MPE % Time point (hours) 0.5 6 rectal formulation 72.3 75.4 Oral solution 13.8 43.4

[0205] The results indicate that CBD administration to mice male CD-1 ICR mice from the new formulation of the invention lead to rapid and prolonged significant analgesic effect starting from 0.5 hour with 72.3% MPE and reaching to 6 hours with MPE % value of 75.4%. On the other hand, administration of equal dose of CBD from oral solution lead to minimal analgesic effect after 0.5 hour with 13.8% MPE. This effect was increased after 6 hours to 43.4%.